Harvoni
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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 



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This medicinal product is subject to additional monitoring. This will allow quick identification of 
new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 
See section 4.8 for how to report adverse reactions. 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Harvoni 90 mg/400 mg film-coated tablets 
Harvoni 45 mg/200 mg film-coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Harvoni 90 mg/400 mg film-coated tablets 
Each film-coated tablet contains 90 mg ledipasvir and 400 mg sofosbuvir. 
 
Excipients with known effect 
Each film-coated tablet contains 157 mg of lactose (as monohydrate) and 27 micrograms of sunset 
yellow FCF. 
 
Harvoni 45 mg/200 mg film-coated tablets 
Each film-coated tablet contains 45 mg ledipasvir and 200 mg sofosbuvir. 
 
Excipients with known effect 
Each film-coated tablet contains 78 mg of lactose (as monohydrate). 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet. 
 
Harvoni 90 mg/400 mg film-coated tablets 
Orange, diamond-shaped, film-coated tablet of dimensions of approximately 19 mm x 10 mm, 
debossed with “GSI” on one side and “7985” on the other side. 
 
Harvoni 45 mg/200 mg film-coated tablets 
White, capsule-shaped, film-coated tablet of dimensions of approximately 14 mm x 7 mm, debossed 
with “GSI” on one side and “HRV” on the other side. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Harvoni is indicated for the treatment of chronic hepatitis C (CHC) in adult and paediatric patients 
aged 3 years and above (see sections 4.2, 4.4 and 5.1). 
 
For hepatitis C virus (HCV) genotype-specific activity see sections 4.4 and 5.1. 
 
4.2 Posology and method of administration 
 
Harvoni treatment should be initiated and monitored by a physician experienced in the management of 
patients with CHC. 
 



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Posology 
 
The recommended dose of Harvoni in adults is 90 mg/400 mg once daily with or without food (see 
section 5.2). 
 
The recommended dose of Harvoni in paediatric patients aged 3 years and above is based on weight 
(as detailed in Table 2) and can be taken with or without food (see section 5.2). 
 
A granule formulation of Harvoni is available for the treatment of chronic HCV-infection in paediatric 
patients aged 3 years and above having difficulty swallowing film-coated tablets. Please refer to the 
Summary of Product Characteristics for Harvoni 33.75 mg/150 mg or 45 mg/200 mg granules. 
 
Table 1: Recommended treatment duration for Harvoni and the recommended use of co-administered 
ribavirin for certain subgroups 

Patient population 
(including HIV co-infected patients) 

Treatment and duration 

Adult and paediatric patients aged 3 years and abovea with genotype 1, 4, 5 or 6 CHC 
Patients without cirrhosis Harvoni for 12 weeks. 

- Harvoni for 8 weeks may be considered in previously 
untreated genotype 1-infected patients (see section 5.1, 
ION-3 study). 

Patients with compensated cirrhosis Harvoni + ribavirinb,c for 12 weeks 
or 
Harvoni (without ribavirin) for 24 weeks. 
 
- Harvoni (without ribavirin) for 12 weeks may be considered 

for patients deemed at low risk for clinical disease 
progression and who have subsequent retreatment options 
(see section 4.4). 

Patients who are post-liver transplant 
without cirrhosis or with compensated 
cirrhosis 

Harvoni + ribavirinb,c for 12 weeks (see section 5.1). 
- Harvoni (without ribavirin) for 12 weeks (in patients 

without cirrhosis) or 24 weeks (in patients with cirrhosis) 
may be considered for patients who are ineligible for or 
intolerant to ribavirin. 

Patients with decompensated cirrhosis 
irrespective of transplant status 

Harvoni + ribavirind for 12 weeks (see section 5.1) 
- Harvoni (without ribavirin) for 24 weeks may be considered 

in patients who are ineligible for or intolerant to ribavirin. 
Adult and paediatric patients 3 years of ageand abovea with genotype 3 CHC 
Patients with compensated cirrhosis and/or 
prior treatment failure 

Harvoni + ribavirinb for 24 weeks (see sections 4.4 and 5.1). 

a See Table 2 for weight-based Harvoni dosing recommendations for paediatric patients aged 3 years and above.. 
b Adults: weight based ribavirin (< 75 kg = 1,000 mg and ≥ 75 kg = 1,200 mg), administered orally in two divided doses 

with food. 
c Paediatric patients: for ribavirin dosing recommendations see table 4 below.  
d For ribavirin dosing recommendations in adult patients with decompensated cirrhosis, see table 3 below. 
 
Table 2: Dosing for paediatric patients aged 3 years and above using Harvoni Tablets* 
Body Weight (kg)  Dosing of Harvoni Tablets Ledipasvir/Sofosbuvir Daily 

Dose 
≥ 35 one 90 mg/400 mg tablet once daily  

or 
two 45 mg/200 mg tablets once 
daily 

90 mg/400 mg/day  

17 to < 35  one 45 mg/200 mg tablet once daily 45 mg/200 mg/day  

* Harvoni is also available as granules for use in paediatric patients with CHC aged 3 years and above (see section 5.1). 
Patients that weigh < 17 kg are not recommended to take tablets. Please refer to the Summary of Product Characteristics for 
Harvoni 33.75 mg/150 mg or 45 mg/200 mg granules. 
 



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Table 3: Guidance for ribavirin dosing when administered with Harvoni to adult patients with 
decompensated cirrhosis 

Patient Ribavirin dose* 
Child-Pugh-Turcotte (CPT) Class B 
cirrhosis pre-transplant 

1,000 mg per day for patients < 75 kg and 1,200 mg for those 
weighing ≥ 75 kg 

CPT Class C cirrhosis pre-transplant 
 
CPT Class B or C cirrhosis post-
transplant 

Starting dose of 600 mg, which can be titrated up to a maximum 
of 1,000/1,200 mg (1,000 mg for patients weighing < 75 kg and 
1,200 mg for patients weighing ≥ 75 kg) if well tolerated. If the 
starting dose is not well tolerated, the dose should be reduced as 
clinically indicated based on haemoglobin levels 

* If a more normalized dose of ribavirin (by weight and renal function) cannot be reached for reasons of tolerability, 
24 weeks of Harvoni + ribavirin should be considered in order to minimize the risk for relapse. 
 
For adults when ribavirin is added to Harvoni, refer also to the Summary of Product Characteristics of 
ribavirin. 
 
In paediatric patients aged 3 years and above the following ribavirin dosing is recommended where 
ribavirin is divided into two daily doses and given with food: 
 
Table 4: Guidance for ribavirin dosing when administered with Harvoni to paediatric patients aged 
3 years and above. 

Body weight kg Ribavirin Dose* 
< 47 15 mg/kg/day 
47-49 600 mg/day 
50-65 800 mg/day 
66-74 1000 mg/day 
> or = 75 1200 mg/day 

* The daily dosage of ribavirin is weight-based and administered orally in two divided doses with food. 
 
Dose modification of ribavirin in adults taking 1,000-1,200 mg daily 
If Harvoni is used in combination with ribavirin and a patient has a serious adverse reaction potentially 
related to ribavirin, the ribavirin dose should be modified or discontinued, if appropriate, until the 
adverse reaction abates or decreases in severity. Table 5 provides guidelines for dose modifications 
and discontinuation based on the patient’s haemoglobin concentration and cardiac status. 
 
Table 5: Ribavirin dose modification guideline for co-administration with Harvoni in adults 

Laboratory values Reduce ribavirin dose to 
600 mg/day if: 

Discontinue ribavirin if: 

Haemoglobin in patients with no 
cardiac disease 

< 10 g/dL < 8.5 g/dL 

Haemoglobin in patients with 
history of stable cardiac disease 

≥ 2 g/dL decrease in haemoglobin 
during any 4-week treatment 
period 

< 12 g/dL despite 4 weeks at 
reduced dose 

 
Once ribavirin has been withheld due to either a laboratory abnormality or clinical manifestation, an 
attempt may be made to restart ribavirin at 600 mg daily and further increase the dose to 800 mg daily. 
However, it is not recommended that ribavirin be increased to the originally assigned dose (1,000 mg 
to 1,200 mg daily). 
 
Paediatric population aged < 3 years 
The safety and efficacy of Harvoni in paediatric patients aged < 3 years have not been established. No 
data are available. 
 
Missed dose 
Patients should be instructed that if vomiting occurs within 5 hours of dosing an additional tablet 
should be taken. If vomiting occurs more than 5 hours after dosing, no further dose is needed (see 
section 5.1). 
 



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If a dose is missed and it is within 18 hours of the normal time, patients should be instructed to take 
the tablet as soon as possible and then patients should take the next dose at the usual time. If it is after 
18 hours then patients should be instructed to wait and take the next dose at the usual time. Patients 
should be instructed not to take a double dose. 
 
Elderly 
No dose adjustment is warranted for elderly patients (see section 5.2). 
 
Renal impairment 
No dose adjustment of Harvoni is required for patients with mild or moderate renal impairment.  
 
Safety data are limited in patients with severe renal impairment (estimated glomerular filtration rate 
[eGFR] < 30 mL/min/1.73 m2) and end stage renal disease (ESRD) requiring dialysis. Harvoni can be 
used in these patients with no dose adjustment when no other relevant treatment options are available 
(see section 4.4, 4.8, 5.1 and 5.2). 
 
Hepatic impairment 
No dose adjustment of Harvoni is required for patients with mild, moderate or severe hepatic 
impairment (Child-Pugh-Turcotte [CPT] class A, B or C) (see section 5.2). Safety and efficacy of 
ledipasvir/sofosbuvir have been established in patients with decompensated cirrhosis (see section 5.1). 
 
Method of administration 
 
For oral use. 
 
Patients should be instructed to swallow the tablet(s) whole with or without food. Due to the bitter 
taste, it is recommended that film-coated tablets are not chewed or crushed (see section 5.2). 
 
4.3 Contraindications 
 
Hypersensitivity to the active substances or to any of the excipients listed in section 6.1. 
 
Co-administration with rosuvastatin (see section 4.5). 
 
Use with strong P-gp inducers 
 
Medicinal products that are strong P-glycoprotein (P-gp) inducers in the intestine (carbamazepine, 
phenobarbital, phenytoin, rifampicin, rifabutin and St. John’s wort). Co-administration will 
significantly decrease ledipasvir and sofosbuvir plasma concentrations and could result in loss of 
efficacy of Harvoni (see section 4.5). 
 
4.4 Special warnings and precautions for use 
 
Harvoni should not be administered concomitantly with other medicinal products containing 
sofosbuvir. 
 
Genotype-specific activity 
 
Concerning recommended regimens with different HCV genotypes, see section 4.2. Concerning 
genotype-specific virological and clinical activity, see section 5.1. 
 
The clinical data to support the use of Harvoni in adults infected with HCV genotype 3 are limited (see 
section 5.1). The relative efficacy of a 12-week regimen consisting of ledipasvir/sofosbuvir 
+ ribavirin, compared to a 24-week regimen of sofosbuvir + ribavirin has not been investigated. A 
conservative 24 weeks of therapy is advised in all treatment-experienced genotype 3 patients and those 
treatment-naïve genotype 3 patients with cirrhosis (see section 4.2). In genotype 3-infection, the use of 



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Harvoni (always in combination with ribavirin) should only be considered for patients who are 
deemed at high risk for clinical disease progression and who do not have alternative treatment options. 
 
The clinical data to support the use of Harvoni in adults infected with HCV genotype 2 and 6 are 
limited (see section 5.1). 
 
Severe bradycardia and heart block 
 
Life-threatening cases of severe bradycardia and heart block have been observed when sofosbuvir-
containing regimens are used in combination with amiodarone. Bradycardia has generally occurred 
within hours to days, but cases with a longer time to onset have been observed mostly up to 2 weeks 
after initiating HCV treatment. 
 
Amiodarone should only be used in patients on Harvoni when other alternative anti-arrhythmic 
treatments are not tolerated or are contraindicated. 
 
Should concomitant use of amiodarone be considered necessary it is recommended that patients 
undergo cardiac monitoring in an in-patient setting for the first 48 hours of coadministration, after 
which outpatient or self-monitoring of the heart rate should occur on a daily basis through at least the 
first 2 weeks of treatment. 
 
Due to the long half-life of amiodarone, cardiac monitoring as outlined above should also be carried 
out for patients who have discontinued amiodarone within the past few months and are to be initiated 
on Harvoni. 
 
All patients with concurrent or recent use of amiodarone should be warned of the symptoms of 
bradycardia and heart block and should be advised to seek medical advice urgently should they 
experience them. 
 
Use in diabetic patients 
 
Diabetics may experience improved glucose control, potentially resulting in symptomatic 
hypoglycaemia, after initiating HCV direct-acting antiviral treatment. Glucose levels of diabetic 
patients initiating direct-acting antiviral therapy should be closely monitored, particularly within the 
first 3 months, and their diabetic medication modified when necessary. The physician in charge of the 
diabetic care of the patient should be informed when direct-acting antiviral therapy is initiated. 
 
HCV/HBV (hepatitis B virus) co-infection 
 
Cases of hepatitis B virus (HBV) reactivation, some of them fatal, have been reported during or after 
treatment with direct-acting antiviral agents. HBV screening should be performed in all patients before 
initiation of treatment. HBV/HCV co-infected patients are at risk of HBV reactivation, and should 
therefore be monitored and managed according to current clinical guidelines. 
 
Treatment of patients with prior exposure to HCV direct-acting antivirals 
 
In patients who fail treatment with ledipasvir/sofosbuvir, selection of NS5A resistance mutations that 
substantially reduce the susceptibility to ledipasvir is seen in the majority of cases (see section 5.1). 
Limited data indicate that such NS5A mutations do not revert on long-term follow-up. There are 
presently no data to support the effectiveness of retreatment of patients who have failed 
ledipasvir/sofosbuvir with a subsequent regimen that contains an NS5A inhibitor. Similarly, there are 
presently no data to support the effectiveness of NS3/4A protease inhibitors in patients who previously 
failed prior therapy that included an NS3/4A protease inhibitor. Such patients may therefore be 
dependent on other classes of medicinal products for clearance of HCV infection. Consequently, 
consideration should be given to longer treatment for patients with uncertain subsequent retreatment 
options. 
 



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Renal impairment 
 
Safety data are limited in patients with severe renal impairment (estimated glomerular filtration rate 
[eGFR] < 30 mL/min/1.73 m2) and ESRD requiring haemodialysis. Harvoni can be used in these 
patients with no dose adjustment when no other relevant treatment options are available (see 
sections 4.8, 5.1 and 5.2). When Harvoni is used in combination with ribavirin refer also to the 
Summary of Product Characteristics for ribavirin for patients with creatinine clearance (CrCl) 
< 50 mL/min (see section 5.2). 
 
Adults with decompensated cirrhosis and/or who are awaiting liver transplant or post-liver transplant 
 
The efficacy of ledipasvir/sofosbuvir in genotype 5 and genotype 6 HCV-infected patients with 
decompensated cirrhosis and/or who are awaiting liver transplant or post-liver transplant has not been 
investigated. Treatment with Harvoni should be guided by an assessment of the potential benefits and 
risks for the individual patient. 
 
Use with moderate P-gp inducers 
 
Medicinal products that are moderate P-gp inducers in the intestine (e.g. oxcarbazepine) may decrease 
ledipasvir and sofosbuvir plasma concentrations leading to reduced therapeutic effect of Harvoni. 
Co-administration of such medicinal products is not recommended with Harvoni (see section 4.5). 
 
Use with certain HIV antiretroviral regimens 
 
Harvoni has been shown to increase tenofovir exposure, especially when used together with an HIV 
regimen containing tenofovir disoproxil fumarate and a pharmacokinetic enhancer (ritonavir or 
cobicistat). The safety of tenofovir disoproxil fumarate in the setting of Harvoni and a 
pharmacokinetic enhancer has not been established. The potential risks and benefits associated with 
co-administration of Harvoni with the fixed-dose combination tablet containing 
elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate or tenofovir disoproxil fumarate 
given in conjunction with a boosted HIV protease inhibitor (e.g. atazanavir or darunavir) should be 
considered, particularly in patients at increased risk of renal dysfunction. Patients receiving Harvoni 
concomitantly with elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate or with 
tenofovir disoproxil fumarate and a boosted HIV protease inhibitor should be monitored for tenofovir-
associated adverse reactions. Refer to tenofovir disoproxil fumarate, emtricitabine/tenofovir disoproxil 
fumarate, or elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate Summary of Product 
Characteristics for recommendations on renal monitoring. 
 
Use with HMG-CoA reductase inhibitors 
 
Co-administration of Harvoni and HMG-CoA reductase inhibitors (statins) can significantly increase 
the concentration of the statin, which increases the risk of myopathy and rhabdomyolysis (see 
section 4.5). 
 
Paediatric population 
 
Harvoni is not recommended for use in paediatric patients aged < 3 years because the safety and 
efficacy have not been established in this population. 
 
Excipients 
 
Harvoni contains the azo colouring agent sunset yellow FCF (E110), which may cause allergic 
reactions. It also contains lactose. Patients with rare hereditary problems of galactose intolerance, total 
lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product. 
 



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4.5 Interaction with other medicinal products and other forms of interaction 
 
As Harvoni contains ledipasvir and sofosbuvir, any interactions that have been identified with these 
active substances individually may occur with Harvoni. 
 
Potential for Harvoni to affect other medicinal products 
 
Ledipasvir is an in vitro inhibitor of drug transporter P-gp and breast cancer resistance protein (BCRP) 
and may increase intestinal absorption of co-administered substrates for these transporters.  
 
Potential for other medicinal products to affect Harvoni 
 
Ledipasvir and sofosbuvir are substrates of drug transporter P-gp and BCRP while GS-331007 is not. 
 
Medicinal products that are strong P-gp inducers (carbamazepine, phenobarbital, phenytoin, 
rifampicin, rifabutin and St. John’s wort) may significantly decrease ledipasvir and sofosbuvir plasma 
concentrations leading to reduced therapeutic effect of ledipasvir/sofosbuvir and thus are 
contraindicated with Harvoni (see section 4.3). Medicinal products that are moderate P-gp inducers in 
the intestine (e.g. oxcarbazepine) may decrease ledipasvir and sofosbuvir plasma concentrations 
leading to reduced therapeutic effect of Harvoni. Co-administration with such medicinal products is 
not recommended with Harvoni (see section 4.4). Co-administration with medicinal products that 
inhibit P-gp and/or BCRP may increase ledipasvir and sofosbuvir plasma concentrations without 
increasing GS-331007 plasma concentration; Harvoni may be co-administered with P-gp and/or 
BCRP inhibitors. Clinically significant medicinal product interactions with ledipasvir/sofosbuvir 
mediated by CYP450s or UGT1A1 enzymes are not expected. 
 
Patients treated with vitamin K antagonists 
 
As liver function may change during treatment with Harvoni, a close monitoring of International 
Normalised Ratio (INR) values is recommended. 
 
Impact of DAA therapy on drugs metabolized by the liver 
 
The pharmacokinetics of drugs that are metabolized by the liver (e.g. immunosuppressive agents such 
as calcineurin inhibitors) may be impacted by changes in liver function during DAA therapy, related to 
clearance of HCV virus. 
 
Interactions between Harvoni and other medicinal products 
 
Table 6 provides a listing of established or potentially clinically significant medicinal product 
interactions (where 90% confidence interval [CI] of the geometric least-squares mean [GLSM] ratio 
were within “↔”, extended above “↑”, or extended below “↓” the predetermined equivalence 
boundaries). The medicinal product interactions described are based on studies conducted with either 
ledipasvir/sofosbuvir or ledipasvir and sofosbuvir as individual agents, or are predicted medicinal 
product interactions that may occur with ledipasvir/sofosbuvir. The table is not all-inclusive. 
 
Table 6: Interactions between Harvoni and other medicinal products 

Medicinal product by 
therapeutic areas 

Effects on medicinal 
product levels. 

Mean ratio (90% 
confidence interval) for 

AUC, Cmax, Cmina, b 

Recommendation concerning co-administration 
with Harvoni 

ACID REDUCING AGENTS 
 Ledipasvir solubility decreases as pH increases. 

Medicinal products that increase gastric pH are 
expected to decrease concentration of ledipasvir. 



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Medicinal product by 
therapeutic areas 

Effects on medicinal 
product levels. 

Mean ratio (90% 
confidence interval) for 

AUC, Cmax, Cmina, b 

Recommendation concerning co-administration 
with Harvoni 

Antacids 
e.g. Aluminium or 
magnesium hydroxide; 
calcium carbonate 

Interaction not studied. 
Expected: 
↓ Ledipasvir 
↔ Sofosbuvir 
↔ GS-331007 
 
(Increase in gastric pH) 

It is recommended to separate antacid and Harvoni 
administration by 4 hours. 

H2-receptor antagonists 
Famotidine 
(40 mg single dose)/ 
ledipasvir (90 mg single 
dose)c/ sofosbuvir (400 mg 
single dose)c, d 
 
Famotidine dosed 
simultaneously with 
Harvonid 
 
 
Cimetidinee 
Nizatidinee 
Ranitidinee 

Ledipasvir 
↓ Cmax 0.80 (0.69, 0.93) 
↔ AUC 0.89 (0.76, 1.06) 
 
Sofosbuvir 
↑ Cmax 1.15 (0.88, 1.50) 
↔ AUC 1.11 (1.00, 1.24) 
 
GS-331007 
↔ Cmax 1.06 (0.97, 1.14) 
↔ AUC 1.06 (1.02, 1.11) 
 
(Increase in gastric pH) 

H2-receptor antagonists may be administered 
simultaneously with or staggered from Harvoni at a 
dose that does not exceed doses comparable to 
famotidine 40 mg twice daily. 

Famotidine 
(40 mg single dose)/ 
ledipasvir (90 mg single 
dose)c/ sofosbuvir (400 mg 
single dose)c, d 
 
Famotidine dosed 12 hours 
prior to Harvonid 

Ledipasvir 
↓ Cmax 0.83 (0.69, 1.00) 
↔ AUC 0.98 (0.80, 1.20) 
 
Sofosbuvir 
↔ Cmax 1.00 (0.76, 1.32) 
↔ AUC 0.95 (0.82, 1.10) 
 
GS-331007 
↔ Cmax 1.13 (1.07, 1.20) 
↔ AUC 1.06 (1.01, 1.12) 
 
(Increase in gastric pH) 

Proton pump inhibitors 
Omeprazole 
(20 mg once daily)/ 
ledipasvir (90 mg single 
dose)c/ sofosbuvir (400 mg 
single dose)c 
 
Omeprazole dosed 
simultaneously with Harvoni 
 
Lansoprazolee 
Rabeprazolee 
Pantoprazolee 
Esomeprazolee 

Ledipasvir 
↓ Cmax 0.89 (0.61, 1.30) 
↓ AUC 0.96 (0.66, 1.39) 
 
Sofosbuvir 
↔ Cmax 1.12 (0.88, 1.42) 
↔ AUC 1.00 (0.80, 1.25) 
 
GS-331007 
↔ Cmax 1.14 (1.01, 1.29) 
↔ AUC 1.03 (0.96, 1.12) 
 
(Increase in gastric pH) 

Proton pump inhibitor doses comparable to 
omeprazole 20 mg can be administered 
simultaneously with Harvoni. Proton pump 
inhibitors should not be taken before Harvoni. 



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Medicinal product by 
therapeutic areas 

Effects on medicinal 
product levels. 

Mean ratio (90% 
confidence interval) for 

AUC, Cmax, Cmina, b 

Recommendation concerning co-administration 
with Harvoni 

ANTIARRHYTHMICS 
Amiodarone Effect on amiodarone, 

sofosbuvir and ledipasvir 
concentrations unknown. 

Coadministration of amiodarone with a sofosbuvir-
containing regimen may result in serious 
symptomatic bradycardia.  
Use only if no other alternative is available. Close 
monitoring is recommended if this medicinal 
product is administered with Harvoni (see 
sections 4.4 and 4.8). 

Digoxin Interaction not studied. 
Expected: 
↑ Digoxin 
↔ Ledipasvir 
↔ Sofosbuvir 
↔ GS-331007 
 
(Inhibition of P-gp) 

Co-administration of Harvoni with digoxin may 
increase the concentration of digoxin. Caution is 
warranted and therapeutic concentration monitoring 
of digoxin is recommended when co-administered 
with Harvoni. 

ANTICOAGULANTS 
Dabigatran etexilate Interaction not studied. 

Expected: 
↑ Dabigatran 
↔ Ledipasvir 
↔ Sofosbuvir 
↔ GS-331007 
 
(Inhibition of P-gp) 

Clinical monitoring, looking for signs of bleeding 
and anaemia, is recommended when dabigatran 
etexilate is co-administered with Harvoni. A 
coagulation test helps to identify patients with an 
increased bleeding risk due to increased dabigatran 
exposure. 

Vitamin K antagonists Interaction not studied. Close monitoring of INR is recommended with all 
vitamin K antagonists. This is due to liver function 
changes during treatment with Harvoni. 

ANTICONVULSANTS 
Phenobarbital 
Phenytoin 

Interaction not studied. 
Expected: 
↓ Ledipasvir 
↓ Sofosbuvir 
↔ GS-331007 
 
(Induction of P-gp) 

Harvoni is contraindicated with phenobarbital and 
phenytoin (see section 4.3). 

Carbamazepine Interaction not studied 
Expected: 
↓ Ledipasvir 
 
Observed: 
Sofosbuvir 
↓ Cmax 0.52 (0.43, 0.62) 
↓ AUC 0.52 (0.46, 0.59) 
Cmin (NA) 
 
GS-331007 
↔ Cmax 1.04 (0.97, 1.11) 
↔ AUC 0.99 (0.94, 1.04) 
Cmin (NA) 
 
(Induction of P-gp) 

Harvoni is contraindicated with carbamazepine (see 
section 4.3). 



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Medicinal product by 
therapeutic areas 

Effects on medicinal 
product levels. 

Mean ratio (90% 
confidence interval) for 

AUC, Cmax, Cmina, b 

Recommendation concerning co-administration 
with Harvoni 

Oxcarbazepine Interaction not studied. 
Expected: 
↓ Ledipasvir 
↓ Sofosbuvir 
↔ GS-331007 
 
(Induction of P-gp) 

Co-administration of Harvoni with oxcarbazepine is 
expected to decrease the concentration of ledipasvir 
and sofosbuvir leading to reduced therapeutic effect 
of Harvoni. Such co-administration is not 
recommended (see section 4.4). 

ANTIMYCOBACTERIALS 
Rifampicin (600 mg once 
daily)/ ledipasvir (90 mg 
single dose)d 

Interaction not studied. 
Expected: 
Rifampicin 
↔ Cmax 
↔ AUC 
↔ Cmin 
 
Observed: 
Ledipasvir 
↓ Cmax 0.65 (0.56, 0.76) 
↓ AUC 0.41 (0.36, 0.48) 
 
(Induction of P-gp) 

Harvoni is contraindicated with rifampicin (see 
section 4.3). 

Rifampicin (600 mg once 
daily)/ sofosbuvir (400 mg 
single dose)d 

Interaction not studied. 
Expected: 
Rifampicin 
↔ Cmax 
↔ AUC 
↔ Cmin 
 
Observed: 
Sofosbuvir 
↓ Cmax 0.23 (0.19, 0.29) 
↓ AUC 0.28 (0.24, 0.32) 
 
GS-331007 
↔ Cmax 1.23 (1.14, 1.34) 
↔ AUC 0.95 (0.88, 1.03) 
 
(Induction of P-gp) 

Rifabutin Interaction not studied. 
Expected: 
↓ Ledipasvir 
 
Observed: 
Sofosbuvir 
↓ Cmax 0.64 (0.53, 0.77) 
↓ AUC 0.76 (0.63, 0.91) 
Cmin (NA) 
 
GS-331007 
↔ Cmax 1.15 (1.03, 1.27) 
↔ AUC 1.03 (0.95, 1.12) 
Cmin (NA) 
 
(Induction of P-gp) 

Harvoni is contraindicated with rifabutin (see 
section 4.3). 



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Medicinal product by 
therapeutic areas 

Effects on medicinal 
product levels. 

Mean ratio (90% 
confidence interval) for 

AUC, Cmax, Cmina, b 

Recommendation concerning co-administration 
with Harvoni 

Rifapentine Interaction not studied. 
Expected: 
↓ Ledipasvir 
↓ Sofosbuvir 
↔ GS-331007 
(Induction of P-gp) 

Co-administration of Harvoni with rifapentine is 
expected to decrease the concentration of ledipasvir 
and sofosbuvir, leading to reduced therapeutic effect 
of Harvoni. Such co-administration is not 
recommended. 

SEDATIVES/HYPNOTICS 
Midazolam (2.5 mg single 
dose)/ ledipasvir (90 mg 
single dose) 
 
 
 
Ledipasvir (90 mg once 
daily) 

Observed: 
Midazolam 
↔ Cmax 1.07 (1.00, 1.14) 
↔ AUC 0.99 (0.95, 1.04) 
(Inhibition of CYP3A) 
 
Midazolam 
↔ Cmax 0.95 (0.87, 1.04) 
↔ AUC 0.89 (0.84, 0.95) 
(Induction of CYP3A) 
 
Expected: 
↔ Sofosbuvir 
↔ GS-331007 

No dose adjustment of Harvoni or midazolam is 
required. 

HIV ANTIVIRAL AGENTS: REVERSE TRANSCRIPTASE INHIBITORS 
Efavirenz/ emtricitabine/ 
tenofovir disoproxil 
fumarate 
(600 mg/ 200 mg/ 300 mg/ 
once daily)/ ledipasvir 
(90 mg once daily)c/ 
sofosbuvir (400 mg once 
daily)c, d 

Efavirenz 
↔ Cmax 0.87 (0.79, 0.97) 
↔ AUC 0.90 (0.84, 0.96) 
↔ Cmin 0.91 (0.83, 0.99) 
 
Emtricitabine 
↔ Cmax 1.08 (0.97, 1.21) 
↔ AUC 1.05 (0.98, 1.11) 
↔ Cmin 1.04 (0.98, 1.11) 
 
Tenofovir 
↑ Cmax 1.79 (1.56, 2.04) 
↑ AUC 1.98 (1.77, 2.23) 
↑ Cmin 2.63 (2.32, 2.97) 
 
Ledipasvir 
↓ Cmax 0.66 (0.59, 0.75) 
↓ AUC 0.66 (0.59, 0.75) 
↓ Cmin 0.66 (0.57, 0.76) 
 
Sofosbuvir 
↔ Cmax 1.03 (0.87, 1.23) 
↔ AUC 0.94 (0.81, 1.10) 
 
GS-331007 
↔ Cmax 0.86 (0.76, 0.96) 
↔ AUC 0.90 (0.83, 0.97) 
↔ Cmin 1.07 (1.02, 1.13) 

No dose adjustment of Harvoni or efavirenz/ 
emtricitabine/ tenofovir disoproxil fumarate is 
required. 



13 

Medicinal product by 
therapeutic areas 

Effects on medicinal 
product levels. 

Mean ratio (90% 
confidence interval) for 

AUC, Cmax, Cmina, b 

Recommendation concerning co-administration 
with Harvoni 

Emtricitabine/ rilpivirine/ 
tenofovir disoproxil 
fumarate 
(200 mg/ 25 mg/ 300 mg 
once daily)/ ledipasvir 
(90 mg once daily)c/ 
sofosbuvir (400 mg once 
daily)c, d 

Emtricitabine 
↔ Cmax 1.02 (0.98, 1.06) 
↔ AUC 1.05 (1.02, 1.08) 
↔ Cmin 1.06 (0.97, 1.15) 
 
Rilpivirine 
↔ Cmax 0.97 (0.88, 1.07) 
↔ AUC 1.02 (0.94, 1.11) 
↔ Cmin 1.12 (1.03, 1.21) 
 
Tenofovir 
↔ Cmax 1.32 (1.25, 1.39) 
↑ AUC 1.40 (1.31, 1.50) 
↑ Cmin 1.91 (1.74, 2.10) 
 
Ledipasvir 
↔ Cmax 1.01 (0.95, 1.07) 
↔ AUC 1.08 (1.02, 1.15) 
↔ Cmin 1.16 (1.08, 1.25) 
 
Sofosbuvir 
↔ Cmax 1.05 (0.93, 1.20) 
↔ AUC 1.10 (1.01, 1.21) 
 
GS-331007 
↔ Cmax 1.06 (1.01, 1.11) 
↔ AUC 1.15 (1.11, 1.19) 
↔ Cmin 1.18 (1.13, 1.24) 

No dose adjustment of Harvoni or emtricitabine/ 
rilpivirine/ tenofovir disoproxil fumarate is 
required. 

Abacavir/ lamivudine 
(600 mg/ 300 mg once 
daily)/ ledipasvir (90 mg 
once daily)c/ sofosbuvir 
(400 mg once daily)c, d 

Abacavir 
↔ Cmax 0.92 (0.87, 0.97) 
↔ AUC 0.90 (0.85, 0.94) 
 
Lamivudine 
↔ Cmax 0.93 (0.87, 1.00) 
↔ AUC 0.94 (0.90, 0.98) 
↔ Cmin 1.12 (1.05, 1.20) 
 
Ledipasvir 
↔ Cmax 1.10 (1.01, 1.19) 
↔ AUC 1.18 (1.10, 1.28) 
↔ Cmin 1.26 (1.17, 1.36) 
 
Sofosbuvir 
↔ Cmax 1.08 (0.85, 1.35) 
↔ AUC 1.21 (1.09, 1.35) 
 
GS-331007 
↔ Cmax 1.00 (0.94, 1.07) 
↔ AUC 1.05 (1.01, 1.09) 
↔ Cmin 1.08 (1.01, 1.14) 

No dose adjustment of Harvoni or abacavir/ 
lamivudine is required. 



14 

Medicinal product by 
therapeutic areas 

Effects on medicinal 
product levels. 

Mean ratio (90% 
confidence interval) for 

AUC, Cmax, Cmina, b 

Recommendation concerning co-administration 
with Harvoni 

HIV ANTIVIRAL AGENTS: HIV PROTEASE INHIBITORS 
Atazanavir boosted with 
ritonavir 
(300 mg/ 100 mg once 
daily)/ ledipasvir (90 mg 
once daily)c/ sofosbuvir 
(400 mg once daily)c, d 

Atazanavir 
↔ Cmax 1.07 (1.00, 1.15) 
↔ AUC 1.33 (1.25, 1.42) 
↑ Cmin 1.75 (1.58, 1.93) 
 
Ledipasvir 
↑ Cmax 1.98 (1.78, 2.20) 
↑ AUC 2.13 (1.89, 2.40) 
↑ Cmin 2.36 (2.08, 2.67) 
 
Sofosbuvir 
↔ Cmax 0.96 (0.88, 1.05) 
↔ AUC 1.08 (1.02, 1.15) 
 
GS-331007 
↔ Cmax 1.13 (1.08, 1.19) 
↔ AUC 1.23 (1.18, 1.29) 
↔ Cmin 1.28 (1.21, 1.36) 

No dose adjustment of Harvoni or atazanavir 
(ritonavir boosted) is required. 
 
For the combination of tenofovir/emtricitabine + 
atazanavir/ritonavir, please see below. 

Atazanavir boosted with 
ritonavir (300 mg/ 100 mg 
once daily) + emtricitabine/ 
tenofovir disoproxil 
fumarate (200 mg/ 300 mg 
once daily)/ ledipasvir 
(90 mg once daily)c/ 
sofosbuvir (400 mg once 
daily)c, d 
 
Dosed simultaneouslyf 

Atazanavir 
↔ Cmax 1.07 (0.99, 1.14) 
↔ AUC 1.27 (1.18, 1.37) 
↑ Cmin 1.63 (1.45, 1.84) 
 
Ritonavir 
↔ Cmax 0.86 (0.79, 0.93) 
↔ AUC 0.97 (0.89, 1.05) 
↑ Cmin 1.45 (1.27, 1.64) 
 
Emtricitabine 
↔ Cmax 0.98 (0.94, 1.02) 
↔ AUC 1.00 (0.97, 1.04) 
↔ Cmin 1.04 (0.96, 1.12) 
 
Tenofovir 
↑ Cmax 1.47 (1.37, 1.58) 
↔ AUC 1.35 (1.29, 1.42) 
↑ Cmin 1.47 (1.38, 1.57) 
 
Ledipasvir 
↑ Cmax 1.68 (1.54, 1.84) 
↑ AUC 1.96 (1.74, 2.21) 
↑ Cmin 2.18 (1.91, 2.50) 
 
Sofosbuvir 
↔ Cmax 1.01 (0.88, 1.15) 
↔ AUC 1.11 (1.02, 1.21) 
 
GS-331007 
↔ Cmax 1.17 (1.12, 1.23) 
↔ AUC 1.31 (1.25, 1.36) 
↑ Cmin 1.42 (1.34, 1.49) 

When given with tenofovir disoproxil fumarate used 
in conjunction with atazanavir/ritonavir, Harvoni 
increased the concentration of tenofovir. 
 
The safety of tenofovir disoproxil fumarate in the 
setting of Harvoni and a pharmacokinetic enhancer 
(e.g. ritonavir or cobicistat) has not been 
established. 
 
The combination should be used with caution with 
frequent renal monitoring, if other alternatives are 
not available (see section 4.4). 
 
Atazanavir concentrations are also increased, with a 
risk for an increase in bilirubin levels/icterus. That 
risk is even higher if ribavirin is used as part of the 
HCV treatment. 



15 

Medicinal product by 
therapeutic areas 

Effects on medicinal 
product levels. 

Mean ratio (90% 
confidence interval) for 

AUC, Cmax, Cmina, b 

Recommendation concerning co-administration 
with Harvoni 

Darunavir boosted with 
ritonavir 
(800 mg/ 100 mg once 
daily)/ ledipasvir (90 mg 
once daily)d 

Darunavir 
↔ Cmax 1.02 (0.88, 1.19) 
↔ AUC 0.96 (0.84, 1.11) 
↔ Cmin 0.97 (0.86, 1.10) 
 
Ledipasvir 
↑ Cmax 1.45 (1.34, 1.56) 
↑ AUC 1.39 (1.28, 1.49) 
↑ Cmin 1.39 (1.29, 1.51) 

No dose adjustment of Harvoni or darunavir 
(ritonavir boosted) is required. 
 
For the combination of tenofovir/emtricitabine + 
darunavir/ritonavir, please see below. 

Darunavir boosted with 
ritonavir 
(800 mg/ 100 mg once 
daily)/ sofosbuvir (400 mg 
once daily) 

Darunavir 
↔ Cmax 0.97 (0.94, 1.01) 
↔ AUC 0.97 (0.94, 1.00) 
↔ Cmin 0.86 (0.78, 0.96) 
 
Sofosbuvir 
↑ Cmax 1.45 (1.10, 1.92) 
↑ AUC 1.34 (1.12, 1.59) 
 
GS-331007 
↔ Cmax 0.97 (0.90, 1.05) 
↔ AUC 1.24 (1.18, 1.30) 

Darunavir boosted with 
ritonavir (800 mg/ 100 mg 
once daily) + emtricitabine/ 
tenofovir disoproxil 
fumarate (200 mg/ 300 mg 
once daily)/ ledipasvir 
(90 mg once daily)c/ 
sofosbuvir (400 mg once 
daily)c, d 
 
Dosed simultaneouslyf 

Darunavir 
↔ Cmax 1.01 (0.96, 1.06) 
↔ AUC 1.04 (0.99, 1.08) 
↔ Cmin 1.08 (0.98, 1.20) 
 
Ritonavir 
↔ Cmax 1.17 (1.01, 1.35) 
↔ AUC 1.25 (1.15, 1.36) 
↑ Cmin 1.48 (1.34, 1.63) 
 
Emtricitabine 
↔ Cmax 1.02 (0.96, 1.08) 
↔ AUC 1.04 (1.00, 1.08) 
↔ Cmin 1.03 (0.97, 1.10) 
 
Tenofovir 
↑ Cmax 1.64 (1.54, 1.74) 
↑ AUC 1.50 (1.42, 1.59) 
↑ Cmin 1.59 (1.49, 1.70) 
 
Ledipasvir 
↔ Cmax 1.11 (0.99, 1.24) 
↔ AUC 1.12 (1.00, 1.25) 
↔ Cmin 1.17 (1.04, 1.31) 
 
Sofosbuvir 
↓ Cmax 0.63 (0.52, 0.75) 
↓ AUC 0.73 (0.65, 0.82) 
 
GS-331007 
↔ Cmax 1.10 (1.04, 1.16) 
↔ AUC 1.20 (1.16, 1.24) 
↔ Cmin 1.26 (1.20, 1.32) 

When given with darunavir/ritonavir used in 
conjunction with tenofovir disoproxil fumarate, 
Harvoni increased the concentration of tenofovir. 
 
The safety of tenofovir disoproxil fumarate in the 
setting of Harvoni and a pharmacokinetic enhancer 
(e.g. ritonavir or cobicistat) has not been 
established. 
 
The combination should be used with caution with 
frequent renal monitoring, if other alternatives are 
not available (see section 4.4). 



16 

Medicinal product by 
therapeutic areas 

Effects on medicinal 
product levels. 

Mean ratio (90% 
confidence interval) for 

AUC, Cmax, Cmina, b 

Recommendation concerning co-administration 
with Harvoni 

Lopinavir boosted with 
ritonavir + emtricitabine/ 
tenofovir disoproxil 
fumarate 

Interaction not studied. 
Expected: 
↑ Lopinavir 
↑ Ritonavir 
 
↔ Emtricitabine 
↑ Tenofovir 
 
↑ Ledipasvir 
↔ Sofosbuvir 
↔ GS-331007 

When given with lopinavir/ritonavir used in 
conjunction with tenofovir disoproxil fumarate, 
Harvoni is expected to increase the concentration of 
tenofovir. 
 
The safety of tenofovir disoproxil fumarate in the 
setting of Harvoni and a pharmacokinetic enhancer 
(e.g. ritonavir or cobicistat) has not been 
established. 
 
The combination should be used with caution with 
frequent renal monitoring, if other alternatives are 
not available (see section 4.4). 

Tipranavir boosted with 
ritonavir 

Interaction not studied. 
Expected: 
↓ Ledipasvir 
↓ Sofosbuvir 
↔ GS-331007 
 
(Induction of P-gp) 

Co-administration of Harvoni with tipranavir 
(ritonavir boosted) is expected to decrease the 
concentration of ledipasvir, leading to reduced 
therapeutic effect of Harvoni. Co-administration is 
not recommended. 

HIV ANTIVIRAL AGENTS: INTEGRASE INHIBITORS 
Raltegravir 
(400 mg twice daily)/ 
ledipasvir (90 mg once 
daily)d 

Raltegravir 
↓ Cmax 0.82 (0.66, 1.02) 
↔ AUC 0.85 (0.70, 1.02) 
↑ Cmin 1.15 (0.90, 1.46) 
 
Ledipasvir 
↔ Cmax 0.92 (0.85, 1.00) 
↔ AUC 0.91 (0.84, 1.00) 
↔ Cmin 0.89 (0.81, 0.98) 

No dose adjustment of Harvoni or raltegravir is 
required. 

Raltegravir 
(400 mg twice daily)/ 
sofosbuvir (400 mg once 
daily)d 

Raltegravir 
↓ Cmax 0.57 (0.44, 0.75) 
↓ AUC 0.73 (0.59, 0.91) 
↔ Cmin 0.95 (0.81, 1.12) 
 
Sofosbuvir 
↔ Cmax 0.87 (0.71, 1.08) 
↔ AUC 0.95 (0.82, 1.09) 
 
GS-331007 
↔ Cmax 1.09 (0.99, 1.19) 
↔ AUC 1.02 (0.97, 1.08) 



17 

Medicinal product by 
therapeutic areas 

Effects on medicinal 
product levels. 

Mean ratio (90% 
confidence interval) for 

AUC, Cmax, Cmina, b 

Recommendation concerning co-administration 
with Harvoni 

Elvitegravir/ cobicistat/ 
emtricitabine/ tenofovir 
disoproxil fumarate 
(150 mg/ 150 mg/ 200 mg/ 
300 mg once daily)/ 
ledipasvir (90 mg once 
daily)c/ sofosbuvir (400 mg 
once daily)c 

Interaction not studied. 
Expected: 
↔ Emtricitabine 
↑ Tenofovir 
 
Observed: 
Elvitegravir 
↔ Cmax 0.88 (0.82, 0.95) 
↔ AUC 1.02 (0.95, 1.09) 
↑ Cmin 1.36 (1.23, 1.49) 
 
Cobicistat 
↔ Cmax 1.25 (1.18, 1.32) 
↑ AUC 1.59 (1.49, 1.70) 
↑ Cmin 4.25 (3.47, 5.22) 
 
Ledipasvir 
↑ Cmax 1.63 (1.51, 1.75) 
↑ AUC 1.78 (1.64, 1.94) 
↑ Cmin 1.91 (1.76, 2.08) 
 
Sofosbuvir 
↑ Cmax 1.33 (1.14, 1.56) 
↑ AUC 1.36 (1.21, 1.52) 
 
GS-331007 
↑ Cmax 1.33 (1.22, 1.44) 
↑ AUC 1.44 (1.41, 1.48) 
↑ Cmin 1.53 (1.47, 1.59) 

When given with elvitegravir/ cobicistat/ 
emtricitabine/ tenofovir disoproxil fumarate, 
Harvoni is expected to increase the concentration of 
tenofovir. 
 
The safety of tenofovir disoproxil fumarate in the 
setting of Harvoni and a pharmacokinetic enhancer 
(e.g. ritonavir or cobicistat) has not been 
established. 
 
The combination should be used with caution with 
frequent renal monitoring, if other alternatives are 
not available (see section 4.4). 

Dolutegravir Interaction not studied. 
Expected: 
↔ Dolutegravir 
↔ Ledipasvir 
↔ Sofosbuvir 
↔ GS-331007 

No dose adjustment required. 

HERBAL SUPPLEMENTS 
St. John’s wort Interaction not studied. 

Expected: 
↓ Ledipasvir 
↓ Sofosbuvir 
↔ GS-331007 
 
(Induction of P-gp) 

Harvoni is contraindicated with St. John’s wort (see 
section 4.3). 

HMG-CoA REDUCTASE INHIBITORS 
Rosuvastating ↑ Rosuvastatin 

 
(Inhibition of drug 
transporters OATP and 
BCRP) 

Co-administration of Harvoni with rosuvastatin may 
significantly increase the concentration of 
rosuvastatin (several fold-increase in AUC) which 
is associated with increased risk of myopathy, 
including rhabdomyolysis. Co-administration of 
Harvoni with rosuvastatin is contraindicated (see 
section 4.3). 

Pravastating ↑ Pravastatin Co-administration of Harvoni with pravastatin may 
significantly increase the concentration of 
pravastatin which is associated with increased risk 
of myopathy. Clinical and biochemical control is 
recommended in these patients and a dose 
adjustment may be needed (see section 4.4). 



18 

Medicinal product by 
therapeutic areas 

Effects on medicinal 
product levels. 

Mean ratio (90% 
confidence interval) for 

AUC, Cmax, Cmina, b 

Recommendation concerning co-administration 
with Harvoni 

Other statins Expected: 
↑ Statins 

Interactions cannot be excluded with other 
HMG-CoA reductase inhibitors. When 
co-administered with Harvoni, a reduced dose of 
statins should be considered and careful monitoring 
for statin adverse reactions should be undertaken 
(see section 4.4). 

NARCOTIC ANALGESICS 
Methadone Interaction not studied. 

Expected: 
↔ Ledipasvir 

No dose adjustment of Harvoni or methadone is 
required. 

Methadone 
(Methadone maintenance 
therapy [30 to 130 mg/ 
daily])/ sofosbuvir (400 mg 
once daily)d 

R-methadone 
↔ Cmax 0.99 (0.85, 1.16) 
↔ AUC 1.01 (0.85, 1.21) 
↔ Cmin 0.94 (0.77, 1.14) 
 
S-methadone 
↔ Cmax 0.95 (0.79, 1.13) 
↔ AUC 0.95 (0.77, 1.17) 
↔ Cmin 0.95 (0.74, 1.22) 
 
Sofosbuvir 
↓ Cmax 0.95 (0.68, 1.33) 
↑ AUC 1.30 (1.00, 1.69) 
 
GS-331007 
↓ Cmax 0.73 (0.65, 0.83) 
↔ AUC 1.04 (0.89, 1.22) 

IMMUNOSUPPRESSANTS 
Ciclosporing Interaction not studied. 

Expected: 
↑ Ledipasvir 
↔ Ciclosporin 

No dose adjustment of Harvoni or ciclosporin is 
required at initiation of co-administration. 
Afterwards, close monitoring and potential dose 
adjustment of ciclosporin may be required. 

Ciclosporin 
(600 mg single dose)/ 
sofosbuvir (400 mg single 
dose)h 

Ciclosporin 
↔ Cmax 1.06 (0.94, 1.18) 
↔ AUC 0.98 (0.85, 1.14) 
 
Sofosbuvir 
↑ Cmax 2.54 (1.87, 3.45) 
↑ AUC 4.53 (3.26, 6.30) 
 
GS-331007 
↓ Cmax 0.60 (0.53, 0.69) 
↔ AUC 1.04 (0.90, 1.20) 

Tacrolimus Interaction not studied. 
Expected: 
↔ Ledipasvir 

No dose adjustment of Harvoni or tacrolimus is 
required at initiation of co-administration. 
Afterwards, close monitoring and potential dose 
adjustment of tacrolimus may be required. Tacrolimus 

(5 mg single dose)/ 
sofosbuvir (400 mg single 
dose)h 

Tacrolimus 
↓ Cmax 0.73 (0.59, 0.90) 
↑ AUC 1.09 (0.84, 1.40) 
 
Sofosbuvir 
↓ Cmax 0.97 (0.65, 1.43) 
↑ AUC 1.13 (0.81, 1.57) 
 
GS-331007 
↔ Cmax 0.97 (0.83, 1.14) 
↔ AUC 1.00 (0.87, 1.13) 



19 

Medicinal product by 
therapeutic areas 

Effects on medicinal 
product levels. 

Mean ratio (90% 
confidence interval) for 

AUC, Cmax, Cmina, b 

Recommendation concerning co-administration 
with Harvoni 

ORAL CONTRACEPTIVES 
Norgestimate/ ethinyl 
estradiol (norgestimate 
0.180 mg/ 0.215 mg/ 
0.25 mg/ ethinyl estradiol 
0.025 mg)/ ledipasvir 
(90 mg once daily)d 

Norelgestromin 
↔ Cmax 1.02 (0.89, 1.16) 
↔ AUC 1.03 (0.90, 1.18) 
↔ Cmin 1.09 (0.91, 1.31) 
 
Norgestrel 
↔ Cmax 1.03 (0.87, 1.23) 
↔ AUC 0.99 (0.82, 1.20) 
↔ Cmin 1.00 (0.81, 1.23) 
 
Ethinyl estradiol 
↑ Cmax 1.40 (1.18, 1.66) 
↔ AUC 1.20 (1.04, 1.39) 
↔ Cmin 0.98 (0.79, 1.22) 

No dose adjustment of oral contraceptives is 
required. 

Norgestimate/ ethinyl 
estradiol (norgestimate 
0.180 mg/ 0.215 mg/ 
0.25 mg/ ethinyl estradiol 
0.025 mg)/ sofosbuvir 
(400 mg once daily)d 

Norelgestromin 
↔ Cmax 1.07 (0.94, 1.22) 
↔ AUC 1.06 (0.92, 1.21) 
↔ Cmin 1.07 (0.89, 1.28) 
 
Norgestrel 
↔ Cmax 1.18 (0.99, 1.41) 
↑ AUC 1.19 (0.98, 1.45) 
↑ Cmin 1.23 (1.00, 1.51) 
 
Ethinyl estradiol 
↔ Cmax 1.15 (0.97, 1.36) 
↔ AUC 1.09 (0.94, 1.26) 
↔ Cmin 0.99 (0.80, 1.23) 

a Mean ratio (90% CI) of co-administered drug pharmacokinetics of study medicinal products alone or in combination. No 
effect = 1.00. 

b All interaction studies conducted in healthy volunteers. 
c Administered as Harvoni. 
d Lack of pharmacokinetics interaction bounds 70-143%. 
e These are drugs within class where similar interactions could be predicted. 
f Staggered administration (12 hours apart) of atazanavir/ritonavir + emtricitabine/tenofovir disoproxil fumarate or 

darunavir/ritonavir + emtricitabine/tenofovir disoproxil fumarate and Harvoni provided similar results. 
g This study was conducted in the presence of another two direct-acting antiviral agents. 
h Bioequivalence/Equivalence boundary 80-125%. 
 
4.6 Fertility, pregnancy and lactation 
 
Women of childbearing potential / contraception in males and females 
 
When Harvoni is used in combination with ribavirin, extreme care must be taken to avoid pregnancy 
in female patients and in female partners of male patients. Significant teratogenic and/or embryocidal 
effects have been demonstrated in all animal species exposed to ribavirin. Women of childbearing 
potential or their male partners must use an effective form of contraception during treatment and for a 
period of time after the treatment has concluded as recommended in the Summary of Product 
Characteristics for ribavirin. Refer to the Summary of Product Characteristics for ribavirin for 
additional information. 
 
Pregnancy 
 
There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of ledipasvir, 
sofosbuvir or Harvoni in pregnant women. 
 



20 

Animal studies do not indicate direct harmful effects with respect to reproductive toxicity. No 
significant effects on foetal development have been observed with ledipasvir or sofosbuvir in rats and 
rabbits. However, it has not been possible to fully estimate exposure margins achieved for sofosbuvir 
in the rat relative to the exposure in humans at the recommended clinical dose (see section 5.3). 
 
As a precautionary measure, it is preferable to avoid the use of Harvoni during pregnancy. 
 
Breast-feeding 
 
It is unknown whether ledipasvir or sofosbuvir and its metabolites are excreted in human milk. 
 
Available pharmacokinetic data in animals has shown excretion of ledipasvir and metabolites of 
sofosbuvir in milk (see section 5.3). 
 
A risk to the newborns/infants cannot be excluded. Therefore, Harvoni should not be used during 
breast-feeding. 
 
Fertility 
 
No human data on the effect of Harvoni on fertility are available. Animal studies do not indicate 
harmful effects of ledipasvir or sofosbuvir on fertility. 
 
If ribavirin is co-administered with Harvoni, the contraindications regarding use of ribavirin during 
pregnancy and breast-feeding apply (see also the Summary of Product Characteristics for ribavirin). 
 
4.7 Effects on ability to drive and use machines 
 
Harvoni (administered alone or in combination with ribavirin) has no or negligible influence on the 
ability to drive and use machines. However, patients should be advised that fatigue was more common 
in patients treated with ledipasvir/sofosbuvir compared to placebo. 
 
4.8 Undesirable effects 
 
Summary of the safety profile in adults 
 
The safety assessment of Harvoni was mainly based on pooled Phase 3 clinical studies, without a 
control, in 1952 patients who received Harvoni for 8, 12 or 24 weeks, including 872 patients who 
received Harvoni in combination with ribavirin. 
 
The proportion of patients who permanently discontinued treatment due to adverse events was 0%, 
< 1% and 1% for patients receiving ledipasvir/sofosbuvir for 8, 12 and 24 weeks, respectively; and 
< 1%, 0%, and 2% for patients receiving ledipasvir/sofosbuvir + ribavirin combination therapy for 8, 
12 and 24 weeks, respectively. 
 
In clinical studies, fatigue and headache were more common in patients treated with 
ledipasvir/sofosbuvir compared to placebo. When ledipasvir/sofosbuvir was studied with ribavirin, the 
most frequent adverse drug reactions to ledipasvir/sofosbuvir + ribavirin combination therapy were 
consistent with the known safety profile of ribavirin, without increasing the frequency or severity of 
the expected adverse drug reactions. 
 
Tabulated list of adverse events 
 
The following adverse drug reactions have been identified with Harvoni (Table 7). The adverse 
reactions are listed below by body system organ class and frequency. Frequencies are defined as 
follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare 
(≥ 1/10,000 to < 1/1,000) or very rare (< 1/10,000). 
 



21 

Table 7: Adverse drug reactions identified with Harvoni 
Frequency Adverse drug reaction 

Nervous system disorders: 
Very common headache 
Skin and subcutaneous tissue disorders: 
Common rash 
Not known angioedema 
General disorders: 
Very common fatigue 
 
Adults with decompensated cirrhosis and/or who are awaiting liver transplant or post-liver transplant 
 
The safety profile of ledipasvir/sofosbuvir with ribavirin for 12 or 24 weeks in adults with 
decompensated liver disease and/or those post-liver transplant was assessed in two open-label studies 
(SOLAR-1 and SOLAR-2). No new adverse drug reactions were detected among patients with 
decompensated cirrhosis and/or who were post-liver transplant and who received ledipasvir/sofosbuvir 
with ribavirin. Although adverse events, including serious adverse events, occurred more frequently in 
this study compared to studies that excluded decompensated patients and/or patients who were post-
liver transplantation, the adverse events observed were those expected as clinical sequelae of advanced 
liver disease and/or transplantation or were consistent with the known safety profile of ribavirin (see 
section 5.1 for details of this study). 
 
Decreases in haemoglobin to < 10 g/dL and < 8.5 g/dL during treatment were experienced by 39% and 
13% of patients treated with ledipasvir/sofosbuvir with ribavirin, respectively. Ribavirin was 
discontinued in 15% of the patients. 
 
7% of liver transplant recipients had a modification of their immunosuppressive agents. 
 
Patients with renal impairment 
 
Ledipasvir/sofosbuvir was administered for 12 weeks to 18 patients with genotype 1 CHC and severe 
renal impairment in an open-label study (Study 0154). In this limited clinical safety data set, the rate 
of adverse events was not clearly elevated from what is expected in patients with severe renal 
impairment. 
 
The safety of Harvoni has been evaluated in a 12-week non-controlled study including 95 patients 
with ESRD requiring dialysis (Study 4063). In this setting, exposure of sofosbuvir metabolite GS-
331007 is 20-fold increased, exceeding levels where adverse reactions have been observed in 
preclinical trials. In this limited clinical safety data set, the rate of adverse events and deaths was not 
clearly elevated from what is expected in ESRD patients. 
 
Paediatric population 
 
The safety and efficacy of Harvoni in paediatric patients aged 3 years and above are based on data 
from a Phase 2, open-label clinical study (Study 1116) that enrolled 226 patients who were treated 
with ledipasvir/sofosbuvir for 12 or 24 weeks or ledipasvir/sofosbuvir plus ribavirin for 24 weeks. The 
adverse reactions observed were consistent with those observed in clinical studies of 
ledipasvir/sofosbuvir in adults (see Table 7). 
 
Description of selected adverse reactions 
 
Cardiac arrhythmias 
Cases of severe bradycardia and heart block have been observed when Harvoni is used with 
amiodarone and/or other drugs that lower heart rate (see sections 4.4 and 4.5). 
 
Skin disorders 
Frequency not known: Stevens-Johnson syndrome 
 



22 

Reporting of suspected adverse reactions 
 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
The highest documented doses of ledipasvir and sofosbuvir were 120 mg twice daily for 10 days and a 
single dose of 1,200 mg, respectively. In these healthy volunteer studies, there were no untoward 
effects observed at these dose levels, and adverse reactions were similar in frequency and severity to 
those reported in the placebo groups. The effects of higher doses are not known. 
 
No specific antidote is available for overdose with Harvoni. If overdose occurs the patient must be 
monitored for evidence of toxicity. Treatment of overdose with Harvoni consists of general supportive 
measures including monitoring of vital signs as well as observation of the clinical status of the patient. 
Haemodialysis is unlikely to result in significant removal of ledipasvir as ledipasvir is highly bound to 
plasma protein. Haemodialysis can efficiently remove the predominant circulating metabolite of 
sofosbuvir, GS-331007, with an extraction ratio of 53%. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Direct-acting antiviral, ATC code: J05AP51 
 
Mechanism of action 
 
Ledipasvir is a HCV inhibitor targeting the HCV NS5A protein, which is essential for both RNA 
replication and the assembly of HCV virions. Biochemical confirmation of NS5A inhibition by 
ledipasvir is not currently possible as NS5A has no enzymatic function. In vitro resistance selection 
and cross-resistance studies indicate ledipasvir targets NS5A as its mode of action. 
 
Sofosbuvir is a pan-genotypic inhibitor of the HCV NS5B RNA-dependent RNA polymerase, which is 
essential for viral replication. Sofosbuvir is a nucleotide prodrug that undergoes intracellular 
metabolism to form the pharmacologically active uridine analogue triphosphate (GS-461203), which 
can be incorporated into HCV RNA by the NS5B polymerase and acts as a chain terminator. 
GS-461203 (the active metabolite of sofosbuvir) is neither an inhibitor of human DNA and 
RNA polymerases nor an inhibitor of mitochondrial RNA polymerase. 
 
Antiviral activity 
 
The EC50 values of ledipasvir and sofosbuvir against full-length or chimeric replicons encoding NS5A 
and NS5B sequences from clinical isolates are detailed in Table 8. The presence of 40% human serum 
had no effect on the anti-HCV activity of sofosbuvir but reduced the anti-HCV activity of ledipasvir 
by 12-fold against genotype 1a HCV replicons. 
 
Table 8: Activity of ledipasvir and sofosbuvir against chimeric replicons 

Genotype 
replicons 

Ledipasvir activity (EC50, nM) Sofosbuvir activity (EC50, nM) 
Stable replicons NS5A transient 

replicons 
Median (range)a 

Stable replicons NS5B transient 
replicons 

Median (range)a 
Genotype 1a 0.031 0.018 (0.009-0.085) 40 62 (29-128) 
Genotype 1b 0.004 0.006 (0.004-0.007) 110 102 (45-170) 
Genotype 2a 21-249 - 50 29 (14-81) 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


23 

Genotype 
replicons 

Ledipasvir activity (EC50, nM) Sofosbuvir activity (EC50, nM) 
Stable replicons NS5A transient 

replicons 
Median (range)a 

Stable replicons NS5B transient 
replicons 

Median (range)a 
Genotype 2b 16-530b - 15b - 
Genotype 3a 168 - 50 81 (24-181) 
Genotype 4a 0.39 - 40 - 
Genotype 4d 0.60 - - - 
Genotype 5a 0.15b - 15b - 
Genotype 6a 1.1b - 14b - 
Genotype 6e 264b - - - 
a Transient replicons carrying NS5A or NS5B from patient isolates. 
b The chimeric replicons carrying NS5A genes from genotype 2b, 5a, 6a and 6e were used for testing ledipasvir while the 

chimeric replicons carrying NS5B genes from genotype 2b, 5a or 6a were used for testing sofosbuvir. 
 
Resistance 
 
In cell culture 
HCV replicons with reduced susceptibility to ledipasvir have been selected in cell culture for 
genotype 1a and 1b. Reduced susceptibility to ledipasvir was associated with the primary NS5A 
substitution Y93H in both genotype 1a and 1b. Additionally a Q30E substitution developed in 
genotype 1a replicons. Site-directed mutagenesis of NS5A RAVs showed that substitutions conferring 
a fold-change > 100 and ≤ 1,000 in ledipasvir susceptibility are Q30H/R, L31I/M/V, P32L and Y93T 
in genotype 1a and P58D and Y93S in genotype 1b; and substitutions conferring a fold-change 
> 1,000 are M28A/G, Q30E/G/K, H58D, Y93C/H/N/S in genotype 1a and A92K and Y93H in 
genotype 1b. 
 
HCV replicons with reduced susceptibility to sofosbuvir have been selected in cell culture for multiple 
genotypes including 1b, 2a, 2b, 3a, 4a, 5a and 6a. Reduced susceptibility to sofosbuvir was associated 
with the primary NS5B substitution S282T in all replicon genotypes examined. Site-directed 
mutagenesis of the S282T substitution in replicons of 8 genotypes conferred 2- to 18-fold reduced 
susceptibility to sofosbuvir and reduced the viral replication capacity by 89% to 99% compared to the 
corresponding wild-type. 
 
In clinical studies – Adults-Genotype 1 
In a pooled analysis of patients who received ledipasvir/sofosbuvir in Phase 3 studies (ION-3, ION-1 
and ION-2), 37 patients (29 with genotype 1a and 8 with genotype 1b) qualified for resistance analysis 
due to virologic failure or early study drug discontinuation and having HCV RNA > 1,000 IU/mL. 
Post-baseline NS5A and NS5B deep sequencing data (assay cut off of 1%) were available for 37/37 
and 36/37 patients, respectively. 
 
NS5A resistance-associated variants (RAVs) were observed in post-baseline isolates from 
29/37 patients (22/29 genotype 1a and 7/8 genotype 1b) not achieving sustained virologic response 
(SVR). Of the 29 genotype 1a patients who qualified for resistance testing, 22/29 (76%) patients 
harboured one or more NS5A RAVs at positions K24, M28, Q30, L31, S38 and Y93 at failure, while 
the remaining 7/29 patients had no NS5A RAVs detected at failure. The most common variants were 
Q30R, Y93H and L31M. Of the 8 genotype 1b patients who qualified for resistance testing, 7/8 (88%) 
harboured one or more NS5A RAVs at positions L31 and Y93 at failure, while 1/8 patients had no 
NS5A RAVs at failure. The most common variant was Y93H. Among the 8 patients who had no 
NS5A RAVs at failure, 7 patients received 8 weeks of treatment (n = 3 with ledipasvir/sofosbuvir; 
n = 4 with ledipasvir/sofosbuvir + ribavirin) and 1 patient received ledipasvir/sofosbuvir for 12 weeks. 
In phenotypic analyses, post-baseline isolates from patients who harboured NS5A RAVs at failure 
showed 20- to at least a 243-fold (the highest dose tested) reduced susceptibility to ledipasvir. 
Site-directed mutagenesis of the Y93H substitution in both genotype 1a and 1b as well as the Q30R 
and L31M substitution in genotype 1a conferred high levels of reduced susceptibility to ledipasvir 
(fold-change in EC50 ranging from 544-fold to 1,677-fold). 
 



24 

Among post-transplant patients with compensated liver disease or patients with decompensated liver 
disease either pre- or post-transplant (SOLAR-1 and SOLAR-2 studies), relapse was associated with 
the detection of one or more of the following NS5A RAVs: K24R, M28T, Q30R/H/K, L31V, H58D 
and Y93H/C in 12/14 genotype 1a patients, and L31M, Y93H/N in 6/6 genotype 1b patients. 
 
A NS5B substitution E237G was detected in 3 patients (1 genotype 1b and 2 genotype 1a) in the 
Phase 3 studies (ION-3, ION-1 and ION-2) and 3 patients with genotype 1a infection in the SOLAR-1 
and SOLAR-2 studies at the time of relapse. The E237G substitution showed a 1.3-fold reduction in 
susceptibility to sofosbuvir in the genotype 1a replicon assay. The clinical significance of this 
substitution is currently unknown. 
 
The sofosbuvir resistance-associated substitution S282T in NS5B was not detected in any virologic 
failure isolate from the Phase 3 studies. However, the NS5B S282T substitution in combination with 
NS5A substitutions L31M, Y93H and Q30L were detected in one patient at failure following 8 weeks 
of treatment with ledipasvir/sofosbuvir from a Phase 2 study (LONESTAR). This patient was 
subsequently retreated with ledipasvir/sofosbuvir + ribavirin for 24 weeks and achieved SVR 
following retreatment. 
 
In the SIRIUS study (see “Clinical efficacy and safety”, below) 5 patients with genotype 1 infection 
relapsed after treatment with ledipasvir/sofosbuvir with or without ribavirin. NS5A RAVs were seen at 
relapse in 5/5 patients (for genotype 1a: Q30R/H + L31M/V [n = 1] and Q30R [n = 1]; for 
genotype 1b: Y93H [n = 3]). 
 
In clinical studies – Adults-Genotype 2, 3, 4, 5 and 6 
NS5A RAVs: No genotype 2 infected patients experienced relapse in the clinical study and therefore 
there are no data regarding NS5A RAVs at the time of failure. 
 
In genotype 3 infected patients experiencing virologic failure, development of NS5A RAVs (including 
enrichment of RAVs present at baseline) was typically not detected at the time of failure (n = 17). 
 
In genotype 4, 5 and 6 infection, only small numbers of patients have been evaluated (total of 
5 patients with failure). The NS5A substitution Y93C emerged in the HCV of 1 patient (genotype 4), 
while NS5A RAVs present at baseline were observed at the time of failure in all patients. In the 
SOLAR-2 study, one patient with genotype 4d developed NS5B substitution E237G at the time of 
relapse. The clinical significance of this substitution is currently unknown. 
 
NS5B RAVs: The NS5B substitution S282T emerged in the HCV of 1/17 genotype 3-failures, and in 
the HCV of 1/3, 1/1 and 1/1 of genotype 4-, 5- and 6-failures, respectively. 
 
Effect of baseline HCV resistance-associated variants on treatment outcome 
 
Adults-Genotype 1 
Analyses were conducted to explore the association between pre-existing baseline NS5A RAVs and 
treatment outcome. In the pooled analysis of the Phase 3 studies, 16% of patients had baseline 
NS5A RAVs identified by population or deep sequencing irrespective of subtype. Baseline 
NS5A RAVs were overrepresented in patients who experienced relapse in the Phase 3 studies (see 
“Clinical efficacy and safety”). 
 
Following 12 weeks of treatment with ledipasvir/sofosbuvir (without ribavirin) in treatment-
experienced patients (arm 1 of ION-2 study) 4/4 patients with baseline NS5A RAVs conferring a 
ledipasvir fold-change of ≤ 100 achieved SVR. For the same treatment arm, patients with baseline 
NS5A RAVs conferring a fold-change of > 100, relapse occurred in 4/13 (31%), as compared to 3/95 
(3%) in those without any baseline RAVs or RAVs conferring a fold-change of ≤ 100. 
 
Following 12 weeks of treatment with ledipasvir/sofosbuvir with ribavirin in treatment-experienced 
patients with compensated cirrhosis (SIRIUS, n = 77), 8/8 patients with baseline NS5A RAVs 
conferring > 100-fold reduced susceptibility to ledipasvir achieved SVR12. 



25 

 
Among post-transplant patients with compensated liver disease (SOLAR-1 and SOLAR-2 studies), no 
relapse occurred in patients with baseline NS5A RAVs (n = 23) following 12 weeks of treatment with 
ledipasvir/sofosbuvir + ribavirin. Among patients with decompensated liver disease (pre- and post-
transplant), 4/16 (25%) patients with NS5A RAVs conferring > 100-fold resistance relapsed after 
12 weeks treatment with ledipasvir/sofosbuvir + ribavirin compared to 7/120 (6%) in those without 
any baseline NS5A RAVs or RAVs conferring a fold-change of ≤ 100. 
 
The group of NS5A RAVs that conferred > 100-fold shift and was observed in patients were the 
following substitutions in genotype 1a (M28A, Q30H/R/E, L31M/V/I, H58D, Y93H/N/C) or in 
genotype 1b (Y93H). The proportion of such baseline NS5A RAVs seen with deep sequencing varied 
from very low (cut off for assay = 1%) to high (main part of the plasma population). 
 
The sofosbuvir resistance-associated substitution S282T was not detected in the baseline NS5B 
sequence of any patient in Phase 3 studies by population or deep sequencing. SVR was achieved in all 
24 patients (n = 20 with L159F+C316N; n = 1 with L159F; and n = 3 with N142T) who had baseline 
variants associated with resistance to NS5B nucleoside inhibitors. 
 
Adults-Genotype 2, 3, 4, 5 and 6 
Due to the limited size of studies, the impact of baseline NS5A RAVs on treatment outcome for 
patients with genotype 2, 3, 4, 5 or 6 CHC has not been fully evaluated. No major differences in 
outcomes were observed by the presence or absence of baseline NS5A RAVs. 
 
Paediatric Patients 
 
The presence of pre-treatment NS5A and/or NS5B RAVs did not impact treatment outcome as all 
subjects with pre-treatment RAVs achieved SVR12 and SVR24. One 8-year-old subject infected with 
genotype 1a HCV who failed to achieve SVR12 had no NS5A or NS5B nucleoside inhibitor RAVs at 
baseline and had emergent NS5A RAV Y93H at relapse. 
 
Cross-resistance 
 
Ledipasvir was fully active against the sofosbuvir resistance-associated substitution S282T in NS5B 
while all ledipasvir resistance-associated substitutions in NS5A were fully susceptible to sofosbuvir. 
Both sofosbuvir and ledipasvir were fully active against substitutions associated with resistance to 
other classes of direct-acting antivirals with different mechanisms of actions, such as NS5B 
non-nucleoside inhibitors and NS3 protease inhibitors. NS5A substitutions conferring resistance to 
ledipasvir may reduce the antiviral activity of other NS5A inhibitors. 
 
Clinical efficacy and safety 
 
The efficacy of ledipasvir [LDV]/sofosbuvir [SOF] was evaluated in three open-label Phase 3 studies 
with data available for a total of 1,950 patients with genotype 1 CHC. The three Phase 3 studies 
included one study conducted in non-cirrhotic treatment-naïve patients (ION-3); one study in cirrhotic 
and non-cirrhotic treatment-naïve patients (ION-1); and one study in cirrhotic and non-cirrhotic 
patients who failed prior therapy with an interferon-based regimen, including regimens containing an 
HCV protease inhibitor (ION-2). Patients in these studies had compensated liver disease. All three 
Phase 3 studies evaluated the efficacy of ledipasvir/sofosbuvir with or without ribavirin. 
 
Treatment duration was fixed in each study. Serum HCV RNA values were measured during the 
clinical studies using the COBAS TaqMan HCV test (version 2.0), for use with the High Pure System. 
The assay had a lower limit of quantification (LLOQ) of 25 IU/mL. SVR was the primary endpoint to 
determine the HCV cure rate which was defined as HCV RNA less than LLOQ at 12 weeks after the 
cessation of treatment. 
 



26 

Treatment-naïve adults without cirrhosis – ION-3 (study 0108) – Genotype 1 
ION-3 evaluated 8 weeks of treatment with ledipasvir/sofosbuvir with or without ribavirin and 
12 weeks of treatment with ledipasvir/sofosbuvir in treatment-naïve non-cirrhotic patients with 
genotype 1 CHC. Patients were randomised in a 1:1:1 ratio to one of the three treatment groups and 
stratified by HCV genotype (1a versus 1b). 
 
Table 9: Demographics and baseline characteristics in study ION-3 

Patient disposition LDV/SOF 
8 weeks 
(n = 215) 

LDV/SOF+RBV 
8 weeks 
(n = 216) 

LDV/SOF 
12 weeks 
(n = 216) 

TOTAL 
 

(n = 647) 
Age (years): median (range) 53 (22-75) 51 (21-71) 53 (20-71) 52 (20-75) 
Male gender 60% (130)  54% (117) 59% (128) 58% (375) 
Race: Black/ African American 21% (45) 17% (36) 19% (42) 19% (123) 
 White 76% (164) 81% (176) 77% (167) 78% (507) 
Genotype 1a 80% (171) 80% (172) 80% (172) 80% (515)a 
IL28CC genotype 26% (56) 28% (60) 26% (56) 27% (172) 
FibroTest-Determined Metavir scoreb 
 F0-F1 33% (72) 38% (81) 33% (72) 35% (225) 
 F2 30% (65) 28% (61) 30% (65) 30% (191) 
 F3-F4 36% (77) 33% (71) 37% (79) 35% (227) 
 Not interpretable < 1% (1) 1% (3) 0% (0) < 1% (4) 
a One patient in the LDV/SOF 8-week treatment arm did not have a confirmed genotype 1 subtype. 
b Non-missing FibroTest results are mapped to Metavir scores according to: 0-0.31 = F0-F1; 0.32-0.58 = F2; 

0.59-1.00 = F3-F4. 
 
Table 10: Response rates in study ION-3 

 LDV/SOF 
8 weeks 
(n = 215) 

LDV/SOF+RBV 
8 weeks 
(n = 216) 

LDV/SOF 
12 weeks 
(n = 216) 

SVR 94% (202/215) 93% (201/216) 96% (208/216) 
Outcome for patients without SVR 
 On-treatment virologic failure 0/215 0/216 0/216 
 Relapsea 5% (11/215) 4% (9/214) 1% (3/216) 
 Otherb < 1% (2/215) 3% (6/216) 2% (5/216) 
Genotype 
 Genotype 1a 93% (159/171) 92% (159/172) 96% (165/172) 
 Genotype 1b 98% (42/43) 95% (42/44) 98% (43/44) 
a The denominator for relapse is the number of patients with HCV RNA < LLOQ at their last on-treatment assessment. 
b Other includes patients who did not achieve SVR and did not meet virologic failure criteria (e.g. lost to follow-up). 
 
The 8-week treatment of ledipasvir/sofosbuvir without ribavirin was non-inferior to the 8-week 
treatment of ledipasvir/sofosbuvir with ribavirin (treatment difference 0.9%; 95% confidence interval: 
-3.9% to 5.7%) and the 12-week treatment of ledipasvir/sofosbuvir (treatment difference -2.3%; 97.5% 
confidence interval: -7.2% to 3.6%). Among patients with a baseline HCV RNA < 6 million IU/mL, 
the SVR was 97% (119/123) with 8-week treatment of ledipasvir/sofosbuvir and 96% (126/131) with 
12-week treatment of ledipasvir/sofosbuvir. 
 



27 

Table 11: Relapse rates by baseline characteristics in the ION-3 study, virological failure population* 
 LDV/SOF 

8 weeks 
(n = 213) 

LDV/SOF+RBV 
8 weeks 
(n = 210) 

LDV/SOF 
12 weeks 
(n = 211) 

Gender 
 Male 8% (10/129) 7% (8/114) 2% (3/127) 
 Female 1% (1/84) 1% (1/96) 0% (0/84) 
IL28 genotype 
 CC 4% (2/56) 0% (0/57) 0% (0/54) 
 Non-CC 6% (9/157) 6% (9/153) 2% (3/157) 
Baseline HCV RNAa 
 HCV RNA < 6 million IU/mL 2% (2/121) 2% (3/136) 2% (2/128) 
 HCV RNA ≥ 6 million IU/mL 10% (9/92) 8% (6/74) 1% (1/83) 
* Patients lost to follow-up or who withdrew consent excluded. 
a HCV RNA values were determined using the Roche TaqMan Assay; a patient’s HCV RNA may vary from visit to visit. 
 
Treatment-naïve adults with or without cirrhosis – ION-1 (study 0102) – Genotype 1 
ION-1 was a randomised, open-label study that evaluated 12 and 24 weeks of treatment with 
ledipasvir/sofosbuvir with or without ribavirin in 865 treatment-naïve patients with genotype 1 CHC 
including those with cirrhosis (randomised 1:1:1:1). Randomisation was stratified by the presence or 
absence of cirrhosis and HCV genotype (1a versus 1b). 
 
Table 12: Demographics and baseline characteristics in study ION-1 

Patient disposition LDV/SOF 
12 weeks 
(n = 214) 

LDV/SOF+ 
RBV 

12 weeks 
(n = 217) 

LDV/SOF 
24 weeks 
(n = 217) 

LDV/SOF+ 
RBV 

24 weeks 
(n = 217) 

TOTAL 
 

(n = 865) 

Age (years): median (range) 52 (18-75) 52 (18-78) 53 (22-80) 53 (24-77) 52 (18-80) 
Male gender 59% (127) 59% (128) 64% (139) 55% (119) 59% (513) 
Race: Black/ African 

American 
11% (24) 12% (26) 15% (32) 12% (26) 12% (108) 

 White 87% (187) 87% (188) 82% (177) 84% (183) 85% (735) 
Genotype 1aa 68% (145) 68% (148) 67% (146) 66% (143) 67% (582) 
IL28CC genotype 26% (55) 35% (76) 24% (52) 34% (73) 30% (256) 
FibroTest-Determined Metavir scoreb 
 F0-F1 27% (57) 26% (56) 29% (62) 30% (66) 28% (241) 
 F2 26% (56) 25% (55) 22% (47) 28% (60) 25% (218) 
 F3-F4 47% (100) 48% (104) 49% (107) 42% (91) 46% (402) 
 Not interpretable < 1% (1) 1% (2) < 1% (1) 0% (0) < 1% (4) 
a Two patients in the LDV/SOF 12-week treatment arm, one patient in the LDV/SOF+RBV 12-week treatment arm, two 

patients in the LDV/SOF 24-week treatment arm, and two patients in the LDV/SOF+RBV 24-week treatment arm did not 
have a confirmed genotype 1 subtype. 

b Non-missing FibroTest results are mapped to Metavir scores according to: 0-0.31 = F0-F1; 0.32-0.58 = F2; 
0.59-1.00 = F3-F4. 

 



28 

Table 13: Response rates in study ION-1 
 LDV/SOF 

12 weeks 
(n = 214) 

LDV/SOF+RBV 
12 weeks 
(n = 217) 

LDV/SOF 
24 weeks 
(n = 217) 

LDV/SOF+RBV 
24 weeks 
(n = 217) 

SVR 99% (210/213)  97% (211/217) 98% (213/217) 99% (215/217) 
Outcome for patients without SVR 
 On-treatment virologic 

failure 
0/213a 0/217 < 1% (1/217) 0/216 

 Relapseb < 1% (1/212) 0/217 < 1% (1/215) 0/216 
 Otherc < 1% (2/213) 3% (6/217) < 1% (2/217) < 1% (2/217) 
SVR rates for selected subgroups 
Genotype 
 Genotype 1a 98% (142/145) 97% (143/148) 99% (144/146) 99% (141/143) 
 Genotype 1b 100% (67/67) 99% (67/68) 97% (67/69) 100% (72/72) 
Cirrhosisd 
 No 99% (176/177) 97% (177/183) 98% (181/184) 99% (178/180) 
 Yes 94% (32/34) 100% (33/33) 97% (32/33) 100% (36/36) 
a One patient was excluded from the LDV/SOF 12-week treatment arm and one patient was excluded from the 

LDV/SOF+RBV 24-week treatment arm as both patients were infected with genotype 4 CHC. 
b The denominator for relapse is the number of patients with HCV RNA < LLOQ at their last on-treatment assessment. 
c Other includes patients who did not achieve SVR and did not meet virologic failure criteria (e.g. lost to follow-up). 
d Patients with missing cirrhosis status were excluded from this subgroup analysis. 
 
Previously treated adults with or without cirrhosis – ION-2 (study 0109) – Genotype 1 
ION-2 was a randomised, open-label study that evaluated 12 and 24 weeks of treatment with 
ledipasvir/sofosbuvir with or without ribavirin (randomised 1:1:1:1) in genotype 1 HCV-infected 
patients with or without cirrhosis who failed prior therapy with an interferon-based regimen, including 
regimens containing an HCV protease inhibitor. Randomisation was stratified by the presence or 
absence of cirrhosis, HCV genotype (1a versus 1b) and response to prior HCV therapy 
(relapse/breakthrough versus non-response). 
 
Table 14: Demographics and baseline characteristics in study ION-2 
Patient disposition LDV/SOF 

12 weeks 
(n = 109) 

LDV/SOF+ 
RBV 

12 weeks 
(n = 111) 

LDV/SOF 
24 weeks 
(n = 109) 

LDV/SOF+ 
RBV 

24 weeks 
(n = 111) 

TOTAL 
 

(n = 440) 

Age (years): median 
(range) 

56 (24-67) 57 (27-75) 56 (25-68) 55 (28-70) 56 (24-75) 

Male gender 68% (74) 64% (71) 68% (74) 61% (68) 65% (287) 
Race: Black/ African 

American 
22% (24) 14% (16) 16% (17) 18% (20) 18% (77) 

 White 77% (84) 85% (94) 83% (91) 80% (89) 81% (358) 
Genotype 1a 79% (86) 79% (88) 78% (85) 79% (88) 79% (347) 
Prior HCV therapy 
 PEG-IFN+RBV 39% (43) 42% (47) 53% (58) 53% (59) 47% (207)a 
 HCV protease 

inhibitor + 
PEG-IFN+RBV 

61% (66) 58% (64) 46% (50) 46% (51) 53% (231)a 

IL28CC genotype 9% (10) 10% (11) 14% (16) 16% (18) 13% (55) 
FibroTest-Determined Metavir scoreb 
 F0-F1 14% (15) 10% (11) 12% (13) 16% (18) 13% (57) 
 F2 28% (31) 26% (29) 28% (31) 30% (33) 28% (124) 
 F3-F4 58% (63) 64% (71) 58% (63) 54% (60) 58% (257) 
 Not interpretable 0% (0) 0% (0) 2% (2) 0% (0) < 1% (2) 
a One patient in the LDV/SOF 24-week treatment arms and one patient in the LDV/SOF+RBV 24-week treatment arm 

were prior treatment failures of a non-pegylated interferon-based regimen. 
b Non-missing FibroTest results are mapped to Metavir scores according to: 0-0.31 = F0-F1; 0.32-0.58 = F2; 

0.59-1.00 = F3-F4. 
 



29 

Table 15: Response rates in study ION-2 
 LDV/SOF 

12 weeks 
(n = 109) 

LDV/SOF+RBV 
12 weeks 
(n = 111) 

LDV/SOF 
24 weeks 
(n = 109) 

LDV/SOF+RBV 
24 weeks 
(n = 111) 

SVR 94% (102/109) 96% (107/111) 99% (108/109) 99% (110/111) 
Outcome for patients without SVR 
 On-treatment virologic 

failure 
0/109 0/111 0/109 < 1% (1/111) 

 Relapsea 6% (7/108) 4% (4/111) 0/109 0/110 
 Otherb 0/109 0/111 < 1% (1/109) 0/111 
SVR rates for selected subgroups 
Genotype 
 Genotype 1a 95% (82/86) 95% (84/88) 99% (84/85) 99% (87/88) 
 Genotype 1b 87% (20/23) 100% (23/23) 100% (24/24) 100% (23/23) 
Cirrhosis 
 No 95% (83/87) 100% (88/88)c 99% (85/86)c 99% (88/89) 
 Yesd 86% (19/22) 82% (18/22) 100% (22/22) 100% (22/22) 
Prior HCV therapy 
 PEG-IFN+RBV 93% (40/43) 96% (45/47) 100% (58/58) 98% (58/59) 
 HCV protease inhibitor 

+ PEG-IFN+RBV 
94% (62/66) 97% (62/64) 98% (49/50) 100% (51/51) 

a The denominator for relapse is the number of patients with HCV RNA < LLOQ at their last on-treatment assessment. 
b Other includes patients who did not achieve SVR and did not meet virologic failure criteria (e.g. lost to follow-up). 
c Patients with missing cirrhosis status were excluded from this subgroup analysis. 
d Metavir score = 4 or Ishak score ≥ 5 by liver biopsy, or FibroTest score of > 0.75 and (APRI) of > 2. 
 
Table 16 presents relapse rates with the 12-week regimens (with or without ribavirin) for selected 
subgroups (see also previous section “Effect of baseline HCV resistance-associated variants on 
treatment outcome”). In non-cirrhotic patients relapses only occurred in the presence of baseline 
NS5A RAVs, and during therapy with ledipasvir/sofosbuvir without ribavirin. In cirrhotic patients 
relapses occurred with both regimens, and in the absence and presence of baseline NS5A RAVs. 
 
Table 16: Relapse rates for selected subgroups in study ION-2 

 LDV/SOF 
12 weeks 
(n = 109) 

LDV/SOF+RBV 
12 weeks 
(n = 111) 

LDV/SOF 
24 weeks 
(n = 109) 

LDV/SOF+RBV 
24 weeks 
(n = 111) 

Number of responders at end of 
treatment 

108 111 109 110 

Cirrhosis 
 No 5% (4/86)a 0% (0/88)b 0% (0/86)b 0% (0/88) 
 Yes 14% (3/22) 18% (4/22) 0% (0/22) 0% (0/22) 
Presence of baseline NS5A resistance-associated substitutionsc 
 No 3% (3/91)d 2% (2/94) 0% (0/96) 0% (0/95)f 
 Yes 24% (4/17)e 12% (2/17) 0% (0/13) 0% (0/14) 
a These 4 non-cirrhotic relapsers all had baseline NS5A resistance-associated polymorphisms. 
b Patients with missing cirrhosis status were excluded from this subgroup analysis. 
c Analysis (by deep sequencing) included NS5A resistance-associated polymorphisms that conferred > 2.5-fold change in 

EC50 (K24G/N/R, M28A/G/T, Q30E/G/H/L/K/R/T, L31I/F/M/V, P32L, S38F, H58D, A92K/T, and Y93C/F/H/N/S for 
genotype 1a and L31I/F/M/V, P32L, P58D, A92K, and Y93C/H/N/S for genotype 1b HCV infection). 

d 3/3 of these patients had cirrhosis. 
e 0/4 of these patients had cirrhosis. 
f One patient who achieved a viral load < LLOQ at end of treatment had missing baseline NS5A data and was excluded 

from the analysis. 
 
Previously treated adults with cirrhosis – SIRIUS – Genotype 1 
SIRIUS included patients with compensated cirrhosis who first failed therapy with pegylated 
interferon (PEG-IFN) + ribavirin, and then failed a regimen consisting of a pegylated 
interferon + ribavirin + an NS3/4A protease inhibitor. Cirrhosis was defined by biopsy, Fibroscan 
(> 12.5 kPa) or FibroTest > 0.75 and an AST:platelet ratio index (APRI) of > 2. 
 



30 

The study (double-blind and placebo-controlled) evaluated 24 weeks of treatment 
ledipasvir/sofosbuvir (with ribavirin placebo) versus 12 weeks of treatment with ledipasvir/sofosbuvir 
with ribavirin. Patients in the latter treatment arm received placebo (for ledipasvir/sofosbuvir and 
ribavirin) during the first 12 weeks, followed by active blinded therapy during the subsequent 
12 weeks. Patients were stratified by HCV genotype (1a versus 1b) and prior treatment response 
(whether HCV RNA < LLOQ had been achieved). 
 
Demographics and baseline characteristics were balanced across the two treatment groups. The 
median age was 56 years (range: 23 to 77); 74% of patients were male; 97% were white; 63% had 
genotype 1a HCV infection; 94% had non-CC IL28B alleles (CT or TT). 
 
Of the 155 patients enrolled, 1 patient discontinued treatment whilst on placebo. Of the remaining 
154 patients, a total of 149 achieved SVR12 across both treatment groups; 96% (74/77) of patients in 
the ledipasvir/sofosbuvir with ribavirin 12-week group and 97% (75/77) of patients in the 
ledipasvir/sofosbuvir 24-week group. All 5 patients who did not achieve SVR12 relapsed after having 
end-of-treatment response (see section “Resistance” – “In clinical studies” above). 
 
Previously treated adults who have failed on sofosbuvir + ribavirin ± PEG-IFN 
The efficacy of ledipasvir/sofosbuvir in patients who had previously failed treatment with sofosbuvir + 
ribavirin ± PEG-IFN is supported by two clinical studies. In study 1118, 44 patients with genotype 1 
infection, including 12 cirrhotic patients, who had previously failed treatment with sofosbuvir + 
ribavirin + PEG-IFN or with sofosbuvir + ribavirin were treated with ledipasvir/sofosbuvir + ribavirin 
for 12 weeks; the SVR was 100% (44/44). In study ION-4, 13 HCV/HIV-1 co-infected patients with 
genotype 1, including 1 cirrhotic patient, who had failed a sofosbuvir + ribavirin regimen were 
enrolled; the SVR was 100% (13/13) after 12 weeks of treatment with ledipasvir/sofosbuvir. 
 
HCV/HIV co-infected adults – ION-4 
ION-4 was an open-label clinical study that evaluated the safety and efficacy of 12 weeks of treatment 
with ledipasvir/sofosbuvir without ribavirin in HCV treatment-naïve and treatment-experienced 
patients with genotype 1 or 4 CHC who were co-infected with HIV-1. Treatment-experienced patients 
had failed prior treatment with PEG-IFN + ribavirin ± an HCV protease inhibitor or sofosbuvir + 
ribavirin ± PEG-IFN. Patients were on a stable HIV-1 antiretroviral therapy that included 
emtricitabine/tenofovir disoproxil fumarate, administered with efavirenz, rilpivirine or raltegravir. 
 
The median age was 52 years (range: 26 to 72); 82% of the patients were male; 61% were white; 34% 
were black; 75% had genotype 1a HCV infection; 2% had genotype 4 infection; 76% had non-CC 
IL28B alleles (CT or TT); and 20% had compensated cirrhosis. Fifty-five percent (55%) of the 
patients were treatment-experienced. 
 
Table 17: Response rates in study ION-4 

 LDV/SOF 
12 weeks 
(n = 335) 

SVR 96% (321/335)a 
Outcome for patients without SVR 
 On-treatment virologic failure < 1% (2/335) 
 Relapseb 3% (10/333) 
 Otherc < 1% (2/335) 
SVR rates for selected subgroups 
 Patients with cirrhosis 94% (63/67) 
  Previously treated patients with cirrhosis 98% (46/47) 
a 8 patients with genotype 4 HCV infection were enrolled in the study with 8/8 achieving SVR12. 
b The denominator for relapse is the number of patients with HCV RNA < LLOQ at their last on-treatment assessment. 
c Other includes patients who did not achieve SVR and did not meet virologic failure criteria (e.g. lost to follow-up). 
 
HCV/HIV co-infected adults – ERADICATE 
ERADICATE was an open-label study to evaluate 12 weeks of treatment with ledipasvir/sofosbuvir in 
50 patients with genotype 1 CHC co-infected with HIV. All patients were treatment-naïve to HCV 



31 

therapy without cirrhosis, 26% (13/50) of patients were HIV antiretroviral naïve and 74% (37/50) of 
patients were receiving concomitant HIV antiretroviral therapy. At the time of the interim analysis 
40 patients have reached 12 weeks post treatment and SVR12 was 98% (39/40). 
 
Patients awaiting liver transplantation and post-liver transplant – SOLAR-1 and SOLAR-2 
SOLAR-1 and SOLAR-2 were two open-label clinical studies that evaluated 12 and 24 weeks of 
treatment with ledipasvir/sofosbuvir in combination with ribavirin in genotype 1 and 4 HCV-infected 
patients who have undergone liver transplantation and/or who have decompensated liver disease. The 
two studies were identical in study design. Patients were enrolled in one of the seven groups based on 
liver transplantation status and severity of hepatic impairment (see Table 18). Patients with a CPT 
score > 12 were excluded. Within each group, patients were randomized in a 1:1 ratio to receive 
ledipasvir/sofosbuvir + ribavirin for 12 or 24 weeks. 
 
Demographics and baseline characteristics were balanced across the treatment groups. Of the 670 
treated patients, the median age was 59 years (range: 21 to 81 years); 77% of the patients were male; 
91% were White; mean body mass index was 28 kg/m2 (range: 18 to 49 kg/m2); 94% and 6% had 
genotype 1 and 4 HCV infection, respectively; 78% of the patients failed a prior HCV therapy. Among 
the patients who had decompensated cirrhosis (pre- or post-transplant), 64% and 36% were CPT 
class B and C at screening, respectively, 24% had a baseline Model for End Stage Liver Disease 
(MELD) score greater than 15. 
 
Table 18: Combined response rates (SVR12) in studies SOLAR-1 and SOLAR-2 

 LDV/SOF+RBV 
12 weeks 

(n = 307)a,b 

LDV/SOF+RBV 
24 weeks 

(n = 307)a,b 
 SVR SVR 

Pre-transplant 
CPT B 87% (45/52) 92% (46/50) 
CPT C 88% (35/40) 83% (38/46) 

Post-transplant 
Metavir score F0-F3 95% (94/99) 99% (99/100) 
CPT Ac 98% (55/56) 96% (51/53) 
CPT Bc 89% (41/46) 96% (43/45) 
CPT Cc 57% (4/7) 78% (7/9) 
FCH 100% (7/7) 100% (4/4) 

a Twelve patients transplanted prior to post-treatment Week 12 with HCV RNA< LLOQ at last measurement prior to 
transplant were excluded. 

b Two patients who did not have decompensated cirrhosis and had also not received a liver transplant were excluded due to 
failure to meet the inclusion criteria for any of the treatment groups. 

c CPT = Child-Pugh-Turcotte, FCH = Fibrosing cholestatic hepatitis. CPT A = CPT score 5-6 (compensated), 
CPT B = CPT score 7-9 (decompensated), CPT C = CPT score 10-12 (decompensated). 

 
Forty patients with genotype 4 CHC were enrolled in SOLAR-1 and SOLAR-2 studies, SVR12 were 
92% (11/12) and 100% (10/10) in post-transplant patients without decompensated cirrhosis and 60% 
(6/10) and 75% (6/8) in patients with decompensated cirrhosis (pre- and post-liver transplantation) 
treated for 12 or 24 weeks, respectively. Of the 7 patients who failed to achieve SVR12, 3 relapsed, all 
had decompensated cirrhosis and were treated with ledipasvir/sofosbuvir + ribavirin for 12 weeks. 
 
Changes in MELD and CPT score from baseline to post-treatment Week 12 were analyzed for all 
patients with decompensated cirrhosis (pre- or post-transplant) who achieved SVR12 and for whom 
data were available (n = 123) to assess the effect of SVR12 on hepatic function. 
 
Change in MELD score: Among those who achieved SVR12 with 12 weeks treatment with 
ledipasvir/sofosbuvir + ribavirin, 57% (70/123) and 19% (23/123) had an improvement or no change 
in MELD score from baseline to post-treatment week 12, respectively; of the 32 patients whose 
MELD score was ≥ 15 at baseline, 59% (19/32) had a MELD score < 15 at post-treatment Week 12. 
The improvement in MELD scores observed was driven largely by improvements in total bilirubin. 
 



32 

Change in CPT score and class: Among those who achieved SVR12 with 12 weeks treatment with 
ledipasvir/sofosbuvir with ribavirin, 60% (74/123) and 34% (42/123) had an improvement or no 
change of CPT scores from baseline to post-treatment week 12, respectively; of the 32 patients who 
had CPT C cirrhosis at baseline, 53% (17/32) had CPT B cirrhosis at post-treatment Week 12; of the 
88 patients who had CPT B cirrhosis at baseline, 25% (22/88) had CPT A cirrhosis at post-treatment 
Week 12. The improvement in CPT scores observed was driven largely by improvements in total 
bilirubin and albumin. 
 
Clinical efficacy and safety in genotype 2, 3, 4, 5 and 6 (see also section 4.4) 
Ledipasvir/sofosbuvir has been evaluated for the treatment of non-genotype 1 infection in small 
Phase 2 studies, as summarised below. 
 
The clinical studies enrolled patients with or without cirrhosis, who were treatment-naïve or with prior 
treatment failure after therapy with PEG-IFN + ribavirin +/- an HCV protease inhibitor. 
 
For genotype 2, 4, 5 and 6 infection, therapy consisted of ledipasvir/sofosbuvir without ribavirin, 
given for 12 weeks (Table 19). For genotype 3 infection, ledipasvir/sofosbuvir was given with or 
without ribavirin, also for 12 weeks (Table 20). 
 
Table 19: Response rates (SVR12) with ledipasvir/sofosbuvir for 12 weeks in patients with genotype 2, 4, 5 
and 6 HCV infection 

Study GT n TEa SVR12 Relapseb 
Overall Cirrhosis  

Study 1468 (LEPTON) 2 26 19% (5/26) 96% (25/26) 100% (2/2) 0% (0/25) 
Study 1119  4 44 50% (22/44) 93% (41/44) 100% (10/10) 7% (3/44) 
Study 1119 5 41 49% (20/41) 93% (38/41) 89% (8/9) 5% (2/40) 
Study 0122 (ELECTRON-2) 6 25 0% (0/25) 96% (24/25) 100% (2/2) 4% (1/25) 
a TE: number of treatment-experienced patients. 
b The denominator for relapse is the number of patients with HCV RNA < LLOQ at their last on-treatment assessment. 
 
Table 20: Response rates (SVR12) in patients with genotype 3 infection (ELECTRON-2) 

 LDV/SOF+RBV 
12 weeks 

LDV/SOF 
12 weeks 

 SVR Relapsea SVR Relapsea 
Treatment-naïve 100% (26/26) 0% (0/26) 64% (16/25) 33% (8/24) 

Patients without cirrhosis 100% (20/20) 0% (0/21) 71% (15/21) 25% (5/20) 
Patients with cirrhosis 100% (6/6) 0% (0/5) 25% (1/4) 75% (3/4) 

Treatment-experienced 82% (41/50) 16% (8/49) NS NS 
Patients without cirrhosis 89% (25/28) 7% (2/27) NS NS 
Patients with cirrhosis 73% (16/22) 27% (6/22) NS NS 

NS: not studied. 
a The denominator for relapse is the number of patients with HCV RNA < LLOQ at their last on-treatment assessment. 
 
Patients with renal impairment 
Study 0154 was an open-label clinical study that evaluated the safety and efficacy of 12 weeks of 
treatment with ledipasvir/sofosbuvir in 18 genotype 1 HCV-infected patients with severe renal 
impairment not requiring dialysis. At baseline, two patients had cirrhosis and the mean eGFR was 
24.9 mL/min (range: 9.0-39.6). SVR12 was achieved in 18/18 patients. 
 
Study 4063 was an open-label three-arm clinical study that evaluated 8, 12, and 24 weeks of treatment 
with ledipasvir/sofosbuvir in a total of 95 patients with genotype 1 (72%), 2 (22%), 4 (2%), 5 (1%), or 
6 (2%) CHC and ESRD requiring dialysis: 45 treatment-naïve genotype 1 HCV-infected patients 
without cirrhosis received ledipasvir/sofosbuvir for 8 weeks; 31 treatment-experienced genotype 1 
HCV-infected patients and treatment-naïve or treatment-experienced patients with genotype 2, 5, and 
6 infection without cirrhosis received ledipasvir/sofosbuvir for 12 weeks; and 19 genotype 1, 2, and 4 
HCV-infected patients with compensated cirrhosis received ledipasvir/sofosbuvir for 24 weeks. Of the 
95 total patients, at baseline, 20% of patients had cirrhosis, 22% were treatment experienced, 21% had 
received a kidney transplant, 92% were on hemodialysis, and 8% were on peritoneal dialysis; mean 



33 

duration on dialysis was 11.5 years (range: 0.2 to 43.0 years). The SVR rates for the 8, 12, and 24 
week ledipasvir/sofosbuvir treatment groups were 93% (42/45), 100% (31/31), and 79% (15/19), 
respectively. Of the seven patients who did not achieve SVR12, none experienced virologic failure or 
relapsed. 
 
Paediatric population 
The efficacy of ledipasvir/sofosbuvir in HCV infected patients aged 3 years and above was evaluated 
in a Phase 2, open label clinical study that enrolled 226 patients: 221 patients with genotype 1, 2 
patients with genotype 3, and 3 patients with genotype 4 CHC (Study 1116) (see section 4.2 for 
information on paediatric use). 
 
Patients aged 12 to < 18 Years: 
Ledipasvir/sofosbuvir was evaluated in 100 patients aged 12 to < 18 years with genotype 1 HCV 
infection. A total of 80 patients (n=80) were treatment-naïve, while 20 patients (n=20) were 
treatment-experienced. All patients were treated with ledipasvir/sofosbuvir for 12 weeks. 
 
Demographics and baseline characteristics were balanced across treatment-naïve and 
treatment-experienced patients. The median age was 15 years (range: 12 to 17); 63% of the patients 
were female; 91% were White, 7% were Black, and 2% were Asian; 13% were Hispanic/Latino; mean 
weight was 61.3 kg (range: 33.0 to 126.0 kg); 55% had baseline HCV RNA levels greater than or 
equal to 800,000 IU/mL; 81% had genotype 1a HCV infection; and 1 patient who was treatment naïve 
was known to have cirrhosis. The majority of patients (84%) had been infected through vertical 
transmission. 
 
The SVR12 rate was 98% overall (98% [78/80] in treatment-naïve patients and 100% [20/20] in 
treatment experienced patients). A total of 2 out of 100 patients (2%), both treatment- naïve, did not 
achieve SVR12 (due to loss to follow-up). No patient experienced virologic failure. 
 
Patients aged 6 to < 12 Years:  
Ledipasvir/sofosbuvir was evaluated in 92 patients aged 6 to < 12 years with genotype 1, 3, or 4 
HCV-infection. A total of 72 patients (78%) were treatment-naïve and 20 patients (22%) were 
treatment-experienced. Eighty-nine of the patients (87 patients with genotype 1 HCV infection and 2 
patients with genotype 4 HCV infection) were treated with ledipasvir/sofosbuvir for 12 weeks, 1 
treatment experienced patient with genotype 1 HCV infection and cirrhosis was treated with 
ledipasvir/sofosbuvir for 24 weeks, and 2 treatment experienced patients with genotype 3 HCV 
infection were treated with ledipasvir/sofosbuvir plus ribavirin for 24 weeks.  
 
The median age was 9 years (range: 6 to 11); 59% of the patients were male; 79% were White, 8% 
were Black, and 5% were Asian; 10% were Hispanic/Latino; mean weight was 32.8 kg (range: 17.5 to 
76.4 kg); 59% had baseline HCV RNA levels greater than or equal to 800,000  IU/ mL; 84% had 
genotype 1a HCV infection; 2 patients (1 treatment-naïve, 1 treatment-experienced) had known 
cirrhosis. The majority of patients (97%) had been infected through vertical transmission.  
 
The SVR rate was 99% overall (99% [88/89], 100% [1/1], and 100% [2/2] in patients treated with 
ledipasvir/sofosbuvir for 12 weeks, ledipasvir/sofosbuvir for 24 weeks, and ledipasvir/sofosbuvir plus 
ribavirin for 24 weeks, respectively). The one treatment-naïve patient with genotype 1 HCV infection 
and cirrhosis who was treated with Harvoni for 12 weeks did not achieve SVR12 and relapsed.  
 
Patients aged 3 to < 6 Years:  
Ledipasvir/sofosbuvir was evaluated in 34 patients aged 3 to < 6 years with genotype 1 (n = 33) or 
genotype 4 (n = 1) HCV-infection. All of the patients were treatment-naïve and treated with 
ledipasvir/sofosbuvir for 12 weeks. The median age was 5 years (range: 3 to 5); 71% of the patients 
were female; 79% were White, 3% were Black, and 6% were Asian; 18% were Hispanic/Latino; mean 
weight was 19.2 kg (range: 10.7 to 33.6 kg); 56% had baseline HCV RNA levels greater than or equal 
to 800,000 IU/ mL; 82% had genotype 1a HCV infection; no patients had known cirrhosis. All patients 
(100%) had been infected through vertical transmission.  
 



34 

The SVR rate was 97% overall (97% [32/33] in patients with genotype 1 HCV infection and 100% 
[1/1] in patients with genotype 4 HCV infection). One patient who prematurely discontinued study 
treatment after five days due to abnormal taste of the medication did not achieve SVR. 
 
5.2 Pharmacokinetic properties 
 
Absorption 
 
Following oral administration of ledipasvir/sofosbuvir to HCV-infected patients, ledipasvir median 
peak plasma concentration was observed at 4.0 hours post-dose. Sofosbuvir was absorbed quickly and 
the median peak plasma concentrations were observed ~ 1 hour post-dose. Median peak plasma 
concentration of GS-331007 was observed at 4 hours post-dose. 
 
Based on the population pharmacokinetic analysis in HCV-infected patients, geometric mean 
steady-state AUC0-24 for ledipasvir (n = 2,113), sofosbuvir (n = 1,542), and GS-331007 (n = 2,113) 
were 7,290, 1,320 and 12,000 ng•h/mL, respectively. Steady-state Cmax for ledipasvir, sofosbuvir and 
GS-331007 were 323, 618 and 707 ng/mL, respectively. Sofosbuvir and GS-331007 AUC0-24 and Cmax 
were similar in healthy adult subjects and patients with HCV infection. Relative to healthy subjects 
(n = 191), ledipasvir AUC0-24 and Cmax were 24% lower and 32% lower, respectively, in HCV-infected 
patients. Ledipasvir AUC is dose proportional over the dose range of 3 to 100 mg. Sofosbuvir and 
GS-331007 AUCs are near dose proportional over the dose range of 200 mg to 400 mg. 
 
Effects of food 
Relative to fasting conditions, the administration of a single dose of ledipasvir/sofosbuvir with a 
moderate fat or high fat meal increased the sofosbuvir AUC0-inf by approximately 2-fold, but did not 
significantly affect the sofosbuvir Cmax. The exposures to GS-331007 and ledipasvir were not altered in 
the presence of either meal type. Harvoni can be administered without regard to food. 
 
Distribution 
 
Ledipasvir is > 99.8% bound to human plasma proteins. After a single 90 mg dose of [14C]-ledipasvir 
in healthy subjects, the blood to plasma ratio of [14C]-radioactivity ranged between 0.51 and 0.66. 
 
Sofosbuvir is approximately 61-65% bound to human plasma proteins and the binding is independent 
of drug concentration over the range of 1 µg/mL to 20 µg/mL. Protein binding of GS-331007 was 
minimal in human plasma. After a single 400 mg dose of [14C]-sofosbuvir in healthy subjects, the 
blood to plasma ratio of [14C]-radioactivity was approximately 0.7. 
 
Biotransformation 
 
In vitro, no detectable metabolism of ledipasvir was observed by human CYP1A2, CYP2C8, 
CYP2C9, CYP2C19, CYP2D6 and CYP3A4. Evidence of slow oxidative metabolism via an unknown 
mechanism has been observed. Following a single dose of 90 mg [14C]-ledipasvir, systemic exposure 
was almost exclusively due to the parent drug (> 98%). Unchanged ledipasvir is also the major species 
present in faeces. 
 
Sofosbuvir is extensively metabolised in the liver to form the pharmacologically active nucleoside 
analogue triphosphate GS-461203. The active metabolite is not observed. The metabolic activation 
pathway involves sequential hydrolysis of the carboxyl ester moiety catalysed by human cathepsin A 
or carboxylesterase 1 and phosphoramidate cleavage by histidine triad nucleotide-binding protein 1 
followed by phosphorylation by the pyrimidine nucleotide biosynthesis pathway. Dephosphorylation 
results in the formation of nucleoside metabolite GS-331007 that cannot be efficiently 
rephosphorylated and lacks anti-HCV activity in vitro. Within ledipasvir/sofosbuvir, GS-331007 
accounts for approximately 85% of total systemic exposure. 
 



35 

Elimination 
 
Following a single 90 mg oral dose of [14C]-ledipasvir, mean total recovery of the [14C]-radioactivity 
in faeces and urine was 87%, with most of the radioactive dose recovered from faeces (86%). 
Unchanged ledipasvir excreted in faeces accounted for a mean of 70% of the administered dose and 
the oxidative metabolite M19 accounted for 2.2% of the dose. These data suggest that biliary excretion 
of unchanged ledipasvir is a major route of elimination with renal excretion being a minor pathway 
(approximately 1%). The median terminal half-life of ledipasvir in healthy volunteers following 
administration of ledipasvir/sofosbuvir in the fasted state was 47 hours. 
 
Following a single 400 mg oral dose of [14C]-sofosbuvir, mean total recovery of the dose was greater 
than 92%, consisting of approximately 80%, 14%, and 2.5% recovered in urine, faeces, and expired 
air, respectively. The majority of the sofosbuvir dose recovered in urine was GS-331007 (78%) while 
3.5% was recovered as sofosbuvir. This data indicate that renal clearance is the major elimination 
pathway for GS-331007 with a large part actively secreted. The median terminal half-lives of 
sofosbuvir and GS-331007 following administration of ledipasvir/sofosbuvir were 0.5 and 27 hours, 
respectively. 
 
Neither ledipasvir nor sofosbuvir are substrates for hepatic uptake transporters, organic cation 
transporter (OCT) 1, organic anion-transporting polypeptide (OATP) 1B1 or OATP1B3. GS-331007 is 
not a substrate for renal transporters including organic anion transporter (OAT) 1 or OAT3, or OCT2. 
 
In vitro potential for ledipasvir/sofosbuvir to affect other medicinal products 
 
At concentrations achieved in the clinic, ledipasvir is not an inhibitor of hepatic transporters including 
the OATP 1B1 or 1B3, BSEP, OCT1, OCT2, OAT1, OAT3, multidrug and toxic compound extrusion 
(MATE) 1 transporter, multidrug resistance protein (MRP) 2 or MRP4. Sofosbuvir and GS-331007 are 
not inhibitors of drug transporters P-gp, BCRP, MRP2, BSEP, OATP1B1, OATP1B3, OCT1 and 
GS-331007 is not an inhibitor of OAT1, OCT2 and MATE1. 
 
Sofosbuvir and GS-331007 are not inhibitors or inducers of CYP or uridine diphosphate 
glucuronosyltransferase (UGT) 1A1 enzymes. 
 
Pharmacokinetics in special populations 
 
Race and gender 
No clinically relevant pharmacokinetic differences due to race have been identified for ledipasvir, 
sofosbuvir or GS-331007. No clinically relevant pharmacokinetic differences due to gender have been 
identified for sofosbuvir or GS-331007. AUC and Cmax of ledipasvir were 77% and 58% higher, 
respectively, in females than males; however, the relationship between gender and ledipasvir 
exposures was not considered clinically relevant. 
 
Elderly 
Population pharmacokinetic analysis in HCV-infected patients showed that within the age range (18 to 
80 years) analysed, age did not have a clinically relevant effect on the exposure to ledipasvir, 
sofosbuvir or GS-331007. Clinical studies of ledipasvir/sofosbuvir included 235 patients (8.6% of total 
number of patients) aged 65 years and over. 
 
Renal impairment 
A summary of the effect of varying degrees of renal impairment (RI) on the exposures of the 
components of Harvoni compared to subjects with normal renal function, as described in the text 
below, are provided in Table 21. 
 



36 

Table 21: Effect of Varying Degrees of Renal Impairment on Exposures (AUC) of Sofosbuvir, GS-331007, 
and Ledipasvir Compared to Subjects with Normal Renal Function 
 HCV-Negative Subjects HCV-Infected 

Subjects 
Mild RI 

(eGFR ≥50 
and 

<80 mL/ 
min/ 

1.73m2) 

Moderate RI 
(eGFR ≥30 

and <50 mL/ 
min/ 

1.73m2) 

Severe RI 
(eGFR 

<30 mL/ 
min/ 

1.73m2) 

ESRD Requiring 
Dialysis 

Severe RI 
(eGFR 

<30 mL/ 
min/ 

1.73m2) 

ESRD 
Requiring 
Dialysis Dosed 

1 hr 
Before 
Dialysis 

Dosed 
1 hr After 
Dialysis 

Sofosbuvir 1.6-fold↑ 2.1-fold↑ 2.7-fold↑ 1.3-fold↑ 1.6-fold↑ ~2-fold↑ 1.9-fold↑ 
GS-331007 1.6-fold↑ 1.9-fold↑ 5.5-fold↑ ≥10-fold↑ ≥20-fold↑ ~6-fold↑ 23-fold↑ 
Ledipasvir - - ↔ - - - 1.6-fold↑ 
↔ indicates no clinically relevant change in the exposure of Ledipasvir. 
 
The pharmacokinetics of ledipasvir were studied with a single dose of 90 mg ledipasvir in 
HCV negative adult patients with severe renal impairment (eGFR < 30 mL/min by Cockcroft-Gault, 
median [range] CrCl 22 [17-29] mL/min).  
 
The pharmacokinetics of sofosbuvir were studied in HCV negative adult patients with mild (eGFR 
≥ 50 and < 80 mL/min/1.73 m2), moderate (eGFR ≥ 30 and < 50 mL/min/1.73 m2), severe renal 
impairment (eGFR < 30 mL/min/1.73 m2) and patients with ESRD requiring haemodialysis following 
a single 400 mg dose of sofosbuvir,relative to patients with normal renal function (eGFR 
> 80 mL/min/1.73 m2). GS-331007 is efficiently removed by haemodialysis with an extraction 
coefficient of approximately 53%. Following a single 400 mg dose of sofosbuvir, a 4 hour 
haemodialysis removed 18% of administered sofosbuvir dose. 
 
In HCV-infected adult patients with severe renal impairment treated with ledipasvir/sofosbuvir for 
12 weeks (n = 18), the pharmacokinetics of ledipasvir, sofosbuvir, and GS-331007 were consistent 
with that observed in HCV negative patients with severe renal impairment. 
 
The pharmacokinetics of ledipasvir, sofosbuvir, and GS-331007 were studied in HCV-infected adult 
patients with ESRD requiring dialysis treated with ledipasvir/sofosbuvir (n=94) for 8, 12, or 24 weeks, 
and compared to patients without renal impairment in the ledipasvir/sofosbuvir Phase 2/3 trials. 
 
Hepatic impairment 
The pharmacokinetics of ledipasvir were studied with a single dose of 90 mg ledipasvir in 
HCV negative adult patients with severe hepatic impairment (CPT class C). Ledipasvir plasma 
exposure (AUCinf) was similar in patients with severe hepatic impairment and control patients with 
normal hepatic function. Population pharmacokinetics analysis in HCV-infected adult patients 
indicated that cirrhosis (including decompensated cirrhosis) had no clinically relevant effect on the 
exposure to ledipasvir. 
 
The pharmacokinetics of sofosbuvir were studied following 7-day dosing of 400 mg sofosbuvir in 
HCV-infected adult patients with moderate and severe hepatic impairment (CPT class B and C). 
Relative to patients with normal hepatic function, the sofosbuvir AUC0-24 was 126% and 143% higher 
in moderate and severe hepatic impairment, while the GS-331007 AUC0-24 was 18% and 9% higher, 
respectively. Population pharmacokinetics analysis in HCV-infected patients indicated that cirrhosis 
(including decompensated cirrhosis) had no clinically relevant effect on the exposure to sofosbuvir 
and GS-331007. 
 
Body weight 
Body weight did not have a significant effect on sofosbuvir exposure according to a population 
pharmacokinetic analysis. Exposure to ledipasvir decreases with increasing body weight but the effect 
is not considered to be clinically relevant. 
 



37 

Paediatric population 
Ledipasvir, sofosbuvir, and GS-331007 exposures in paediatric patients aged 3 years and above were 
similar to those in adults from Phase 2/3 studies, following administration of ledipasvir/sofosbuvir. 
The 90% confidence intervals of geometric least-squares mean ratios for all PK parameters of interest 
were contained within the predetermined similarity bounds of less than 2-fold (50% to 200%) with the 
exception of ledipasvir Ctau in paediatric patients 12 years and above which was 84% higher (90%CI: 
168% to 203%) and was not considered clinically relevant. 
 
The pharmacokinetics of ledipasvir, sofosbuvir, and GS-331007 have not been established in 
paediatric patients aged < 3 years (see section 4.2). 
 
5.3 Preclinical safety data 
 
Ledipasvir 
 
No target organs of toxicity were identified in rat and dog studies with ledipasvir at AUC exposures 
approximately 7 times the human exposure at the recommended clinical dose. 
 
Ledipasvir was not genotoxic in a battery of in vitro or in vivo assays, including bacterial 
mutagenicity, chromosome aberration using human peripheral blood lymphocytes and in vivo rat 
micronucleus assays. 
 
Ledipasvir was not carcinogenic in the 26-week rasH2 transgenic mouse and the 2-year rat 
carcinogenicity studies at exposures up to 26-times in mice and 8-times in rats higher than human 
exposure. 
 
Ledipasvir had no adverse effects on mating and fertility. In female rats, the mean number of corpora 
lutea and implantation sites were slightly reduced at maternal exposures 6-fold the exposure in humans 
at the recommended clinical dose. At the no observed effect level, AUC exposure to ledipasvir was 
approximately 7- and 3-fold, in males and females, respectively, the human exposure at the 
recommended clinical dose. 
 
No teratogenic effects were observed in rat and rabbit developmental toxicity studies with ledipasvir. 
 
In a rat pre- and postnatal study, at a maternally toxic dose, the developing rat offspring exhibited 
mean decreased body weight and body weight gain when exposed in utero (via maternal dosing) and 
during lactation (via maternal milk) at a maternal exposure 4 times the exposure in humans at the 
recommended clinical dose. There were no effects on survival, physical and behavioural development 
and reproductive performance in the offspring at maternal exposures similar to the exposure in humans 
at the recommended clinical dose. 
 
When administered to lactating rats, ledipasvir was detected in plasma of suckling rats likely due to 
excretion of ledipasvir via milk. 
 
Environmental risk assessment (ERA) 
 
Environmental risk assessment studies have shown that ledipasvir has the potential to be very 
persistent and very bioaccumulative (vPvB) in the environment (see section 6.6). 
 
Sofosbuvir 
 
In repeat dose toxicology studies in rat and dog, high doses of the 1:1 diastereomeric mixture caused 
adverse liver (dog) and heart (rat) effects and gastrointestinal reactions (dog). Exposure to sofosbuvir 
in rodent studies could not be detected likely due to high esterase activity; however, exposure to the 
major metabolite GS-331007 at doses which cause adverse effects was 16 times (rat) and 71 times 
(dog) higher than the clinical exposure at 400 mg sofosbuvir. No liver or heart findings were observed 
in chronic toxicity studies at exposures 5 times (rat) and 16 times (dog) higher than the clinical 



38 

exposure. No liver or heart findings were observed in the 2-year carcinogenicity studies at exposures 
17 times (mouse) and 9 times (rat) higher than the clinical exposure. 
 
Sofosbuvir was not genotoxic in a battery of in vitro or in vivo assays, including bacterial 
mutagenicity, chromosome aberration using human peripheral blood lymphocytes and in vivo mouse 
micronucleus assays. 
 
Carcinogenicity studies in mice and rats do not indicate any carcinogenicity potential of sofosbuvir 
administered at doses up to 600 mg/kg/day in mouse and 750 mg/kg/day in rat. Exposure to 
GS-331007 in these studies was up to 17 times (mouse) and 9 times (rat) higher than the clinical 
exposure at 400 mg sofosbuvir. 
 
Sofosbuvir had no effects on embryo-foetal viability or on fertility in rat and was not teratogenic in rat 
and rabbit development studies. No adverse effects on behaviour, reproduction or development of 
offspring in rat were reported. In rabbit studies exposure to sofosbuvir was 6 times the expected 
clinical exposure. In the rat studies, exposure to sofosbuvir could not be determined but exposure 
margins based on the major human metabolite was approximately 5 times higher than the clinical 
exposure at 400 mg sofosbuvir. 
 
Sofosbuvir-derived material was transferred through the placenta in pregnant rats and into the milk of 
lactating rats. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core 
 
Copovidone 
Lactose monohydrate 
Microcrystalline cellulose 
Croscarmellose sodium 
Colloidal anhydrous silica 
Magnesium stearate 
 
Film-coating 
 
Polyvinyl alcohol 
Titanium dioxide partially hydrolyzed 
Macrogol 
Talc 
Sunset yellow FCF (E110) (Harvoni 90 mg/400 mg film-coated tablet only) 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
6 years. 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions. 
 



39 

6.5 Nature and contents of container 
 
Harvoni tablets are supplied in high density polyethylene (HDPE) bottles with a polypropylene 
child-resistant closure containing 28 film-coated tablets with a silica gel desiccant and polyester coil. 
 
The following pack sizes are available:  

• outer cartons containing 1 bottle of 28 film-coated tablets 
• and for the 90 mg/400 mg tablets only; outer cartons containing 84 (3 bottles of 

28) film-coated tablets. 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
This medicinal product may pose a risk to the environment (see section 5.3). 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Gilead Sciences Ireland UC 
Carrigtohill 
County Cork, T45 DP77 
Ireland 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/14/958/001 
EU/1/14/958/002 
EU/1/14/958/003 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 17 November 2014 
Date of latest renewal: 01 August 2019 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu 

http://www.ema.europa.eu/


40 

This medicinal product is subject to additional monitoring. This will allow quick identification of 
new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 
See section 4.8 for how to report adverse reactions. 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Harvoni 33.75 mg/150 mg coated granules in sachet 
Harvoni 45 mg/200 mg coated granules in sachet  
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Harvoni 33.75 mg/150 mg coated granules in sachet 
Each sachet contains 33.75 mg ledipasvir and 150 mg sofosbuvir. 
 
Excipients with known effect 
Each sachet contains 220 mg of lactose (as monohydrate). 
 
Harvoni 45 mg/200 mg coated granules in sachet 
Each sachet contains 45 mg ledipasvir and 200 mg sofosbuvir. 
 
Excipients with known effect 
Each sachet contains 295 mg of lactose (as monohydrate). 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Coated granules in sachet. 
 
Orange, coated granules in sachet. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Harvoni is indicated for the treatment of chronic hepatitis C (CHC) in adult and paediatric patients 
aged 3 years and above (see sections 4.2, 4.4 and 5.1). 
 
For hepatitis C virus (HCV) genotype-specific activity see sections 4.4 and 5.1. 
 
4.2 Posology and method of administration 
 
Harvoni treatment should be initiated and monitored by a physician experienced in the management of 
patients with CHC. 
 
Posology 
The recommended dose of Harvoni in paediatric patients aged 3 years and above is based on weight 
(as detailed in Table 2) and can be taken with or without food (see section 5.2). 
 



41 

Table 1: Recommended treatment duration for Harvoni and the recommended use of co-administered 
ribavirin for certain subgroups 
Patient population 
(including HIV co-infected patients) 

Treatment and duration 

Adult and paediatric patients aged 3 years and abovea with genotype 1, 4, 5 or 6 CHC 

Patients without cirrhosis 

Harvoni for 12 weeks. 
- Harvoni for 8 weeks may be considered in previously 

untreated genotype 1-infected patients (see section 5.1, 
ION-3 study). 

Patients with compensated cirrhosis 

Harvoni + ribavirinb,c for 12 weeks 
or 
Harvoni (without ribavirin) for 24 weeks. 
 
- Harvoni (without ribavirin) for 12 weeks may be 

considered for patients deemed at low risk for clinical 
disease progression and who have subsequent retreatment 
options (see section 4.4). 

Patients who are post-liver transplant 
without cirrhosis or with compensated 
cirrhosis 

Harvoni + ribavirinb,c for 12 weeks (see section 5.1). 
- Harvoni (without ribavirin) for 12 weeks (in patients 

without cirrhosis) or 24 weeks (in patients with cirrhosis) 
may be considered for patients who are ineligible for or 
intolerant to ribavirin. 

Patients with decompensated cirrhosis 
irrespective of transplant status 

Harvoni + ribavirind for 12 weeks (see section 5.1) 
- Harvoni (without ribavirin) for 24 weeks may be 

considered in patients who are ineligible for or intolerant 
to ribavirin. 

Adult and paediatric patients aged 3 years and abovea with genotype 3 CHC 

Patients with compensated cirrhosis and/or 
prior treatment failure Harvoni + ribavirin

b for 24 weeks (see sections 4.4 and 5.1). 

a See Table 2 for weight-based Harvoni dosing recommendations for paediatric patients aged 3 years and above. 
b Adults: weight-based ribavirin (< 75 kg = 1,000 mg and ≥ 75 kg = 1,200 mg), administered orally in two divided doses 

with food. 
c Paediatric patients: for ribavirin dosing recommendations see Table 4 below. 
d  For ribavirin dosing recommendations in adult patients with decompensated cirrhosis, see Table 3 below. 
 
Table 2: Dosing for paediatric patients aged 3 years and above using Harvoni oral granules* 
Body Weight (kg)  Dosing of Oral Granules in Sachet Ledipasvir/Sofosbuvir Daily Dose 

≥ 35 two 45 mg/200 mg sachets of 
granules once daily 

90 mg/400 mg/day  

17 to < 35  one 45 mg/200 mg sachet of 
granules once daily 

45 mg/200 mg/day  

< 17  one 33.75 mg/150 mg sachet of 
granules once daily  

33.75 mg/150 mg/day  

* Harvoni is also available as 45 mg/200 mg and 90 mg/400 mg film-coated tablets (see section 5.1). Please refer to the 
Summaries of Product Characteristics for Harvoni film-coated tablets. 
 



42 

Table 3: Guidance for ribavirin dosing when administered with Harvoni to adult patients with 
decompensated cirrhosis 
Patient Ribavirin dose* 
Child-Pugh-Turcotte (CPT) Class B 
cirrhosis pre-transplant 

1,000 mg per day for patients < 75 kg and 1,200 mg for those 
weighing ≥ 75 kg 

CPT Class C cirrhosis pre-transplant 
 
CPT Class B or C cirrhosis post-
transplant 
 

Starting dose of 600 mg, which can be titrated up to a maximum 
of 1,000/1,200 mg (1,000 mg for patients weighing < 75 kg and 
1,200 mg for patients weighing ≥ 75 kg) if well tolerated.  If the 
starting dose is not well tolerated, the dose should be reduced as 
clinically indicated based on haemoglobin levels 

* - If a more normalized dose of ribavirin (by weight and renal function) cannot be reached for reasons of tolerability, 
24 weeks of Harvoni + ribavirin should be considered in order to minimize the risk for relapse. 
 
For adults when ribavirin is added to Harvoni, refer also to the Summary of Product Characteristics of 
ribavirin. 
 
In paediatric patients aged 3 years and above the following ribavirin dosing is recommended where 
ribavirin is divided into two daily doses and given with food: 
 
Table 4: Guidance for ribavirin dosing when administered with Harvoni to paediatric patients aged 
3 years and above. 

Body weight kg Ribavirin Dose* 
< 47 15 mg/kg/day 
47-49 600 mg/day 
50-65 800 mg/day 
66-74 1000 mg/day 
> or = 75 1200 mg/day 

* The daily dosage of ribavirin is weight-based and administered orally in two divided doses with food. 
 
Dose modification of ribavirin in adults taking 1,000-1,200 mg daily 
If Harvoni is used in combination with ribavirin and a patient has a serious adverse reaction potentially 
related to ribavirin, the ribavirin dose should be modified or discontinued, if appropriate, until the 
adverse reaction abates or decreases in severity. Table 5 provides guidelines for dose modifications 
and discontinuation based on the patient’s haemoglobin concentration and cardiac status. 
 
Table 5: Ribavirin dose modification guideline for co-administration with Harvoni in adults 

Laboratory values Reduce ribavirin dose to 
600 mg/day if: 

Discontinue ribavirin if: 

Haemoglobin in patients with no 
cardiac disease 

< 10 g/dL < 8.5 g/dL 

Haemoglobin in patients with history 
of stable cardiac disease 

≥ 2 g/dL decrease in haemoglobin 
during any 4-week treatment 
period 

< 12 g/dL despite 4 weeks at 
reduced dose 

 
Once ribavirin has been withheld due to either a laboratory abnormality or clinical manifestation, an 
attempt may be made to restart ribavirin at 600 mg daily and further increase the dose to 800 mg daily.  
However, it is not recommended that ribavirin be increased to the originally assigned dose (1,000 mg 
to 1,200 mg daily). 
 
Paediatric population aged < 3 years 
The safety and efficacy of Harvoni in paediatric patients aged < 3 years have not been established.  No 
data are available. 
 
Missed dose 
Patients should be instructed that if vomiting occurs within 5 hours of dosing an additional dose 
should be taken.  If vomiting occurs more than 5 hours after dosing, no further dose is needed (see 
section 5.1). 
 



43 

If a dose is missed and it is within 18 hours of the normal time, patients should be instructed to take 
the additional dose as soon as possible and then patients should take the next dose at the usual time. If 
it is after 18 hours then patients should be instructed to wait and take the next dose at the usual time.  
Patients should be instructed not to take a double dose. 
 
Elderly 
No dose adjustment is warranted for elderly patients (see section 5.2). 
 
Renal impairment 
No dose adjustment of Harvoni is required for patients with mild or moderate renal impairment.   
 
Safety data are limited in patients with severe renal impairment (estimated glomerular filtration rate 
[eGFR] < 30 mL/min/1.73 m2) and end stage renal disease (ESRD) requiring dialysis. Harvoni can be 
used in these patients with no dose adjustment when no other relevant treatment options are available 
(see section 4.4, 4.8, 5.1 and 5.2). 
 
Hepatic impairment 
No dose adjustment of Harvoni is required for patients with mild, moderate or severe hepatic 
impairment (Child-Pugh-Turcotte [CPT] class A, B or C) (see section 5.2). Safety and efficacy of 
ledipasvir/sofosbuvir have been established in patients with decompensated cirrhosis (see section 5.1). 
 
Method of administration 
 
For oral use. 
 
Harvoni can be taken either with or without food. 
 
To help with swallowing of the Harvoni oral granules you can use food or water as detailed below. 
Alternatively, Harvoni can be swallowed without food or water. 
 
Taking Harvoni granules with food to aid swallowing 
To administer with food to aid swallowability of the granules, patients should be instructed to sprinkle 
the granules on one or more spoonfuls of non-acidic soft food at or below room temperature. Patients 
should be instructed to take the Harvoni granules within 30 minutes of gently mixing with food and to 
swallow the entire contents without chewing to avoid a bitter taste. Examples of non-acidic foods 
include chocolate syrup, mashed potato, and ice-cream.  
 
Taking Harvoni granules with water to aid swallowing 
To administer with water, patients should be instructed that the granules can be taken directly into the 
mouth and swallowed with water.  
 
Taking Harvoni granules without food or water 
To administer without food or water, patients should be instructed that the granules can be taken 
directly into the mouth and swallowed. Patients should be instructed to swallow the entire contents 
without chewing (see section 5.2). 
 
4.3 Contraindications 
 
Hypersensitivity to the active substances or to any of the excipients listed in section 6.1. 
 
Co-administration with rosuvastatin (see section 4.5). 
 
Use with strong P-gp inducers 
 
Medicinal products that are strong P-glycoprotein (P-gp) inducers in the intestine (carbamazepine, 
phenobarbital, phenytoin, rifampicin, rifabutin and St. John’s wort). Co-administration will 



44 

significantly decrease ledipasvir and sofosbuvir plasma concentrations and could result in loss of 
efficacy of Harvoni (see section 4.5). 
 
4.4 Special warnings and precautions for use 
 
Harvoni should not be administered concomitantly with other medicinal products containing 
sofosbuvir. 
 
Genotype-specific activity 
 
Concerning recommended regimens with different HCV genotypes, see section 4.2. Concerning 
genotype-specific virological and clinical activity, see section 5.1. 
 
The clinical data to support the use of Harvoni in adults infected with HCV genotype 3 are limited (see 
section 5.1). The relative efficacy of a 12-week regimen consisting of ledipasvir/sofosbuvir 
+ ribavirin, compared to a 24-week regimen of sofosbuvir + ribavirin has not been investigated. A 
conservative 24 weeks of therapy is advised in all treatment-experienced genotype 3 patients and those 
treatment-naïve genotype 3 patients with cirrhosis (see section 4.2). In genotype 3-infection, the use of 
Harvoni (always in combination with ribavirin) should only be considered for patients who are 
deemed at high risk for clinical disease progression and who do not have alternative treatment options. 
 
The clinical data to support the use of Harvoni in adults infected with HCV genotype 2 and 6 are 
limited (see section 5.1). 
 
Severe bradycardia and heart block 
 
Life-threatening cases of severe bradycardia and heart block have been observed when sofosbuvir-
containing regimens are used in combination with amiodarone. Bradycardia has generally occurred 
within hours to days, but cases with a longer time to onset have been observed mostly up to 2 weeks 
after initiating HCV treatment. 
 
Amiodarone should only be used in patients on Harvoni when other alternative anti-arrhythmic 
treatments are not tolerated or are contraindicated. 
 
Should concomitant use of amiodarone be considered necessary it is recommended that patients 
undergo cardiac monitoring in an in-patient setting for the first 48 hours of coadministration, after 
which outpatient or self-monitoring of the heart rate should occur on a daily basis through at least the 
first 2 weeks of treatment. 
 
Due to the long half-life of amiodarone, cardiac monitoring as outlined above should also be carried 
out for patients who have discontinued amiodarone within the past few months and are to be initiated 
on Harvoni. 
 
All patients with concurrent or recent use of amiodarone should be warned of the symptoms of 
bradycardia and heart block and should be advised to seek medical advice urgently should they 
experience them. 
 
Use in diabetic patients  
 
Diabetics may experience improved glucose control, potentially resulting in symptomatic 
hypoglycaemia, after initiating HCV direct-acting antiviral treatment. Glucose levels of diabetic 
patients initiating direct-acting antiviral therapy should be closely monitored, particularly within the 
first 3 months, and their diabetic medication modified when necessary. The physician in charge of the 
diabetic care of the patient should be informed when direct-acting antiviral therapy is initiated. 



45 

 
HCV/HBV (hepatitis B virus) co-infection 
 
Cases of hepatitis B virus (HBV) reactivation, some of them fatal, have been reported during or after 
treatment with direct-acting antiviral agents. HBV screening should be performed in all patients before 
initiation of treatment.  HBV/HCV co-infected patients are at risk of HBV reactivation, and should 
therefore be monitored and managed according to current clinical guidelines. 
 
Treatment of patients with prior exposure to HCV direct-acting antivirals 
 
In patients who fail treatment with ledipasvir/sofosbuvir, selection of NS5A resistance mutations that 
substantially reduce the susceptibility to ledipasvir is seen in the majority of cases (see section 5.1). 
Limited data indicate that such NS5A mutations do not revert on long-term follow-up.  There are 
presently no data to support the effectiveness of retreatment of patients who have failed 
ledipasvir/sofosbuvir with a subsequent regimen that contains an NS5A inhibitor. Similarly, there are 
presently no data to support the effectiveness of NS3/4A protease inhibitors in patients who previously 
failed prior therapy that included an NS3/4A protease inhibitor. Such patients may therefore be 
dependent on other classes of medicinal products for clearance of HCV infection. Consequently, 
consideration should be given to longer treatment for patients with uncertain subsequent retreatment 
options. 
 
Renal impairment 
 
Safety data are limited in patients with severe renal impairment (estimated glomerular filtration rate 
[eGFR] < 30 mL/min/1.73 m2) and ESRD requiring haemodialysis. Harvoni can be used in these 
patients with no dose adjustment when no other relevant treatment options are available (see 
sections 4.8, 5.1 and 5.2). When Harvoni is used in combination with ribavirin refer also to the 
Summary of Product Characteristics for ribavirin for patients with creatinine clearance (CrCl) 
< 50 mL/min (see section 5.2). 
 
Adults with decompensated cirrhosis and/or who are awaiting liver transplant or post-liver transplant 
 
The efficacy of ledipasvir/sofosbuvir in genotype 5 and genotype 6 HCV-infected patients with 
decompensated cirrhosis and/or who are awaiting liver transplant or post-liver transplant has not been 
investigated. Treatment with Harvoni should be guided by an assessment of the potential benefits and 
risks for the individual patient. 
 
Use with moderate P-gp inducers 
 
Medicinal products that are moderate P-gp inducers in the intestine (e.g. oxcarbazepine) may decrease 
ledipasvir and sofosbuvir plasma concentrations leading to reduced therapeutic effect of Harvoni.  
Co-administration of such medicinal products is not recommended with Harvoni (see section 4.5). 
 
Use with certain HIV antiretroviral regimens 
 
Harvoni has been shown to increase tenofovir exposure, especially when used together with an HIV 
regimen containing tenofovir disoproxil fumarate and a pharmacokinetic enhancer (ritonavir or 
cobicistat). The safety of tenofovir disoproxil fumarate in the setting of Harvoni and a 
pharmacokinetic enhancer has not been established. The potential risks and benefits associated with 
co-administration of Harvoni with the fixed-dose combination tablet containing 
elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate or tenofovir disoproxil fumarate 
given in conjunction with a boosted HIV protease inhibitor (e.g. atazanavir or darunavir) should be 
considered, particularly in patients at increased risk of renal dysfunction. Patients receiving Harvoni 
concomitantly with elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate or with 
tenofovir disoproxil fumarate and a boosted HIV protease inhibitor should be monitored for tenofovir-
associated adverse reactions. Refer to tenofovir disoproxil fumarate, emtricitabine/tenofovir disoproxil 



46 

fumarate, or elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate Summary of Product 
Characteristics for recommendations on renal monitoring. 
 
Use with HMG-CoA reductase inhibitors 
 
Co-administration of Harvoni and HMG-CoA reductase inhibitors (statins) can significantly increase 
the concentration of the statin, which increases the risk of myopathy and rhabdomyolysis (see 
section 4.5). 
 
Paediatric population 
 
Harvoni is not recommended for use in paediatric patients aged < 3 years because the safety and 
efficacy have not been established in this population. 
 
Excipients 
 
Harvoni contains the azo colouring agent sunset yellow FCF (E110), which may cause allergic 
reactions. It also contains lactose. Patients with rare hereditary problems of galactose intolerance, total 
lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
As Harvoni contains ledipasvir and sofosbuvir, any interactions that have been identified with these 
active substances individually may occur with Harvoni. 
 
Potential for Harvoni to affect other medicinal products 
 
Ledipasvir is an in vitro inhibitor of drug transporter P-gp and breast cancer resistance protein (BCRP) 
and may increase intestinal absorption of co-administered substrates for these transporters.   
 
Potential for other medicinal products to affect Harvoni 
 
Ledipasvir and sofosbuvir are substrates of drug transporter P-gp and BCRP while GS-331007 is not. 
 
Medicinal products that are strong P-gp inducers (carbamazepine, phenobarbital, phenytoin, 
rifampicin, rifabutin and St. John’s wort) may significantly decrease ledipasvir and sofosbuvir plasma 
concentrations leading to reduced therapeutic effect of ledipasvir/sofosbuvir and thus are 
contraindicated with Harvoni (see section 4.3). Medicinal products that are moderate P-gp inducers in 
the intestine (e.g. oxcarbazepine) may decrease ledipasvir and sofosbuvir plasma concentrations 
leading to reduced therapeutic effect of Harvoni. Co-administration with such medicinal products is 
not recommended with Harvoni (see section 4.4). Co-administration with medicinal products that 
inhibit P-gp and/or BCRP may increase ledipasvir and sofosbuvir plasma concentrations without 
increasing GS-331007 plasma concentration; Harvoni may be co-administered with P-gp and/or 
BCRP inhibitors.  Clinically significant medicinal product interactions with ledipasvir/sofosbuvir 
mediated by CYP450s or UGT1A1 enzymes are not expected. 
 
Patients treated with vitamin K antagonists 
 
As liver function may change during treatment with Harvoni, a close monitoring of International 
Normalised Ratio (INR) values is recommended. 
 
Impact of DAA therapy on drugs metabolized by the liver 
 
The pharmacokinetics of drugs that are metabolized by the liver (e.g. immunosuppressive agents such 
as calcineurin inhibitors) may be impacted by changes in liver function during DAA therapy, related to 
clearance of HCV virus. 
 



47 

Interactions between Harvoni and other medicinal products 
 
Table 6 provides a listing of established or potentially clinically significant medicinal product 
interactions (where 90% confidence interval [CI] of the geometric least-squares mean [GLSM] ratio 
were within “↔”, extended above “↑”, or extended below “↓” the predetermined equivalence 
boundaries). The medicinal product interactions described are based on studies conducted with either 
ledipasvir/sofosbuvir or ledipasvir and sofosbuvir as individual agents, or are predicted medicinal 
product interactions that may occur with ledipasvir/sofosbuvir. The table is not all-inclusive. 
 
Table 6: Interactions between Harvoni and other medicinal products 
Medicinal product by 
therapeutic areas 

Effects on medicinal 
product levels. 
Mean ratio (90% 
confidence interval) for 
AUC, Cmax, Cmina, b 

Recommendation concerning co-administration 
with Harvoni 

ACID REDUCING AGENTS 
 Ledipasvir solubility decreases as pH increases.  

Medicinal products that increase gastric pH are 
expected to decrease concentration of ledipasvir. 

Antacids  
e.g. Aluminium or 
magnesium hydroxide; 
calcium carbonate 

Interaction not studied. 
Expected: 
↓ Ledipasvir 
↔ Sofosbuvir 
↔ GS-331007 
 
(Increase in gastric pH) 

It is recommended to separate antacid and Harvoni 
administration by 4 hours. 

H2-receptor antagonists  
Famotidine 
(40 mg single dose)/ 
ledipasvir (90 mg single 
dose)c/ sofosbuvir (400 mg 
single dose)c, d 
 
Famotidine dosed 
simultaneously with 
Harvonid 
 
 
Cimetidinee 
Nizatidinee 
Ranitidinee 

Ledipasvir 
↓ Cmax 0.80 (0.69, 0.93) 
↔ AUC 0.89 (0.76, 1.06) 
 
Sofosbuvir 
↑ Cmax 1.15 (0.88, 1.50) 
↔ AUC 1.11 (1.00, 1.24) 
 
GS-331007 
↔ Cmax 1.06 (0.97, 1.14) 
↔ AUC 1.06 (1.02, 1.11) 
 
(Increase in gastric pH) 

H2-receptor antagonists may be administered 
simultaneously with or staggered from Harvoni at a 
dose that does not exceed doses comparable to 
famotidine 40 mg twice daily. 

Famotidine 
(40 mg single dose)/ 
ledipasvir (90 mg single 
dose)c/ sofosbuvir (400 mg 
single dose)c, d 
 
Famotidine dosed 12 hours 
prior to Harvonid 

Ledipasvir 
↓ Cmax 0.83 (0.69, 1.00) 
↔ AUC 0.98 (0.80, 1.20) 
 
Sofosbuvir 
↔ Cmax 1.00 (0.76, 1.32) 
↔ AUC 0.95 (0.82, 1.10) 
 
GS-331007 
↔ Cmax 1.13 (1.07, 1.20) 
↔ AUC 1.06 (1.01, 1.12) 
 
(Increase in gastric pH) 



48 

Medicinal product by 
therapeutic areas 

Effects on medicinal 
product levels. 
Mean ratio (90% 
confidence interval) for 
AUC, Cmax, Cmina, b 

Recommendation concerning co-administration 
with Harvoni 

Proton pump inhibitors  
Omeprazole 
(20 mg once daily)/ 
ledipasvir (90 mg single 
dose)c/ sofosbuvir (400 mg 
single dose)c 
 
Omeprazole dosed 
simultaneously with 
Harvoni 
 
Lansoprazolee 
Rabeprazolee 
Pantoprazolee 
Esomeprazolee 

Ledipasvir 
↓ Cmax 0.89 (0.61, 1.30) 
↓ AUC 0.96 (0.66, 1.39) 
 
Sofosbuvir 
↔ Cmax 1.12 (0.88, 1.42) 
↔ AUC 1.00 (0.80, 1.25) 
 
GS-331007 
↔ Cmax 1.14 (1.01, 1.29) 
↔ AUC 1.03 (0.96, 1.12) 
 
(Increase in gastric pH) 

Proton pump inhibitor doses comparable to 
omeprazole 20 mg can be administered 
simultaneously with Harvoni. Proton pump 
inhibitors should not be taken before Harvoni. 

ANTIARRHYTHMICS 
Amiodarone Effect on amiodarone, 

sofosbuvir and ledipasvir 
concentrations unknown. 

Coadministration of amiodarone with a sofosbuvir-
containing regimen may result in serious 
symptomatic bradycardia.  
Use only if no other alternative is available. Close 
monitoring is recommended if this medicinal 
product is administered with Harvoni (see 
sections 4.4 and 4.8). 

Digoxin Interaction not studied. 
Expected: 
↑ Digoxin 
↔ Ledipasvir 
↔ Sofosbuvir 
↔ GS-331007 
 
(Inhibition of P-gp) 

Co-administration of Harvoni with digoxin may 
increase the concentration of digoxin. Caution is 
warranted and therapeutic concentration monitoring 
of digoxin is recommended when co-administered 
with Harvoni. 

ANTICOAGULANTS 
Dabigatran etexilate Interaction not studied. 

Expected: 
↑ Dabigatran 
↔ Ledipasvir 
↔ Sofosbuvir 
↔ GS-331007 
 
(Inhibition of P-gp) 

Clinical monitoring, looking for signs of bleeding 
and anaemia, is recommended when dabigatran 
etexilate is co-administered with Harvoni. A 
coagulation test helps to identify patients with an 
increased bleeding risk due to increased dabigatran 
exposure. 

Vitamin K antagonists Interaction not studied. Close monitoring of INR is recommended with all 
vitamin K antagonists. This is due to liver function 
changes during treatment with Harvoni. 

ANTICONVULSANTS 
Phenobarbital 
Phenytoin 

Interaction not studied. 
Expected: 
↓ Ledipasvir 
↓ Sofosbuvir 
↔ GS-331007 
 
(Induction of P-gp) 

Harvoni is contraindicated with phenobarbital and 
phenytoin (see section 4.3). 



49 

Medicinal product by 
therapeutic areas 

Effects on medicinal 
product levels. 
Mean ratio (90% 
confidence interval) for 
AUC, Cmax, Cmina, b 

Recommendation concerning co-administration 
with Harvoni 

Carbamazepine Interaction not studied 
Expected: 
↓ Ledipasvir 
 
Observed: 
Sofosbuvir 
↓ Cmax 0.52 (0.43, 0.62) 
↓ AUC 0.52 (0.46, 0.59) 
Cmin (NA) 
 
GS 331007 
↔ Cmax 1.04 (0.97, 1.11) 
↔ AUC 0.99 (0.94, 1.04) 
Cmin (NA) 
 
(Induction of P-gp) 

Harvoni is contraindicated with carbamazepine (see 
section 4.3). 

Oxcarbazepine Interaction not studied. 
Expected: 
↓ Ledipasvir 
↓ Sofosbuvir 
↔ GS-331007 
 
(Induction of P-gp) 

Co-administration of Harvoni with oxcarbazepine is 
expected to decrease the concentration of ledipasvir 
and sofosbuvir leading to reduced therapeutic effect 
of Harvoni. Such co-administration is not 
recommended (see section 4.4). 

ANTIMYCOBACTERIALS 
Rifampicin (600 mg once 
daily)/ ledipasvir (90 mg 
single dose)d 

Interaction not studied. 
Expected: 
Rifampicin 
↔ Cmax 
↔ AUC 
↔ Cmin 
 
Observed: 
Ledipasvir 
↓ Cmax 0.65 (0.56, 0.76) 
↓ AUC 0.41 (0.36, 0.48) 
 
(Induction of P-gp) 

Harvoni is contraindicated with rifampicin (see 
section 4.3). 

Rifampicin (600 mg once 
daily)/ sofosbuvir (400 mg 
single dose)d 

Interaction not studied. 
Expected: 
Rifampicin 
↔ Cmax 
↔ AUC 
↔ Cmin 
 
Observed: 
Sofosbuvir 
↓ Cmax 0.23 (0.19, 0.29) 
↓ AUC 0.28 (0.24, 0.32) 
 
GS-331007 
↔ Cmax 1.23 (1.14, 1.34) 
↔ AUC 0.95 (0.88, 1.03) 
 
(Induction of P-gp) 

 



50 

Medicinal product by 
therapeutic areas 

Effects on medicinal 
product levels. 
Mean ratio (90% 
confidence interval) for 
AUC, Cmax, Cmina, b 

Recommendation concerning co-administration 
with Harvoni 

Rifabutin Interaction not studied. 
Expected: 
↓ Ledipasvir 
 
Observed: 
Sofosbuvir 
↓ Cmax 0.64 (0.53, 0.77) 
↓ AUC 0.76 (0.63, 0.91) 
Cmin (NA) 
 
GS 331007 
↔ Cmax 1.15 (1.03, 1.27) 
↔ AUC 1.03 (0.95, 1.12) 
Cmin (NA) 
 
(Induction of P-gp) 

Harvoni is contraindicated with rifabutin (see 
section 4.3). 
 

Rifapentine Interaction not studied. 
Expected: 
↓ Ledipasvir 
↓ Sofosbuvir 
↔ GS-331007 
 
(Induction of P-gp) 

Co-administration of Harvoni with rifapentine is 
expected to decrease the concentration of ledipasvir 
and sofosbuvir, leading to reduced therapeutic effect 
of Harvoni. Such co-administration is not 
recommended. 

SEDATIVES/HYPNOTICS 
Midazolam (2.5 mg single 
dose)/ ledipasvir (90 mg 
single dose) 
 
 
 
Ledipasvir (90 mg once 
daily) 

Observed: 
Midazolam 
↔ Cmax 1.07 (1.00, 1.14) 
↔ AUC 0.99 (0.95, 1.04) 
(Inhibition of CYP3A) 
 
Midazolam 
↔ Cmax 0.95 (0.87, 1.04) 
↔ AUC 0.89 (0.84, 0.95) 
(Induction of CYP3A) 
 
Expected: 
↔ Sofosbuvir 
↔ GS-331007 

No dose adjustment of Harvoni or midazolam is 
required. 



51 

Medicinal product by 
therapeutic areas 

Effects on medicinal 
product levels. 
Mean ratio (90% 
confidence interval) for 
AUC, Cmax, Cmina, b 

Recommendation concerning co-administration 
with Harvoni 

HIV ANTIVIRAL AGENTS: REVERSE TRANSCRIPTASE INHIBITORS 
Efavirenz/ emtricitabine/ 
tenofovir disoproxil 
fumarate 
(600 mg/ 200 mg/ 300 mg/ 
once daily)/ ledipasvir 
(90 mg once daily)c/ 
sofosbuvir (400 mg once 
daily)c, d 

Efavirenz 
↔ Cmax 0.87 (0.79, 0.97) 
↔ AUC 0.90 (0.84, 0.96) 
↔ Cmin 0.91 (0.83, 0.99) 
 
Emtricitabine 
↔ Cmax 1.08 (0.97, 1.21) 
↔ AUC 1.05 (0.98, 1.11) 
↔ Cmin 1.04 (0.98, 1.11) 
 
Tenofovir 
↑ Cmax 1.79 (1.56, 2.04) 
↑ AUC 1.98 (1.77, 2.23) 
↑ Cmin 2.63 (2.32, 2.97) 
 
Ledipasvir 
↓ Cmax 0.66 (0.59, 0.75) 
↓ AUC 0.66 (0.59, 0.75) 
↓ Cmin 0.66 (0.57, 0.76) 
 
Sofosbuvir 
↔ Cmax 1.03 (0.87, 1.23) 
↔ AUC 0.94 (0.81, 1.10) 
 
GS-331007 
↔ Cmax 0.86 (0.76, 0.96) 
↔ AUC 0.90 (0.83, 0.97) 
↔ Cmin 1.07 (1.02, 1.13) 

No dose adjustment of Harvoni or efavirenz/ 
emtricitabine/ tenofovir disoproxil fumarate is 
required. 

Emtricitabine/ rilpivirine/ 
tenofovir disoproxil 
fumarate 
(200 mg/ 25 mg/ 300 mg 
once daily)/ ledipasvir 
(90 mg once daily)c/ 
sofosbuvir (400 mg once 
daily)c, d 

Emtricitabine 
↔ Cmax 1.02 (0.98, 1.06) 
↔ AUC 1.05 (1.02, 1.08) 
↔ Cmin 1.06 (0.97, 1.15) 
 
Rilpivirine 
↔ Cmax 0.97 (0.88, 1.07) 
↔ AUC 1.02 (0.94, 1.11) 
↔ Cmin 1.12 (1.03, 1.21) 
 
Tenofovir 
↔ Cmax 1.32 (1.25, 1.39) 
↑ AUC 1.40 (1.31, 1.50) 
↑ Cmin 1.91 (1.74, 2.10) 
 
Ledipasvir 
↔ Cmax 1.01 (0.95, 1.07) 
↔ AUC 1.08 (1.02, 1.15) 
↔ Cmin 1.16 (1.08, 1.25) 
 
Sofosbuvir 
↔ Cmax 1.05 (0.93, 1.20) 
↔ AUC 1.10 (1.01, 1.21) 
 
GS-331007 
↔ Cmax 1.06 (1.01, 1.11) 
↔ AUC 1.15 (1.11, 1.19) 
↔ Cmin 1.18 (1.13, 1.24) 

No dose adjustment of Harvoni or emtricitabine/ 
rilpivirine/ tenofovir disoproxil fumarate is 
required. 



52 

Medicinal product by 
therapeutic areas 

Effects on medicinal 
product levels. 
Mean ratio (90% 
confidence interval) for 
AUC, Cmax, Cmina, b 

Recommendation concerning co-administration 
with Harvoni 

Abacavir/ lamivudine 
(600 mg/ 300 mg once 
daily)/ ledipasvir (90 mg 
once daily)c/ sofosbuvir 
(400 mg once daily)c, d 

Abacavir 
↔ Cmax 0.92 (0.87, 0.97) 
↔ AUC 0.90 (0.85, 0.94) 
 
Lamivudine 
↔ Cmax 0.93 (0.87, 1.00) 
↔ AUC 0.94 (0.90, 0.98) 
↔ Cmin 1.12 (1.05, 1.20) 
 
Ledipasvir 
↔ Cmax 1.10 (1.01, 1.19) 
↔ AUC 1.18 (1.10, 1.28) 
↔ Cmin 1.26 (1.17, 1.36) 
 
Sofosbuvir 
↔ Cmax 1.08 (0.85, 1.35) 
↔ AUC 1.21 (1.09, 1.35) 
 
GS-331007 
↔ Cmax 1.00 (0.94, 1.07) 
↔ AUC 1.05 (1.01, 1.09) 
↔ Cmin 1.08 (1.01, 1.14) 

No dose adjustment of Harvoni or abacavir/ 
lamivudine is required. 

HIV ANTIVIRAL AGENTS: HIV PROTEASE INHIBITORS 
Atazanavir boosted with 
ritonavir 
(300 mg/ 100 mg once 
daily)/ ledipasvir (90 mg 
once daily)c/ sofosbuvir 
(400 mg once daily)c, d 

Atazanavir 
↔ Cmax 1.07 (1.00, 1.15) 
↔ AUC 1.33 (1.25, 1.42) 
↑ Cmin 1.75 (1.58, 1.93) 
 
Ledipasvir 
↑ Cmax 1.98 (1.78, 2.20) 
↑ AUC 2.13 (1.89, 2.40) 
↑ Cmin 2.36 (2.08, 2.67) 
 
Sofosbuvir 
↔ Cmax 0.96 (0.88, 1.05) 
↔ AUC 1.08 (1.02, 1.15) 
 
GS-331007 
↔ Cmax 1.13 (1.08, 1.19) 
↔ AUC 1.23 (1.18, 1.29) 
↔ Cmin 1.28 (1.21, 1.36) 

No dose adjustment of Harvoni or atazanavir 
(ritonavir boosted) is required. 
 
For the combination of tenofovir/emtricitabine + 
atazanavir/ritonavir, please see below. 



53 

Medicinal product by 
therapeutic areas 

Effects on medicinal 
product levels. 
Mean ratio (90% 
confidence interval) for 
AUC, Cmax, Cmina, b 

Recommendation concerning co-administration 
with Harvoni 

Atazanavir boosted with 
ritonavir (300 mg/ 100 mg 
once daily) + emtricitabine/ 
tenofovir disoproxil 
fumarate (200 mg/ 300 mg 
once daily)/ ledipasvir 
(90 mg once daily)c/ 
sofosbuvir (400 mg once 
daily)c, d 
 
Dosed simultaneouslyf 

Atazanavir 
↔ Cmax 1.07 (0.99, 1.14) 
↔ AUC 1.27 (1.18, 1.37) 
↑ Cmin 1.63 (1.45, 1.84) 
 
Ritonavir 
↔ Cmax 0.86 (0.79, 0.93) 
↔ AUC 0.97 (0.89, 1.05) 
↑ Cmin 1.45 (1.27, 1.64) 
 
Emtricitabine 
↔ Cmax 0.98 (0.94, 1.02) 
↔ AUC 1.00 (0.97, 1.04) 
↔ Cmin 1.04 (0.96, 1.12) 
 
Tenofovir 
↑ Cmax 1.47 (1.37, 1.58) 
↔ AUC 1.35 (1.29, 1.42) 
↑ Cmin 1.47 (1.38, 1.57) 
 
Ledipasvir 
↑ Cmax 1.68 (1.54, 1.84) 
↑ AUC 1.96 (1.74, 2.21) 
↑ Cmin 2.18 (1.91, 2.50) 
 
Sofosbuvir 
↔ Cmax 1.01 (0.88, 1.15) 
↔ AUC 1.11 (1.02, 1.21) 
 
GS-331007 
↔ Cmax 1.17 (1.12, 1.23) 
↔ AUC 1.31 (1.25, 1.36) 
↑ Cmin 1.42 (1.34, 1.49) 

When given with tenofovir disoproxil fumarate used 
in conjunction with atazanavir/ritonavir, Harvoni 
increased the concentration of tenofovir. 
 
The safety of tenofovir disoproxil fumarate in the 
setting of Harvoni and a pharmacokinetic enhancer 
(e.g. ritonavir or cobicistat) has not been 
established. 
 
The combination should be used with caution with 
frequent renal monitoring, if other alternatives are 
not available (see section 4.4). 
 
Atazanavir concentrations are also increased, with a 
risk for an increase in bilirubin levels/icterus. That 
risk is even higher if ribavirin is used as part of the 
HCV treatment. 

Darunavir boosted with 
ritonavir 
(800 mg/ 100 mg once 
daily)/ ledipasvir (90 mg 
once daily)d 

Darunavir 
↔ Cmax 1.02 (0.88, 1.19) 
↔ AUC 0.96 (0.84, 1.11) 
↔ Cmin 0.97 (0.86, 1.10) 
 
Ledipasvir 
↑ Cmax 1.45 (1.34, 1.56) 
↑ AUC 1.39 (1.28, 1.49) 
↑ Cmin 1.39 (1.29, 1.51) 

No dose adjustment of Harvoni or darunavir 
(ritonavir boosted) is required. 
 
For the combination of tenofovir/emtricitabine + 
darunavir/ritonavir, please see below. 

Darunavir boosted with 
ritonavir 
(800 mg/ 100 mg once 
daily)/ sofosbuvir (400 mg 
once daily) 

Darunavir 
↔ Cmax 0.97 (0.94, 1.01) 
↔ AUC 0.97 (0.94, 1.00) 
↔ Cmin 0.86 (0.78, 0.96) 
 
Sofosbuvir 
↑ Cmax 1.45 (1.10, 1.92) 
↑ AUC 1.34 (1.12, 1.59) 
 
GS-331007 
↔ Cmax 0.97 (0.90, 1.05) 
↔ AUC 1.24 (1.18, 1.30) 



54 

Medicinal product by 
therapeutic areas 

Effects on medicinal 
product levels. 
Mean ratio (90% 
confidence interval) for 
AUC, Cmax, Cmina, b 

Recommendation concerning co-administration 
with Harvoni 

Darunavir boosted with 
ritonavir (800 mg/ 100 mg 
once daily) + emtricitabine/ 
tenofovir disoproxil 
fumarate (200 mg/ 300 mg 
once daily)/ ledipasvir 
(90 mg once daily)c/ 
sofosbuvir (400 mg once 
daily)c, d 
 
Dosed simultaneouslyf 

Darunavir 
↔ Cmax 1.01 (0.96, 1.06) 
↔ AUC 1.04 (0.99, 1.08) 
↔ Cmin 1.08 (0.98, 1.20) 
 
Ritonavir 
↔ Cmax 1.17 (1.01, 1.35) 
↔ AUC 1.25 (1.15, 1.36) 
↑ Cmin 1.48 (1.34, 1.63) 
 
Emtricitabine 
↔ Cmax 1.02 (0.96, 1.08) 
↔ AUC 1.04 (1.00, 1.08) 
↔ Cmin 1.03 (0.97, 1.10) 
 
Tenofovir 
↑ Cmax 1.64 (1.54, 1.74) 
↑ AUC 1.50 (1.42, 1.59) 
↑ Cmin 1.59 (1.49, 1.70) 
 
Ledipasvir 
↔ Cmax 1.11 (0.99, 1.24) 
↔ AUC 1.12 (1.00, 1.25) 
↔ Cmin 1.17 (1.04, 1.31) 
 
Sofosbuvir 
↓ Cmax 0.63 (0.52, 0.75) 
↓ AUC 0.73 (0.65, 0.82) 
 
GS-331007 
↔ Cmax 1.10 (1.04, 1.16) 
↔ AUC 1.20 (1.16, 1.24) 
↔ Cmin 1.26 (1.20, 1.32) 

When given with darunavir/ritonavir used in 
conjunction with tenofovir disoproxil fumarate, 
Harvoni increased the concentration of tenofovir. 
 
The safety of tenofovir disoproxil fumarate in the 
setting of Harvoni and a pharmacokinetic enhancer 
(e.g. ritonavir or cobicistat) has not been 
established. 
 
The combination should be used with caution with 
frequent renal monitoring, if other alternatives are 
not available (see section 4.4). 

Lopinavir boosted with 
ritonavir + emtricitabine/ 
tenofovir disoproxil 
fumarate 

Interaction not studied. 
Expected: 
↑ Lopinavir 
↑ Ritonavir 
 
↔ Emtricitabine 
↑ Tenofovir 
 
↑ Ledipasvir 
↔ Sofosbuvir 
↔ GS-331007 

When given with lopinavir/ritonavir used in 
conjunction with tenofovir disoproxil fumarate, 
Harvoni is expected to increase the concentration of 
tenofovir. 
 
The safety of tenofovir disoproxil fumarate in the 
setting of Harvoni and a pharmacokinetic enhancer 
(e.g. ritonavir or cobicistat) has not been 
established. 
 
The combination should be used with caution with 
frequent renal monitoring, if other alternatives are 
not available (see section 4.4). 

Tipranavir boosted with 
ritonavir 

Interaction not studied. 
Expected: 
↓ Ledipasvir 
↓ Sofosbuvir 
↔ GS-331007 
 
(Induction of P-gp) 

Co-administration of Harvoni with tipranavir 
(ritonavir boosted) is expected to decrease the 
concentration of ledipasvir, leading to reduced 
therapeutic effect of Harvoni.  Co-administration is 
not recommended. 



55 

Medicinal product by 
therapeutic areas 

Effects on medicinal 
product levels. 
Mean ratio (90% 
confidence interval) for 
AUC, Cmax, Cmina, b 

Recommendation concerning co-administration 
with Harvoni 

HIV ANTIVIRAL AGENTS: INTEGRASE INHIBITORS 
Raltegravir 
(400 mg twice daily)/ 
ledipasvir (90 mg once 
daily)d 

Raltegravir 
↓ Cmax 0.82 (0.66, 1.02) 
↔ AUC 0.85 (0.70, 1.02) 
↑ Cmin 1.15 (0.90, 1.46) 
 
Ledipasvir 
↔ Cmax 0.92 (0.85, 1.00) 
↔ AUC 0.91 (0.84, 1.00) 
↔ Cmin 0.89 (0.81, 0.98) 

No dose adjustment of Harvoni or raltegravir is 
required. 

Raltegravir 
(400 mg twice daily)/ 
sofosbuvir (400 mg once 
daily)d 

Raltegravir 
↓ Cmax 0.57 (0.44, 0.75) 
↓ AUC 0.73 (0.59, 0.91) 
↔ Cmin 0.95 (0.81, 1.12) 
 
Sofosbuvir 
↔ Cmax 0.87 (0.71, 1.08) 
↔ AUC 0.95 (0.82, 1.09) 
 
GS-331007 
↔ Cmax 1.09 (0.99, 1.19) 
↔ AUC 1.02 (0.97, 1.08) 

Elvitegravir/ cobicistat/ 
emtricitabine/ tenofovir 
disoproxil fumarate 
(150 mg/ 150 mg/ 200 mg/ 
300 mg once daily)/ 
ledipasvir (90 mg once 
daily)c/ sofosbuvir (400 mg 
once daily)c 

Interaction not studied. 
Expected: 
↔ Emtricitabine 
↑ Tenofovir 
 
Observed: 
Elvitegravir 
↔ Cmax 0.88 (0.82, 0.95) 
↔ AUC 1.02 (0.95, 1.09) 
↑ Cmin 1.36 (1.23, 1.49) 
 
Cobicistat 
↔ Cmax 1.25 (1.18, 1.32) 
↑ AUC 1.59 (1.49, 1.70) 
↑ Cmin 4.25 (3.47, 5.22) 
 
Ledipasvir 
↑ Cmax 1.63 (1.51, 1.75) 
↑ AUC 1.78 (1.64, 1.94) 
↑ Cmin 1.91 (1.76, 2.08) 
 
Sofosbuvir 
↑ Cmax 1.33 (1.14, 1.56) 
↑ AUC 1.36 (1.21, 1.52) 
 
GS-331007 
↑ Cmax 1.33 (1.22, 1.44) 
↑ AUC 1.44 (1.41, 1.48) 
↑ Cmin 1.53 (1.47, 1.59) 

When given with elvitegravir/ cobicistat/ 
emtricitabine/ tenofovir disoproxil fumarate, 
Harvoni is expected to increase the concentration of 
tenofovir. 
 
The safety of tenofovir disoproxil fumarate in the 
setting of Harvoni and a pharmacokinetic enhancer 
(e.g. ritonavir or cobicistat) has not been 
established. 
 
The combination should be used with caution with 
frequent renal monitoring, if other alternatives are 
not available (see section 4.4). 

Dolutegravir Interaction not studied. 
Expected: 
↔ Dolutegravir 
↔ Ledipasvir 
↔ Sofosbuvir 
↔ GS-331007 

No dose adjustment required. 



56 

Medicinal product by 
therapeutic areas 

Effects on medicinal 
product levels. 
Mean ratio (90% 
confidence interval) for 
AUC, Cmax, Cmina, b 

Recommendation concerning co-administration 
with Harvoni 

HERBAL SUPPLEMENTS 
St. John’s wort Interaction not studied. 

Expected: 
↓ Ledipasvir 
↓ Sofosbuvir 
↔ GS-331007 
 
(Induction of P-gp) 

Harvoni is contraindicated with St. John’s wort (see 
section 4.3). 

HMG-CoA REDUCTASE INHIBITORS 
Rosuvastating ↑ Rosuvastatin 

 
(Inhibition of drug 
transporters OATP and 
BCRP) 

Co-administration of Harvoni with rosuvastatin may 
significantly increase the concentration of 
rosuvastatin (several fold-increase in AUC) which 
is associated with increased risk of myopathy, 
including rhabdomyolysis. Co-administration of 
Harvoni with rosuvastatin is contraindicated (see 
section 4.3). 

Pravastating ↑ Pravastatin Co-administration of Harvoni with pravastatin may 
significantly increase the concentration of 
pravastatin which is associated with increased risk 
of myopathy. Clinical and biochemical control is 
recommended in these patients and a dose 
adjustment may be needed (see section 4.4). 

Other statins Expected: 
↑ Statins 

Interactions cannot be excluded with other 
HMG-CoA reductase inhibitors. When 
co-administered with Harvoni, a reduced dose of 
statins should be considered and careful monitoring 
for statin adverse reactions should be undertaken 
(see section 4.4). 

NARCOTIC ANALGESICS 
Methadone Interaction not studied. 

Expected: 
↔ Ledipasvir 

No dose adjustment of Harvoni or methadone is 
required. 

Methadone 
(Methadone maintenance 
therapy [30 to 
130 mg/daily])/ sofosbuvir 
(400 mg once daily)d 

R-methadone 
↔ Cmax 0.99 (0.85, 1.16) 
↔ AUC 1.01 (0.85, 1.21) 
↔ Cmin 0.94 (0.77, 1.14) 
 
S-methadone 
↔ Cmax 0.95 (0.79, 1.13) 
↔ AUC 0.95 (0.77, 1.17) 
↔ Cmin 0.95 (0.74, 1.22) 
 
Sofosbuvir 
↓ Cmax 0.95 (0.68, 1.33) 
↑ AUC 1.30 (1.00, 1.69) 
 
GS-331007 
↓ Cmax 0.73 (0.65, 0.83) 
↔ AUC 1.04 (0.89, 1.22) 

IMMUNOSUPPRESSANTS 
Ciclosporing Interaction not studied. 

Expected: 
↑ Ledipasvir 
↔ Ciclosporin 

No dose adjustment of Harvoni or ciclosporin is 
required at initiation of co-administration. 
Afterwards, close monitoring and potential dose 
adjustment of ciclosporin may be required. 



57 

Medicinal product by 
therapeutic areas 

Effects on medicinal 
product levels. 
Mean ratio (90% 
confidence interval) for 
AUC, Cmax, Cmina, b 

Recommendation concerning co-administration 
with Harvoni 

Ciclosporin 
(600 mg single dose)/ 
sofosbuvir (400 mg single 
dose)h 

Ciclosporin 
↔ Cmax 1.06 (0.94, 1.18) 
↔ AUC 0.98 (0.85, 1.14) 
 
Sofosbuvir 
↑ Cmax 2.54 (1.87, 3.45) 
↑ AUC 4.53 (3.26, 6.30) 
 
GS-331007 
↓ Cmax 0.60 (0.53, 0.69) 
↔ AUC 1.04 (0.90, 1.20) 

Tacrolimus Interaction not studied. 
Expected: 
↔ Ledipasvir 

No dose adjustment of Harvoni or tacrolimus is 
required at initiation of co-administration. 
Afterwards, close monitoring and potential dose 
adjustment of tacrolimus may be required. Tacrolimus 

(5 mg single dose)/ 
sofosbuvir (400 mg single 
dose)h 

Tacrolimus 
↓ Cmax 0.73 (0.59, 0.90) 
↑ AUC 1.09 (0.84, 1.40) 
 
Sofosbuvir 
↓ Cmax 0.97 (0.65, 1.43) 
↑ AUC 1.13 (0.81, 1.57) 
 
GS-331007 
↔ Cmax 0.97 (0.83, 1.14) 
↔ AUC 1.00 (0.87, 1.13) 

ORAL CONTRACEPTIVES 
Norgestimate/ ethinyl 
estradiol (norgestimate 
0.180 mg/ 0.215 mg/ 
0.25 mg/ ethinyl estradiol 
0.025 mg)/ ledipasvir 
(90 mg once daily)d 

Norelgestromin 
↔ Cmax 1.02 (0.89, 1.16) 
↔ AUC 1.03 (0.90, 1.18) 
↔ Cmin 1.09 (0.91, 1.31) 
 
Norgestrel 
↔ Cmax 1.03 (0.87, 1.23) 
↔ AUC 0.99 (0.82, 1.20) 
↔ Cmin 1.00 (0.81, 1.23) 
 
Ethinyl estradiol 
↑ Cmax 1.40 (1.18, 1.66) 
↔ AUC 1.20 (1.04, 1.39) 
↔ Cmin 0.98 (0.79, 1.22) 

No dose adjustment of oral contraceptives is 
required. 

Norgestimate/ ethinyl 
estradiol (norgestimate 
0.180 mg/ 0.215 mg/ 
0.25 mg/ ethinyl estradiol 
0.025 mg)/ sofosbuvir 
(400 mg once daily)d 

Norelgestromin 
↔ Cmax 1.07 (0.94, 1.22) 
↔ AUC 1.06 (0.92, 1.21) 
↔ Cmin 1.07 (0.89, 1.28) 
 
Norgestrel 
↔ Cmax 1.18 (0.99, 1.41) 
↑ AUC 1.19 (0.98, 1.45) 
↑ Cmin 1.23 (1.00, 1.51) 
 
Ethinyl estradiol 
↔ Cmax 1.15 (0.97, 1.36) 
↔ AUC 1.09 (0.94, 1.26) 
↔ Cmin 0.99 (0.80, 1.23) 

a Mean ratio (90% CI) of co-administered drug pharmacokinetics of study medicinal products alone or in combination.  No 
effect = 1.00. 

b All interaction studies conducted in healthy volunteers. 
c Administered as Harvoni. 



58 

d Lack of pharmacokinetics interaction bounds 70-143%. 
e These are drugs within class where similar interactions could be predicted. 
f Staggered administration (12 hours apart) of atazanavir/ritonavir + emtricitabine/tenofovir disoproxil fumarate or 

darunavir/ritonavir + emtricitabine/tenofovir disoproxil fumarate and Harvoni provided similar results. 
g This study was conducted in the presence of another two direct-acting antiviral agents. 
h Bioequivalence/Equivalence boundary 80-125%. 
 
4.6 Fertility, pregnancy and lactation 
 
Women of childbearing potential / contraception in males and females 
 
When Harvoni is used in combination with ribavirin, extreme care must be taken to avoid pregnancy 
in female patients and in female partners of male patients. Significant teratogenic and/or embryocidal 
effects have been demonstrated in all animal species exposed to ribavirin. Women of childbearing 
potential or their male partners must use an effective form of contraception during treatment and for a 
period of time after the treatment has concluded as recommended in the Summary of Product 
Characteristics for ribavirin. Refer to the Summary of Product Characteristics for ribavirin for 
additional information. 
 
Pregnancy 
 
There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of ledipasvir, 
sofosbuvir or Harvoni in pregnant women. 
 
Animal studies do not indicate direct harmful effects with respect to reproductive toxicity. No 
significant effects on foetal development have been observed with ledipasvir or sofosbuvir in rats and 
rabbits. However, it has not been possible to fully estimate exposure margins achieved for sofosbuvir 
in the rat relative to the exposure in humans at the recommended clinical dose (see section 5.3). 
 
As a precautionary measure, it is preferable to avoid the use of Harvoni during pregnancy. 
 
Breast-feeding 
 
It is unknown whether ledipasvir or sofosbuvir and its metabolites are excreted in human milk. 
 
Available pharmacokinetic data in animals has shown excretion of ledipasvir and metabolites of 
sofosbuvir in milk (see section 5.3). 
 
A risk to the newborns/infants cannot be excluded. Therefore, Harvoni should not be used during 
breast-feeding. 
 
Fertility 
 
No human data on the effect of Harvoni on fertility are available. Animal studies do not indicate 
harmful effects of ledipasvir or sofosbuvir on fertility. 
 
If ribavirin is co-administered with Harvoni, the contraindications regarding use of ribavirin during 
pregnancy and breast-feeding apply (see also the Summary of Product Characteristics for ribavirin). 
 
4.7 Effects on ability to drive and use machines 
 
Harvoni (administered alone or in combination with ribavirin) has no or negligible influence on the 
ability to drive and use machines. However, patients should be advised that fatigue was more common 
in patients treated with ledipasvir/sofosbuvir compared to placebo. 
 



59 

4.8 Undesirable effects 
 
Summary of the safety profile in adults 
The safety assessment of Harvoni was mainly based on pooled Phase 3 clinical studies, without a 
control, in 1952 patients who received Harvoni for 8, 12 or 24 weeks, including 872 patients who 
received Harvoni in combination with ribavirin. 
 
The proportion of patients who permanently discontinued treatment due to adverse events was 0%, 
< 1% and 1% for patients receiving ledipasvir/sofosbuvir for 8, 12 and 24 weeks, respectively; and 
< 1%, 0%, and 2% for patients receiving ledipasvir/sofosbuvir + ribavirin combination therapy for 8, 
12 and 24 weeks, respectively. 
 
In clinical studies, fatigue and headache were more common in patients treated with 
ledipasvir/sofosbuvir compared to placebo. When ledipasvir/sofosbuvir was studied with ribavirin, the 
most frequent adverse drug reactions to ledipasvir/sofosbuvir + ribavirin combination therapy were 
consistent with the known safety profile of ribavirin, without increasing the frequency or severity of 
the expected adverse drug reactions. 
 
Tabulated list of adverse events 
 
The following adverse drug reactions have been identified with Harvoni (Table 7). The adverse 
reactions are listed below by body system organ class and frequency.  Frequencies are defined as 
follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare 
(≥ 1/10,000 to < 1/1,000) or very rare (< 1/10,000). 
 
Table 7: Adverse drug reactions identified with Harvoni 
Frequency Adverse drug reaction 
Nervous system disorders: 
Very common headache 
Skin and subcutaneous tissue disorders: 
Common rash 
Not known angioedema 
General disorders: 
Very common fatigue 
 
Adults with decompensated cirrhosis and/or who are awaiting liver transplant or post-liver transplant 
 
The safety profile of ledipasvir/sofosbuvir with ribavirin for 12 or 24 weeks in adults with 
decompensated liver disease and/or those post-liver transplant was assessed in two open-label studies 
(SOLAR-1 and SOLAR-2). No new adverse drug reactions were detected among patients with 
decompensated cirrhosis and/or who were post-liver transplant and who received ledipasvir/sofosbuvir 
with ribavirin. Although adverse events, including serious adverse events, occurred more frequently in 
this study compared to studies that excluded decompensated patients and/or patients who were post-
liver transplantation, the adverse events observed were those expected as clinical sequelae of advanced 
liver disease and/or transplantation or were consistent with the known safety profile of ribavirin (see 
section 5.1 for details of this study). 
 
Decreases in haemoglobin to < 10 g/dL and < 8.5 g/dL during treatment were experienced by 39% and 
13% of patients treated with ledipasvir/sofosbuvir with ribavirin, respectively. Ribavirin was 
discontinued in 15% of the patients. 
 
7% of liver transplant recipients had a modification of their immunosuppressive agents. 
 
Patients with renal impairment 
Ledipasvir/sofosbuvir was administered for 12 weeks to 18 patients with genotype 1 CHC and severe 
renal impairment in an open-label study (Study 0154). In this limited clinical safety data set, the rate 
of adverse events was not clearly elevated from what is expected in patients with severe renal 
impairment. 



60 

 
The safety of Harvoni has been evaluated in a 12-week non-controlled study including 95 patients 
with ESRD requiring dialysis (Study 4063). In this setting, exposure of sofosbuvir metabolite GS-
331007 is 20-fold increased, exceeding levels where adverse reactions have been observed in 
preclinical trials. In this limited clinical safety data set, the rate of adverse events and deaths was not 
clearly elevated from what is expected in ESRD patients. 
 
Paediatric population 
 
The safety and efficacy of Harvoni in paediatric patients aged 3 years and above are based on data 
from a Phase 2, open-label clinical study (Study 1116) that enrolled 226 patients who were treated 
with ledipasvir/sofosbuvir for 12 or 24 weeks or ledipasvir/sofosbuvir plus ribavirin for 24 weeks.  
The adverse reactions observed were consistent with those observed in clinical studies of 
ledipasvir/sofosbuvir in adults (see Table 7). 
 
Description of selected adverse reactions 
 
Cardiac arrhythmias 
Cases of severe bradycardia and heart block have been observed when Harvoni is used with 
amiodarone and/or other drugs that lower heart rate (see sections 4.4 and 4.5). 
 
Skin disorders 
Frequency not known: Stevens-Johnson syndrome 
 
Reporting of suspected adverse reactions 
 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product.  Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
The highest documented doses of ledipasvir and sofosbuvir were 120 mg twice daily for 10 days and a 
single dose of 1,200 mg, respectively. In these healthy volunteer studies, there were no untoward 
effects observed at these dose levels, and adverse reactions were similar in frequency and severity to 
those reported in the placebo groups. The effects of higher doses are not known. 
 
No specific antidote is available for overdose with Harvoni.  If overdose occurs the patient must be 
monitored for evidence of toxicity. Treatment of overdose with Harvoni consists of general supportive 
measures including monitoring of vital signs as well as observation of the clinical status of the patient. 
Haemodialysis is unlikely to result in significant removal of ledipasvir as ledipasvir is highly bound to 
plasma protein. Haemodialysis can efficiently remove the predominant circulating metabolite of 
sofosbuvir, GS-331007, with an extraction ratio of 53%. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Direct-acting antiviral, ATC code: J05AP51 
 
Mechanism of action 
 
Ledipasvir is a HCV inhibitor targeting the HCV NS5A protein, which is essential for both RNA 
replication and the assembly of HCV virions. Biochemical confirmation of NS5A inhibition by 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


61 

ledipasvir is not currently possible as NS5A has no enzymatic function. In vitro resistance selection 
and cross-resistance studies indicate ledipasvir targets NS5A as its mode of action. 
 
Sofosbuvir is a pan-genotypic inhibitor of the HCV NS5B RNA-dependent RNA polymerase, which is 
essential for viral replication. Sofosbuvir is a nucleotide prodrug that undergoes intracellular 
metabolism to form the pharmacologically active uridine analogue triphosphate (GS-461203), which 
can be incorporated into HCV RNA by the NS5B polymerase and acts as a chain terminator.  
GS-461203 (the active metabolite of sofosbuvir) is neither an inhibitor of human DNA and 
RNA polymerases nor an inhibitor of mitochondrial RNA polymerase. 
 
Antiviral activity 
 
The EC50 values of ledipasvir and sofosbuvir against full-length or chimeric replicons encoding NS5A 
and NS5B sequences from clinical isolates are detailed in Table 8. The presence of 40% human serum 
had no effect on the anti-HCV activity of sofosbuvir but reduced the anti-HCV activity of ledipasvir 
by 12-fold against genotype 1a HCV replicons. 
 
Table 8: Activity of ledipasvir and sofosbuvir against chimeric replicons 
Genotype 
replicons 

Ledipasvir activity (EC50, nM) Sofosbuvir activity (EC50, nM) 
Stable replicons NS5A transient 

replicons 
Median (range)a 

Stable replicons NS5B transient 
replicons 
Median (range)a 

Genotype 1a 0.031 0.018 (0.009-0.085) 40 62 (29-128) 
Genotype 1b 0.004 0.006 (0.004-0.007) 110 102 (45-170) 
Genotype 2a 21-249 - 50 29 (14-81) 
Genotype 2b 16-530b - 15b - 
Genotype 3a 168 - 50 81 (24-181) 
Genotype 4a 0.39 - 40 - 
Genotype 4d 0.60 - - - 
Genotype 5a 0.15b - 15b - 
Genotype 6a 1.1b - 14b - 
Genotype 6e 264b - - - 
a. Transient replicons carrying NS5A or NS5B from patient isolates. 
b. The chimeric replicons carrying NS5A genes from genotype 2b, 5a, 6a and 6e were used for testing ledipasvir while the 
chimeric replicons carrying NS5B genes from genotype 2b, 5a or 6a were used for testing sofosbuvir. 
 
Resistance 
 
In cell culture 
HCV replicons with reduced susceptibility to ledipasvir have been selected in cell culture for 
genotype 1a and 1b. Reduced susceptibility to ledipasvir was associated with the primary NS5A 
substitution Y93H in both genotype 1a and 1b. Additionally a Q30E substitution developed in 
genotype 1a replicons.  Site-directed mutagenesis of NS5A RAVs showed that substitutions conferring 
a fold-change > 100 and ≤ 1,000 in ledipasvir susceptibility are Q30H/R, L31I/M/V, P32L and Y93T 
in genotype 1a and P58D and Y93S in genotype 1b; and substitutions conferring a fold-change 
> 1,000 are M28A/G, Q30E/G/K, H58D, Y93C/H/N/S in genotype 1a and A92K and Y93H in 
genotype 1b. 
 
HCV replicons with reduced susceptibility to sofosbuvir have been selected in cell culture for multiple 
genotypes including 1b, 2a, 2b, 3a, 4a, 5a and 6a.  Reduced susceptibility to sofosbuvir was associated 
with the primary NS5B substitution S282T in all replicon genotypes examined. Site-directed 
mutagenesis of the S282T substitution in replicons of 8 genotypes conferred 2- to 18-fold reduced 
susceptibility to sofosbuvir and reduced the viral replication capacity by 89% to 99% compared to the 
corresponding wild-type. 
 
In clinical studies – Adults-Genotype 1 
In a pooled analysis of patients who received ledipasvir/sofosbuvir in Phase 3 studies (ION-3, ION-1 
and ION-2), 37 patients (29 with genotype 1a and 8 with genotype 1b) qualified for resistance analysis 



62 

due to virologic failure or early study drug discontinuation and having HCV RNA > 1,000 IU/mL.  
Post-baseline NS5A and NS5B deep sequencing data (assay cut off of 1%) were available for 37/37 
and 36/37 patients, respectively. 
 
NS5A resistance-associated variants (RAVs) were observed in post-baseline isolates from 
29/37 patients (22/29 genotype 1a and 7/8 genotype 1b) not achieving sustained virologic response 
(SVR). Of the 29 genotype 1a patients who qualified for resistance testing, 22/29 (76%) patients 
harboured one or more NS5A RAVs at positions K24, M28, Q30, L31, S38 and Y93 at failure, while 
the remaining 7/29 patients had no NS5A RAVs detected at failure. The most common variants were 
Q30R, Y93H and L31M.  Of the 8 genotype 1b patients who qualified for resistance testing, 7/8 (88%) 
harboured one or more NS5A RAVs at positions L31 and Y93 at failure, while 1/8 patients had no 
NS5A RAVs at failure. The most common variant was Y93H.  Among the 8 patients who had no 
NS5A RAVs at failure, 7 patients received 8 weeks of treatment (n = 3 with ledipasvir/sofosbuvir; 
n = 4 with ledipasvir/sofosbuvir + ribavirin) and 1 patient received ledipasvir/sofosbuvir for 12 weeks. 
In phenotypic analyses, post-baseline isolates from patients who harboured NS5A RAVs at failure 
showed 20- to at least a 243-fold (the highest dose tested) reduced susceptibility to ledipasvir. 
Site-directed mutagenesis of the Y93H substitution in both genotype 1a and 1b as well as the Q30R 
and L31M substitution in genotype 1a conferred high levels of reduced susceptibility to ledipasvir 
(fold-change in EC50 ranging from 544-fold to 1,677-fold). 
 
Among post-transplant patients with compensated liver disease or patients with decompensated liver 
disease either pre- or post-transplant (SOLAR-1 and SOLAR-2 studies), relapse was associated with 
the detection of one or more of the following NS5A RAVs: K24R, M28T, Q30R/H/K, L31V, H58D 
and Y93H/C in 12/14 genotype 1a patients, and L31M, Y93H/N in 6/6 genotype 1b patients. 
 
A NS5B substitution E237G was detected in 3 patients (1 genotype 1b and 2 genotype 1a) in the 
Phase 3 studies (ION-3, ION-1 and ION-2) and 3 patients with genotype 1a infection in the SOLAR-1 
and SOLAR-2 studies at the time of relapse. The E237G substitution showed a 1.3-fold reduction in 
susceptibility to sofosbuvir in the genotype 1a replicon assay. The clinical significance of this 
substitution is currently unknown. 
 
The sofosbuvir resistance-associated substitution S282T in NS5B was not detected in any virologic 
failure isolate from the Phase 3 studies.  However, the NS5B S282T substitution in combination with 
NS5A substitutions L31M, Y93H and Q30L were detected in one patient at failure following 8 weeks 
of treatment with ledipasvir/sofosbuvir from a Phase 2 study (LONESTAR). This patient was 
subsequently retreated with ledipasvir/sofosbuvir + ribavirin for 24 weeks and achieved SVR 
following retreatment. 
 
In the SIRIUS study (see “Clinical efficacy and safety”, below) 5 patients with genotype 1 infection 
relapsed after treatment with ledipasvir/sofosbuvir with or without ribavirin.  NS5A RAVs were seen 
at relapse in 5/5 patients (for genotype 1a: Q30R/H + L31M/V [n = 1] and Q30R [n = 1]; for 
genotype 1b: Y93H [n = 3]). 
 
In clinical studies – Adults-Genotype 2, 3, 4, 5 and 6 
NS5A RAVs: No genotype 2 infected patients experienced relapse in the clinical study and therefore 
there are no data regarding NS5A RAVs at the time of failure. 
 
In genotype 3 infected patients experiencing virologic failure, development of NS5A RAVs (including 
enrichment of RAVs present at baseline) was typically not detected at the time of failure (n = 17). 
 
In genotype 4, 5 and 6 infection, only small numbers of patients have been evaluated (total of 
5 patients with failure). The NS5A substitution Y93C emerged in the HCV of 1 patient (genotype 4), 
while NS5A RAVs present at baseline were observed at the time of failure in all patients. In the 
SOLAR-2 study, one patient with genotype 4d developed NS5B substitution E237G at the time of 
relapse. The clinical significance of this substitution is currently unknown. 
 



63 

NS5B RAVs: The NS5B substitution S282T emerged in the HCV of 1/17 genotype 3-failures, and in 
the HCV of 1/3, 1/1 and 1/1 of genotype 4-, 5- and 6-failures, respectively. 
 
Effect of baseline HCV resistance-associated variants on treatment outcome 
 
Adults-Genotype 1 
Analyses were conducted to explore the association between pre-existing baseline NS5A RAVs and 
treatment outcome. In the pooled analysis of the Phase 3 studies, 16% of patients had baseline 
NS5A RAVs identified by population or deep sequencing irrespective of subtype. Baseline 
NS5A RAVs were overrepresented in patients who experienced relapse in the Phase 3 studies (see 
“Clinical efficacy and safety”). 
 
Following 12 weeks of treatment with ledipasvir/sofosbuvir (without ribavirin) in treatment-
experienced patients (arm 1 of ION-2 study) 4/4 patients with baseline NS5A RAVs conferring a 
ledipasvir fold-change of ≤ 100 achieved SVR. For the same treatment arm, patients with baseline 
NS5A RAVs conferring a fold-change of > 100, relapse occurred in 4/13 (31%), as compared to 3/95 
(3%) in those without any baseline RAVs or RAVs conferring a fold-change of ≤ 100. 
 
Following 12 weeks of treatment with ledipasvir/sofosbuvir with ribavirin in treatment-experienced 
patients with compensated cirrhosis (SIRIUS, n = 77), 8/8 patients with baseline NS5A RAVs 
conferring > 100-fold reduced susceptibility to ledipasvir achieved SVR12. 
 
Among post-transplant patients with compensated liver disease (SOLAR-1 and SOLAR-2 studies), no 
relapse occurred in patients with baseline NS5A RAVs (n = 23) following 12 weeks of treatment with 
ledipasvir/sofosbuvir + ribavirin. Among patients with decompensated liver disease (pre- and post-
transplant), 4/16 (25%) patients with NS5A RAVs conferring > 100-fold resistance relapsed after 
12 weeks treatment with ledipasvir/sofosbuvir + ribavirin compared to 7/120 (6%) in those without 
any baseline NS5A RAVs or RAVs conferring a fold-change of ≤ 100. 
 
The group of NS5A RAVs that conferred > 100-fold shift and was observed in patients were the 
following substitutions in genotype 1a (M28A, Q30H/R/E, L31M/V/I, H58D, Y93H/N/C) or in 
genotype 1b (Y93H). The proportion of such baseline NS5A RAVs seen with deep sequencing varied 
from very low (cut off for assay = 1%) to high (main part of the plasma population). 
 
The sofosbuvir resistance-associated substitution S282T was not detected in the baseline NS5B 
sequence of any patient in Phase 3 studies by population or deep sequencing.  SVR was achieved in all 
24 patients (n = 20 with L159F+C316N; n = 1 with L159F; and n = 3 with N142T) who had baseline 
variants associated with resistance to NS5B nucleoside inhibitors. 
 
Adults-Genotype 2, 3, 4, 5 and 6 
Due to the limited size of studies, the impact of baseline NS5A RAVs on treatment outcome for 
patients with genotype 2, 3, 4, 5 or 6 CHC has not been fully evaluated. No major differences in 
outcomes were observed by the presence or absence of baseline NS5A RAVs. 
 
Paediatric Patients 
 
The presence of pre-treatment NS5A and/or NS5B RAVs did not impact treatment outcome as all 
subjects with pre-treatment RAVs achieved SVR12 and SVR24. One 8-year-old subject infected with 
genotype 1a HCV who failed to achieve SVR12 had no NS5A or NS5B nucleoside inhibitor RAVs at 
baseline and had emergent NS5A RAV Y93H at relapse. 
 
Cross-resistance 
 
Ledipasvir was fully active against the sofosbuvir resistance-associated substitution S282T in NS5B 
while all ledipasvir resistance-associated substitutions in NS5A were fully susceptible to sofosbuvir. 
Both sofosbuvir and ledipasvir were fully active against substitutions associated with resistance to 
other classes of direct-acting antivirals with different mechanisms of actions, such as NS5B 



64 

non-nucleoside inhibitors and NS3 protease inhibitors. NS5A substitutions conferring resistance to 
ledipasvir may reduce the antiviral activity of other NS5A inhibitors. 
 
Clinical efficacy and safety 
 
The efficacy of ledipasvir [LDV]/sofosbuvir [SOF] was evaluated in three open-label Phase 3 studies 
with data available for a total of 1,950 patients with genotype 1 CHC. The three Phase 3 studies 
included one study conducted in non-cirrhotic treatment-naïve patients (ION-3); one study in cirrhotic 
and non-cirrhotic treatment-naïve patients (ION-1); and one study in cirrhotic and non-cirrhotic 
patients who failed prior therapy with an interferon-based regimen, including regimens containing an 
HCV protease inhibitor (ION-2). Patients in these studies had compensated liver disease. All three 
Phase 3 studies evaluated the efficacy of ledipasvir/sofosbuvir with or without ribavirin. 
 
Treatment duration was fixed in each study.  Serum HCV RNA values were measured during the 
clinical studies using the COBAS TaqMan HCV test (version 2.0), for use with the High Pure System.  
The assay had a lower limit of quantification (LLOQ) of 25 IU/mL. SVR was the primary endpoint to 
determine the HCV cure rate which was defined as HCV RNA less than LLOQ at 12 weeks after the 
cessation of treatment. 
 
Treatment-naïve adults without cirrhosis – ION-3 (study 0108) – Genotype 1 
ION-3 evaluated 8 weeks of treatment with ledipasvir/sofosbuvir with or without ribavirin and 
12 weeks of treatment with ledipasvir/sofosbuvir in treatment-naïve non-cirrhotic patients with 
genotype 1 CHC. Patients were randomised in a 1:1:1 ratio to one of the three treatment groups and 
stratified by HCV genotype (1a versus 1b). 
 
Table 9: Demographics and baseline characteristics in study ION-3 
Patient disposition LDV/SOF 

8 weeks 
(n = 215) 

LDV/SOF+RBV 
8 weeks 
(n = 216) 

LDV/SOF 
12 weeks 
(n = 216) 

TOTAL 
 
(n = 647) 

Age (years): median (range) 53 (22-75) 51 (21-71) 53 (20-71) 52 (20-75) 
Male gender 60% (130)  54% (117) 59% (128) 58% (375) 
Race: Black/ African American 21% (45) 17% (36) 19% (42) 19% (123) 
 White 76% (164) 81% (176) 77% (167) 78% (507) 
Genotype 1a 80% (171) 80% (172) 80% (172) 80% (515)a 
IL28CC genotype 26% (56) 28% (60) 26% (56) 27% (172) 
FibroTest-Determined Metavir scoreb 
 F0-F1 33% (72) 38% (81) 33% (72) 35% (225) 
 F2 30% (65) 28% (61) 30% (65) 30% (191) 
 F3-F4 36% (77) 33% (71) 37% (79) 35% (227) 
 Not interpretable < 1% (1) 1% (3) 0% (0) < 1% (4) 
a One patient in the LDV/SOF 8-week treatment arm did not have a confirmed genotype 1 subtype. 
b Non-missing FibroTest results are mapped to Metavir scores according to: 0-0.31 = F0-F1; 0.32-0.58 = F2; 

0.59-1.00 = F3-F4. 
 
Table 10: Response rates in study ION-3 
 LDV/SOF 

8 weeks 
(n = 215) 

LDV/SOF+RBV 
8 weeks 
(n = 216) 

LDV/SOF 
12 weeks 
(n = 216) 

SVR 94% (202/215) 93% (201/216) 96% (208/216) 
Outcome for patients without SVR 
 On-treatment virologic failure 0/215 0/216 0/216 
 Relapsea 5% (11/215) 4% (9/214) 1% (3/216) 
 Otherb < 1% (2/215) 3% (6/216) 2% (5/216) 
Genotype 
 Genotype 1a 93% (159/171) 92% (159/172) 96% (165/172) 
 Genotype 1b 98% (42/43) 95% (42/44) 98% (43/44) 
a The denominator for relapse is the number of patients with HCV RNA < LLOQ at their last on-treatment assessment. 
b Other includes patients who did not achieve SVR and did not meet virologic failure criteria (e.g. lost to follow-up). 
 



65 

The 8-week treatment of ledipasvir/sofosbuvir without ribavirin was non-inferior to the 8-week 
treatment of ledipasvir/sofosbuvir with ribavirin (treatment difference 0.9%; 95% confidence interval: 
-3.9% to 5.7%) and the 12-week treatment of ledipasvir/sofosbuvir (treatment difference -2.3%; 97.5% 
confidence interval: -7.2% to 3.6%). Among patients with a baseline HCV RNA < 6 million IU/mL, 
the SVR was 97% (119/123) with 8-week treatment of ledipasvir/sofosbuvir and 96% (126/131) with 
12-week treatment of ledipasvir/sofosbuvir. 
 
Table 11: Relapse rates by baseline characteristics in the ION-3 study, virological failure population* 
 LDV/SOF 

8 weeks 
(n = 213) 

LDV/SOF+RBV 
8 weeks 
(n = 210) 

LDV/SOF 
12 weeks 
(n = 211) 

Gender 
 Male 8% (10/129) 7% (8/114) 2% (3/127) 
 Female 1% (1/84) 1% (1/96) 0% (0/84) 
IL28 genotype 
 CC 4% (2/56) 0% (0/57) 0% (0/54) 
 Non-CC 6% (9/157) 6% (9/153) 2% (3/157) 
Baseline HCV RNAa 
 HCV RNA < 6 million IU/mL 2% (2/121) 2% (3/136) 2% (2/128) 
 HCV RNA ≥ 6 million IU/mL 10% (9/92) 8% (6/74) 1% (1/83) 
* Patients lost to follow-up or who withdrew consent excluded. 
a HCV RNA values were determined using the Roche TaqMan Assay; a patient’s HCV RNA may vary from visit to visit. 
 
Treatment-naïve adults with or without cirrhosis – ION-1 (study 0102) – Genotype 1 
ION-1 was a randomised, open-label study that evaluated 12 and 24 weeks of treatment with 
ledipasvir/sofosbuvir with or without ribavirin in 865 treatment-naïve patients with genotype 1 CHC 
including those with cirrhosis (randomised 1:1:1:1). Randomisation was stratified by the presence or 
absence of cirrhosis and HCV genotype (1a versus 1b). 
 
Table 12: Demographics and baseline characteristics in study ION-1 
Patient disposition LDV/SOF 

12 weeks 
(n = 214) 

LDV/SOF+ 
RBV 
12 weeks 
(n = 217) 

LDV/SOF 
24 weeks 
(n = 217) 

LDV/SOF+ 
RBV 
24 weeks 
(n = 217) 

TOTAL 
 
(n = 865) 

Age (years): median (range) 52 (18-75) 52 (18-78) 53 (22-80) 53 (24-77) 52 (18-80) 
Male gender 59% (127) 59% (128) 64% (139) 55% (119) 59% (513) 
Race: Black/ African 

American 
11% (24) 12% (26) 15% (32) 12% (26) 12% (108) 

 White 87% (187) 87% (188) 82% (177) 84% (183) 85% (735) 
Genotype 1aa 68% (145) 68% (148) 67% (146) 66% (143) 67% (582) 
IL28CC genotype 26% (55) 35% (76) 24% (52) 34% (73) 30% (256) 
FibroTest-Determined Metavir scoreb 
 F0-F1 27% (57) 26% (56) 29% (62) 30% (66) 28% (241) 
 F2 26% (56) 25% (55) 22% (47) 28% (60) 25% (218) 
 F3-F4 47% (100) 48% (104) 49% (107) 42% (91) 46% (402) 
 Not interpretable < 1% (1) 1% (2) < 1% (1) 0% (0) < 1% (4) 
a Two patients in the LDV/SOF 12-week treatment arm, one patient in the LDV/SOF+RBV 12-week treatment arm, two 

patients in the LDV/SOF 24-week treatment arm, and two patients in the LDV/SOF+RBV 24-week treatment arm did not 
have a confirmed genotype 1 subtype. 

b Non-missing FibroTest results are mapped to Metavir scores according to: 0-0.31 = F0-F1; 0.32-0.58 = F2; 
0.59-1.00 = F3-F4. 

 



66 

Table 13: Response rates in study ION-1 
 LDV/SOF 

12 weeks 
(n = 214) 

LDV/SOF+RBV 
12 weeks 
(n = 217) 

LDV/SOF 
24 weeks 
(n = 217) 

LDV/SOF+RBV 
24 weeks 
(n = 217) 

SVR 99% (210/213)  97% (211/217) 98% (213/217) 99% (215/217) 
Outcome for patients without SVR 
 On-treatment virologic 

failure 
0/213a 0/217 < 1% (1/217) 0/216 

 Relapseb < 1% (1/212) 0/217 < 1% (1/215) 0/216 
 Otherc < 1% (2/213) 3% (6/217) < 1% (2/217) < 1% (2/217) 
SVR rates for selected subgroups 
Genotype 
 Genotype 1a 98% (142/145) 97% (143/148) 99% (144/146) 99% (141/143) 
 Genotype 1b 100% (67/67) 99% (67/68) 97% (67/69) 100% (72/72) 
Cirrhosisd 
 No 99% (176/177) 97% (177/183) 98% (181/184) 99% (178/180) 
 Yes 94% (32/34) 100% (33/33) 97% (32/33) 100% (36/36) 
a One patient was excluded from the LDV/SOF 12-week treatment arm and one patient was excluded from the 

LDV/SOF+RBV 24-week treatment arm as both patients were infected with genotype 4 CHC. 
b The denominator for relapse is the number of patients with HCV RNA < LLOQ at their last on-treatment assessment. 
c Other includes patients who did not achieve SVR and did not meet virologic failure criteria (e.g. lost to follow-up). 
d Patients with missing cirrhosis status were excluded from this subgroup analysis. 
 
Previously treated adults with or without cirrhosis – ION-2 (study 0109) – Genotype 1 
ION-2 was a randomised, open-label study that evaluated 12 and 24 weeks of treatment with 
ledipasvir/sofosbuvir with or without ribavirin (randomised 1:1:1:1) in genotype 1 HCV-infected 
patients with or without cirrhosis who failed prior therapy with an interferon-based regimen, including 
regimens containing an HCV protease inhibitor. Randomisation was stratified by the presence or 
absence of cirrhosis, HCV genotype (1a versus 1b) and response to prior HCV therapy 
(relapse/breakthrough versus non-response). 
 
Table 14: Demographics and baseline characteristics in study ION-2 
Patient disposition LDV/SOF 

12 weeks 
(n = 109) 

LDV/SOF+ 
RBV 
12 weeks 
(n = 111) 

LDV/SOF 
24 weeks 
(n = 109) 

LDV/SOF+ 
RBV 
24 weeks 
(n = 111) 

TOTAL 
 
(n = 440) 

Age (years): median 
(range) 

56 (24-67) 57 (27-75) 56 (25-68) 55 (28-70) 56 (24-75) 

Male gender 68% (74) 64% (71) 68% (74) 61% (68) 65% (287) 
Race: Black/ African 

American 
22% (24) 14% (16) 16% (17) 18% (20) 18% (77) 

 White 77% (84) 85% (94) 83% (91) 80% (89) 81% (358) 
Genotype 1a 79% (86) 79% (88) 78% (85) 79% (88) 79% (347) 
Prior HCV therapy 
 PEG-IFN+RBV 39% (43) 42% (47) 53% (58) 53% (59) 47% (207)a 
 HCV protease 

inhibitor + 
PEG-IFN+RBV 

61% (66) 58% (64) 46% (50) 46% (51) 53% (231)a 

IL28CC genotype 9% (10) 10% (11) 14% (16) 16% (18) 13% (55) 
FibroTest-Determined Metavir scoreb 
 F0-F1 14% (15) 10% (11) 12% (13) 16% (18) 13% (57) 
 F2 28% (31) 26% (29) 28% (31) 30% (33) 28% (124) 
 F3-F4 58% (63) 64% (71) 58% (63) 54% (60) 58% (257) 
 Not interpretable 0% (0) 0% (0) 2% (2) 0% (0) < 1% (2) 
a One patient in the LDV/SOF 24-week treatment arms and one patient in the LDV/SOF+RBV 24-week treatment arm 

were prior treatment failures of a non-pegylated interferon-based regimen. 
b Non-missing FibroTest results are mapped to Metavir scores according to: 0-0.31 = F0-F1; 0.32-0.58 = F2; 

0.59-1.00 = F3-F4. 
 



67 

Table 15: Response rates in study ION-2 
 LDV/SOF 

12 weeks 
(n = 109) 

LDV/SOF+RBV 
12 weeks 
(n = 111) 

LDV/SOF 
24 weeks 
(n = 109) 

LDV/SOF+RBV 
24 weeks 
(n = 111) 

SVR 94% (102/109) 96% (107/111) 99% (108/109) 99% (110/111) 
Outcome for patients without SVR 
 On-treatment virologic 

failure 
0/109 0/111 0/109 < 1% (1/111) 

 Relapsea 6% (7/108) 4% (4/111) 0/109 0/110 
 Otherb 0/109 0/111 < 1% (1/109) 0/111 
SVR rates for selected subgroups 
Genotype 
 Genotype 1a 95% (82/86) 95% (84/88) 99% (84/85) 99% (87/88) 
 Genotype 1b 87% (20/23) 100% (23/23) 100% (24/24) 100% (23/23) 
Cirrhosis 
 No 95% (83/87) 100% (88/88)c 99% (85/86)c 99% (88/89) 
 Yesd 86% (19/22) 82% (18/22) 100% (22/22) 100% (22/22) 
Prior HCV therapy 
 PEG-IFN+RBV 93% (40/43) 96% (45/47) 100% (58/58) 98% (58/59) 
 HCV protease inhibitor 

+ PEG-IFN+RBV 
94% (62/66) 97% (62/64) 98% (49/50) 100% (51/51) 

a The denominator for relapse is the number of patients with HCV RNA < LLOQ at their last on-treatment assessment. 
b Other includes patients who did not achieve SVR and did not meet virologic failure criteria (e.g. lost to follow-up). 
c Patients with missing cirrhosis status were excluded from this subgroup analysis. 
d Metavir score = 4 or Ishak score ≥ 5 by liver biopsy, or FibroTest score of > 0.75 and (APRI) of > 2. 
 
Table 16 presents relapse rates with the 12-week regimens (with or without ribavirin) for selected 
subgroups (see also previous section “Effect of baseline HCV resistance-associated variants on 
treatment outcome”). In non-cirrhotic patients relapses only occurred in the presence of baseline 
NS5A RAVs, and during therapy with ledipasvir/sofosbuvir without ribavirin. In cirrhotic patients 
relapses occurred with both regimens, and in the absence and presence of baseline NS5A RAVs. 
 
Table 16: Relapse rates for selected subgroups in study ION-2 
 LDV/SOF 

12 weeks 
(n = 109) 

LDV/SOF+RBV 
12 weeks 
(n = 111) 

LDV/SOF 
24 weeks 
(n = 109) 

LDV/SOF+RBV 
24 weeks 
(n = 111) 

Number of responders at end of 
treatment 

108 111 109 110 

Cirrhosis 
 No 5% (4/86)a 0% (0/88)b 0% (0/86)b 0% (0/88) 
 Yes 14% (3/22) 18% (4/22) 0% (0/22) 0% (0/22) 
Presence of baseline NS5A resistance-associated substitutionsc 
 No 3% (3/91)d 2% (2/94) 0% (0/96) 0% (0/95)f 
 Yes 24% (4/17)e 12% (2/17) 0% (0/13) 0% (0/14) 
a These 4 non-cirrhotic relapsers all had baseline NS5A resistance-associated polymorphisms. 
b Patients with missing cirrhosis status were excluded from this subgroup analysis. 
c Analysis (by deep sequencing) included NS5A resistance-associated polymorphisms that conferred > 2.5-fold change in 

EC50 (K24G/N/R, M28A/G/T, Q30E/G/H/L/K/R/T, L31I/F/M/V, P32L, S38F, H58D, A92K/T, and Y93C/F/H/N/S for 
genotype 1a and L31I/F/M/V, P32L, P58D, A92K, and Y93C/H/N/S for genotype 1b HCV infection). 

d 3/3 of these patients had cirrhosis. 
e 0/4 of these patients had cirrhosis. 
f One patient who achieved a viral load < LLOQ at end of treatment had missing baseline NS5A data and was excluded 

from the analysis. 
 
Previously treated adults with cirrhosis – SIRIUS – Genotype 1 
SIRIUS included patients with compensated cirrhosis who first failed therapy with pegylated 
interferon (PEG-IFN) + ribavirin, and then failed a regimen consisting of a pegylated 
interferon + ribavirin + an NS3/4A protease inhibitor. Cirrhosis was defined by biopsy, Fibroscan 
(> 12.5 kPa) or FibroTest > 0.75 and an AST:platelet ratio index (APRI) of > 2. 
 



68 

The study (double-blind and placebo-controlled) evaluated 24 weeks of treatment 
ledipasvir/sofosbuvir (with ribavirin placebo) versus 12 weeks of treatment with ledipasvir/sofosbuvir 
with ribavirin. Patients in the latter treatment arm received placebo (for ledipasvir/sofosbuvir and 
ribavirin) during the first 12 weeks, followed by active blinded therapy during the subsequent 
12 weeks. Patients were stratified by HCV genotype (1a versus 1b) and prior treatment response 
(whether HCV RNA < LLOQ had been achieved). 
 
Demographics and baseline characteristics were balanced across the two treatment groups. The 
median age was 56 years (range: 23 to 77); 74% of patients were male; 97% were white; 63% had 
genotype 1a HCV infection; 94% had non-CC IL28B alleles (CT or TT). 
 
Of the 155 patients enrolled, 1 patient discontinued treatment whilst on placebo. Of the remaining 
154 patients, a total of 149 achieved SVR12 across both treatment groups; 96% (74/77) of patients in 
the ledipasvir/sofosbuvir with ribavirin 12-week group and 97% (75/77) of patients in the 
ledipasvir/sofosbuvir 24-week group. All 5 patients who did not achieve SVR12 relapsed after having 
end-of-treatment response (see section “Resistance” – “In clinical studies” above). 
 
Previously treated adults who have failed on sofosbuvir + ribavirin ± PEG-IFN 
The efficacy of ledipasvir/sofosbuvir in patients who had previously failed treatment with sofosbuvir + 
ribavirin ± PEG-IFN is supported by two clinical studies. In study 1118, 44 patients with genotype 1 
infection, including 12 cirrhotic patients, who had previously failed treatment with sofosbuvir + 
ribavirin + PEG-IFN or with sofosbuvir + ribavirin were treated with ledipasvir/sofosbuvir + ribavirin 
for 12 weeks; the SVR was 100% (44/44). In study ION-4, 13 HCV/HIV-1 co-infected patients with 
genotype 1, including 1 cirrhotic patient, who had failed a sofosbuvir + ribavirin regimen were 
enrolled; the SVR was 100% (13/13) after 12 weeks of treatment with ledipasvir/sofosbuvir. 
 
HCV/HIV co-infected adults – ION-4 
ION-4 was an open-label clinical study that evaluated the safety and efficacy of 12 weeks of treatment 
with ledipasvir/sofosbuvir without ribavirin in HCV treatment-naïve and treatment-experienced 
patients with genotype 1 or 4 CHC who were co-infected with HIV-1. Treatment-experienced patients 
had failed prior treatment with PEG-IFN + ribavirin ± an HCV protease inhibitor or sofosbuvir + 
ribavirin ± PEG-IFN.  Patients were on a stable HIV-1 antiretroviral therapy that included 
emtricitabine/tenofovir disoproxil fumarate, administered with efavirenz, rilpivirine or raltegravir. 
 
The median age was 52 years (range: 26 to 72); 82% of the patients were male; 61% were white; 34% 
were black; 75% had genotype 1a HCV infection; 2% had genotype 4 infection; 76% had non-CC 
IL28B alleles (CT or TT); and 20% had compensated cirrhosis.  Fifty-five percent (55%) of the 
patients were treatment-experienced. 
 
Table 17: Response rates in study ION-4 
 LDV/SOF 

12 weeks 
(n = 335) 

SVR 96% (321/335)a 
Outcome for patients without SVR 
 On-treatment virologic failure < 1% (2/335) 
 Relapseb 3% (10/333) 
 Otherc < 1% (2/335) 
SVR rates for selected subgroups 
 Patients with cirrhosis 94% (63/67) 
  Previously treated patients with cirrhosis 98% (46/47) 
a 8 patients with genotype 4 HCV infection were enrolled in the study with 8/8 achieving SVR12. 
b The denominator for relapse is the number of patients with HCV RNA < LLOQ at their last on-treatment assessment. 
c Other includes patients who did not achieve SVR and did not meet virologic failure criteria (e.g. lost to follow-up). 
 
HCV/HIV co-infected adults – ERADICATE 
ERADICATE was an open-label study to evaluate 12 weeks of treatment with ledipasvir/sofosbuvir in 
50 patients with genotype 1 CHC co-infected with HIV. All patients were treatment-naïve to HCV 



69 

therapy without cirrhosis, 26% (13/50) of patients were HIV antiretroviral naïve and 74% (37/50) of 
patients were receiving concomitant HIV antiretroviral therapy. At the time of the interim analysis 
40 patients have reached 12 weeks post treatment and SVR12 was 98% (39/40). 
 
Patients awaiting liver transplantation and post-liver transplant – SOLAR-1 and SOLAR-2 
SOLAR-1 and SOLAR-2 were two open-label clinical studies that evaluated 12 and 24 weeks of 
treatment with ledipasvir/sofosbuvir in combination with ribavirin in genotype 1 and 4 HCV-infected 
patients who have undergone liver transplantation and/or who have decompensated liver disease. The 
two studies were identical in study design. Patients were enrolled in one of the seven groups based on 
liver transplantation status and severity of hepatic impairment (see Table 18). Patients with a CPT 
score > 12 were excluded. Within each group, patients were randomized in a 1:1 ratio to receive 
ledipasvir/sofosbuvir + ribavirin for 12 or 24 weeks. 
 
Demographics and baseline characteristics were balanced across the treatment groups. Of the 670 
treated patients, the median age was 59 years (range: 21 to 81 years); 77% of the patients were male; 
91% were White; mean body mass index was 28 kg/m2 (range: 18 to 49 kg/m2); 94% and 6% had 
genotype 1 and 4 HCV infection, respectively; 78% of the patients failed a prior HCV therapy.  
Among the patients who had decompensated cirrhosis (pre- or post-transplant), 64% and 36% were 
CPT class B and C at screening, respectively, 24% had a baseline Model for End Stage Liver Disease 
(MELD) score greater than 15. 
 
Table 18: Combined response rates (SVR12) in studies SOLAR-1 and SOLAR-2 
 LDV/SOF+RBV 

12 weeks 
(n = 307)a,b 

LDV/SOF+RBV 
24 weeks 

(n = 307)a,b 
 SVR SVR 
Pre-transplant 

CPT B 87% (45/52) 92% (46/50) 
CPT C 88% (35/40) 83% (38/46) 

Post-transplant 
Metavir score F0-F3 95% (94/99) 99% (99/100) 
CPT Ac 98% (55/56) 96% (51/53) 
CPT Bc 89% (41/46) 96% (43/45) 
CPT Cc 57% (4/7) 78% (7/9) 
FCH 100% (7/7) 100% (4/4) 

a Twelve patients transplanted prior to post-treatment Week 12 with HCV RNA< LLOQ at last measurement prior to 
transplant were excluded. 

b Two patients who did not have decompensated cirrhosis and had also not received a liver transplant were excluded due to 
failure to meet the inclusion criteria for any of the treatment groups. 

c CPT = Child-Pugh-Turcotte, FCH = Fibrosing cholestatic hepatitis.  CPT A = CPT score 5-6 (compensated), 
CPT B = CPT score 7-9 (decompensated), CPT C = CPT score 10-12 (decompensated). 

 
Forty patients with genotype 4 CHC were enrolled in SOLAR-1 and SOLAR-2 studies, SVR12 were 
92% (11/12) and 100% (10/10) in post-transplant patients without decompensated cirrhosis and 60% 
(6/10) and 75% (6/8) in patients with decompensated cirrhosis (pre- and post-liver transplantation) 
treated for 12 or 24 weeks, respectively. Of the 7 patients who failed to achieve SVR12, 3 relapsed, all 
had decompensated cirrhosis and were treated with ledipasvir/sofosbuvir + ribavirin for 12 weeks. 
 
Changes in MELD and CPT score from baseline to post-treatment Week 12 were analyzed for all 
patients with decompensated cirrhosis (pre- or post-transplant) who achieved SVR12 and for whom 
data were available (n = 123) to assess the effect of SVR12 on hepatic function. 
 
Change in MELD score: Among those who achieved SVR12 with 12 weeks treatment with 
ledipasvir/sofosbuvir + ribavirin, 57% (70/123) and 19% (23/123) had an improvement or no change 
in MELD score from baseline to post-treatment week 12, respectively; of the 32 patients whose 
MELD score was ≥ 15 at baseline, 59% (19/32) had a MELD score < 15 at post-treatment Week 12. 
The improvement in MELD scores observed was driven largely by improvements in total bilirubin. 
 



70 

Change in CPT score and class: Among those who achieved SVR12 with 12 weeks treatment with 
ledipasvir/sofosbuvir with ribavirin, 60% (74/123) and 34% (42/123) had an improvement or no 
change of CPT scores from baseline to post-treatment week 12, respectively; of the 32 patients who 
had CPT C cirrhosis at baseline, 53% (17/32) had CPT B cirrhosis at post-treatment Week 12; of the 
88 patients who had CPT B cirrhosis at baseline, 25% (22/88) had CPT A cirrhosis at post-treatment 
Week 12.  The improvement in CPT scores observed was driven largely by improvements in total 
bilirubin and albumin. 
 
Clinical efficacy and safety in genotype 2, 3, 4, 5 and 6 (see also section 4.4) 
Ledipasvir/sofosbuvir has been evaluated for the treatment of non-genotype 1 infection in small 
Phase 2 studies, as summarised below. 
 
The clinical studies enrolled patients with or without cirrhosis, who were treatment-naïve or with prior 
treatment failure after therapy with PEG-IFN + ribavirin +/- an HCV protease inhibitor. 
 
For genotype 2, 4, 5 and 6 infection, therapy consisted of ledipasvir/sofosbuvir without ribavirin, 
given for 12 weeks (Table 19). For genotype 3 infection, ledipasvir/sofosbuvir was given with or 
without ribavirin, also for 12 weeks (Table 20). 
 
Table 19: Response rates (SVR12) with ledipasvir/sofosbuvir for 12 weeks in patients with genotype 2, 4, 5 
and 6 HCV infection 
Study GT n TEa SVR12 Relapseb 

Overall Cirrhosis  
Study 1468 (LEPTON) 2 26 19% (5/26) 96% (25/26) 100% (2/2) 0% (0/25) 
Study 1119  4 44 50% (22/44) 93% (41/44) 100% (10/10) 7% (3/44) 
Study 1119 5 41 49% (20/41) 93% (38/41) 89% (8/9) 5% (2/40) 
Study 0122 (ELECTRON-2) 6 25 0% (0/25) 96% (24/25) 100% (2/2) 4% (1/25) 
a TE: number of treatment-experienced patients. 
b The denominator for relapse is the number of patients with HCV RNA < LLOQ at their last on-treatment assessment. 
 
Table 20: Response rates (SVR12) in patients with genotype 3 infection (ELECTRON-2) 
 LDV/SOF+RBV 

12 weeks 
LDV/SOF 
12 weeks 

 SVR Relapsea SVR Relapsea 
Treatment-naïve 100% (26/26) 0% (0/26) 64% (16/25) 33% (8/24) 

Patients without cirrhosis 100% (20/20) 0% (0/21) 71% (15/21) 25% (5/20) 
Patients with cirrhosis 100% (6/6) 0% (0/5) 25% (1/4) 75% (3/4) 

Treatment-experienced 82% (41/50) 16% (8/49) NS NS 
Patients without cirrhosis 89% (25/28) 7% (2/27) NS NS 
Patients with cirrhosis 73% (16/22) 27% (6/22) NS NS 

NS: not studied. 
a The denominator for relapse is the number of patients with HCV RNA < LLOQ at their last on-treatment assessment. 
 
Patients with renal impairment 
Study 0154 was an open-label clinical study that evaluated the safety and efficacy of 12 weeks of 
treatment with ledipasvir/sofosbuvir in 18 genotype 1 HCV-infected patients with severe renal 
impairment not requiring dialysis. At baseline, two patients had cirrhosis and the mean eGFR was 
24.9 mL/min (range: 9.0-39.6). SVR12 was achieved in 18/18 patients. 
 
Study 4063 was an open-label three-arm clinical study that evaluated 8, 12, and 24 weeks of treatment 
with ledipasvir/sofosbuvir in a total of 95 patients with genotype 1 (72%), 2 (22%), 4 (2%), 5 (1%), or 
6 (2%) CHC and ESRD requiring dialysis: 45 treatment-naïve genotype 1 HCV-infected patients 
without cirrhosis received ledipasvir/sofosbuvir for 8 weeks; 31 treatment-experienced genotype 1 
HCV-infected patients and treatment-naïve or treatment-experienced patients with genotype 2, 5, and 
6 infection without cirrhosis received ledipasvir/sofosbuvir for 12 weeks; and 19 genotype 1, 2, and 4 
HCV-infected patients with compensated cirrhosis received ledipasvir/sofosbuvir for 24 weeks.  Of 
the 95 total patients, at baseline, 20% of patients had cirrhosis, 22% were treatment experienced, 21% 
had received a kidney transplant, 92% were on hemodialysis, and 8% were on peritoneal dialysis; 



71 

mean duration on dialysis was 11.5 years (range: 0.2 to 43.0 years).  The SVR rates for the 8, 12, and 
24 week ledipasvir/sofosbuvir treatment groups were 93% (42/45), 100% (31/31), and 79% (15/19), 
respectively. Of the seven patients who did not achieve SVR12, none experienced virologic failure or 
relapsed. 
 
Paediatric population 
The efficacy of ledipasvir/sofosbuvir in HCV infected patients aged 3  years and above was evaluated 
in a Phase 2, open label clinical study that enrolled 226 patients, 221 patients with genotype 1, 2 
patients with genotype 3, and 3 patients with genotype 4 CHC (Study 1116) (see section 4.2 for 
information on paediatric use).   
 
Patients aged 12 to < 18 Years: 
Ledipasvir/sofosbuvir was evaluated in 100 patients aged 12 to < 18 years with genotype 1 
HCV-infection. A total of 80 patients (n=80) were treatment-naïve, while 20 patients (n=20) were 
treatment-experienced. All patients were treated with ledipasvir/sofosbuvir for 12 weeks. 
 
Demographics and baseline characteristics were balanced across treatment-naïve and 
treatment-experienced patients. The median age was 15 years (range: 12 to 17); 63% of the patients 
were female; 91% were White, 7% were Black, and 2% were Asian; 13% were Hispanic/Latino; mean 
weight was 61.3 kg (range: 33.0 to 126.0 kg); 55% had baseline HCV RNA levels greater than or 
equal to 800,000 IU/mL; 81% had genotype 1a HCV infection; and 1 patient who was treatment naïve 
was known to have cirrhosis. The majority of patients (84%) had been infected through vertical 
transmission. 
 
The SVR12 rate was 98% overall (98% [78/80] in treatment-naïve patients and 100% [20/20] in 
treatment experienced patients). A total of 2 out of 100 patients (2%), both treatment- naïve, did not 
achieve SVR12 (due to loss to follow-up). No patient experienced virologic failure. 
 
Patients aged 6 to < 12 Years:  
Ledipasvir/sofosbuvir was evaluated in 92 patients aged 6 to < 12 years with genotype 1, 3, or 4 
HCV-infection. A total of 72 patients (78%) were treatment-naïve and 20 patients (22%) were 
treatment-experienced. Eighty-nine of the patients (87 patients with genotype 1 HCV infection and 2 
patients with genotype 4 HCV infection) were treated with ledipasvir/sofosbuvir for 12 weeks, 1 
treatment experienced patient with genotype 1 HCV infection and cirrhosis was treated with 
ledipasvir/sofosbuvir for 24 weeks, and 2 treatment experienced patients with genotype 3 HCV 
infection were treated with ledipasvir/sofosbuvir plus ribavirin for 24 weeks. The median age was 9 
years (range: 6 to 11); 59% of the patients were male; 79% were White, 8% were Black, and 5% were 
Asian; 10% were Hispanic/Latino; mean weight was 32.8 kg (range: 17.5 to 76.4 kg); 59% had 
baseline HCV RNA levels greater than or equal to 800,000 IU/mL; 84% had genotype 1a HCV 
infection; 2 patients (1 treatment-naïve, 1 treatment-experienced) had known cirrhosis. The majority of 
patients (97%) had been infected through vertical transmission.  
 
The SVR rate was 99% overall (99% [88/89], 100% [1/1], and 100% [2/2] in patients treated with 
ledipasvir/sofosbuvir for 12 weeks, ledipasvir/sofosbuvir for 24 weeks, and ledipasvir/sofosbuvir plus 
ribavirin for 24 weeks, respectively). The one treatment-naïve patient with genotype 1 HCV infection 
and cirrhosis who was treated with Harvoni for 12 weeks did not achieve SVR12 and relapsed.  
 
Patients aged 3 to <6 Years:  
Ledipasvir/sofosbuvir was evaluated in 34 patients aged 3 to < 6 years with genotype 1 (n = 33) or 
genotype 4 (n = 1) HCV-infection. All of the patients were treatment-naïve and treated with 
ledipasvir/sofosbuvir for 12 weeks. The median age was 5 years (range: 3 to 5); 71% of the patients 
were female; 79% were White, 3% were Black, and 6% were Asian; 18% were Hispanic/Latino; mean 
weight was 19.2 kg (range: 10.7 to 33.6 kg); 56% had baseline HCV RNA levels greater than or equal 
800,000 IU/mL; 82% had genotype 1a HCV infection; no patients had known cirrhosis. All patients 
(100%) had been infected through vertical transmission.  
 



72 

The SVR rate was 97% overall (97% [32/33] in patients with genotype 1 HCV infection and 100% 
[1/1] in patients with genotype 4 HCV infection). One patient who prematurely discontinued study 
treatment after five days due to abnormal taste of the medication did not achieve SVR. 
 
5.2 Pharmacokinetic properties 
 
Absorption 
 
Following oral administration of ledipasvir/sofosbuvir to HCV-infected patients, ledipasvir median 
peak plasma concentration was observed at 4.0 hours post-dose. Sofosbuvir was absorbed quickly and 
the median peak plasma concentrations were observed ~ 1 hour post-dose. Median peak plasma 
concentration of GS-331007 was observed at 4 hours post-dose. 
 
Based on the population pharmacokinetic analysis in HCV-infected patients, geometric mean 
steady-state AUC0-24 for ledipasvir (n = 2,113), sofosbuvir (n = 1,542), and GS-331007 (n = 2,113) 
were 7,290, 1,320 and 12,000 ng•h/mL, respectively.  Steady-state Cmax for ledipasvir, sofosbuvir and 
GS-331007 were 323, 618 and 707 ng/mL, respectively. Sofosbuvir and GS-331007 AUC0-24 and Cmax 
were similar in healthy adult subjects and patients with HCV infection.  Relative to healthy subjects 
(n = 191), ledipasvir AUC0-24 and Cmax were 24% lower and 32% lower, respectively, in HCV-infected 
patients. Ledipasvir AUC is dose proportional over the dose range of 3 to 100 mg.  Sofosbuvir and 
GS-331007 AUCs are near dose proportional over the dose range of 200 mg to 400 mg. 
 
Effects of food 
Relative to fasting conditions, the administration of a single dose of ledipasvir/sofosbuvir with a 
moderate fat or high fat meal increased the sofosbuvir AUC0-inf by approximately 2-fold, but did not 
significantly affect the sofosbuvir Cmax. The exposures to GS-331007 and ledipasvir were not altered 
in the presence of either meal type. Harvoni can be administered without regard to food. 
 
Distribution 
 
Ledipasvir is > 99.8% bound to human plasma proteins.  After a single 90 mg dose of [14C]-ledipasvir 
in healthy subjects, the blood to plasma ratio of [14C]-radioactivity ranged between 0.51 and 0.66. 
 
Sofosbuvir is approximately 61-65% bound to human plasma proteins and the binding is independent 
of drug concentration over the range of 1 µg/mL to 20 µg/mL. Protein binding of GS-331007 was 
minimal in human plasma. After a single 400 mg dose of [14C]-sofosbuvir in healthy subjects, the 
blood to plasma ratio of [14C]-radioactivity was approximately 0.7. 
 
Biotransformation 
 
In vitro, no detectable metabolism of ledipasvir was observed by human CYP1A2, CYP2C8, 
CYP2C9, CYP2C19, CYP2D6 and CYP3A4. Evidence of slow oxidative metabolism via an unknown 
mechanism has been observed. Following a single dose of 90 mg [14C]-ledipasvir, systemic exposure 
was almost exclusively due to the parent drug (> 98%). Unchanged ledipasvir is also the major species 
present in faeces. 
 
Sofosbuvir is extensively metabolised in the liver to form the pharmacologically active nucleoside 
analogue triphosphate GS-461203. The active metabolite is not observed. The metabolic activation 
pathway involves sequential hydrolysis of the carboxyl ester moiety catalysed by human cathepsin A 
or carboxylesterase 1 and phosphoramidate cleavage by histidine triad nucleotide-binding protein 1 
followed by phosphorylation by the pyrimidine nucleotide biosynthesis pathway. Dephosphorylation 
results in the formation of nucleoside metabolite GS-331007 that cannot be efficiently 
rephosphorylated and lacks anti-HCV activity in vitro. Within ledipasvir/sofosbuvir, GS-331007 
accounts for approximately 85% of total systemic exposure. 
 



73 

Elimination 
 
Following a single 90 mg oral dose of [14C]-ledipasvir, mean total recovery of the [14C]-radioactivity 
in faeces and urine was 87%, with most of the radioactive dose recovered from faeces (86%).  
Unchanged ledipasvir excreted in faeces accounted for a mean of 70% of the administered dose and 
the oxidative metabolite M19 accounted for 2.2% of the dose. These data suggest that biliary excretion 
of unchanged ledipasvir is a major route of elimination with renal excretion being a minor pathway 
(approximately 1%). The median terminal half-life of ledipasvir in healthy volunteers following 
administration of ledipasvir/sofosbuvir in the fasted state was 47 hours. 
 
Following a single 400 mg oral dose of [14C]-sofosbuvir, mean total recovery of the dose was greater 
than 92%, consisting of approximately 80%, 14%, and 2.5% recovered in urine, faeces, and expired 
air, respectively. The majority of the sofosbuvir dose recovered in urine was GS-331007 (78%) while 
3.5% was recovered as sofosbuvir. This data indicate that renal clearance is the major elimination 
pathway for GS-331007 with a large part actively secreted. The median terminal half-lives of 
sofosbuvir and GS-331007 following administration of ledipasvir/sofosbuvir were 0.5 and 27 hours, 
respectively. 
 
Neither ledipasvir nor sofosbuvir are substrates for hepatic uptake transporters, organic cation 
transporter (OCT) 1, organic anion-transporting polypeptide (OATP) 1B1 or OATP1B3.  GS-331007 
is not a substrate for renal transporters including organic anion transporter (OAT) 1 or OAT3, or 
OCT2. 
 
In vitro potential for ledipasvir/sofosbuvir to affect other medicinal products 
 
At concentrations achieved in the clinic, ledipasvir is not an inhibitor of hepatic transporters including 
the OATP 1B1 or 1B3, BSEP, OCT1, OCT2, OAT1, OAT3, multidrug and toxic compound extrusion 
(MATE) 1 transporter, multidrug resistance protein (MRP) 2 or MRP4.  Sofosbuvir and GS-331007 
are not inhibitors of drug transporters P-gp, BCRP, MRP2, BSEP, OATP1B1, OATP1B3, OCT1 and 
GS-331007 is not an inhibitor of OAT1, OCT2 and MATE1. 
 
Sofosbuvir and GS-331007 are not inhibitors or inducers of CYP or uridine diphosphate 
glucuronosyltransferase (UGT) 1A1 enzymes. 
 
Pharmacokinetics in special populations 
 
Race and gender 
No clinically relevant pharmacokinetic differences due to race have been identified for ledipasvir, 
sofosbuvir or GS-331007. No clinically relevant pharmacokinetic differences due to gender have been 
identified for sofosbuvir or GS-331007. AUC and Cmax of ledipasvir were 77% and 58% higher, 
respectively, in females than males; however, the relationship between gender and ledipasvir 
exposures was not considered clinically relevant. 
 
Elderly 
Population pharmacokinetic analysis in HCV-infected patients showed that within the age range (18 to 
80 years) analysed, age did not have a clinically relevant effect on the exposure to ledipasvir, 
sofosbuvir or GS-331007. Clinical studies of ledipasvir/sofosbuvir included 235 patients (8.6% of total 
number of patients) aged 65 years and over. 
 
Renal impairment 
A summary of the effect of varying degrees of renal impairment (RI) on the exposures of the 
components of Harvoni compared to subjects with normal renal function, as described in the text 
below, are provided in Table 21. 
 



74 

Table 21: Effect of Varying Degrees of Renal Impairment on Exposures (AUC) of Sofosbuvir, GS-331007, 
and Ledipasvir Compared to Subjects with Normal Renal Function 
 HCV-Negative Subjects HCV-Infected Subjects 

Mild RI 
(eGFR 
≥50 and 
<80 
mL/min/1.
73m2) 

Moderate RI 
(eGFR ≥30 
and <50 
mL/min/1.73
m2) 

Severe RI 
(eGFR <30 
mL/min/1.73
m2) 

ESRD Requiring 
Dialysis 

Severe RI 
(eGFR 
<30 
mL/min/1.
73m2) 

ESRD 
Requiring 
Dialysis Dosed 1 

hr Before 
Dialysis 

Dosed 1 
hr After 
Dialysis 

Sofosbuvir 1.6-fold↑ 2.1-fold↑ 2.7-fold↑ 1.3-fold↑ 1.6-fold↑ ~2-fold↑ 1.9-fold↑ 
GS-331007 1.6-fold↑ 1.9-fold↑ 5.5-fold↑ ≥10-fold↑ ≥20-fold↑ ~6-fold↑ 23-fold↑ 
Ledipasvir - - ↔ - - - 1.6-fold↑ 
↔ indicates no clinically relevant change in the exposure of Ledipasvir. 
 
The pharmacokinetics of ledipasvir were studied with a single dose of 90 mg ledipasvir in 
HCV negative adult patients with severe renal impairment (eGFR < 30 mL/min by Cockcroft-Gault, 
median [range] CrCl 22 [17-29] mL/min).   
 
The pharmacokinetics of sofosbuvir were studied in HCV negative adult patients with mild (eGFR 
≥ 50 and < 80 mL/min/1.73 m2), moderate (eGFR ≥ 30 and < 50 mL/min/1.73 m2), severe renal 
impairment (eGFR < 30 mL/min/1.73 m2) and patients with ESRD requiring haemodialysis following 
a single 400 mg dose of sofosbuvir,relative to patients with normal renal function (eGFR 
> 80 mL/min/1.73 m2). GS-331007 is efficiently removed by haemodialysis with an extraction 
coefficient of approximately 53%. Following a single 400 mg dose of sofosbuvir, a 4 hour 
haemodialysis removed 18% of administered sofosbuvir dose. 
 
In HCV-infected adult patients with severe renal impairment treated with ledipasvir/sofosbuvir for 
12 weeks (n = 18), the pharmacokinetics of ledipasvir, sofosbuvir, and GS-331007 were consistent 
with that observed in HCV negative patients with severe renal impairment. 
 
The pharmacokinetics of ledipasvir, sofosbuvir, and GS-331007 were studied in HCV-infected adult 
patients with ESRD requiring dialysis treated with ledipasvir/sofosbuvir (n=94) for 8, 12, or 24 weeks, 
and compared to patients without renal impairment in the ledipasvir/sofosbuvir Phase 2/3 trials. 
 
Hepatic impairment 
The pharmacokinetics of ledipasvir were studied with a single dose of 90 mg ledipasvir in 
HCV negative adult patients with severe hepatic impairment (CPT class C).  Ledipasvir plasma 
exposure (AUCinf) was similar in patients with severe hepatic impairment and control patients with 
normal hepatic function. Population pharmacokinetics analysis in HCV-infected adult patients 
indicated that cirrhosis (including decompensated cirrhosis) had no clinically relevant effect on the 
exposure to ledipasvir. 
 
The pharmacokinetics of sofosbuvir were studied following 7-day dosing of 400 mg sofosbuvir in 
HCV-infected adult patients with moderate and severe hepatic impairment (CPT class B and C).  
Relative to patients with normal hepatic function, the sofosbuvir AUC0-24 was 126% and 143% higher 
in moderate and severe hepatic impairment, while the GS-331007 AUC0-24 was 18% and 9% higher, 
respectively. Population pharmacokinetics analysis in HCV-infected patients indicated that cirrhosis 
(including decompensated cirrhosis) had no clinically relevant effect on the exposure to sofosbuvir 
and GS-331007. 
 
Body weight 
Body weight did not have a significant effect on sofosbuvir exposure according to a population 
pharmacokinetic analysis. Exposure to ledipasvir decreases with increasing body weight but the effect 
is not considered to be clinically relevant. 
 



75 

Paediatric population 
Ledipasvir, sofosbuvir, and GS-331007 exposures in paediatric patients aged 3 years and above were 
similar to those in adults from Phase 2/3 studies, following administration of ledipasvir/sofosbuvir. 
The 90% confidence intervals of geometric least-squares mean ratios for all PK parameters of interest 
were contained within the predetermined similarity bounds of less than 2-fold (50% to 200%) with the 
exception of ledipasvir Ctau in paediatric patients 12 years and above which was 84% higher (90%CI: 
168% to 203%) and was not considered clinically relevant.  
 
The pharmacokinetics of ledipasvir, sofosbuvir, and GS-331007 have not been established in 
paediatric patients aged < 3 years (see section 4.2). 
 
5.3 Preclinical safety data 
 
Ledipasvir 
 
No target organs of toxicity were identified in rat and dog studies with ledipasvir at AUC exposures 
approximately 7 times the human exposure at the recommended clinical dose. 
 
Ledipasvir was not genotoxic in a battery of in vitro or in vivo assays, including bacterial 
mutagenicity, chromosome aberration using human peripheral blood lymphocytes and in vivo rat 
micronucleus assays. 
 
Ledipasvir was not carcinogenic in the 26-week rasH2 transgenic mouse and the 2-year rat 
carcinogenicity studies at exposures up to 26-times in mice and 8-times in rats higher than human 
exposure.  
 
Ledipasvir had no adverse effects on mating and fertility. In female rats, the mean number of corpora 
lutea and implantation sites were slightly reduced at maternal exposures 6-fold the exposure in humans 
at the recommended clinical dose. At the no observed effect level, AUC exposure to ledipasvir was 
approximately 7- and 3-fold, in males and females, respectively, the human exposure at the 
recommended clinical dose. 
 
No teratogenic effects were observed in rat and rabbit developmental toxicity studies with ledipasvir. 
 
In a rat pre- and postnatal study, at a maternally toxic dose, the developing rat offspring exhibited 
mean decreased body weight and body weight gain when exposed in utero (via maternal dosing) and 
during lactation (via maternal milk) at a maternal exposure 4 times the exposure in humans at the 
recommended clinical dose. There were no effects on survival, physical and behavioural development 
and reproductive performance in the offspring at maternal exposures similar to the exposure in humans 
at the recommended clinical dose. 
 
When administered to lactating rats, ledipasvir was detected in plasma of suckling rats likely due to 
excretion of ledipasvir via milk. 
 
Environmental risk assessment (ERA) 
 
Environmental risk assessment studies have shown that ledipasvir has the potential to be very 
persistent and very bioaccumulative (vPvB) in the environment (See section 6.6). 
 
Sofosbuvir 
 
In repeat dose toxicology studies in rat and dog, high doses of the 1:1 diastereomeric mixture caused 
adverse liver (dog) and heart (rat) effects and gastrointestinal reactions (dog). Exposure to sofosbuvir 
in rodent studies could not be detected likely due to high esterase activity; however, exposure to the 
major metabolite GS-331007 at doses which cause adverse effects was 16 times (rat) and 71 times 
(dog) higher than the clinical exposure at 400 mg sofosbuvir. No liver or heart findings were observed 
in chronic toxicity studies at exposures 5 times (rat) and 16 times (dog) higher than the clinical 



76 

exposure. No liver or heart findings were observed in the 2-year carcinogenicity studies at exposures 
17 times (mouse) and 9 times (rat) higher than the clinical exposure. 
 
Sofosbuvir was not genotoxic in a battery of in vitro or in vivo assays, including bacterial 
mutagenicity, chromosome aberration using human peripheral blood lymphocytes and in vivo mouse 
micronucleus assays. 
 
Carcinogenicity studies in mice and rats do not indicate any carcinogenicity potential of sofosbuvir 
administered at doses up to 600 mg/kg/day in mouse and 750 mg/kg/day in rat. Exposure to 
GS-331007 in these studies was up to 17 times (mouse) and 9 times (rat) higher than the clinical 
exposure at 400 mg sofosbuvir. 
 
Sofosbuvir had no effects on embryo-foetal viability or on fertility in rat and was not teratogenic in rat 
and rabbit development studies. No adverse effects on behaviour, reproduction or development of 
offspring in rat were reported. In rabbit studies exposure to sofosbuvir was 6 times the expected 
clinical exposure. In the rat studies, exposure to sofosbuvir could not be determined but exposure 
margins based on the major human metabolite was approximately 5 times higher than the clinical 
exposure at 400 mg sofosbuvir. 
 
Sofosbuvir-derived material was transferred through the placenta in pregnant rats and into the milk of 
lactating rats. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Granule cores 
 
Copovidone 
Lactose monohydrate 
Microcrystalline cellulose 
Croscarmellose sodium 
Colloidal anhydrous silica 
Magnesium stearate 
 
Film-coating 
 
Hypromellose 
Titanium dioxide (E171) 
Macrogol 
Iron oxide yellow (E172) 
Iron oxide red (E172) 
Basic butylated methacrylate copolymer 
Talc 
Colloidal anhydrous silica 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
2 years. 
 



77 

6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions. 
 
6.5 Nature and contents of container 
 
Harvoni 33.75 mg/150 mg and 45 mg/200 mg coated granules are supplied in 
polyester/aluminium/polyethylene film sachets in cartons. Each carton contains 28 sachets. 
 
6.6 Special precautions for disposal 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
This medicinal product may pose a risk to the environment (See section 5.3). 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Gilead Sciences Ireland UC 
Carrigtohill 
County Cork, T45 DP77 
Ireland 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/14/958/004 
EU/1/14/958/005 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 17 November 2014 
Date of latest renewal: 01 August 2019 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu 
 



78 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH 
RELEASE 

 
B. CONDITIONS OR RESTRICTIONS REGARDING 

SUPPLY AND USE 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF 

THE MARKETING AUTHORISATION 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD 

TO THE SAFE AND EFFECTIVE USE OF THE 
MEDICINAL PRODUCT 

 



79 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer(s) responsible for batch release 
 
Gilead Sciences Ireland UC 
IDA Business & Technology Park 
Carrigtohill 
County Cork 
Ireland 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
• Periodic safety update reports (PSURs) 
 
The marketing authorisation holder shall submit the first PSURs for this product within 6 months 
following authorisation. Subsequently, the marketing authorisation holder (MAH) shall submit PSUR 
for this product in accordance with the requirements set out in the list of Union reference dates (EURD 
list) provided for under Article 107c(7) of Directive 2001/83/EC and published on the European 
medicines web-portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
• Risk management plan (RMP) 
 
The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities 
and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing authorisation 
and any agreed subsequent updates of the RMP. 
 
An updated RMP should be submitted: 
• At the request of the European Medicines Agency; 
• Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached. 

 
• Obligation to conduct post-authorisation measures 
 
The MAH shall complete, within the stated timeframe, the below measures: 
 

Description Due date 
In order to evaluate the recurrence of hepatocellular carcinoma associated with Harvoni, the 
MAH shall conduct and submit the results of a prospective safety study using data deriving 
from a cohort of a well-defined group of patients, based on an agreed protocol. The final study 
report shall be submitted by: 

Q2 2023 



80 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
 



81 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



82 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 
PACKAGING 
 
BOTTLE AND CARTON LABELLING 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Harvoni 90 mg/400 mg film-coated tablets 
ledipasvir/sofosbuvir 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 90 mg ledipasvir and 400 mg sofosbuvir. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose and sunset yellow FCF (E110). See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
28 film-coated tablets. 
84 (3 bottles of 28) film-coated tablets. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 



83 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Gilead Sciences Ireland UC 
Carrigtohill 
County Cork, T45 DP77 
Ireland  
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/14/958/001 28 film-coated tablets 
EU/1/14/958/002 84 (3 bottles of 28) film-coated tablets 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Harvoni 90 mg/400 mg film-coated tablets [Outer packaging only] 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: {number}  
SN: {number}  
NN: {number} 



84 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 
PACKAGING 
 
BOTTLE AND CARTON LABELLING 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Harvoni 45 mg/200 mg film-coated tablets 
ledipasvir/sofosbuvir 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 45 mg ledipasvir and 200 mg sofosbuvir. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
28 film-coated tablets. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 



85 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Gilead Sciences Ireland UC 
Carrigtohill 
County Cork, T45 DP77 
Ireland  
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/14/958/003 28 film-coated tablets 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Harvoni 45 mg/200 mg film-coated tablets [Outer packaging only] 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: {number} 
SN: {number} 
NN: {number}



86 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 
PACKAGING 
 
CARTON LABELLING 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Harvoni 33.75 mg/150 mg coated granules in sachet 
ledipasvir/sofosbuvir 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each sachet of coated granules contains 33.75 mg ledipasvir and 150 mg sofosbuvir. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
28 sachets in a carton. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 



87 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Gilead Sciences Ireland UC 
Carrigtohill 
County Cork, T45 DP77 
Ireland  
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/14/958/004 28 sachets 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Harvoni 33.75 mg/150 mg coated granules in sachet [Outer packaging only] 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: {number} 
SN: {number} 
NN: {number} 



88 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNIT 
 
SACHET 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Harvoni 33.75 mg/150 mg coated granules in sachet 
ledipasvir/sofosbuvir 
Oral use 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER < DONATION AND PRODUCT CODES> 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
 
6. OTHER 
 
GILEAD 
 
 



89 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 
PACKAGING 
 
CARTON LABELLING 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Harvoni 45 mg/200 mg coated granules in sachet 
ledipasvir/sofosbuvir 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each sachet of coated granules contains 45 mg ledipasvir and 200 mg sofosbuvir. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
28 sachets in a carton. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 



90 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Gilead Sciences Ireland UC 
Carrigtohill 
County Cork, T45 DP77 
Ireland  
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/14/958/005 28 sachets 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Harvoni 45 mg/200 mg coated granules in sachet [Outer packaging only] 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: {number} 
SN: {number} 
NN: {number} 



91 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNIT 
 
SACHET 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Harvoni 45 mg/200 mg coated granules in sachet 
ledipasvir/sofosbuvir 
Oral use 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER < DONATION AND PRODUCT CODES> 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
 
6. OTHER 
 
GILEAD 
 
 



92 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
 



93 

Package leaflet: Information for the user 
 

Harvoni 90 mg/400 mg film-coated tablets 
Harvoni 45 mg/200 mg film-coated tablets 

ledipasvir/sofosbuvir 
 

This medicine is subject to additional monitoring. This will allow quick identification of new 
safety information. You can help by reporting any side effects you may get. See the end of section 4 
for how to report side effects. 
 
Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor or pharmacist. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
- If you get any side effects talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
1. What Harvoni is and what it is used for 
2. What you need to know before you take Harvoni 
3. How to take Harvoni 
4. Possible side effects 
5. How to store Harvoni 
6. Contents of the pack and other information 
 
If Harvoni has been prescribed for your child, please note that all the information in this leaflet 
is applicable to your child (in this case please read “your child” instead of “you”). 
 
1. What Harvoni is and what it is used for 
 
Harvoni is a medicine that contains the active substances ledipasvir and sofosbuvir. Harvoni is given 
to treat chronic (long-term) hepatitis C virus infection in adults and children 3  years of age and 
older. 
 
Hepatitis C is a virus that infects the liver. The active substances in the medicine work together by 
blocking two different proteins that the virus needs to grow and reproduce itself, allowing the infection 
to be permanently eliminated from the body. 
 
Harvoni is sometimes taken with another medicine, ribavirin. 
 
It is very important that you also read the leaflets for the other medicines that you will be taking with 
Harvoni. If you have any questions about your medicines, please ask your doctor or pharmacist. 
 
 
2. What you need to know before you take Harvoni 
 
Do not take Harvoni 
• If you are allergic to ledipasvir, sofosbuvir or any of the other ingredients of this medicine 

(listed in section 6 of this leaflet). 
 
 



94 

• If you are currently taking any of the following medicines: 
• rifampicin and rifabutin (antibiotics used to treat infections, including tuberculosis); 
• St. John’s wort (herbal medicine used to treat depression); 
• carbamazepine, phenobarbital and phenytoin (medicines used to treat epilepsy and 

prevent seizures); 
• rosuvastatin (a medicine used to treat high cholesterol). 

 
 If any of these conditions apply to you, do not take Harvoni and tell your doctor immediately. 
 
Warnings and precautions 
Your doctor will know if any of the following conditions apply to you. These will be considered 
before treatment with Harvoni is started. 
• other liver problems apart from hepatitis C, for instance 

• if you are awaiting a liver transplant; 
• if you have a current or previous infection with the hepatitis B virus, since your 

doctor may want to monitor you more closely; 
• kidney problems or if you are on kidney dialysis, since Harvoni has not been fully tested in 

patients with severe kidney problems; 
• ongoing treatment for HIV infection, since your doctor may want to monitor you more 

closely. 
 
Talk to your doctor or pharmacist before taking Harvoni if: 
• you currently take, or have taken in the last few months, the medicine amiodarone to treat 

irregular heartbeats, as it may result in a life-threatening slowing of your heart beat. Your doctor 
may consider different treatments if you have taken this medicine. If treatment with Harvoni is 
needed, you may require additional heart monitoring. 

• you have diabetes. You may need closer monitoring of your blood glucose levels and/or 
adjustment of your diabetes medication after starting Harvoni. Some diabetic patients have 
experienced low sugar levels in the blood (hypoglycaemia) after starting treatment with 
medicines like Harvoni. 

 
Tell your doctor immediately if you currently take, or have taken in the last months, any medicines 
for heart problems and during treatment you experience: 
• slow or irregular heartbeat, or heart rhythm problems; 
• shortness of breath or worsening of existing shortness of breath; 
• chest-pain; 
• light-headedness 
• palpitations 
• near fainting or fainting 
 
Blood tests 
Your doctor will test your blood before, during and after your treatment with Harvoni. This is so that: 
• Your doctor can decide if you should take Harvoni and for how long; 
• Your doctor can confirm that your treatment has worked and you are free of the hepatitis C 

virus. 
 
Children and adolescents 
Do not give this medicine to children under 3 years of age. The use of Harvoni in children under 3 
years of age has not yet been studied. 
 
Other medicines and Harvoni 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines.  
 
Warfarin and other similar medicines called vitamin K antagonists used to thin the blood. Your doctor 
may need to increase the frequency of your blood tests to check how well your blood can clot. 



95 

 
Your liver function may change with treatment of hepatitis C and therefore may affect other 
medications (e.g. medicines used to suppress your immune system, etc.). Your doctor may need to 
closely monitor these other medicines you are taking and make adjustments after starting Harvoni. 
 
If you are not sure about taking any other medicines, talk to your doctor or pharmacist. 
 
Some medicines should not be taken with Harvoni. 
 
• Do not take any other medicine that contains sofosbuvir, one of the active substances in 

Harvoni. 
 
• Tell your doctor or pharmacist if you are taking any of the medicines below: 

• amiodarone used to treat irregular heartbeats 
• tenofovir disoproxil fumarate or any medicine containing tenofovir disoproxil fumarate, 

used to treat HIV infection 
• digoxin used to treat heart conditions 
• dabigatran used to thin the blood 
• statins used to treat high cholesterol 
• rifapentine (antibiotic used to treat infections, including tuberculosis) 
• oxcarbazepine (a medicine used to treat epilepsy and prevent seizures) 
• tipranavir (used to treat HIV infection). 

 
Taking Harvoni with any of these may stop your medicines from working properly, or make any side 
effects worse. Your doctor may need to give you a different medicine or adjust the dose of medicine 
you are taking. 
 
• Get advice from a doctor or pharmacist if you take medicines used to treat stomach ulcers, 

heartburn or acid reflux. This includes: 
• antacids (such as aluminium/magnesium hydroxide or calcium carbonate). These should 

be taken at least 4 hours before or 4 hours after Harvoni; 
• proton pump inhibitors (such as omeprazole, lansoprazole, rabeprazole, pantoprazole and 

esomeprazole). These should be taken at the same time as Harvoni. Do not take proton 
pump inhibitors before Harvoni. Your doctor may give you a different medicine or adjust 
the dose of the medicine you are taking; 

• H2-receptor antagonists (such as famotidine, cimetidine, nizatidine or ranitidine). Your 
doctor may give you a different medicine or adjust the dose of the medicine you are 
taking. 

These medicines can decrease the amount of ledipasvir in your blood. If you are taking one of these 
medicines your doctor will either give you a different medicine for stomach ulcers, heartburn or acid 
reflux, or recommend how and when you take that medicine. 
 
Pregnancy and contraception 
The effects of Harvoni during pregnancy are not known. If you are pregnant, think you may be 
pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine. 
 
Pregnancy must be avoided if Harvoni is taken together with ribavirin. It is very important that you 
read the "Pregnancy" section in the ribavirin package leaflet very carefully. Ribavirin can be very 
damaging to an unborn baby. Therefore, special precautions in sexual activity must be taken if there is 
any chance for pregnancy to occur. 
 
• You or your partner must use an effective birth control method during treatment with Harvoni 

together with ribavirin and for some time afterwards. It is very important that you read the 
“Pregnancy” section in the ribavirin package leaflet very carefully. Ask your doctor for an 
effective contraceptive method suitable for you. 



96 

• If you or your partner become pregnant during Harvoni and ribavirin treatment or in the months 
that follow, you must contact your doctor immediately. 

 
Breast-feeding 
Do not breast-feed during treatment with Harvoni. It is not known whether ledipasvir or 
sofosbuvir, the two active substances of Harvoni, pass into human breast milk. 
 
Driving and using machines 
If you feel tired after taking Harvoni you should not take part in activities that require concentration, 
for example, do not drive, ride a bike or operate machines. 
 
Harvoni 90 mg/400 mg and 45 mg/200 mg film-coated tablets contain lactose 
• If you have been told by your doctor that you have an intolerance to some sugars, contact 

your doctor before taking this medicinal product. 
 
Harvoni 90 mg/400 mg film-coated tablets contains sunset yellow FCF (E110) which can cause 
allergic reactions  
• Tell your doctor if you are allergic to sunset yellow FCF, also called “E110” before taking 

this medicine. 
 
 
3. How to take Harvoni 
 
Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist 
if you are not sure. 
 
Recommended dose 
Harvoni is to be taken as advised by your doctor. The recommended dose of Harvoni in adults is 
one 90 mg/400 mg film-coated tablet once a day. Your doctor will tell you for how many weeks you 
should take Harvoni. 
 
The recommended dose of Harvoni in children aged 3 years and above is based on weight. Take 
Harvoni as advised by your doctor.  
 
Swallow the tablet(s) whole with or without food. Do not chew, crush or split the tablet as it has a very 
bitter taste. Tell your doctor or pharmacist if you have problems swallowing tablets. 
 
If you are taking an antacid, take it at least 4 hours before or at least 4 hours after Harvoni. 
 
If you are taking a proton pump inhibitor, take the proton pump inhibitor at the same time as 
Harvoni. Do not take it before Harvoni. 
 
If you are sick (vomit) after taking Harvoni it may affect the amount of Harvoni in your blood. This 
may make Harvoni work less well. 
• If you are sick (vomit) less than 5 hours after taking Harvoni, take another dose. 
• If you are sick (vomit) more than 5 hours after taking Harvoni, you do not need to take 

another dose until your next scheduled dose. 
 
If you take more Harvoni than you should 
If you accidentally take more than the recommended dose you should contact your doctor or nearest 
emergency department immediately for advice. Keep the tablet bottle with you so that you can easily 
describe what you have taken. 
 
If you forget to take Harvoni 
It is important not to miss a dose of this medicine. 
 
If you do miss a dose, work out how long it is since you last took your Harvoni: 



97 

• If you notice within 18 hours of the time you usually take Harvoni, you must take the dose as 
soon as possible. Then take the next dose at your usual time. 

• If it’s 18 hours or more after the time you usually take Harvoni, wait and take the next dose at 
your usual time. Do not take a double dose (two doses close together). 

 
Do not stop taking Harvoni 
Do not stop taking this medicine unless your doctor tells you to. It is very important that you complete 
the full course of treatment to give the medicine the best chance to treat your hepatitis C virus 
infection. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine may cause side effects. If you take Harvoni you may get one or more 
of the side effects below: 
 
Very common side effects 
(may affect more than 1 in 10 people) 
• headache 
• feeling tired 
 
Common side effects 
(may affect up to 1 in 10 people) 
• rash 
 
Other effects that may be seen during treatment with Harvoni 
The frequency of the following side effects is not known (frequency cannot be estimated from the 
available data). 
• swelling of the face, lips, tongue or throat (angioedema). 
 
Other effects that may be seen during treatment with sofosbuvir: 
The frequency of the following side effects is not known (frequency cannot be estimated from the 
available data). 
• a wide-spread severe rash with peeling skin which may be accompanied by fever, flu-like 

symptoms, blisters in the mouth, eyes, and/or genitals (Stevens-Johnson syndrome). 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine. 
 
 
5. How to store Harvoni 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the bottle and carton after “EXP”. 
The expiry date refers to the last day of that month. 
 
This medicine does not require any special storage conditions. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


98 

 
6. Contents of the pack and other information 
 
What Harvoni contains 
 
• The active substances are ledipasvir and sofosbuvir. Each film-coated tablet contains 90 mg 

ledipasvir and 400 mg sofosbuvir or 45 mg ledipasvir and 200 mg sofosbuvir. 
 
• The other ingredients are 

Tablet core: 
Copovidone, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, colloidal 
anhydrous silica, magnesium stearate 

 
Film-coating: 
Polyvinyl alcohol, titanium dioxide, macrogol, talc, and for the 90 mg/400 mg tablet only; 
sunset yellow FCF (E110) 

 
What Harvoni looks like and contents of the pack 
Harvoni 90 mg/400 mg film-coated tablets are orange, diamond-shaped tablets debossed with “GSI” 
on one side and “7985” on the other side. The tablet is approximately 19 mm long and 10 mm wide. 
 
Harvoni 45 mg/200 mg film-coated tablets are white, capsule-shaped, debossed with “GSI” on one 
side and “HRV” on the other side. The tablet is approximately 14 mm long and 7 mm wide. 
 
Each bottle contains a silica gel desiccant (drying agent) that must be kept in the bottle to help protect 
your tablets. The silica gel desiccant is contained in a separate sachet or canister and should not be 
swallowed. 
The following pack sizes are available: 
• outer cartons containing 1 bottle of 28 film-coated tablets for the 90 mg/400 mg and the 

45 mg/ 200 mg film-coated tablets. 
• outer cartons containing 3 bottles of 28 (84) film-coated tablets for the 90 mg/400 mg 

film-coated tablets only. Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder 
Gilead Sciences Ireland UC 
Carrigtohill 
County Cork, T45 DP77 
Ireland 
 
Manufacturer 
Gilead Sciences Ireland UC 
IDA Business & Technology Park 
Carrigtohill 
County Cork 
Ireland 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
Gilead Sciences Belgium SPRL-BVBA 
Tél/Tel: + 32 (0) 24 01 35 50 
 

Lietuva 
Gilead Sciences Poland Sp. z o.o. 
Tel: + 48 22 262 8702 
 

България 
Gilead Sciences Ireland UC 
Тел.: + 353 (0) 1 686 1888 
 

Luxembourg/Luxemburg 
Gilead Sciences Belgium SPRL-BVBA 
Tél/Tel: + 32 (0) 24 01 35 50 
 



99 

Česká republika 
Gilead Sciences s.r.o. 
Tel: + 420 910 871 986 
 

Magyarország 
Gilead Sciences Ireland UC 
Tel: + 353 (0) 1 686 1888 
 

Danmark 
Gilead Sciences Sweden AB 
Tlf: + 46 (0) 8 5057 1849 
 

Malta 
Gilead Sciences Ireland UC 
Tel: + 353 (0) 1 686 1888 
 

Deutschland 
Gilead Sciences GmbH 
Tel: + 49 (0) 89 899890-0 
 

Nederland 
Gilead Sciences Netherlands B.V. 
Tel: + 31 (0) 20 718 36 98 
 

Eesti 
Gilead Sciences Poland Sp. z o.o. 
Tel: + 48 22 262 8702 
 

Norge 
Gilead Sciences Sweden AB 
Tlf: + 46 (0) 8 5057 1849 
 

Ελλάδα 
Gilead Sciences Ελλάς Μ.ΕΠΕ. 
Τηλ: + 30 210 8930 100 
 

Österreich 
Gilead Sciences GesmbH 
Tel: + 43 1 260 830 
 

España 
Gilead Sciences, S.L. 
Tel: + 34 91 378 98 30 
 

Polska 
Gilead Sciences Poland Sp. z o.o. 
Tel: + 48 22 262 8702 
 

France 
Gilead Sciences 
Tél: + 33 (0) 1 46 09 41 00 
 

Portugal 
Gilead Sciences, Lda. 
Tel: + 351 21 7928790 
 

Hrvatska 
Gilead Sciences Ireland UC 
Tel: + 353 (0) 1 686 1888 
 

România 
Gilead Sciences Ireland UC 
Tel: + 353 (0) 1 686 1888 
 

Ireland 
Gilead Sciences Ireland UC 
Tel: + 353 (0) 214 825 999 
 

Slovenija 
Gilead Sciences Ireland UC 
Tel: + 353 (0) 1 686 1888 
 

Ísland 
Gilead Sciences Sweden AB 
Sími: + 46 (0) 8 5057 1849 
 

Slovenská republika 
Gilead Sciences Slovakia s.r.o. 
Tel: + 421 232 121 210 
 

Italia 
Gilead Sciences S.r.l. 
Tel: + 39 02 439201 
 

Suomi/Finland 
Gilead Sciences Sweden AB 
Puh/Tel: + 46 (0) 8 5057 1849 
 

Κύπρος 
Gilead Sciences Ελλάς Μ.ΕΠΕ. 
Τηλ: + 30 210 8930 100 
 

Sverige 
Gilead Sciences Sweden AB 
Tel: + 46 (0) 8 5057 1849 
 

Latvija 
Gilead Sciences Poland Sp. z o.o. 
Tel: + 48 22 262 8702 
 

United Kingdom 
Gilead Sciences Ltd. 
Tel: + 44 (0) 8000 113700 
 

 
This leaflet was last revised in  
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu

http://www.ema.europa.eu/


100 

 
Package leaflet: Information for the user 

 
Harvoni 33.75 mg/150 mg coated granules in sachet 

Harvoni 45 mg/200 mg coated granules in sachet 
ledipasvir/sofosbuvir 

 
This medicine is subject to additional monitoring. This will allow quick identification of new 

safety information. You can help by reporting any side effects you may get. See the end of section 4 
for how to report side effects. 
 
Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor or pharmacist. 
- This medicine has been prescribed for you only. Do not pass it on to others.  It may harm them, 

even if their signs of illness are the same as yours. 
- If you get any side effects talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
1. What Harvoni is and what it is used for 
2. What you need to know before you take Harvoni 
3. How to take Harvoni 
4. Possible side effects 
5. How to store Harvoni 
6. Contents of the pack and other information 
 
If Harvoni has been prescribed for your child, please note that all the information in this leaflet 
is applicable to your child (in this case please read “your child” instead of “you”). 
 
 
1. What Harvoni is and what it is used for 
 
Harvoni granules are a medicine that contain the active substances ledipasvir and sofosbuvir which are 
given in a granule formulation. Harvoni is given to treat chronic (long-term) hepatitis C virus infection 
in adults and children 3 years of age and older. 
 
Hepatitis C is a virus that infects the liver. The active substances in the medicine work together by 
blocking two different proteins that the virus needs to grow and reproduce itself, allowing the infection 
to be permanently eliminated from the body. 
 
Harvoni is sometimes taken with another medicine, ribavirin. 
 
It is very important that you also read the leaflets for the other medicines that you will be taking with 
Harvoni. If you have any questions about your medicines, please ask your doctor or pharmacist. 
 
 
2. What you need to know before you take Harvoni 
 
Do not take Harvoni 
• If you are allergic to ledipasvir, sofosbuvir or any of the other ingredients of this medicine 

(listed in section 6 of this leaflet). 
 

 



101 

• If you are currently taking any of the following medicines: 
• rifampicin and rifabutin (antibiotics used to treat infections, including tuberculosis); 
• St. John’s wort (herbal medicine used to treat depression); 
• carbamazepine, phenobarbital and phenytoin (medicines used to treat epilepsy and prevent 

seizures); 
• rosuvastatin (a medicine used to treat high cholesterol). 
 

 If any of these conditions apply to you, do not take Harvoni and tell your doctor immediately. 
 

Warnings and precautions 
Your doctor will know if any of the following conditions apply to you.  These will be considered 
before treatment with Harvoni is started. 
• other liver problems apart from hepatitis C, for instance 

• if you are awaiting a liver transplant; 
• if you have a current or previous infection with the hepatitis B virus, since your doctor 

may want to monitor you more closely; 
• kidney problems or if you are on kidney dialysis, since Harvoni has not been fully tested in 

patients with severe kidney problems; 
• ongoing treatment for HIV infection, since your doctor may want to monitor you more 

closely. 
 
Talk to your doctor or pharmacist before taking Harvoni if: 
• you currently take, or have taken in the last few months, the medicine amiodarone to treat 

irregular heartbeats, as it may result in a life-threatening slowing of your heart beat. Your doctor 
may consider different treatments if you have taken this medicine. If treatment with Harvoni is 
needed, you may require additional heart monitoring. 

• you have diabetes. You may need closer monitoring of your blood glucose levels and/or 
adjustment of your diabetes medication after starting Harvoni. Some diabetic patients have 
experienced low sugar levels in the blood (hypoglycaemia) after starting treatment with medicines 
like Harvoni. 

 
Tell your doctor immediately if you currently take, or have taken in the last months, any medicines 
for heart problems and during treatment you experience: 
• slow or irregular heartbeat, or heart rhythm problems; 
• shortness of breath or worsening of existing shortness of breath; 
• chest-pain; 
• light-headedness 
• palpitations 
• near fainting or fainting 
 
Blood tests 
Your doctor will test your blood before, during and after your treatment with Harvoni. This is so that: 
• Your doctor can decide if you should take Harvoni and for how long 
• Your doctor can confirm that your treatment has worked and you are free of the hepatitis C 

virus. 
 
Children and adolescents 
Do not give this medicine to children under 3 years of age. The use of Harvoni in children under 3 
years of age has not yet been studied. 
 
Other medicines and Harvoni 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines.   
 
Warfarin and other similar medicines called vitamin K antagonists used to thin the blood. Your doctor 
may need to increase the frequency of your blood tests to check how well your blood can clot. 



102 

 
Your liver function may change with treatment of hepatitis C and therefore may affect other 
medications (e.g. medicines used to suppress your immune system, etc.). Your doctor may need to 
closely monitor these other medicines you are taking and make adjustments after starting Harvoni. 
 
If you are not sure about taking any other medicines, talk to your doctor or pharmacist. 
 
Some medicines should not be taken with Harvoni. 
 
• Do not take any other medicine that contains sofosbuvir, one of the active substances in 

Harvoni. 
 
• Tell your doctor or pharmacist if you are taking any of the medicines below: 

• amiodarone used to treat irregular heartbeats 
• tenofovir disoproxil fumarate or any medicine containing tenofovir disoproxil fumarate, 
used to treat HIV infection 
• digoxin used to treat heart conditions 
• dabigatran used to thin the blood 
• statins used to treat high cholesterol 
• rifapentine (antibiotic used to treat infections, including tuberculosis) 
• oxcarbazepine (a medicine used to treat epilepsy and prevent seizures) 
• tipranavir (used to treat HIV infection). 
 

Taking Harvoni with any of these may stop your medicines from working properly, or make any side 
effects worse. Your doctor may need to give you a different medicine or adjust the dose of medicine 
you are taking. 
 
• Get advice from a doctor or pharmacist if you take medicines used to treat stomach ulcers, 

heartburn or acid reflux. This includes: 
• antacids (such as aluminium/magnesium hydroxide or calcium carbonate). These should be 

taken at least 4 hours before or 4 hours after Harvoni; 
• proton pump inhibitors (such as omeprazole, lansoprazole, rabeprazole, pantoprazole and 

esomeprazole). These should be taken at the same time as Harvoni. Do not take proton 
pump inhibitors before Harvoni. Your doctor may give you a different medicine or adjust 
the dose of the medicine you are taking; 

• H2-receptor antagonists (such as famotidine, cimetidine, nizatidine or ranitidine). Your doctor 
may give you a different medicine or adjust the dose of the medicine you are taking. 

These medicines can decrease the amount of ledipasvir in your blood.  If you are taking one of these 
medicines your doctor will either give you a different medicine for stomach ulcers, heartburn or acid 
reflux, or recommend how and when you take that medicine. 
 
Pregnancy and contraception 
The effects of Harvoni during pregnancy are not known. If you are pregnant, think you may be 
pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine. 
 
Pregnancy must be avoided if Harvoni is taken together with ribavirin. It is very important that you 
read the "Pregnancy" section in the ribavirin package leaflet very carefully. Ribavirin can be very 
damaging to an unborn baby. Therefore, special precautions in sexual activity must be taken if there is 
any chance for pregnancy to occur. 
 



103 

• You or your partner must use an effective birth control method during treatment with Harvoni 
together with ribavirin and for some time afterwards. It is very important that you read the 
“Pregnancy” section in the ribavirin package leaflet very carefully. Ask your doctor for an 
effective contraceptive method suitable for you. 

• If you or your partner become pregnant during Harvoni and ribavirin treatment or in the months 
that follow, you must contact your doctor immediately. 

 
Breast-feeding 
Do not breast-feed during treatment with Harvoni. It is not known whether ledipasvir or 
sofosbuvir, the two active substances of Harvoni, pass into human breast milk. 
 
Driving and using machines 
If you feel tired after taking Harvoni you should not take part in activities that require concentration, 
for example, do not drive, ride a bike or operate machines. 
 
Harvoni granules contain lactose 

• If you have been told by your doctor that you have an intolerance to some sugars, 
contact your doctor before taking this medicinal product. 

 
 
3. How to take Harvoni 
 
Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist 
if you are not sure. 
 
Recommended dose 
Harvoni is to be taken as advised by your doctor. Your doctor will tell you for how long you should 
take Harvoni and how many sachets you should take. 
 
The recommended dose is the entire contents of the sachet(s), taken once daily with or without 
food.  
 
Giving Harvoni granules with food to aid swallowing: 
1. Hold sachet with cut line on top 
2. Shake sachet gently to settle contents 
3. Tear sachet open along cut line, or use scissors to cut across line 
4. Carefully pour entire contents of sachet onto one or more spoonfuls of non-acidic soft food such as 
chocolate syrup, mashed potato, or ice-cream at or below room temperature 
5. Make sure no granules remain in the sachet 
6. Take all the granules within 30 minutes of gently mixing with food 
7. Swallow combination of food and granules without chewing to avoid a bitter taste. Make sure that 
all the food is eaten.  
 
Giving Harvoni granules without food or water or with water to aid swallowing: 
1. Hold sachet with cut line on top 
2. Shake sachet gently to settle contents 
3. Tear sachet open along cut line, or use scissors to cut across line 
4. The granules can be taken directly in the mouth and swallowed without chewing to avoid a bitter 
taste or with non-acidic liquids such as water. Do not use fruit juices, for example apple, cranberry, 
grape, orange, pineapple as these are acidic and should not be used 
5. Make sure no granules remain in the sachet 
6. Swallow all the granules. 
 
If you are taking an antacid, take it at least 4 hours before or at least 4 hours after Harvoni. 
 
If you are taking a proton pump inhibitor, take the proton pump inhibitor at the same time as 
Harvoni. Do not take it before Harvoni. 



104 

 
If you are sick (vomit) after taking Harvoni it may affect the amount of Harvoni in your blood.  
This may make Harvoni work less well. 
• If you are sick (vomit) less than 5 hours after taking Harvoni, take another dose. 
• If you are sick (vomit) more than 5 hours after taking Harvoni, you do not need to take 

another dose until your next scheduled dose. 
 
If you take more Harvoni than you should 
If you accidentally take more than the recommended dose you should contact your doctor or nearest 
emergency department immediately for advice. Keep the sachet and carton with you so that you can 
easily describe what you have taken. 
 
If you forget to take Harvoni 
It is important not to miss a dose of this medicine. 
 
If you do miss a dose, work out how long it is since you last took your Harvoni: 
• If you notice within 18 hours of the time you usually take Harvoni, you must take the dose as 

soon as possible. Then take the next dose at your usual time. 
• If it’s 18 hours or more after the time you usually take Harvoni, wait and take the next dose at 

your usual time. Do not take a double dose (two doses close together). 
 
Do not stop taking Harvoni 
Do not stop taking this medicine unless your doctor tells you to. It is very important that you complete 
the full course of treatment to give the medicine the best chance to treat your hepatitis C virus 
infection. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine may cause side effects. If you take Harvoni you may get one or more 
of the side effects below: 
 
Very common side effects 
(may affect more than 1 in 10 people) 
• headache 
• feeling tired 
 
Common side effects 
(may affect up to 1 in 10 people) 
• rash 
 
Other effects that may be seen during treatment with Harvoni 
The frequency of the following side effects is not known (frequency cannot be estimated from the 
available data). 
• swelling of the face, lips, tongue or throat (angioedema). 
 
Other effects that may be seen during treatment with sofosbuvir: 
The frequency of the following side effects is not known (frequency cannot be estimated from the 
available data). 
• a wide-spread severe rash with peeling skin which may be accompanied by fever, flu-like 

symptoms, blisters in the mouth, eyes, and/or genitals (Stevens-Johnson syndrome). 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 



105 

listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine. 
 
 
5. How to store Harvoni 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the bottle and carton after “EXP”. 
The expiry date refers to the last day of that month. 
 
This medicine does not require any special storage conditions. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Harvoni contains 
 
The active substances are ledipasvir and sofosbuvir. 
• Harvoni 33.75 mg/150 mg coated granules in sachet contains 33.75 mg ledipasvir and 150 mg 

sofosbuvir. 
• Harvoni 45 mg/200 mg coated granules in sachet contains 45 mg ledipasvir and 200 mg 

sofosbuvir. 
• The other ingredients are copovidone, lactose monohydrate, microcrystalline cellulose, 

croscarmellose sodium, colloidal anhydrous silica, magnesium stearate, hypromellose, talc, 
titanium dioxide, macrogol, iron oxide yellow, iron oxide red, amino-methacrylate copolymer 

 
What Harvoni looks like and contents of the pack 
The granules are orange and contained in a sachet. 
 
The following pack sizes is available: 
• outer carton containing 28  sachets 
 
Marketing Authorisation Holder 
Gilead Sciences Ireland UC 
Carrigtohill 
County Cork, T45 DP77 
Ireland 
 
Manufacturer 
Gilead Sciences Ireland UC 
IDA Business & Technology Park 
Carrigtohill 
County Cork 
Ireland 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
Gilead Sciences Belgium SPRL-BVBA 
Tél/Tel: + 32 (0) 24 01 35 50 
 

Lietuva 
Gilead Sciences Poland Sp. z o.o. 
Tel: + 48 22 262 8702 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


106 

България 
Gilead Sciences Ireland UC 
Тел.: + 353 (0) 1 686 1888 
 

Luxembourg/Luxemburg 
Gilead Sciences Belgium SPRL-BVBA 
Tél/Tel: + 32 (0) 24 01 35 50 
 

Česká republika 
Gilead Sciences s.r.o. 
Tel: + 420 910 871 986 
 

Magyarország 
Gilead Sciences Ireland UC 
Tel: + 353 (0) 1 686 1888 
 

Danmark 
Gilead Sciences Sweden AB 
Tlf: + 46 (0) 8 5057 1849 
 

Malta 
Gilead Sciences Ireland UC 
Tel: + 353 (0) 1 686 1888 
 

Deutschland 
Gilead Sciences GmbH 
Tel: + 49 (0) 89 899890-0 
 

Nederland 
Gilead Sciences Netherlands B.V. 
Tel: + 31 (0) 20 718 36 98 
 

Eesti 
Gilead Sciences Poland Sp. z o.o. 
Tel: + 48 22 262 8702 
 

Norge 
Gilead Sciences Sweden AB 
Tlf: + 46 (0) 8 5057 1849 
 

Ελλάδα 
Gilead Sciences Ελλάς Μ.ΕΠΕ. 
Τηλ: + 30 210 8930 100 
 

Österreich 
Gilead Sciences GesmbH 
Tel: + 43 1 260 830 
 

España 
Gilead Sciences, S.L. 
Tel: + 34 91 378 98 30 
 

Polska 
Gilead Sciences Poland Sp. z o.o. 
Tel: + 48 22 262 8702 
 

France 
Gilead Sciences 
Tél: + 33 (0) 1 46 09 41 00 
 

Portugal 
Gilead Sciences, Lda. 
Tel: + 351 21 7928790 
 

Hrvatska 
Gilead Sciences Ireland UC 
Tel: + 353 (0) 1 686 1888 
 

România 
Gilead Sciences Ireland UC 
Tel: + 353 (0) 1 686 1888 
 

Ireland 
Gilead Sciences Ireland UC 
Tel: + 353 (0) 214 825 999 
 

Slovenija 
Gilead Sciences Ireland UC 
Tel: + 353 (0) 1 686 1888 
 

Ísland 
Gilead Sciences Sweden AB 
Sími: + 46 (0) 8 5057 1849 
 

Slovenská republika 
Gilead Sciences Slovakia s.r.o. 
Tel: + 421 232 121 210 
 

Italia 
Gilead Sciences S.r.l. 
Tel: + 39 02 439201 
 

Suomi/Finland 
Gilead Sciences Sweden AB 
Puh/Tel: + 46 (0) 8 5057 1849 
 

Κύπρος 
Gilead Sciences Ελλάς Μ.ΕΠΕ. 
Τηλ: + 30 210 8930 100 
 

Sverige 
Gilead Sciences Sweden AB 
Tel: + 46 (0) 8 5057 1849 
 

Latvija 
Gilead Sciences Poland Sp. z o.o. 
Tel: + 48 22 262 8702 
 

United Kingdom 
Gilead Sciences Ltd. 
Tel: + 44 (0) 8000 113700 
 

 



107 

This leaflet was last revised in  
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu 
 

http://www.ema.europa.eu/

	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET
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{'Title': '2. what you need to know before you take harvoni', 'Section_Content': 'do not take harvoni if you are allergic to ledipasvir, sofosbuvir or any of the other ingredients of this medicine (listed in section 6 of this leaflet). if you are currently taking any of the following medicines: rifampicin and rifabutin (antibiotics used to treat infections, including tuberculosis); st. john\'s wort (herbal medicine used to treat depression); carbamazepine, phenobarbital and phenytoin (medicines used to treat epilepsy and prevent seizures); rosuvastatin (a medicine used to treat high cholesterol). if any of these conditions apply to you, do not take harvoni and tell your doctor immediately. warnings and precautions your doctor will know if any of the following conditions apply to you. these will be considered before treatment with harvoni is started. other liver problems apart from hepatitis c, for instance if you are awaiting a liver transplant; if you have a current or previous infection with the hepatitis b virus, since your doctor may want to monitor you more closely; kidney problems or if you are on kidney dialysis, since harvoni has not been fully tested in patients with severe kidney problems; ongoing treatment for hiv infection, since your doctor may want to monitor you more closely. talk to your doctor or pharmacist before taking harvoni if: you currently take, or have taken in the last few months, the medicine amiodarone to treat irregular heartbeats, as it may result in a life-threatening slowing of your heart beat. your doctor may consider different treatments if you have taken this medicine. if treatment with harvoni is needed, you may require additional heart monitoring. you have diabetes. you may need closer monitoring of your blood glucose levels and/or adjustment of your diabetes medication after starting harvoni. some diabetic patients have experienced low sugar levels in the blood (hypoglycaemia) after starting treatment with medicines like harvoni. tell your doctor immediately if you currently take, or have taken in the last months, any medicines for heart problems and during treatment you experience: slow or irregular heartbeat, or heart rhythm problems; shortness of breath or worsening of existing shortness of breath; chest-pain; light-headedness palpitations near fainting or fainting blood tests your doctor will test your blood before, during and after your treatment with harvoni. this is so that: your doctor can decide if you should take harvoni and for how long; your doctor can confirm that your treatment has worked and you are free of the hepatitis c virus. children and adolescents do not give this medicine to children under 3 years of age. the use of harvoni in children under 3 years of age has not yet been studied. other medicines and harvoni tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. warfarin and other similar medicines called vitamin k antagonists used to thin the blood. your doctor may need to increase the frequency of your blood tests to check how well your blood can clot. your liver function may change with treatment of hepatitis c and therefore may affect other medications (e.g. medicines used to suppress your immune system, etc.). your doctor may need to closely monitor these other medicines you are taking and make adjustments after starting harvoni. if you are not sure about taking any other medicines, talk to your doctor or pharmacist. some medicines should not be taken with harvoni. do not take any other medicine that contains sofosbuvir, one of the active substances in harvoni. tell your doctor or pharmacist if you are taking any of the medicines below: amiodarone used to treat irregular heartbeats tenofovir disoproxil fumarate or any medicine containing tenofovir disoproxil fumarate, used to treat hiv infection digoxin used to treat heart conditions dabigatran used to thin the blood statins used to treat high cholesterol rifapentine (antibiotic used to treat infections, including tuberculosis) oxcarbazepine (a medicine used to treat epilepsy and prevent seizures) tipranavir (used to treat hiv infection). taking harvoni with any of these may stop your medicines from working properly, or make any side effects worse. your doctor may need to give you a different medicine or adjust the dose of medicine you are taking. get advice from a doctor or pharmacist if you take medicines used to treat stomach ulcers, heartburn or acid reflux. this includes: antacids (such as aluminium/magnesium hydroxide or calcium carbonate). these should be taken at least 4 hours before or 4 hours after harvoni; proton pump inhibitors (such as omeprazole, lansoprazole, rabeprazole, pantoprazole and esomeprazole). these should be taken at the same time as harvoni. do not take proton pump inhibitors before harvoni. your doctor may give you a different medicine or adjust the dose of the medicine you are taking; h2-receptor antagonists (such as famotidine, cimetidine, nizatidine or ranitidine). your doctor may give you a different medicine or adjust the dose of the medicine you are taking. these medicines can decrease the amount of ledipasvir in your blood. if you are taking one of these medicines your doctor will either give you a different medicine for stomach ulcers, heartburn or acid reflux, or recommend how and when you take that medicine. pregnancy and contraception the effects of harvoni during pregnancy are not known. if you are pregnant, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine. pregnancy must be avoided if harvoni is taken together with ribavirin. it is very important that you read the "pregnancy" section in the ribavirin package leaflet very carefully. ribavirin can be very damaging to an unborn baby. therefore, special precautions in sexual activity must be taken if there is any chance for pregnancy to occur. you or your 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{'Title': '3. how to take harvoni', 'Section_Content': "always take this medicine exactly as your doctor has told you. check with your doctor or pharmacist if you are not sure. recommended dose harvoni is to be taken as advised by your doctor. the recommended dose of harvoni in adults is one 90 mg/400 mg film-coated tablet once a day. your doctor will tell you for how many weeks you should take harvoni. the recommended dose of harvoni in children aged 3 years and above is based on weight. take harvoni as advised by your doctor. swallow the tablet(s) whole with or without food. do not chew, crush or split the tablet as it has a very bitter taste. tell your doctor or pharmacist if you have problems swallowing tablets. if you are taking an antacid, take it at least 4 hours before or at least 4 hours after harvoni. if you are taking a proton pump inhibitor, take the proton pump inhibitor at the same time as harvoni. do not take it before harvoni. if you are sick (vomit) after taking harvoni it may affect the amount of harvoni in your blood. this may make harvoni work less well. if you are sick (vomit) less than 5 hours after taking harvoni, take another dose. if you are sick (vomit) more than 5 hours after taking harvoni, you do not need to take another dose until your next scheduled dose. if you take more harvoni than you should if you accidentally take more than the recommended dose you should contact your doctor or nearest emergency department immediately for advice. keep the tablet bottle with you so that you can easily describe what you have taken. if you forget to take harvoni it is important not to miss a dose of this medicine. if you do miss a dose, work out how long it is since you last took your harvoni: 97 if you notice within 18 hours of the time you usually take harvoni, you must take the dose as soon as possible. then take the next dose at your usual time. if it's 18 hours or more after the time you usually take harvoni, wait and take the next dose at your usual time. do not take a double dose (two doses close together). do not stop taking harvoni do not stop taking this medicine unless your doctor tells you to. it is very important that you complete the full course of treatment to give the medicine the best chance to treat your hepatitis c virus infection. if you have any further questions on the use of this medicine, ask your doctor or pharmacist.", 'Entity_Recognition': [{'Text': 'harvoni', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 12, 'EndOffset': 25}, {'Text': 'dose harvoni', 'Type': 'TREATMENT', 'BeginOffset': 133, 'EndOffset': 145}, {'Text': 'harvoni in adults', 'Type': 'TREATMENT', 'BeginOffset': 212, 'EndOffset': 229}, {'Text': '90', 'Type': 'NUMBER', 'BeginOffset': 237, 'EndOffset': 239}, {'Id': 6, 'BeginOffset': 342, 'EndOffset': 349, 'Score': 0.6944428086280823, 'Text': 'harvoni', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': 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{'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine may cause side effects. if you take harvoni you may get one or more of the side effects below: very common side effects (may affect more than 1 in 10 people) headache feeling tired common side effects (may affect up to 1 in 10 people) rash other effects that may be seen during treatment with harvoni the frequency of the following side effects is not known (frequency cannot be estimated from the available data). swelling of the face, lips, tongue or throat (angioedema). other effects that may be seen during treatment with sofosbuvir: the frequency of the following side effects is not known (frequency cannot be estimated from the available data). a wide-spread severe rash with peeling skin which may be accompanied by fever, flu-like symptoms, blisters in the mouth, eyes, and/or genitals (stevens-johnson syndrome). reporting of side effects if you get any side effects, talk to your doctor or pharmacist. this includes any possible side effects not listed in this leaflet. you can also report side effects directly via the national reporting system listed in appendix v. by reporting side effects you can help provide more information on the safety of this medicine.', 'Entity_Recognition': [{'Text': 'harvoni', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'all medicines', 'Type': 'TREATMENT', 'BeginOffset': 5, 'EndOffset': 18}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 20, 'EndOffset': 33}, {'Id': 12, 'BeginOffset': 44, 'EndOffset': 56, 'Score': 0.9578280448913574, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6320724487304688}]}, {'Id': 9, 'BeginOffset': 70, 'EndOffset': 77, 'Score': 0.7235056161880493, 'Text': 'harvoni', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Id': 13, 'BeginOffset': 109, 'EndOffset': 121, 'Score': 0.8643175363540649, 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{'Title': '5. how to store harvoni', 'Section_Content': None, 'Entity_Recognition': None}
{'Title': '6. contents of the pack and other information if harvoni has been prescribed for your child, please note that all the information in this leaflet is applicable to your child (in this case please read “your child” instead of “you”).', 'Section_Content': 'what harvoni contains the active substances are ledipasvir and sofosbuvir. each film-coated tablet contains 90 mg ledipasvir and 400 mg sofosbuvir or 45 mg ledipasvir and 200 mg sofosbuvir. the other ingredients are tablet core: copovidone, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, colloidal anhydrous silica, magnesium stearate film-coating: polyvinyl alcohol, titanium dioxide, macrogol, talc, and for the 90 mg/400 mg tablet only; sunset yellow fcf (e110) what harvoni looks like and contents of the pack harvoni 90 mg/400 mg film-coated tablets are orange, diamond-shaped tablets debossed with "gsi" on one side and "7985" on the other side. the tablet is approximately 19 mm long and 10 mm wide. harvoni 45 mg/200 mg film-coated tablets are white, capsule-shaped, debossed with "gsi" on one side and "hrv" on the other side. the tablet is approximately 14 mm long and 7 mm wide. each bottle contains a silica gel desiccant (drying agent) that must be kept in the bottle to help protect your tablets. the silica gel desiccant is contained in a separate sachet or canister and should not be swallowed. the following pack sizes are available: outer cartons containing 1 bottle of 28 film-coated tablets for the 90 mg/400 mg and the 45 mg/ 200 mg film-coated tablets. outer cartons containing 3 bottles of 28 (84) film-coated tablets for the 90 mg/400 mg film-coated tablets only. not all pack sizes may be marketed.', 'Entity_Recognition': [{'Text': 'harvoni', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 0, 'BeginOffset': 5, 'EndOffset': 12, 'Score': 0.5299569964408875, 'Text': 'harvoni', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Id': 1, 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