Kaftrio
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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 
 
Kaftrio 75 mg/50 mg/100 mg film-coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each film-coated tablet contains 75 mg of ivacaftor, 50 mg of tezacaftor and 100 mg of elexacaftor. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet (tablet) 
 
Orange, capsule-shaped tablet debossed with “T100” on one side and plain on the other (dimensions 
7.9 mm x 15.5 mm). 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Kaftrio is indicated in a combination regimen with ivacaftor 150 mg tablets for the treatment of cystic 
fibrosis (CF) in patients aged 12 years and older who are homozygous for the F508del mutation in the 
cystic fibrosis transmembrane conductance regulator (CFTR) gene or heterozygous for F508del in the 
CFTR gene with a minimal function (MF) mutation (see section 5.1). 
 
4.2 Posology and method of administration 
 
Kaftrio should only be prescribed by healthcare professionals with experience in the treatment of CF. 
If the patient’s genotype is unknown, an accurate and validated genotyping method should be 
performed to confirm the presence of two F508del mutations or the presence of one F508del mutation 
and a minimal function mutation using a genotyping assay (see section 5.1). 
 
Posology 
 
The recommended dose is two tablets (each containing 
ivacaftor 75 mg/tezacaftor 50 mg/elexacaftor 100 mg) taken in the morning, and one ivacaftor 150 mg 
tablet taken in the evening, approximately 12 hours apart (see Method of administration). 
 
Missed dose 
If 6 hours or less have passed since the missed morning or evening dose, the patient should take the 
missed dose as soon as possible and continue on the original schedule.  
If more than 6 hours have passed since: 
• the missed morning dose, the patient should take the missed dose as soon as possible and should 

not take the evening dose. The next scheduled morning dose should be taken at the usual time. 
• the missed evening dose, the patient should not take the missed dose. The next scheduled 

morning dose should be taken at the usual time.  
Morning and evening doses should not be taken at the same time. 
 



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Concomitant use of CYP3A inhibitors 
When co-administered with moderate CYP3A inhibitors (e.g., fluconazole, erythromycin, verapamil) 
or strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, posaconazole, voriconazole, 
telithromycin, and clarithromycin), the dose should be reduced as in Table 1 (see sections 4.4 and 4.5). 
 

Table 1: Dosing schedule for concomitant use with moderate and strong CYP3A inhibitors 
Moderate CYP3A Inhibitors 

 Day 1 Day 2 Day 3 Day 4* 
Morning 
Dose 

Two 
ivacaftor/tezacaftor/elexacaftor 
tablets 

One 
ivacaftor 
tablet 

Two 
ivacaftor/tezacaftor/elexacaftor 
tablets 

One 
ivacaftor 
tablet 

Evening 
Dose^ No dose 

* Continue dosing with two ivacaftor/tezacaftor/elexacaftor tablets and one ivacaftor tablet on alternate days. 
^ The evening dose of ivacaftor tablet should not be taken. 
 

Strong CYP3A Inhibitors 
 Day 1 Day 2 Day 3 Day 4# 
Morning 
Dose 

Two 
ivacaftor/tezacaftor/elexacaftor 
tablets 

No dose No dose 
Two 
ivacaftor/tezacaftor/elexacaftor 
tablets 

Evening 
Dose^ No dose 
# Continue dosing with two ivacaftor/tezacaftor/elexacaftor tablets twice a week, approximately 3 to 4 days 
apart. 
^ The evening dose of ivacaftor tablet should not be taken. 

 
Special populations  
 
Elderly population 
No dose adjustment is recommended for the elderly patient population (see sections 4.4 and 5.2). 
 
Hepatic impairment 
Treatment of patients with moderate hepatic impairment (Child-Pugh Class B) is not recommended. 
For patients with moderate hepatic impairment, the use of Kaftrio should only be considered when 
there is a clear medical need and the benefits are expected to outweigh the risks. If used, it should be 
used with caution at a reduced dose (see Table 2). 
 
Studies have not been conducted in patients with severe hepatic impairment (Child-Pugh Class C), but 
the exposure is expected to be higher than in patients with moderate hepatic impairment. Patients with 
severe hepatic impairment should not be treated with Kaftrio. 
 
No dose adjustment is recommended for patients with mild (Child-Pugh Class A) hepatic impairment 
(see Table 2) (see sections 4.4 and 5.2).  
 

Table 2: Recommendation for use in patients with hepatic impairment 
 Mild (Child-Pugh Class A) Moderate (Child-Pugh Class B)* Severe (Child-Pugh Class C) 

Morning  

No dose adjustment 
(Two 

ivacaftor/tezacaftor/elexacaftor 
tablets) 

Use not recommended* 
If used: alternate each day between two 

ivacaftor/tezacaftor/elexacaftor tablets and 
one ivacaftor/tezacaftor/elexacaftor tablet 

Should not be used 

Evening  No dose adjustment (One ivacaftor tablet) No ivacaftor tablet Should not be used 

* For patients with moderate hepatic impairment, use of Kaftrio should only be considered when there is a clear 
medical need and the benefits are expected to outweigh the risks. 

 



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Renal impairment 
No dose adjustment is recommended for patients with mild and moderate renal impairment. There is 
no experience in patients with severe renal impairment or end-stage renal disease (see sections 4.4 
and 5.2). 
 
Paediatric population 
The safety and efficacy of Kaftrio in combination with ivacaftor in children aged less than 12 years 
have not yet been established.  
No data are available (see section 5.1). 
 
Method of administration  
 
For oral use. Patients should be instructed to swallow the tablets whole. The tablets should not be 
chewed, crushed, or broken before swallowing because there are no clinical data currently available to 
support other methods of administration; chewing or crushing the tablet is not recommended. 
 
Kaftrio tablets should be taken with fat-containing food. Examples of meals or snacks that contain fat 
are those prepared with butter or oils or those containing eggs, cheeses, nuts, whole milk, or meats 
(see section 5.2). 
 
Food or drink containing grapefruit should be avoided during treatment with Kaftrio (see section 4.5). 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1. 
 
4.4 Special warnings and precautions for use 
 
Effect on liver function tests 
 
Elevated transaminases are common in patients with CF and have been observed in some patients 
treated with Ivacaftor/Tezacaftor/Elexacaftor (IVA/TEZ/ELX) in combination with ivacaftor. 
Assessments of transaminases (ALT and AST) are recommended for all patients prior to initiating 
treatment, every 3 months during the first year of treatment, and annually thereafter. For patients with 
a history of transaminase elevations, more frequent monitoring should be considered. In the event of 
ALT or AST >5 x the upper limit of normal (ULN), or ALT or AST >3 x ULN with bilirubin 
>2 x ULN, dosing should be interrupted, and laboratory tests closely followed until the abnormalities 
resolve. Following the resolution of transaminase elevations, the benefits and risks of resuming 
treatment should be considered (see section 4.8). 
 
Hepatic impairment  
 
Treatment of patients with moderate hepatic impairment is not recommended. For patients with 
moderate hepatic impairment, the use of IVA/TEZ/ELX should only be considered when there is a 
clear medical need and the benefits are expected to outweigh the risks. If used, it should be used with 
caution at a reduced dose (see Table 2). 
Patients with severe hepatic impairment should not be treated with IVA/TEZ/ELX (see 
sections 4.2 and 5.2). 
 
Renal impairment  
 
There is no experience in patients with severe renal impairment/end-stage renal disease therefore 
caution is recommended in this population (see section 5.2). 
 



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Patients after organ transplantation  
 
IVA/TEZ/ELX in combination with ivacaftor has not been studied in patients with CF who have 
undergone organ transplantation. Therefore, use in transplanted patients is not recommended. See 
section 4.5 for interactions with commonly used immunosuppressants. 
 
Rash events  
 
The incidence of rash events was higher in females than in males, particularly in females taking 
hormonal contraceptives. A role for hormonal contraceptives in the occurrence of rash cannot be 
excluded. For patients taking hormonal contraceptives who develop rash, interrupting treatment with 
IVA/TEZ/ELX in combination with ivacaftor and hormonal contraceptives should be considered. 
Following the resolution of rash, it should be considered if resuming IVA/TEZ/ELX in combination 
with ivacaftor without hormonal contraceptives is appropriate. If rash does not recur, resumption of 
hormonal contraceptives can be considered (see section 4.8). 
 
Elderly population 
 
Clinical studies of IVA/TEZ/ELX in combination with ivacaftor did not include any patients over 
59 years of age. Dose recommendations are based on the pharmacokinetic profile and knowledge from 
studies with tezacaftor/ivacaftor in combination with ivacaftor and ivacaftor monotherapy. 
 
Interactions with medicinal products  
 
CYP3A inducers 
Exposure to ivacaftor is significantly decreased and exposures to elexacaftor and tezacaftor are 
expected to decrease by the concomitant use of CYP3A inducers, potentially resulting in the reduced 
efficacy of IVA/TEZ/ELX and ivacaftor; therefore, co-administration with strong CYP3A inducers is 
not recommended (see section 4.5). 
 
CYP3A inhibitors 
Exposure to elexacaftor, tezacaftor and ivacaftor are increased when co-administered with strong or 
moderate CYP3A inhibitors. The dose of IVA/TEZ/ELX and ivacaftor should be adjusted when used 
concomitantly with strong or moderate CYP3A inhibitors (see section 4.5 and Table 1 in section 4.2). 
 
Cataracts  
 
Cases of non-congenital lens opacities without impact on vision have been reported in paediatric 
patients treated with ivacaftor-containing regimens. Although other risk factors were present in some 
cases (such as corticosteroid use, exposure to radiation) a possible risk attributable to treatment with 
ivacaftor cannot be excluded. Baseline and follow-up ophthalmological examinations are 
recommended in paediatric patients initiating treatment with IVA/TEZ/ELX in combination with 
ivacaftor (see section 5.3). 
 
Sodium content  
 
This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 
‘sodium-free’. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Medicinal products affecting the pharmacokinetics of elexacaftor, tezacaftor and/or ivacaftor  
 
CYP3A inducers 
Elexacaftor, tezacaftor and ivacaftor are substrates of CYP3A (ivacaftor is a sensitive substrate of 
CYP3A). Concomitant use of strong CYP3A inducers may result in reduced exposures and thus 
reduced IVA/TEZ/ELX efficacy. Co-administration of ivacaftor with rifampicin, a strong CYP3A 



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inducer, significantly decreased ivacaftor area under the curve (AUC) by 89%. Elexacaftor and 
tezacaftor exposures are also expected to decrease during co-administration with strong CYP3A 
inducers; therefore, co-administration with strong CYP3A inducers is not recommended. 
 
Examples of strong CYP3A inducers include: 
• rifampicin, rifabutin, phenobarbital, carbamazepine, phenytoin, and St. John’s wort (Hypericum 

perforatum) 
 
CYP3A inhibitors 
Co-administration with itraconazole, a strong CYP3A inhibitor, increased elexacaftor AUC by 
2.8-fold and tezacaftor AUC by 4.0- to 4.5-fold. When co-administered with itraconazole and 
ketoconazole, ivacaftor AUC increased by 15.6-fold and 8.5-fold, respectively. The dose of 
IVA/TEZ/ELX and ivacaftor should be reduced when co-administered with strong CYP3A inhibitors 
(see Table 1 in section 4.2 and section 4.4). 
 
Examples of strong CYP3A inhibitors include: 
• ketoconazole, itraconazole, posaconazole, and voriconazole 
• telithromycin and clarithromycin 
 
Simulations indicated that co-administration with moderate CYP3A inhibitors fluconazole, 
erythromycin, and verapamil, may increase elexacaftor and tezacaftor AUC by approximately 1.9- to 
2.3-fold. Co-administration of fluconazole increased ivacaftor AUC by 2.9-fold. The dose of 
IVA/TEZ/ELX and ivacaftor should be reduced when co-administered with moderate CYP3A 
inhibitors (see Table 1 in section 4.2 and section 4.4). 
 
Examples of moderate CYP3A inhibitors include: 
• fluconazole 
• erythromycin 
 
Co-administration with grapefruit juice, which contains one or more components that moderately 
inhibit CYP3A, may increase exposure of elexacaftor, tezacaftor and ivacaftor. Food or drink 
containing grapefruit should be avoided during treatment with IVA/TEZ/ELX and ivacaftor (see 
section 4.2). 
 
Potential for interaction with transporters  
In vitro studies showed that elexacaftor is a substrate for the efflux transporters P-gp and Breast 
Cancer Resistance Protein (BCRP) but is not a substrate for OATP1B1 or OATP1B3. Exposure to 
elexacaftor is not expected to be affected significantly by concomitant use of P-gp and BCRP 
inhibitors due to its high intrinsic permeability and low likelihood of being excreted intact. 
 
In vitro studies showed that tezacaftor is a substrate for the uptake transporter OATP1B1, and efflux 
transporters P-gp and BCRP. Tezacaftor is not a substrate for OATP1B3. Exposure to tezacaftor is not 
expected to be affected significantly by concomitant inhibitors of OATP1B1, P-gp, or BCRP due to its 
high intrinsic permeability and low likelihood of being excreted intact. However, exposure to M2-TEZ 
(tezacaftor metabolite) may be increased by inhibitors of P-gp. Therefore, caution should be used 
when P-gp inhibitors (e.g. ciclosporin) are used with IVA/TEZ/ELX. 
 
In vitro studies showed that ivacaftor is not a substrate for OATP1B1, OATP1B3, or P-gp. Ivacaftor 
and its metabolites are substrates of BCRP in vitro. Due to its high intrinsic permeability and low 
likelihood of being excreted intact, co-administration of BCRP inhibitors is not expected to alter 
exposure of ivacaftor and M1-IVA, while any potential changes in M6-IVA exposures are not 
expected to be clinically relevant. 
 



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Medicinal products affected by elexacaftor, tezacaftor and/or ivacaftor  
 
CYP2C9 substrates  
Ivacaftor may inhibit CYP2C9; therefore, monitoring of the international normalised ratio (INR) 
during co-administration of warfarin with IVA/TEZ/ELX and ivacaftor is recommended. Other 
medicinal products for which exposure may be increased include glimepiride and glipizide; these 
medicinal products should be used with caution. 
  
Potential for interaction with transporters 
Co-administration of ivacaftor or tezacaftor/ivacaftor with digoxin, a sensitive P-gp substrate, 
increased digoxin AUC by 1.3-fold, consistent with weak inhibition of P-gp by ivacaftor. 
Administration of IVA/TEZ/ELX and ivacaftor may increase systemic exposure of medicinal products 
that are sensitive substrates of P-gp, which may increase or prolong their therapeutic effect and 
adverse reactions. When used concomitantly with digoxin or other substrates of P-gp with a narrow 
therapeutic index such as ciclosporin, everolimus, sirolimus, and tacrolimus, caution and appropriate 
monitoring should be used. 
 
Elexacaftor and M23-ELX inhibit uptake by OATP1B1 and OATP1B3 in vitro. Tezacaftor/ivacaftor 
increased the AUC of pitavastatin, an OATP1B1 substrate, by 1.2-fold. Co-administration with 
IVA/TEZ/ELX in combination with ivacaftor may increase exposures of medicinal products that are 
substrates of these transporters, such as statins, glyburide, nateglinide and repaglinide. When used 
concomitantly with substrates of OATP1B1 or OATP1B3, caution and appropriate monitoring should 
be used. Bilirubin is an OATP1B1 and OATP1B3 substrate. In study 445-102, mild increases in mean 
total bilirubin were observed (up to 4.0 µmol/L change from baseline). This finding is consistent with 
the in vitro inhibition of bilirubin transporters OATP1B1 and OATP1B3 by elexacaftor and 
M23-ELX.  
 
Elexacaftor and ivacaftor are inhibitors of BCRP. Co-administration of IVA/TEZ/ELX and ivacaftor 
may increase exposures of medicinal products that are substrates of BCRP, such as rosuvastatin. When 
used concomitantly with substrates of BCRP, appropriate monitoring should be used. 
 
Hormonal contraceptives  
 
IVA/TEZ/ELX in combination with ivacaftor has been studied with ethinyl estradiol/levonorgestrel 
and was found to have no clinically relevant effect on the exposures of the oral contraceptive. 
IVA/TEZ/ELX and ivacaftor is not expected to have an impact on the efficacy of oral contraceptives. 
 
Paediatric population  
 
Interaction studies have only been performed in adults. 
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy  
 
There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of 
elexacaftor, tezacaftor or ivacaftor in pregnant women. Animal studies do not indicate direct or 
indirect harmful effects with respect to reproductive toxicity (see section 5.3). As a precautionary 
measure, it is preferable to avoid the use of IVA/TEZ/ELX during pregnancy. 
 
Breast-feeding  
 
It is unknown whether elexacaftor, tezacaftor, ivacaftor, or their metabolites are excreted in human 
milk. Available pharmacokinetic/toxicological data in animals have shown excretion of elexacaftor, 
tezacaftor and ivacaftor into the milk of lactating female rats (see section 5.3). A risk to the 
newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding 



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or to discontinue/abstain from IVA/TEZ/ELX therapy taking into account the benefit of breast-feeding 
for the child and the benefit of therapy for the woman. 
 
Fertility  
 
There are no data available on the effect of elexacaftor, tezacaftor and ivacaftor on fertility in humans. 
Tezacaftor had no effects on fertility and reproductive performance indices in male and female rats at 
clinically relevant exposures. Elexacaftor and ivacaftor had an effect on fertility in rats (see 
section 5.3). 
 
4.7 Effects on ability to drive and use machines 
 
IVA/TEZ/ELX in combination with ivacaftor has a minor influence on the ability to drive or use 
machines. Dizziness has been reported in patients receiving IVA/TEZ/ELX in combination with 
ivacaftor, tezacaftor/ivacaftor in combination with ivacaftor as well as ivacaftor monotherapy (see 
section 4.8). Patients experiencing dizziness should be advised not to drive or use machines until 
symptoms abate. 
  
4.8 Undesirable effects 
 
Summary of the safety profile  
 
The most common adverse reactions experienced by patients aged 12 years and older who received 
IVA/TEZ/ELX in combination with ivacaftor were headache (17.3%), diarrhoea (12.9%) and upper 
respiratory tract infection (11.9%).  
 
Serious adverse reactions of rash were reported in 3 (1.5%) patients treated with IVA/TEZ/ELX in 
combination with ivacaftor compared to 1 (0.5%) in placebo. 
 
Tabulated list of adverse reactions  
 
Table 3 reflects adverse reactions observed with IVA/TEZ/ELX in combination with ivacaftor, 
tezacaftor/ivacaftor in combination with ivacaftor and ivacaftor monotherapy. Adverse reactions are 
listed by MedDRA system organ class and frequency: 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); very rare (<1/10,000); not 
known (cannot be estimated from the available data). 
 



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Table 3: Adverse reactions 
MedDRA System Organ Class Adverse Reactions Frequency 

Infections and infestations 
Upper respiratory tract infection*, 
Nasopharyngitis very common 

Rhinitis*, Influenza* common  
Metabolism and nutrition 
disorders Hypoglycaemia* common 

Nervous system disorders Headache*, Dizziness* very common 

Ear and labyrinth disorders 

Ear pain, Ear discomfort, Tinnitus, 
Tympanic membrane hyperaemia, 
Vestibular disorder 

common 

Ear congestion uncommon 

Respiratory, thoracic and 
mediastinal disorders 

Oropharyngeal pain, Nasal 
congestion* very common 

Rhinorrhoea*, Sinus congestion, 
Pharyngeal erythema, Abnormal 
breathing* 

common 

Wheezing* uncommon 

Gastrointestinal disorders 
Diarrhoea*, Abdominal pain* very common 
Nausea, Abdominal pain upper*, 
Flatulence* common 

Hepatobiliary disorders 
Transaminase elevations very common 
Alanine aminotransferase increased*, 
Aspartate aminotransferase increased* common 

Skin and subcutaneous tissue 
disorders 

Rash* very common 
Acne*, Pruritus* common 

Reproductive system and breast 
disorders 

Breast mass common 
Breast inflammation, Gynaecomastia, 
Nipple disorder, Nipple pain uncommon 

Investigations 

Bacteria in sputum very common 
Blood creatine phosphokinase 
increased* common 

Blood pressure increased* uncommon 
*Adverse reactions observed during clinical studies with IVA/TEZ/ELX in combination with ivacaftor. 

 
Safety data from the following studies were consistent with the safety data observed in study 445-102. 
• A 4-week, randomised, double-blind, active-controlled study in 107 patients (study 445-103). 
• A 96-week, open-label safety and efficacy study (study 445-105) for patients rolled over from 

studies 445-102 and 445-103, with interim analysis performed on 510 patients including 
271 patients with ≥48 weeks of cumulative treatment with IVA/TEZ/ELX in combination with 
ivacaftor. 

 
Description of selected adverse reactions  
 
Transaminase elevations 
In study 445-102, the incidence of maximum transaminase (ALT or AST) >8, >5, or >3 x the ULN 
was 1.5%, 2.5%, and 7.9% in IVA/TEZ/ELX-treated patients and 1.0%, 1.5%, and 5.5% in 
placebo-treated patients. The incidence of adverse reactions of transaminase elevations was 10.9% in 
IVA/TEZ/ELX-treated patients and 4.0% in placebo-treated patients. No patients treated with 
IVA/TEZ/ELX discontinued treatment for elevated transaminases (see section 4.4). 
 
Rash events 
In study 445-102, the incidence of rash events (e.g., rash, rash pruritic) was 10.9% in 
IVA/TEZ/ELX- and 6.5% in placebo-treated patients. The rash events were generally mild to 
moderate in severity. The incidence of rash events by patient sex was 5.8% in males and 16.3% in 
females in IVA/TEZ/ELX-treated patients and 4.8% in males and 8.3% in females in placebo-treated 



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patients. In patients treated with IVA/TEZ/ELX, the incidence of rash events was 20.5% in females 
taking hormonal contraceptive and 13.6% in females not taking hormonal contraceptive (see 
section 4.4). 
 
Increased creatine phosphokinase  
In study 445-102, the incidence of maximum creatine phosphokinase >5 x the ULN was 10.4% in 
IVA/TEZ/ELX- and 5.0% in placebo-treated patients. The observed creatine phosphokinase elevations 
were generally transient and asymptomatic, and many were preceded by exercise. No 
IVA/TEZ/ELX-treated patients discontinued treatment for increased creatine phosphokinase. 
 
Increased blood pressure 
In study 445-102, the maximum increase from baseline in mean systolic and diastolic blood pressure 
was 3.5 mmHg and 1.9 mmHg, respectively for IVA/TEZ/ELX-treated patients (baseline: 113 mmHg 
systolic and 69 mmHg diastolic) and 0.9 mmHg and 0.5 mmHg, respectively for placebo-treated 
patients (baseline: 114 mmHg systolic and 70 mmHg diastolic). 
 
The proportion of patients who had systolic blood pressure >140 mmHg or diastolic blood pressure 
>90 mmHg on at least two occasions was 5.0% and 3.0%, respectively in IVA/TEZ/ELX-treated 
patients compared with 3.5% and 3.5%, respectively in placebo-treated patients. 
 
Paediatric population  
 
The safety data of IVA/TEZ/ELX in combination with ivacaftor was evaluated in 72 patients between 
12 to less than 18 years of age. The safety profile is generally consistent among adolescents and adult 
patients. 
 
Other special populations  
 
With the exception of sex differences in rash, the safety profile of IVA/TEZ/ELX in combination with 
ivacaftor was generally similar across all subgroups of patients, including analysis by age, baseline 
percent predicted forced expiratory volume in one second (ppFEV1), and geographic regions. 
 
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 
 
No specific antidote is available for overdose with IVA/TEZ/ELX. Treatment of overdose consists of 
general supportive measures including monitoring of vital signs and observation of the clinical status 
of the patient. 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: Other respiratory system products, ATC code: R07AX32 
 
Mechanism of action  
 
Elexacaftor and tezacaftor are CFTR correctors that bind to different sites on the CFTR protein and 
have an additive effect in facilitating the cellular processing and trafficking of F508del-CFTR to 

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


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increase the amount of CFTR protein delivered to the cell surface compared to either molecule alone. 
Ivacaftor potentiates the channel open probability (or gating) of the CFTR protein at the cell surface.  
  
The combined effect of elexacaftor, tezacaftor and ivacaftor is increased quantity and function of 
F508del-CFTR at the cell surface, resulting in increased CFTR activity as measured by CFTR 
mediated chloride transport. With regard to MF-CFTR variant it is not clear whether and to what 
extent the combination of elexacaftor, tezacaftor and ivacaftor also increases the amount of mutated 
MF-CFTR variant on the cell surface and potentiates its channel open probability (or gating).  
 
Pharmacodynamic effects  
 
Effects on sweat chloride 
In study 445-102 (patients with an F508del mutation on one allele and a mutation on the second allele 
that predicts either no production of a CFTR protein or a CFTR protein that is not responsive to 
ivacaftor and tezacaftor/ivacaftor in vitro), a reduction in sweat chloride was observed from baseline at 
week 4 and sustained through the 24-week treatment period. The treatment difference between 
IVA/TEZ/ELX in combination with ivacaftor and placebo for mean absolute change in sweat chloride 
from baseline through week 24 was -41.8 mmol/L (95% CI: -44.4, -39.3; P<0.0001). 
 
In study 445-103 (patients homozygous for the F508del mutation), the treatment difference between 
IVA/TEZ/ELX in combination with ivacaftor and tezacaftor/ivacaftor for mean absolute change in 
sweat chloride from baseline at week 4 was -45.1 mmol/L (95% CI: -50.1, -40.1; P<0.0001). 
 
Cardiovascular effects 
 
Effect on QT interval  
At doses up to 2 times the maximum recommended dose of elexacaftor and 3 times the maximum 
recommended dose of tezacaftor and ivacaftor, the QT/QTc interval in healthy subjects was not 
prolonged to any clinically relevant extent. 
 
Heart rate  
In study 445-102, mean decreases in heart rate of 3.7 to 5.8 beats per minute (bpm) from baseline 
(76 bpm) were observed in IVA/TEZ/ELX-treated patients. 
 
Clinical efficacy and safety 
 
The efficacy of IVA/TEZ/ELX in combination with ivacaftor in patients with CF was demonstrated in 
two Phase 3 studies. Study 445-102 was a study of patients who had one F508del mutation and a 
second minimal function (MF) mutation. An MF mutation is defined as one that either leads to no 
CFTR protein being produced (e.g. Class I) or a CFTR protein that does not function to transport 
chloride and is unlikely to respond to other CFTR modulators (TEZ, IVA, or TEZ/IVA). Study 445-
103 was a study of patients homozygous for the F508del mutation. Not all CF genotypes have been 
clinically evaluated with IVA/TEZ/ELX in combination with ivacaftor; to date there are clinical data 
only for F/MF and F/F genotypes. 
 
Study 445-102 was a 24-week, randomised, double-blind, placebo-controlled study in patients who 
had an F508del mutation on one allele and an MF mutation on the second allele. CF patients eligible 
for this study were required to have Class I mutations that predicted no CFTR protein being produced 
(including nonsense mutations, canonical splice mutations, and insertion/deletion frameshift mutations 
both small (≤3 nucleotide) and non-small (>3 nucleotide)), as well as missense mutations which 
results in CFTR protein that does not transport chloride and is not responsive to ivacaftor and 
tezacaftor/ ivacaftor in vitro. The most frequent alleles with minimal function assessed in the study 
were G542X, W1282X, R553X, and R1162X; 621+1G→T, 1717-1G→A, and 1898+1G→A; 3659delC, 
and 394delTT; CFTRdele2,3; and N1303K, I507del, G85E, R347P, and R560T. Not all genotypes were 
assessed in the study. A total of 403 patients aged 12 years and older (mean age 26.2 years) were 
randomised and dosed to receive IVA/TEZ/ELX in combination with ivacaftor or placebo. Patients 



12 

had a ppFEV1 at screening between 40-90%. The mean ppFEV1 at baseline was 61.4% (range: 32.3%, 
97.1%).  
 
Study 445-103 was a 4-week, randomised, double-blind, active-controlled study in patients who are 
homozygous for the F508del mutation. A total of 107 patients aged 12 years and older (mean age 
28.4 years) received tezacaftor/ivacaftor and ivacaftor regimen (tezacaftor/ivacaftor) during a 4-week 
open-label run-in period and were then randomised and dosed to receive IVA/TEZ/ELX in 
combination with ivacaftor or tezacaftor/ivacaftor during a 4-week double-blind treatment period. 
Patients had a ppFEV1 at screening between 40-90%. The mean ppFEV1 at baseline, following the 
tezacaftor/ivacaftor run-in period was 60.9% (range: 35.0%, 89.0%). 
 
Patients in studies 445-102 and 445-103 continued on their CF therapies (e.g., bronchodilators, inhaled 
antibiotics, dornase alfa, and hypertonic saline), but discontinued any previous CFTR modulator 
therapies. Patients had a confirmed diagnosis of CF. 
 
Patients who had lung infection with organisms associated with a more rapid decline in pulmonary 
status, including but not limited to Burkholderia cenocepacia, Burkholderia dolosa, or Mycobacterium 
abscessus, or who had an abnormal liver function test at screening (ALT, AST, ALP, or GGT 
≥3 x ULN, or total bilirubin ≥2 x ULN), were excluded. Patients in studies 445-102 and 445-103 were 
eligible to roll over into a 96-week open-label extension study. 
 
Study 445-102 
In study 445-102 the primary endpoint was mean absolute change in ppFEV1 from baseline through 
week 24. Treatment with IVA/TEZ/ELX in combination with ivacaftor compared to placebo resulted 
in statistically significant improvement in ppFEV1 of 14.3 percentage points (95% CI: 12.7, 15.8; 
P<0.0001) (Table 4). Mean improvement in ppFEV1 was observed at the first assessment on Day 15 
and sustained through the 24-week treatment period. Improvements in ppFEV1 were observed 
regardless of age, baseline ppFEV1, sex, and geographic region.  
A total of 18 patients receiving IVA/TEZ/ELX in combination with ivacaftor had ppFEV1 <40 
percentage points at baseline. The safety and efficacy in this subgroup were consistent to those 
observed in the overall population. The mean treatment difference between IVA/TEZ/ELX in 
combination with ivacaftor and placebo-treated patients for absolute change in ppFEV1 through 
week 24 in this subgroup was 18.4 percentage points (95% CI: 11.5, 25.3).  
 
See Table 4 for a summary of primary and key secondary outcomes. 
 

Table 4: Primary and key secondary efficacy analyses, full analysis set (study 445-102) 

Analysis Statistic Placebo N=203 

IVA/TEZ/ELX in 
combination with 

ivacaftor 
N=200 

Primary 
Baseline ppFEV1 (percentage 
points) Mean (SD) 61.3 (15.5) 61.6 (15.0) 

Absolute change in ppFEV1 
from baseline through week 24 
(percentage points) 

Treatment difference (95% CI) 
P value 

Within-group change (SE) 

NA 
NA 

-0.4 (0.5) 

14.3 (12.7, 15.8) 
P<0.0001 
13.9 (0.6) 

Key Secondary 
Absolute change in 
ppFEV1 from baseline at 
week 4 (percentage points) 

Treatment difference (95% CI) 
P value 

Within-group change (SE) 

NA 
NA 

-0.2 (0.6) 

13.7 (12.0, 15.3) 
P<0.0001 
13.5 (0.6) 

Number of pulmonary 
exacerbations from baseline 
through week 24‡ 

Number of events (event rate per 
year††) 

Rate ratio (95% CI) 
P value 

113 (0.98) 
 

NA 
NA 

41 (0.37) 
 

0.37 (0.25, 0.55) 
P<0.0001 

Baseline sweat chloride 
(mmol/L) Mean (SD) 102.9 (9.8) 102.3 (11.9) 



13 

Table 4: Primary and key secondary efficacy analyses, full analysis set (study 445-102) 

Analysis Statistic Placebo N=203 

IVA/TEZ/ELX in 
combination with 

ivacaftor 
N=200 

Absolute change in sweat 
chloride from baseline through 
week 24 (mmol/L) 

Treatment difference (95% CI) 
P value 

Within-group change (SE) 

NA 
NA 

-0.4 (0.9) 

-41.8 (-44.4, -39.3) 
P<0.0001 
-42.2 (0.9) 

Absolute change in sweat 
chloride from baseline at 
week 4 (mmol/L) 

Treatment difference (95% CI) 
P value 

Within-group change (SE) 

NA 
NA 

0.1 (1.0) 

-41.2 (-44.0, -38.5) 
P<0.0001 
-41.2 (1.0) 

Baseline CF Questionnaire -
Revised (CFQ-R) respiratory 
domain score (points) 

Mean (SD) 70.0 (17.8) 68.3 (16.9) 

Absolute change in CFQ-R 
respiratory domain score from 
baseline through week 24 
(points) 

Treatment difference (95% CI) 
P value 

Within-group change (SE) 

NA 
NA 

-2.7 (1.0) 

20.2 (17.5, 23.0) 
P<0.0001 
17.5 (1.0) 

Absolute change in CFQ-R 
respiratory domain score from 
baseline at week 4 (points) 

Treatment difference (95% CI) 
P value 

Within-group change (SE) 

NA 
NA 

-1.9 (1.1) 

20.1 (16.9, 23.2) 
P<0.0001 
18.1 (1.1) 

Baseline BMI (kg/m2) Mean (SD) 21.31 (3.14) 21.49 (3.07) 

Absolute change in BMI from 
baseline at week 24 (kg/m2) 

Treatment difference (95% CI) 
P value 

Within-group change (SE) 

NA 
NA 

0.09 (0.07) 

1.04 (0.85, 1.23) 
P<0.0001 

1.13 (0.07) 
ppFEV1: percent predicted forced expiratory volume in 1 second; CI: confidence interval; SD: Standard 
Deviation; SE: Standard Error; NA: not applicable; CFQ-R: Cystic Fibrosis Questionnaire-Revised; 
BMI: body mass index. 
‡ A pulmonary exacerbation was defined as a change in antibiotic therapy (IV, inhaled, or oral) as a result of 
4 or more of 12 pre-specified sino-pulmonary signs/symptoms. 
†† Estimated event rate per year was calculated based on 48 weeks per year. 

 
Study 445-103 
In study 445-103 the primary endpoint was mean absolute change in ppFEV1 from baseline at week 4 
of the double-blind treatment period. Treatment with IVA/TEZ/ELX in combination with ivacaftor 
compared to the tezacaftor/ivacaftor and ivacaftor regimen (tezacaftor/ivacaftor) resulted in a 
statistically significant improvement in ppFEV1 of 10.0 percentage points (95% CI: 7.4, 12.6; 
P<0.0001) (Table 5). Improvements in ppFEV1 were observed regardless of age, sex, baseline ppFEV1 
geographic region. 
 
See Table 5 for a summary of primary and key secondary outcomes in the overall trial population.  
 
In a post hoc analysis of patients with (N=66) and without (N=41) recent CFTR modulator use, an 
improvement in ppFEV1 of 7.8 percentage points (95% CI: 4.8, 10.8) and 13.2 percentage points 
(95% CI: 8.5, 17.9), respectively was observed. 
 



14 

Table 5: Primary and key secondary efficacy analyses, full analysis set (study 445-103) 

Analysis* Statistic 
Tezacaftor/
Ivacaftor# 

N=52 

IVA/TEZ/ELX in 
combination with 

ivacaftor 
N=55 

Primary 
Baseline ppFEV1 
(percentage points) Mean (SD) 60.2 (14.4) 61.6 (15.4) 

Average absolute change in 
ppFEV1 from baseline at 
week 4 (percentage points) 

Treatment difference (95% CI) 
P value 

Within-group change (SE) 

NA 
NA 

0.4 (0.9) 

10.0 (7.4, 12.6) 
P<0.0001 
10.4 (0.9) 

Key secondary 
Baseline Sweat Chloride 
(mmol/L) Mean (SD) 90.0 (12.3) 91.4 (11.0) 

Average absolute change in 
sweat chloride from baseline 
at week 4 (mmol/L) 

Treatment difference (95% CI) 
P value 

Within-group change (SE) 

NA 
NA 

1.7 (1.8) 

-45.1 (-50.1, -40.1) 
P<0.0001 
-43.4 (1.7) 

Baseline CF Questionnaire -
Revised (CFQ-R) respiratory 
domain score (points) 

Mean (SD) 72.6 (17.9) 70.6 (16.2) 

Absolute change in CFQ-R 
respiratory domain score 
from baseline at week 4 
(points) 

Treatment difference (95% CI) 
P value 

Within-group change (SE) 

NA 
NA 

-1.4 (2.0) 

17.4 (11.8, 23.0) 
P<0.0001 
16.0 (2.0) 

ppFEV1: percent predicted forced expiratory volume in 1 second; CI: confidence interval; SD: Standard 
Deviation; SE: Standard Error; NA: not applicable; CFQ-R: Cystic Fibrosis Questionnaire-Revised. 
* Baseline for primary and key secondary endpoints is defined as the end of the 4-week 
tezacaftor/ivacaftor and ivacaftor run-in period. 
# Regimen of tezacaftor/ivacaftor and ivacaftor 

 
Study 445-105 
An ongoing, 96-week open-label extension study to evaluate the safety and efficacy of long-term 
treatment with IVA/TEZ/ELX in combination with ivacaftor is being conducted in patients who rolled 
over from studies 445-102 and 445-103. In this open-label extension study all patients received 
IVA/TEZ/ELX. For patients who rolled over from studies 445-102 (N=400) and 445-103 (N=107), an 
interim efficacy analysis was conducted when they completed the week 24 visit of study 445-105.  
 
Patients homozygous for the F508del mutation who received IVA/TEZ/ELX in combination with 
ivacaftor in study 445-103, and continued on the same treatment in study 445-105, showed sustained 
improvements in ppFEV1, CFQ-R respiratory domain score, and sweat chloride, through 28 weeks of 
cumulative treatment (i.e., through week 24 in study 445-105). The outcomes of annualised pulmonary 
exacerbation event rate through 28 weeks of cumulative treatment (i.e. through week 24 in 
study 445-105), and BMI and BMI-z score at 28 weeks of cumulative treatment (at week 24 in 
study 445-105), were consistent with those seen in patients with the genotypes studied in 
study 445-102. 
 
Paediatric population 
 
The European Medicines Agency has deferred the obligation to submit the results of studies with 
IVA/TEZ/ELX in combination with ivacaftor in one or more subset of the paediatric population in 
cystic fibrosis (see section 4.2 for information on paediatric use). 
  
5.2 Pharmacokinetic properties 
 
The pharmacokinetics of elexacaftor, tezacaftor and ivacaftor are similar between healthy adult 
subjects and patients with CF. Following initiation of once-daily dosing of elexacaftor and tezacaftor 
and twice-daily dosing of ivacaftor, plasma concentrations of elexacaftor, tezacaftor and ivacaftor 
reach steady state within approximately 7 days for elexacaftor, within 8 days for tezacaftor, and within 
3-5 days for ivacaftor. Upon dosing IVA/TEZ/ELX to steady state, the accumulation ratio is 



15 

approximately 3.6 for elexacaftor, 2.8 for tezacaftor and 4.7 for ivacaftor. Key pharmacokinetic 
parameters for elexacaftor, tezacaftor and ivacaftor at steady state in patients with CF aged 12 years 
and older are shown in Table 6. 
 
Table 6: Mean (SD) pharmacokinetic parameters of elexacaftor, tezacaftor and ivacaftor at steady state 
in patients with CF aged 12 years and older 

 Active Substance Cmax (mcg/mL) 
AUC0-24h or AUC0-12h 

(mcg∙h/mL)* 
Ivacaftor 150 mg every 
12 hours/tezacaftor 100 mg 
and elexacaftor 200 mg 
once daily 

Elexacaftor 9.15 (2.09) 162 (47.5) 

Tezacaftor 7.67 (1.68) 89.3 (23.2) 
Ivacaftor 1.24 (0.34) 11.7 (4.01) 

*AUC0-24h for elexacaftor and tezacaftor and AUC0-12h for ivacaftor 
SD: Standard Deviation; Cmax: maximum observed concentration; AUC: area under the concentration versus 
time curve. 
 
Absorption  
 
The absolute bioavailability of elexacaftor when administered orally in the fed state is approximately 
80%. Elexacaftor is absorbed with a median (range) time to maximum concentration (tmax) of 
approximately 6 hours (4 to 12 hours) while the median (range) tmax of tezacaftor and ivacaftor is 
approximately 3 hours (2 to 4 hours) and 4 (3 to 6 hours), respectively. 
Elexacaftor exposure (AUC) increases approximately 1.9- to 2.5-fold when administered with a 
moderate-fat meal relative to fasted conditions. Ivacaftor exposure increases approximately 2.5- to 
4-fold when administered with fat-containing meals relative to fasted conditions, while food has no 
effect on the exposure of tezacaftor. 
 
Distribution  
 
Elexacaftor is >99% bound to plasma proteins and tezacaftor is approximately 99% bound to plasma 
proteins, in both cases primarily to albumin. Ivacaftor is approximately 99% bound to plasma proteins, 
primarily to albumin, and also to alpha 1-acid glycoprotein and human gamma-globulin. After oral 
administration of IVA/TEZ/ELX in combination with ivacaftor, the mean (±SD) apparent volume of 
distribution of elexacaftor, tezacaftor and ivacaftor was 53.7 L (17.7), 82.0 L (22.3) and 293 L (89.8), 
respectively. Elexacaftor, tezacaftor and ivacaftor do not partition preferentially into human red blood 
cells. 
 
Biotransformation  
 
Elexacaftor is metabolized extensively in humans, mainly by CYP3A4/5. Following oral 
administration of a single dose of 200 mg 14C-elexacaftor to healthy male subjects, M23-ELX was the 
only major circulating metabolite. M23-ELX has similar potency to elexacaftor and is considered 
pharmacologically active. 
 
Tezacaftor is metabolized extensively in humans, mainly by CYP3A4/5. Following oral administration 
of a single dose of 100 mg 14C-tezacaftor to healthy male subjects, M1-TEZ, M2-TEZ, and M5-TEZ 
were the 3 major circulating metabolites of tezacaftor in humans. M1-TEZ has similar potency to that 
of tezacaftor and is considered pharmacologically active. M2-TEZ is much less pharmacologically 
active than tezacaftor or M1-TEZ, and M5-TEZ is not considered pharmacologically active. Another 
minor circulating metabolite, M3-TEZ, is formed by direct glucuronidation of tezacaftor. 
 
Ivacaftor is also metabolized extensively in humans. In vitro and in vivo data indicate that ivacaftor is 
metabolized primarily by CYP3A4/5. M1-IVA and M6-IVA are the two major metabolites of 
ivacaftor in humans. M1-IVA has approximately one-sixth the potency of ivacaftor and is considered 
pharmacologically active. M6-IVA is not considered pharmacologically active. 
 
The effect of the CYP3A4*22 heterozygous genotype on tezacaftor, ivacaftor and elexacaftor 
exposure is consistent with the effect of co-administration of a weak CYP3A4 inhibitor, which is not 



16 

clinically relevant. No dose-adjustment of tezacaftor, ivacaftor or elexacaftor is considered necessary. 
The effect in CYP3A4*22 homozygous genotype patients is expected to be stronger. However, no data 
are available for such patients. 
 
Elimination  
 
Following multiple dosing in the fed state, the mean (±SD) apparent clearance values of elexacaftor, 
tezacaftor and ivacaftor at steady state were 1.18 (0.29) L/h, 0.79 (0.10) L/h and 10.2 (3.13) L/h, 
respectively. The mean (SD) terminal half-lives of elexacaftor, tezacaftor and ivacaftor following 
administration of the ivacaftor/tezacaftor/elexacaftor fixed-dose combination tablets are approximately 
24.7 (4.87) hours, 60.3 (15.7) hours and 13.1 (2.98) hours, respectively. The mean (SD) effective 
half-life of tezacaftor following administration of the ivacaftor/tezacaftor/elexacaftor fixed-dose 
combination tablets is 11.9 (3.79) hours. 
 
Following oral administration of 14C-elexacaftor alone, the majority of elexacaftor (87.3%) was 
eliminated in the faeces, primarily as metabolites. 
 
Following oral administration of 14C-tezacaftor alone, the majority of the dose (72%) was excreted in 
the faeces (unchanged or as the M2-TEZ) and about 14% was recovered in urine (mostly as M2-TEZ), 
resulting in a mean overall recovery of 86% up to 26 days after the dose. 
 
Following oral administration of 14C-ivacaftor alone, the majority of ivacaftor (87.8%) was eliminated 
in the faeces after metabolic conversion.  
 
For elexacaftor, tezacaftor and ivacaftor there was negligible urinary excretion of unchanged 
medicine. 
 
Hepatic impairment 
 
Elexacaftor alone or in combination with tezacaftor and ivacaftor has not been studied in subjects with 
severe hepatic impairment (Child-Pugh Class C, score 10-15). Following multiple doses of 
elexacaftor, tezacaftor and ivacaftor for 10 days, subjects with moderately impaired hepatic function 
(Child-Pugh Class B, score 7 to 9) had an approximately 25% higher AUC and a 12% higher Cmax for 
elexacaftor, 73% higher AUC and a 70% higher Cmax for M23-ELX, 20% higher AUC but similar Cmax 
for tezacaftor, 22% lower AUC and a 20% lower Cmax for M1-TEZ, and a 1.5-fold higher AUC and a 
10% higher Cmax for ivacaftor compared with healthy subjects matched for demographics. The effect 
of moderately impaired hepatic function on total exposure (based on summed values of elexacaftor 
and its M23-ELX metabolite) was 36% higher AUC and a 24% higher Cmax compared with healthy 
subjects matched for demographics. 
 
Tezacaftor and ivacaftor 
Following multiple doses of tezacaftor and ivacaftor for 10 days, subjects with moderately impaired 
hepatic function had an approximately 36% higher AUC and a 10% higher Cmax for tezacaftor, and a 
1.5-fold higher AUC but similar Cmax for ivacaftor compared with healthy subjects matched for 
demographics.  
 
Ivacaftor 
In a study with ivacaftor alone, subjects with moderately impaired hepatic function had similar 
ivacaftor Cmax, but an approximately 2.0-fold higher ivacaftor AUC0-∞ compared with healthy subjects 
matched for demographics.  
 
Renal impairment 
 
Elexacaftor alone or in combination with tezacaftor and ivacaftor has not been studied in patients with 
severe renal impairment (eGFR less than 30 mL/min) or in patients with end-stage renal disease. 
 



17 

In human pharmacokinetic studies of elexacaftor, tezacaftor, and ivacaftor, there was minimal 
elimination of elexacaftor, tezacaftor, and ivacaftor in urine (only 0.23%, 13.7% [0.79% as unchanged 
medicine], and 6.6% of total radioactivity, respectively). 
 
Based on population pharmacokinetic (PK) analysis, exposure of elexacaftor was similar in those with 
mild renal impairment (N=75, eGFR 60 to less than 90 mL/min) relative to those with normal renal 
function (N=341, eGFR 90 mL/min or greater). 
 
In population PK analysis conducted in 817 patients administered tezacaftor alone or in combination 
with ivacaftor in Phase 2 or Phase 3 studies indicated that mild renal impairment (N=172; eGFR 60 to 
less than 90 mL/min) and moderate renal impairment (N=8; eGFR 30 to less than 60 mL/min) did not 
affect the clearance of tezacaftor significantly. 
 
Gender  
 
The pharmacokinetic parameters of elexacaftor (244 males compared to 174 females), tezacaftor and 
ivacaftor are similar in males and females.  
 
Race  
 
Race had no clinically meaningful effect on elexacaftor exposure based on population PK analysis in 
whites (N=373) and non-whites (N=45). The non-white races consisted of 30 Black or African 
American, 1 with multiple racial background and 14 with other ethnic background (no Asian). 
 
Very limited PK data indicate comparable exposure of tezacaftor in whites (N=652) and non-whites 
(N=8). The non-white races consisted of 5 Black or African American and 3 Native Hawaiian or other 
Pacific Islander.   
 
Race had no clinically meaningful effect on the PK of ivacaftor in whites (N=379) and non-whites 
(N=29) based on a population PK analysis. The non-white races consisted of 27 African American and 
2 Asian. 
 
Elderly  
 
Clinical trials of IVA/TEZ/ELX in combination with ivacaftor did not include any patients over 
59 years of age to determine whether response in these patients is different from younger adults. 
 
Paediatric population  
 
Elexacaftor, tezacaftor and ivacaftor exposures observed in Phase 3 studies as determined using 
population PK analysis are presented by age group in Table 7. Exposures of elexacaftor, tezacaftor and 
ivacaftor in patients aged 12 to less than 18 years of age are similar to that of adult patients. 
 

Table 7. Mean (SD) elexacaftor, tezacaftor and ivacaftor exposures by age group 

Age group Dose 
Elexacaftor  
AUC0-24h,ss 
(mcg∙h/mL) 

Tezacaftor  
AUC0-24h,ss 
(mcg∙h/mL) 

Ivacaftor  
AUC0-12h,ss 
(mcg∙h/mL) 

Adolescent patients 
(12 to <18 years) (N=72) ivacaftor 150 mg q12h/ tezacaftor 100 mg qd/ 

elexacaftor 200 mg qd 

147 (36.8) 88.8 (21.8) 10.6 (3.35) 

Adult patients (≥18 years) 
(N=179) 168 (49.9) 89.5 (23.7) 12.1 (4.17) 

SD: Standard Deviation; AUCss: area under the concentration versus time curve at steady state. 
 



18 

5.3 Preclinical safety data 
 
Elexacaftor  
 
Non-clinical data reveal no special hazard for humans based on conventional studies of safety 
pharmacology, repeated dose toxicity, genotoxicity. Assessment of the carcinogenic potential of 
elexacaftor is currently being conducted. 
 
Fertility and pregnancy  
The No Observed Adverse Effect Level (NOAEL) for fertility findings was 55 mg/kg/day (2 times the 
maximum recommended human dose (MRHD) based on summed AUCs of elexacaftor and its 
metabolite) in male rats and 25 mg/kg/day (4 times the MRHD based on summed AUCs of elexacaftor 
and its metabolite) in female rats. In rat, at doses exceeding the maximum tolerated dose (MTD), 
degeneration and atrophy of seminiferous tubules are correlated to oligo-/aspermia and cellular debris 
in epididymides. In dog testes, minimal or mild, bilateral degeneration/atrophy of the seminiferous 
tubules was present in males administered 14 mg/kg/day elexacaftor (14 times the MRHD based on 
summed AUCs of elexacaftor and its metabolite) that did not resolve during the recovery period, 
however without further sequelae. The human relevance of these findings is unknown. 
 
Elexacaftor was not teratogenic in rats at 40 mg/kg/day and at 125 mg/kg/day in rabbits 
(approximately 9 and 4 times, respectively, the MRHD based on summed AUCs of elexacaftor and its 
metabolites [for rat] and AUC of elexacaftor [for rabbit]) with developmental findings being limited to 
lower mean foetal body weight at ≥25 mg/kg/day. 
 
Placental transfer of elexacaftor was observed in pregnant rats.  
 
Tezacaftor  
 
Non-clinical data reveal no special hazard for humans based on conventional studies of safety 
pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to 
reproduction and development. Placental transfer of tezacaftor was observed in pregnant rats. 
 
Ivacaftor  
 
Non-clinical data reveal no special hazard for humans based on conventional studies of safety 
pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential. 
 
Fertility and pregnancy  
The NOAEL for fertility findings was 100 mg/kg/day (5 times the MRHD based on summed AUCs of 
ivacaftor and its metabolites) in male rats and 100 mg/kg/day (3 times the MRHD based on summed 
AUCs of ivacaftor and its metabolites) in female rats.  
 
In the pre- and post-natal study ivacaftor decreased survival and lactation indices and caused a 
reduction in pup body weights. The NOAEL for viability and growth in the offspring provides an 
exposure level of approximately 3 times the systemic exposure of ivacaftor and its metabolites in adult 
humans at the MRHD. Placental transfer of ivacaftor was observed in pregnant rats and rabbits. 
 
Juvenile animals  
Findings of cataracts were observed in juvenile rats dosed from postnatal day 7 through day 35 at 
ivacaftor exposure levels of 0.21 times the MRHD based on systemic exposure of ivacaftor and its 
metabolites. This finding has not been observed in foetuses derived from rat dams treated with 
ivacaftor on gestation days 7 to day 17, in rat pups exposed to ivacaftor through milk ingestion up to 
postnatal day 20, in 7-week-old rats, nor in 3.5- to 5-month-old dogs treated with ivacaftor. The 
potential relevance of these findings in humans is unknown. 
 



19 

Ivacaftor/tezacaftor/elexacaftor  
 
Combination repeat-dose toxicity studies in rats and dogs involving the co-administration of 
elexacaftor, tezacaftor and ivacaftor to assess the potential for additive and/or synergistic toxicity did 
not produce any unexpected toxicities or interactions. The potential for synergistic toxicity on male 
reproduction has not been assessed. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core  
 
Hypromellose (E464) 
Hypromellose acetate succinate 
Sodium laurilsulfate (E487) 
Croscarmellose sodium (E468) 
Microcrystalline cellulose (E460(i)) 
Magnesium stearate (E470b) 
 
Tablet film coat  
 
Hypromellose (E464) 
Hydroxypropyl cellulose (E463) 
Titanium dioxide (E171) 
Talc (E553b) 
Iron oxide yellow (E172) 
Iron oxide red (E172) 
 
6.2 Incompatibilities 
 
Not applicable.  
 
6.3 Shelf life 
 
2 years 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions. 
 
6.5 Nature and contents of container 
 
Blister consisting of PCTFE (polychlorotrifluoroethylene)/PVC (polyvinyl chloride) with a paper 
backed aluminium foil lidding. 
 
Pack size of 56 tablets (4 blister cards, each with 14 tablets). 
 
6.6 Special precautions for disposal 
 
No special requirements for disposal. 
 
 



20 

7. MARKETING AUTHORISATION HOLDER 
 
Vertex Pharmaceuticals (Ireland) Limited 
28-32 Pembroke Street Upper 
Dublin 2, D02 EK84 
Ireland 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/20/1468/001 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation:  
 
 
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/


21 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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 
 
  



22 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer(s) responsible for batch release  
 
Almac Pharma Services (Ireland) Limited 
Finnabair Industrial Estate 
Dundalk 
Co. Louth 
A91 P9KD 
Ireland 
 
Almac Pharma Services Ltd. 
Seagoe Industrial Estate 
Craigavon 
Co. Armagh BT63 5UA 
United Kingdom 
 
The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch. 
 
 
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 requirements for submission of PSURs for this medicinal product are set out in the list of Union 
reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any 
subsequent updates published on the European medicines web-portal. 
 
The marketing authorisation holder (MAH) shall submit the first PSUR for this product within 6 
months following authorisation.  
 
 
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. 

 
  



23 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
  



24 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
  



25 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Kaftrio 75 mg/50 mg/100 mg film-coated tablets 
ivacaftor/tezacaftor/elexacaftor 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 75 mg of ivacaftor, 50 mg of tezacaftor and 100 mg of elexacaftor. 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
56 tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
Oral use 
 
Take the tablets with fat-containing food. 
 
You may start taking Kaftrio on any day of the week. 
 
Open 
 
Insert tab below to close 
 
 
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 
 



26 

 
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 
 
Vertex Pharmaceuticals (Ireland) Limited 
28-32 Pembroke Street Upper 
Dublin 2, D02 EK84 
Ireland  
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/20/1468/001 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Kaftrio  
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN 
 
 
  



27 

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 
 
BLISTER CARD 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Kaftrio 75 mg/50 mg/100 mg film-coated tablets 
ivacaftor/tezacaftor/elexacaftor 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 75 mg of ivacaftor, 50 mg of tezacaftor and 100 mg of elexacaftor. 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
14 tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
Oral use 
 
Take the tablets with fat-containing food. 
 
You may start taking Kaftrio on any day of the week. 
 
Mon.  Tue.  Wed.  Thu.  Fri.  Sat.  Sun.  
 
 
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 
 
 



28 

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 
 
Vertex Pharmaceuticals (Ireland) Limited 
28-32 Pembroke Street Upper 
Dublin 2, D02 EK84 
Ireland 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/20/1468/001 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
 
  



29 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER FOIL 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Kaftrio 75 mg/50 mg/100 mg tablets 
ivacaftor/tezacaftor/elexacaftor 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Vertex 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
 
  



30 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
 

  



31 

Package leaflet: Information for the patient 
 

Kaftrio 75 mg/50 mg/100 mg film-coated tablets 
ivacaftor/tezacaftor/elexacaftor 

 
 

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 Kaftrio is and what it is used for 
2. What you need to know before you take Kaftrio 
3. How to take Kaftrio 
4. Possible side effects 
5. How to store Kaftrio 
6. Contents of the pack and other information 
 
 
1. What Kaftrio is and what it is used for 
 
Kaftrio contains three active substances: ivacaftor, tezacaftor and elexacaftor. The medicine helps 
lung cells to work better in some patients with cystic fibrosis (CF). CF is an inherited condition in 
which the lungs and the digestive system can become clogged with thick, sticky mucus. 
 
Kaftrio taken with ivacaftor is for patients aged 12 years and over who have CF, with certain 
genetic mutations. These can be either two F508del mutations or an F508del mutation and a second 
mutation called a minimal function mutation. A minimal function mutation is defined as one that 
results either in no CFTR protein being produced or a CFTR protein that does not function, and which 
is unlikely to respond to other CFTR modulator treatments (ivacaftor and tezacaftor/ivacaftor). Kaftrio 
is intended as a long-term treatment. 
 
Kaftrio works on a protein called CFTR (cystic fibrosis transmembrane conductance regulator). The 
protein is damaged in some people with CF, if they have a mutation in the CFTR gene. 
 
Kaftrio is normally taken with another medicine, ivacaftor. Ivacaftor causes the protein to work 
better, while tezacaftor and elexacaftor increase the amount of protein at the cell surface. 
 
Kaftrio (taken with ivacaftor) helps your breathing by improving your lung function. You may also 
notice that you do not get ill as often, or that it is easier to gain weight. 
 
 



32 

2. What you need to know before you take Kaftrio 
 
Do not take Kaftrio: 
• If you are allergic to ivacaftor, tezacaftor, elexacaftor, or any other ingredients of this medicine 

(listed in section 6). 
Talk to your doctor and do not take the tablets, if this applies to you. 
 
Warnings and precautions 
• Talk to your doctor if you have liver problems, or have had them previously. Your doctor 

may need to adjust your dose. 
• Your doctor will do some blood tests to check your liver before and during treatment with 

Kaftrio, especially if your blood tests showed high liver enzymes in the past. Liver enzymes in 
the blood can increase in patients receiving Kaftrio. 

Tell your doctor right away if you have any symptoms of liver problems. These are listed in 
section 4. 
• Talk to your doctor if you have kidney problems, or you have previously had them. 

 
• Talk to your doctor before starting treatment with Kaftrio if you have received an organ 

transplant. 
 
• Talk to your doctor if you are using hormonal contraception – for example, women using the 

contraceptive pill. This may mean you are more likely to get a rash while taking Kaftrio.   
 

• Your doctor may do eye examinations before and during treatment with Kaftrio. Cloudiness 
of the eye lens (cataract) without any effect on vision has occurred in some children and 
adolescents receiving this treatment. 

 
Children under 12 
Do not give this medicine to children under the age of 12 years because it is not known if Kaftrio is 
safe and effective in this age group. 
 
Other medicines and Kaftrio 
Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other 
medicines. Some medicines can affect how Kaftrio works or may make side effects more likely. In 
particular, tell your doctor if you take any of the medicines listed below. Your doctor may change the 
dose of one of the medicines if you take any of these. 
• Antifungal medicines (used for the treatment of fungal infections). These include fluconazole, 

itraconazole, ketoconazole, posaconazole, and voriconazole. 
• Antibiotic medicines (used for the treatment of bacterial infections). These include 

clarithromycin, erythromycin, rifampicin, rifabutin, and telithromycin. 
• Epilepsy medicines (used for the treatment of epileptic seizures or fits). These include 

carbamazepine, phenobarbital, and phenytoin. 
• Herbal medicines. These include St. John’s wort (Hypericum perforatum). 
• Immunosuppressants (used after an organ transplantation). These include ciclosporin, 

everolimus, sirolimus, and tacrolimus. 
• Cardiac glycosides (used for the treatment of some heart conditions). These include digoxin. 
• Anticoagulant medicines (used to prevent blood clots). These include warfarin. 
• Medicines for diabetes. These include glimepiride, glipizide, glyburide, nateglinide, and 

repaglinide. 
• Medicines for lowering blood cholesterol. These include pitavastatin, and rosuvastatin. 
• Medicines for lowering blood pressure. These include verapamil. 
 
Kaftrio with food and drink 
Avoid food or drinks containing grapefruit during treatment as these may increase the side effects of 
Kaftrio by increasing the amount of Kaftrio in your body. 
 



33 

Pregnancy and breast-feeding 
• Ask your doctor for advice before taking this medicine if you are pregnant or breast-feeding, 

think you may be pregnant or are planning to have a baby.  
• Pregnancy: It may be better to avoid using this medicine during pregnancy. Your doctor will 

help you decide what is best for you and your child. 
• Breast-feeding: It is not known if ivacaftor, tezacaftor or elexacaftor pass into breast milk. 

Your doctor will consider the benefit of breast-feeding for your baby and the benefit of 
treatment for you to help you decide whether to stop breast-feeding or to stop treatment. 

 
Driving and using machines 
Kaftrio can make you dizzy. If you feel dizzy, do not drive, cycle, or use machines unless you are not 
affected. 
 
Kaftrio contains sodium 
This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially 
“sodium-free”. 
 
 
3. How to take Kaftrio 
 
Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor 
or pharmacist if you are not sure. 
 
Recommended dose for patients aged 12 years and over 
Kaftrio is usually taken with ivacaftor. 
• In the morning, take two Kaftrio tablets. They are stamped with “T100”. 
• In the evening, take one ivacaftor 150 mg tablet. 
Take the morning and evening tablets about 12 hours apart. 
 
The tablets are for oral use. 
 
Take both Kaftrio and ivacaftor tablets with food that contains fat. Meals or snacks that contain 
fat include those prepared with butter or oils or those containing eggs. Other fat-containing foods are: 
• Cheese, whole milk, whole milk dairy products, yogurt, chocolate 
• Meats, oily fish 
• Avocados, hummus, soy-based products (tofu) 
• Nuts, fat-containing nutritional bars or drinks 
 
Avoid food and drink containing grapefruit while you are taking Kaftrio. See Kaftrio with food and 
drink in section 2 for more details. 
 
Swallow the tablets whole. Do not chew, crush or break the tablets before swallowing. 
 
You must keep using all your other medicines, unless your doctor tells you to stop. 
 
If you have liver problems, either moderate or severe, your doctor may reduce the dose of your 
tablets or decide to stop treatment with Kaftrio. See also Warnings and precautions in section 2. 
 
If you take more Kaftrio than you should 
Contact your doctor or pharmacist for advice. If possible, take your medicine and this leaflet with 
you. You may get side effects, including those mentioned in section 4 below. 
 
If you forget to take Kaftrio 
If you forget a dose, work out how long it is since the dose you missed. 
• If less than 6 hours have passed since you missed a dose, either morning or evening, take the 

forgotten tablet(s) as soon as possible. Then go back to your usual schedule. 



34 

• If more than 6 hours have passed: 
• If you missed a morning dose of Kaftrio, take it as soon as you remember. Do not take 

the evening dose of ivacaftor. Take the next morning dose at the usual time. 
• If you missed an evening dose of ivacaftor, do not take the missed dose. Wait for the next 

day and take the morning dose of Kaftrio tablets as usual. 
Do not take a double dose to make up for any missed tablets. 
  
If you stop taking Kaftrio 
Your doctor will tell you how long you need to keep taking Kaftrio. It is important to take this 
medicine regularly. Do not make changes unless your doctor tells you. 
 
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 can cause side effects, although not everybody gets them. 
 
Serious side effects 
Possible signs of liver problems 
Increased liver enzymes in the blood are common in patients with CF. These may be signs of liver 
problems: 
• Pain or discomfort in the upper right area of the stomach (abdominal) area 
• Yellowing of the skin or the white part of the eyes 
• Loss of appetite 
• Nausea or vomiting 
• Dark urine 
Tell your doctor straight away if you have any of these symptoms. 
 
Very common side effects (may affect more than 1 in 10 people) 
• Rash (more common in women that in men) 
Tell your doctor straight away if you notice a rash. 
 
Other side effects seen with Kaftrio: 
Very common (may affect more than 1 in 10 people) 
• Headache 
• Dizziness 
• Upper respiratory tract infection (common cold)  
• Oropharyngeal pain (sore throat) 
• Nasal congestion 
• Stomach or abdominal pain 
• Diarrhoea 
• Increased liver enzymes (signs of stress on the liver) 
• Changes in the type of bacteria in mucus 
 
Common (may affect up to 1 in 10 people) 
• Flu 
• Abnormal breathing (Shortness of breath or difficulty breathing) 
• Low blood sugar (hypoglycaemia) 
• Runny nose 
• Sinus problems (sinus congestion) 
• Redness or soreness in the throat 
• Ear problems: ear pain or discomfort, ringing in the ears, inflamed eardrum 
• Spinning sensation (inner ear disorder) 
• Wind (flatulence) 



35 

• Spots (acne) 
• Itchy skin 
• Breast mass 
• Feeling nauseous 
• Increased creatine phosphokinase (sign of muscle breakdown) seen in blood tests 
 
Uncommon (may affect up to 1 in 100 people) 
• Breast and nipple problems: inflammation, pain 
• Enlargement of the breast in men 
• Increases in blood pressure 
• Wheezing 
• Blocked ears (ear congestion) 
 
Additional side effects in adolescents 
Side effects in adolescents are similar to those observed in adults. 
 
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 Kaftrio 
 
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 outer carton and on the blister 
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 to protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Kaftrio contains 
• The active substances are ivacaftor, tezacaftor and elexacaftor. Each film-coated tablet contains 

75 mg of ivacaftor, 50 mg of tezacaftor and 100 mg elexacaftor. 
• The other ingredients are: 

− Tablet core: Hypromellose (E464), hypromellose acetate succinate, sodium laurilsulfate 
(E487), croscarmellose sodium (E468), microcrystalline cellulose (E460(i)), and magnesium 
stearate (E470b). 

− Tablet film coating: Hypromellose (E464), hydroxypropyl cellulose (E463), titanium dioxide 
(E171), talc (E553b), iron oxide yellow (E172), and iron oxide red (E172). 

 
See the end of section 2 for important information about the contents of Kaftrio. 
 
What Kaftrio looks like and contents of the pack 
Kaftrio 75 mg/50 mg/100 mg film-coated tablets are orange, capsule-shaped tablets stamped with 
“T100” on one side and plain on the other. 
 
Kaftrio is available in pack size of 56 tablets (4 blister cards, each with 14 tablets). 
 

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


36 

Marketing Authorisation Holder 
Vertex Pharmaceuticals (Ireland) Limited 
28-32 Pembroke Street Upper 
Dublin 2, D02 EK84 
Ireland 
Tel: +353 (0)1 761 7299 
 
Manufacturer 
Almac Pharma Services (Ireland) Limited 
Finnabair Industrial Estate 
Dundalk 
Co. Louth 
A91 P9KD 
Ireland 
 
Almac Pharma Services Limited 
Seagoe Industrial Estate 
Craigavon 
County Armagh 
BT63 5UA 
United Kingdom 
 
This leaflet was last revised in 
 
Other sources of information 
Detailed information on this medicine is available on the European Medicines Agency website: 
http://www.ema.europa.eu. There are also links to other websites about rare diseases and treatments. 
 
 


	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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is damaged in some people with cf, if they have a mutation in the cftr gene. kaftrio is normally taken with another medicine, ivacaftor. ivacaftor causes the protein to work better, while tezacaftor and elexacaftor increase the amount of protein at the cell surface. kaftrio (taken with ivacaftor) helps your breathing by improving your lung function. you may also notice that you do not get ill as often, or that it is easier to gain weight.', 'Entity_Recognition': [{'Text': 'kaftrio', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'kaftrio', 'Type': 'TREATMENT', 'BeginOffset': 0, 'EndOffset': 7}, {'Id': 4, 'BeginOffset': 42, 'EndOffset': 51, 'Score': 0.8048577308654785, 'Text': 'ivacaftor', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Id': 5, 'BeginOffset': 53, 'EndOffset': 63, 'Score': 0.6933346390724182, 'Text': 'tezacaftor', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Id': 6, 'BeginOffset': 68, 'EndOffset': 79, 'Score': 0.2110132873058319, 'Text': 'elexacaftor', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'the medicine', 'Type': 'TREATMENT', 'BeginOffset': 81, 'EndOffset': 93}, {'Id': 15, 'BeginOffset': 100, 'EndOffset': 125, 'Score': 0.422272264957428, 'Text': 'lung cells to work better', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.4573906660079956, 'RelationshipScore': 0.5789123177528381, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 0, 'BeginOffset': 100, 'EndOffset': 104, 'Text': 'lung', 'Category': 'ANATOMY', 'Traits': []}]}, {'Id': 16, 'BeginOffset': 148, 'EndOffset': 163, 'Score': 0.8480408191680908, 'Text': 'cystic fibrosis', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9507509469985962}]}, {'Id': 17, 'BeginOffset': 165, 'EndOffset': 167, 'Score': 0.6115393042564392, 'Text': 'cf', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 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{'Title': '2. what you need to know before you take kaftrio', 'Section_Content': 'do not take kaftrio: if you are allergic to ivacaftor, tezacaftor, elexacaftor, or any other ingredients of this medicine (listed in section 6). talk to your doctor and do not take the tablets, if this applies to you. warnings and precautions talk to your doctor if you have liver problems, or have had them previously. your doctor may need to adjust your dose. your doctor will do some blood tests to check your liver before and during treatment with kaftrio, especially if your blood tests showed high liver enzymes in the past. liver enzymes in the blood can increase in patients receiving kaftrio. tell your doctor right away if you have any symptoms of liver problems. these are listed in section 4. talk to your doctor if you have kidney problems, or you have previously had them. talk to your doctor before starting treatment with kaftrio if you have received an organ transplant. talk to your doctor if you are using hormonal contraception for example, women using the contraceptive pill. this may mean you are more likely to get a rash while taking kaftrio. your doctor may do eye examinations before and during treatment with kaftrio. cloudiness of the eye lens (cataract) without any effect on vision has occurred in some children and adolescents receiving this treatment. children under 12 do not give this medicine to children under the age of 12 years because it is not known if kaftrio is safe and effective in this age group. other medicines and kaftrio tell your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines. some medicines can affect how kaftrio works or may make side effects more likely. in particular, tell your doctor if you take any of the medicines listed below. your doctor may change the dose of one of the medicines if you take any of these. antifungal medicines (used for the treatment of fungal infections). these include fluconazole, itraconazole, ketoconazole, posaconazole, and voriconazole. antibiotic medicines (used for the treatment of bacterial infections). these include clarithromycin, erythromycin, rifampicin, rifabutin, and telithromycin. epilepsy medicines (used for the treatment of epileptic seizures or fits). these include carbamazepine, phenobarbital, and phenytoin. herbal medicines. these include st. john\'s wort (hypericum perforatum). immunosuppressants (used after an organ transplantation). these include ciclosporin, everolimus, sirolimus, and tacrolimus. cardiac glycosides (used for the treatment of some heart conditions). these include digoxin. anticoagulant medicines (used to prevent blood clots). these include warfarin. medicines for diabetes. these include glimepiride, glipizide, glyburide, nateglinide, and repaglinide. medicines for lowering blood cholesterol. these include pitavastatin, and rosuvastatin. medicines for lowering blood pressure. these include verapamil. kaftrio with food and drink avoid food or drinks containing grapefruit during treatment as these may increase the side effects of kaftrio by increasing the amount of kaftrio in your body. pregnancy and breast-feeding ask your doctor for advice before taking this medicine if you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby. pregnancy: it may be better to avoid using this medicine during pregnancy. your doctor will help you decide what is best for you and your child. breast-feeding: it is not known if ivacaftor, tezacaftor or elexacaftor pass into breast milk. your doctor will consider the benefit of breast-feeding for your baby and the benefit of treatment for you to help you decide whether to stop breast-feeding or to stop treatment. driving and using machines kaftrio can make you dizzy. if you feel dizzy, do not drive, cycle, or use machines unless you are not affected. kaftrio contains sodium this medicine contains less than 1 mmol sodium (23 mg) per dose, that 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{'Title': '3. how to take kaftrio', 'Section_Content': 'always take this medicine exactly as your doctor or pharmacist has told you. check with your doctor or pharmacist if you are not sure. recommended dose for patients aged 12 years and over kaftrio is usually taken with ivacaftor. in the morning, take two kaftrio tablets. they are stamped with "t100". in the evening, take one ivacaftor 150 mg tablet. take the morning and evening tablets about 12 hours apart. the tablets are for oral use. take both kaftrio and ivacaftor tablets with food that contains fat. meals or snacks that contain fat include those prepared with butter or oils or those containing eggs. other fat-containing foods are: cheese, whole milk, whole milk dairy products, yogurt, chocolate meats, oily fish avocados, hummus, soy-based products (tofu) nuts, fat-containing nutritional bars or drinks avoid food and drink containing grapefruit while you are taking kaftrio. see kaftrio with food and drink in section 2 for more details. swallow the tablets whole. do not chew, crush or break the tablets before swallowing. you must keep using all your other medicines, unless your doctor tells you to stop. if you have liver problems, either moderate or severe, your doctor may reduce the dose of your tablets or decide to stop treatment with kaftrio. see also warnings and precautions in section 2. if you take more kaftrio than you should contact your doctor or pharmacist for advice. if possible, take your medicine and this leaflet with you. you may get side effects, including those mentioned in section 4 below. if you forget to take kaftrio if you forget a dose, work out how long it is since the dose you missed. if less than 6 hours have passed since you missed a dose, either morning or evening, take the forgotten tablet(s) as soon as possible. then go back to your usual schedule. if more than 6 hours have passed: if you missed a morning dose of kaftrio, take it as soon as you remember. do not take the evening dose of ivacaftor. take the next morning dose at the usual time. if you missed an evening dose of ivacaftor, do not take the missed dose. wait for the next day and take the morning dose of kaftrio tablets as usual. do not take a double dose to make up for any missed tablets. if you stop taking kaftrio your doctor will tell you how long you need to keep taking kaftrio. it is important to take this medicine regularly. do not make changes unless your doctor tells you. if you have any further questions on the use of this medicine, ask your doctor or pharmacist.', 'Entity_Recognition': [{'Text': 'kaftrio', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 12, 'EndOffset': 25}, {'Id': 14, 'BeginOffset': 170, 'EndOffset': 172, 'Score': 0.3804514706134796, 'Text': '12', 'Category': 'PROTECTED_HEALTH_INFORMATION', 'Type': 'AGE', 'Traits': []}, {'Id': 1, 'BeginOffset': 218, 'EndOffset': 227, 'Score': 0.9851657152175903, 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{'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. serious side effects possible signs of liver problems increased liver enzymes in the blood are common in patients with cf. these may be signs of liver problems: pain or discomfort in the upper right area of the stomach (abdominal) area yellowing of the skin or the white part of the eyes loss of appetite nausea or vomiting dark urine tell your doctor straight away if you have any of these symptoms. very common side effects (may affect more than 1 in 10 people) rash (more common in women that in men) tell your doctor straight away if you notice a rash. other side effects seen with kaftrio: very common (may affect more than 1 in 10 people) headache dizziness upper respiratory tract infection (common cold) oropharyngeal pain (sore throat) nasal congestion stomach or abdominal pain diarrhoea increased liver enzymes (signs of stress on the liver) changes in the type of bacteria in mucus common (may affect up to 1 in 10 people) flu abnormal breathing (shortness of breath or difficulty breathing) low blood sugar (hypoglycaemia) runny nose sinus problems (sinus congestion) redness or soreness in the throat ear problems: ear pain or discomfort, ringing in the ears, inflamed eardrum spinning sensation (inner ear disorder) wind (flatulence) 35 spots (acne) itchy skin breast mass feeling nauseous increased creatine phosphokinase (sign of muscle breakdown) seen in blood tests uncommon (may affect up to 1 in 100 people) breast and nipple problems: inflammation, pain enlargement of the breast in men increases in blood pressure wheezing blocked ears (ear congestion) additional side effects in adolescents side effects in adolescents are similar to those observed in adults. 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 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{'Title': '5. how to store kaftrio', 'Section_Content': '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 outer carton and on the blister 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 to protect the environment.', 'Entity_Recognition': None}
{'Title': '6. contents of the pack and other information', 'Section_Content': 'what kaftrio contains the active substances are ivacaftor, tezacaftor and elexacaftor. each film-coated tablet contains 75 mg of ivacaftor, 50 mg of tezacaftor and 100 mg elexacaftor. the other ingredients are: − tablet core: hypromellose (e464), hypromellose acetate succinate, sodium laurilsulfate (e487), croscarmellose sodium (e468), microcrystalline cellulose (e460(i)), and magnesium stearate (e470b). − tablet film coating: hypromellose (e464), hydroxypropyl cellulose (e463), titanium dioxide (e171), talc (e553b), iron oxide yellow (e172), and iron oxide red (e172). see the end of section 2 for important information about the contents of kaftrio. what kaftrio looks like and contents of the pack kaftrio 75 mg/50 mg/100 mg film-coated tablets are orange, capsule-shaped tablets stamped with "t100" on one side and plain on the other. kaftrio is available in pack size of 56 tablets (4 blister cards, each with 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