Kalydeco
1 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 

 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Kalydeco 75 mg film-coated tablets 
Kalydeco 150 mg film-coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Kalydeco 75 mg film-coated tablets 
 
Each film-coated tablet contains 75 mg of ivacaftor. 
 
Excipient with known effect 
 
Each film-coated tablet contains 83.6 mg of lactose monohydrate. 
 
Kalydeco 150 mg film-coated tablets 
 
Each film-coated tablet contains 150 mg of ivacaftor. 
 
Excipient with known effect 
 
Each film-coated tablet contains 167.2 mg of lactose monohydrate. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet (tablet) 
 
Kalydeco 75 mg film-coated tablets 
 
Light blue, capsule-shaped film-coated tablets, printed with “V 75” in black ink on one side and plain 
on the other (12.7 mm x 6.8 mm in modified tablet shape). 
 
Kalydeco 150 mg film-coated tablets 
 
Light blue, capsule-shaped film-coated tablets, printed with “V 150” in black ink on one side and plain 
on the other (16.5 mm x 8.4 mm in modified tablet shape). 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Kalydeco tablets are indicated:  
• As monotherapy for the treatment of adults, adolescents, and children aged 6 years and older 

and weighing 25 kg or more with cystic fibrosis (CF) who have an R117H CFTR mutation or 
one of the following gating (class III) mutations in the cystic fibrosis transmembrane 
conductance regulator (CFTR) gene: G551D, G1244E, G1349D, G178R, G551S, S1251N, 
S1255P, S549N or S549R (see sections 4.4 and 5.1). 
 

• In a combination regimen with tezacaftor/ivacaftor tablets for the treatment of adults, 
adolescents, and children aged 6 years and older with cystic fibrosis (CF) who are homozygous 
for the F508del mutation or who are heterozygous for the F508del mutation and have one of the 
following mutations in the CFTR gene: P67L, R117C, L206W, R352Q, A455E, D579G, 



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711+3A→G, S945L, S977F, R1070W, D1152H, 2789+5G→A, 3272-26A→G, and 
3849+10kbC→T. 
 

• In a combination regimen with ivacaftor /tezacaftor /elexacaftor tablets for the treatment of 
adults and adolescents aged 12 years and older with cystic fibrosis (CF) who are homozygous 
for the F508del mutation in the CFTR gene or heterozygous for F508del and have a minimal 
function (MF) mutation in the CFTR gene (see section 5.1). 

 
4.2 Posology and method of administration 
 
Kalydeco should only be prescribed by physicians with experience in the treatment of cystic fibrosis. 
If the patient's genotype is unknown, an accurate and validated genotyping method should be 
performed before starting treatment to confirm the presence of an indicated mutation in the CFTR gene 
(see section 4.1). The phase of the poly-T variant identified with the R117H mutation should be 
determined in accordance with local clinical recommendations. 
 
Posology 
 
Adults, adolescents, and children aged 6 years and older should be dosed according to Table 1.  
 
Table 1: Dosing recommendations 

 Morning Evening 
Ivacaftor as monotherapy 
6 years and older, 
≥25 kg One ivacaftor 150 mg tablet One ivacaftor 150 mg 

tablet 
Ivacaftor in combination with tezacaftor/ivacaftor 
6 years to <12 years, 
<30 kg One tezacaftor 50 mg/ivacaftor 75 mg tablet One ivacaftor 75 mg 

tablet 
6 years to <12 years, 
≥30 kg One tezacaftor 100 mg/ivacaftor 150 mg tablet One ivacaftor 150 mg 

tablet 

12 years and older One tezacaftor 100 mg/ivacaftor 150 mg tablet One ivacaftor 150 mg 
tablet 

Ivacaftor in combination with ivacaftor/tezacaftor/elexacaftor 

12 years and older 
Two 
ivacaftor 75 mg/tezacaftor 50 mg/elexacaftor 100 
mg tablets 

One ivacaftor 150 mg 
tablet 

  
The morning and evening dose should be taken approximately 12 hours apart with fat-containing food 
(see Method of administration). 
 
Missed dose 
 
If 6 hours or less have passed since the missed morning or evening dose, the patient should be advised 
to take it as soon as possible and then take the next dose at the regularly scheduled time. If more than 
6 hours have passed since the time the dose is usually taken, the patient should be advised to wait until 
the next scheduled dose. 
 
Patients receiving Kalydeco in a combination regimen should be advised not to take more than one 
dose of either medicine at the same time. 
 
Concomitant use of CYP3A inhibitors 
 
When co-administered with moderate or strong inhibitors of CYP3A, either as monotherapy or in a 
combination regimen with tezacaftor/ivacaftor or ivacaftor/tezacaftor/elexacaftor, the dose should be 



4 

reduced (see Table 2 for the recommended dose). Dosing intervals should be modified according to 
clinical response and tolerability (see sections 4.4 and 4.5). 
 
Table 2: Dosing recommendations for concomitant use with moderate or strong CYP3A 
inhibitors 

 Moderate CYP3A inhibitors Strong CYP3A inhibitors 
Ivacaftor as monotherapy 
6 years 
and older, 
≥25 kg 

One morning tablet of ivacaftor 150 mg once 
daily.  
 
No evening dose. 

One morning tablet of ivacaftor 150 mg 
twice a week, approximately 3 to 4 days 
apart. 
 
No evening dose. 

Ivacaftor in a combination regimen with tezacaftor/ivacaftor 
6 years to 
<12 years,  
<30 kg 

Alternate each morning:  
- one tablet of tezacaftor 

50 mg/ivacaftor 75 mg on the first 
day  

- one tablet of ivacaftor 75 mg on the 
next day.   

Continue alternating tablets each day. 
 
No evening dose. 

One morning tablet of tezacaftor 
50 mg/ivacaftor 75 mg twice a week, 
approximately 3 to 4 days apart.  
 
No evening dose. 

6 years 
<12 years, 
≥30 kg 

Alternate each morning:  
- one tablet of tezacaftor 100 

mg/ivacaftor 150 mg once daily on 
the first day 

- one tablet of ivacaftor 150 mg on the 
next day.   

Continue alternating each day. 
 
No evening dose. 

One morning tablet of tezacaftor 
100 mg/ivacaftor 150 mg twice a week, 
approximately 3 to 4 days apart. 
 
No evening dose. 

12 years 
and older 

Alternate each morning: 
- one tablet of 

tezacaftor 100 mg/ivacaftor 150 mg on 
the first day 

- one tablet of ivacaftor 150 mg on the 
next day 

Continue alternating tablets each day. 
 
No evening dose. 

One morning tablet of tezacaftor 
100 mg/ivacaftor 150 mg twice a week, 
approximately 3 to 4 days apart. 
 
No evening dose. 

Ivacaftor in a combination regimen with ivacaftor/tezacaftor/elexacaftor 
12 years 
and older 

Alternate each morning:  
- two tablets of 

ivacaftor 75 mg/tezacaftor 50 mg/elexac
aftor 100 mg on the first day  

- one tablet of ivacaftor 150 mg on the 
next day  

Continue alternating tablets each day. 
 
No evening dose. 

Two morning tablets of 
ivacaftor 75 mg/tezacaftor 50 mg/elexacaf
tor 100 mg twice a week, approximately 3 
to 4 days apart. 
 
No evening dose. 

 



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Special populations 
 
Elderly 
 
Very limited data are available for elderly patients treated with ivacaftor (administered as monotherapy 
or in a combination regimen). No dose adjustment specific to this patient population is required (see 
section 5.2). 
 
Renal impairment 
 
No dose adjustment is necessary for patients with mild to moderate renal impairment. Caution is 
recommended in patients with severe renal impairment (creatinine clearance less than or equal to 
30 mL/min) or end-stage renal disease (see sections 4.4 and 5.2). 
 
Hepatic impairment 
 
No dose adjustment is necessary for ivacaftor as monotherapy or in a combination regimen in patients 
with mild hepatic impairment (Child-Pugh Class A).  
 
For patients with moderate hepatic impairment (Child-Pugh Class B) the dose of ivacaftor as 
monotherapy should be reduced to 150 mg once daily.  
 
For patients with severe hepatic impairment (Child-Pugh Class C), the dose of ivacaftor as 
monotherapy should be reduced to 150 mg every other day or less frequently.  
 
For use as an evening dose in a combination regimen with tezacaftor/ivacaftor or 
ivacaftor/tezacaftor/elexacaftor see Table 3 for dosing regimen recommendations.  
 
Table 3: Dosing recommendations for patients with moderate or severe hepatic impairment  

 Moderate (Child-Pugh Class B) Severe (Child-Pugh Class C) 
Ivacaftor as monotherapy 
6 years and 
older, 
≥25 kg 

One morning tablet of 
ivacaftor 150 mg once daily.  
 
No evening dose. 

Use is not recommended unless the benefits are 
expected to outweigh the risks.  
 
If used: one morning tablet of ivacaftor 150 mg every 
other day or less frequently.  
 
Dosing interval should be modified according to 
clinical response and tolerability.  
 
No evening dose. 



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Ivacaftor in a combination regimen with tezacaftor/ivacaftor 
6 years to 
<12 years,  
<30 kg 

One morning tablet of tezacaftor 
50 mg/ivacaftor 75 mg once daily.  
 
No evening dose. 

Use is not recommended unless the benefits are 
expected to outweigh the risks.  
 
If used: one morning tablet of tezacaftor 
50 mg/ivacaftor 75 mg once daily or less frequently.  
 
Dosing interval should be modified according to 
clinical response and tolerability.  
 
No evening dose. 

6 years to 
<12 years, 
≥30 kg 

One morning tablet of tezacaftor 
100 mg/ivacaftor 150 mg once 
daily.  
 
No evening dose. 

Use is not recommended unless the benefits are 
expected to outweigh the risks.  
 
If used: one morning tablet of tezacaftor 
100 mg/ivacaftor 150 mg once daily or less 
frequently. 
  
Dosing interval should be modified according to 
clinical response and tolerability.  
 
No evening dose. 

12 years 
and older 

One morning tablet of 
tezacaftor 100 mg/ivacaftor 150 m
g once daily. 
 
No evening dose. 

Use is not recommended unless the benefits are 
expected to outweigh the risks.  
 
If used: one morning tablet of 
tezacaftor 100 mg/ivacaftor 150 mg once daily or less 
frequently.  
 
Dosing interval should be modified according to 
clinical response and tolerability.  
 
No evening dose. 

Ivacaftor in a combination regimen with ivacaftor/tezacaftor/elexacaftor  
12 years 
and older 

Use not recommended. 
Use should only be considered 
when there is a clear medical need 
and the benefits are expected to 
outweigh the risks. 
 
If used: alternate each day 
between two 
ivacaftor 75 mg/tezacaftor 50 mg/
elexacaftor 100 mg tablets and one 
ivacaftor 75 mg/tezacaftor 50 mg/
elexacaftor 100 mg tablet. 
 
No evening dose. 

Should not be used. 
 
 

 

Paediatric population 
 
The safety and efficacy of ivacaftor have not been established in children less than 4 months of age as 
monotherapy, neither in combination with tezacaftor/ivacaftor in children less than 6 years of age or in 



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combination with ivacaftor/tezacaftor/elexacaftor in children less than 12 years of age. No data are 
available. 
 
Limited data are available in patients less than 6 years of age with an R117H mutation in the CFTR 
gene. Available data in patients aged 6 years and older are described in sections 4.8, 5.1, and 5.2. 
 
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. 
 
Ivacaftor tablets should be taken with fat-containing food. 
 
Food or drink containing grapefruit should be avoided during treatment (see section 4.5). 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
 
4.4 Special warnings and precautions for use 
 
Only patients with CF who had a G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, 
S549N, S549R gating (class III), G970R or R117H mutation in at least one allele of the CFTR gene 
were included in studies 1, 2, 5 and 6 (see section 5.1). 
 
In study 5, four patients with the G970R mutation were included. In three of four patients the change 
in the sweat chloride test was < 5 mmol/L and this group did not demonstrate a clinically relevant 
improvement in FEV1 after 8 weeks of treatment. Clinical efficacy in patients with the G970R 
mutation of the CFTR gene could not be established (see section 5.1). 
 
Efficacy results from a phase 2 study in patients with CF who are homozygous for the F508del 
mutation in the CFTR gene showed no statistically significant difference in FEV1 over 16 weeks of 
ivacaftor treatment compared to placebo (see section 5.1). Therefore, use of ivacaftor as monotherapy 
in these patients is not recommended. 
 
Less evidence of a positive effect of ivacaftor has been shown for patients with an R117H-7T mutation 
associated with less severe disease in study 6 (see section 5.1).  
 
Ivacaftor in a combination regimen with tezacaftor/ivacaftor should not be prescribed in patients with 
CF who are heterozygous for the F508del mutation and have a second CFTR mutation not listed in 
section 4.1. 
 
Effect on liver function tests 
 
Moderate transaminase (alanine transaminase [ALT] or aspartate transaminase [AST]) elevations are 
common in subjects with CF. Transaminase elevations have been observed in some patients treated 
with ivacaftor as monotherapy and in combination regimens with tezacaftor/ivacaftor or 
ivacaftor/tezacaftor/elexacaftor. Therefore, liver function tests are recommended for all patients prior 
to initiating ivacaftor, every 3 months during the first year of treatment and annually thereafter. For all 
patients with a history of transaminase elevations, more frequent monitoring of liver function tests 
should be considered. In the event of significant elevations of transaminases (e.g., patients with 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. 



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Following resolution of transaminase elevations, the benefits and risks of resuming treatment should 
be considered (see section 4.8). 
 
Hepatic impairment 
 
Use of ivacaftor, either as monotherapy or in a combination regimen with tezacaftor/ivacaftor, is not 
recommended in patients with severe hepatic impairment unless the benefits are expected to outweigh 
the risks. Patients with severe hepatic impairment should not be treated with ivacaftor in a combination 
regimen with ivacaftor/tezacaftor/elexacaftor. (See Table 3 and sections 4.2 and 5.2).  
 
For patients with moderate hepatic impairment, use of ivacaftor in a combination regimen with 
ivacaftor/tezacaftor/elexacaftor is not recommended. Treatment 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 3 and sections 4.2 and 5.2). 
 
Renal impairment 
 
Caution is recommended while using ivacaftor, either as monotherapy or in a combination regimen 
with tezacaftor/ivacaftor or ivacaftor/tezacaftor/elexacaftor, in patients with severe renal impairment or 
end-stage renal disease (see sections 4.2 and 5.2). 
 
Patients after organ transplantation 
 
Ivacaftor, either as monotherapy or in a combination regimen with tezacaftor/ivacaftor or 
ivacaftor/tezacaftor/elexacaftor, 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 ciclosporin or tacrolimus. 
 
Rash events  
 
The incidence of rash events with ivacaftor in a combination regimen with 
ivacaftor/tezacaftor/elexacaftor 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 
ivacaftor in a combination regimen with ivacaftor/tezacaftor/elexacaftor and hormonal contraceptives 
should be considered. Following the resolution of rash, it should be considered if resuming ivacaftor in 
a combination regimen with ivacaftor/tezacaftor/elexacaftor without hormonal contraceptives is 
appropriate. If rash does not recur, resumption of hormonal contraceptives can be considered (see 
section 4.8).  
 
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 loss of 
ivacaftor efficacy; therefore, co-administration of ivacaftor (as monotherapy or in a combination 
regimen with tezacaftor/ivacaftor or ivacaftor/tezacaftor/elexacaftor) with strong CYP3A inducers is 
not recommended (see section 4.5).  
 



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CYP3A inhibitors 
 
Exposure to ivacaftor, tezacaftor and elexacaftor are increased when co-administered with strong or 
moderate CYP3A inhibitors. The dose of ivacaftor (as monotherapy or in a combination regimen with 
tezacaftor/ivacaftor or ivacaftor/tezacaftor/elexacaftor) must be adjusted when used concomitantly 
with strong or moderate CYP3A inhibitors (see Table 2 and sections 4.2 and 4.5). 
 
Paediatric population 
 
Cases of non-congenital lens opacities/cataracts without impact on vision have been reported in 
paediatric patients treated with ivacaftor and ivacaftor-containing regimens. Although other risk 
factors were present in some cases (such as corticosteroid use and 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 ivacaftor treatment, 
either as monotherapy or in a combination regimen with tezacaftor/ivacaftor or 
ivacaftor/tezacaftor/elexacaftor (see section 5.3). 
 
Lactose content 
 
Kalydeco contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase 
deficiency or glucose-galactose malabsorption should not take this medicine. 
 
Sodium content 
 
This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially 
‘sodium-free’. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Ivacaftor is a substrate of CYP3A4 and CYP3A5. It is a weak inhibitor of CYP3A and P-gp and a 
potential inhibitor of CYP2C9. In vitro studies showed that ivacaftor is not a substrate for P-gp.  
 
Medicinal products affecting the pharmacokinetics of ivacaftor 
 
CYP3A inducers 
 
Co-administration of ivacaftor with rifampicin, a strong CYP3A inducer, decreased ivacaftor exposure 
(AUC) by 89% and decreased hydroxymethyl ivacaftor (M1) to a lesser extent than ivacaftor. 
Co-administration of ivacaftor (as monotherapy or in a combination regimen with tezacaftor/ivacaftor 
or ivacaftor/tezacaftor/elexacaftor) with strong CYP3A inducers, such as rifampicin, rifabutin, 
phenobarbital, carbamazepine, phenytoin and St. John’s wort (Hypericum perforatum), is not 
recommended (see section 4.4). 
 
No dose adjustment is recommended when ivacaftor (as monotherapy or in a combination regimen 
with tezacaftor/ivacaftor or ivacaftor/tezacaftor/elexacaftor) is used with moderate or weak CYP3A 
inducers.  
 
CYP3A inhibitors 
 
Ivacaftor is a sensitive CYP3A substrate. Co-administration with ketoconazole, a strong CYP3A 
inhibitor, increased ivacaftor exposure (measured as area under the curve [AUC]) by 8.5-fold and 
increased M1 to a lesser extent than ivacaftor. A reduction of the ivacaftor dose (as monotherapy or in 
a combination regimen with tezacaftor/ivacaftor or ivacaftor/tezacaftor/elexacaftor) is recommended 
for co-administration with strong CYP3A inhibitors, such as ketoconazole, itraconazole, posaconazole, 
voriconazole, telithromycin and clarithromycin (see Table 2 and sections 4.2 and 4.4). 
 



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Co-administration with fluconazole, a moderate inhibitor of CYP3A, increased ivacaftor exposure by 
3-fold and increased M1 to a lesser extent than ivacaftor. A reduction of the ivacaftor dose (as 
monotherapy or in a combination regimen with tezacaftor/ivacaftor or ivacaftor/tezacaftor/elexacaftor) 
is recommended for patients taking concomitant moderate CYP3A inhibitors, such as fluconazole, 
erythromycin, and verapamil (see Table 2 and sections 4.2 and 4.4). 
 
Co-administration of ivacaftor with grapefruit juice, which contains one or more components that 
moderately inhibit CYP3A, may increase exposure to ivacaftor. Food or drink containing grapefruit 
should be avoided during treatment with ivacaftor (as monotherapy or in a combination regimen with 
tezacaftor/ivacaftor or ivacaftor/tezacaftor/elexacaftor, see section 4.2). 
 
Potential for ivacaftor to interact with transporters 
 
In vitro studies showed that ivacaftor is not a substrate for OATP1B1 or OATP1B3. 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.  
 
Ciprofloxacin 
 
Co-administration of ciprofloxacin with ivacaftor did not affect the exposure of ivacaftor. No dose 
adjustment is required when ivacaftor (as monotherapy or in a combination regimen with 
tezacaftor/ivacaftor or ivacaftor/tezacaftor/elexacaftor) is co-administered with ciprofloxacin. 
 
Medicinal products affected by ivacaftor 
 
Administration of ivacaftor may increase systemic exposure of medicinal products that are sensitive 
substrates of CYP2C9, and/or P-gp, and/or CYP3A which may increase or prolong their therapeutic 
effect and adverse reactions. 
 
CYP2C9 substrates 
 
Ivacaftor may inhibit CYP2C9. Therefore, monitoring of the international normalised ratio (INR) is 
recommended during co-administration of warfarin with ivacaftor (as monotherapy or in a 
combination regimen with tezacaftor/ivacaftor or ivacaftor/tezacaftor/elexacaftor). Other medicinal 
products for which exposure may be increased include glimepiride and glipizide; these medicinal 
products should be used with caution. 
 
Digoxin and other P-gp substrates 
 
Co-administration with digoxin, a sensitive P-gp substrate, increased digoxin exposure by 1.3-fold, 
consistent with weak inhibition of P-gp by ivacaftor. Administration of ivacaftor (as monotherapy or 
in a combination regimen with tezacaftor/ivacaftor or ivacaftor/tezacaftor/elexacaftor) 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 or 
tacrolimus, caution and appropriate monitoring should be used. 
 
CYP3A substrates  
 
Co-administration with (oral) midazolam, a sensitive CYP3A substrate, increased midazolam exposure 
1.5-fold, consistent with weak inhibition of CYP3A by ivacaftor. No dose adjustment of CYP3A 
substrates, such as midazolam, alprazolam, diazepam or triazolam, is required when these are 
co-administered with ivacaftor (as monotherapy or in a combination regimen with tezacaftor/ivacaftor 
or ivacaftor/tezacaftor/elexacaftor).  
 



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Hormonal contraceptives 
 
Ivacaftor (as monotherapy or in a combination regimen with tezacaftor/ivacaftor or 
ivacaftor/tezacaftor/elexacaftor) has been studied with an oestrogen/progesterone oral contraceptive 
and was found to have no significant effect on the exposures of the oral contraceptive. Therefore, no 
dose adjustment of oral contraceptives is necessary. 
 
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 ivacaftor in 
pregnant women. Animals 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 
ivacaftor during pregnancy. 
 
Breast-feeding 
 
It is unknown whether ivacaftor and/or its metabolites are excreted in human milk. Available 
pharmacokinetic data in animals have shown excretion of ivacaftor into the milk of lactating female 
rats. As such, a risk to the newborns/infants cannot be excluded. A decision must be made whether to 
discontinue breast-feeding or to discontinue/abstain from ivacaftor 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 ivacaftor on fertility in humans. Ivacaftor had an effect on 
fertility in rats (see section 5.3). 
 
4.7 Effects on ability to drive and use machines 
 
Ivacaftor has minor influence on the ability to drive or use machines. Ivacaftor may cause dizziness 
(see section 4.8) and, therefore, 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 6 years and older who received 
ivacaftor are headache (23.9%), oropharyngeal pain (22.0%), upper respiratory tract infection (22.0%), 
nasal congestion (20.2%), abdominal pain (15.6%), nasopharyngitis (14.7%), diarrhoea (12.8%), 
dizziness (9.2%), rash (12.8%) and bacteria in sputum (12.8%). Transaminase elevations occurred in 
12.8% of ivacaftor-treated patients versus 11.5% of placebo-treated patients. 
 
In patients aged 2 to less than 6 years the most common adverse reactions were nasal congestion 
(26.5%), upper respiratory tract infection (23.5%), transaminase elevations (14.7%), rash (11.8%), and 
bacteria in sputum (11.8%). 
 
Serious adverse reactions in patients who received ivacaftor included abdominal pain and transaminase 
elevations (see section 4.4). 
 



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Tabulated list of adverse reactions 
 
Table 4 reflects the adverse reactions observed with ivacaftor monotherapy in clinical trials (placebo-
controlled and uncontrolled studies) in which the length of exposure to ivacaftor ranged from 16 weeks 
to 144 weeks. Additional adverse reactions observed with ivacaftor in a combination regimen with 
tezacaftor/ivacaftor and/or in a combination regimen with ivacaftor/tezacaftor/elexacaftor are also 
provided in Table 4. The frequency of adverse reactions is 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); very 
rare (< 1/10,000); not known (cannot be estimated from the available data). Within each frequency 
grouping, adverse reactions are presented in order of decreasing seriousness. 
 
Table 4: Adverse reactions 

System organ class Adverse reactions Frequency 
Infections and infestations Upper respiratory tract infection very common 

Nasopharyngitis very common 
Influenza † common  
Rhinitis common 

Metabolism and nutrition 
disorders 

Hypoglycaemia †  common  

Nervous system disorders Headache very common 
Dizziness very common 

Ear and labyrinth disorders Ear pain common 
Ear discomfort common 
Tinnitus common 
Tympanic membrane hyperaemia common 
Vestibular disorder common 
Ear congestion uncommon 

Respiratory, thoracic and 
mediastinal disorders 

Oropharyngeal pain very common 
Nasal congestion very common 
Abnormal breathing † common  
Rhinorrhoea † common  
Sinus congestion common 
Pharyngeal erythema common 
Wheezing † uncommon 

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

Hepatobiliary disorders Transaminase elevations very common 
Alanine aminotransferase 
increased † 

common 

Aspartate aminotransferase 
increased † 

common  

Skin and subcutaneous tissue 
disorders 

Rash very common 
Acne † common 
Pruritus † common  

Reproductive system and breast 
disorders 

Breast mass common 
Breast inflammation uncommon 
Gynaecomastia uncommon 



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System organ class Adverse reactions Frequency 
Nipple disorder uncommon 
Nipple pain uncommon 

Investigations Bacteria in sputum very common 
Blood creatine phosphokinase 
increased † 

common 

Blood pressure increased † uncommon  
* Adverse reaction and frequency reported from clinical studies with ivacaftor in combination with tezacaftor/ivacaftor 
† Adverse reaction and frequency reported from clinical studies with ivacaftor in combination with 

ivacaftor/tezacaftor/elexacaftor 
 
Description of selected adverse reactions 
 
Transaminase elevations  
 
During the 48-week placebo-controlled studies 1 and 2 of ivacaftor as monotherapy in patients aged 
6 years and older, the incidence of maximum transaminase (ALT or AST) > 8, > 5 or > 3 x ULN was 
3.7%, 3.7% and 8.3% in ivacaftor-treated patients and 1.0%, 1.9% and 8.7% in placebo-treated 
patients, respectively. Two patients, one on placebo and one on ivacaftor permanently discontinued 
treatment for elevated transaminases, each > 8 x ULN. No ivacaftor-treated patients experienced a 
transaminase elevation > 3 x ULN associated with elevated total bilirubin > 1.5 x ULN. In 
ivacaftor-treated patients, most transaminase elevations up to 5 x ULN resolved without treatment 
interruption. Ivacaftor dosing was interrupted in most patients with transaminase elevations > 5 x 
ULN. In all instances where dosing was interrupted for elevated transaminases and subsequently 
resumed, ivacaftor dosing was able to be resumed successfully (see section 4.4). 
 
During the placebo controlled phase 3 studies (up to 24 weeks) of tezacaftor/ivacaftor, the incidence of 
maximum transaminase (ALT or AST) > 8, > 5, or > 3 x ULN were 0.2%, 1.0%, and 3.4% in 
tezacaftor/ivacaftor treated patients, and 0.4%, 1.0%, and 3.4% in placebo-treated patients. One patient 
(0.2%) on therapy and 2 patients (0.4%) on placebo permanently discontinued treatment for elevated 
transaminases. No patients treated with tezacaftor/ivacaftor experienced a transaminase elevation >3 x 
ULN associated with elevated total bilirubin >2 x ULN.  
 
During the 24-week, placebo-controlled, phase 3 study of ivacaftor/tezacaftor/elexacaftor, these 
figures were 1.5%, 2.5%, and 7.9% in ivacaftor/tezacaftor/elexacaftor-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 ivacaftor in a combination regimen with ivacaftor/tezacaftor/elexacaftor treated patients 
and 4.0% in placebo-treated patients. 
 
Rash events 
 
Rash events, generally mild to moderate in severity, have been observed with the use of ivacaftor in a 
combination regimen with ivacaftor/tezacaftor/elexacaftor and occurred more frequently in female-
treated patients (16.3%) and in those taking hormonal contraceptives (20.5%). See section 4.4. 
 
Increased creatine phosphokinase  
 
Generally transient and asymptomatic increases in creatine phosphokinase were observed in patients 
treated with ivacaftor in a combination regimen with ivacaftor/tezacaftor/elexacaftor, which did not 
lead to treatment discontinuation. 
 



14 

Increased blood pressure 
 
An increase from baseline in mean systolic and diastolic blood pressure of 3.5 mmHg and 1.9 mmHg, 
respectively was observed in patients treated with ivacaftor in a combination regimen with 
ivacaftor/tezacaftor/elexacaftor.  
 
Paediatric population 
 
The safety data of ivacaftor as monotherapy were evaluated in 6 patients between 4 months to less than 
6 months of age, 11 patients between 6 months to less than 12 months of age, 19 patients between 
12 months to less than 24 months of age, 34 patients between 2 to less than 6 years of age, 61 patients 
between 6 to less than 12 years of age and 94 patients between 12 to less than 18 years of age.  
 
The safety profile of ivacaftor (as monotherapy or in a combination regimen) is generally consistent 
among paediatric patients and is also consistent with adult patients. 
 
The incidence of transaminase elevations (ALT or AST) observed in studies 2, 5 and 6 (patients aged 
6 to less than 12 years), study 7 (patients aged 2 to less than 6 years), and study 8 (patients aged 6 to 
less than 24 months) are described in Table 5. In the placebo controlled studies, the incidence of 
transaminase elevations were similar between treatment with ivacaftor (15.0%) and placebo (14.6%). 
Peak LFT elevations were generally higher in paediatric patients than in older patients. Across all 
populations, peak LFT elevations returned to baseline levels following interruption, and in almost all 
instances where dosing was interrupted for elevated transaminases and subsequently resumed, 
ivacaftor dosing was able to be resumed successfully (see section 4.4). Cases suggestive of positive 
rechallenge were observed. In study 7 ivacaftor was permanently discontinued in one patient. In 
study 8 no patients had elevations in total bilirubin or discontinued ivacaftor treatment due to 
transaminase elevations in either age cohort (see section 4.4 for management of elevated 
transaminases). 
 
Table 5: Transaminase elevations in patients 4 months to < 12 years treated with ivacaftor as 
monotherapy 

 n % of Patients 
> 3 x ULN  

% of Patients 
>5 x ULN 

% of Patients 
> 8 x ULN 

6 to <12 years 40 15.0% (6) 2.5% (1) 2.5% (1) 
2 to <6 years 34 14.7% (5) 14.7% (5) 14.7% (5) 
12 to <24 months 18 27.8% (5) 11.1% (2) 11.1% (2) 
6 to <12 months 11 9.1% (1) 0.0% (0) 0.0% (0) 
4 to <6 months 6 0.0% (0) 0.0% (0) 0.0% (0) 

 
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 ivacaftor. Treatment of overdose consists of general 
supportive measures including monitoring of vital signs, liver function tests and observation of the 
clinical status of the patient. 
 
 

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


15 

5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Other respiratory system products, ATC code: R07AX02 
 
Mechanism of action 
 
Ivacaftor is a potentiator of the CFTR protein, i.e., in vitro ivacaftor increases CFTR channel gating to 
enhance chloride transport in specified gating mutations (as listed in section 4.1) with reduced 
channel-open probability compared to normal CFTR. Ivacaftor also potentiated the channel-open 
probability of R117H-CFTR, which has both low channel-open probability (gating) and reduced 
channel current amplitude (conductance). The G970R mutation causes a splicing defect resulting in 
little-to-no CFTR protein at the cell surface which may explain the results observed in subjects with 
this mutation in study 5 (see Pharmacodynamic effects and Clinical efficacy data). 
 
In vitro responses seen in single channel patch clamp experiments using membrane patches from 
rodent cells expressing mutant CFTR forms do not necessarily correspond to in vivo pharmacodynamic 
response (e.g., sweat chloride) or clinical benefit. The exact mechanism leading ivacaftor to potentiate 
the gating activity of normal and some mutant CFTR forms in this system has not been completely 
elucidated. 
 
Pharmacodynamic effects 
 
Ivacaftor as monotherapy 
 
In studies 1 and 2 in patients with the G551D mutation in one allele of the CFTR gene, ivacaftor led to 
rapid (15 days), substantial (the mean change in sweat chloride from baseline through week 24 
was -48 mmol/L [95% CI -51, -45] and -54 mmol/L [95% CI -62, -47], respectively) and sustained 
(through 48 weeks) reductions in sweat chloride concentration. 
 
In study 5, part 1 in patients who had a non-G551D gating mutation in the CFTR gene, treatment with 
ivacaftor led to a rapid (15 days) and substantial mean change from baseline in sweat chloride 
of -49 mmol/L (95% CI -57, -41) through 8 weeks of treatment. However, in patients with the 
G970R-CFTR mutation, the mean (SD) absolute change in sweat chloride at week 8 was -6.25 
(6.55) mmol/L. Similar results to part 1 were seen in part 2 of the study. At the 4-week follow-up visit 
(4 weeks after dosing with ivacaftor ended), mean sweat chloride values for each group were trending 
to pre-treatment levels. 
 
In study 6 in patients aged 6 years or older with CF who had an R117H mutation in the CFTR gene, 
the treatment difference in mean change in sweat chloride from baseline through 24 weeks of 
treatment was -24 mmol/L (95% CI -28, -20). In subgroup analyses by age, the treatment difference 
was -21.87 mmol/L (95% CI: -26.46, -17.28) in patients aged 18 years or older, and -27.63 mmol/L 
(95% CI: -37.16, -18.10) in patients aged 6-11 years. Two patients 12 to 17 years of age were enrolled 
in this study. 
 
Ivacaftor in a combination regimen with tezacaftor/ivacaftor 
 
In patients homozygous for the F508del mutation, the treatment difference between ivacaftor in 
combination with tezacaftor/ivacaftor and placebo in mean absolute change from baseline in sweat 
chloride through week 24, was -10.1 mmol/L (95% CI: -11.4, -8.8). 
 
In patients heterozygous for the F508del mutation and a second mutation associated with residual 
CFTR activity, the treatment difference in mean absolute change from baseline in sweat chloride 
through week 8 was -9.5 mmol/L (95% CI: -11.7, -7.3) between tezacaftor/ivacaftor and placebo, 
and -4.5 mmol/L (95% CI: -6.7, -2.3) between ivacaftor and placebo. 
 



16 

In patients aged 6 to less than 12 years who were homozygous or heterozygous for the F508del 
mutation and a second mutation associated with residual CFTR activity, mean within-group absolute 
change in sweat chloride from baseline at week 8 was -12.3 mmol/L (95% CI: -15.3, -9.3) in the 
tezacaftor/ivacaftor group. 
 
Ivacaftor in a combination regimen with ivacaftor/tezacaftor/elexacaftor 
 
In patients with an F508del mutation on one allele and a mutation on the second allele that predicts 
either no production of CFTR protein or a CFTR protein that is not responsive to ivacaftor and 
tezacaftor/ivacaftor, the treatment difference between ivacaftor/tezacaftor/elexacaftor 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). 
 
In patients homozygous for the F508del mutation, the treatment difference between 
ivacaftor/tezacaftor/elexacaftor 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). 
 
Clinical efficacy and safety 
 
Ivacaftor as monotherapy 
 
Studies 1 and 2: studies in patients with CF with G551D gating mutations 
 
The efficacy of ivacaftor has been evaluated in two phase 3 randomised, double-blind, 
placebo-controlled, multi-centre studies of clinically stable patients with CF who had the G551D 
mutation in the CFTR gene on at least 1 allele and had FEV1 ≥ 40% predicted. 
 
Patients in both studies were randomised 1:1 to receive either 150 mg of ivacaftor or placebo every 
12 hours with food containing fat for 48 weeks in addition to their prescribed CF therapies (e.g., 
tobramycin, dornase alfa). The use of inhaled hypertonic sodium chloride was not permitted. 
 
Study 1 evaluated 161 patients who were 12 years of age or older; 122 (75.8%) patients had the 
F508del mutation in the second allele. At the start of the study, patients in the placebo group used 
some medicinal products at a higher frequency than the ivacaftor group. These medications included 
dornase alfa (73.1% versus 65.1%), salbutamol (53.8% versus 42.2%), tobramycin (44.9% versus 
33.7%) and salmeterol/fluticasone (41.0% versus 27.7%). At baseline, mean predicted FEV1 was 
63.6% (range: 31.6% to 98.2%) and mean age was 26 years (range: 12 to 53 years). 
 
Study 2 evaluated 52 patients who were 6 to 11 years of age at screening; mean (SD) body weight was 
30.9 (8.63) kg; 42 (80.8%) patients had the F508del mutation in the second allele. At baseline, mean 
predicted FEV1 was 84.2% (range: 44.0% to 133.8%) and mean age was 9 years (range: 6 to 12 years); 
8 (30.8%) patients in the placebo group and 4 (15.4%) patients in the ivacaftor group had an FEV1 less 
than 70% predicted at baseline. 
 
The primary efficacy endpoint in both studies was the mean absolute change from baseline in percent 
predicted FEV1 through 24 weeks of treatment. 
 
The treatment difference between ivacaftor and placebo for the mean absolute change (95% CI) in 
percent predicted FEV1 from baseline through week 24 was 10.6 percentage points (8.6, 12.6) in study 
1 and 12.5 percentage points (6.6, 18.3) in study 2. The treatment difference between ivacaftor and 
placebo for the mean relative change (95% CI) in percent predicted FEV1 from baseline through 
week 24 was 17.1% (13.9, 20.2) in study 1 and 15.8% (8.4, 23.2) in study 2. The mean change from 
baseline through week 24 in FEV1 (L) was 0.37 L in the ivacaftor group and 0.01 L in the placebo 
group in study 1 and 0.30 L in the ivacaftor group and 0.07 L in the placebo group in study 2. In both 
studies, improvements in FEV1 were rapid in onset (day 15) and durable through 48 weeks. 
 



17 

The treatment difference between ivacaftor and placebo for the mean absolute change (95% CI) in 
percent predicted FEV1 from baseline through week 24 in patients 12 to 17 years of age in study 1 was 
11.9 percentage points (5.9, 17.9). The treatment difference between ivacaftor and placebo for the 
mean absolute change (95% CI) in percent predicted FEV1 from baseline through week 24 in patients 
with baseline predicted FEV1 greater than 90% in study 2 was 6.9 percentage points (-3.8, 17.6). 
 
The results for clinically relevant secondary endpoints are shown in Table 6. 
 
Table 6: Effect of ivacaftor on other efficacy endpoints in studies 1 and 2 

Endpoint 

Study 1 Study 2 
Treatment 
differencea 
(95% CI) P value 

Treatment 
differencea 
(95% CI) P value 

Mean absolute change from baseline in CFQ-Rb respiratory domain score (points)c 
Through week 24 8.1 

(4.7, 11.4) 
< 0.0001 6.1 

(-1.4, 13.5) 
0.1092 

Through week 48 8.6 
(5.3, 11.9) 

< 0.0001 5.1 
(-1.6, 11.8) 

0.1354 

Relative risk of pulmonary exacerbation 
Through week 24 0.40d 0.0016 NA NA 
Through week 48 0.46d 0.0012 NA NA 
Mean absolute change from baseline in body weight (kg) 
At week 24 2.8 

(1.8, 3.7) 
< 0.0001 1.9 

(0.9, 2.9) 
0.0004 

At week 48 2.7 
(1.3, 4.1) 

0.0001 2.8 
(1.3, 4.2) 

0.0002 

Mean absolute change from baseline in BMI (kg/m2) 
At week 24 0.94 

(0.62, 1.26) 
< 0.0001 0.81 

(0.34, 1.28) 
0.0008 

At week 48 0.93 
(0.48, 1.38) 

< 0.0001 1.09 
(0.51, 1.67) 

0.0003 

Mean change from baseline in z-scores 
Weight-for-age z-score 
at week 48e 

0.33 
(0.04, 0.62) 

0.0260 0.39 
(0.24, 0.53) 

< 0.0001 

BMI-for-age z-score at 
week 48e 

0.33 
(0.002, 0.65) 

0.0490 0.45 
(0.26, 0.65) 

< 0.0001 

CI: confidence interval; NA: not analysed due to low incidence of events 
a Treatment difference = effect of ivacaftor – effect of placebo 
b CFQ-R: Cystic Fibrosis Questionnaire-Revised is a disease-specific, health-related quality-of-life measure for CF. 
c Study 1 data were pooled from CFQ-R for adults/adolescents and CFQ-R for children 12 to 13 years of age; Study 2 data 

were obtained from CFQ-R for children 6 to 11 years of age. 
d Hazard ratio for time to first pulmonary exacerbation 
e In subjects under 20 years of age (CDC growth charts) 
 
Study 5: study in patients with CF with non-G551D gating mutations 
 
Study 5 was a phase 3, two-part, randomised, double-blind, placebo-controlled, crossover study 
(part 1) followed by a 16-week open-label extension period (part 2) to evaluate the efficacy and safety 
of ivacaftor in patients with CF aged 6 years and older who have a G970R or non-G551D gating 
mutation in the CFTR gene (G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P or G1349D). 
 
In part 1, patients were randomised 1:1 to receive either 150 mg of ivacaftor or placebo every 12 hours 
with fat-containing food for 8 weeks in addition to their prescribed CF therapies and crossed over to 
the other treatment for the second 8 weeks after a 4- to 8-week washout period. The use of inhaled 
hypertonic saline was not permitted. In part 2, all patients received ivacaftor as indicated in part 1 for 
16 additional weeks. The duration of continuous ivacaftor treatment was 24 weeks for patients 



18 

randomised to part 1 placebo/ivacaftor treatment sequence and 16 weeks for patients randomised to 
part 1 ivacaftor/placebo treatment sequence. 
 
Thirty-nine patients (mean age 23 years) with baseline FEV1 ≥ 40% predicted (mean FEV1 78% 
predicted [range: 43% to 119%]) were enrolled. Sixty-two percent (24/39) of them carried the 
F508del-CFTR mutation in the second allele. A total of 36 patients continued into part 2 (18 per 
treatment sequence). 
 
In part 1 of study 5, the mean FEV1 percent predicted at baseline in placebo-treated patients was 
79.3% while in ivacaftor-treated patients this value was 76.4%. The mean overall post-baseline value 
was 76.0% and 83.7%, respectively. The mean absolute change from baseline through week 8 in 
percent predicted FEV1 (primary efficacy endpoint) was 7.5% in the ivacaftor period and -3.2% in the 
placebo period. The observed treatment difference (95% CI) between ivacaftor and placebo was 10.7% 
(7.3, 14.1) (P < 0.0001). 
 
The effect of ivacaftor in the overall population of study 5 (including the secondary endpoints absolute 
change in BMI at 8 weeks of treatment and absolute change in the respiratory domain score of the 
CFQ-R through 8 weeks of treatment) and by individual mutation (absolute change in sweat chloride 
and in percent predicted FEV1 at week 8) is shown in Table 7. Based on clinical (percent predicted 
FEV1) and pharmacodynamic (sweat chloride) responses to ivacaftor, efficacy in patients with the 
G970R mutation could not be established. 
 
Table 7: Effect of ivacaftor for efficacy variables in the overall population and for specific CFTR 

mutations 

Absolute change in percent 
predicted FEV1 

BMI 
(kg/m2) 

CFQ-R respiratory domain 
score (points) 

Through week 8 At week 8 Through week 8 
All patients (N = 39) 
Results shown as mean (95% CI) change from baseline ivacaftor vs placebo-treated patients: 

10.7 (7.3, 14.1) 0.66 (0.34, 0.99) 9.6 (4.5, 14.7) 
Patients grouped under mutation types (n) 
Results shown as mean (minimum, maximum) change from baseline for ivacaftor-treated patients 
at week 8*: 
Mutation (n) 
 

Absolute change in sweat chloride 
(mmol/L) 

Absolute change in percent predicted 
FEV1 (percentage points) 

At week 8 At week 8 
G1244E (5) 
G1349D (2) 
G178R (5) 
G551S (2) 
G970R# (4) 
S1251N (8) 
S1255P (2) 
S549N (6) 
S549R (4) 

‑55 (-75, -34) 
-80 (-82, -79) 
-53 (-65, -35) 

-68† 
-6 (-16, -2) 
-54 (-84, -7) 

-78 (-82, -74) 
-74 (-93, -53) 

-61†† (-71, -54) 

8 (-1, 18) 
20 (3, 36) 
8 (-1, 18) 

3† 
3 (-1, 5) 

9 (-20, 21) 
3 (-1, 8) 

11 (-2, 20) 
5 (-3, 13) 

* Statistical testing was not performed due to small numbers for individual mutations. 
† Reflects results from the one patient with the G551S mutation with data at the 8-week time point. 
†† n = 3 for the analysis of absolute change in sweat chloride. 
# Causes a splicing defect resulting in little-to-no CFTR protein at the cell surface 
 
In part 2 of study 5, the mean (SD) absolute change in percent predicted FEV1 following 16 weeks 
(patients randomised to the ivacaftor/placebo treatment sequence in part 1) of continuous ivacaftor 
treatment was 10.4% (13.2%). At the follow-up visit, 4 weeks after ivacaftor dosing had ended, the 
mean (SD) absolute change in percent predicted FEV1 from part 2 week 16 was -5.9% (9.4%). For 
patients randomised to the placebo/ivacaftor treatment sequence in part 1 there was a further mean 
(SD) change of 3.3% (9.3%) in percent predicted FEV1 after the additional 16 weeks of treatment with 



19 

ivacaftor. At the follow up visit, 4 weeks after ivacaftor dosing had ended, the mean (SD) absolute 
change in percent predicted FEV1 from part 2 week 16 was -7.4% (5.5%). 
 
Study 3: study in patients with CF with the F508del mutation in the CFTR gene 
 
Study 3 (part A) was a 16-week, 4:1 randomised, double-blind, placebo-controlled, parallel-group 
phase 2 study of ivacaftor (150 mg every 12 hours) in 140 patients with CF age 12 years and older 
who were homozygous for the F508del mutation in the CFTR gene and who had FEV1 ≥ 40% 
predicted. 
 
The mean absolute change from baseline through week 16 in percent predicted FEV1 (primary efficacy 
endpoint) was 1.5 percentage points in the ivacaftor group and -0.2 percentage points in the placebo 
group. The estimated treatment difference for ivacaftor versus placebo was 1.7 percentage points 
(95% CI -0.6, 4.1); this difference was not statistically significant (P = 0.15). 
 
Study 4: open-label extension study 
 
In study 4 patients who completed treatment in studies 1 and 2 with placebo were switched to ivacaftor 
while patients on ivacaftor continued to receive it for a minimum of 96 weeks, i.e., the length of 
treatment with ivacaftor was at least 96 weeks for patients in the placebo/ivacaftor group and at least 
144 weeks for patients in the ivacaftor/ivacaftor group. 
 
One hundred and forty-four (144) patients from study 1 were rolled over in study 4, 67 in the 
placebo/ivacaftor group and 77 in the ivacaftor/ivacaftor group. Forty-eight (48) patients from study 2 
were rolled over in study 4, 22 in the placebo/ivacaftor group and 26 in the ivacaftor/ivacaftor group. 
 
Table 8 shows the results of the mean (SD) absolute change in percent predicted FEV1 for both groups 
of patients. For patients in the placebo/ivacaftor group baseline percent predicted FEV1 is that of 
study 4 while for patients in the ivacaftor/ivacaftor group the baseline value is that of studies 1 and 2. 
 
Table 8: Effect of ivacaftor on percent predicted FEV1 in study 4 

Original study 
and treatment 
group 

Duration of ivacaftor 
treatment (weeks) 

Absolute change from baseline in percent 
predicted FEV1 (percentage points) 

  N Mean (SD) 
Study 1 

Ivacaftor 48* 77 9.4 (8.3) 
 144 72 9.4 (10.8) 

Placebo 0* 67 -1.2 (7.8)† 
 96 55 9.5 (11.2) 
Study 2 

Ivacaftor 48* 26 10.2 (15.7) 
 144 25 10.3 (12.4) 

Placebo 0* 22 -0.6 (10.1)† 
 96 21 10.5 (11.5) 

* Treatment occurred during blinded, controlled, 48-week phase 3 study. 
† Change from prior study baseline after 48 weeks of placebo treatment. 
 
When the mean (SD) absolute change in percent predicted FEV1 is compared from study 4 baseline for 
patients in the ivacaftor/ivacaftor group (n = 72) who rolled over from study 1, the mean (SD) absolute 
change in percent predicted FEV1 was 0.0% (9.05), while for patients in the ivacaftor/ivacaftor group 
(n = 25) who rolled over from study 2 this figure was 0.6% (9.1). This shows that patients in the 
ivacaftor/ivacaftor group maintained the improvement seen at week 48 of the initial study (day 0 
through week 48) in percent predicted FEV1 through week 144. There were no additional 
improvements in study 4 (week 48 through week 144). 
 



20 

For patients in the placebo/ivacaftor group from study 1, the annualised rate of pulmonary 
exacerbations was higher in the initial study when patients were on placebo (1.34 events/year) than 
during the subsequent study 4 when patients rolled over to ivacaftor (0.48 events/year across day 1 to 
week 48, and 0.67 events/year across weeks 48 to 96). For patients in the ivacaftor/ivacaftor group 
from study 1, the annualised rate of pulmonary exacerbations was 0.57 events/year across day 1 to 
week 48 when patients were on ivacaftor. When they rolled over into study 4, the rate of annualised 
pulmonary exacerbations was 0.91 events/year across day 1 to week 48 and 0.77 events/year across 
weeks 48 to 96. 
 
For patients who rolled over from study 2 the number of events was, overall, low. 
 
Study 6: study in patients with CF with an R117H mutation in the CFTR gene 
 
Study 6 evaluated 69 patients who were 6 years of age or older; 53 (76.8%) patients had the F508del 
mutation in the second allele. The confirmed R117H poly-T variant was 5T in 38 patients and 7T in 
16 patients. At baseline, mean predicted FEV1 was 73% (range: 32.5% to 105.5%) and mean age was 
31 years (range: 6 to 68 years). The mean absolute change from baseline through week 24 in percent 
predicted FEV1 (primary efficacy endpoint) was 2.57 percentage points in the ivacaftor group and 
0.46 percentage points in the placebo group. The estimated treatment difference for ivacaftor versus 
placebo was 2.1 percentage points (95% CI -1.1, 5.4). 
 
A pre-planned subgroup analysis was conducted in patients 18 years and older (26 patients on placebo 
and 24 on ivacaftor). Treatment with ivacaftor resulted in a mean absolute change in percent predicted 
FEV1 through week 24 of 4.5 percentage points in the ivacaftor group versus -0.46 percentage points 
in the placebo group. The estimated treatment difference for ivacaftor versus placebo was 5.0 
percentage points (95% CI 1.1, 8.8). 
 
In a subgroup analysis in patients with a confirmed R117H-5T genetic variant, the difference in the 
mean absolute change from baseline through week 24 in percent predicted FEV1 between ivacaftor and 
placebo was 5.3% (95% CI 1.3, 9.3). In patients with a confirmed R117H-7T genetic variant, the 
treatment difference between ivacaftor and placebo was 0.2% (95% CI -8.1, 8.5). 
 
For secondary efficacy variables, no treatment differences were observed for ivacaftor versus placebo 
in absolute change from baseline in BMI at week 24 or time to first pulmonary exacerbation. 
Treatment differences were observed in absolute change in CFQ-R respiratory domain score through 
week 24 (treatment difference of ivacaftor versus placebo was 8.4 [95% CI 2.2, 14.6] points) and for 
the mean change from baseline in sweat chloride (see Pharmacodynamic effects). 
 
Ivacaftor in a combination regimen with tezacaftor/ivacaftor or with ivacaftor/tezacaftor/elexacaftor 
 
The efficacy and safety of ivacaftor in a combination regimen with tezacaftor/ivacaftor in patients with 
CF aged 12 years and older was assessed in two clinical studies; a 24 week, randomised, double-blind, 
placebo-controlled study with 504 patients who were homozygous for the F508del mutation; and a 
randomised, double-blind, placebo-controlled and ivacaftor-controlled, 2 period, 3 treatment, 8-week 
crossover study with 244 patients who were heterozygous for the F508del mutation and a second 
mutation associated with residual CFTR activity. The long-term safety and efficacy of the combination 
regimen was also assessed in both patient populations in a 96-week open-label, rollover, long-term 
extension study. Refer to the Summary of Product Characteristics of tezacaftor/ivacaftor for additional 
data. 
 
The efficacy and safety of ivacaftor in a combination regimen with ivacaftor/tezacaftor/elexacaftor in 
patients aged 12 years and older was demonstrated in two phase 3 studies, randomised, double blind, 
placebo-controlled (heterozygous F508del patients, n=403) and active-controlled (homozygous 
F508del patients, n=107) of 24 and 4 weeks of duration, respectively. Heterozygous F508del patients 
had a minimal function mutation on the second allele 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 (tezacaftor, ivacaftor or the combination of both). 



21 

Homozygous F508del patients received tezacaftor/ivacaftor and ivacaftor regimen during a 4-week 
open-label run-in period and were then randomised and dosed to receive ivacaftor in combination with 
ivacaftor/tezacaftor/elexacaftor during a 4-week double-blind treatment period. Patients from both 
studies were eligible to enter an open-label, rollover, 96-week study. Refer to the Summary of Product 
Characteristics of ivacaftor/tezacaftor/elexacaftor for additional data. 
 
Paediatric population 
 
Ivacaftor in a combination regimen with tezacaftor/ivacaftor 
 
The efficacy and safety in patients aged 6 to less than 12 years (mean age 8.6 years) were assessed in 
an 8-week, double-blind, phase 3 trial with 67 patients who were randomised 4:1 to either ivacaftor in 
a combination regimen with tezacaftor/ivacaftor or a blinding group. Forty-two patients were 
homozygous for the F508del mutation (F/F) and 12 were heterozygous for the F508del mutation and a 
second mutation associated with residual CFTR activity (F/RF). Refer to the Summary of Product 
Characteristics of tezacaftor/ivacaftor for additional data. 
 
The European Medicines Agency has deferred the obligation to submit the results of studies with 
Kalydeco in one or more subsets of the paediatric population in cystic fibrosis (see section 4.2 for 
information on paediatric use). 
 
5.2 Pharmacokinetic properties 
 
The pharmacokinetics of ivacaftor are similar between healthy adult volunteers and patients with CF. 
 
After oral administration of a single 150 mg dose to healthy volunteers in a fed state, the mean (± SD) 
for AUC and Cmax were 10600 (5260) ng*hr/mL and 768 (233) ng/mL, respectively. After every 
12-hour dosing, steady-state plasma concentrations of ivacaftor were reached by days 3 to 5, with an 
accumulation ratio ranging from 2.2 to 2.9. 
 
Absorption 
 
Following multiple oral dose administrations of ivacaftor, the exposure of ivacaftor generally 
increased with dose from 25 mg every 12 hours to 450 mg every 12 hours. When given with fat-
containing food, the exposure of ivacaftor increased approximately 2.5- to 4-fold. When co-
administered with tezacaftor and elexacaftor, the increase in AUC was similar (approximately 3-fold 
and 2.5-to 4-fold respectively). Therefore, ivacaftor, administered as monotherapy or in a combination 
regimen with tezacaftor/ivacaftor or ivacaftor/tezacaftor/elexacaftor, should be administered with 
fat-containing food. The median (range) tmax is approximately 4.0 (3.0; 6.0) hours in the fed state. 
 
Ivacaftor granules (2 x 75 mg sachets) had similar bioavailability as the 150 mg tablet when given with 
fat-containing food to healthy adult subjects. The geometric least squares mean ratio (90% CI) for the 
granules relative to tablets was 0.951 (0.839, 1.08) for AUC0-∞ and 0.918 (0.750, 1.12) for Cmax. The 
effect of food on ivacaftor absorption is similar for both formulations, i.e., tablets and granules. 
 
Distribution 
 
Ivacaftor is approximately 99% bound to plasma proteins, primarily to alpha 1-acid glycoprotein and 
albumin. Ivacaftor does not bind to human red blood cells. After oral administration of 
ivacaftor150 mg every 12 hours for 7 days in healthy volunteers in a fed state, the mean (± SD) 
apparent volume of distribution was 353 L (122) . 
 
Biotransformation 
 
Ivacaftor is extensively metabolised in humans. In vitro and in vivo data indicate that ivacaftor is 
primarily metabolised by CYP3A. M1 and M6 are the two major metabolites of ivacaftor in humans. 



22 

M1 has approximately one-sixth the potency of ivacaftor and is considered pharmacologically active. 
M6 has less than one-fiftieth the potency of ivacaftor and is not considered pharmacologically active. 
 
The effect of the CYP3A4*22 heterozygous genotype on ivacaftor, tezacaftor, and elexacaftor 
exposure is consistent with the effect of co-administration of a weak CYP3A4 inhibitor, which is not 
clinically relevant. No dose-adjustment of ivacaftor, tezacaftor, 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 oral administration in healthy volunteers, the majority of ivacaftor (87.8%) was eliminated 
in the faeces after metabolic conversion. The major metabolites M1 and M6 accounted for 
approximately 65% of the total dose eliminated with 22% as M1 and 43% as M6. There was negligible 
urinary excretion of ivacaftor as unchanged parent. The apparent terminal half-life was approximately 
12 hours following a single dose in the fed state. The apparent clearance (CL/F) of ivacaftor was 
similar for healthy subjects and patients with CF. The mean (± SD) CL/F for a single 150 mg dose was 
17.3 (8.4) L/hr in healthy subjects. 
 
Linearity/non-linearity 
 
The pharmacokinetics of ivacaftor are generally linear with respect to time or dose ranging from 
25 mg to 250 mg. 
 
Special populations 
 
Hepatic impairment 
 
Following a single dose of 150 mg of ivacaftor, adult subjects with moderately impaired hepatic 
function (Child-Pugh Class B, score 7 to 9) had similar ivacaftor Cmax (mean [± SD] of 735 
[331] ng/mL) but an approximately two-fold increase in ivacaftor AUC0-∞ (mean [± SD] of 16800 
[6140] ng*hr/mL) compared with healthy subjects matched for demographics. Simulations for 
predicting the steady-state exposure of ivacaftor showed that by reducing the dosage from 
150 mg q12h to 150 mg once daily, adults with moderate hepatic impairment would have comparable 
steady-state Cmin values as those obtained with a dose of 150 mg q12h in adults without hepatic 
impairment.  
 
In subjects with moderately impaired hepatic function (Child Pugh Class B, score 7 to 9), ivacaftor 
AUC increased approximately by 50% following multiple doses for 10 days of either tezacaftor and 
ivacaftor or of ivacaftor, tezacaftor and elexacaftor.  
 
The impact of severe hepatic impairment (Child Pugh Class C, score 10 to15) on the pharmacokinetics 
of ivacaftor as monotherapy or in a combination regimen with tezacaftor/ivacaftor or 
ivacaftor/tezacaftor/elexacaftor has not been studied. The magnitude of increase in exposure in these 
patients is unknown but is expected to be higher than that observed in patients with moderate hepatic 
impairment.  
 
For guidance on appropriate use and dose modification see Table 3 in section 4.2. 
 
Renal impairment 
 
Pharmacokinetic studies have not been performed with ivacaftor in patients with renal impairment, 
either as monotherapy or in a combination regimen with tezacaftor/ivacaftor or with 
ivacaftor/tezacaftor/elexacaftor. In a human pharmacokinetic study with ivacaftor monotherapy, there 
was minimal elimination of ivacaftor and its metabolites in urine (only 6.6% of total radioactivity was 



23 

recovered in the urine). There was negligible urinary excretion of ivacaftor as unchanged parent (less 
than 0.01% following a single oral dose of 500 mg).  
 
No dose adjustments are recommended for mild and moderate renal impairment. Caution is 
recommended when administering ivacaftor, either as monotherapy or in a combination with 
tezacaftor/ivacaftor or with ivacaftor/tezacaftor/elexacaftor, to patients with severe renal impairment 
(creatinine clearance less than or equal to 30 mL/min) or end-stage renal disease (see sections 4.2 and 
4.4). 
 
Race 
 
Race had no clinically meaningful effect on the PK of ivacaftor in white (n = 379) and non-white 
(n = 29) patients based on a population PK analysis. 
 
Gender 
 
The pharmacokinetic parameters of ivacaftor, either as monotherapy or in combination with 
tezacaftor/ivacaftor or ivacaftor/tezacaftor/elexacaftor, are similar in males and females. 
 
Elderly 
 
Clinical studies of ivacaftor as monotherapy did not include sufficient numbers of patients aged 
65 years and older to determine whether pharmacokinetic parameters are similar or not to those in 
younger adults. 
 
The pharmacokinetic parameters of ivacaftor in combination with tezacaftor in the elderly patients 
(65-72 years) are comparable to those in younger adults. No patients aged 65 years and older were 
included in the clinical studies of ivacaftor/tezacaftor/elexacaftor and therefore it cannot be determined 
whether pharmacokinetic parameters are similar or not to those in younger adults. 
 
Paediatric population 
 
Predicted ivacaftor exposure based on observed ivacaftor concentrations in phase 2 and 3 studies as 
determined using population PK analysis is presented by age group in Table 9. 
 
Table 9: Mean (SD) ivacaftor exposure by age group 

Age group Dose Cmin, ss 
(ng/mL) 

AUCτ, ss 
(ng*h/mL) 

6 months to less than 12 months (5 kg to < 7 kg) * 25 mg q12h 336 5410 

6 months to less than 12 months (7 kg to < 14 kg) 50 mg q12h 508 (252) 9140 (4200) 

12 months to less than 24 months (7 kg to < 14 kg) 50 mg q12h 440 (212) 9050 (3050) 

12 months to less than 24 months (≥ 14 kg to < 25 kg) 75 mg q12h 451 (125) 9600 (1800) 

2- to 5-year-olds (< 14 kg) 50 mg q12h 577 (317) 10500 (4260) 

2- to 5-year-olds (≥ 14 kg to < 25 kg) 75 mg q12h 629 (296) 11300 (3820) 

6- to 11-year-olds † (≥ 14 kg to < 25 kg) 75 mg q12h 641 (329) 10760 (4470) 

6- to 11-year-olds † (≥ 25 kg) 150 mg q12h 958 (546) 15300 (7340) 

12- to 17-year-olds 150 mg q12h 564 (242) 9240 (3420) 



24 

Adults (≥ 18 years old)  150 mg q12h 701 (317) 10700 (4100) 

* Values based on data from a single patient; standard deviation not reported. 
†
 Exposures in 6- to 11-year-olds are predictions based on simulations from the population PK model using data obtained 

for this age group. 
 
Ivacaftor exposure in combination with tezacaftor and with tezacaftor/elexacaftor is presented in 
Table 10. 
 
Table 10: Mean (SD) ivacaftor exposure when used in combination, by age group 

Age group Dose Ivacaftor Mean (SD) 
AUC0-12h,ss (ng*h/mL) 

Children (6 years to less than 12 years; 
<30 kg) 
n = 71 

tezacaftor 50 mg qd/ 
ivacaftor 75 mg q12h 7100 (1950) 

Children (6 years to less than 12 years;  
≥30 kg)* 
n = 51 

tezacaftor 100 mg qd/ 
ivacaftor 150 mg q12h 11800 (3890) 

Adolescent patients (12 to less than18 
years)  
n = 97 tezacaftor 100 mg qd/  

ivacaftor 150 mg q12h 

11400 (5500) 

Adult patients (18 years and older) 
n = 389 11400 (4140) 

Adolescent patients (12 to less than 
18 years) 
n = 69 

elexacaftor 200 mg qd/ 
tezacaftor 100 mg qd/ 
ivacaftor 150 mg q12h 

10600 (3350) 

Adult patients (18 years and older) 
n = 186 12100 (4170) 

* Exposures in ≥30 kg to <40 kg weight range are predictions derived from the population PK model. 
 
5.3 Preclinical safety data 
 
Non-clinical data reveal no special hazard for humans based on conventional studies of safety 
pharmacology, repeated dose toxicity, genotoxicity, and carcinogenic potential. 
 
Pregnancy and fertility 
 
Ivacaftor was associated with slight decreases of the seminal vesicle weights, a decrease of overall 
fertility index and number of pregnancies in females mated with treated males and significant 
reductions in number of corpora lutea and implantation sites with subsequent reductions in the average 
litter size and average number of viable embryos per litter in treated females. The 
No-Observed-Adverse-Effect-Level (NOAEL) for fertility findings provides an exposure level of 
approximately 4 times the systemic exposure of ivacaftor and its metabolites when administered as 
ivacaftor monotherapy in adult humans at the maximum recommended human dose (MRHD). 
Placental transfer of ivacaftor was observed in pregnant rats and rabbits. 
 
Peri- and post-natal development 
 
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 when administered as ivacaftor monotherapy in 
adult humans at the MRHD.  
 



25 

Juvenile animal studies 
 
Findings of cataracts were observed in juvenile rats dosed from postnatal day 7 through 35 at ivacaftor 
exposure levels of 0.22 times the MRHD based on systemic exposure of ivacaftor and its metabolites 
when administered as ivacaftor monotherapy. This finding has not been observed in foetuses derived 
from rat dams treated with ivacaftor on gestation days 7 to 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. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core 
 
Cellulose, microcrystalline 
Lactose monohydrate 
Hypromellose acetate succinate 
Croscarmellose sodium 
Sodium laurilsulfate (E487) 
Silica, colloidal anhydrous 
Magnesium stearate 
 
Tablet film coat 
 
Polyvinyl alcohol 
Titanium dioxide (E171) 
Macrogol (PEG 3350) 
Talc 
Indigo carmine aluminium lake (E132) 
Carnauba wax 
 
Printing ink 
 
Shellac 
Iron oxide black (E172) 
Propylene glycol (E1520) 
Ammonia solution, concentrated 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
4 years. 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions. 
 



26 

6.5 Nature and contents of container 
 
The film-coated tablets are packed in a thermoform (PolyChloroTriFluoroEthylene [PCTFE]/foil) 
blister or a High-Density PolyEthylene (HDPE) bottle with a polypropylene child-resistant closure, 
foil-lined induction seal and molecular sieve desiccant. 
 
Kalydeco 75 mg film-coated tablets 
 
The following pack sizes are available:  

− Blister card pack containing 28 film-coated tablets 
 
Kalydeco 150 mg film-coated tablets 
 
The following pack sizes are available: 
− Blister card pack containing 28 film-coated tablets 
− Blister pack containing 56 film-coated tablets 
− Bottle containing 56 film-coated tablets 
 
Not all pack sizes may be marketed 
 
6.6 Special precautions for disposal and other handling 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Vertex Pharmaceuticals (Ireland) Limited 
28-32 Pembroke Street Upper 
Dublin 2, D02 EK84 
Ireland 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/12/782/001 
EU/1/12/782/002 
EU/1/12/782/005 
EU/1/12/782/007 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 23 July 2012 
Date of latest renewal: 28 April 2017 
 
 
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. 
  



27 

 
1. NAME OF THE MEDICINAL PRODUCT 
 
Kalydeco 25 mg granules in sachet 
Kalydeco 50 mg granules in sachet 
Kalydeco 75 mg granules in sachet 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Kalydeco 25 mg granules in sachet 
 
Each sachet contains 25 mg of ivacaftor. 
 
Excipient with known effect 
 
Each sachet contains 36.6 mg of lactose monohydrate. 
 
Kalydeco 50 mg granules in sachet 
 
Each sachet contains 50 mg of ivacaftor. 
 
Excipient with known effect 
 
Each sachet contains 73.2 mg of lactose monohydrate. 
 
Kalydeco 75 mg granules in sachet 
 
Each sachet contains 75 mg of ivacaftor. 
 
Excipient with known effect 
 
Each sachet contains 109.8 mg of lactose monohydrate. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Granules in sachet 
 
White to off-white granules approximately 2 mm in diameter. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Kalydeco granules are indicated for the treatment of infants aged at least 4 months, toddlers and 
children weighing 5 kg to less than 25 kg with cystic fibrosis (CF) who have an R117H CFTR 
mutation or one of the following gating (class III) mutations in the CFTR gene: G551D, G1244E, 
G1349D, G178R, G551S, S1251N, S1255P, S549N or S549R (see sections 4.4 and 5.1). 
 
4.2 Posology and method of administration 
 
Kalydeco should only be prescribed by physicians with experience in the treatment of cystic fibrosis. 
If the patient's genotype is unknown, an accurate and validated genotyping method should be 



28 

performed before starting treatment to confirm the presence of an indicated mutation in at least one 
allele of the CFTR gene (see section 4.1). The phase of the poly-T variant identified with the R117H 
mutation should be determined in accordance with local clinical recommendation. 
 
Posology 
 
Infants aged at least 4 months, toddlers, children, adolescents and adults should be dosed according to 
Table 1. 
 
Table 1: Dosing recommendations for patients aged 4 months and older 

Age Weight Dose Total daily dose 
4 months to less 
than 6 months 

≥ 5 kg 25 mg granules taken orally every 
12 hours with fat-containing food 

50 mg 

6 months and 
older 

≥ 5 kg to < 7 kg 25 mg granules taken orally every 
12 hours with fat-containing food 

50 mg 

≥ 7 kg to < 14 kg 50 mg granules taken orally every 
12 hours with fat-containing food 

100 mg 

≥ 14 kg to < 25 kg 75 mg granules taken orally every 
12 hours with fat-containing food 

150 mg 

≥ 25 kg See Kalydeco tablets SmPC for further details. 
 
Missed dose 
 
If 6 hours or less have passed since the missed morning or evening dose, the patient should be advised 
to take it as soon as possible and then take the next dose at the regularly scheduled time. If more than 
6 hours have passed since the time the dose is usually taken, the patient should be advised to wait until 
the next scheduled dose. 
 
Concomitant use of CYP3A inhibitors 
 
When co-administered with strong inhibitors of CYP3A in patients aged 6 months and older, the 
ivacaftor dose should be reduced to one sachet (ivacaftor 25 mg for patients 5 kg to < 7 kg; ivacaftor 
50 mg for patients 7 kg to < 14 kg; ivacaftor 75 mg for patients 14 kg to < 25 kg) twice a week (see 
sections 4.4 and 4.5). 
 
When co-administered with moderate inhibitors of CYP3A in patients aged 6 months and older, the 
ivacaftor dose is as above recommended but administered once daily (see sections 4.4 and 4.5). 
 
Due to the variability in maturation of the cytochrome (CYP) enzymes involved in ivacaftor 
metabolism, treatment with ivacaftor is not recommended when co-administered with moderate or 
strong inhibitors of CYP3A in patients aged 4 months to less than 6 months, unless the benefits 
outweigh the risks. In such cases, the recommended dose is one packet of 25 mg granules twice 
weekly or less frequently (see sections 4.4 and 4.5). Dosing intervals should be modified according to 
clinical response and tolerability (see sections 4.4 and 5.2) 
 
 



29 

Special populations 
 
Renal impairment 
 
No dose adjustment is necessary for patients with mild to moderate renal impairment. Caution is 
recommended in patients with severe renal impairment (creatinine clearance less than or equal to 
30 mL/min) or end-stage renal disease (see sections 4.4 and 5.2). 
 
Hepatic impairment 
 
No dose adjustment is necessary for patients aged 6 months and older with mild hepatic impairment 
(Child-Pugh Class A). For patients aged 6 months and older with moderate hepatic impairment 
(Child-Pugh Class B), a reduced dose of one sachet (ivacaftor 25 mg for patients 5 kg to < 7 kg; 
ivacaftor 50 mg for patients 7 kg to < 14 kg; ivacaftor 75 mg for patients 14 kg to < 25 kg) once daily 
is recommended. There is no experience of the use of ivacaftor in patients aged 6 months and older 
with severe hepatic impairment (Child-Pugh Class C); therefore, its use is not recommended unless the 
benefits outweigh the risks. In such cases, the starting dose should be as above recommended, 
administered every other day. Dosing intervals should be modified according to clinical response and 
tolerability (see sections 4.4 and 5.2). 
 
Due to variability in maturation of cytochrome (CYP) enzymes involved in ivacaftor metabolism, 
treatment with ivacaftor is not recommended in patients aged 4 months to less than 6 months with 
hepatic impairment, unless the benefits outweigh the risks. In such cases, the recommended dose is 
one sachet (ivacaftor 25 mg) once daily or less frequently. Dosing intervals should be modified 
according to clinical response and tolerability (see sections 4.4 and 5.2). 
 
Paediatric population 
 
The safety and efficacy of ivacaftor in children aged less than 4 months have not been established. No 
data are available. 
 
Limited data are available in patients less than 6 years of age with an R117H mutation in the CFTR 
gene. Available data in patients aged 6 years and older are described in sections 4.8, 5.1 and 5.2. 
 
Method of administration  
 
For oral use. 
 
Each sachet is for single use only. 
 
Each sachet of granules should be mixed with 5 mL of age-appropriate soft food or liquid and 
completely and immediately consumed. Food or liquid should be at room temperature or below. If not 
immediately consumed, the mixture has been shown to be stable for one hour and therefore should be 
ingested during this period. A fat-containing meal or snack should be consumed just before or just 
after dosing. 
 
Food or drink containing grapefruit should be avoided during treatment (see section 4.5). 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
 
4.4 Special warnings and precautions for use 
 
Only patients with CF who had a G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N 
or S549R gating (class III) or G970R mutation in at least one allele of the CFTR gene were included in 
studies 1, 2, 5 and 7 (see section 5.1). 



30 

 
Less evidence of a positive effect of ivacaftor has been shown for patients with an R117H-7T mutation 
associated with less severe disease in study 6 (see section 5.1). 
 
In study 5, four patients with the G970R mutation were included. In three of four patients the change 
in the sweat chloride test was < 5 mmol/L and this group did not demonstrate a clinically relevant 
improvement in FEV1 after 8 weeks of treatment. Clinical efficacy in patients with the G970R 
mutation of the CFTR gene could not be established (see section 5.1). 
 
Efficacy results from a phase 2 study in patients with CF who are homozygous for the F508del 
mutation in the CFTR gene showed no statistically significant difference in FEV1 over 16 weeks of 
ivacaftor treatment compared to placebo (see section 5.1). Therefore, use of ivacaftor as monotherapy 
in these patients is not recommended. 
 
Effect on liver function tests 
 
Moderate transaminase (alanine transaminase [ALT] or aspartate transaminase [AST]) elevations are 
common in subjects with CF. Transaminase elevations have been observed in some patients treated 
with ivacaftor as monotherapy. Therefore, liver function tests are recommended for all patients prior to 
initiating ivacaftor, every 3 months during the first year of treatment and annually thereafter. For all 
patients with a history of transaminase elevations, more frequent monitoring of liver function tests 
should be considered. In the event of significant elevations of transaminases (e.g., patients with 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 resolution of transaminase elevations, the benefits and risks of resuming treatment should 
be considered (see section 4.8). 
 
Hepatic impairment 
 
Use of ivacaftor is not recommended in patients with severe hepatic impairment unless the benefits are 
expected to outweigh the risks (see sections 4.2 and 5.2). No safety data are available in infants aged 4 
to less than 12 months of age with moderate or severe hepatic impairment treated with ivacaftor. 
 
Renal impairment 
 
Caution is recommended while using ivacaftor in patients with severe renal impairment or end-stage 
renal disease (see sections 4.2 and 5.2). 
 
Patients after organ transplantation 
 
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 
ciclosporin or tacrolimus. 
 
Interactions with medicinal products 
 
CYP3A inducers  
 
Exposure to ivacaftor is significantly decreased by the concomitant use of CYP3A inducers, 
potentially resulting in the loss of ivacaftor efficacy; therefore, co-administration of ivacaftor with 
strong CYP3A inducers is not recommended (see section 4.5). 
 
CYP3A inhibitors  
 
Exposure to ivacaftor is increased when co-administered with strong or moderate CYP3A inhibitors. 
The dose of ivacaftor must be adjusted when used concomitantly with strong or moderate CYP3A 
inhibitors (see sections 4.2 and 4.5). No safety data are available in infants aged 4 to less than 



31 

12 months of age who are treated with ivacaftor and moderate or strong CYP3A inhibitors (see 
sections 4.2 and 4.5). 
 
Paediatric population  
 
Cases of non-congenital lens opacities/cataracts without impact on vision have been reported in 
paediatric patients treated with ivacaftor. Although other risk factors were present in some cases (such 
as corticosteroid use and 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 ivacaftor treatment. 
 
Lactose content 
 
Kalydeco contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase 
deficiency or glucose-galactose malabsorption should not take this medicine. 
 
Sodium content 
 
This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially 
‘sodium-free’. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Ivacaftor is a substrate of CYP3A4 and CYP3A5. It is a weak inhibitor of CYP3A and P-gp and a 
potential inhibitor of CYP2C9. In vitro studies showed that ivacaftor is not a substrate for P-gp.  
 
Medicinal products affecting the pharmacokinetics of ivacaftor 
 
CYP3A inducers 
 
Co-administration of ivacaftor with rifampicin, a strong CYP3A inducer, decreased ivacaftor exposure 
(AUC) by 89% and decreased hydroxymethyl ivacaftor (M1) to a lesser extent than ivacaftor. 
Co-administration of ivacaftor with strong CYP3A inducers, such as rifampicin, rifabutin, 
phenobarbital, carbamazepine, phenytoin and St. John’s wort (Hypericum perforatum), is not 
recommended (see section 4.4). 
 
No dose adjustment is recommended when ivacaftor is used with moderate or weak CYP3A inducers.  
 
CYP3A inhibitors 
 
Ivacaftor is a sensitive CYP3A substrate. Co-administration with ketoconazole, a strong CYP3A 
inhibitor, increased ivacaftor exposure (measured as area under the curve [AUC]) by 8.5-fold and 
increased M1 to a lesser extent than ivacaftor. A reduction of the ivacaftor dose is recommended for 
co-administration with strong CYP3A inhibitors, such as ketoconazole, itraconazole, posaconazole, 
voriconazole, telithromycin and clarithromycin (see sections 4.2 and 4.4). 
 
Co-administration with fluconazole, a moderate inhibitor of CYP3A, increased ivacaftor exposure by 
3-fold and increased M1 to a lesser extent than ivacaftor. A reduction of the ivacaftor dose is 
recommended for patients taking concomitant moderate CYP3A inhibitors, such as fluconazole, 
erythromycin, and verapamil (see sections 4.2 and 4.4). 
 
Co-administration of ivacaftor with grapefruit juice, which contains one or more components that 
moderately inhibit CYP3A, may increase exposure to ivacaftor. Food or drink containing grapefruit 
should be avoided during treatment with ivacaftor (see section 4.2). 
 



32 

Potential for ivacaftor to interact with transporters 
 
In vitro studies showed that ivacaftor is not a substrate for OATP1B1 or OATP1B3. 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.  
 
Ciprofloxacin 
 
Co-administration of ciprofloxacin with ivacaftor did not affect the exposure of ivacaftor. No dose 
adjustment is required when ivacaftor is co-administered with ciprofloxacin. 
 
Medicinal products affected by ivacaftor 
 
Administration of ivacaftor may increase systemic exposure of medicinal products that are sensitive 
substrates of CYP2C9, and/or P-gp, and/or CYP3A which may increase or prolong their therapeutic 
effect and adverse reactions. 
 
CYP2C9 substrates 
 
Ivacaftor may inhibit CYP2C9. Therefore, monitoring of the international normalised ratio (INR) is 
recommended during co-administration of warfarin with ivacaftor. Other medicinal products for which 
exposure may be increased include glimepiride and glipizide; these medicinal products should be used 
with caution. 
 
Digoxin and other P-gp substrates 
 
Co-administration with digoxin, a sensitive P-gp substrate, increased digoxin exposure by 1.3-fold, 
consistent with weak inhibition of P-gp by ivacaftor. Administration of 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 or 
tacrolimus, caution and appropriate monitoring should be used. 
 
CYP3A substrates  
 
Co-administration with (oral) midazolam, a sensitive CYP3A substrate, increased midazolam exposure 
1.5-fold, consistent with weak inhibition of CYP3A by ivacaftor. No dose adjustment of CYP3A 
substrates, such as midazolam, alprazolam, diazepam or triazolam, is required when these are co-
administered with ivacaftor.  
 
Hormonal contraceptives 
 
Ivacaftor has been studied with an oestrogen/progesterone oral contraceptive and was found to have no 
significant effect on the exposures of the oral contraceptive. Therefore, no dose adjustment of oral 
contraceptives is necessary. 
 
Paediatric population 
 
Interaction studies have only been performed in adults.  
 



33 

4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
 
There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of ivacaftor in 
pregnant women. Animals 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 avoid the use of 
ivacaftor during pregnancy. 
 
Breast-feeding 
 
It is unknown whether ivacaftor and/or its metabolites are excreted in human milk. Available 
pharmacokinetic data in animals have shown excretion of ivacaftor into the milk of lactating female 
rats. As such, a risk to the newborns/infants cannot be excluded. A decision must be made whether to 
discontinue breast-feeding or to discontinue/abstain from ivacaftor 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 ivacaftor on fertility in humans. Ivacaftor had an effect on 
fertility in rats (see section 5.3). 
 
4.7 Effects on ability to drive and use machines 
 
Ivacaftor has minor influence on the ability to drive or use machines. Ivacaftor may cause dizziness 
(see section 4.8) and, therefore, 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 6 years and older are headache 
(23.9%), oropharyngeal pain (22.0%), upper respiratory tract infection (22.0%), nasal congestion 
(20.2%), abdominal pain (15.6%), nasopharyngitis (14.7%), diarrhoea (12.8%), dizziness (9.2%), rash 
(12.8%) and bacteria in sputum (12.8%). Transaminase elevations occurred in 12.8% of 
ivacaftor-treated patients versus 11.5% of placebo-treated patients. 
 
In patients aged 2 to less than 6 years the most common adverse reactions were nasal congestion 
(26.5%), upper respiratory tract infection (23.5%), transaminase elevations (14.7%), rash (11.8%), and 
bacteria in sputum (11.8%). 
 
Serious adverse reactions in patients who received ivacaftor included abdominal pain and transaminase 
elevations (see section 4.4). 
 
Tabulated list of adverse reactions 
 
Table 2 reflects the adverse reactions observed with ivacaftor in clinical trials (placebo-controlled and 
uncontrolled studies) in which the length of exposure to ivacaftor ranged from 16 weeks to 144 weeks. 
The frequency of adverse reactions is 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); very rare (< 1/10,000); not 
known (cannot be estimated from the available data). Within each frequency grouping, adverse 
reactions are presented in order of decreasing seriousness. 
 



34 

Table 2: Adverse reactions 

System organ class Adverse reactions Frequency  
Infections and infestations Upper respiratory tract 

infection 
very common 

Nasopharyngitis very common 
Rhinitis  common 

Nervous system disorders Headache very common 
Dizziness very common 

Ear and labyrinth disorders Ear pain common 
Ear discomfort common 
Tinnitus common 
Tympanic membrane 
hyperaemia 

common 

Vestibular disorder common 
Ear congestion uncommon 

Respiratory, thoracic and 
mediastinal disorders 

Oropharyngeal pain very common 
Nasal congestion very common 
Sinus congestion  common 
Pharyngeal erythema common 

Gastrointestinal disorders Abdominal pain very common 

Diarrhoea very common 

Hepatobiliary disorders Transaminase elevations very common 

Skin and subcutaneous tissue 
disorders 

Rash very common 

Reproductive system and 
breast disorders 

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

Investigations Bacteria in sputum very common 
 
Description of selected adverse reactions 
 
Transaminase elevations 
 
During the 48-week placebo-controlled studies 1 and 2 in patients aged 6 years and older, the 
incidence of maximum transaminase (ALT or AST) > 8, > 5 or > 3 x ULN was 3.7%, 3.7% and 8.3% 
in ivacaftor-treated patients and 1.0%, 1.9% and 8.7% in placebo-treated patients, respectively. Two 
patients, one on placebo and one on ivacaftor, permanently discontinued treatment for elevated 
transaminases, each > 8 x ULN. No ivacaftor-treated patients experienced a transaminase elevation 
> 3 x ULN associated with elevated total bilirubin > 1.5 x ULN. In ivacaftor-treated patients, most 
transaminase elevations up to 5 x ULN resolved without treatment interruption. Ivacaftor dosing was 
interrupted in most patients with transaminase elevations > 5 x ULN. In all instances where dosing 
was interrupted for elevated transaminases and subsequently resumed, ivacaftor dosing was able to be 
resumed successfully (see section 4.4). 
 
During the placebo controlled phase 3 studies (up to 24 weeks) of tezacaftor/ivacaftor, the incidence of 
maximum transaminase (ALT or AST) > 8, > 5, or > 3 x ULN were 0.2%, 1.0%, and 3.4% in 
tezacaftor/ivacaftor treated patients, and 0.4%, 1.0%, and 3.4% in placebo-treated patients. One patient 
(0.2%) on therapy and 2 patients (0.4%) on placebo permanently discontinued treatment for elevated 
transaminases. No patients treated with tezacaftor/ivacaftor experienced a transaminase elevation >3 x 
ULN associated with elevated total bilirubin >2 x ULN.  
 



35 

During the 24-week, placebo-controlled, phase 3 study of ivacaftor/tezacaftor/elexacaftor, these 
figures were 1.5%, 2.5%, and 7.9% in ivacaftor/tezacaftor/elexacaftor-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 ivacaftor in a combination regimen with ivacaftor/tezacaftor/elexacaftor treated patients 
and 4.0% in placebo-treated patients. 
 
Paediatric population 
 
The safety data of ivacaftor were evaluated in 6 patients between 4 months to less than 6 months of 
age, 11 patients between 6 months to less than 12 months of age, 19 patients between 12 months to 
less than 24 months of age, 34 patients between 2 to less than 6 years of age, 61 patients between 6 to 
less than 12 years of age and 94 patients between 12 to less than 18 years of age. 
 
The safety profile is generally consistent among paediatric patients aged 4 months and older and is 
also consistent with adult patients. 
 
The incidence of transaminase elevations (ALT or AST) observed in studies 2, 5 and 6 (patients aged 6 
to less than 12 years), study 7 (patients aged 2 to less than 6 years), and study 8 (patients aged 6 to less 
than 24 months) are described in Table 3. In the placebo controlled studies, the incidence of 
transaminase elevations were similar between treatment with ivacaftor (15.0%) and placebo (14.6%). 
Peak LFT elevations were generally higher in paediatric patients than in older patients. Across all 
populations, peak LFT elevations returned to baseline levels following interruption, and in almost all 
instances where dosing was interrupted for elevated transaminases and subsequently resumed, 
ivacaftor dosing was able to be resumed successfully (see section 4.4). Cases suggestive of positive 
rechallenge were observed. In study 7 ivacaftor was permanently discontinued in one patient. In study 
8 no patients had elevations in total bilirubin or discontinued ivacaftor treatment due to transaminase 
elevations in either age cohort (see section 4.4 for management of elevated transaminases). 
 
Table 3: Transaminase elevations in patients 4 months to < 12 years treated with ivacaftor as 
monotherapy 

 n % of Patients 
> 3 x ULN  

% of Patients 
>5 x ULN 

% of Patients 
> 8 x ULN 

6 to <12 years 40 15.0% (6) 2.5% (1) 2.5% (1) 
2 to <6 years 34 14.7% (5) 14.7% (5) 14.7% (5) 
12 to <24 months 18 27.8% (5) 11.1% (2) 11.1% (2) 
6 to <12 months 11 9.1% (1) 0.0% (0) 0.0% (0) 
4 to <6 months 6 0.0% (0) 0.0% (0) 0.0% (0) 

 
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 ivacaftor. Treatment of overdose consists of general 
supportive measures including monitoring of vital signs, liver function tests and observation of the 
clinical status of the patient. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 

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


36 

5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Other respiratory system products, ATC code: R07AX02 
 
Mechanism of action 
 
Ivacaftor is a potentiator of the CFTR protein, i.e., in vitro ivacaftor increases CFTR channel gating to 
enhance chloride transport in specified gating mutations (as listed in section 4.1) with reduced 
channel-open probability compared to normal CFTR. Ivacaftor also potentiated the channel-open 
probability of R117H-CFTR, which has both low channel-open probability (gating) and reduced 
channel current amplitude (conductance). The G970R mutation causes a splicing defect resulting in 
little-to-no CFTR protein at the cell surface which may explain the results observed in subjects with 
this mutation in study 5 (see Pharmacodynamic effects and Clinical efficacy data).  
 
In vitro responses seen in single channel patch clamp experiments using membrane patches from 
rodent cells expressing mutant CFTR forms do not necessarily correspond to in vivo pharmacodynamic 
response (e.g., sweat chloride) or clinical benefit. The exact mechanism leading ivacaftor to potentiate 
the gating activity of normal and some mutant CFTR forms in this system has not been completely 
elucidated. 
 
Pharmacodynamic effects 
 
In studies 1 and 2 in patients with the G551D mutation in one allele of the CFTR gene, ivacaftor led to 
rapid (15 days), substantial (the mean change in sweat chloride from baseline through week 24 
was -48 mmol/L [95% CI -51, -45] and -54 mmol/L [95% CI -62, -47], respectively) and sustained 
(through 48 weeks) reductions in sweat chloride concentration. 
 
In study 5, part 1 in patients who had a non-G551D gating mutation in the CFTR gene, treatment with 
ivacaftor led to a rapid (15 days) and substantial mean change from baseline in sweat chloride 
of -49 mmol/L (95% CI -57, -41) through 8 weeks of treatment. However, in patients with the 
G970R-CFTR mutation, the mean (SD) absolute change in sweat chloride at week 8 was -6.25 
(6.55) mmol/L. Similar results to part 1 were seen in part 2 of the study. At the 4-week follow-up visit 
(4 weeks after dosing with ivacaftor ended), mean sweat chloride values for each group were trending 
to pre-treatment levels. 
 
In study 6 in patients aged 6 years or older with CF who had an R117H mutation in the CFTR gene, 
the treatment difference in mean change in sweat chloride from baseline through 24 weeks of 
treatment was -24 mmol/L (95% CI -28, -20). In subgroup analyses by age, the treatment difference 
was -21.87 mmol/L (95% CI: -26.46, -17.28) in patients aged 18 years or older, and -27.63 mmol/L 
(95% CI: -37.16, -18.10) in patients aged 6-11 years. Two patients 12 to 17 years of age were enrolled 
in this study. 
 
In study 7 in patients aged 2 to less than 6 years with a gating mutation on at least 1 allele of the CFTR 
gene administered either 50 mg or 75 mg of ivacaftor twice daily, the mean absolute change from 
baseline in sweat chloride was -47 mmol/L (95% CI -58, -36) at week 24. 
 
In study 8 in patients with CF aged less than 24 months, the mean absolute change from baseline in 
sweat chloride was -65.1 mmol/L (95% CI -74.1, -56.0) at week 24. Results were consistent in the 
12 months to less than 24 months, 6 months to less than 12 months, and 4 months to less than 6 
months age cohorts. 
 



37 

Clinical efficacy and safety 
 
Studies 1 and 2: studies in patients with CF with G551D gating mutations 
 
The efficacy of ivacaftor has been evaluated in two phase 3 randomised, double-blind, 
placebo-controlled, multi-centre studies of clinically stable patients with CF who had the G551D 
mutation in the CFTR gene on at least 1 allele and had FEV1 ≥ 40% predicted. 
 
Patients in both studies were randomised 1:1 to receive either 150 mg of ivacaftor or placebo every 
12 hours with food containing fat for 48 weeks in addition to their prescribed CF therapies (e.g., 
tobramycin, dornase alfa). The use of inhaled hypertonic sodium chloride was not permitted. 
 
Study 1 evaluated 161 patients who were 12 years of age or older; 122 (75.8%) patients had the 
F508del mutation in the second allele. At the start of the study, patients in the placebo group used 
some medicinal products at a higher frequency than the ivacaftor group. These medications included 
dornase alfa (73.1% versus 65.1%), salbutamol (53.8% versus 42.2%), tobramycin (44.9% versus 
33.7%) and salmeterol/fluticasone (41.0% versus 27.7%). At baseline, mean predicted FEV1 was 
63.6% (range: 31.6% to 98.2%) and mean age was 26 years (range: 12 to 53 years). 
 
Study 2 evaluated 52 patients who were 6 to 11 years of age at screening; mean (SD) body weight was 
30.9 (8.63) kg; 42 (80.8%) patients had the F508del mutation in the second allele. At baseline, mean 
predicted FEV1 was 84.2% (range: 44.0% to 133.8%) and mean age was 9 years (range: 6 to 12 years); 
8 (30.8%) patients in the placebo group and 4 (15.4%) patients in the ivacaftor group had an FEV1 less 
than 70% predicted at baseline. 
 
The primary efficacy endpoint in both studies was the mean absolute change from baseline in percent 
predicted FEV1 through 24 weeks of treatment. 
 
The treatment difference between ivacaftor and placebo for the mean absolute change (95% CI) in 
percent predicted FEV1 from baseline through week 24 was 10.6 percentage points (8.6, 12.6) in 
study 1 and 12.5 percentage points (6.6, 18.3) in study 2. The treatment difference between ivacaftor 
and placebo for the mean relative change (95% CI) in percent predicted FEV1 from baseline through 
week 24 was 17.1% (13.9, 20.2) in study 1 and 15.8% (8.4, 23.2) in study 2. The mean change from 
baseline through week 24 in FEV1 (L) was 0.37 L in the ivacaftor group and 0.01 L in the placebo 
group in study 1 and 0.30 L in the ivacaftor group and 0.07 L in the placebo group in study 2. In both 
studies, improvements in FEV1 were rapid in onset (day 15) and durable through 48 weeks. 
 
The treatment difference between ivacaftor and placebo for the mean absolute change (95% CI) in 
percent predicted FEV1 from baseline through week 24 in patients 12 to 17 years of age in study 1 was 
11.9 percentage points (5.9, 17.9). The treatment difference between ivacaftor and placebo for the 
mean absolute change (95% CI) in percent predicted FEV1 from baseline through week 24 in patients 
with baseline predicted FEV1 greater than 90% in study 2 was 6.9 percentage points (-3.8, 17.6). 
 
The results for clinically relevant secondary endpoints are shown in Table 4. 
 
Table 4: Effect of ivacaftor on other efficacy endpoints in studies 1 and 2 

Endpoint 

Study 1 Study 2 
Treatment 
differencea 
(95% CI) P value 

Treatment 
differencea 
(95% CI) P value 

Mean absolute change from baseline in CFQ-Rb respiratory domain score (points)c 
Through week 24 8.1 

(4.7, 11.4) 
< 0.0001 6.1 

(-1.4, 13.5) 
0.1092 

Through week 48 8.6 
(5.3, 11.9) 

< 0.0001 5.1 
(-1.6, 11.8) 

0.1354 



38 

Endpoint 

Study 1 Study 2 
Treatment 
differencea 
(95% CI) P value 

Treatment 
differencea 
(95% CI) P value 

Relative risk of pulmonary exacerbation 
Through week 24 0.40d 0.0016 NA NA 
Through week 48 0.46d 0.0012 NA NA 
Mean absolute change from baseline in body weight (kg) 
At week 24 2.8 

(1.8, 3.7) 
< 0.0001 1.9 

(0.9, 2.9) 
0.0004 

At week 48 2.7 
(1.3, 4.1) 

0.0001 2.8 
(1.3, 4.2) 

0.0002 

Mean absolute change from baseline in BMI (kg/m2) 
At week 24 0.94 

(0.62, 1.26) 
< 0.0001 0.81 

(0.34, 1.28) 
0.0008 

At week 48 0.93 
(0.48, 1.38) 

< 0.0001 1.09 
(0.51, 1.67) 

0.0003 

Mean change from baseline in z-scores 
Weight-for-age z-score 
at week 48e 

0.33 
(0.04, 0.62) 

0.0260 0.39 
(0.24, 0.53) 

< 0.0001 

BMI-for-age z-score at 
week 48e 

0.33 
(0.002, 0.65) 

0.0490 0.45 
(0.26, 0.65) 

< 0.0001 

CI: confidence interval; NA: not analysed due to low incidence of events  
a Treatment difference = effect of ivacaftor – effect of placebo 
b CFQ-R: Cystic Fibrosis Questionnaire-Revised is a disease-specific, health-related quality-of-life measure for CF. 
c Study 1 data were pooled from CFQ-R for adults/adolescents and CFQ-R for children 12 to 13 years of age; Study 2 data 

were obtained from CFQ-R for children 6 to 11 years of age. 
d Hazard ratio for time to first pulmonary exacerbation 
e In subjects under 20 years of age (CDC growth charts) 
 
Study 5: study in patients with CF with non-G551D gating mutations 
 
Study 5 was a phase 3, two-part, randomised, double-blind, placebo-controlled, crossover study 
(part 1) followed by a 16-week open-label extension period (part 2) to evaluate the efficacy and safety 
of ivacaftor in patients with CF aged 6 years and older who have a G970R or non-G551D gating 
mutation in the CFTR gene (G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P or G1349D). 
 
In part 1, patients were randomised 1:1 to receive either 150 mg of ivacaftor or placebo every 12 hours 
with fat-containing food for 8 weeks in addition to their prescribed CF therapies and crossed over to 
the other treatment for the second 8 weeks after a 4- to 8-week washout period. The use of inhaled 
hypertonic saline was not permitted. In part 2, all patients received ivacaftor as indicated in part 1 for 
16 additional weeks. The duration of continuous ivacaftor treatment was 24 weeks for patients 
randomised to the part 1 placebo/ivacaftor treatment sequence and 16 weeks for patients randomised to 
part 1 ivacaftor/placebo treatment sequence. 
 
Thirty-nine patients (mean age 23 years) with baseline FEV1 ≥ 40% predicted (mean FEV1 78% 
predicted [range: 43% to 119%]) were enrolled. Sixty-two percent (24/39) of them carried the 
F508del-CFTR mutation in the second allele. A total of 36 patients continued into part 2 (18 per 
treatment sequence). 
 
In part 1 of study 5, the mean FEV1 percent predicted at baseline in placebo-treated patients was 
79.3% while in ivacaftor-treated patients this value was 76.4%. The mean overall post-baseline value 
was 76.0% and 83.7%, respectively. The mean absolute change from baseline through week 8 in 
percent predicted FEV1 (primary efficacy endpoint) was 7.5% in the ivacaftor period and -3.2% in the 
placebo period. The observed treatment difference (95% CI) between ivacaftor and placebo was 10.7% 
(7.3, 14.1) (P < 0.0001). 



39 

 
The effect of ivacaftor in the overall population of study 5 (including the secondary endpoints absolute 
change in BMI at 8 weeks of treatment and absolute change in the respiratory domain score of the 
CFQ-R through 8 weeks of treatment) and by individual mutation (absolute change in sweat chloride 
and in percent predicted FEV1 at week 8) is shown in Table 5. Based on clinical (percent predicted 
FEV1) and pharmacodynamic (sweat chloride) responses to ivacaftor, efficacy in patients with the 
G970R mutation could not be established. 
 
Table 5: Effect of ivacaftor for efficacy variables in the overall population and for specific CFTR 
mutations 

Absolute change in percent 
predicted FEV1 

BMI 
(kg/m2) 

CFQ-R 
respiratory 

domain score 
(points) 

Through week 8 At week 8 Through week 8 
All patients (N = 39) 
Results shown as mean (95% CI) change from baseline ivacaftor vs. placebo-treated patients: 

10.7 (7.3, 14.1) 0.66 (0.34, 0.99) 9.6 (4.5, 14.7) 
Patients grouped under mutation types (n) 
Results shown as mean (minimum, maximum) change from baseline for ivacaftor-treated patients  
at week 8*: 

Mutation (n) 

Absolute change in sweat chloride 
(mmol/L) 

Absolute change in percent 
predicted FEV1 (percentage points) 

At week 8 At week 8 
G1244E (5) 
G1349D (2) 
G178R (5) 
G551S (2) 
G970R# (4) 
S1251N (8) 
S1255P (2) 
S549N (6) 
S549R (4) 

-55 (-75, -34) 
-80 (-82, -79) 
-53 (-65, -35) 

-68† 
-6 (-16, -2) 
-54 (-84, -7) 

-78 (-82, -74) 
-74 (-93, -53) 

-61†† (-71, -54) 

8 (-1, 18) 
20 (3, 36) 
8 (-1, 18) 

3† 
3 (-1, 5) 

9 (-20, 21) 
3 (-1, 8) 

11 (-2, 20) 
5 (-3, 13) 

* Statistical testing was not performed due to small numbers for individual mutations. 
† Reflects results from the one patient with the G551S mutation with data at the 8-week time point. 
†† n = 3 for the analysis of absolute change in sweat chloride. 
# Causes a splicing defect resulting in little-to-no CFTR protein at the cell surface 
 
In part 2 of study 5, the mean (SD) absolute change in percent predicted FEV1 following 16 weeks 
(patients randomised to the ivacaftor/placebo treatment sequence in part 1) of continuous ivacaftor 
treatment was 10.4% (13.2%). At the follow-up visit 4 weeks after ivacaftor dosing had ended, the 
mean (SD) absolute change in percent predicted FEV1 from part 2 week 16 was -5.9% (9.4%). For 
patients randomised to the placebo/ivacaftor treatment sequence in part 1 there was a further mean 
(SD) change of 3.3% (9.3%) in percent predicted FEV1 after the additional 16 weeks of treatment with 
ivacaftor. At the follow up visit 4 weeks after ivacaftor dosing had ended, the mean (SD) absolute 
change in percent predicted FEV1 from part 2 week 16 was -7.4% (5.5%). 
 
Study 3: study in patients with CF with the F508del mutation in the CFTR gene 
 
Study 3 (part A) was a 16-week, 4:1 randomised, double-blind, placebo-controlled, parallel-group 
phase 2 study of ivacaftor (150 mg every 12 hours) in 140 patients with CF age 12 years and older 
who were homozygous for the F508del mutation in the CFTR gene and who had FEV1 ≥ 40% 
predicted. 
 
The mean absolute change from baseline through week 16 in percent predicted FEV1 (primary efficacy 
endpoint) was 1.5 percentage points in the ivacaftor group and -0.2 percentage points in the placebo 



40 

group. The estimated treatment difference for ivacaftor versus placebo was 1.7 percentage points (95% 
CI -0.6, 4.1); this difference was not statistically significant (P = 0.15). 
 
Study 4: open-label extension study 
 
In study 4, patients who completed treatment in studies 1 and 2 with placebo were switched to 
ivacaftor while patients on ivacaftor continued to receive it for a minimum of 96 weeks, i.e., the length 
of treatment with ivacaftor was at least 96 weeks for patients in the placebo/ivacaftor group and at 
least 144 weeks for patients in the ivacaftor/ivacaftor group. 
 
One hundred and forty-four (144) patients from study 1 were rolled over in study 4, 67 in the 
placebo/ivacaftor group and 77 in the ivacaftor/ivacaftor group. Forty-eight (48) patients from study 2 
were rolled over in study 4, 22 in the placebo/ivacaftor group and 26 in the ivacaftor/ivacaftor group. 
 
Table 6 shows the results of the mean (SD) absolute change in percent predicted FEV1 for both groups 
of patients. For patients in the placebo/ivacaftor group baseline percent predicted FEV1 is that of 
study 4 while for patients in the ivacaftor/ivacaftor group the baseline value is that of studies 1 and 2. 
 
Table 6: Effect of ivacaftor on percent predicted FEV1 in study 4 

Original study and 
treatment group 

Duration of ivacaftor 
treatment (weeks) 

Absolute change from baseline in percent 
predicted FEV1 (percentage points) 

N Mean (SD) 
Study 1 

Ivacaftor 48* 77 9.4 (8.3) 
144 72 9.4 (10.8) 

Placebo 0* 67 -1.2 (7.8)† 
96 55 9.5 (11.2) 

Study 2 
Ivacaftor 48* 26 10.2 (15.7) 

144 25 10.3 (12.4) 
Placebo 0* 22 -0.6 (10.1)† 

96 21 10.5 (11.5) 
* Treatment occurred during blinded, controlled, 48-week phase 3 study. 
† Change from prior study baseline after 48 weeks of placebo treatment. 
 
When the mean (SD) absolute change in percent predicted FEV1 is compared from study 4 baseline for 
patients in the ivacaftor/ivacaftor group (n = 72) who rolled over from study 1, the mean (SD) absolute 
change in percent predicted FEV1 was 0.0% (9.05), while for patients in the ivacaftor/ivacaftor group 
(n = 25) who rolled over from study 2 this figure was 0.6% (9.1). This shows that patients in the 
ivacaftor/ivacaftor group maintained the improvement seen at week 48 of the initial study (day 0 
through week 48) in percent predicted FEV1 through week 144. There were no additional 
improvements in study 4 (week 48 through week 144). 
 
For patients in the placebo/ivacaftor group from study 1, the annualised rate of pulmonary 
exacerbations was higher in the initial study when patients were on placebo (1.34 events/year) than 
during the subsequent study 4 when patients rolled over to ivacaftor (0.48 events/year across day 1 to 
week 48, and 0.67 events/year across weeks 48 to 96). For patients in the ivacaftor/ivacaftor group 
from study 1, the annualised rate of pulmonary exacerbations was 0.57 events/year across day 1 to 
week 48 when patients were on ivacaftor. When they rolled over into study 4, the rate of annualised 
pulmonary exacerbations was 0.91 events/year across day 1 to week 48 and 0.77 events/year across 
weeks 48 to 96. 
 
For patients who rolled over from study 2 the number of events was, overall, low. 
 



41 

Study 6: study in patients with CF with an R117H mutation in the CFTR gene 
 
Study 6 evaluated 69 patients who were 6 years of age or older; 53 (76.8%) patients had the F508del 
mutation in the second allele. The confirmed R117H poly-T variant was 5T in 38 patients and 7T in 
16 patients. At baseline, mean predicted FEV1 was 73% (range: 32.5% to 105.5%) and mean age was 
31 years (range: 6 to 68 years). The mean absolute change from baseline through week  24 in percent 
predicted FEV1 (primary efficacy endpoint) was 2.57 percentage points in the ivacaftor group and 
0.46 percentage points in the placebo group. The estimated treatment difference for ivacaftor versus 
placebo was 2.1 percentage points (95% CI -1.1, 5.4). 
 
A pre-planned subgroup analysis was conducted in patients 18 years and older (26 patients on placebo 
and 24 on ivacaftor). Treatment with ivacaftor resulted in a mean absolute change in percent predicted 
FEV1 through week  24 of 4.5 percentage points in the ivacaftor group versus -0.46 percentage points 
in the placebo group. The estimated treatment difference for ivacaftor versus placebo was 5.0 
percentage points (95% CI 1.1, 8.8). 
 
In a subgroup analysis in patients with a confirmed R117H-5T genetic variant, the difference in the 
mean absolute change from baseline through week  24 in percent predicted FEV1 between ivacaftor 
and placebo was 5.3% (95% CI 1.3, 9.3). In patients with a confirmed R117H-7T genetic variant, the 
treatment difference between ivacaftor and placebo was 0.2% (95% CI -8.1, 8.5). 
 
For secondary efficacy variables, no treatment differences were observed for ivacaftor versus placebo 
in absolute change from baseline in BMI at week 24 or time to first pulmonary exacerbation. 
Treatment differences were observed in absolute change in CFQ-R respiratory domain score through 
week 24 (treatment difference of ivacaftor versus placebo was 8.4 [95% CI 2.2, 14.6] points) and for 
the mean change from baseline in sweat chloride (see Pharmacodynamic effects). 
 
Study 7: study in paediatric patients with CF aged 2 to less than 6 years with G551D or another 
gating mutation 
 
The pharmacokinetic profile, safety and efficacy of ivacaftor in 34 patients aged 2 to less than 6 years 
with CF who had a G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N or S549R 
mutation in the CFTR gene were assessed in a 24-week uncontrolled study with ivacaftor (patients 
weighing less than 14 kg received ivacaftor 50 mg and patients weighing 14 kg or more received 
ivacaftor 75 mg). Ivacaftor was administered orally every 12 hours with fat-containing food in addition 
to their prescribed CF therapies. 
 
Patients in study 7 were aged 2 to less than 6 years (mean age 3 years). Twenty-six patients out of the 
34 enrolled (76.5%) had a CFTR genotype G551D/F508del with only 2 patients with a non-G551D 
mutation (S549N). The mean (SD) sweat chloride at baseline (n = 25) was 97.88 mmol/L (14.00). The 
mean (SD) faecal elastase-1 value at baseline (n = 27) was 28 µg/g (95). 
 
The primary endpoint of safety was evaluated through week 24 (see section 4.8). Secondary and 
exploratory efficacy endpoints evaluated were absolute change from baseline in sweat chloride 
through 24 weeks of treatment, absolute change from baseline in weight, body mass index (BMI) and 
stature (supported by weight, BMI and stature z-scores) at 24 weeks of treatment, and measures of 
pancreatic function such as faecal elastase-1. Data on percent predicted FEV1 (exploratory endpoint) 
were available for 3 patients in the ivacaftor 50 mg group and 17 patients in the 75 mg dosing group. 
 
The mean (SD) overall (both ivacaftor dosing groups combined) absolute change from baseline in 
BMI at week 24 was 0.32 kg/m2 (0.54) and the mean (SD) overall change in BMI-for-age z-score was 
0.37 (0.42). The mean (SD) overall change in stature-for-age z-score was -0.01 (0.33). The mean (SD) 
overall change from baseline in faecal elastase-1 (n = 27) was 99.8 µg/g (138.4). Six patients with 
initial levels below 200 µg/g achieved, at week 24, a level of ≥ 200 µg/g. The mean (SD) overall 
change in percent predicted FEV1 from baseline at week 24 (exploratory endpoint) was 1.8 (17.81). 
 



42 

Study 8: study in paediatric patients with CF aged less than 24 months 
 
The pharmacokinetic profile, safety, and efficacy of ivacaftor in patients with CF aged 6 months to 
less than 24 months were assessed in a completed cohort of patients in an on-going 24-week, 
open-label, phase 3 clinical study in patients aged less than 24 months (study 8). 
 
Part B of study 8 enrolled 19 patients aged 12 months to less than 24 months (mean age 15.2 months at 
baseline), with 18 patients completing the 24-week treatment period, 11 patients aged 6 months to less 
than 12 months (mean age 9.0 months at baseline) with all 11 patients completing the 24-week 
treatment period, and 6 patients aged 4 months to less than 6 months (mean age 4.5 months at 
baseline) with all 6 patients completing the 24-week treatment period. Patients received ivacaftor 
25 mg, 50 mg or 75 mg according to their age and weight at each study visit (see section 4.2). 
Ivacaftor was administered orally every 12 hours with fat-containing food. Patients continued on their 
prescribed standard-of-care CF therapies. 
 
In part B of study 8 the primary endpoint of safety was evaluated through 24 weeks (see section 4.8). 
Secondary endpoints were evaluation of pharmacokinetics and the absolute change from baseline in 
sweat chloride through 24 weeks of treatment (see Pharmacodynamic effects). Tertiary endpoints 
included efficacy measures such as faecal elastase-1 and growth parameters. 
 
For patients aged 4 months to less than 24 months, with both baseline and week 24 values available, 
mean (SD) weight-for-age, length-for-age, and weight-for-length z-scores are provided in Table 7. 
 
Table 7: Effect of ivacaftor on growth parameters in patients aged 4 months to less than 

24 months with baseline and week 24 values 

Parameter 

Number 
of 

patients 

Baseline 
 

Absolute change at week 24 
 

Mean 
(SD) 

Median 
(min, max) 

Mean 
(SD) 

Median 
(min, max) 

Weight–for-age z-score 35 0.17  
(0.85) 

0.20 
[-1.92, 1.79] 

0.33 
(0.53) 

0.26 
[-0.54, 1.63] 

Length-for-age z-score 34 0.06  
(1.03)  

0.12 
[-1.99, 2.79] 

0.32 
(0.92) 

0.47 
[-1.81, 3.38] 

Weight-for-length z-score 34 0.24 
(1.01) 

0.26 
[-1.72, 2.16] 

0.24 
(0.98) 

0.29 
[-2.04, 2.22] 

 
In patients aged 4 months to less than 24 months, with both baseline and week 24 values available, 18 
patients were pancreatic insufficient at baseline (defined as faecal elastase-1 < 200 µg/g) with mean 
(SD) faecal elastase-1 values at baseline and week 24 of 25.5 µg/g (27.6) and 253.6 µg/g (128.3), 
respectively (mean [SD] absolute change 228.41 µg/g [128.3]). Results were consistent in the 
12 months to less than 24 months, 6 months to less than 12 months, and 4 months to less than 6 
months age cohorts. 
 
Paediatric population 
 
The European Medicines Agency has deferred the obligation to submit the results of studies with 
Kalydeco in one or more subsets of the paediatric population in cystic fibrosis (see section 4.2 for 
information on paediatric use). 
 
5.2 Pharmacokinetic properties 
 
The pharmacokinetics of ivacaftor are similar between healthy adult volunteers and patients with CF. 
 
After oral administration of a single 150 mg dose to healthy volunteers in a fed state, the mean (± SD) 
for AUC and Cmax were 10600 (5260) ng*hr/mL and 768 (233) ng/mL, respectively. After every 



43 

12-hour dosing, steady-state plasma concentrations of ivacaftor were reached by days 3 to 5, with an 
accumulation ratio ranging from 2.2 to 2.9. 
 
Absorption 
 
Following multiple oral dose administrations of ivacaftor, the exposure of ivacaftor generally 
increased with dose from 25 mg every 12 hours to 450 mg every 12 hours. When given with fat-
containing food the exposure of ivacaftor increased approximately 2.5- to 4-fold. Therefore, ivacaftor 
should be administered with fat-containing food. The median (range) tmax is approximately 4.0 (3.0; 
6.0) hours in the fed state. 
 
Ivacaftor granules (2 x 75 mg sachets) had similar bioavailability as the 150 mg tablet when given with 
fat-containing food to healthy adult subjects. The geometric least squares mean ratio (90% CI) for the 
granules relative to tablets was 0.951 (0.839, 1.08) for AUC0-∞ and 0.918 (0.750, 1.12) for Cmax. The 
effect of food on ivacaftor absorption is similar for both formulations, i.e., tablets and granules. 
 
Distribution 
 
Ivacaftor is approximately 99% bound to plasma proteins, primarily to alpha 1-acid glycoprotein and 
albumin. Ivacaftor does not bind to human red blood cells. After oral administration of ivacaftor 
150 mg every 12 hours for 7 days in healthy volunteers in a fed state, the mean (± SD) apparent 
volume of distribution was 353 L (122) . 
 
Biotransformation 
 
Ivacaftor is extensively metabolised in humans. In vitro and in vivo data indicate that ivacaftor is 
primarily metabolised by CYP3A. M1 and M6 are the two major metabolites of ivacaftor in humans. 
M1 has approximately one-sixth the potency of ivacaftor and is considered pharmacologically active. 
M6 has less than one-fiftieth the potency of ivacaftor and is not considered pharmacologically active. 
 
The effect of the CYP3A4*22 heterozygous genotype on ivacaftor exposure is consistent with the 
effect of co-administration of a weak CYP3A4 inhibitor, which is not clinically relevant. No dose 
adjustment of ivacaftor 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 oral administration in healthy volunteers, the majority of ivacaftor (87.8%) was eliminated 
in the faeces after metabolic conversion. The major metabolites M1 and M6 accounted for 
approximately 65% of the total dose eliminated with 22% as M1 and 43% as M6. There was negligible 
urinary excretion of ivacaftor as unchanged parent. The apparent terminal half-life was approximately 
12 hours following a single dose in the fed state. The apparent clearance (CL/F) of ivacaftor was 
similar for healthy subjects and patients with CF. The mean (±SD) CL/F for a single 150 mg dose was 
17.3 (8.4) L/hr in healthy subjects. 
 
Linearity/non-linearity 
 
The pharmacokinetics of ivacaftor are generally linear with respect to time or dose ranging from 
25 mg to 250 mg. 
 
Special populations 
 
Hepatic impairment 
 
Following a single dose of 150 mg of ivacaftor, adult subjects with moderately impaired hepatic 
function (Child-Pugh Class B, score 7 to 9) had similar ivacaftor Cmax (mean [± SD] of 735 
[331] ng/mL) but an approximately two-fold increase in ivacaftor AUC0-∞ (mean [± SD] of 16800 



44 

[6140] ng*hr/mL) compared with healthy subjects matched for demographics. Simulations for 
predicting the steady-state exposure of ivacaftor showed that by reducing the dosage from 
150 mg q12h to 150 mg once daily, adults with moderate hepatic impairment would have comparable 
steady-state Cmin values as those obtained with a dose of 150 mg q12h in adults without hepatic 
impairment. Based on these results, a modified regimen of Kalydeco as monotherapy is recommended 
for patients with moderate hepatic impairment (see section 4.2) 
 
The impact of severe hepatic impairment (Child Pugh Class C, score 10 to15) on the pharmacokinetics 
of ivacaftor have not been studied. The magnitude of increase in exposure in these patients is unknown 
but is expected to be higher than that observed in patients with moderate hepatic impairment. The use 
of Kalydeco in patients with severe hepatic impairment is therefore not recommended unless the 
benefits outweigh the risks (see section 4.2 and section 4.4). 
 
No dose adjustment is considered necessary for patients with mild hepatic impairment. 
 
Renal impairment 
 
Pharmacokinetic studies have not been performed with ivacaftor in patients with renal impairment. In 
a human pharmacokinetic study, there was minimal elimination of ivacaftor and its metabolites in 
urine (only 6.6% of total radioactivity was recovered in the urine). There was negligible urinary 
excretion of ivacaftor as unchanged parent (less than 0.01% following a single oral dose of 500 mg).  
 
No dose adjustments are recommended for mild and moderate renal impairment. However, caution is 
recommended when administering ivacaftor to patients with severe renal impairment (creatinine 
clearance less than or equal to 30 mL/min) or end-stage renal disease (see sections 4.2 and 4.4). 
 
Race 
 
Race had no clinically meaningful effect on the PK of ivacaftor in white (n = 379) and non-white 
(n = 29) patients based on a population PK analysis. 
 
Gender 
 
The pharmacokinetic parameters of ivacaftor are similar in males and females. 
 
Elderly 
 
Clinical studies of ivacaftor as monotherapy did not include sufficient numbers of patients aged 
65 years and older to determine whether pharmacokinetic parameters are similar or not to those in 
younger adults. 
 
Paediatric population 
 
Predicted ivacaftor exposure based on observed ivacaftor concentrations in phase 2 and 3 studies as 
determined using population PK analysis is presented by age group in Table 8.  
 
Table 8: Mean (SD) ivacaftor exposure by age group 

Age group Dose Cmin, ss 
(ng/mL) 

AUCτ,ss 
(ng*h/mL) 

4 months to less than 6 months (≥5 kg) 25 mg q12h 371 (183) 6480 (2520) 

6 months to less than 12 months (5 kg to < 7 kg) * 25 mg q12h 336 5410 

6 months to less than 12 months (7 kg to < 14 kg) 50 mg q12h 508 (252) 9140 (4200) 

12 months to less than 24 months (7 kg to < 14 kg) 50 mg q12h 440 (212) 9050 (3050) 



45 

Age group Dose Cmin, ss 
(ng/mL) 

AUCτ,ss 
(ng*h/mL) 

12 months to less than 24 months (≥ 14 kg to < 25 kg) 75 mg q12h 451 (125) 9600 (1800) 

2- to 5-year-olds (< 14 kg) 50 mg q12h 577 (317) 10500 (4260) 

2- to 5-year-olds (≥ 14 kg to < 25 kg) 75 mg q12h 629 (296) 11300 (3820) 

6- to 11-year-olds † (≥ 14 kg to < 25 kg) 75 mg q12h 641 (329) 10760 (4470) 

6- to 11-year-olds † (≥ 25 kg) 150 mg q12h 958 (546) 15300 (7340) 

12- to 17-year-olds 150 mg q12h 564 (242) 9240 (3420) 

Adults (≥ 18 years old) 150 mg q12h 701 (317) 10700 (4100) 
* Values based on data from a single patient; standard deviation not reported. 
†
 Exposures in 6- to 11-year-olds are predictions based on simulations from the population PK model using data obtained 

for this age group. 
 
5.3 Preclinical safety data 
 
Non-clinical data reveal no special hazard for humans based on conventional studies of safety 
pharmacology, repeated dose toxicity, genotoxicity, and carcinogenic potential. 
 
Pregnancy and fertility 
 
Ivacaftor was associated with slight decreases of the seminal vesicle weights, a decrease of overall 
fertility index and number of pregnancies in females mated with treated males and significant 
reductions in number of corpora lutea and implantation sites with subsequent reductions in the average 
litter size and average number of viable embryos per litter in treated females. The 
No-Observed-Adverse-Effect-Level (NOAEL) for fertility findings provides an exposure level of 
approximately 4 times the systemic exposure of ivacaftor and its metabolites when administered as 
ivacaftor monotherapy in adult humans at the maximum recommended human dose (MRHD). 
Placental transfer of ivacaftor was observed in pregnant rats and rabbits. 
 
Peri- and post-natal development 
 
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 approximately 3 times the 
systemic exposure of ivacaftor and its metabolites when administered as ivacaftor monotherapy in 
adult humans at the MRHD.  
 
Juvenile animal studies 
 
Findings of cataracts were observed in juvenile rats dosed from postnatal day 7 through 35 at ivacaftor 
exposure levels of 0.22 times the MRHD based on systemic exposure of ivacaftor and its metabolites 
when administered as ivacaftor monotherapy. This finding has not been observed in foetuses derived 
from rat dams treated with ivacaftor on gestation days 7 to 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. 
 
 



46 

6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Silica, colloidal anhydrous 
Croscarmellose sodium 
Hypromellose acetate succinate 
Lactose monohydrate 
Magnesium stearate 
Mannitol 
Sucralose 
Sodium laurilsulfate (E487) 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
3 years. 
 
Once mixed, the mixture has been shown to be stable for one hour. 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions. 
 
6.5 Nature and contents of container 
 
The granules are packed in a Biaxially Oriented Polyethylene 
Terephthalate/Polyethylene/Foil/Polyethylene (BOPET/PE/Foil/PE) sachet. 
 
Pack size of 56 sachets (contains 4 individual wallets with 14 sachets per wallet) 
 
6.6 Special precautions for disposal and other handling 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Vertex Pharmaceuticals (Ireland) Limited 
28-32 Pembroke Street Upper 
Dublin 2, D02 EK84 
Ireland 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/12/782/003 
EU/1/12/782/004 
EU/1/12/782/006 
 
 



47 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 23 July 2012 
Date of latest renewal: 28 April 2017 
 
 
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. 
  



48 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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 
 



49 

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. 
 
 
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 
 



50 

The MAH shall complete, within the stated timeframe, the below measures: 
 
Description Due date 
Long-term effectiveness study to compare disease 
progression among children with CF who have a 
specified CFTR gating mutation and are aged 2 through 5 
years at the time of Kalydeco treatment initiation versus 
disease progression among concurrent matched cohort of 
children with CF who have never received Kalydeco 
treatment. 

Interim analysis 1: December 2017 
 
Interim analysis 2: December 2019 
 
Interim analysis 3: December 2021 
 
Final report: December 2023 

 
  



51 

 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
 
 
 
 
 
 
 
 
 
 
 
 

  



52 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
  



53 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON FOR BLISTER – 56-TABLET PACK 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Kalydeco 150 mg film-coated tablets 
ivacaftor 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 150 mg of ivacaftor. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. 
 
See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
56 tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
Oral use  
 
Instructions for use 
 
Take with fat-containing food.  
 
Do not break, chew or dissolve the tablets. 
 
 
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 
 
 



54 

9. SPECIAL STORAGE CONDITIONS 
 
 
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/1/12/782/002 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Kalydeco 150 mg tablets 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC 
SN 
NN 
 



55 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTERS – 56-TABLET PACK 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Kalydeco 150 mg tablets 
ivacaftor 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Vertex Pharmaceuticals (Ireland) Limited 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
 



56 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON FOR BLISTER CARD – 28-TABLET PACK  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Kalydeco 150 mg film-coated tablets 
ivacaftor 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 150 mg of ivacaftor. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. 
 
See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
28 tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
Oral use  
 
Instructions for use 
 
Always take this medicine exactly as your doctor has told you to. 
 
Take with fat-containing food. 
 
Do not break, chew or dissolve the tablets. 
 
Insert tab below to close 
 
Open 
 
 
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 
 



57 

 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
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/1/12/782/005 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Kalydeco 150 mg tablets 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC 
SN 
NN 



58 

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 
 
BLISTER CARD – 28-TABLET PACK  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Kalydeco 150 mg film-coated tablets 
ivacaftor 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 150 mg of ivacaftor. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. 
 
See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
7 tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
Oral use  
 
Instructions for use 
 
Always take this medicine exactly as your doctor has told you to. 
 
Take with fat-containing food. 
 
Do not break, chew or dissolve the tablets. 
 
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 
 
 



59 

8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
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/1/12/782/005 
 
 
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 
 
 



60 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTERS – 28-TABLET PACK 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Kalydeco 150 mg tablets 
ivacaftor 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Vertex 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
  



61 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON FOR BLISTER CARD – 28-TABLET PACK  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Kalydeco 75 mg film-coated tablets 
ivacaftor 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 75 mg of ivacaftor. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. 
 
See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
28 tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
Oral use  
 
Instructions for use 
 
Always take this medicine exactly as your doctor has told you to. 
 
Take with fat-containing food. 
 
Do not break, chew or dissolve the tablets. 
 
Insert tab below to close 
 
Open 
 
 
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 
 



62 

 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
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/1/12/782/007 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Kalydeco 75 mg tablets 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC 
SN 
NN 
  



63 

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 
 
BLISTER CARD – 28-TABLET PACK  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Kalydeco 75 mg film-coated tablets 
ivacaftor 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 75 mg of ivacaftor. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. 
 
See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
7 tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
Oral use  
 
Instructions for use 
 
Always take this medicine exactly as your doctor has told you to. 
 
Take with fat-containing food. 
 
Do not break, chew or dissolve the tablets. 
 
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 
 
 



64 

8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
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/1/12/782/007 
 
 
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 
  



65 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTERS – 28-TABLET PACK 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Kalydeco 75 mg tablets 
ivacaftor 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Vertex 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
 
  



66 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON FOR BOTTLE 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Kalydeco 150 mg film-coated tablets 
ivacaftor 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 150 mg of ivacaftor. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. 
 
See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
56 tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
Oral use 
 
Instructions for use 
 
Take with fat-containing food. 
 
Do not break, chew or dissolve the tablets. 
 
 
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 
 
 



67 

9. SPECIAL STORAGE CONDITIONS 
 
 
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/1/12/782/001 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Kalydeco 150 mg tablets 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC 
SN 
NN 
 



68 

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 
 
BOTTLE LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Kalydeco 150 mg film-coated tablets 
ivacaftor 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 150 mg of ivacaftor. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. 
 
See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
56 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 
 
 



69 

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/1/12/782/001 
 
 
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 
 
 
  



70 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
OUTER CARTON FOR SACHET 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Kalydeco 25 mg granules in sachet 
ivacaftor 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE 
 
Each sachet of granules contains 25 mg of ivacaftor. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. 
 
See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Granules in sachet 
 
56 sachets 
 
4 individual wallets with 14 sachets per wallet 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
Oral use 
 
Instructions for use 
 
Mix the entire content of a sachet with 5 mL of age-appropriate soft food or liquid that is at or below 
room temperature and consume it completely. 
 
Use within one hour after mixing, just before or after a fat-containing meal or snack. 
 
Lift here to open 
 
 
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 
 



71 

 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
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/1/12/782/006 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Kalydeco 25 mg granules 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC 
SN 
NN 



72 

PARTICULARS TO APPEAR ON THE INTERMEDIATE PACKAGING 
 
WALLET FOR SACHET 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Kalydeco 25 mg granules in sachet 
ivacaftor 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE 
 
Each sachet of granules contains 25 mg of ivacaftor. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. 
 
See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Granules in sachet 
 
14 sachets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
Oral use 
 
Instructions for use 
 
Mix the entire content of a sachet with 5 mL of age-appropriate soft food or liquid that is at or below 
room temperature and consume it completely.  
 
Use within one hour after mixing, just before or after a fat-containing meal or snack. 
 
Use all 7 days’ doses before starting a new wallet. 
 
Morning 
 
Evening 
 
Mon. Tue. Wed. Thu. Fri. Sat. Sun. 
 
 



73 

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 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
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/1/12/782/006 
 
 
13. BATCH NUMBER 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
 



74 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
SACHETS 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Kalydeco 25 mg granules 
ivacaftor 
Oral use 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
 
6. OTHER 
 
Vertex Pharmaceuticals (Ireland) Limited 
 
 



75 

 PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON FOR SACHET 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Kalydeco 50 mg granules in sachet 
ivacaftor 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE 
 
Each sachet of granules contains 50 mg of ivacaftor. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. 
 
See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Granules in sachet 
 
56 sachets 
 
4 individual wallets with 14 sachets per wallet 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
Oral use 
 
Instructions for use 
 
Mix the entire content of a sachet with 5 mL of age-appropriate soft food or liquid that is at or below 
room temperature and consume it completely. 
 
Use within one hour after mixing, just before or after a fat-containing meal or snack. 
 
Lift here to open 
 
 
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 



76 

 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
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/1/12/782/003 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Kalydeco 50 mg granules 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC 
SN 
NN 



77 

PARTICULARS TO APPEAR ON THE INTERMEDIATE PACKAGING 
 
WALLET FOR SACHET 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Kalydeco 50 mg granules in sachet 
ivacaftor 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE 
 
Each sachet of granules contains 50 mg of ivacaftor. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. 
 
See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Granules in sachet 
 
14 sachets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
Oral use 
 
Instructions for use 
 
Mix the entire content of a sachet with 5 mL of age-appropriate soft food or liquid that is at or below 
room temperature and consume it completely.  
 
Use within one hour after mixing, just before or after a fat-containing meal or snack. 
 
Use all 7 days’ doses before starting a new wallet. 
 
Morning 
 
Evening 
 
Mon. Tue. Wed. Thu. Fri. Sat. Sun. 
 
 



78 

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 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
 
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/1/12/782/003 
 
 
13. BATCH NUMBER 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
 



79 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
SACHETS 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Kalydeco 50 mg granules 
ivacaftor 
Oral use 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
 
6. OTHER 
 
Vertex Pharmaceuticals (Ireland) Limited 
 



80 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON FOR SACHET 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Kalydeco 75 mg granules in sachet 
ivacaftor 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE 
 
Each sachet of granules contains 75 mg of ivacaftor. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. 
 
See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Granules in sachet 
 
56 sachets 
 
4 individual wallets with 14 sachets per wallet 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
Oral use 
 
Instructions for use 
 
Mix the entire content of a sachet with 5 mL of age-appropriate soft food or liquid that is at or below 
room temperature and consume it completely. 
 
Use within one hour after mixing, just before or after a fat-containing meal or snack. 
 
Lift here to open 
 
 
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 



81 

 
 
8. EXPIRY DATE 
 
EXP  
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
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/1/12/782/004 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Kalydeco 75 mg granules 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC 
SN 
NN 



82 

PARTICULARS TO APPEAR ON THE INTERMEDIATE PACKAGING 
 
WALLET FOR SACHET 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Kalydeco 75 mg granules in sachet 
ivacaftor 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE 
 
Each sachet of granules contains 75 mg of ivacaftor. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. 
 
See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Granules in sachet 
 
14 sachets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
Oral use 
 
Instructions for use 
 
Mix the entire content of a sachet with 5 mL of age-appropriate soft food or liquid that is at or below 
room temperature and consume it completely. 
 
Use within one hour after mixing, just before or after a fat-containing meal or snack. 
 
Use all 7 days’ doses before starting a new wallet. 
 
Morning 
 
Evening 
 
Mon. Tue. Wed. Thu. Fri. Sat. Sun. 
 
 



83 

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 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
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/1/12/782/004 
 
 
13. BATCH NUMBER 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
 



84 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
SACHETS 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Kalydeco 75 mg granules 
ivacaftor 
Oral use 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
 
6. OTHER 
 
Vertex Pharmaceuticals (Ireland) Limited 
 
  



85 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
 

  



86 

Package leaflet: Information for the patient 
 

Kalydeco 75 mg film-coated tablets 
Kalydeco 150 mg film-coated tablets 

ivacaftor 
 
 
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 Kalydeco is and what it is used for 
2. What you need to know before you take Kalydeco 
3. How to take Kalydeco 
4. Possible side effects 
5. How to store Kalydeco 
6. Contents of the pack and other information 
 
 
1. What Kalydeco is and what it is used for 
 
Kalydeco contains the active ingredient ivacaftor. Ivacaftor acts at the level of the cystic fibrosis 
transmembrane conductance regulator (CFTR), a protein that forms a channel at the cell surface that 
allows the movement of particles such as chloride in and out of the cell. Due to mutations in the CFTR 
gene (see below), chloride movement is reduced in those with cystic fibrosis (CF). Ivacaftor helps 
certain abnormal CFTR proteins open more often to improve chloride movement in and out of the cell. 
 
Kalydeco tablets are indicated:  
• As monotherapy for patients aged 6 years and older and weighing 25 kg or more with cystic 

fibrosis (CF) who have an R117H CFTR mutation or one of the following gating mutations in 
the CFTR gene: G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N or S549R. 
 

• In combination with tezacaftor/ivacaftor tablets for patients aged 6 years and older with CF who 
have two F508del mutations in the CFTR gene (homozygous for the F508del mutation) or who 
have an F508del mutation and certain other second mutations that result in reduced amount 
and/or function of the CFTR protein (heterozygous for the F508del mutation with a residual 
function (RF) mutation). If you have been prescribed Kalydeco to be taken with 
tezacaftor/ivacaftor, read the package leaflet of the latter. It contains important information 
about how to take these two medicines. 
 

• In combination with ivacaftor/tezacaftor/elexacaftor tablets for patients aged 12 years and over 
with CF who are homozygous for the F508del mutation in the CFTR gene or heterozygous for 
F508del in the CFTR gene with a minimal function (MF) 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 ivacaftor alone and 
tezacaftor/ivacaftor. If you have been prescribed Kalydeco to be taken with 
ivacaftor/tezacaftor/elexacaftor, read the package leaflet of the latter. It contains important 
information about how to take these two medicines. 

 



87 

2. What you need to know before you take Kalydeco 
 
Do not take Kalydeco 
 
• if you are allergic to ivacaftor or any of the other ingredients of this medicine (listed in 

section 6). 
 
Warnings and precautions 
 
• Talk to your doctor if you have liver problems or have previously had them. Your doctor may 

need to adjust your dose. 
• Increased liver enzymes in the blood have been seen in some people receiving Kalydeco (alone 

or in combination with tezacaftor/ivacaftor or ivacaftor/tezacaftor/elexacaftor). Tell your doctor 
right away if you have any of these symptoms, which may be a sign of liver problems: 
• Pain or discomfort in the upper right stomach (abdominal) area 
• Yellowing of the skin or the white part of the eyes 
• Loss of appetite 
• Nausea or vomiting 
• Dark urine 

Your doctor will do some blood tests to check your liver before and during treatment, particularly 
during the first year and especially if your blood tests showed high liver enzymes in the past. 
 

• Talk to your doctor if you have kidney problems or have previously had them. 
 
• Kalydeco (alone or in combination with tezacaftor/ivacaftor or ivacaftor/tezacaftor/elexacaftor) 

is not recommended if you have undergone 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 Kalydeco in 
combination with ivacaftor/tezacaftor/elexacaftor. 

 
• Abnormality of the eye lens (cataract) without any effect on vision has been noted in some 

children and adolescents treated with Kalydeco (alone or in combination with 
tezacaftor/ivacaftor or ivacaftor/tezacaftor/elexacaftor). Your doctor may perform some eye 
examinations prior to and during treatment. 

 
• Kalydeco (alone or in combination with tezacaftor/ivacaftor or ivacaftor/tezacaftor/elexacaftor) 

should only be used if you have one of the mutations in the CFTR gene indicated in section 1 
(What Kalydeco is and what it is used for). 

 
Children and adolescents 
 
Do not give this medicine to children under 4 months of age as it is not known if ivacaftor is safe and 
effective in these children. 
 
Do not give this medicine in combination with tezacaftor/ivacaftor to children under 6 years of age or 
in combination with ivacaftor/tezacaftor/elexacaftor to children under 12 years of age as it is not 
known if they are safe and effective for them. 
 
Other medicines and Kalydeco 
 
Tell your doctor or pharmacist if you are using, have recently used or might use any other medicines. 
Some medicines can affect how Kalydeco works or make side effects more likely. In particular, tell 
your doctor if you are taking any of the medicines listed below. Your doctor may decide to adjust your 
dose or that you need extra check-ups. 
 



88 

• 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, rifabutin, rifampicin, 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 and glipizide.  
• Medicines for lowering blood pressure. These include verapamil. 

 
 
Kalydeco with food and drink 
 
Avoid food or drink containing grapefruit during treatment with Kalydeco as they may increase the 
side effects of Kalydeco by increasing the amount of ivacaftor in your body. 
 
Pregnancy and breast-feeding 
 
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor for advice before taking this medicine. It may be better to avoid using Kalydeco during 
pregnancy, if possible, and your doctor will help you decide what is best for you and your child. 
 
It is unknown whether ivacaftor is excreted in human milk. If you plan to breast-feed, ask your doctor 
for advice before taking Kalydeco. Your doctor will decide whether to recommend that you stop 
breast-feeding or for you to stop ivacaftor therapy. Your doctor will take into account the benefit of 
breast-feeding for the child and the benefit of therapy for you. 
 
Driving and using machines 
 
Kalydeco can make you dizzy. If you feel dizzy, do not drive, cycle or use machines. 
 
Important information about the contents of Kalydeco 
 
Kalydeco contains lactose. If you have been told by your doctor that you have an intolerance to some 
sugars, contact your doctor before taking this medicine. 
 
Kalydeco contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially 
‘sodium-free’. 
 
 
3. How to take Kalydeco 
 
Always take this medicine exactly as your doctor has told you to. Check with your doctor if you are 
not sure. 
 
Your doctor will determine which medicine and dose is right for you. 
 
Kalydeco dosing recommendations are provided in Table 1. 
 



89 

Table 1: Dosing recommendations 

 Morning Evening 
Kalydeco as monotherapy 

6 years and older, ≥25 kg One Kalydeco 150 mg tablet One Kalydeco 150 mg 
tablet 

Kalydeco in combination with tezacaftor/ivacaftor 
6 years to less than 12 years, 
<30 kg 

One tezacaftor 50 mg/ivacaftor 75 mg 
tablet 

One Kalydeco 75 mg 
tablet 

6 years to less than 12 years, 
≥30 kg 

One tezacaftor 100 mg/ivacaftor 150 mg 
tablet 

One Kalydeco 150 mg 
tablet 

12 years and older One tezacaftor 100 mg/ivacaftor 150 mg 
tablet 

One Kalydeco 150 mg 
tablet 

Kalydeco in combination with ivacaftor/tezacaftor/elexacaftor 

12 years and older Two ivacaftor 75 mg/tezacaftor 
50 mg/elexacaftor 100 mg tablets 

One Kalydeco 150 mg 
tablet 

 
Take the morning and evening doses approximately 12 hours apart with food that contains fat.  
 
You must keep using all other medicines you use, unless your doctor tells you to stop using any. 
 
If you have liver problems, either moderate or severe, your doctor may need to reduce the dose of your 
tablets, because your liver will not clear the medicine as fast as in people who have normal liver 
function. 
 
Use in children 
 
This medicine is for oral use.  
 
Swallow the tablet whole. Do not break, chew or dissolve the tablets. Take Kalydeco 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 

 
If you take more Kalydeco than you should 
 
You may experience side effects, including those mentioned in section 4 below. If so, contact your 
doctor or pharmacist to ask for advice. If possible, have your medicine and this leaflet with you. 
 
If you forget to take Kalydeco 
 
Take the missed dose if less than 6 hours have passed since the time you missed the dose. Otherwise, 
wait until your next scheduled dose as you normally would. Do not take a double dose to make up for 
a forgotten dose. 
 
If you stop taking Kalydeco 
 
Take Kalydeco for as long as your doctor recommends. Do not stop unless your doctor advises you to. 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 



90 

4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Serious side effects  
 
Stomach (abdominal) ache and increased liver enzymes in the blood.  
 
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 white part of the eyes 
• Loss of appetite 
• Nausea or vomiting 
• Dark urine 

 
Tell your doctor straight away if you get any of these. 
 
Very common side effects (may affect more than 1 in 10 people) 
• Upper respiratory tract infection (the common cold), including sore throat and nasal congestion 
• Headache 
• Dizziness 
• Diarrhoea 
• Stomach or abdominal pain 
• Changes in the type of bacteria in mucus 
• Increased liver enzymes (signs of stress on the liver) 
• Rash  

 
Common side effects (may affect up to 1 in 10 people) 
• Runny nose 
• Ear pain, ear discomfort 
• Ringing in the ears 
• Redness inside the ear 
• Inner ear disorder (feeling dizzy or spinning) 
• Sinus problems (sinus congestion) 
• Redness in the throat 
• Breast mass 
• Feeling sick (nausea) 
• Flu 
• Low blood sugar (hypoglycaemia) 
• Abnormal breathing (shortness of breath or difficulty breathing) 
• Wind (flatulence) 
• Spots (acne) 
• Itchy skin  
• Increased creatine phosphokinase (sign of muscle breakdown) seen in blood tests 

 
Uncommon side effects (may affect up to 1 in 100 people) 
• Ear congestion 
• Breast inflammation  
• Enlargement of the breast in males 
• Nipple changes or pain 
• Wheezing 
• Increased blood pressure 

 



91 

Additional side effects in children and adolescents 
 
Side effects seen in children and adolescents are similar to those observed in adults. However, 
increased liver enzymes in the blood are more frequently seen in young children. 
 
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 Kalydeco 
 
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 package 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 Kalydeco contains 
 
The active substance is ivacaftor.  
 
Kalydeco 75 mg film-coated tablets 
 
Each 75 mg film-coated tablet contains 75 mg of ivacaftor. 
 
Kalydeco 150 mg film-coated tablets 
 
Each 150 mg film-coated tablet contains 150 mg of ivacaftor. 
 
The other ingredients are: 

• Tablet core: cellulose microcrystalline, lactose monohydrate, hypromellose acetate succinate, 
croscarmellose sodium, sodium laurilsulfate (E487), silica, colloidal anhydrous, and magnesium 
stearate. 

• Coating: polyvinyl alcohol, titanium dioxide (E171), macrogol (PEG 3350), talc, indigo carmine 
aluminium lake (E132) and carnauba wax. 

• Printing ink: shellac, iron oxide black (E172), propylene glycol (E1520) and ammonia solution, 
concentrated. 

See the end of section 2 - Important information about the contents of Kalydeco. 
 
What Kalydeco looks like and contents of the pack 
 
Kalydeco 75 mg film-coated tablets are light blue, capsule-shaped, 12.7 mm x 6.8 mm, and printed 
with “V 75” in black ink on one side and plain on the other side. 
 
The following pack sizes are available:  
• Blister card pack containing 28 film-coated tablets 

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


92 

 
Kalydeco 150 mg film-coated tablets are light blue, capsule-shaped, 16.5 mm x 8.4 mm, and printed 
with “V 150” in black ink on one side and plain on the other. 
 
The following pack sizes are available: 
• Blister card pack containing 28 film-coated tablets 
• Blister pack containing 56 film-coated tablets 
• Bottle containing 56 film-coated tablets 

 
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 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 

België/Belgique/Belgien, България, Česká 
republika, Danmark, Deutschland, Eesti, 
France, Hrvatska, Ireland, Ísland, Κύπρος, 
Latvija, Lietuva, Luxembourg/Luxemburg, 
Magyarország, Malta, Nederland, Norge, 
Österreich, Polska, Portugal, România, 
Slovenija, Slovenská republika, 
Suomi/Finland, Sverige, United Kingdom 
Vertex Pharmaceuticals (Ireland) Limited 
Tél/Tel/Teл/Tlf/Sími/Τηλ/Puh:  
+353 (0) 1 761 7299 
 

España 
Vertex Pharmaceuticals Spain, S.L. 
Tel: + 34 91 7892800 
 

Ελλάδα 
Vertex Φαρμακευτική Μονοπρόσωπη Ανώνυμη 
Εταιρία 
Λ. Κηφισίας 62 
GR-151 25 Αθήνα 
Τηλ: +30 (211) 2120535 
 

Italia 
Vertex Pharmaceuticals 
(Italy) S.r.l. 
Tel: +39 0697794000 
 



93 

 
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. 

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


94 

Package leaflet: Information for the patient 
 

Kalydeco 25 mg granules in sachet 
Kalydeco 50 mg granules in sachet 
Kalydeco 75 mg granules in sachet 

ivacaftor 
 

 
Read all of this leaflet carefully before your child starts taking this medicine because it contains 
important information for your child. 
• Keep this leaflet. You may need to read it again. 
• If you have any further questions, ask your child’s doctor or pharmacist. 
• This medicine has been prescribed for your child only. Do not pass it on to others. It may harm 

them, even if their signs of illness are the same as your child’s. 
• If your child gets any side effects, talk to your child’s doctor or pharmacist. This includes any 

possible side effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
 
1. What Kalydeco is and what it is used for 
2. What you need to know before your child takes Kalydeco 
3. How to take Kalydeco 
4. Possible side effects 
5. How to store Kalydeco 
6. Contents of the pack and other information 
 
 
1. What Kalydeco is and what it is used for 
 
Kalydeco contains the active ingredient ivacaftor. Ivacaftor acts at the level of the cystic fibrosis 
transmembrane conductance regulator (CFTR), a protein that forms a channel at the cell surface that 
allows the movement of particles such as chloride in and out of the cell. Due to mutations in the CFTR 
gene (see below), chloride movement is reduced in those with cystic fibrosis (CF). Ivacaftor helps 
certain abnormal CFTR proteins open more often to improve chloride movement in and out of the cell. 
 
Kalydeco granules are indicated for the treatment of babies and children aged 4 months and older and 
weighing 5 kg to less than 25 kg with cystic fibrosis (CF) who have an R117H CFTR mutation or one 
of the following gating mutations in the CFTR gene: G551D, G1244E, G1349D, G178R, G551S, 
S1251N, S1255P, S549N or S549R. 
 
 
2. What you need to know before your child takes Kalydeco 
 
Do not take Kalydeco 
 
• if your child is allergic to ivacaftor or any of the other ingredients of this medicine (listed in 

section 6). 
 
Warnings and precautions 
 
• Talk to your child’s doctor if your child has liver problems or has had them previously. Your 

child’s doctor may need to adjust your child’s dose. 
• Increased liver enzymes in the blood have been seen in some people receiving Kalydeco. Tell 

your child’s doctor right away if your child has any of these symptoms, which may be a sign of 
liver problems: 
• Pain or discomfort in the upper right stomach (abdominal) area 
• Yellowing of the skin or the white part of the eyes 



95 

• Loss of appetite 
• Nausea or vomiting 
• Dark urine 

Your child’s doctor will do some blood tests to check your child’s liver before and during 
treatment, particularly during the first year and especially if blood tests showed high liver enzymes 
in the past. 
 

• Talk to your child’s doctor if you have been told your child has kidney problems or has 
previously had them.  
 

• Kalydeco is not recommended for patients who have undergone an organ transplant. 
 

• Abnormality of the eye lens (cataract) without any effect on vision has been noted in some 
children and adolescents during treatment.  
Your child’s doctor may perform some eye examinations prior to and during treatment with 
ivacaftor. 

 
Children 
 
Do not give this medicine to children under 4 months of age as it is not known if ivacaftor is safe and 
effective in these children. 
 
Other medicines and Kalydeco 
 
Tell your child’s doctor or pharmacist if your child is using, has recently used or might use any other 
medicines. Some medicines can affect how Kalydeco works or make side effects more likely. In 
particular, tell your child’s doctor if your child is taking any of the medicines listed below. Your 
child’s doctor may decide to adjust your child’s dose or if extra check-ups are needed. 
• 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, rifabutin, rifampicin 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 and glipizide. 
• Medicines for lowering blood pressure. These include verapamil. 

 
Kalydeco with food and drink 
 
Avoid giving your child food or drink containing grapefruit during treatment with Kalydeco as they 
may increase the side effects of Kalydeco by increasing the amount of ivacaftor in your child’s body. 
 
Driving and using machines 
 
Kalydeco can make your child dizzy. If your child feels dizzy, it is advised that your child does not 
ride his/her bike or do anything else that needs his/her full attention. 
 



96 

Important information about the contents of Kalydeco 
 
Kalydeco contains lactose. If you have been told by your child’s doctor that your child has an 
intolerance to some sugars, contact your child’s doctor before your child takes this medicine. 
 
Kalydeco contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially 
‘sodium-free’. 
 
 
3. How to take Kalydeco 
 
Always give your child this medicine exactly as your child’s doctor has told you to. Check with your 
child’s doctor if you are not sure. 
 
Your child’s doctor will determine the correct dose for your child. Your child must keep using all 
other medicines, unless your child’s doctor tells him/her to stop using any. 
 
Kalydeco dosing recommendations are provided in Table 1. 
 
Table 1: Dosing recommendations for children aged 4 months and older 

Age Weight Dose Total daily 
dose 

4 months to less 
than 6 months 

5 kg or more One sachet of 25 mg granules taken 
orally every 12 hours with 
fat-containing food 

50 mg 

6 months and 
older 

5 kg to less than 
7 kg 

One Kalydeco sachet of 25 mg 
granules taken orally every 12 hours 
with fat-containing food 

50 mg 

7 kg to less than 
14 kg 

One Kalydeco sachet of 50 mg 
granules taken orally every 12 hours 
with fat-containing food  

100 mg 

14 kg to less than 
25 kg 

One Kalydeco sachet of 75 mg 
granules taken orally every 12 hours 
with fat-containing food  

150 mg 

25 kg or more Please refer to Kalydeco tablets Package Leaflet 
 
If your child has liver problems, your child’s doctor may need to reduce the dose of Kalydeco as 
your child’s liver will not clear the medicine as fast as in children who have normal liver function. 
• Moderate liver problems in children 6 months of age or older: the dose may be reduced to 

one half of the indicated dose in the table above, that is one sachet once daily. 
• Severe liver problems in children 6 months of age or older: the use is not recommended but 

your child’s doctor will decide if it is appropriate for your child to use this medicine in which 
case the dose (as indicated in the table above) must be reduced to one sachet every other day. 

• Liver problems in children between 4 months and 6 months of age: the use is not 
recommended but your child’s doctor will decide if it is appropriate for your child to use and 
what dose your child should have. 

 
Kalydeco is for oral use. 
 
Each sachet is for single use only. 
 
Giving Kalydeco to your child: 
• Hold sachet of granules with cut line on top. 
• Shake sachet gently to settle contents. 
• Tear or cut sachet open along cut line. 



97 

• Mix the entire content of a sachet with 5 mL of age-appropriate soft food or liquid. Food or 
liquid should be at room temperature or below. Some examples of age-appropriate soft foods or 
liquids include puréed fruits or vegetables, yogurt, applesauce, water, milk, breast milk, infant 
formula, or juice. 

• Once mixed, give the product to your child immediately. If this is not possible, give it within the 
following hour after mixing. Ensure that the mixture is completely and immediately consumed. 

• A fat-containing meal or snack should be given to your child just before or just after dosing 
(some examples are provided below). 

 
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, breast milk, infant formula, chocolate 
• Meats, oily fish 
• Avocados, hummus, soy-based products (tofu) 
• Nuts, fat-containing nutritional bars or drinks 

 
If your child takes more Kalydeco than he/she should 
 
Your child may experience side effects, including those mentioned in section 4 below. If so, contact 
your child’s doctor or pharmacist to ask for advice. If possible, have your child’s medicine and this 
leaflet with you. 
 
If you forget to give your child Kalydeco 
 
Give the missed dose if less than 6 hours have passed since the time your child missed the dose. 
Otherwise, wait until your child’s next scheduled dose as you normally would. Do not give your child 
a double dose to make up for a forgotten dose. 
 
If you stop giving your child Kalydeco 
 
Give Kalydeco to your child for as long as your child’s doctor recommends. Do not stop unless your 
child’s doctor advises you to. If you have any further questions on the use of this medicine, ask your 
child’s doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Serious side effects 
 
Stomach (abdominal) ache and increased liver enzymes in the blood.  
 
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 white part of the eyes 
• Loss of appetite 
• Nausea or vomiting 
• Dark urine 

 
Tell your child’s doctor straight away if he/she gets any of these. 
 
Very common side effects (may affect more than 1 in 10 people) 
• Upper respiratory tract infection (the common cold), including sore throat and nasal congestion 
• Headache 



98 

• Dizziness 
• Diarrhoea 
• Rash 
• Changes in the type of bacteria in mucus 

 
Common side effects (may affect up to 1 in 10 people) 
• Runny nose 
• Ear pain, ear discomfort 
• Ringing in the ears 
• Redness inside the ear 
• Inner ear disorder (feeling dizzy or spinning) 
• Sinus congestion 
• Redness in the throat 
• Breast mass 

 
Uncommon side effects (may affect up to 1 in 100 people) 
• Ear congestion 
• Breast inflammation 
• Enlargement of the breast in males 
• Nipple changes or pain 

 
Additional side effects in children and adolescents 
Side effects seen in children and adolescents are similar to those observed in adults. However, 
increased liver enzymes in the blood are more frequently seen in young children.  
 
Reporting of side effects 
 
If your child gets any side effects, talk to your child’s 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 Kalydeco 
 
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 package after EXP. The expiry 
date refers to the last day of that month. 
 
This medicine does not require any special storage conditions. 
 
Once mixed, the mixture has been shown to be stable for one hour. 
 
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 Kalydeco contains 

 
Kalydeco 25 mg granules in sachet: 
The active substance is ivacaftor. Each sachet contains 25 mg of ivacaftor. 
 
Kalydeco 50 mg granules in sachet: 
The active substance is ivacaftor. Each sachet contains 50 mg of ivacaftor. 

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99 

 
Kalydeco 75 mg granules in sachet: 
The active substance is ivacaftor. Each sachet contains 75 mg of ivacaftor. 
 
The other ingredients are: silica, colloidal anhydrous, croscarmellose sodium, hypromellose 
acetate succinate, lactose monohydrate, magnesium stearate, mannitol, sucralose and sodium 
laurilsulfate (E487). 

 
See the end of section 2 - Important information about the contents of Kalydeco. 
 
What Kalydeco looks like and contents of the pack 
 
Kalydeco 25 mg granules in sachet are white to off-white granules. 
Kalydeco 50 mg granules in sachet are white to off-white granules. 
Kalydeco 75 mg granules in sachet are white to off-white granules. 
 
The granules are supplied in sachets. 
• Pack size of 56 sachets (contains 4 individual wallets with 14 sachets per wallet) 

 
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 
 



100 

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 

België/Belgique/Belgien, България, Česká 
republika, Danmark, Deutschland, Eesti, 
France, Hrvatska, Ireland, Ísland, Κύπρος, 
Latvija, Lietuva, Luxembourg/Luxemburg, 
Magyarország, Malta, Nederland, Norge, 
Österreich, Polska, Portugal, România, 
Slovenija, Slovenská republika, 
Suomi/Finland, Sverige, United Kingdom 
Vertex Pharmaceuticals (Ireland) Limited 
Tél/Tel/Teл/Tlf/Sími/Τηλ/Puh:  
+353 (0) 1 761 7299 
 

España 
Vertex Pharmaceuticals Spain, S.L. 
Tel: + 34 91 7892800 
 

Ελλάδα 
Vertex Φαρμακευτική Μονοπρόσωπη Ανώνυμη 
Εταιρία 
Λ. Κηφισίας 62 
GR-151 25 Αθήνα 
Τηλ: +30 (211) 2120535 
 

Italia 
Vertex Pharmaceuticals 
(Italy) S.r.l. 
Tel: +39 0697794000 
 

 
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. 
 

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

	1. NAME OF THE MEDICINAL PRODUCT
	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
{'Title': '1. what kalydeco is and what it is used for', 'Section_Content': 'kalydeco contains the active ingredient ivacaftor. ivacaftor acts at the level of the cystic fibrosis transmembrane conductance regulator (cftr), a protein that forms a channel at the cell surface that allows the movement of particles such as chloride in and out of the cell. due to mutations in the cftr gene (see below), chloride movement is reduced in those with cystic fibrosis (cf). ivacaftor helps certain abnormal cftr proteins open more often to improve chloride movement in and out of the cell. kalydeco tablets are indicated: as monotherapy for patients aged 6 years and older and weighing 25 kg or more with cystic fibrosis (cf) who have an r117h cftr mutation or one of the following gating mutations in the cftr gene: g551d, g1244e, g1349d, g178r, g551s, s1251n, s1255p, s549n or s549r. in combination with tezacaftor/ivacaftor tablets for patients aged 6 years and older with cf who have two f508del mutations in the cftr gene (homozygous for the f508del mutation) or who have an f508del mutation and certain other second mutations that result in reduced amount and/or function of the cftr protein (heterozygous for the f508del mutation with a residual function (rf) mutation). if you have been prescribed kalydeco to be taken with tezacaftor/ivacaftor, read the package leaflet of the latter. it contains important information about how to take these two medicines. in combination with ivacaftor/tezacaftor/elexacaftor tablets for patients aged 12 years and over with cf who are homozygous for the f508del mutation in the cftr gene or heterozygous for f508del in the cftr gene with a minimal function (mf) 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 ivacaftor alone and tezacaftor/ivacaftor. if you have been prescribed kalydeco to be taken with 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{'Title': '2. what you need to know before you take kalydeco', 'Section_Content': "do not take kalydeco if you are allergic to ivacaftor or any of the other ingredients of this medicine (listed in section 6). warnings and precautions talk to your doctor if you have liver problems or have previously had them. your doctor may need to adjust your dose. increased liver enzymes in the blood have been seen in some people receiving kalydeco (alone or in combination with tezacaftor/ivacaftor or ivacaftor/tezacaftor/elexacaftor). tell your doctor right away if you have any of these symptoms, which may be a sign of liver problems: pain or discomfort in the upper right stomach (abdominal) area yellowing of the skin or the white part of the eyes loss of appetite nausea or vomiting dark urine your doctor will do some blood tests to check your liver before and during treatment, particularly during the first year and especially if your blood tests showed high liver enzymes in the past. talk to your doctor if you have kidney problems or have previously had them. kalydeco (alone or in combination with tezacaftor/ivacaftor or ivacaftor/tezacaftor/elexacaftor) is not recommended if you have undergone 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 kalydeco in combination with ivacaftor/tezacaftor/elexacaftor. abnormality of the eye lens (cataract) without any effect on vision has been noted in some children and adolescents treated with kalydeco (alone or in combination with tezacaftor/ivacaftor or ivacaftor/tezacaftor/elexacaftor). your doctor may perform some eye examinations prior to and during treatment. kalydeco (alone or in combination with tezacaftor/ivacaftor or ivacaftor/tezacaftor/elexacaftor) should only be used if you have one of the mutations in the cftr gene indicated in section 1 (what kalydeco is and what it is used for). children and adolescents do not give this medicine to children under 4 months of age as it is not known if ivacaftor is safe and effective in these children. do not give this medicine in combination with tezacaftor/ivacaftor to children under 6 years of age or in combination with ivacaftor/tezacaftor/elexacaftor to children under 12 years of age as it is not known if they are safe and effective for them. other medicines and kalydeco tell your doctor or pharmacist if you are using, have recently used or might use any other medicines. some medicines can affect how kalydeco works or make side effects more likely. in particular, tell your doctor if you are taking any of the medicines listed below. your doctor may decide to adjust your dose or that you need extra check-ups. 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, rifabutin, rifampicin, 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 and glipizide. medicines for lowering blood pressure. these include verapamil. kalydeco with food and drink avoid food or drink containing grapefruit during treatment with kalydeco as they may increase the side effects of kalydeco by increasing the amount of ivacaftor in your body. pregnancy and breast-feeding if you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine. it may be better to avoid using kalydeco during pregnancy, if possible, and your doctor will help you decide what is best for you and your child. it is unknown whether ivacaftor is excreted in human milk. if you plan to breast-feed, ask your doctor for advice before taking kalydeco. your doctor will decide whether to recommend that you stop breast-feeding or for you to stop ivacaftor therapy. your doctor will take into account the benefit of breast-feeding for the child and the benefit of therapy for you. driving and using machines kalydeco can make you dizzy. if you feel dizzy, do not drive, cycle or use machines. important information about the contents of kalydeco kalydeco contains lactose. if you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine. kalydeco contains less than 1 mmol 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{'Title': '3. how to take kalydeco', 'Section_Content': 'always take this medicine exactly as your doctor has told you to. check with your doctor if you are not sure. your doctor will determine which medicine and dose is right for you. kalydeco dosing recommendations are provided in table 1. table 1: dosing recommendations morning evening kalydeco as monotherapy 6 years and older, ≥25 kg one kalydeco 150 mg tablet one kalydeco 150 mg tablet kalydeco in combination with tezacaftor/ivacaftor 6 years to less than 12 years, <30 kg one tezacaftor 50 mg/ivacaftor 75 mg tablet one kalydeco 75 mg tablet 6 years to less than 12 years, ≥30 kg one tezacaftor 100 mg/ivacaftor 150 mg tablet one kalydeco 150 mg tablet 12 years and older one tezacaftor 100 mg/ivacaftor 150 mg tablet one kalydeco 150 mg tablet kalydeco in combination with ivacaftor/tezacaftor/elexacaftor 12 years and older two ivacaftor 75 mg/tezacaftor 50 mg/elexacaftor 100 mg tablets one kalydeco 150 mg tablet take the morning and evening doses approximately 12 hours apart with food that contains fat. you must keep using all other medicines you use, unless your doctor tells you to stop using any. if you have liver problems, either moderate or severe, your doctor may need to reduce the dose of your tablets, because your liver will not clear the medicine as fast as in people who have normal liver function. use in children this medicine is for oral use. swallow the tablet whole. do not break, chew or dissolve the tablets. take kalydeco 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 if you take more kalydeco than you should you may experience side effects, including those mentioned in section 4 below. if so, contact your doctor or pharmacist to ask for advice. if possible, have your medicine and this leaflet with you. if you forget to take kalydeco take the missed dose if less than 6 hours have passed since the time you missed the dose. otherwise, wait until your next scheduled dose as you normally would. do not take a double dose to make up for a forgotten dose. if you stop taking kalydeco take kalydeco for as long as your doctor recommends. do not stop unless your doctor advises you to. if you have any further questions on the use of this medicine, ask your doctor or pharmacist.', 'Entity_Recognition': [{'Text': 'kalydeco', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 12, 'EndOffset': 25}, {'Text': 'kalydeco dosing', 'Type': 'TREATMENT', 'BeginOffset': 179, 'EndOffset': 194}, {'Text': '1.', 'Type': 'NUMBER', 'BeginOffset': 233, 'EndOffset': 235}, {'Text': '1.', 'Type': 'NUMBER', 'BeginOffset': 242, 'EndOffset': 244}, {'Id': 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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 stomach (abdominal) ache and increased liver enzymes in the blood. 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 white part of the eyes loss of appetite nausea or vomiting dark urine tell your doctor straight away if you get any of these. very common side effects (may affect more than 1 in 10 people) upper respiratory tract infection (the common cold), including sore throat and nasal congestion headache dizziness diarrhoea stomach or abdominal pain changes in the type of bacteria in mucus increased liver enzymes (signs of stress on the liver) rash common side effects (may affect up to 1 in 10 people) runny nose ear pain, ear discomfort ringing in the ears redness inside the ear inner ear disorder (feeling dizzy or spinning) sinus problems (sinus congestion) redness in the throat breast mass feeling sick (nausea) flu low blood sugar (hypoglycaemia) abnormal breathing (shortness of breath or difficulty breathing) wind (flatulence) spots (acne) itchy skin increased creatine phosphokinase (sign of muscle breakdown) seen in blood tests uncommon side effects (may affect up to 1 in 100 people) ear congestion breast inflammation enlargement of the breast in males nipple changes or pain wheezing increased blood pressure 91 additional side effects in children and adolescents side effects seen in children and adolescents are similar to those observed in adults. however, increased liver enzymes in the blood are more frequently seen in young children. 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 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{'Title': '5. how to store kalydeco', '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 package 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 kalydeco contains the active substance is ivacaftor. kalydeco 75 mg film-coated tablets each 75 mg film-coated tablet contains 75 mg of ivacaftor. kalydeco 150 mg film-coated tablets each 150 mg film-coated tablet contains 150 mg of ivacaftor. the other ingredients are: tablet core: cellulose microcrystalline, lactose monohydrate, hypromellose acetate succinate, croscarmellose sodium, sodium laurilsulfate (e487), silica, colloidal anhydrous, and magnesium stearate. coating: polyvinyl alcohol, titanium dioxide (e171), macrogol (peg 3350), talc, indigo carmine aluminium lake (e132) and carnauba wax. printing ink: shellac, iron oxide black (e172), propylene glycol (e1520) and ammonia solution, concentrated. see the end of section 2 - important information about the contents of kalydeco. what kalydeco looks like and contents of the pack kalydeco 75 mg film-coated tablets are light blue, capsule-shaped, 12.7 mm x 6.8 mm, and printed with "v 75" in black ink on one side and plain on the other side. the following pack sizes are available: blister card pack containing 28 film-coated tablets 92 kalydeco 150 mg film-coated tablets are light blue, capsule-shaped, 16.5 mm x 8.4 mm, and printed with "v 150" in black ink on one side and plain on the other. the following pack sizes are available: blister card pack containing 28 film-coated tablets blister pack containing 56 film-coated tablets bottle containing 56 film-coated tablets', 'Entity_Recognition': [{'Text': 'kalydeco', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 0, 'BeginOffset': 5, 'EndOffset': 13, 'Score': 0.47696128487586975, 'Text': 'kalydeco', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Id': 1, 'BeginOffset': 47, 'EndOffset': 56, 'Score': 0.9904542565345764, 'Text': 'ivacaftor', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': [], 'Attributes': [{'Type': 'FORM', 'Score': 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