KALYDECO 75mg pellets medication leaflet

Kalydeco 13.4 mg granules in sachet

Kalydeco 59.5 mg granules in sachet

Kalydeco 13.4 mg granules in sachet

Each sachet contains 13.4 mg of ivacaftor.

Each sachet contains 19.7 mg of lactose monohydrate.

Each sachet contains 25 mg of ivacaftor.

Each sachet contains 36.6 mg of lactose monohydrate.

Each sachet contains 50 mg of ivacaftor.

Each sachet contains 73.2 mg of lactose monohydrate.

Kalydeco 59.5 mg granules in sachet

Each sachet contains 59.5 mg of ivacaftor.

Each sachet contains 87.3 mg of lactose monohydrate.

Each sachet contains 75 mg of ivacaftor.

Each sachet contains 109.8 mg of lactose monohydrate.

For the full list of excipients, see section 6.1.

Granule in sachet (granule)

White to off-white granules approximately 2 mm in diameter.

Kalydeco granules are indicated:

* As monotherapy for the treatment of infants aged at least 1 month, toddlers and children weighing3 kg to less than 25 kg with cystic fibrosis (CF) who have an R117H CFTR mutation or one of thefollowing 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).

* In a combination regimen with ivacaftor/tezacaftor/elexacaftor for the treatment of cystic fibrosis(CF) in paediatric patients aged 2 to less than 6 years who have at least one F508del mutation inthe CFTR gene (see section 5.1).

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 beperformed before starting treatment to confirm the presence of an indicated mutation in at least oneallele of the CFTR gene (see section 4.1). The phase of the poly-T variant identified with the R117Hmutation should be determined in accordance with local clinical recommendation.

Dosing recommendations are shown in Table 1.

Table 1: Dosing recommendations

Age Weight Morning dose Evening dose

Ivacaftor as monotherapy1 month to less ≥ 3 kg One sachet of ivacaftor No evening dosethan 2 months 13.4 mg granules2 months to less ≥ 3 kg One sachet of ivacaftor One sachet of ivacaftorthan 4 months 13.4 mg granules 13.4 mg granules4 months to less ≥ 5 kg One sachet of ivacaftor 25 mg One sachet of ivacaftorthan 6 months granules 25 mg granules≥ 5 kg to < 7 kg One sachet of ivacaftor 25 mg One sachet of ivacaftorgranules 25 mg granules≥ 7 kg to < 14 kg One sachet of ivacaftor 50 mg One sachet of ivacaftor6 months and granules 50 mg granulesolder ≥ 14 kg to < 25 kg One sachet of ivacaftor 75 mg One sachet of ivacaftorgranules 75 mg granules≥ 25 kg See Kalydeco tablets SmPC for further details.

Ivacaftor in a combination regimen with ivacaftor/tezacaftor/elexacaftor10 kg to < 14 kg One sachet of ivacaftor One sachet of ivacaftor60 mg/tezacaftor 59.5 mg granules40 mg/elexacaftor 80 mg2 years to less granulesthan 6 years ≥ 14 kg One sachet of ivacaftor One sachet of ivacaftor75 mg/tezacaftor 75 mg granules

Age Weight Morning dose Evening dose50 mg/elexacaftor 100 mggranules

The morning and evening dose should be taken approximately 12 hours apart with fat-containing food(see Method of administration).

If 6 hours or less have passed since the missed morning or evening dose, the patient should be advisedto take it as soon as possible and then take the next dose at the regularly scheduled time. If more than6 hours have passed since the time the dose is usually taken, the patient should be advised to wait untilthe next scheduled dose.

Patients receiving Kalydeco in a combination regimen should be advised not to take more than onedose of either medicinal product at the same time.

During concomitant administration with moderate or strong inhibitors of CYP3A, the ivacaftor doseshould be adjusted as detailed in Table 2 (see sections 4.4 and 4.5).

Table 2: Dosing recommendations for concomitant use with moderate or strong CYP3Ainhibitors

Age/weight Moderate CYP3A inhibitors Strong CYP3A inhibitors

Ivacaftor as monotherapy1 month to Use is not recommended. Use is not recommended.less than6 months6 months One sachet of ivacaftor 25 mg granules One sachet of ivacaftor 25 mg granulesand older, once daily. twice a week.≥ 5 kg to< 7 kg No evening ivacaftor dose. No evening ivacaftor dose.6 months One sachet of ivacaftor 50 mg granules One sachet of ivacaftor 50 mg granulesand older, once daily. twice a week.≥ 7 kg to< 14 kg No evening ivacaftor dose. No evening ivacaftor dose.6 months One sachet of ivacaftor 75 mg granules One sachet of ivacaftor 75 mg granulesand older, once daily. twice a week.≥ 14 kg to< 25 kg No evening ivacaftor dose. No evening ivacaftor dose.

Ivacaftor in a combination regimen with ivacaftor/tezacaftor/elexacaftor2 years to Alternate each day: One sachet of ivacaftor 60 mg/tezacaftorless than * One morning sachet of ivacaftor 40 mg/elexacaftor 80 mg granules twice a6 years, 60 mg/tezacaftor 40 mg/elexacaftor week, approximately 3 to 4 days apart.10 kg to 80 mg granules on the first day< 14 kg * One morning sachet of ivacaftor No evening ivacaftor dose.

59.5 mg granules on the next day

No evening ivacaftor dose.

Age/weight Moderate CYP3A inhibitors Strong CYP3A inhibitors2 years to Alternate each day: One sachet of ivacaftor 75 mg/tezacaftorless than * One morning sachet of ivacaftor 50 mg/elexacaftor 100 mg granules twice a6 years, 75 mg/tezacaftor 50 mg/elexacaftor week, approximately 3 to 4 days apart.≥ 14 kg 100 mg granules on the first day

* One morning sachet of ivacaftor No evening ivacaftor dose.75 mg granules on the next day

No evening ivacaftor dose.

No dose adjustment is necessary for patients with mild to moderate renal impairment. Caution isrecommended in patients with severe renal impairment (creatinine clearance less than or equal to30 mL/min) or end-stage renal disease (see sections 4.4 and 5.2).

No dose adjustment is necessary for patients aged 6 months and older with mild hepatic impairment(Child-Pugh Class A). Treatment with ivacaftor is not recommended in patients aged 1 month to lessthan 6 months with any level of hepatic impairment.

In patients with moderate hepatic impairment (Child-Pugh Class B), or severe hepatic impairment(Child-Pugh Class C), the ivacaftor dose should be adjusted as detailed in Table 3 (see sections 4.4,4.8, and 5.2).

Table 3: Dosing recommendations for patients with moderate or severe hepatic impairment

Age/weight Moderate (Child-Pugh Class B) Severe (Child-Pugh Class C)

Ivacaftor as monotherapy1 month to Use is not recommended. Use is not recommended.less than6 months6 months One sachet of ivacaftor 25 mg granules Use is not recommended, unless theand older, once daily. benefits are expected to outweigh the risks.≥ 5 kg to< 7 kg No evening ivacaftor dose. If used, one sachet of ivacaftor 25 mggranules every other day according toclinical response and tolerability.

No evening ivacaftor dose.

6 months One sachet of ivacaftor 50 mg granules Use is not recommended, unless theand older, once daily. benefits are expected to outweigh the risks.≥ 7 kg to< 14 kg No evening ivacaftor dose. If used, one sachet of ivacaftor 50 mggranules every other day according toclinical response and tolerability.

No evening ivacaftor dose.

6 months One sachet of ivacaftor 75 mg granules Use is not recommended, unless theand older, once daily. benefits are expected to outweigh the risks.≥ 14 kg to< 25 kg No evening ivacaftor dose.

Age/weight Moderate (Child-Pugh Class B) Severe (Child-Pugh Class C)

If used, one sachet of ivacaftor 75 mggranules every other day according toclinical response and tolerability.

No evening ivacaftor dose.

Ivacaftor in a combination regimen with ivacaftor/tezacaftor/elexacaftor2 years to Use is not recommended, unless the Should not be used.less than benefits are expected to outweigh the risks.6 years,10 kg to If used, the dose should be adjusted as< 14 kg follows:

* Days 1-3: one sachet of ivacaftor60 mg/tezacaftor 40 mg/elexacaftor80 mg granules each day

* Day 4: no dose

* Days 5-6: one sachet of ivacaftor60 mg/tezacaftor 40 mg/elexacaftor80 mg granules each day

* Day 7: no dose

Repeat above dosing schedule each week.

No evening ivacaftor dose.

2 years to Use is not recommended, unless the Should not be used.less than benefits are expected to outweigh the risks.6 years,≥ 14 kg If used, the dose should be adjusted asfollows:

* Days 1-3: one sachet of ivacaftor75 mg/tezacaftor 50 mg/elexacaftor100 mg granules each day

* Day 4: no dose

* Days 5-6: one sachet of ivacaftor75 mg/tezacaftor 50 mg/elexacaftor100 mg granules each day

* Day 7: no dose

Repeat above dosing schedule each week.

No evening ivacaftor dose.

The safety and efficacy of ivacaftor as monotherapy have not been established in children less than1 month of age or in children less than 6 months of age born prematurely (less than 37 weeks ofgestational age), neither in combination with ivacaftor/tezacaftor/elexacaftor in children less than 2years of age. No data are available.

Limited data are available in patients less than 6 years of age with an R117H mutation in the CFTRgene. Available data in patients aged 6 years and older are described in sections 4.8, 5.1, and 5.2.

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 andcompletely and immediately consumed. Food or liquid should be at room temperature or below. If notimmediately consumed, the mixture has been shown to be stable for one hour and therefore should beingested during this period. A fat-containing meal or snack should be consumed just before or justafter dosing.

Food or drink containing grapefruit should be avoided during treatment (see section 4.5).

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Only patients with CF who had a G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549Nor S549R gating (class III) or G970R mutation in at least one allele of the CFTR gene were included instudies 770-102, 770-103, 770-111 and 770-108 (see section 5.1).

Less evidence of a positive effect of ivacaftor has been shown for patients with an R117H-7T mutationassociated with less severe disease in study 770-110 (see section 5.1).

In study 770-111, four patients with the G970R mutation were included. In three of four patients thechange in the sweat chloride test was < 5 mmol/L and this group did not demonstrate a clinicallyrelevant improvement in FEV1 after 8 weeks of treatment. Clinical efficacy in patients with the G970Rmutation 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 F508delmutation in the CFTR gene showed no statistically significant difference in FEV1 over 16 weeks ofivacaftor treatment compared to placebo (see section 5.1). Therefore, use of ivacaftor as monotherapyin these patients is not recommended.

In a patient with cirrhosis and portal hypertension, liver failure leading to transplantation has beenreported while receiving ivacaftor in a combination regimen with ivacaftor/tezacaftor/elexacaftor. Thismedicinal product should be used with caution in patients with pre-existing advanced liver disease(e.g., cirrhosis, portal hypertension) and only if the benefits are expected to outweigh the risks. If usedin these patients, they should be closely monitored after the initiation of treatment (see sections 4.2,4.8, and 5.2).

Moderate transaminase (alanine transaminase [ALT] or aspartate transaminase [AST]) elevations arecommon in subjects with CF. Transaminase elevations have been observed in some patients treatedwith ivacaftor as monotherapy and in combination regimens with ivacaftor/tezacaftor/elexacaftor. Inpatients taking ivacaftor in a combination regimen with ivacaftor/tezacaftor/elexacaftor, theseelevations have sometimes been associated with concomitant elevations in total bilirubin. Therefore,assessments of transaminases (ALT and AST) and total bilirubin are recommended for all patientsprior to initiating ivacaftor, every 3 months during the first year of treatment and annually thereafter.

For all patients with a history of liver disease or transaminase elevations, more frequent monitoring ofliver function tests should be considered. In the event of significant elevations of transaminases (e.g.,patients with ALT or AST > 5 × the upper limit of normal (ULN), or ALT or AST > 3 × ULN withbilirubin > 2 × ULN), dosing should be interrupted, and laboratory tests closely followed until theabnormalities resolve. Following resolution of transaminase elevations, the benefits and risks ofresuming treatment should be considered (see sections 4.2, pct. 4.8, and 5.2).

Use of ivacaftor as monotherapy is not recommended in patients aged 1 month to less than 6 months ofage with any level of hepatic impairment. Use of ivacaftor as monotherapy is not recommended inpatients aged 6 months and older weighing less than 25 kg with severe hepatic impairment unless thebenefits are expected to outweigh the risks. Patients with severe hepatic impairment should not betreated with ivacaftor in a combination regimen with ivacaftor/tezacaftor/elexacaftor (see Table 3 insection 4.2, and sections 4.8 and 5.2).

For patients with moderate hepatic impairment, use of ivacaftor in a combination regimen withivacaftor/tezacaftor/elexacaftor is not recommended. Treatment should only be considered when thereis a clear medical need and the benefits are expected to outweigh the risks. If used, it should be usedwith caution at a reduced dose (see Table 3 in section 4.2, and sections 4.8 and 5.2).

Depression

Depression (including suicidal ideation and suicide attempt) has been reported in patients whilereceiving ivacaftor, mainly in a combination regimen with ivacaftor/tezacaftor/elexacaftor, usuallyoccurring within three months of treatment initiation and in patients with a history of psychiatricdisorders. In some cases, symptom improvement was reported after dose reduction or treatmentdiscontinuation. Patients (and caregivers) should be alerted about the need to monitor for depressedmood, suicidal thoughts, or unusual changes in behaviour and to seek medical advice immediately ifthese symptoms present.

Caution is recommended while using ivacaftor in patients with severe renal impairment or end-stagerenal disease (see sections 4.2 and 5.2).

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 withciclosporin or tacrolimus.

The incidence of rash events with ivacaftor in a combination regimen withivacaftor/tezacaftor/elexacaftor was higher in females than in males, particularly in females takinghormonal contraceptives. A role for hormonal contraceptives in the occurrence of rash cannot beexcluded. For patients taking hormonal contraceptives who develop rash, interrupting treatment withivacaftor in a combination regimen with ivacaftor/tezacaftor/elexacaftor and hormonal contraceptivesshould be considered. Following the resolution of rash, it should be considered if resuming ivacaftor ina combination regimen with ivacaftor/tezacaftor/elexacaftor without hormonal contraceptives isappropriate. If rash does not recur, resumption of hormonal contraceptives can be considered (seesection 4.8).

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 withstrong CYP3A inducers is not recommended (see section 4.5).

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 CYP3Ainhibitors (see Table 2 in section 4.2 and section 4.5). Treatment with ivacaftor monotherapy is notrecommended in patients aged 1 month to less than 6 months taking strong or moderate CYP3Ainhibitors.

Cases of non-congenital lens opacities/cataracts without impact on vision have been reported inpaediatric patients treated with ivacaftor and ivacaftor-containing regimens. Although other riskfactors were present in some cases (such as corticosteroid use and exposure to radiation), a possiblerisk attributable to treatment with ivacaftor cannot be excluded. Baseline and follow-upophthalmological examinations are recommended in paediatric patients initiating ivacaftor treatment(see section 5.3).

This medicinal product contains lactose. Patients with rare hereditary problems of galactoseintolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinalproduct.

This medicinal product contains less than 1 mmol sodium (23 mg) per sachet, that is to say essentially‘sodium-free’.

Ivacaftor is a substrate of CYP3A4 and CYP3A5. It is a weak inhibitor of CYP3A and P-glycoprotein(P-gp) and a potential inhibitor of CYP2C9. In vitro studies showed that ivacaftor is not a substrate for

P-gp.

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 notrecommended (see section 4.4).

No dose adjustment is recommended when ivacaftor is used with moderate or weak CYP3A inducers.

Ivacaftor is a sensitive CYP3A substrate. Co-administration with ketoconazole, a strong CYP3Ainhibitor, increased ivacaftor exposure (measured as area under the curve [AUC]) by 8.5-fold andincreased M1 to a lesser extent than ivacaftor. Co-administration with fluconazole, a moderateinhibitor of CYP3A, increased ivacaftor exposure by 3-fold and increased M1 to a lesser extent thanivacaftor. A reduction of the ivacaftor dose is recommended for co-administration with strong CYP3Ainhibitors, such as ketoconazole, itraconazole, posaconazole, voriconazole, telithromycin andclarithromycin as well as for co-administration with moderate CYP3A inhibitors, such as fluconazole,erythromycin, and verapamil. Treatment with ivacaftor monotherapy is not recommended whenconcomitantly used with strong or moderate CYP3A inhibitors in patients aged 1 month to less than6 months (see Table 2 in section 4.2 and section 4.4).

Co-administration of ivacaftor with grapefruit juice, which contains one or more components thatmoderately inhibit CYP3A, may increase exposure to ivacaftor. Food or drink containing grapefruitshould be avoided during treatment with ivacaftor (see section 4.2).

In vitro studies showed that ivacaftor is not a substrate for OATP1B1 or OATP1B3. Ivacaftor and itsmetabolites are substrates of BCRP in vitro. Due to its high intrinsic permeability and low likelihoodof being excreted intact, co-administration of BCRP inhibitors is not expected to alter exposure ofivacaftor and M1-IVA, while any potential changes in M6-IVA exposures are not expected to beclinically relevant.

Co-administration of ciprofloxacin with ivacaftor did not affect the exposure of ivacaftor. No doseadjustment is required when ivacaftor is co-administered with ciprofloxacin.

Administration of ivacaftor may increase systemic exposure of medicinal products that are sensitivesubstrates of CYP2C9, and/or P-gp, and/or CYP3A which may increase or prolong their therapeuticeffect and adverse reactions.

Ivacaftor may inhibit CYP2C9. Therefore, monitoring of the international normalised ratio (INR) isrecommended during co-administration of warfarin with ivacaftor. Other medicinal products for whichexposure may be increased include glimepiride and glipizide; these medicinal products should be usedwith caution.

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 increasesystemic exposure of medicinal products that are sensitive substrates of P-gp, which may increase orprolong their therapeutic effect and adverse reactions. When used concomitantly with digoxin or othersubstrates of P-gp with a narrow therapeutic index, such as ciclosporin, everolimus, sirolimus ortacrolimus, caution and appropriate monitoring should be used.

Co-administration with (oral) midazolam, a sensitive CYP3A substrate, increased midazolam exposure1.5-fold, consistent with weak inhibition of CYP3A by ivacaftor. No dose adjustment of CYP3Asubstrates, such as midazolam, alprazolam, diazepam or triazolam, is required when these are co-administered with ivacaftor.

Ivacaftor has been studied with an oestrogen/progesterone oral contraceptive and was found to have nosignificant effect on the exposures of the oral contraceptive. Therefore, no dose adjustment of oralcontraceptives is necessary.

Interaction studies have only been performed in adults.

There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of ivacaftor inpregnant women. Animals studies do not indicate direct or indirect harmful effects with respect toreproductive toxicity (see section 5.3). As a precautionary measure, it is preferable avoid the use ofivacaftor during pregnancy.

Limited data show that ivacaftor is excreted into human milk. A risk to the newborns/infants cannot beexcluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstainfrom ivacaftor therapy taking into account the benefit of breast-feeding for the child and the benefit oftherapy for the woman.

There are no data available on the effect of ivacaftor on fertility in humans. Ivacaftor had an effect onfertility in rats (see section 5.3).

Ivacaftor has minor influence on the ability to drive and use machines. Ivacaftor may cause dizziness(see section 4.8) and, therefore, patients experiencing dizziness should be advised not to drive or usemachines until symptoms abate.

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% ofivacaftor-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%) andbacteria in sputum (11.8%).

Serious adverse reactions included abdominal pain (0.9%) and transaminase elevations (1.8%) inpatients who received ivacaftor, while serious adverse reactions of rash were reported in 1.5% patientsaged 12 years and older treated with a combination regimen with ivacaftor/tezacaftor/elexacaftor (seesection 4.4).

Table 4 reflects the adverse reactions observed with ivacaftor in clinical trials (placebo-controlled anduncontrolled 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); notknown (cannot be estimated from the available data). Within each frequency grouping, adversereactions are presented in order of decreasing seriousness.

Table 4: Adverse reactions

System organ class Adverse reactions Frequency

Infections and infestations Upper respiratory tract very commoninfection

Nasopharyngitis very common

Influenza* common

Rhinitis common

Metabolism and nutrition Hypoglycaemia* commondisorders

Psychiatric disorders Depression not known

Nervous system disorders Headache very common

Dizziness very common

Ear and labyrinth Ear pain commondisorders Ear discomfort common

Tinnitus common

Tympanic membrane commonhyperaemia

Vestibular disorder common

Ear congestion uncommon

Respiratory, thoracic and Oropharyngeal pain very commonmediastinal disorders 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

Hepatobiliary disorders Transaminase elevations very common

Alanine aminotransferase very commonincreased*

Aspartate aminotransferase commonincreased*

Liver injury† not known

Total bilirubin increase† not known

System organ class Adverse reactions Frequency

Skin and subcutaneous Rash very commontissue disorders Acne* common

Pruritus* common

Reproductive system and Breast mass commonbreast disorders Breast inflammation uncommon

Gynaecomastia uncommon

Nipple disorder uncommon

Nipple pain uncommon

Investigations Bacteria in sputum very common

Blood creatine phosphokinase commonincreased*

Blood pressure increased* uncommon

* Adverse reaction and frequency reported from clinical studies with ivacaftor in combination withivacaftor/tezacaftor/elexacaftor.

† Liver injury (ALT and AST and total bilirubin increase) reported from post-marketing data with ivacaftor incombination with ivacaftor/tezacaftor/elexacaftor. This also included liver failure leading to transplantation ina patient with pre-existing cirrhosis and portal hypertension. Frequency cannot be estimated from theavailable data.

During the 48-week placebo-controlled studies 770-102 and 770-103 in patients aged 6 years andolder, the incidence of maximum transaminase (ALT or AST) > 8, > 5 or > 3 × 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 treatmentfor elevated transaminases, each > 8 × ULN. No ivacaftor-treated patients experienced a transaminaseelevation > 3 × ULN associated with elevated total bilirubin > 1.5 × ULN. In ivacaftor-treated patients,most transaminase elevations up to 5 × ULN resolved without treatment interruption. Ivacaftor dosingwas interrupted in most patients with transaminase elevations > 5 × ULN. In all instances wheredosing was interrupted for elevated transaminases and subsequently resumed, ivacaftor dosing wasable to be resumed successfully (see section 4.4).

During the placebo-controlled phase 3 studies (up to 24 weeks) of tezacaftor/ivacaftor, the incidence ofmaximum transaminase (ALT or AST) > 8, > 5, or > 3 × ULN were 0.2%, 1.0%, and 3.4% intezacaftor/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 elevatedtransaminases. No patients treated with tezacaftor/ivacaftor experienced a transaminase elevation> 3 ×ULN associated with elevated total bilirubin > 2 × ULN.

During the 24-week, placebo-controlled, phase 3 study of ivacaftor/tezacaftor/elexacaftor, thesefigures 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 elevationswas 10.9% in ivacaftor in a combination regimen with ivacaftor/tezacaftor/elexacaftor-treated patientsand 4.0% in placebo-treated patients.

Post-marketing cases of treatment discontinuation due to elevated transaminases have been reportedwith ivacaftor/tezacaftor/elexacaftor (see section 4.4).

In study 445-102, the incidence of rash events (e.g., rash, rash pruritic) was 10.9% inivacaftor/tezacaftor/elexacaftor-treated patients and 6.5% in placebo-treated patients. The rash eventswere generally mild to moderate in severity. The incidence of rash events by patient sex was 5.8% inmales and 16.3% in females in ivacaftor/tezacaftor/elexacaftor-treated patients and 4.8% in males and8.3% in females in placebo-treated patients. In patients treated with ivacaftor/tezacaftor/elexacaftor,the incidence of rash events was 20.5% in females taking hormonal contraceptive and 13.6% infemales not taking hormonal contraceptive (see section 4.4).

In study 445-102, the incidence of maximum creatine phosphokinase > 5 x the ULN was 10.4% inivacaftor/tezacaftor/elexacaftor-treated patients and 5.0% in placebo-treated patients. The observedcreatine phosphokinase elevations were generally transient and asymptomatic and many were precededby exercise. No ivacaftor/tezacaftor/elexacaftor-treated patients discontinued treatment for increasedcreatine phosphokinase.

In study 445-102, the maximum increase from baseline in mean systolic and diastolic blood pressurewas 3.5 mmHg and 1.9 mmHg, respectively for ivacaftor/tezacaftor/elexacaftor-treated patients(baseline: 113 mmHg systolic and 69 mmHg diastolic) and 0.9 mmHg and 0.5 mmHg, respectively forplacebo-treated patients (baseline: 114 mmHg systolic and 70 mmHg diastolic).

The proportion of patients who had systolic blood pressure > 140 mmHg or diastolic blood pressure> 90 mmHg on at least two occasions was 5.0% and 3.0%, respectively inivacaftor/tezacaftor/elexacaftor-treated patients compared with 3.5% and 3.5%, respectively inplacebo-treated patients.

Ivacaftor as monotherapy

Safety of ivacaftor as monotherapy for 24 weeks was evaluated in 43 patients between 1 month to lessthan 24 months of age (with 7 of them less than 4 months old), 34 patients between 2 to less than6 years of age, 61 patients between 6 to less than 12 years of age and 94 patients between 12 to lessthan 18 years of age.

The safety profile is generally consistent among paediatric patients aged 1 month and older and is alsoconsistent with adult patients.

The incidence of transaminase elevations (ALT or AST) observed in studies 770-103, 770-111 and770-110 (patients aged 6 to less than 12 years), study 770-108 (patients aged 2 to less than 6 years),and study 770-124 (patients aged 1 to less than 24 months) are described in Table 5. In the placebo-controlled studies, the incidence of transaminase elevations were similar between treatment withivacaftor (15.0%) and placebo (14.6%). Peak LFT elevations were generally higher in paediatricpatients than in older patients. Across all populations, peak LFT elevations returned to baseline levelsfollowing interruption, and in almost all instances where dosing was interrupted for elevatedtransaminases and subsequently resumed, ivacaftor dosing was able to be resumed successfully (seesection 4.4). Cases suggestive of positive rechallenge were observed.

In study 770-108 ivacaftor was permanently discontinued in one patient. In study 770-124, in thecohort of patients aged 1 month to less than 4 months, a 1-month old (14.3%) patient had transaminasevalues of ALT > 8 × ULN and AST of > 3 to ≤ 5 × ULN, which led to discontinuation of ivacaftortreatment (see section 4.4 for management of elevated transaminases).

Table 5: Transaminase elevations in patients aged 1 month to < 12 years treated with ivacaftoras monotherapyn % of Patients % of Patients % of Patients> 3 × ULN > 5 × ULN > 8 × ULN6 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)1 to < 12 months 24 8.3% (2) 4.2% (1) 4.2% (1)

Ivacaftor in a combination regimen with tezacaftor/ivacaftor

The safety of tezacaftor/ivacaftor in combination with ivacaftor was evaluated in 124 patients between6 to less than 12 years of age. The tezacaftor 100 mg/ivacaftor 150 mg and ivacaftor 150 mg dose hasnot been investigated in clinical studies in children aged 6 to less than 12 years weighing 30 to< 40 kg.

The safety profile is generally consistent among children and adolescents, and is also consistent withadult patients.

During the 24-week, open-label phase 3 study in patients aged 6 to less than 12 years (study 661-113part B, n = 70), the incidence of maximum transaminase (ALT or AST) > 8, > 5, and > 3 × ULN were1.4%, pct. 4.3%, and 10.0%, respectively. No tezacaftor/ivacaftor-treated patients experienced atransaminase elevation > 3 × ULN associated with elevated total bilirubin > 2 × ULN or discontinuedtezacaftor/ivacaftor treatment due to transaminase elevations. One patient interrupted treatment due toelevated transaminases, and subsequently resumed tezacaftor/ivacaftor treatment successfully (seesection 4.4 for management of elevated transaminases).

Ivacaftor in a combination regimen with ivacaftor/tezacaftor/elexacaftor

The safety data of ivacaftor/tezacaftor/elexacaftor in combination with ivacaftor in studies 445-102,445-103, 445-104, 445-106 and 445-111 was evaluated in 228 patients between 2 to less than 18 yearsof age. The safety profile is generally consistent among paediatric and adult patients.

During study 445-106 in patients aged 6 to less than 12 years, the incidence of maximum transaminase(ALT or AST) > 8, > 5, and > 3 × ULN were 0.0%, 1.5%, and 10.6%, respectively. Noivacaftor/tezacaftor/elexacaftor-treated patients had transaminase elevation > 3 × ULN associated withelevated total bilirubin > 2 × ULN or discontinued treatment due to transaminase elevations (seesection 4.4).

During study 445-111 in patients aged 2 to less than 6 years, the incidence of maximum transaminase(ALT or AST) > 8, > 5, and > 3 × ULN were 1.3%, 2.7%, and 8.0%, respectively. Noivacaftor/tezacaftor/elexacaftor-treated patients had transaminase elevation > 3 × ULN associated withelevated total bilirubin > 2 × ULN or discontinued treatment due to transaminase elevations (seesection 4.4).

During study 445-111 in patients aged 2 to less than 6 years, 15 (20.0%) subjects had at least 1 rashevent, 4 (9.8%) females and 11 (32.4%) males.

Lenticular opacity

One patient had an adverse event of lenticular opacity.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

No specific antidote is available for overdose with ivacaftor. Treatment of overdose consists of generalsupportive measures including monitoring of vital signs, liver function tests and observation of theclinical status of the patient.

Pharmacotherapeutic group: Other respiratory system products, ATC code: R07AX02

Ivacaftor is a potentiator of the CFTR protein, i.e., in vitro ivacaftor increases CFTR channel gating toenhance chloride transport in specified gating mutations (as listed in section 4.1) with reducedchannel-open probability compared to normal CFTR. Ivacaftor also potentiated the channel-openprobability of R117H-CFTR, which has both low channel-open probability (gating) and reducedchannel current amplitude (conductance). The G970R mutation causes a splicing defect resulting inlittle-to-no CFTR protein at the cell surface which may explain the results observed in subjects withthis mutation in study 770-111 (see Pharmacodynamic effects and Clinical efficacy and safety).

In vitro responses seen in single channel patch clamp experiments using membrane patches fromrodent cells expressing mutant CFTR forms do not necessarily correspond to in vivo pharmacodynamicresponse (e.g., sweat chloride) or clinical benefit. The exact mechanism leading ivacaftor to potentiatethe gating activity of normal and some mutant CFTR forms in this system has not been completelyelucidated.

Ivacaftor as monotherapy

In studies 770-102 and 770-103 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 throughweek 24 was -48 mmol/L [95% CI: -51, -45] and -54 mmol/L [95% CI: -62, -47], respectively) andsustained (through 48 weeks) reductions in sweat chloride concentration.

In study 770-111, 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 sweatchloride of -49 mmol/L (95% CI: -57, -41) through 8 weeks of treatment. However, in patients withthe 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 trendingto pre-treatment levels.

In study 770-110 in patients aged 6 years or older with CF who had an R117H mutation in the CFTRgene, the treatment difference in mean change in sweat chloride from baseline through 24 weeks oftreatment was -24 mmol/L (95% CI: -28, -20). In subgroup analyses by age, the treatment differencewas -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 to 11 years. Two patients 12 to 17 years of age wereenrolled in this study.

In study 770-108 in patients aged 2 to less than 6 years with a gating mutation on at least one allele ofthe CFTR gene administered either 50 mg or 75 mg of ivacaftor twice daily, the mean absolute changefrom baseline in sweat chloride was -47 mmol/L (95% CI: -58, -36) at week 24.

In study 770-124 in patients with CF aged 1 month to less than 24 months, the mean absolute changefrom baseline in sweat chloride was -62.0 mmol/L (95% CI: -71.6, -52.4) at week 24. Results wereconsistent in the 12 months to less than 24 months, 6 months to less than 12 months, and 4 months toless than 6 months age cohorts.

Ivacaftor in a combination regimen with ivacaftor/tezacaftor/elexacaftor

In study 445-111 in patients aged 2 to less than 6 years who are homozygous for the F508del mutationor heterozygous for the F508del mutation and a minimal function mutation, the mean absolute changein sweat chloride from baseline through week 24 was -57.9 mmol/L (95% CI: -61.3, -54.6).

Ivacaftor as monotherapy

Studies 770-102 and 770-103: 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 G551Dmutation in the CFTR gene on at least one allele and had FEV1 ≥ 40% predicted.

Patients in both studies were randomised 1:1 to receive either 150 mg of ivacaftor or placebo every12 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 770-102 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 usedsome medicinal products at a higher frequency than the ivacaftor group. These medicinal productsincluded 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 FEV1was 63.6% (range: 31.6% to 98.2%) and mean age was 26 years (range: 12 to 53 years).

Study 770-103 evaluated 52 patients who were 6 to 11 years of age at screening; mean (SD) bodyweight was 30.9 (8.63) kg; 42 (80.8%) patients had the F508del mutation in the second allele. Atbaseline, 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 ivacaftorgroup had an FEV1 less than 70% predicted at baseline.

The primary efficacy endpoint in both studies was the mean absolute change from baseline in percentpredicted FEV1 through 24 weeks of treatment.

The treatment difference between ivacaftor and placebo for the mean absolute change (95% CI) inpercent predicted FEV1 from baseline through week 24 was 10.6 percentage points (8.6, 12.6) instudy 770-102 and 12.5 percentage points (6.6, 18.3) in study 770-103. The treatment differencebetween ivacaftor and placebo for the mean relative change (95% CI) in percent predicted FEV1 frombaseline through week 24 was 17.1% (13.9, 20.2) in study 770-102 and 15.8% (8.4, 23.2) instudy 770-103. The mean change from baseline through week 24 in FEV1 (L) was 0.37 L in theivacaftor group and 0.01 L in the placebo group in study 770-102 and 0.30 L in the ivacaftor group and0.07 L in the placebo group in study 770-103. In both studies, improvements in FEV1 were rapid inonset (day 15) and durable through 48 weeks.

The treatment difference between ivacaftor and placebo for the mean absolute change (95% CI) inpercent predicted FEV1 from baseline through week 24 in patients 12 to 17 years of age in study 770-102 was 11.9 percentage points (5.9, 17.9). The treatment difference between ivacaftor and placebo forthe mean absolute change (95% CI) in percent predicted FEV1 from baseline through week 24 inpatients with baseline predicted FEV1 greater than 90% in study 770-103 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 770-102 and 770-103

Study 770-102 Study 770-103

Treatment Treatmentdifferencea differencea

Endpoint (95% CI) P-value (95% CI) P-value

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

Through week 24 8.1 < 0.0001 6.1 0.1092(4.7, 11.4) (-1.4, 13.5)

Through week 48 8.6 < 0.0001 5.1 0.1354(5.3, 11.9) (-1.6, 11.8)

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 < 0.0001 1.9 0.0004(1.8, 3.7) (0.9, 2.9)

At week 48 2.7 0.0001 2.8 0.0002(1.3, 4.1) (1.3, 4.2)

Mean absolute change from baseline in BMI (kg/m2)

At week 24 0.94 < 0.0001 0.81 0.0008(0.62, 1.26) (0.34, 1.28)

At week 48 0.93 < 0.0001 1.09 0.0003(0.48, 1.38) (0.51, 1.67)

Mean change from baseline in z-scores

Weight-for-age z-score 0.33 0.0260 0.39 < 0.0001at week 48e (0.04, 0.62) (0.24, 0.53)

BMI-for-age z-score at 0.33 0.0490 0.45 < 0.0001week 48e (0.002, 0.65) (0.26, 0.65)

CI: Confidence Interval; NA: not analysed due to low incidence of eventsa Treatment difference = effect of ivacaftor - effect of placebob CFQ-R: Cystic Fibrosis Questionnaire-Revised is a disease-specific, health-related quality-of-life measure for

CF.c Study 770-102 data were pooled from CFQ-R for adults/adolescents and CFQ-R for children 12 to 13 yearsof age; study 770-103 data were obtained from CFQ-R for children 6 to 11 years of age.d Hazard ratio for time to first pulmonary exacerbatione In subjects under 20 years of age (CDC growth charts)

Study 770-111: study in patients with CF with non-G551D gating mutations

Study 770-111 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 safetyof ivacaftor in patients with CF aged 6 years and older who have a G970R or non-G551D gatingmutation 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 hourswith fat-containing food for 8 weeks in addition to their prescribed CF therapies and crossed over tothe other treatment for the second 8 weeks after a 4- to 8-week washout period. The use of inhaledhypertonic saline was not permitted. In part 2, all patients received ivacaftor as indicated in part 1 for16 additional weeks. The duration of continuous ivacaftor treatment was 24 weeks for patientsrandomised to the part 1 placebo/ivacaftor treatment sequence and 16 weeks for patients randomised topart 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 pertreatment sequence).

In part 1 of study 770-111, the mean FEV1 percent predicted at baseline in placebo-treated patientswas 79.3% while in ivacaftor-treated patients this value was 76.4%. The mean overall post-baselinevalue was 76.0% and 83.7%, respectively. The mean absolute change from baseline through week 8 inpercent predicted FEV1 (primary efficacy endpoint) was 7.5% in the ivacaftor period and -3.2% in theplacebo 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 770-111 (including the secondary endpointsabsolute change in BMI at 8 weeks of treatment and absolute change in the respiratory domain score ofthe CFQ-R through 8 weeks of treatment) and by individual mutation (absolute change in sweatchloride and in percent predicted FEV1 at week 8) is shown in Table 7. Based on clinical (percentpredicted FEV1) and pharmacodynamic (sweat chloride) responses to ivacaftor, efficacy in patientswith the G970R mutation could not be established.

Table 7: Effect of ivacaftor for efficacy variables in the overall population and for specific CFTRmutations

Absolute change in percent BMI CFQ-Rpredicted FEV (kg/m21 ) respiratorydomain 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 patientsat week 8*:

Absolute change in sweat chloride Absolute change in percent(mmol/L) predicted FEV1 (percentage points)

Mutation (n) At week 8 At week 8

G1244E (5) -55 (-75, -34) 8 (-1, 18)

G1349D (2) -80 (-82, -79) 20 (3, 36)

G178R (5) -53 (-65, -35) 8 (-1, 18)

G551S (2) † †

- 68 3

G970R# (4) -6 (-16, -2) 3 (-1, 5)

S1251N (8) -54 (-84, -7) 9 (-20, 21)

S1255P (2) -78 (-82, -74) 3 (-1, 8)

S549N (6) -74 (-93, -53) 11 (-2, 20)

S549R (4) ††

- 61 (-71, -54) 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 770-111, the mean (SD) absolute change in percent predicted FEV1 following16 weeks (patients randomised to the ivacaftor/placebo treatment sequence in part 1) of continuousivacaftor treatment was 10.4% (13.2%). At the follow-up visit 4 weeks after ivacaftor dosing hadended, 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 afurther mean (SD) change of 3.3% (9.3%) in percent predicted FEV1 after the additional 16 weeks oftreatment 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 770-104: study in patients with CF with the F508del mutation in the CFTR gene

Study 770-104 (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 aged12 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 efficacyendpoint) was 1.5 percentage points in the ivacaftor group and -0.2 percentage points in the placebogroup. 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 770-105: open-label extension study

In study 770-105, patients who completed treatment in studies 770-102 and 770-103 with placebowere switched to ivacaftor while patients on ivacaftor continued to receive it for a minimum of96 weeks, i.e., the length of treatment with ivacaftor was at least 96 weeks for patients in theplacebo/ivacaftor group and at least 144 weeks for patients in the ivacaftor/ivacaftor group.

One hundred and forty-four (144) patients from study 770-102 were rolled over in study 770-105, 67in the placebo/ivacaftor group and 77 in the ivacaftor/ivacaftor group. Forty-eight (48) patients fromstudy 770-103 were rolled over in study 770-105, 22 in the placebo/ivacaftor group and 26 in theivacaftor/ivacaftor group.

Table 8 shows the results of the mean (SD) absolute change in percent predicted FEV1 for both groupsof patients. For patients in the placebo/ivacaftor group baseline percent predicted FEV1 is that ofstudy 770-105 while for patients in the ivacaftor/ivacaftor group the baseline value is that ofstudies 770-102 and 770-103.

Table 8: Effect of ivacaftor on percent predicted FEV1 in study 770-105

Absolute change from baseline in percent

Original study and Duration of ivacaftor predicted FEV1 (percentage points)treatment group treatment (weeks) N Mean (SD)

Study 770-102

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 770-103

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

Absolute change from baseline in percent

Original study and Duration of ivacaftor predicted FEV1 (percentage points)treatment group treatment (weeks) N Mean (SD)

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 770-105baseline for patients in the ivacaftor/ivacaftor group (n = 72) who rolled over from study 770-102, themean (SD) absolute change in percent predicted FEV1 was 0.0% (9.05), while for patients in theivacaftor/ivacaftor group (n = 25) who rolled over from study 770-103 this figure was 0.6% (9.1). Thisshows that patients in the ivacaftor/ivacaftor group maintained the improvement seen at week 48 of theinitial study (day 0 through week 48) in percent predicted FEV1 through week 144. There were noadditional improvements in study 770-105 (week 48 through week 144).

For patients in the placebo/ivacaftor group from study 770-102, the annualised rate of pulmonaryexacerbations was higher in the initial study when patients were on placebo (1.34 events/year) thanduring the subsequent study 770-105 when patients rolled over to ivacaftor (0.48 events/year acrossday 1 to week 48, and 0.67 events/year across weeks 48 to 96). For patients in the ivacaftor/ivacaftorgroup from study 770-102, the annualised rate of pulmonary exacerbations was 0.57 events/year acrossday 1 to week 48 when patients were on ivacaftor. When they rolled over into study 770-105, the rateof annualised pulmonary exacerbations was 0.91 events/year across day 1 to week 48 and0.77 events/year across weeks 48 to 96.

For patients who rolled over from study 770-103 the number of events was overall low.

Study 770-110: study in patients with CF with an R117H mutation in the CFTR gene

Study 770-110 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 and7T in 16 patients. At baseline, mean predicted FEV1 was 73% (range: 32.5% to 105.5%) and mean agewas 31 years (range: 6 to 68 years). The mean absolute change from baseline through week 24 inpercent predicted FEV1 (primary efficacy endpoint) was 2.57 percentage points in the ivacaftor groupand 0.46 percentage points in the placebo group. The estimated treatment difference for ivacaftorversus placebo was 2.1 percentage points (95% CI: -1.1, 5.4).

A pre-planned subgroup analysis was conducted in patients aged 18 years and older (26 patients onplacebo and 24 patients on ivacaftor). Treatment with ivacaftor resulted in a mean absolute change inpercent predicted FEV1 through week 24 of 4.5 percentage points in the ivacaftor groupversus -0.46 percentage points in the placebo group. The estimated treatment difference for ivacaftorversus 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 themean absolute change from baseline through week 24 in percent predicted FEV1 between ivacaftor andplacebo was 5.3% (95% CI: 1.3, 9.3). In patients with a confirmed R117H-7T genetic variant, thetreatment 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 placeboin 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 throughweek 24 (treatment difference of ivacaftor versus placebo was 8.4 [95% CI: 2.2, 14.6] points) and forthe mean change from baseline in sweat chloride (see Pharmacodynamic effects).

Study 770-108: study in paediatric patients with CF aged 2 to less than 6 years with G551D oranother gating mutation

The pharmacokinetic profile, safety and efficacy of ivacaftor in 34 patients aged 2 to less than 6 yearswith CF who had a G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N or S549Rmutation in the CFTR gene were assessed in a 24-week uncontrolled study with ivacaftor (patientsweighing less than 14 kg received ivacaftor 50 mg and patients weighing 14 kg or more receivedivacaftor 75 mg). Ivacaftor was administered orally every 12 hours with fat-containing food in additionto their prescribed CF therapies.

Patients in study 770-108 were aged 2 to less than 6 years (mean age 3 years). Twenty-six patients outof the 34 enrolled (76.5%) had a CFTR genotype G551D/F508del with only 2 patients with anon-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 andexploratory efficacy endpoints evaluated were absolute change from baseline in sweat chloridethrough 24 weeks of treatment, absolute change from baseline in weight, body mass index (BMI) andstature (supported by weight, BMI and stature z-scores) at 24 weeks of treatment, and measures ofpancreatic 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 was0.37 (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 withinitial levels below 200 µg/g achieved, at week 24, a level of ≥ 200 µg/g. The mean (SD) overallchange in percent predicted FEV1 from baseline at week 24 (exploratory endpoint) was 1.8 (17.81).

Study 770-124: study in paediatric patients with CF aged less than 24 months

The pharmacokinetics and safety of ivacaftor in patients with CF aged 1 month to less than 24 monthswere assessed in a 24-week (part B only), open-label single arm study where 19 patients aged12 months to less than 24 months (mean age 15.2 months at baseline), 11 patients aged 6 months toless than 12 months, 6 patients aged 4 months to less than 6 months, and 7 patients (part A/B) aged 1month to less than 4 months were enrolled and treated with ivacaftor according to their age and bodyweight. Mean age at baseline of each cohort was 15.2 months, 9.0 months, 4.5 months, and 1.9months, respectively.

Primary endpoint in part B and part A/B was safety through 24 weeks. Pharmacokinetics and theabsolute change from baseline in sweat chloride through 24 weeks (see Pharmacodynamic effects)were secondary endpoints. Tertiary endpoints included efficacy measures such as faecal elastase-1 andgrowth parameters.

For patients aged 1 month 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 9.

Table 9: Effect of ivacaftor on growth parameters in patients aged 1 month to less than24 months with baseline and week 24 values

Number Baseline Absolute change at week 24

Parameter ofpatients Mean Median Mean Median(SD) (min, max) (SD) (min, max)

Weight-for-age z-score 41 0.00 0.07 0.45 0.30(0.94) [-1.93, 1.79] (0.64) [-0.54, 2.66]

Number Baseline Absolute change at week 24

Parameter ofpatients Mean Median Mean Median(SD) (min, max) (SD) (min, max)

Length-for-age z-score 40 -0.03 -0.03 0.44 0.52(1.11) [-1.99, 2.79] (0.92) [-1.81, 3.38]

Weight-for-length z-score 40 0.07 0.14 0.32 0.32(1.02) [-1.72, 2.16] (0.99) [-2.04, 2.22]

In patients aged 1 month to less than 24 months, out of the 24 subjects who were pancreaticinsufficient at baseline (defined as faecal elastase-1 < 200 µg/g), 14 had faecal elastase-1 values above200 μg/g at week 24. In the overall population of part B and part A/B, the median (min, max) value offaecal elastase-1 (μg/g) was 55.5 (7.5, 500.0) at baseline. The median (min, max) absolute change infaecal elastase-1 from baseline (n = 40) to week 24 (n = 33) was 126.0 (-23.0, 423.5).

Ivacaftor in a combination regimen with ivacaftor/tezacaftor/elexacaftor

The efficacy and safety of ivacaftor in a combination regimen with ivacaftor/tezacaftor/elexacaftor inpatients aged 12 years and older was demonstrated in three phase 3, randomised, double-blind,placebo-controlled (patients were heterozygous for the F508del mutation and a mutation with minimalfunction on the second allele, n = 403) and active-controlled (patients were homozygous for the

F508del mutation, n = 107, or heterozygous for the F508del mutation and a gating or residual CFTRactivity mutation on the second allele, n = 258) studies of 24, 4, and 8 weeks of duration respectively.

Patients from all studies were eligible to enter open-label, rollover, long-term extension studies (study445-105 or study 445-110). Refer to the Summary of Product Characteristics ofivacaftor/tezacaftor/elexacaftor for additional data.

Ivacaftor in a combination regimen with ivacaftor/tezacaftor/elexacaftor

The pharmacokinetics and safety in patients aged 6 to less than 12 years (n = 66) and in those from 2to less than 6 years (n = 75) who have at least one F508del mutation were assessed in two 24-weekopen-label studies (study 445-106 and study 445-111), respectively. Refer to the Summary of Product

Characteristics of ivacaftor/tezacaftor/elexacaftor for additional data.

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 10.60 (5.26) µg∙h/mL and 0.768 (0.233) µg/mL, respectively. After every12-hour dosing, steady-state plasma concentrations of ivacaftor were reached by days 3 to 5, with anaccumulation ratio ranging from 2.2 to 2.9.

Following multiple oral dose administrations of ivacaftor, the exposure of ivacaftor generallyincreased 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-foldand 2.5- to 4-fold, respectively). Therefore, ivacaftor, administered as monotherapy or in acombination regimen with ivacaftor/tezacaftor/elexacaftor, should be administered with fat-containingfood. The median (range) tmax is approximately 4.0 (3.0; 6.0) hours in the fed state.

Ivacaftor granules (2 × 75 mg sachets) had similar bioavailability as the 150 mg tablet when givenwith fat-containing food to healthy adult subjects. The geometric least squares mean ratio (90% CI) forthe 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.

Ivacaftor is approximately 99% bound to plasma proteins, primarily to alpha 1-acid glycoprotein andalbumin. 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) apparentvolume of distribution was 353 L (122).

Ivacaftor is extensively metabolised in humans. In vitro and in vivo data indicate that ivacaftor isprimarily 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, tezacaftor and elexacaftor exposureis consistent with the effect of co-administration of a weak CYP3A4 inhibitor, which is not clinicallyrelevant. No dose adjustment of ivacaftor, tezacaftor, or elexacaftor is considered necessary. The effectin CYP3A4*22 homozygous genotype patients is expected to be stronger. However, no data areavailable for such patients.

Following oral administration in healthy volunteers, the majority of ivacaftor (87.8%) was eliminatedin the faeces after metabolic conversion. The major metabolites M1 and M6 accounted forapproximately 65% of the total dose eliminated with 22% as M1 and 43% as M6. There was negligibleurinary excretion of ivacaftor as unchanged parent. The apparent terminal half-life was approximately12 hours following a single dose in the fed state. The apparent clearance (CL/F) of ivacaftor wassimilar for healthy subjects and patients with CF. The mean (±SD) CL/F for a single 150 mg dose was17.3 (8.4) L/hr in healthy subjects.

The pharmacokinetics of ivacaftor are generally linear with respect to time or dose ranging from25 mg to 250 mg.

Following a single dose of 150 mg of ivacaftor, adult subjects with moderately impaired hepaticfunction (Child-Pugh Class B, score 7 to 9) had similar ivacaftor Cmax (mean [± SD] of0.735 [0.331] µg/mL) but an approximately 2-fold increase in ivacaftor AUC0-∞ (mean [± SD] of 16.80[6.14] µg∙h/mL) compared with healthy subjects matched for demographics. Simulations for predictingthe steady-state exposure of ivacaftor showed that by reducing the dose from 150 mg q12h to 150 mgonce daily, adults with moderate hepatic impairment would have comparable steady-state Cmin valuesas 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 ivacaftor, tezacaftorand elexacaftor.

The impact of severe hepatic impairment (Child-Pugh Class C, score 10 to 15) on thepharmacokinetics of ivacaftor or in a combination regimen with ivacaftor/tezacaftor/elexacaftor havenot been studied. The magnitude of increase in exposure in these patients is unknown but is expectedto 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.

Pharmacokinetic studies have not been performed with ivacaftor in patients with renal impairment. Ina human pharmacokinetic study, there was minimal elimination of ivacaftor and its metabolites inurine (only 6.6% of total radioactivity was recovered in the urine). There was negligible urinaryexcretion 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 isrecommended when administering ivacaftor to patients with severe renal impairment (creatinineclearance less than or equal to 30 mL/min) or end-stage renal disease (see sections 4.2 and 4.4).

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.

The pharmacokinetic parameters of ivacaftor are similar in males and females.

Clinical studies of ivacaftor as monotherapy did not include sufficient numbers of patients aged65 years and older to determine whether pharmacokinetic parameters are similar or not to those inyounger adults.

Predicted ivacaftor exposure based on observed ivacaftor concentrations in phase 2 and 3 studies asdetermined using compartmental analysis is presented by age group in Table 10.

Table 10: Mean (SD) ivacaftor exposure by age group

Age group Dose C (µg/mL) AUC0-12h, ssmin, ss (µg∙h/mL)1 month to less than 2 months 13.4 mg q24h 0.300 (0.221)† 5.84 (2.98)†(≥ 3 kg)⁎2 months to less than 4 months 13.4 mg q12h 0.406 (0.266)† 6.45 (3.43)†(≥ 3 kg)⁎4 months to less than 6 months 25 mg q12h 0.371 (0.183) 6.48 (2.52)(≥ 5 kg)⁎6 months to less than 12 months 25 mg q12h(≥5 kg to < 7 kg) ‡ 0.336 5.416 months to less than 12 months 50 mg q12h(7 kg to < 14 kg) 0.508 (0.252) 9.14 (4.20)12 months to less than 24 months 50 mg q12h 0.440 (0.212) 9.05 (3.05)(7 kg to < 14 kg)12 months to less than 24 months 75 mg q12h 0.451 (0.125) 9.60 (1.80)(≥ 14 kg to < 25 kg)2- to 5-year-olds (< 14 kg) 50 mg q12h 0.577 (0.317) 10.50 (4.26)2- to 5-year-olds (≥ 14 kg to 75 mg q12h 0.629 (0.296) 11.30 (3.82)< 25 kg)

Age group Dose C (µg/mL) AUC0-12h, ssmin, ss (µg∙h/mL)6- to 11-year-olds§ (≥ 14 kg to 75 mg q12h 0.641 (0.329) 10.76 (4.47)< 25 kg)6- to 11-year-olds§ (≥ 25 kg) 150 mg q12h 0.958 (0.546) 15.30 (7.34)12- to 17-year-olds 150 mg q12h 0.564 (0.242) 9.24 (3.42)

Adults (≥ 18 years old) 150 mg q12h 0.701 (0.317) 10.70 (4.10)⁎ Patients 1 month to less than 6 months of age were ≥37 weeks gestational age.† Exposures for 1 month to less than 4 months of age are predictions based on simulations from thephysiologically based PK model incorporating data from the given age group.‡ 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 usingdata obtained for this age group.

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity, genotoxicity, and carcinogenic potential.

Ivacaftor was associated with slight decreases of the seminal vesicle weights, a decrease of overallfertility index and number of pregnancies in females mated with treated males and significantreductions in number of corpora lutea and implantation sites with subsequent reductions in the averagelitter 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 ofapproximately 4 times the systemic exposure of ivacaftor and its metabolites when administered asivacaftor monotherapy in adult humans at the maximum recommended human dose (MRHD).

Placental transfer of ivacaftor was observed in pregnant rats and rabbits.

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 thesystemic exposure of ivacaftor and its metabolites when administered as ivacaftor monotherapy inadult humans at the MRHD.

Findings of cataracts were observed in juvenile rats dosed from postnatal day 7 through 35 at ivacaftorexposure levels of 0.22 times the MRHD based on systemic exposure of ivacaftor and its metaboliteswhen administered as ivacaftor monotherapy. This finding has not been observed in foetuses derivedfrom rat dams treated with ivacaftor on gestation days 7 to 17, in rat pups exposed to ivacaftor throughmilk ingestion up to postnatal day 20, in 7-week old rats, nor in 3.5 to 5-month old dogs treated withivacaftor. The potential relevance of these findings in humans is unknown.

Silica, colloidal anhydrous

Croscarmellose sodium

Hypromellose acetate succinate

Lactose monohydrate

Magnesium stearate

Mannitol

Sucralose

Sodium laurilsulfate (E487)

Not applicable.

4 years.

Once mixed, the mixture has been shown to be stable for one hour.

This medicinal product does not require any special storage conditions.

Biaxially Oriented Polyethylene Terephthalate/Polyethylene/Foil/Polyethylene (BOPET/PE/Foil/PE)sachet.

Kalydeco 13.4 mg granules in sachet, Kalydeco 25 mg granules in sachet, Kalydeco 50 mg granules insachet, and Kalydeco 75 mg granules in sachet

Pack size of 56 sachets (contains 4 individual wallets with 14 sachets per wallet).

Kalydeco 13.4 mg granules in sachet, Kalydeco 59.5 mg granules in sachet, and Kalydeco 75 mggranules in sachet

Pack size of 28 sachets (contains 4 individual wallets with 7 sachets per wallet).

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Vertex Pharmaceuticals (Ireland) Limited

Unit 49, Block 5, Northwood Court, Northwood Crescent,

Dublin 9, D09 T665,

Ireland

EU/1/12/782/003

EU/1/12/782/004

EU/1/12/782/006

EU/1/12/782/008

EU/1/12/782/009

EU/1/12/782/010

EU/1/12/782/011

Date of first authorisation: 23 July 2012

Date of latest renewal: 29 April 2022

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.