Kalydeco · 4.4 Special warnings and precautions for use · 2

HOS-096276 · has-adverse-reaction-information · PDF-Seite 43

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 included abdominal pain (0.9%) and transaminase elevations (1.8%) in patients who received ivacaftor, while serious adverse reactions of rash were reported in 1.5% patients aged 12 years and older treated with a combination regimen with ivacaftor/tezacaftor/elexacaftor (see section 4.4). Tabulated list of adverse reactions Table 4 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. Table 4: Adverse reactions System organ class Adverse reactions Frequency Infections and infestations Upper respiratory tract very common infection Nasopharyngitis very common Influenza* common Rhinitis common Metabolism and nutrition Hypoglycaemia* common disorders Psychiatric disorders Depression not known Nervous system disorders Headache very common Dizziness very common Ear and labyrinth Ear pain common disorders E

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HOS-096270 · has-adverse-reaction-information · PDF-Seite 13

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 included abdominal pain (0.9%) and transaminase elevations (1.8%) in patients who received ivacaftor, while serious adverse reactions of rash were reported in 1.5% patients aged 12 years and older treated with a combination regimen with ivacaftor/tezacaftor/elexacaftor (see section 4.4). 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 Hypoglycaemia† common disorders Psychiatric disorders Depression not known Ne

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HOS-096266 · has-contraindication-information · PDF-Seite 8

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

HOS-096272 · has-contraindication-information · PDF-Seite 38

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

HOS-096265 · has-indication-information · PDF-Seite 2

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, 2  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, adolescents, and children aged 6 years and older with cystic fibrosis (CF) who have at least one non-Class I mutation in the CFTR gene (see sections 4.2 and 5.1).

HOS-096271 · has-indication-information · PDF-Seite 34

Kalydeco granules are indicated: • As monotherapy for the treatment of infants aged at least 1 month, toddlers and children weighing 3 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 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 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 non-Class I mutation in the CFTR gene (see sections 4.2 and 5.1).

HOS-096274 · has-interaction-information · PDF-Seite 41

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. 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. 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 co-administration with strong CYP3A inhibitors, such as ketoconazole, itraconazole, posaconazole, voriconazole, telithromycin and clarithromycin as well as for co-administration with moderate CYP3A inhibitors, such as fluconazole, erythromycin, and verapamil. Treatment with ivacaftor monotherapy is not recommended when concomitantly used with strong or moderate CYP3A inhibitors in patients aged 1 month to less than 6 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 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). 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-administr

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HOS-096268 · has-interaction-information · PDF-Seite 11

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. 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 Table 2 in section 4.2 and section 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 Table 2 in section 4.2 and section 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). 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.

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HOS-096275 · has-pregnancy-information · PDF-Seite 42

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 Limited data show that ivacaftor is excreted into human milk. 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). 42

HOS-096269 · has-pregnancy-information · PDF-Seite 12

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 Limited data show that ivacaftor is excreted into human milk. 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. 12 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).

HOS-096267 · has-warning-information · PDF-Seite 8

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 770-102, 770-103, 770-111 and 770-110 (see section 5.1). In study 770-111, 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 770-110 (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. 8 Elevated transaminases and hepatic injury In a patient with cirrhosis and portal hypertension, liver failure leading to transplantation has been reported while receiving ivacaftor in a combination regimen with ivacaftor/tezacaftor/elexacaftor. This medicinal 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 used in 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 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. In patients taking ivacaftor in a combination regimen with ivacaftor/tezacaftor/elexacaftor, these elevations have sometimes been associated with concomitant elevations in total bilirubin. Theref

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HOS-096273 · has-warning-information · PDF-Seite 38

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 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 mutation associated 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 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. Elevated transaminases and hepatic injury In a patient with cirrhosis and portal hypertension, liver failure leading to transplantation has been reported while receiving ivacaftor in a combination regimen with ivacaftor/tezacaftor/elexacaftor. This medicinal 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 used 38 in 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 are common in subjects with CF. Transaminase elevations have been observed in some patients treated with ivacaftor as monotherapy and in combination regimens with ivacaftor/tezacaftor/elexacaftor. In patients taking ivacaftor in a combination regimen with ivacaftor/tezacaftor/elexacaftor, these elevations have sometimes been associated with concomitant elevations in total bilirubin. Therefore, assessments of transaminases (ALT and AST) and total bilirubin 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

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