4.1. Therapeutic indications

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 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 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 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 1 month, toddlers, children, adolescents and adults should be dosed according to Table 1.

Table 1: Dosing recommendations

Age

Weight

Morning dose

Evening dose

Ivacaftor as monotherapy

1 month to less than 3 months*†

≥ 3 kg

One sachet of ivacaftor 13.4 mg granules

One sachet of ivacaftor 13.4 mg granules

3 months to less than 6 months

≥ 3 kg

One sachet of ivacaftor 25 mg granules

One sachet of ivacaftor 25 mg granules

6 months and older

≥ 5 kg to < 7 kg

One sachet of ivacaftor 25 mg granules

One sachet of ivacaftor 25 mg granules

≥ 7 kg to < 14 kg

One sachet of ivacaftor 50 mg granules

One sachet of ivacaftor 50 mg granules

≥ 14 kg to < 25 kg

One sachet of ivacaftor 75 mg granules

One sachet of ivacaftor 75 mg granules

≥ 25 kg

See Kalydeco tablets SmPC for further details.

Ivacaftor in a combination regimen with ivacaftor/tezacaftor/elexacaftor

2 years to less than 6 years

< 14 kg

One sachet of ivacaftor 60 mg/tezacaftor 40 mg/elexacaftor 80 mg granules

One sachet of ivacaftor 59.5 mg granules

≥ 14 kg

One sachet of ivacaftor 75 mg/tezacaftor 50 mg/elexacaftor 100 mg granules

One sachet of ivacaftor 75 mg granules

* Ivacaftor is not recommended for use in children under 1 month of age.

† Use of ivacaftor in patients aged 1 to less than 6 months born at a gestational age < 37 weeks has not been evaluated.

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 medicinal product 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 ivacaftor/tezacaftor/elexacaftor, in patients aged 6 months and older, the dosing should be reduced (see Table 2 for the recommended dosing).

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 dosing should be reduced (see Table 2 for dosing recommendations). Dosing intervals should be modified according to clinical response and tolerability (see sections 4.2, 4.4, and 5.2).

Treatment with ivacaftor is not recommended in patients aged 1 month to less than 4 months who are taking concomitant strong or moderate CYP3A inhibitors.

Table 2: Dosing recommendations for concomitant use with moderate or strong CYP3A inhibitors

Moderate CYP3A inhibitors

Strong CYP3A inhibitors

Ivacaftor as monotherapy

4 months to less than 6 months

One sachet of ivacaftor 25 mg granules twice weekly, or less frequently.

Dosing intervals should be modified according to clinical response and tolerability.

No evening dose.

One sachet of ivacaftor 25 mg granules twice weekly, or less frequently.

Dosing intervals should be modified according to clinical response and tolerability.

No evening dose.

6 months and older, ≥ 5 kg to < 7 kg

One sachet of ivacaftor 25 mg granules once daily.

No evening dose.

One sachet of ivacaftor 25 mg granules twice weekly.

No evening dose.

6 months and older, ≥ 7 kg to < 14 kg

One sachet of ivacaftor 50 mg granules once daily.

No evening dose.

One sachet of ivacaftor 50 mg granules twice a week.

No evening dose.

6 months and older, ≥ 14 kg to < 25 kg

One sachet of ivacaftor 75 mg granules once daily.

No evening dose.

One sachet of ivacaftor 75 mg granules twice a week.

No evening dose.

Ivacaftor in a combination regimen with ivacaftor/tezacaftor/elexacaftor

2 years to less than 6 years, < 14 kg

Alternate each day:

• One sachet of ivacaftor 60 mg/tezacaftor 40 mg/elexacaftor 80 mg granules on the first day

• One sachet of ivacaftor 59.5 mg granules on the next day

No evening dose of ivacaftor granules.

One sachet of ivacaftor 60 mg/tezacaftor 40 mg/elexacaftor 80 mg granules twice a week, approximately 3 to 4 days apart.

No evening dose of ivacaftor granules.

2 years to less than 6 years, ≥ 14 kg

Alternate each day:

• One sachet of ivacaftor 75 mg/tezacaftor 50 mg/elexacaftor 100 mg granules on the first day

• One sachet of ivacaftor 75 mg granules on the next day

No evening dose of ivacaftor granules.

One sachet of ivacaftor 75 mg/tezacaftor 50 mg/elexacaftor 100 mg granules twice a week, approximately 3 to 4 days apart.

No evening dose of ivacaftor granules.

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), neither as monotherapy or in a combination regimen with ivacaftor/tezacaftor/elexacaftor, dosing should be reduced (see Table 3 for the recommended dosing). 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 dosing should be reduced (see Table 3 for dosing recommendations). Dosing intervals should be modified according to clinical response and tolerability (see sections 4.4 and 5.2).

Treatment with ivacaftor is not recommended in patients aged 4 months to less than 6 months with any level of hepatic impairment, unless the benefits outweigh the risks. In such cases, the dosing should be reduced (see Table 3 for dosing recommendations). Dosing intervals should be modified according to clinical response and tolerability (see sections 4.4 and 5.2).

Treatment with ivacaftor is not recommended in patients aged 1 month to less than 4 months with any level of hepatic impairment.

For use as an evening dose in a combination regimen with 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 monotherapy

4 months to less than 6 months

Use is not recommended unless the benefits are expected to outweigh the risks.

If used: one sachet of ivacaftor 25 mg granules once daily or less frequently.

Dosing intervals should be modified according to clinical response and tolerability.

Use is not recommended unless the benefits are expected to outweigh the risks.

If used: one sachet of ivacaftor 25 mg granules once daily or less frequently.

Dosing intervals should be modified according to clinical response and tolerability.

6 months and older, ≥ 5 kg to < 7 kg

One sachet of ivacaftor 25 mg granules once daily.

No evening dose.

Use is not recommended unless the benefits are expected to outweigh the risks.

If used: one sachet of ivacaftor 25 mg granules every other day.

Dosing intervals should be modified according to clinical response and tolerability.

6 months and older, ≥ 7 kg to < 14 kg

One sachet of ivacaftor 50 mg granules once daily.

No evening dose.

Use is not recommended unless the benefits are expected to outweigh the risks.

If used: one sachet of ivacaftor 50 mg granules every other day.

Dosing intervals should be modified according to clinical response and tolerability.

6 months and older, ≥ 14 kg to < 25 kg

One sachet of ivacaftor 75 mg granules once daily.

No evening dose.

Use is not recommended unless the benefits are expected to outweigh the risks.

If used: one sachet of ivacaftor 75 mg granules every other day.

Dosing intervals should be modified according to clinical response and tolerability.

Ivacaftor in a combination regimen with ivacaftor/tezacaftor/elexacaftor

2 years to less than 6 years, < 14 kg

Use not recommended. Treatment of patients with moderate hepatic impairment should only be considered when there is a clear medical need and the benefits are expected to outweigh the risks.

If used, ivacaftor/tezacaftor/elexacaftor should be used with caution at a reduced dose, as follows:

• Days 1-3: one sachet of ivacaftor 60 mg/tezacaftor 40 mg/elexacaftor 80 mg granules each day

• Day 4: no dose

• Days 5-6: one sachet of ivacaftor 60 mg/tezacaftor 40 mg/elexacaftor 80 mg granules each day

• Day 7: no dose

Repeat above dosing schedule each week.

The evening dose of the ivacaftor granules should not be taken.

Should not be used.

2 years to less than 6 years, ≥ 14 kg

Use not recommended. Treatment of patients with moderate hepatic impairment should only be considered when there is a clear medical need and the benefits are expected to outweigh the risks.

If used, ivacaftor/tezacaftor/elexacaftor should be used with caution at a reduced dose, as follows:

• Days 1-3: one sachet of ivacaftor 75 mg/tezacaftor 50 mg/elexacaftor 100 mg granules each day

• Day 4: no dose

• Days 5-6: one sachet of ivacaftor 75 mg/tezacaftor 50 mg/elexacaftor 100 mg granules each day

• Day 7: no dose

Repeat above dosing schedule each week.

The evening dose of the ivacaftor granules should not be taken.

Should not be used.

Paediatric population

The safety and efficacy of ivacaftor have not been established in children less than 1 month of age as monotherapy or in combination with ivacaftor/tezacaftor/elexacaftor in children less than 2 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.

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. Some examples of age-appropriate soft foods or liquids include puréed fruits or vegetables, yogurt, applesauce, water, milk, breast milk, infant formula, or juice. 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).

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.

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. Use 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 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 of liver disease or 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 × the upper limit of normal (ULN), or ALT or AST > 3 × ULN with bilirubin > 2 × 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 4.2, 4.8, and 5.2).

Hepatic impairment

Use of ivacaftor, either as monotherapy or in a combination regimen with ivacaftor/tezacaftor/elexacaftor, 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, 4.8, 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, 4.8, and 5.2).

Renal impairment

Caution is recommended while using ivacaftor, either as monotherapy or in a combination regimen with 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 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 ivacaftor/tezacaftor/elexacaftor) 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 (as monotherapy or in a combination regimen with ivacaftor/tezacaftor/elexacaftor) must be adjusted in patients aged 6 months and older, and only if benefits outweigh the risks for patients aged 4 months to less than 6 months when used concomitantly with strong or moderate CYP3A inhibitors (see sections 4.2 and 4.5). No safety data are available in infants aged 1 to less than 12 months of age who are treated with ivacaftor and moderate or strong CYP3A inhibitors (see sections 4.2 and 4.5). Treatment with ivacaftor is not recommended when concomitantly used with moderate or strong CYP3A inhibitors in patients aged 1 month to less than 4 months.

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 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 medicinal product.

Sodium content

This medicinal product contains less than 1 mmol sodium (23 mg) per sachet, 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 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 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 in patients aged 6 months and older, and only if benefits outweigh the risks for patients aged 4 months to less than 6 months (as monotherapy or in a combination regimen with ivacaftor/tezacaftor/elexacaftor) is recommended for co-administration with strong CYP3A inhibitors, such as ketoconazole, itraconazole, posaconazole, voriconazole, telithromycin and clarithromycin. Treatment with ivacaftor is not recommended when concomitantly used with strong CYP3A inhibitors in patients aged 1 month to less than 4 months (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 (as monotherapy or in a combination regimen with ivacaftor/tezacaftor/elexacaftor) is recommended for patients aged 6 months and older, and only if benefits outweigh the risks for patients aged 4 months to less than 6 months, taking concomitant moderate CYP3A inhibitors, such as fluconazole, erythromycin, and verapamil. Treatment with ivacaftor is not recommended when concomitantly used with moderate CYP3A inhibitors in patients aged 1 month to less than 4 months (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 (as monotherapy or in a combination regimen with 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 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 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 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 ivacaftor/tezacaftor/elexacaftor).

Hormonal contraceptives

Ivacaftor (as monotherapy or in a combination regimen with 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 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 in 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 and 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 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 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

Hepatobiliary disorders

Transaminase elevations

very common

Alanine aminotransferase increased*

common

Aspartate aminotransferase increased*

common

Liver injury†

not known

Total bilirubin elevations†

not known

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

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 ivacaftor/tezacaftor/elexacaftor.

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

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 × 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 × ULN. No ivacaftor-treated patients experienced a transaminase elevation > 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 dosing was interrupted in most patients with transaminase elevations > 5 × 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 × 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 × ULN associated with elevated total bilirubin > 2 × 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.

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 were evaluated in 7 patients between 1 month to less than 4 months of age, 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 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 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, in the cohort of patients aged 1 month to less than 4 months, 1 patient had maximum ALT or AST > 3 × ULN (ALT > 8 × ULN and AST of > 3 to ≤ 5 × ULN); the subject discontinued ivacaftor treatment (see section 4.4 for management of elevated transaminases).

Table 5: Transaminase elevations in patients 1 month to < 12 years treated with ivacaftor as monotherapy

n

% of Patients > 3 × ULN

% of Patients > 5 × ULN

% of Patients > 8 × 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)

1 to < 4 months

7

14.3% (1)

14.3% (1)

14.3% (1)

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:

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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.