Ivacaftor

Ivacaftor may inhibit CYP2C9. Therefore, monitoring of the international normalised ratio (INR) is recommended during co-administration of warfarin with ivacaftor (as monotherapy or in a combination regimen with tezacaftor/ivacaftor). Other medicinal products for which exposure may be increased include glimepiride and glipizide; these medicinal products should be used with caution.

Ivacaftor is a sensitive CYP3A substrate. Co-administration with ketoconazole, a strong CYP3A inhibitor, increased ivacaftor exposure (measured as area under the curve [AUC]) by 8.5-fold and increased M1 to a lesser extent than ivacaftor. A reduction of the ivacaftor dose (as monotherapy or in a combination regimen with tezacaftor/ivacaftor or ivacaftor/tezacaftor/elexacaftor) is recommended for co-administration with strong CYP3A inhibitors, such as ketoconazole, itraconazole, posaconazole, voriconazole, telithromycin and clarithromycin.

Co-administration with fluconazole, a moderate inhibitor of CYP3A, increased ivacaftor exposure by 3-fold and increased M1 to a lesser extent than ivacaftor. A reduction of the ivacaftor dose (as monotherapy or in a combination regimen with tezacaftor/ivacaftor or ivacaftor/tezacaftor/elexacaftor) is recommended for patients taking concomitant moderate CYP3A inhibitors, such as fluconazole, erythromycin, and verapamil.

Co-administration of ivacaftor with grapefruit juice, which contains one or more components that moderately inhibit CYP3A, may increase exposure to ivacaftor. Food or drink containing grapefruit should be avoided during treatment with ivacaftor (as monotherapy or in a combination regimen with tezacaftor/ivacaftor or ivacaftor/tezacaftor/elexacaftor).

Co-administration with (oral) midazolam, a sensitive CYP3A substrate, increased midazolam exposure 1.5-fold, consistent with weak inhibition of CYP3A by ivacaftor. No dose adjustment of CYP3A substrates, such as midazolam, alprazolam, diazepam or triazolam, is required when these are co-administered with ivacaftor (as monotherapy or in a combination regimen with tezacaftor/ivacaftor or ivacaftor/tezacaftor/elexacaftor).

Co-administration with digoxin, a sensitive P-gp substrate, increased digoxin exposure by 1.3-fold, consistent with weak inhibition of P-gp by ivacaftor. Administration of ivacaftor (as monotherapy or in a combination regimen with tezacaftor/ivacaftor or ivacaftor/tezacaftor/elexacaftor) may increase systemic exposure of medicinal products that are sensitive substrates of P-gp, which may increase or prolong their therapeutic effect and adverse reactions. When used concomitantly with digoxin or other substrates of P-gp with a narrow therapeutic index, such as ciclosporin, everolimus, sirolimus or tacrolimus, caution and appropriate monitoring should be used.

Co-administration of ivacaftor with rifampicin, a strong CYP3A inducer, decreased ivacaftor exposure (AUC) by 89% and decreased hydroxymethyl ivacaftor (M1) to a lesser extent than ivacaftor. Co-administration of ivacaftor (as monotherapy or in a combination regimen with tezacaftor/ivacaftor) with strong CYP3A inducers, such as rifampicin, rifabutin, phenobarbital, carbamazepine, phenytoin and St. John’s wort (Hypericum perforatum), is not recommended.

No dose adjustment is recommended when ivacaftor (as monotherapy or in a combination regimen with tezacaftor/ivacaftor) is used with moderate or weak CYP3A inducers.

Caution is recommended in patients with severe renal impairment (creatinine clearance less than or equal to 30 mL/min) or end-stage renal disease.

No dose adjustment is necessary for patients aged 6 months and older with mild hepatic impairment (Child-Pugh Class A). For patients aged 6 months and older with moderate hepatic impairment (Child-Pugh Class B), a reduced dose of ivacaftor 25 mg for patients 5 kg to <7 kg; ivacaftor 50 mg for patients 7 kg to <14 kg; ivacaftor 75 mg for patients 14 kg to <25 kg once daily is recommended. There is no experience of the use of ivacaftor in patients aged 6 months and older with severe hepatic impairment (Child-Pugh Class C); therefore, its use is not recommended unless the benefits outweigh the risks. In such cases, the starting dose should be as above recommended, administered every other day. Dosing intervals should be modified according to clinical response and tolerability.

Due to variability in maturation of cytochrome (CYP) enzymes involved in ivacaftor metabolism, treatment with ivacaftor is not recommended in patients aged 4 months to less than 6 months with hepatic impairment, unless the benefits outweigh the risks. In such cases, the recommended dose is ivacaftor 25 mg once daily or less frequently. Dosing intervals should be modified according to clinical response and tolerability.

For patients with moderate hepatic impairment (Child-Pugh Class B) the dose of ivacaftor as monotherapy should be reduced to 150 mg once daily.

For patients with severe hepatic impairment (Child-Pugh Class C), the dose of ivacaftor as monotherapy should be reduced to 150 mg every other day or less frequently.

For use as an evening dose in a combination regimen with tezacaftor/ivacaftor or ivacaftor/tezacaftor/elexacaftor see the table for dosing regimen recommendations.

Dosing recommendations for patients with moderate or severe hepatic impairment:

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.

Ivacaftor, either as monotherapy or in a combination regimen with tezacaftor/ivacaftor or ivacaftor/tezacaftor/elexacaftor, has not been studied in patients with cystic fibrosis who have undergone organ transplantation. Therefore, use in transplanted patients is not recommended.

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. As a precautionary measure, it is preferable to avoid the use of ivacaftor during pregnancy.

It is unknown whether ivacaftor and/or its metabolites are excreted in human milk. Available pharmacokinetic data in animals have shown excretion of ivacaftor into the milk of lactating female rats. As such, a risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from ivacaftor therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

There are no data available on the effect of ivacaftor on fertility in humans. Ivacaftor had an effect on fertility in rats.

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

Summary of the safety profile

The most common adverse reactions experienced by patients aged 6 years and older who received ivacaftor are headache (23.9%), oropharyngeal pain (22.0%), upper respiratory tract infection (22.0%), nasal congestion (20.2%), abdominal pain (15.6%), nasopharyngitis (14.7%), diarrhoea (12.8%), dizziness (9.2%), rash (12.8%) and bacteria in sputum (12.8%). Transaminase elevations occurred in 12.8% of ivacaftor-treated patients versus 11.5% of placebo-treated patients.

In patients aged 2 to less than 6 years the most common adverse reactions were nasal congestion (26.5%), upper respiratory tract infection (23.5%), transaminase elevations (14.7%), rash (11.8%), and bacteria in sputum (11.8%).

Serious adverse reactions in patients who received ivacaftor included abdominal pain and transaminase elevations.

Tabulated list of adverse reactions

Table 1 reflects the adverse reactions observed with ivacaftor monotherapy in clinical trials (placebocontrolled 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 1. 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 1. Adverse reactions:

^* Adverse reaction and frequency reported from clinical studies with ivacaftor in combination with tezacaftor/ivacaftor.
^† Adverse reaction and frequency reported from clinical studies with ivacaftor in combination with ivacaftor/tezacaftor/elexacaftor.
^ 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 of ivacaftor as monotherapy 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.

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. Post-marketing cases of treatment discontinuation due to elevated transaminases have been reported.

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 femaletreated patients (16.3%) and in those taking hormonal contraceptives (20.5%).

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 as monotherapy were evaluated in 6 patients between 4 months to less than 6 months of age, 11 patients between 6 months to less than 12 months of age, 19 patients between 12 months to less than 24 months of age, 34 patients between 2 to less than 6 years of age, 61 patients between 6 to less than 12 years of age and 94 patients between 12 to less than 18 years of age.

The safety profile of ivacaftor (as monotherapy or in a combination regimen) is generally consistent among paediatric patients and is also consistent with adult patients.

The incidence of transaminase elevations (ALT or AST) observed in studies 2, 5 and 6 (patients aged 6 to less than 12 years), study 7 (patients aged 2 to less than 6 years), and study 8 (patients aged 6 to less than 24 months) are described in Table 2. 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. Cases suggestive of positive rechallenge were observed. In study 7 ivacaftor was permanently discontinued in one patient. In study 8 no patients had elevations in total bilirubin or discontinued ivacaftor treatment due to transaminase elevations in either age cohort.

Table 2. Transaminase elevations in patients 4 months to <12 years treated with ivacaftor as monotherapy: