ivacaftor: prescribing information – dosing, contraindications, interactions, side effects

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,

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).

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).

Kalydeco should only be prescribed by physicians with experience in the treatment of cystic fibrosis.
If the patient's genotype is unknown, an accurate and validated genotyping method should be performed before starting treatment to confirm the presence of an indicated mutation in the CFTR gene (see section 4.1). The phase of the poly-T variant identified with the R117H mutation should be determined in accordance with local clinical recommendations.

Kalydeco in combination with ivacaftor/tezacaftor/elexacaftor

There are a limited number of patients who harbour mutations not listed in Table 6 that may be responsive to ivacaftor/tezacaftor/elexacaftor (IVA/TEZ/ELX). In these cases, ivacaftor (IVA) in combination with IVA/TEZ/ELX can be considered when the physician deems the potential benefits outweigh the potential risks and under close medical supervision. This excludes patients with two Class I (null) mutations (mutations that are known not to produce CFTR protein) as they are not expected to respond to modulator therapy (see sections 4.1, 4.4 and 5.1).

Posology

Adults, adolescents, and children aged 6 years and older should be dosed according to Table 1.
Table 1: Dosing recommendations
Age/weight
Morning dose
Evening dose
Ivacaftor as monotherapy
6 years and older,
≥ 25 kg
One ivacaftor 150 mg tablet
One ivacaftor
150 mg tablet
Ivacaftor in combination with tezacaftor/ivacaftor
6 years to < 12 years,
< 30 kg
One tezacaftor 50 mg/ivacaftor 75 mg tablet
One ivacaftor
75 mg tablet
6 years to < 12 years,
≥ 30 kg
One tezacaftor 100 mg/ivacaftor 150 mg tablet
One ivacaftor
150 mg tablet
12 years and older
One tezacaftor 100 mg/ivacaftor 150 mg tablet
One ivacaftor
150 mg tablet
Ivacaftor in combination with ivacaftor/tezacaftor/elexacaftor
6 years to < 12 years,
< 30 kg
Two ivacaftor 37.5 mg/tezacaftor 25 mg/elexacaftor
50 mg tablets
One ivacaftor
75 mg tablet
6 years to < 12 years,
≥ 30 kg
Two ivacaftor 75 mg/tezacaftor 50 mg/elexacaftor 100 mg tablets
One ivacaftor
150 mg tablet
12 years and older
Two ivacaftor 75 mg/tezacaftor 50 mg/elexacaftor 100 mg tablets
One ivacaftor
150 mg tablet

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

Missed dose

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

6 hours have passed since the time the dose is usually taken, the patient should be advised to wait until the next scheduled dose.

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

Concomitant use of CYP3A inhibitors

During concomitant administration with moderate or strong inhibitors of CYP3A, the ivacaftor dose should be adjusted as detailed in Table 2. Dosing intervals should be modified according to clinical response and tolerability (see sections 4.4 and 4.5).

Table 2: Dosing recommendations for concomitant use with moderate or strong CYP3A inhibitors Age/ weight Moderate CYP3A inhibitors Strong CYP3A inhibitors Ivacaftor as monotherapy 6 years and older, ≥ 25 kg One morning tablet of ivacaftor 150 mg once daily.

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

No evening ivacaftor dose.
Ivacaftor in a combination regimen with tezacaftor/ivacaftor
6 years to
< 12 years,
< 30 kg
Alternate each day:
- one morning tablet of tezacaftor
50 mg/ivacaftor 75 mg on the first day
- one morning tablet of ivacaftor
75 mg on the next day

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

No evening ivacaftor dose.
6 years to
< 12 years,
≥ 30 kg
Alternate each day:
- one morning tablet of tezacaftor
100 mg/ivacaftor 150 mg on the first day
- one morning tablet of ivacaftor
150 mg on the next day

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

No evening ivacaftor dose.
12 years and older
Alternate each day:
- one morning tablet of tezacaftor
100 mg/ivacaftor 150 mg on the first day
- one morning tablet of ivacaftor
150 mg on the next day

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

No evening ivacaftor dose.

Age/ weight
Moderate CYP3A inhibitors
Strong CYP3A inhibitors
Ivacaftor in a combination regimen with ivacaftor/tezacaftor/elexacaftor
6 years to
< 12 years,
< 30 kg
Alternate each day:
- two morning tablets of ivacaftor 37.5 mg/tezacaftor 25 mg/ elexacaftor 50 mg on the first day
- one morning tablet of ivacaftor 75 mg on the next day

No evening ivacaftor dose.
Two morning tablets of ivacaftor 37.5 mg/tezacaftor 25 mg/ elexacaftor 50 mg twice a week, approximately 3 to 4 days apart.

No evening ivacaftor dose.
6 years to
< 12 years,
≥ 30 kg
Alternate each day:
- two morning tablets of ivacaftor 75 mg/tezacaftor 50 mg/ elexacaftor 100 mg on the first day
- one morning tablet of ivacaftor 150 mg on the next day

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

No evening ivacaftor dose.
12 years and older
Alternate each day:
- two morning tablets of ivacaftor 75 mg/tezacaftor 50 mg/ elexacaftor 100 mg on the first day
- one morning tablet of ivacaftor 150 mg on the next day

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

No evening ivacaftor dose.

Special populations

Elderly

Very limited data are available for elderly patients treated with ivacaftor (administered as monotherapy or in a combination regimen). No dose adjustment specific to this patient population is required (see section 5.2).

Renal impairment

No dose adjustment is necessary for patients with mild to moderate renal impairment. Caution is recommended in patients with severe renal impairment (creatinine clearance less than or equal to 30 mL/min) or end-stage renal disease (see sections 4.4 and 5.2).

Hepatic impairment

No dose adjustment is necessary in patients with mild hepatic impairment (Child-Pugh Class A).

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/weigh t Moderate (Child-Pugh Class B) Severe (Child-Pugh Class C) Ivacaftor as monotherapy 6 years and older, ≥ 25 kg One morning tablet of ivacaftor 150 mg once daily.

No evening ivacaftor dose.
Use is not recommended, unless the benefits are expected to outweigh the risks.

If used, one morning tablet of ivacaftor 150 mg every other day or less frequently according to clinical response and tolerability.

No evening ivacaftor dose.
Ivacaftor in a combination regimen with tezacaftor/ivacaftor
6 years to
< 12 years,
< 30 kg
One morning tablet of tezacaftor
50 mg/ivacaftor 75 mg once daily.

No evening ivacaftor dose.
Use is not recommended, unless the benefits are expected to outweigh the risks.

If used, one morning tablet of tezacaftor
50 mg/ivacaftor 75 mg once daily or less frequently according to clinical response and tolerability.

No evening ivacaftor dose.
6 years to
< 12 years,
≥ 30 kg
One morning tablet of tezacaftor
100 mg/ivacaftor 150 mg once daily.

No evening ivacaftor dose.
Use is not recommended, unless the benefits are expected to outweigh the risks.

If used, one morning tablet of tezacaftor
100 mg/ivacaftor 150 mg once daily or less frequently according to clinical response and tolerability.

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

No evening ivacaftor dose.
Use is not recommended, unless the benefits are expected to outweigh the risks.

If used, one morning tablet of tezacaftor 100 mg/ivacaftor 150 mg once daily or less frequently according to clinical response and tolerability.

No evening ivacaftor dose.

Ivacaftor in a combination regimen with ivacaftor/tezacaftor/elexacaftor
6 years to
< 12 years,
< 30 kg
Use is not recommended, unless the benefits are expected to outweigh the risks.

If used, the dose should be adjusted as follows:
- Day 1: two ivacaftor 37.5 mg/tezacaft or
25 mg/elexacaftor 50 mg tablets in the morning
- Day 2: one ivacaftor 37.5 mg/tezacaft or
25 mg/elexacaftor 50 mg tablet in the morning

Continue alternating Day 1 and
Day 2 dosing thereafter.

No evening ivacaftor dose.
Should not be used.

6 years to
< 12 years,
≥ 30 kg
Use is not recommended, unless the benefits are expected to outweigh the risks.

If used, the dose should be adjusted as follows:
- Day 1: two ivacaftor 75 mg/tezacaftor
50 mg/elexacaftor 100 mg tablets in the morning
- Day 2: one ivacaftor 75 mg/tezacaftor
50 mg/elexacaftor 100 mg tablet in the morning

Continue alternating Day 1 and
Day 2 dosing thereafter.

No evening ivacaftor dose.
Should not be used.

12 years and older
Use is not recommended, unless the benefits are expected to outweigh the risks.

If used, the dose should be adjusted as follows:

- Day 1: two ivacaftor 75 mg/tezacaftor
50 mg/elexacaftor 100 mg tablets in the morning
- Day 2: one ivacaftor 75 mg/tezacaftor
50 mg/elexacaftor 100 mg tablet in the morning
Should not be used.

Continue alternating Day 1 and
Day 2 dosing thereafter.

No evening ivacaftor dose.

Paediatric population

The safety and efficacy of ivacaftor as monotherapy have not been established in children less than 1 month of age or in children less than 6 months of age born prematurely (less than 37 weeks of gestational age), neither in combination with tezacaftor/ivacaftor in children less than 6 years of age 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.

Patients should be instructed to swallow the tablets whole. The tablets should not be chewed, crushed, or broken before swallowing because there are no clinical data currently available to support other methods of administration.

Ivacaftor tablets should be taken with fat-containing food.

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

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.

Kalydeco in combination with ivacaftor/tezacaftor/elexacaftor

There are a limited number of patients who harbour mutations not listed in Table 6 that may be responsive to ivacaftor/tezacaftor/elexacaftor (IVA/TEZ/ELX). In these cases, ivacaftor (IVA) in combination with IVA/TEZ/ELX can be considered when the physician deems the potential benefits outweigh the potential risks and under close medical supervision. This excludes patients with two Class I (null) mutations (mutations that are known not to produce CFTR protein) as they are not expected to respond to modulator therapy (see sections 4.1, 4.4 and 5.1).

Posology

Dosing recommendations are shown in Table 1.
Table 1: Dosing recommendations
Age
Weight
Morning dose
Evening dose
Ivacaftor as monotherapy
1 month to less than 2 months
≥ 3 kg
One sachet of ivacaftor
13.4 mg granules
No evening dose
2 months to less than 4 months
≥ 3 kg
One sachet of ivacaftor
13.4 mg granules
One sachet of ivacaftor
13.4 mg granules
4 months to less than 6 months
≥ 5 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
10 kg to < 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

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

During concomitant administration with moderate or strong inhibitors of CYP3A, the ivacaftor dose should 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 CYP3A inhibitors Age/weight Moderate CYP3A inhibitors Strong CYP3A inhibitors Ivacaftor as monotherapy 1 month to less than 6 months Use is not recommended.
Use is not recommended.
6 months and older,
≥ 5 kg to
< 7 kg
One sachet of ivacaftor 25 mg granules once daily.

No evening ivacaftor dose.
One sachet of ivacaftor 25 mg granules twice a week.

No evening ivacaftor dose.
6 months and older,
≥ 7 kg to
< 14 kg
One sachet of ivacaftor 50 mg granules once daily.

No evening ivacaftor dose.
One sachet of ivacaftor 50 mg granules twice a week.

No evening ivacaftor dose.
6 months and older,
≥ 14 kg to
< 25 kg
One sachet of ivacaftor 75 mg granules once daily.

No evening ivacaftor dose.
One sachet of ivacaftor 75 mg granules twice a week.

No evening ivacaftor dose.

Age/weight
Moderate CYP3A inhibitors
Strong CYP3A inhibitors
Ivacaftor in a combination regimen with ivacaftor/tezacaftor/elexacaftor
2 years to less than
6 years,
10 kg to
< 14 kg
Alternate each day:
- One morning sachet of ivacaftor
60 mg/tezacaftor 40 mg/elexacaftor
80 mg granules on the first day
- One morning sachet of ivacaftor
59.5 mg granules on the next day

No evening ivacaftor dose.
One sachet of ivacaftor 60 mg/tezacaftor
40 mg/elexacaftor 80 mg granules twice a week, approximately 3 to 4 days apart.

No evening ivacaftor dose.

2 years to less than
6 years,
≥ 14 kg
Alternate each day:
- One morning sachet of ivacaftor
75 mg/tezacaftor 50 mg/elexacaftor
100 mg granules on the first day
- One morning sachet of ivacaftor
75 mg granules on the next day

No evening ivacaftor dose.
One sachet of ivacaftor 75 mg/tezacaftor
50 mg/elexacaftor 100 mg granules twice a week, approximately 3 to 4 days apart.

No evening ivacaftor dose.

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). Treatment with ivacaftor is not recommended in patients aged 1 month to less than 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 monotherapy 1 month to less than 6 months Use is not recommended.
Use is not recommended.
6 months and older,
≥ 5 kg to
< 7 kg
One sachet of ivacaftor 25 mg granules once daily.

No evening ivacaftor 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 according to clinical response and tolerability.

No evening ivacaftor dose.

6 months and older,
≥ 7 kg to
< 14 kg
One sachet of ivacaftor 50 mg granules once daily.

No evening ivacaftor 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 according to clinical response and tolerability.

No evening ivacaftor dose.
6 months and older,
≥ 14 kg to
< 25 kg
One sachet of ivacaftor 75 mg granules once daily.

No evening ivacaftor 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 according to clinical response and tolerability.

No evening ivacaftor dose.
Ivacaftor in a combination regimen with ivacaftor/tezacaftor/elexacaftor
2 years to less than
6 years,
10 kg to
< 14 kg
Use is not recommended, unless the benefits are expected to outweigh the risks.

If used, the dose should be adjusted 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.

No evening ivacaftor dose.
Should not be used.

2 years to less than
6 years,
≥ 14 kg
Use is not recommended, unless the benefits are expected to outweigh the risks.

If used, the dose should be adjusted 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.

No evening ivacaftor dose.
Should not be used.

Paediatric population

The safety and efficacy of ivacaftor as monotherapy have not been established in children less than 1 month of age or in children less than 6 months of age born prematurely (less than 37 weeks of gestational age), neither 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. 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).

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

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 disorders
Hypoglycaemia† common
Psychiatric disorders
Depression not known
Nervous system disorders
Headache very common
Dizziness very common
Ear and labyrinth disorders
Ear pain common
Ear discomfort common

System organ class
Adverse reactions
Frequency
Tinnitus common
Tympanic membrane hyperaemia common
Vestibular disorder common
Ear congestion uncommon
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain very common
Nasal congestion very common
Abnormal breathing† common
Rhinorrhoea† common
Sinus congestion common
Pharyngeal erythema common
Wheezing† uncommon
Gastrointestinal disorders
Abdominal pain very common
Diarrhoea very common
Abdominal pain upper† common
Flatulence† common
Nausea* common
Hepatobiliary disorders
Transaminase elevations very common
Alanine aminotransferase increased† very common
Aspartate aminotransferase increased† common
Liver injury^ not known
Total bilirubin increase^ 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 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 increase) 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 770-102 and 770-103 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 (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.

Post-marketing cases of treatment discontinuation due to elevated transaminases have been reported (see section 4.4).

Rash events

In study 445-102, the incidence of rash events (e.g., rash, rash pruritic) was 10.9% in ivacaftor/tezacaftor/elexacaftor-treated patients and 6.5% in placebo-treated patients. The rash events were generally mild to moderate in severity. The incidence of rash events by patient sex was 5.8% in males and 16.3% in females in ivacaftor/tezacaftor/elexacaftor-treated patients and 4.8% in males and 8.3% 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% in females not taking hormonal contraceptive (see section 4.4).

Increased creatine phosphokinase

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

Increased blood pressure

In study 445-102, the maximum increase from baseline in mean systolic and diastolic blood pressure was 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 for placebo-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 in ivacaftor/tezacaftor/elexacaftor-treated patients compared with 3.5% and 3.5%, respectively in placebo-treated patients.

Paediatric population

Ivacaftor as monotherapy

Safety of ivacaftor as monotherapy for 24 weeks was evaluated in 43 patients between 1 month to less than 24 months of age (with 7 of them less than 4 months old), 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 770-103, 770-111 and 770-110 (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 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 770-108 ivacaftor was permanently discontinued in one patient. In study 770-124, in the cohort of patients aged 1 month to less than 4 months, a 1-month old (14.3%) patient had transaminase values of ALT > 8 × ULN and AST > 3 to ≤ 5 × ULN, which led to discontinuation of ivacaftor treatment (see section 4.4 for management of elevated transaminases).
Table 5: Transaminase elevations in patients aged 1 month to < 12 years treated with ivacaftor as monotherapy Age group n % of Patients > 3 × ULN % of Patients > 5 × ULN % of Patients > 8 × ULN 6 to < 12 years 15.0% (6) 2.5% (1) 2.5% (1) 2 to < 6 years 14.7% (5) 14.7% (5) 14.7% (5) 12 to < 24 months 27.8% (5) 11.1% (2) 11.1% (2) 1 to < 12 months 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 between 6 to less than 12 years of age. The tezacaftor 100 mg/ivacaftor 150 mg and ivacaftor 150 mg dose has not 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 with adult patients.

During the 24-week, open-label phase 3 study in patients aged 6 to less than 12 years (study 661-113 part B, n = 70), the incidence of maximum transaminase (ALT or AST) > 8, > 5, and > 3 × ULN were 1.4%, 4.3%, and 10.0%, respectively. No tezacaftor/ivacaftor treated patients experienced a transaminase elevation > 3 × ULN associated with elevated total bilirubin > 2 × ULN or discontinued tezacaftor/ivacaftor treatment due to transaminase elevations. One patient interrupted treatment due to elevated transaminases, and subsequently resumed tezacaftor/ivacaftor treatment successfully (see section 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, 445-111, and 445-124 was evaluated in 272 patients between 2 to less than 18 years of 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. No ivacaftor/tezacaftor/elexacaftor-treated patients had transaminase elevation > 3 × ULN associated with elevated total bilirubin > 2 × ULN or discontinued treatment due to transaminase elevations (see section 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. No ivacaftor/tezacaftor/elexacaftor-treated patients had transaminase elevation > 3 × ULN associated with elevated total bilirubin > 2 × ULN or discontinued treatment due to transaminase elevations (see section 4.4).

Rash

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

Lenticular opacity

One patient had an adverse event of lenticular opacity.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

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 infection very common
Nasopharyngitis very common
Influenza* common
Rhinitis common
Metabolism and nutrition disorders
Hypoglycaemia* common
Psychiatric disorders
Depression not known
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

System organ class
Adverse reactions
Frequency
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* very common
Aspartate aminotransferase increased* common
Liver injury† not known
Total bilirubin increase† 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 increase) 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 770-102 and 770-103 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.

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

Rash events

In study 445-102, the incidence of rash events (e.g., rash, rash pruritic) was 10.9% in ivacaftor/tezacaftor/elexacaftor-treated patients and 6.5% in placebo-treated patients. The rash events were generally mild to moderate in severity. The incidence of rash events by patient sex was 5.8% in males and 16.3% in females in ivacaftor/tezacaftor/elexacaftor-treated patients and 4.8% in males and 8.3% 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% in females not taking hormonal contraceptive (see section 4.4).

Increased creatine phosphokinase

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

Increased blood pressure

In study 445-102, the maximum increase from baseline in mean systolic and diastolic blood pressure was 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 for placebo-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 in ivacaftor/tezacaftor/elexacaftor-treated patients compared with 3.5% and 3.5%, respectively in placebo-treated patients.

Paediatric population

Ivacaftor as monotherapy

Safety of ivacaftor as monotherapy for 24 weeks was evaluated in 43 patients between 1 month to less than 24 months of age (with 7 of them less than 4 months old), 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 1 month and older and is also consistent with adult patients.

The incidence of transaminase elevations (ALT or AST) observed in studies 770-103, 770-111 and 770-110 (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 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 770-108 ivacaftor was permanently discontinued in one patient. In study 770-124, in the cohort of patients aged 1 month to less than 4 months, a 1-month old (14.3%) patient had transaminase values of ALT > 8 × ULN and AST of > 3 to ≤ 5 × ULN, which led to discontinuation of ivacaftor treatment (see section 4.4 for management of elevated transaminases).

Table 5: Transaminase elevations in patients aged 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
15.0% (6)
2.5% (1)
2.5% (1)
2 to < 6 years
14.7% (5)
14.7% (5)
14.7% (5)
12 to < 24 months
27.8% (5)
11.1% (2)
11.1% (2)
1 to < 12 months
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 between 6 to less than 12 years of age. The tezacaftor 100 mg/ivacaftor 150 mg and ivacaftor 150 mg dose has not 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 with adult patients.

During the 24-week, open-label phase 3 study in patients aged 6 to less than 12 years (study 661-113 part B, n = 70), the incidence of maximum transaminase (ALT or AST) > 8, > 5, and > 3 × ULN were 1.4%, 4.3%, and 10.0%, respectively. No tezacaftor/ivacaftor-treated patients experienced a transaminase elevation > 3 × ULN associated with elevated total bilirubin > 2 × ULN or discontinued tezacaftor/ivacaftor treatment due to transaminase elevations. One patient interrupted treatment due to elevated transaminases, and subsequently resumed tezacaftor/ivacaftor treatment successfully (see section 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, 445-111, and 445-124 was evaluated in 272 patients between 2 to less than 18 years of 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. No ivacaftor/tezacaftor/elexacaftor-treated patients had transaminase elevation > 3 × ULN associated with elevated total bilirubin > 2 × ULN or discontinued treatment due to transaminase elevations (see section 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. No ivacaftor/tezacaftor/elexacaftor-treated patients had transaminase elevation > 3 × ULN associated with elevated total bilirubin > 2 × ULN or discontinued treatment due to transaminase elevations (see section 4.4).

Rash

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

Lenticular opacity

One patient had an adverse event of lenticular opacity.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

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.

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. 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 sections 4.2, 4.8, and 5.2).

Hepatic impairment

Use of ivacaftor, either as monotherapy or in a combination regimen with tezacaftor/ivacaftor, is not recommended in patients aged 6 years and older with severe hepatic impairment unless the benefits are expected to outweigh the risks. These patients should not be treated with ivacaftor in a combination regimen with ivacaftor/tezacaftor/elexacaftor (see Table 3 in section 4.2, and sections 4.8 and 5.2).

For patients aged 6 years and older 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 in section 4.2, and sections 4.8 and 5.2).

Depression

Depression (including suicidal ideation and suicide attempt) has been reported in patients while receiving ivacaftor, mainly in a combination regimen with tezacaftor/ivacaftor or ivacaftor/tezacaftor/elexacaftor, usually occurring within three months of treatment initiation and in patients with a history of psychiatric disorders. In some cases, symptom improvement was reported after dose reduction or treatment discontinuation. Patients (and caregivers) should be alerted about the need to monitor for depressed mood, suicidal thoughts, or unusual changes in behaviour and to seek medical advice immediately if these symptoms present.

Renal impairment

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

Mutations unlikely to respond to modulator therapy

Patients with a genotype consisting of two CFTR mutations that are known not to produce CFTR protein (i.e., two Class I mutations) are not expected to respond to CFTR modulator therapy.

Clinical studies comparing ivacaftor/tezacaftor/elexacaftor to tezacaftor/ivacaftor or ivacaftor

No clinical study has been conducted to directly compare ivacaftor/tezacaftor/elexacaftor to tezacaftor/ivacaftor or ivacaftor in patients not harbouring F508del variants.

Patients after organ transplantation

Ivacaftor has not been studied in patients with CF who have undergone organ transplantation.
Therefore, use in transplanted patients is not recommended. See section 4.5 for interactions with ciclosporin or tacrolimus.

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 by the concomitant use of CYP3A inducers, potentially resulting in the loss of ivacaftor efficacy; therefore, co-administration of ivacaftor with strong CYP3A inducers is not recommended (see section 4.5).

CYP3A inhibitors

Exposure to ivacaftor, tezacaftor and elexacaftor are increased when co-administered with strong or moderate CYP3A inhibitors. The dose of ivacaftor must be adjusted when used concomitantly with strong or moderate CYP3A inhibitors (see Table 2 in section 4.2 and section 4.5).

Paediatric population

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

Excipients with known effect

Lactose

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

Sodium

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

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

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 sections 4.2, 4.8, and 5.2).

Hepatic impairment

Use of ivacaftor as monotherapy is not recommended in patients aged 1 month to less than 6 months of age with any level of hepatic impairment. Use of ivacaftor as monotherapy is not recommended in patients aged 6 months and older weighing less than 25 kg 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 in section 4.2, and sections 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 in section 4.2, and sections 4.8 and 5.2).

Depression

Depression (including suicidal ideation and suicide attempt) has been reported in patients while receiving ivacaftor, mainly in a combination regimen with ivacaftor/tezacaftor/elexacaftor, usually occurring within three months of treatment initiation and in patients with a history of psychiatric disorders. In some cases, symptom improvement was reported after dose reduction or treatment discontinuation. Patients (and caregivers) should be alerted about the need to monitor for depressed mood, suicidal thoughts, or unusual changes in behaviour and to seek medical advice immediately if these symptoms present.

Renal impairment

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

Mutations unlikely to respond to modulator therapy

Patients with a genotype consisting of two CFTR mutations that are known not to produce CFTR protein (i.e., two Class I mutations) are not expected to respond to CFTR modulator therapy.

Clinical studies comparing ivacaftor/tezacaftor/elexacaftor to tezacaftor/ivacaftor or ivacaftor

No clinical study has been conducted to directly compare ivacaftor/tezacaftor/elexacaftor to tezacaftor/ivacaftor or ivacaftor in patients not harbouring F508del variant.

Patients after organ transplantation

Ivacaftor has not been studied in patients with CF who have undergone organ transplantation.
Therefore, use in transplanted patients is not recommended. See section 4.5 for interactions with ciclosporin or tacrolimus.

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 by the concomitant use of CYP3A inducers, potentially resulting in the loss of ivacaftor efficacy; therefore, co-administration of ivacaftor with strong CYP3A inducers is not recommended (see section 4.5).

CYP3A inhibitors

Exposure to ivacaftor is increased when co-administered with strong or moderate CYP3A inhibitors.
The dose of ivacaftor must be adjusted when used concomitantly with strong or moderate CYP3A inhibitors (see Table 2 in section 4.2 and section 4.5). Treatment with ivacaftor monotherapy is not recommended in patients aged 1 month to less than 6 months taking strong or moderate CYP3A inhibitors.

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 (see section 5.3).

Excipients with known effect

Lactose

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

Sodium

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.

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. No dose adjustment is required when ivacaftor is co-administered with ciprofloxacin.

Medicinal products affected by ivacaftor

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

CYP2C9 substrates

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

Digoxin and other P-gp substrates

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

CYP3A substrates

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

Hormonal contraceptives

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

Paediatric population

Interaction studies have only been performed in adults.

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

Medicinal products affected by ivacaftor

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

CYP2C9 substrates

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

Digoxin and other P-gp substrates

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

CYP3A substrates

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

Hormonal contraceptives

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

Paediatric population

Interaction studies have only been performed in adults.

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.

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).

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).

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.

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

5.
PHARMACOLOGICAL PROPERTIES

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

Mechanism of action

Ivacaftor as monotherapy

Ivacaftor is a potentiator of the CFTR protein, i.e., in vitro ivacaftor increases CFTR channel gating to enhance chloride transport in specified gating mutations (as listed in section 4.1) with reduced channel-open probability compared to normal CFTR. Ivacaftor also potentiated the channel-open probability of R117H-CFTR, which has both low channel-open probability (gating) and reduced channel current amplitude (conductance). The G970R mutation causes a splicing defect resulting in

little-to-no CFTR protein at the cell surface which may explain the results observed in subjects with this mutation in study 770-111 (see Pharmacodynamic effects and Clinical efficacy and safety).

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

Ivacaftor in a combination regimen with ivacaftor/tezacaftor/elexacaftor

Elexacaftor and tezacaftor are CFTR correctors that bind to different sites on the CFTR protein and have an additive effect in facilitating the cellular processing and trafficking of CFTR to increase the amount of CFTR protein delivered to the cell surface compared to either molecule alone. When ivacaftor is administered in combination with ivacaftor/tezacaftor/elexacaftor, the combined effect is increased quantity and function of CFTR at the cell surface, resulting in increased CFTR activity as measured by CFTR mediated chloride transport.

CFTR Chloride Transport Assay in Fischer Rat Thyroid (FRT) cells expressing mutant CFTR

The chloride transport response of mutant CFTR protein to ivacaftor/tezacaftor/elexacaftor was determined in Ussing chamber electrophysiology studies using a panel of FRT cell lines transfected with individual CFTR mutations. Ivacaftor/tezacaftor/elexacaftor increased chloride transport in FRT cells expressing select CFTR mutations.

The in vitro CFTR chloride transport response threshold was designated as a net increase of at least 10% of normal over baseline because it is predictive or reasonably expected to predict clinical response. For individual mutations, the magnitude of the net change over baseline in CFTR-mediated chloride transport in vitro is not correlated with the magnitude of clinical response.

In CF, the presence of one CFTR mutation responsive to ivacaftor/tezacaftor/elexacaftor based on in vitro data in FRT cells, will likely result in a clinical response.

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

Mechanism of action

Ivacaftor as monotherapy

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

In vitro responses seen in single channel patch clamp experiments using membrane patches from rodent cells expressing mutant CFTR forms do not necessarily correspond to in vivo pharmacodynamic response (e.g., sweat chloride) or clinical benefit. The exact mechanism leading ivacaftor to potentiate

the gating activity of normal and some mutant CFTR forms in this system has not been completely elucidated.

Ivacaftor in a combination regimen with ivacaftor/tezacaftor/elexacaftor

Elexacaftor and tezacaftor are CFTR correctors that bind to different sites on the CFTR protein and have an additive effect in facilitating the cellular processing and trafficking of CFTR to increase the amount of CFTR protein delivered to the cell surface compared to either molecule alone. When ivacaftor is administered in combination with ivacaftor/tezacaftor/elexacaftor, the combined effect is increased quantity and function of CFTR at the cell surface, resulting in increased CFTR activity as measured by CFTR mediated chloride transport.

CFTR Chloride Transport Assay in Fischer Rat Thyroid (FRT) cells expressing mutant CFTR

The chloride transport response of mutant CFTR protein to ivacaftor/tezacaftor/elexacaftor was determined in Ussing chamber electrophysiology studies using a panel of FRT cell lines transfected with individual CFTR mutations. Ivacaftor/tezacaftor/elexacaftor increased chloride transport in FRT cells expressing select CFTR mutations.

The in vitro CFTR chloride transport response threshold was designated as a net increase of at least 10% of normal over baseline because it is predictive or reasonably expected to predict clinical response. For individual mutations, the magnitude of the net change over baseline in CFTR mediated chloride transport in vitro is not correlated with the magnitude of clinical response.

In CF, the presence of one CFTR mutation responsive to ivacaftor/tezacaftor/elexacaftor based on in vitro data in FRT cells, will likely result in a clinical response.

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 every 12-hour dosing, steady-state plasma concentrations of ivacaftor were reached by days 3 to 5, with an accumulation ratio ranging from 2.2 to 2.9.

Absorption

Following multiple oral dose administrations of ivacaftor, the exposure of ivacaftor generally increased with dose from 25 mg every 12 hours to 450 mg every 12 hours. When given with fat- containing food, the exposure of ivacaftor increased approximately 2.5- to 4-fold. When co- administered with tezacaftor and elexacaftor, the increase in AUC was similar (approximately 3-fold and 2.5- to 4-fold respectively). Therefore, ivacaftor, administered as monotherapy or in a combination regimen with tezacaftor/ivacaftor or ivacaftor/tezacaftor/elexacaftor, should be administered with fat-containing food. The median (range) tmax is approximately 4.0 (3.0; 6.0) hours in the fed state.

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

the granules relative to tablets was 0.951 (0.839, 1.08) for AUC0-∞ and 0.918 (0.750, 1.12) for Cmax.
The effect of food on ivacaftor absorption is similar for both formulations, i.e., tablets and granules.

Distribution

Ivacaftor is approximately 99% bound to plasma proteins, primarily to alpha 1-acid glycoprotein and albumin. Ivacaftor does not bind to human red blood cells. After oral administration of ivacaftor 150 mg every 12 hours for 7 days in healthy volunteers in a fed state, the mean (± SD) apparent volume of distribution was 353 L (122).

Biotransformation

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 every 12-hour dosing, steady-state plasma concentrations of ivacaftor were reached by days 3 to 5, with an accumulation ratio ranging from 2.2 to 2.9.

Absorption

Following multiple oral dose administrations of ivacaftor, the exposure of ivacaftor generally increased with dose from 25 mg every 12 hours to 450 mg every 12 hours. When given with fat- containing food the exposure of ivacaftor increased approximately 2.5- to 4-fold. When co- administered with tezacaftor and elexacaftor, the increase in AUC was similar (approximately 3-fold and 2.5- to 4-fold, respectively). Therefore, ivacaftor, administered as monotherapy or in a combination regimen with ivacaftor/tezacaftor/elexacaftor, should be administered with fat-containing food. The median (range) tmax is approximately 4.0 (3.0; 6.0) hours in the fed state.

Ivacaftor granules (2 × 75 mg sachets) had similar bioavailability as the 150 mg tablet when given with fat-containing food to healthy adult subjects. The geometric least squares mean ratio (90% CI) for the granules relative to tablets was 0.951 (0.839, 1.08) for AUC0-∞ and 0.918 (0.750, 1.12) for Cmax.
The effect of food on ivacaftor absorption is similar for both formulations, i.e., tablets and granules.

Distribution

Ivacaftor is approximately 99% bound to plasma proteins, primarily to alpha 1-acid glycoprotein and albumin. Ivacaftor does not bind to human red blood cells. After oral administration of ivacaftor 150 mg every 12 hours for 7 days in healthy volunteers in a fed state, the mean (± SD) apparent volume of distribution was 353 L (122).

Biotransformation