Elexacaftor / Ivacaftor / Tezacaftor: prescribing information – dosing, contraindications, interactions, side effects

Kaftrio tablets are indicated in a combination regimen with ivacaftor for the treatment of cystic fibrosis (CF) in patients aged 6 years and older who have at least one non-Class I mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene (see sections 4.2 and 5.1).

Kaftrio granules are indicated in a combination regimen with ivacaftor 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 cystic fibrosis transmembrane conductance regulator (CFTR) gene (see sections 4.2 and 5.1).

Kaftrio should only be prescribed by healthcare professionals with experience in the treatment of CF. If the patient’s genotype is unknown, an accurate and validated genotyping method should be performed to confirm the presence of at least one CFTR mutation that is responsive based on clinical and/or in vitro data (using a genotype assay) (see section 5.1). Kaftrio should only be used in patients diagnosed with CF. A diagnosis of CF should be made based on diagnostic guidelines and clinical judgement.

There are a limited number of patients who harbour mutations not listed in Table 5 that may be responsive to Kaftrio. In these cases, Kaftrio 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).

Monitoring of transaminases (ALT and AST) and total bilirubin is recommended for all patients prior to initiating treatment, every 3 months during the first year of treatment and annually thereafter. For patients with a history of liver disease or transaminase elevations, more frequent monitoring should be considered (see section 4.4).

Posology

Adults and paediatric patients aged 6 years and older should be dosed according to Table 1.

Table 1: Dosing recommendations for patients aged 6 years and older
Age
Weight
Morning dose
Evening dose
6 to < 12 years
< 30 kg
Two ivacaftor 37.5 mg/tezacaftor
25 mg/elexacaftor 50 mg tablets
One ivacaftor 75 mg tablet
6 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 take the missed dose as soon as possible and continue on the original schedule.
If more than 6 hours have passed since:
- the missed morning dose, the patient should take the missed dose as soon as possible and should not take the evening dose. The next scheduled morning dose should be taken at the usual time.
OR
- the missed evening dose, the patient should not take the missed dose. The next scheduled morning dose should be taken at the usual time.
Morning and evening doses should not be taken at the same time.

Concomitant use of CYP3A inhibitors
When co-administered with moderate CYP3A inhibitors (e.g., fluconazole, erythromycin, verapamil) or strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, posaconazole, voriconazole, telithromycin, and clarithromycin), the dose should be reduced as in Table 2 (see sections 4.4 and 4.5).

Table 2: Dosing schedule for concomitant use with moderate and strong CYP3A inhibitors Age Weight Moderate CYP3A Inhibitors Strong CYP3A Inhibitors 6 to < 12 years < 30 kg Alternate each day:

• Two ivacaftor 37.5 mg/ tezacaftor 25 mg/elexacaftor
50 mg tablets on the first day
• One ivacaftor 75 mg tablet on the next day

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

No evening ivacaftor tablet dose.

6 to
< 12 years
≥ 30 kg
Alternate each day:

• Two ivacaftor 75 mg/ tezacaftor 50 mg/elexacaftor
100 mg tablets on the first day
• One ivacaftor 150 mg tablet on the next day

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

No evening ivacaftor tablet dose.
12 years and older
- Alternate each day:

• Two ivacaftor 75 mg/ tezacaftor 50 mg/elexacaftor
100 mg tablets on the first day
• One ivacaftor 150 mg tablet on the next day

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

No evening ivacaftor tablet dose.

Special populations

Elderly
No dose adjustment is recommended for the elderly patient population (see sections 4.4 and 5.2).

Hepatic impairment
Treatment of patients with moderate hepatic impairment (Child-Pugh Class B) is not recommended. For patients with moderate hepatic impairment, the use of Kaftrio 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).

Studies have not been conducted in patients with severe hepatic impairment (Child-Pugh Class C), but the exposure is expected to be higher than in patients with moderate hepatic impairment. Patients with severe hepatic impairment should not be treated with Kaftrio.

No dose adjustment is recommended for patients with mild (Child-Pugh Class A) hepatic impairment (see Table 3) (see sections 4.4, 4.8, and 5.2).

Table 3: Recommendation for use in patients aged 6 years and older with hepatic impairment Age Weight Mild (Child-Pugh Class A) Moderate (Child-Pugh Class B) Severe (Child-Pugh Class C) 6 to < 12 years < 30 kg No dose adjustment Use not recommended. Treatment of patients with moderate hepatic impairment should only be considered when there is a clear medical need, and the benefits are expected to outweigh the risks.

If used, Kaftrio should be used with caution at a reduced dose, as follows:

Should not be used

- Day 1: two ivacaftor 37.5 mg/ tezacaftor 25 mg/elexacaftor
50 mg tablets in the morning
- Day 2: one ivacaftor 37.5 mg/ tezacaftor 25 mg/elexacaftor
50 mg tablet in the morning

Continue alternating Day 1 and Day 2 dosing thereafter.

The evening dose of the ivacaftor tablet should not be taken.
6 to < 12 years
≥ 30 kg
No dose adjustment
Use not recommended. Treatment of patients with moderate hepatic impairment should only be considered when there is a clear medical need, and the benefits are expected to outweigh the risks.

If used, Kaftrio should be used with caution at a reduced dose, 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.

The evening dose of the ivacaftor tablet should not be taken.
Should not be used
12 years and older
- No dose adjustment
Use not recommended. Treatment of patients with moderate hepatic impairment should only be considered when there is a clear medical need, and the benefits are expected to outweigh the risks.

If used, Kaftrio should be used with caution at a reduced dose, 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.

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

Renal impairment
No dose adjustment is recommended for patients with mild and moderate renal impairment. There is no experience in patients with severe renal impairment or end-stage renal disease (see sections 4.4 and 5.2).

Paediatric population
The safety and efficacy of Kaftrio in combination with ivacaftor (IVA) in children aged less than 2 years have not yet been established. No data are available.

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; chewing or crushing the tablet is not recommended.

Kaftrio should be taken with fat-containing food. Examples of meals or snacks that contain fat are those prepared with butter or oils or those containing eggs, cheeses, nuts, whole milk, or meats (see section 5.2).

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

Kaftrio should only be prescribed by healthcare professionals with experience in the treatment of CF. If the patient’s genotype is unknown, an accurate and validated genotyping method should be performed to confirm the presence of at least one CFTR mutation that is responsive based on clinical and/or in vitro data (using a genotype assay) (see section 5.1). Kaftrio should only be used in patients diagnosed with CF. A diagnosis of CF should be made based on diagnostic guidelines and clinical judgement.

There are a limited number of patients who harbour mutations not listed in Table 5 that may be responsive to Kaftrio. In these cases, Kaftrio 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).

Monitoring of transaminases (ALT and AST) and total bilirubin is recommended for all patients prior to initiating treatment, every 3 months during the first year of treatment and annually thereafter. For patients with a history of liver disease or transaminase elevations, more frequent monitoring should be considered (see section 4.4).

Posology

Paediatric patients aged 2 to less than 6 years should be dosed according to Table 1.

Table 1: Dosing recommendations for patients aged 2 to less than 6 years
Age
Weight
Morning dose
Evening dose
2 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 take the missed dose as soon as possible and continue on the original schedule.
If more than 6 hours have passed since:
- the missed morning dose, the patient should take the missed dose as soon as possible and should not take the evening dose. The next scheduled morning dose should be taken at the usual time.
OR
- the missed evening dose, the patient should not take the missed dose. The next scheduled morning dose should be taken at the usual time.
Morning and evening doses should not be taken at the same time.

Concomitant use of CYP3A inhibitors
When co-administered with moderate CYP3A inhibitors (e.g., fluconazole, erythromycin, verapamil) or strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, posaconazole, voriconazole, telithromycin, and clarithromycin), the dose should be reduced as in Table 2 (see sections 4.4 and 4.5).

Table 2: Dosing schedule for concomitant use with moderate and strong CYP3A inhibitors Age Weight Moderate CYP3A Inhibitors Strong CYP3A Inhibitors 2 years to less than 6 years 10 kg to < 14 kg Alternate each day:

• One sachet of ivacaftor 60 mg/ tezacaftor 40 mg/elexacaftor
80 mg granules on the first day
• One sachet of ivacaftor 59.5 mg granules on the next day

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

No evening sachet of ivacaftor granules.

No evening sachet of ivacaftor granules.
2 years to less than
6 years
≥ 14 kg
Alternate each day:

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

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

No evening sachet of ivacaftor granules.

Special populations

Hepatic impairment
Treatment of patients aged 2 to less than 6 years with moderate hepatic impairment (Child-Pugh Class B) is not recommended. For patients aged 2 to less than 6 years with moderate hepatic impairment, the use of Kaftrio 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).

Studies have not been conducted in patients with severe hepatic impairment (Child-Pugh Class C), but the exposure is expected to be higher than in patients with moderate hepatic impairment. Patients with severe hepatic impairment should not be treated with Kaftrio.

No dose adjustment is recommended for patients with mild (Child-Pugh Class A) hepatic impairment (see Table 3) (see sections 4.4, 4.8, and 5.2).

Table 3: Recommendation for use in patients aged 2 to less than 6 years with hepatic impairment Age Weight Mild (Child-Pug h Class A) Moderate (Child-Pugh Class B) Severe (Child-Pugh Class C) 2 years to less than 6 years 10 kg to < 14 kg No dose adjustment Use not recommended. Treatment of patients with moderate hepatic impairment should only be considered when there is a clear medical need, and the benefits are expected to outweigh the risks.

If used, Kaftrio should be used with caution at a reduced dose, as follows:

• Days 1-3: one sachet of ivacaftor 60 mg/ tezacaftor 40 mg/elexacaftor 80 mg granules each day
• Day 4: no dose
• Days 5-6: one sachet of ivacaftor 60 mg/ tezacaftor 40 mg/elexacaftor 80 mg granules each day
• Day 7: no dose

Repeat above dosing schedule each week.
Should not be used

The evening dose of the ivacaftor granules should not be taken.
2 years to less than
6 years
≥ 14 kg
No dose adjustment
Use not recommended. Treatment of patients with moderate hepatic impairment should only be considered when there is a clear medical need, and the benefits are expected to outweigh the risks.

If used, Kaftrio should be used with caution at a reduced dose, as follows:

• Days 1-3: one sachet of ivacaftor 75 mg/ tezacaftor 50 mg/elexacaftor 100 mg granules each day
• Day 4: no dose
• Days 5-6: one sachet of ivacaftor 75 mg/ tezacaftor 50 mg/elexacaftor 100 mg granules each day
• Day 7: no dose

Repeat above dosing schedule each week.

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

Renal impairment
No dose adjustment is recommended for patients with mild and moderate renal impairment. There is no experience in patients with severe renal impairment or end-stage renal disease (see sections 4.4 and 5.2).

Paediatric population

The safety and efficacy of Kaftrio in combination with ivacaftor (IVA) in children aged less than 2 years have not yet been established. No data are available.

Method of administration

For oral use. The entire contents of each sachet of granules should be mixed with one teaspoon (5 mL) of age-appropriate soft food or liquid and the mixture completely consumed. Food or liquid should be at room temperature or below. Each sachet is for single use only. Once mixed, the product has been shown to be stable for one hour, and therefore should be ingested during this period. Some examples of soft food or liquids include pureed fruits or vegetables, yogurt, water, milk, or juice. A fat-containing meal or snack should be consumed just before or after dosing.

Kaftrio should be taken with fat-containing food. Examples of meals or snacks that contain fat are those prepared with butter or oils or those containing eggs, cheeses, nuts, whole milk, or meats (see section 5.2).

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

Hypersensitivity to the active substance(s) 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 12 years and older who received IVA/TEZ/ELX in combination with IVA were headache (17.3%), diarrhoea (12.9%), upper respiratory tract infection (11.9%) and aminotransferase increased (10.9%).

Serious adverse reactions of rash experienced by patients aged 12 years and older were reported in 1.5% patients treated with IVA/TEZ/ELX in combination with IVA (see section 4.4).

Tabulated list of adverse reactions

Table 4 reflects adverse reactions observed with IVA/TEZ/ELX in combination with IVA, TEZ/IVA in combination with IVA, and IVA monotherapy. Adverse reactions are listed by MedDRA system organ class and frequency: 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 the order of decreasing seriousness.

Table 4: Adverse reactions
MedDRA System Organ Class
Adverse Reactions
Frequency
Infections and infestations
Upper respiratory tract infection*,
Nasopharyngitis very common
Rhinitis*, Influenza* common
Immune system disorders
Hypersensitivity not known
Metabolism and nutrition disorders
Hypoglycaemia* common
Psychiatric disorders
Depression, Behavioural changes not known
Nervous system disorders
Headache*, Dizziness* very common
Ear and labyrinth disorders
Ear pain, Ear discomfort, Tinnitus,
Tympanic membrane hyperaemia,
Vestibular disorder common
Ear congestion uncommon
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain, Nasal congestion* very common
Rhinorrhoea*, Sinus congestion,
Pharyngeal erythema, Abnormal breathing* common
Wheezing* uncommon
Gastrointestinal disorders
Diarrhoea*, Abdominal pain* very common
Nausea, Abdominal pain upper*,
Flatulence* common
Hepatobiliary disorders
Transaminase elevations very common
Alanine aminotransferase increased* very common
Aspartate aminotransferase increased* very common
Liver injury†, Total bilirubin increase† not known
Skin and subcutaneous tissue disorders
Rash* very common
Acne*, Pruritus* common
Reproductive system and breast disorders
Breast mass common
Breast inflammation, Gynaecomastia,
Nipple disorder, Nipple pain uncommon
Investigations
Bacteria in sputum, Blood creatine phosphokinase increased* very common
Blood pressure increased* uncommon
*Adverse reactions observed during clinical studies with IVA/TEZ/ELX in combination with IVA.
† Liver injury (ALT and AST and total bilirubin increase) reported from post-marketing data with IVA/TEZ/ELX in combination with IVA. Frequency cannot be estimated from the available data.

Safety data from the following studies were consistent with the safety data observed in study 445-102.
- A 4-week, randomised, double-blind, active-controlled study in 107 patients aged 12 years and older (study 445-103).
- A 192-week, open-label safety and efficacy study (study 445-105) in 506 patients who rolled over from studies 445-102 and 445-103.
- An 8-week, randomised, double-blind, active-controlled study in 258 patients aged 12 years and older (study 445-104).
- A 24-week, open-label study (study 445-106) in 66 patients aged 6 to less than 12 years.
- A 24-week, randomised, placebo-controlled study (study 445-116) in 121 patients aged 6 to less than 12 years.

• A 192-week, two-part (part A and part B), open-label safety and efficacy study (study 445-107) in 64 patients aged 6 years and older who rolled over from study 445-106.
• A 24-week, open-label study (study 445-111) in 75 patients aged 2 to less than 6 years.
• A 24-week, randomised, double-blind, placebo-controlled study (study 445-124) in 307 patients aged 6 years and older.

Description of selected adverse reactions

Transaminase elevations
In study 445-102, the incidence of maximum transaminase (ALT or AST) > 8, > 5, or > 3 × the ULN was 1.5%, 2.5% and 7.9% in IVA/TEZ/ELX-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 IVA/TEZ/ELX-treated patients and 4.0% in placebo-treated patients.

During the open-label studies, some patients discontinued treatment due to elevated transaminases. Post- marketing cases of treatment discontinuation due to elevated transaminases have been reported (see section 4.4).

Rash events
Studies in IVA/TEZ/ELX-treated patients above 12 years of age showed an incidence of rash events (e.g., rash, rash pruritic) of 10.9% (study 445-102) compared to 6.5% in placebo-treated patients. The paediatric population showed a higher incidence rate (see section Paediatric population for further details). The incidence of rash events by patient sex was 5.8% in males and 16.3% in females in IVA/TEZ/ELX-treated patients and 4.8% in males and 8.3% in females in placebo-treated patients. In patients treated with IVA/TEZ/ELX, 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).

Overall, rash events typically occur during the first month of therapy. Most events were mild to moderate in severity, and in rare cases, rash was associated with additional symptoms such as fever or facial swelling. In the majority of cases, administration of IVA/TEZ/ELX was continued and the rash resolved without treatment.

Increased creatine phosphokinase
In study 445-102, the incidence of maximum creatine phosphokinase >5 × the ULN was 10.4% in IVA/TEZ/ELX- and 5.0% in placebo-treated patients. The observed creatine phosphokinase elevations were generally transient and asymptomatic and many were preceded by exercise.

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 IVA/TEZ/ELX-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 IVA/TEZ/ELX-treated patients compared with 3.5% and 3.5%, respectively in placebo-treated patients.

Paediatric population

The safety data of IVA/TEZ/ELX in combination with IVA in studies 445-102, 445-103, 445-104, 445-106, 445-111, and 445-124 and 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 IVA/TEZ/ELX-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 IVA/TEZ/ELX-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
While studies in patients above 12 years of age showed an incidence rate of 10.9% (study 445-102), patients between 6 and 11 years of age had an incidence rate of 24.2% (study 445-106). 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.

Behavioural changes
Most cases of behavioural changes have been reported in younger children aged 2-5 years.

Other special populations

With the exception of sex differences in rash, the safety profile of IVA/TEZ/ELX in combination with IVA was generally similar across all subgroups of patients, including analysis by age, baseline percent predicted forced expiratory volume in one second (ppFEV1) and geographic regions.

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 12 years and older who received IVA/TEZ/ELX in combination with IVA were headache (17.3%), diarrhoea (12.9%), upper respiratory tract infection (11.9%) and aminotransferase increased (10.9%).

Serious adverse reactions of rash experienced by patients aged 12 years and older were reported in 1.5% patients treated with IVA/TEZ/ELX in combination with IVA (see section 4.4).

Tabulated list of adverse reactions

Table 4 reflects adverse reactions observed with IVA/TEZ/ELX in combination with IVA, TEZ/IVA in combination with IVA, and IVA monotherapy. Adverse reactions are listed by MedDRA system organ class and frequency: 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 the order of decreasing seriousness.

Table 4: Adverse reactions
MedDRA System Organ Class
Adverse Reactions
Frequency
Infections and infestations
Upper respiratory tract infection*,
Nasopharyngitis very common
Rhinitis*, Influenza* common
Immune system disorders
Hypersensitivity not known
Metabolism and nutrition disorders
Hypoglycaemia* common
Psychiatric disorders
Depression, Behavioural changes not known
Nervous system disorders
Headache*, Dizziness* very common
Ear and labyrinth disorders
Ear pain, Ear discomfort, Tinnitus,
Tympanic membrane hyperaemia,
Vestibular disorder common
Ear congestion uncommon
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain, Nasal congestion* very common
Rhinorrhoea*, Sinus congestion,
Pharyngeal erythema, Abnormal breathing* common
Wheezing* uncommon
Gastrointestinal disorders
Diarrhoea*, Abdominal pain* very common
Nausea, Abdominal pain upper*,
Flatulence* common
Hepatobiliary disorders
Transaminase elevations very common
Alanine aminotransferase increased* very common
Aspartate aminotransferase increased* very common
Liver injury†, Total bilirubin increase† not known
Skin and subcutaneous tissue disorders
Rash* very common
Acne*, Pruritus* common
Reproductive system and breast disorders
Breast mass common
Breast inflammation, Gynaecomastia,
Nipple disorder, Nipple pain uncommon
Investigations
Bacteria in sputum, Blood creatine phosphokinase increased* very common
Blood pressure increased* uncommon
*Adverse reactions observed during clinical studies with IVA/TEZ/ELX in combination with IVA.
†Liver injury (ALT and AST and total bilirubin increase) reported from post-marketing data with IVA/TEZ/ELX in combination with IVA. Frequency cannot be estimated from the available data.

Safety data from the following studies were consistent with the safety data observed in study 445-102.
- A 4-week, randomised, double-blind, active-controlled study in 107 patients aged 12 years and older (study 445-103).
- A 192-week, open-label safety and efficacy study (study 445-105) in 506 patients who rolled over from studies 445-102 and 445-103.
- An 8-week, randomised, double-blind, active-controlled study in 258 patients aged 12 years and older (study 445-104).
- A 24-week, open-label study (study 445-106) in 66 patients aged 6 to less than 12 years.
- A 24-week, randomised, placebo-controlled study (study 445-116) in 121 patients aged 6 to less than 12 years.

• A 192-week, two-part (part A and part B), open-label safety and efficacy study (study 445-107) in 64 patients aged 6 years and older who rolled over from study 445-106.
• A 24-week, open-label study (study 445-111) in 75 patients aged 2 to less than 6 years.
• A 24-week, randomised, double-blind, placebo-controlled study (study 445-124) in 307 patients aged 6 years and older.

Description of selected adverse reactions

Transaminase elevations
In study 445-102, the incidence of maximum transaminase (ALT or AST) >8, >5, or >3 × the ULN was 1.5%, 2.5% and 7.9% in IVA/TEZ/ELX-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 IVA/TEZ/ELX-treated patients and 4.0% in placebo-treated patients.

During the open-label studies, some patients discontinued treatment due to elevated transaminases. Post- marketing cases of treatment discontinuation due to elevated transaminases have been reported (see section 4.4).

Rash events
Studies in IVA/TEZ/ELX-treated patients above 12 years of age showed an incidence of rash events (e.g., rash, rash pruritic) of 10.9% (study 445-102) compared to 6.5% in placebo-treated patients. The paediatric population showed a higher incidence rate (see section Paediatric population for further details). The incidence of rash events by patient sex was 5.8% in males and 16.3% in females in IVA/TEZ/ELX-treated patients and 4.8% in males and 8.3% in females in placebo-treated patients. In patients treated with IVA/TEZ/ELX, 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).

Overall, rash events typically occur during the first month of therapy. Most events were mild to moderate in severity, and in rare cases, rash was associated with additional symptoms such as fever or facial swelling. In the majority of cases, administration of IVA/TEZ/ELX was continued and the rash resolved without treatment.

Increased creatine phosphokinase
In study 445-102, the incidence of maximum creatine phosphokinase >5 × the ULN was 10.4% in IVA/TEZ/ELX- and 5.0% in placebo-treated patients. The observed creatine phosphokinase elevations were generally transient and asymptomatic and many were preceded by exercise.

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 IVA/TEZ/ELX-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 IVA/TEZ/ELX-treated patients compared with 3.5% and 3.5%, respectively in placebo-treated patients.

Paediatric population

The safety data of IVA/TEZ/ELX in combination with IVA in studies 445-102, 445-103, 445-104, 445- 106, 445-111, and 445-124 and 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 IVA/TEZ/ELX-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 IVA/TEZ/ELX-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
While studies in patients above 12 years of age showed an incidence rate of 10.9% (study 445-102), patients between 6 and 11 years of age had an incidence rate of 24.2% (study 445-106). 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.

Behavioural changes
Most cases of behavioural changes have been reported in younger children aged 2-5 years.

Other special populations

With the exception of sex differences in rash, the safety profile of IVA/TEZ/ELX in combination with IVA was generally similar across all subgroups of patients, including analysis by age, baseline percent predicted forced expiratory volume in one second (ppFEV1) and geographic regions.

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.

Elevated transaminases and hepatic injury

Cases of liver failure leading to transplantation have been reported within the first 6 months of treatment in patients with and without pre-existing advanced liver disease. Elevated transaminases are common in patients with CF. In clinical studies, elevated transaminases were more frequently observed in patients treated with IVA/TEZ/ELX in combination with IVA compared to placebo. In patients taking IVA/TEZ/ELX in combination with IVA, these elevations have sometimes been associated with concomitant elevations in total bilirubin. Assessments of transaminases (ALT and AST) and total bilirubin are recommended for all patients prior to initiating treatment, every 3 months during the first year of treatment and annually thereafter (see section 4.2).

For patients with a history of liver disease or transaminase elevations, more frequent monitoring should be considered.

Interrupt treatment and promptly measure serum transaminases and total bilirubin if a patient develops clinical signs or symptoms of liver injury. Interrupt dosing in the event of ALT or AST >5 × the upper limit of normal (ULN), or ALT or AST >3 × ULN with total bilirubin >2 × ULN. Closely monitor the

laboratory tests until the abnormalities resolve. Following resolution, consider the benefits and risks of resuming treatment. Patients who resume treatment after interruption should be monitored closely.

In patients with pre-existing advanced liver disease, IVA/TEZ/ELX in combination with IVA should be used with caution and only if the benefits are expected to outweigh the risks (see sections 4.2, 4.8, and 5.2).

Hepatic impairment

Treatment of patients with moderate hepatic impairment is not recommended. For patients with moderate hepatic impairment, the use of IVA/TEZ/ELX 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).

Patients with severe hepatic impairment should not be treated with IVA/TEZ/ELX (see sections 4.2, 4.8, and 5.2).

Depression

Depression (including suicidal ideation and suicide attempt) has been reported in patients treated with IVA/TEZ/ELX, usually occurring within three months of treatment initiation and in patients with a history of psychiatric disorders (see section 4.8). 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, unusual changes in behaviour, anxiety, or insomnia and to seek medical advice immediately if these symptoms present.

Paediatric population
In young children (aged 2-5 years) treated with IVA/TEZ/ELX behavioural changes have been reported, which occurred usually within the first two months of treatment initiation. In some cases, symptom improvement was reported after treatment discontinuation.

Renal impairment

There is no experience in patients with severe renal impairment/end-stage renal disease therefore caution is recommended in this population (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 Kaftrio treatment.

Clinical studies comparing IVA/TEZ/ELX to TEZ/IVA or IVA

No clinical study has been conducted to directly compare IVA/TEZ/ELX to TEZ/IVA or IVA in patients not harbouring F508del variants.

Patients after organ transplantation

IVA/TEZ/ELX in combination with IVA 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 commonly used immunosuppressants.

Rash events

Rash events typically occur during the first month of therapy. Most events were mild to moderate in severity and in rare cases, rash was associated with additional symptoms such as fever or facial swelling.
In the majority of cases, administration of IVA/TEZ/ELX was continued and the rash resolved without treatment. Children have a higher incidence rate compared to adults. The incidence of rash events was also higher in females compared to males, particularly in females taking hormonal contraceptives (see section 4.8). A role for hormonal contraceptives in the occurrence of rash cannot be excluded. For patients taking hormonal contraceptives who develop rash, interrupting treatment with IVA/TEZ/ELX in combination with IVA and hormonal contraceptives should be considered. Following the resolution of rash, it should be considered if resuming IVA/TEZ/ELX in combination with IVA without hormonal contraceptives is appropriate. If rash does not recur, resumption of hormonal contraceptives can be considered (see section 4.8).

Elderly

Clinical studies of IVA/TEZ/ELX in combination with IVA did not include sufficient number of patients aged 65 years and older to determine whether response in these patients is different from younger adults.
Dose recommendations are based on the pharmacokinetic profile and knowledge from studies with tezacaftor/ivacaftor (TEZ/IVA) in combination with IVA, and IVA monotherapy (see sections 4.2 and 5.2).

Interactions with medicinal products

CYP3A inducers
Exposure to IVA is significantly decreased and exposures to ELX and TEZ are expected to decrease by the concomitant use of CYP3A inducers, potentially resulting in the reduced efficacy of IVA/TEZ/ELX and IVA; therefore, co-administration with strong CYP3A inducers is not recommended (see section 4.5).

CYP3A inhibitors
Exposures of ELX, TEZ and IVA are increased when co-administered with strong or moderate CYP3A inhibitors. The dose of IVA/TEZ/ELX and IVA should be adjusted when used concomitantly with strong or moderate CYP3A inhibitors (see section 4.5 and Table 2 in section 4.2).

Cataracts

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

Excipients with known effect

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

Elevated transaminases and hepatic injury

Cases of liver failure leading to transplantation have been reported within the first 6 months of treatment in patients with and without pre-existing advanced liver disease.

Elevated transaminases are common in patients with CF. In clinical studies, elevated transaminases were more frequently observed in patients treated with IVA/TEZ/ELX in combination with IVA compared to placebo. In patients taking IVA/TEZ/ELX in combination with IVA, these elevations have sometimes been associated with concomitant elevations in total bilirubin. Assessments of transaminases (ALT and AST) and total bilirubin are recommended for all patients prior to initiating treatment, every 3 months during the first year of treatment and annually thereafter (see section 4.2).

For patients with a history of liver disease or transaminase elevations, more frequent monitoring should be considered.

Interrupt treatment and promptly measure serum transaminases and total bilirubin if a patient develops clinical signs or symptoms of liver injury. Interrupt dosing in the event of ALT or AST >5 × the upper limit of normal (ULN), or ALT or AST >3 × ULN with total bilirubin >2 × ULN. Closely monitor the laboratory tests until the abnormalities resolve. Following resolution, consider the benefits and risks of resuming treatment. Patients who resume treatment after interruption should be monitored closely.

In patients with pre-existing advanced liver disease, IVA/TEZ/ELX in combination with IVA should be used with caution and only if the benefits are expected to outweigh the risks (see sections 4.2, 4.8, and 5.2).

Hepatic impairment

Treatment of patients with moderate hepatic impairment is not recommended. For patients with moderate hepatic impairment, the use of IVA/TEZ/ELX 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).

Patients with severe hepatic impairment should not be treated with IVA/TEZ/ELX (see sections 4.2, 4.8, and 5.2).

Depression

Depression (including suicidal ideation and suicide attempt) has been reported in patients treated with IVA/TEZ/ELX, usually occurring within three months of treatment initiation and in patients with a history of psychiatric disorders (see section 4.8). 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, unusual changes in behaviour, anxiety, or insomnia and to seek medical advice immediately if these symptoms present.

Paediatric population
In young children (aged 2-5 years) treated with IVA/TEZ/ELX behavioural changes have been reported, which occurred usually within the first two months of treatment initiation. In some cases, symptom improvement was reported after treatment discontinuation.

Renal impairment

There is no experience in patients with severe renal impairment/end-stage renal disease therefore caution is recommended in this population (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 Kaftrio treatment.

Clinical studies comparing IVA/TEZ/ELX to TEZ/IVA or IVA

No clinical study has been conducted to directly compare IVA/TEZ/ELX to TEZ/IVA or IVA in patients not harbouring F508del variants.

Patients after organ transplantation

IVA/TEZ/ELX in combination with IVA 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 commonly used immunosuppressants.

Rash events

Rash events typically occur during the first month of therapy. Most events were mild to moderate in severity and in rare cases, rash was associated with additional symptoms such as fever or facial swelling.
In the majority of cases, administration of IVA/TEZ/ELX was continued and the rash resolved without treatment. Children have a higher incidence rate compared to adults. The incidence of rash events was also higher in females compared to males, particularly in females taking hormonal contraceptives (see section 4.8). A role for hormonal contraceptives in the occurrence of rash cannot be excluded. For patients taking hormonal contraceptives who develop rash, interrupting treatment with IVA/TEZ/ELX in combination with IVA and hormonal contraceptives should be considered. Following the resolution of rash, it should be considered if resuming IVA/TEZ/ELX in combination with IVA without hormonal contraceptives is appropriate. If rash does not recur, resumption of hormonal contraceptives can be considered (see section 4.8).

Elderly

Clinical studies of IVA/TEZ/ELX in combination with IVA did not include sufficient number of patients aged 65 years and older to determine whether response in these patients is different from younger adults.
Dose recommendations are based on the pharmacokinetic profile and knowledge from studies with tezacaftor/ivacaftor (TEZ/IVA) in combination with IVA, and IVA monotherapy (see section 5.2).

Interactions with medicinal products

CYP3A inducers
Exposure to IVA is significantly decreased and exposures to ELX and TEZ are expected to decrease by the concomitant use of CYP3A inducers, potentially resulting in the reduced efficacy of IVA/TEZ/ELX and IVA; therefore, co-administration with strong CYP3A inducers is not recommended (see section 4.5).

CYP3A inhibitors
Exposures of ELX, TEZ and IVA are increased when co-administered with strong or moderate CYP3A inhibitors. The dose of IVA/TEZ/ELX and IVA should be adjusted when used concomitantly with strong or moderate CYP3A inhibitors (see section 4.5 and Table 2 in section 4.2).

Cataracts

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

Medicinal products affecting the pharmacokinetics of ELX, TEZ and/or IVA

CYP3A inducers
ELX, TEZ and IVA are substrates of CYP3A (IVA is a sensitive substrate of CYP3A). Concomitant use of strong CYP3A inducers may result in reduced exposures and thus reduced IVA/TEZ/ELX efficacy.
Co-administration of IVA with rifampicin, a strong CYP3A inducer, significantly decreased IVA area under the curve (AUC) by 89%. ELX and TEZ exposures are also expected to decrease during co-administration with strong CYP3A inducers; therefore, co-administration with strong CYP3A inducers is not recommended (see section 4.4).

Examples of strong CYP3A inducers include:
- rifampicin, rifabutin, phenobarbital, carbamazepine, phenytoin and St. John’s wort (Hypericum perforatum)

CYP3A inhibitors
Co-administration with itraconazole, a strong CYP3A inhibitor, increased ELX AUC by 2.8-fold and TEZ AUC by 4.0- to 4.5-fold. When co-administered with itraconazole and ketoconazole, IVA AUC increased by 15.6-fold and 8.5-fold, respectively. The dose of IVA/TEZ/ELX and IVA should be reduced when co-administered with strong CYP3A inhibitors (see Table 2 in section 4.2 and section 4.4).

Examples of strong CYP3A inhibitors include:
- ketoconazole, itraconazole, posaconazole and voriconazole
- telithromycin and clarithromycin

Simulations indicated that co-administration with moderate CYP3A inhibitors fluconazole, erythromycin and verapamil, may increase ELX and TEZ AUC by approximately 1.9- to 2.3-fold. Co-administration of fluconazole increased IVA AUC by 2.9-fold. The dose of IVA/TEZ/ELX and IVA should be reduced when co-administered with moderate CYP3A inhibitors (see Table 2 in section 4.2 and section 4.4).

Examples of moderate CYP3A inhibitors include:
- fluconazole
- erythromycin

Co-administration with grapefruit juice, which contains one or more components that moderately inhibit CYP3A, may increase exposure of ELX, TEZ and IVA. Food or drink containing grapefruit should be avoided during treatment with IVA/TEZ/ELX and IVA (see section 4.2).

Ciprofloxacin
ELX/TEZ/IVA was not evaluated for concomitant use with ciprofloxacin. However, ciprofloxacin had no clinically relevant effect on the exposure of TEZ or IVA and is not expected to have a clinically relevant effect on the exposure of ELX. Therefore, no dose adjustment is necessary during concomitant administration of IVA/TEZ/ELX with ciprofloxacin.

Potential for interaction with transporters
In vitro studies showed that ELX is a substrate for the efflux transporters P-gp and Breast Cancer Resistance Protein (BCRP) but is not a substrate for OATP1B1 or OATP1B3. Exposure to ELX is not expected to be affected significantly by concomitant use of P-gp and BCRP inhibitors due to its high intrinsic permeability and low likelihood of being excreted intact.

In vitro studies showed that TEZ is a substrate for the uptake transporter OATP1B1 and efflux transporters P-gp and BCRP. TEZ is not a substrate for OATP1B3. Exposure to TEZ is not expected to be affected significantly by concomitant inhibitors of OATP1B1, P-gp, or BCRP due to its high intrinsic permeability and low likelihood of being excreted intact. However, exposure to M2-TEZ (TEZ metabolite) may be increased by inhibitors of P-gp. Therefore, caution should be used when P-gp inhibitors (e.g., ciclosporin) are used with IVA/TEZ/ELX.

In vitro studies showed that IVA is not a substrate for OATP1B1, OATP1B3, or P-gp. IVA 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 IVA and M1-IVA, while any potential changes in M6-IVA exposures are not expected to be clinically relevant.

Medicinal products affected by ELX, TEZ and/or IVA

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

Potential for interaction with transporters
Co-administration of IVA or TEZ/IVA with digoxin, a sensitive P-gp substrate, increased digoxin AUC by 1.3-fold, consistent with weak inhibition of P-gp by IVA. Administration of IVA/TEZ/ELX and IVA 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 and tacrolimus, caution and appropriate monitoring should be used.

ELX and M23-ELX inhibit uptake by OATP1B1 and OATP1B3 in vitro. TEZ/IVA increased the AUC of pitavastatin, an OATP1B1 substrate, by 1.2-fold. Co-administration with IVA/TEZ/ELX in combination with IVA may increase exposures of medicinal products that are substrates of these transporters, such as statins, glyburide, nateglinide and repaglinide. When used concomitantly with substrates of OATP1B1 or OATP1B3, caution and appropriate monitoring should be used. Bilirubin is an OATP1B1 and OATP1B3 substrate. In study 445-102, mild increases in mean total bilirubin were observed (up to 4.0 µmol/L change from baseline). This finding is consistent with the in vitro inhibition of bilirubin transporters OATP1B1 and OATP1B3 by ELX and M23-ELX.

ELX and IVA are inhibitors of BCRP. Co-administration of IVA/TEZ/ELX, and IVA may increase exposures of medicinal products that are substrates of BCRP, such as rosuvastatin. When used concomitantly with substrates of BCRP, appropriate monitoring should be used.

Hormonal contraceptives

IVA/TEZ/ELX in combination with IVA has been studied with ethinyl estradiol/levonorgestrel and was found to have no clinically relevant effect on the exposures of the oral contraceptive. IVA/TEZ/ELX and IVA is not expected to have an impact on the efficacy of oral contraceptives.

Paediatric population

Interaction studies have only been performed in adults.

Medicinal products affecting the pharmacokinetics of ELX, TEZ and/or IVA

CYP3A inducers
ELX, TEZ and IVA are substrates of CYP3A (IVA is a sensitive substrate of CYP3A). Concomitant use of strong CYP3A inducers may result in reduced exposures and thus reduced IVA/TEZ/ELX efficacy.
Co-administration of IVA with rifampicin, a strong CYP3A inducer, significantly decreased IVA area under the curve (AUC) by 89%. ELX and TEZ exposures are also expected to decrease during co-administration with strong CYP3A inducers; therefore, co-administration with strong CYP3A inducers is not recommended (see section 4.4).

Examples of strong CYP3A inducers include:
- rifampicin, rifabutin, phenobarbital, carbamazepine, phenytoin and St. John’s wort (Hypericum perforatum)

CYP3A inhibitors
Co-administration with itraconazole, a strong CYP3A inhibitor, increased ELX AUC by 2.8-fold and TEZ AUC by 4.0- to 4.5-fold. When co-administered with itraconazole and ketoconazole, IVA AUC increased by 15.6-fold and 8.5-fold, respectively. The dose of IVA/TEZ/ELX and IVA should be reduced when co- administered with strong CYP3A inhibitors (see Table 2 in section 4.2 and section 4.4).

Examples of strong CYP3A inhibitors include:

• ketoconazole, itraconazole, posaconazole and voriconazole
• telithromycin and clarithromycin

Simulations indicated that co-administration with moderate CYP3A inhibitors fluconazole, erythromycin and verapamil, may increase ELX and TEZ AUC by approximately 1.9- to 2.3-fold. Co-administration of fluconazole increased IVA AUC by 2.9-fold. The dose of IVA/TEZ/ELX and IVA should be reduced when co-administered with moderate CYP3A inhibitors (see Table 2 in section 4.2 and section 4.4).

Examples of moderate CYP3A inhibitors include:
- fluconazole
- erythromycin

Co-administration with grapefruit juice, which contains one or more components that moderately inhibit CYP3A, may increase exposure of ELX, TEZ and IVA. Food or drink containing grapefruit should be avoided during treatment with IVA/TEZ/ELX and IVA (see section 4.2).

Ciprofloxacin
ELX/TEZ/IVA was not evaluated for concomitant use with ciprofloxacin. However, ciprofloxacin had no clinically relevant effect on the exposure of TEZ or IVA and is not expected to have a clinically relevant effect on the exposure of ELX. Therefore, no dose adjustment is necessary during concomitant administration of IVA/TEZ/ELX with ciprofloxacin.

Potential for interaction with transporters
In vitro studies showed that ELX is a substrate for the efflux transporters P-gp and Breast Cancer Resistance Protein (BCRP) but is not a substrate for OATP1B1 or OATP1B3. Exposure to ELX is not expected to be affected significantly by concomitant use of P-gp and BCRP inhibitors due to its high intrinsic permeability and low likelihood of being excreted intact.

In vitro studies showed that TEZ is a substrate for the uptake transporter OATP1B1 and efflux transporters P-gp and BCRP. TEZ is not a substrate for OATP1B3. Exposure to TEZ is not expected to be affected significantly by concomitant inhibitors of OATP1B1, P-gp, or BCRP due to its high intrinsic permeability and low likelihood of being excreted intact. However, exposure to M2-TEZ (TEZ metabolite) may be increased by inhibitors of P-gp. Therefore, caution should be used when P-gp inhibitors (e.g., ciclosporin) are used with IVA/TEZ/ELX.

In vitro studies showed that IVA is not a substrate for OATP1B1, OATP1B3, or P-gp. IVA 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 IVA and M1-IVA, while any potential changes in M6-IVA exposures are not expected to be clinically relevant.

Medicinal products affected by ELX, TEZ and/or IVA

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

Potential for interaction with transporters
Co-administration of IVA or TEZ/IVA with digoxin, a sensitive P-gp substrate, increased digoxin AUC by 1.3-fold, consistent with weak inhibition of P-gp by IVA. Administration of IVA/TEZ/ELX and IVA 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 and tacrolimus, caution and appropriate monitoring should be used.

ELX and M23-ELX inhibit uptake by OATP1B1 and OATP1B3 in vitro. TEZ/IVA increased the AUC of pitavastatin, an OATP1B1 substrate, by 1.2-fold. Co-administration with IVA/TEZ/ELX in combination with IVA may increase exposures of medicinal products that are substrates of these transporters, such as statins, glyburide, nateglinide and repaglinide. When used concomitantly with substrates of OATP1B1 or OATP1B3, caution and appropriate monitoring should be used. Bilirubin is an OATP1B1 and OATP1B3 substrate. In study 445-102, mild increases in mean total bilirubin were observed (up to 4.0 µmol/L change from baseline). This finding is consistent with the in vitro inhibition of bilirubin transporters OATP1B1 and OATP1B3 by ELX and M23-ELX.

ELX and IVA are inhibitors of BCRP. Co-administration of IVA/TEZ/ELX, and IVA may increase exposures of medicinal products that are substrates of BCRP, such as rosuvastatin. When used concomitantly with substrates of BCRP, appropriate monitoring should be used.

Hormonal contraceptives

IVA/TEZ/ELX in combination with IVA has been studied with ethinyl estradiol/levonorgestrel and was found to have no clinically relevant effect on the exposures of the oral contraceptive. IVA/TEZ/ELX and IVA is not expected to have an impact on the efficacy of oral contraceptives.

Paediatric population

Interaction studies have only been performed in adults.

Pregnancy

A moderate amount of data on pregnant women (between 300-1000 pregnancy outcomes) indicate no malformative or feto/neonatal toxicity of ELX, TEZ, or IVA in pregnant women. Animal 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 IVA/TEZ/ELX during pregnancy.

Breast-feeding

Limited data show that ELX, TEZ, and IVA are excreted in human milk and have been quantified in plasma of breastfed newborns/infants of treated women. There is insufficient information on the effects of IVA/TEZ/ELX in newborns/infants. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from IVA/TEZ/ELX 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 ELX, TEZ and IVA on fertility in humans. TEZ had no effects on fertility and reproductive performance indices in male and female rats at clinically relevant exposures.
ELX and IVA had an effect on fertility in rats (see section 5.3).

IVA/TEZ/ELX in combination with IVA has a minor influence on the ability to drive or use machines.
Dizziness has been reported in patients receiving IVA/TEZ/ELX in combination with IVA, TEZ/IVA in combination with IVA as well as IVA (see section 4.8). Patients experiencing dizziness should be advised not to drive or use machines until symptoms abate.

No specific antidote is available for overdose with IVA/TEZ/ELX. Treatment of overdose consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient.

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Other respiratory system products, ATC code: R07AX32

Mechanism of action

ELX and TEZ 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. IVA potentiates the channel open probability (or gating) of the CFTR protein at the cell surface.

The combined effect of ELX, TEZ and IVA 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 IVA/TEZ/ELX was determined in Ussing chamber electrophysiology studies using a panel of FRT cell lines transfected with individual CFTR mutations. IVA/TEZ/ELX 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 IVA/TEZ/ELX based on in vitro data in FRT cells, will likely result in a clinical response.

Table 5 lists CFTR mutations included in the indication for treatment with Kaftrio. The occurrence of CFTR mutations listed in this table should not be used in lieu of a diagnosis of cystic fibrosis, nor as a sole determinant for prescribing purposes.

Table 5: CFTR mutations identified to be responsive to IVA/TEZ/ELX based on clinical and/or in vitro data 293A→G 314del9 546insCTA 548insTAC 711+3A→G* 1140-1151dup 1461insGAT 1507_1515del9 2055del9 2183A→G 2789+5G→A* 2851A/G 3007del6 3132T→G 3141del9 3143del9 3272-26A→G*† 3331del6 3410T→C 3523A→G 3601A→C 3761T→G E1433K E193K E217G E257G E264V E279D E282D E292K E384K E403D E474K E479D E527G E528A E56K E588K E588V E60K E725K E822K E826K E831X I1023R I1051V I105N I1139V I119M I119V I1203V I1230T I1234L I1234V I125T I1269N I1366N I1366T I148L I148N I175V I203M I331N I336K I336L I444S P1013H P1013L P1021L P1021T P1050A P111A P111L P1372T P140S P205S P355L P41R P439S P477S P499A P499S P5L† P574H P574R P67L* P731L P750L S1251N S1255P S1362N S158G S158N S158R S158T S182R S308P S341P S364P S42F S434P S485C S492F S50P S519G S531P S549I S549N S549R* S557F

3791C/T
3849+10kbC→T*†
3850G→A
3978G→C
A1006E
A1018E
A1025D
A1067P
A1067T
A1067V
A107G
A1081V
A1087P
A1136T
A120T
A1285G
A1285V
A1319E
A1364V
A1374D
A141D
A1466S
A155P
A209S
A234D
A234V
A238V
A300D
A309D
A349V
A357T
A455E*†
A455V
A457T
A462P
A46D
A46V
A534E
A554E
A566D
A62P
A872E
A959V
A9V
C128R

Pharmacotherapeutic group: Other respiratory system products, ATC code: R07AX32

Mechanism of action

ELX and TEZ 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. IVA potentiates the channel open probability (or gating) of the CFTR protein at the cell surface.

The combined effect of ELX, TEZ and IVA 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 IVA/TEZ/ELX was determined in Ussing chamber electrophysiology studies using a panel of FRT cell lines transfected with individual CFTR mutations. IVA/TEZ/ELX 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 IVA/TEZ/ELX based on in vitro data in FRT cells, will likely result in a clinical response.

Table 5 lists CFTR mutations included in the indication for treatment with Kaftrio. The occurrence of CFTR mutations listed in this table should not be used in lieu of a diagnosis of cystic fibrosis, nor as a sole determinant for prescribing purposes.

Table 5: CFTR mutations identified to be responsive to IVA/TEZ/ELX based on clinical and/or in vitro data 293A→G 314del9 546insCTA 548insTAC 711+3A→G* 1140-1151dup 1461insGAT 1507_1515del9 2055del9 2183A→G 2789+5G→A* 2851A/G 3007del6 3132T→G 3141del9 3143del9 3272-26A→G*† 3331del6 3410T→C 3523A→G 3601A→C 3761T→G 3791C/T 3849+10kbC→T*† 3850G→A 3978G→C E1433K E193K E217G E257G E264V E279D E282D E292K E384K E403D E474K E479D E527G E528A E56K E588K E588V E60K E725K E822K E826K E831X E92K F1016S F1052V F1074L I1023R I1051V I105N I1139V I119M I119V I1203V I1230T I1234L I1234V I125T I1269N I1366N I1366T I148L I148N I175V I203M I331N I336K I336L I444S I444T I497S I502T I506L P1013H P1013L P1021L P1021T P1050A P111A P111L P1372T P140S P205S P355L P41R P439S P477S P499A P499S P5L† P574H P574R P67L* P731L P750L P798S P988R P99R Q1012P S1251N S1255P S1362N S158G S158N S158R S158T S182R S308P S341P S364P S42F S434P S485C S492F S50P S519G S531P S549I S549N S549R* S557F S589I S589N S624R S686Y

A1006E
A1018E
A1025D
A1067P
A1067T
A1067V
A107G
A1081V
A1087P
A1136T
A120T
A1285G
A1285V
A1319E
A1364V
A1374D
A141D
A1466S
A155P
A209S
A234D
A234V
A238V
A300D
A309D

The pharmacokinetics of ELX, TEZ and IVA are similar between healthy adult subjects and patients with CF. Following initiation of once-daily dosing of ELX and TEZ and twice-daily dosing of IVA, plasma concentrations of ELX, TEZ and IVA reach steady state within approximately 7 days for ELX, within 8 days for TEZ, and within 3-5 days for IVA. Upon dosing IVA/TEZ/ELX to steady state, the accumulation ratio is approximately 3.6 for ELX, 2.8 for TEZ and 4.7 for IVA. Key pharmacokinetic parameters for ELX, TEZ and IVA at steady state in patients with CF aged 12 years and older are shown in Table 13.

Table 13: Mean (SD) pharmacokinetic parameters of ELX, TEZ and IVA at steady state in patients with CF aged 12 years and older Dose Active Substance Cmax (μg/mL) AUC0-24h, ss or AUC0-12h, ss (μg∙h/mL)* IVA 150 mg every 12 hours/TEZ 100 mg and ELX 200 mg once daily ELX

The pharmacokinetics of ELX, TEZ and IVA are similar between healthy adult subjects and patients with CF. Following initiation of once-daily dosing of ELX and TEZ and twice-daily dosing of IVA, plasma concentrations of ELX, TEZ and IVA reach steady state within approximately 7 days for ELX, within 8 days for TEZ, and within 3-5 days for IVA. Upon dosing IVA/TEZ/ELX to steady state, the accumulation ratio is approximately 3.6 for ELX, 2.8 for TEZ and 4.7 for IVA. Key pharmacokinetic parameters for ELX, TEZ and IVA at steady state in patients with CF aged 12 years and older are shown in Table 14.

Table 14: Mean (SD) pharmacokinetic parameters of ELX, TEZ and IVA at steady state in patients with CF aged 12 years and older Dose Active Substance Cmax (μg/mL) AUC0-24h, ss or AUC0-12h,ss (μg∙h/mL)* IVA 150 mg every 12 hours/TEZ 100 mg and ELX 200 mg once daily ELX