4.1. Therapeutic indications

Alyftrek is indicated for the treatment of cystic fibrosis (CF) in people aged 6 years and older who have at least one F508del mutation or another responsive mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene (see section 5.1, Table 4).

4.2. Posology and method of administration

Alyftrek should only be prescribed by healthcare professionals with experience in the treatment of CF. If the person with CF has an unknown genotype, an accurate and validated genotyping method should be performed to confirm the presence of at least one F508del mutation or another responsive mutation (see section 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 paediatrics aged 6 years and older should be dosed according to Table 1.

Table 1: Dosing recommendation for people with CF aged 6 years and older

Age

Weight

Daily Dose (once daily)

6 to < 12 years

< 40 kg

Three tablets of deutivacaftor 50 mg/tezacaftor 20 mg/vanzacaftor 4 mg (total dose of deutivacaftor 150 mg/tezacaftor 60 mg/vanzacaftor 12 mg)

6 to < 12 years

≥ 40 kg

Two tablets of deutivacaftor 125 mg/tezacaftor 50 mg/vanzacaftor 10 mg (total dose of deutivacaftor 250 mg/tezacaftor 100 mg/vanzacaftor 20 mg)

≥ 12 years

Any weight

Each dose should be taken in its entirety with fat-containing food once daily at approximately the same time each day (see Method of administration).

Missed dose

If 6 hours or less have passed since the missed dose, the missed dose should be taken as soon as possible, and the original schedule should be continued the next day.

If more than 6 hours have passed since the missed dose, the missed dose should be skipped, and the original schedule should be continued the next day.

Concomitant use of CYP3A inhibitors

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

Concomitant use of ciprofloxacin is not expected to have a clinically relevant effect on the exposure of Alyftrek; therefore, no dose adjustment is recommended with concomitant use of ciprofloxacin (see section 4.5).

Table 2: Dosing schedule for concomitant use of Alyftrek with moderate or strong CYP3A inhibitors

Age

Weight

Moderate CYP3A Inhibitors

Strong CYP3A Inhibitors

6 to < 12 years

< 40 kg

Two tablets of deutivacaftor 50 mg/tezacaftor 20 mg/vanzacaftor 4 mg every other day (total dose of deutivacaftor 100 mg/tezacaftor 40 mg/vanzacaftor 8 mg)

Two tablets of deutivacaftor 50 mg/tezacaftor 20 mg/vanzacaftor 4 mg once a week (total dose of deutivacaftor 100 mg/ tezacaftor 40 mg/vanzacaftor 8 mg)

6 to < 12 years

≥ 40 kg

One tablet of deutivacaftor 125 mg/tezacaftor 50 mg/vanzacaftor 10 mg every other day

One tablet of deutivacaftor 125 mg/tezacaftor 50 mg/vanzacaftor 10 mg once a week

≥ 12 years

Any weight

Special populations

Elderly population

Clinical studies of Alyftrek did not include a sufficient number of people with CF aged 65 years and older to determine whether they respond differently from younger people with CF.

Hepatic impairment

• Mild Hepatic Impairment (Child-Pugh Class A): No dose adjustment is recommended. Liver function tests should be closely monitored (see sections 4.4, 4.8, and 5.2).

• Moderate Hepatic Impairment (Child-Pugh Class B): Use not recommended. Alyftrek should only be considered when there is a clear medical need, and the benefit exceeds the risk. If used, no dose adjustment is recommended. Liver function tests should be closely monitored (see sections 4.4, 4.8, and 5.2).

• Severe Hepatic Impairment (Child-Pugh Class C): Should not be used. Alyftrek has not been studied in people with CF with severe hepatic impairment (see section 5.2).

Renal impairment

No dose adjustment is recommended for people with CF who have mild or moderate renal impairment. Caution is recommended for people with CF who have severe renal impairment or end‑stage renal disease (see section 5.2).

Paediatric population

The safety and efficacy of Alyftrek in children aged less than 6 years have not yet been established. No data are available.

Method of administration

For oral use. People with CF 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.

Alyftrek tablets 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 Alyftrek (see section 4.5).

4.3. Contraindications

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

4.4. Special warnings and precautions for use

Elevated transaminases and hepatic injury

Elevated transaminases are common in people with CF and have been observed in some people with CF treated with Alyftrek. Assessments of transaminases (ALT and AST) and total bilirubin are recommended for all people with CF prior to initiating Alyftrek, every 3 months during the first year of treatment, and annually thereafter. For people with CF with a history of liver disease or transaminase elevations, more frequent monitoring should be considered.

In the event of 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, consider the benefits and risks of resuming treatment (see sections 4.2, 4.8, and 5.2).

Alyftrek should be used with caution in people with CF with pre-existing advanced liver disease (e.g., cirrhosis, portal hypertension) and only if the benefits are expected to outweigh the risks. If used, they should be closely monitored after the initiation of treatment (see sections 4.2, 4.8, and 5.2).

Interactions with medicinal products

CYP3A inducers

Exposures to vanzacaftor (VNZ), tezacaftor (TEZ) and deutivacaftor (D-IVA) are expected to decrease by the concomitant use of moderate or strong CYP3A inducers, potentially resulting in the reduction of Alyftrek efficacy; therefore, co‑administration with moderate or strong CYP3A inducers is not recommended (see section 4.5).

CYP3A inhibitors

Exposures to VNZ, TEZ and D-IVA are increased when co-administered with moderate or strong CYP3A inhibitors. Therefore, the dose of Alyftrek should be reduced when used concomitantly with moderate or strong CYP3A inhibitors (see sections 4.2 and 4.5).

Cataracts

Cases of non-congenital lens opacities without impact on vision have been reported in people with CF aged less than 18 years treated with ivacaftor (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. As D-IVA is a deuterated isotopologue of IVA, baseline and follow-up ophthalmological examinations are recommended in people with CF aged less than 18 years initiating treatment with Alyftrek (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'.

4.5. Interaction with other medicinal products and other forms of interaction

Medicinal products affecting the pharmacokinetics of Alyftrek

CYP3A inducers

VNZ, TEZ and D-IVA are substrates of CYP3A. VNZ and D-IVA are sensitive substrates of CYP3A. Concomitant use of CYP3A inducers may result in reduced exposures and thus reduced Alyftrek efficacy. Co-administration of Alyftrek with moderate or strong CYP3A inducers is not recommended (see section 4.4).

Examples of moderate or strong CYP3A inducers include:

• rifampicin, rifabutin, phenobarbital, carbamazepine, phenytoin, St. John's wort (Hypericum perforatum), and efavirenz

CYP3A inhibitors

Co-administration with itraconazole, a strong CYP3A inhibitor, increased VNZ AUC by 10.5‑fold, TEZ AUC by 4.0‑ to 4.5‑fold and D-IVA AUC by 11.1‑fold. The dose of Alyftrek should be reduced when co‑administered with strong CYP3A inhibitors (see sections 4.2 and 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 may increase VNZ, TEZ, and D-IVA AUC by approximately 2.4‑ to 3.9‑fold, 2.1‑fold, and 2.9‑ to 4.8‑fold, respectively. The dose of Alyftrek should be reduced when co‑administered with moderate CYP3A inhibitors (see sections 4.2 and 4.4).

Examples of moderate CYP3A inhibitors include:

• fluconazole

• erythromycin

• verapamil

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

Ciprofloxacin

Alyftrek 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 VNZ or D-IVA. Therefore, no dose adjustment is necessary during concomitant administration of Alyftrek with ciprofloxacin.

Potential for interaction with transporters

In vitro studies showed that VNZ is not a substrate of Breast Cancer Resistance Protein (BCRP), the efflux transporters P-gp, and OATP1B1 or OATP1B3. Exposure to VNZ is not expected to be affected by inhibitors of BCRP, P‑gp, and OATP1B1/3.

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 D‑IVA/TEZ/VNZ.

In vitro studies showed that D-IVA and M1-D-IVA are not substrates for OATP1B1 or OATP1B3. D-IVA and M1-D-IVA are substrates of BCRP and P‑gp in vitro. M6-D-IVA is not a substrate of P-gp, but is a substrate of OATP1B1, OATP1B3, and BCRP. Due to its high intrinsic permeability and low likelihood of being excreted intact, co‑administration of BCRP or P-gp inhibitors is not expected to alter exposure of D-IVA and M1-D-IVA significantly, while any potential changes in M6‑D-IVA exposures are not expected to be clinically relevant.

Medicinal products affected by VNZ, TEZ, and D-IVA

CYP2C9 substrates

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

Potential for interaction with transporters

Alyftrek was not evaluated for concomitant use with P‑glycoprotein (P‑gp) substrates. However, co‑administration of tezacaftor/ivacaftor (TEZ/IVA) with digoxin, a sensitive P‑gp substrate, increased digoxin AUC by 1.3‑fold. Administration of Alyftrek 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.

Based on in vitro data, VNZ, TEZ, and D-IVA have low potential to inhibit OATP1B1 at clinically relevant concentrations. D-IVA has a similar OATP1B1 inhibition potential to IVA in vitro. Co-administration of TEZ/IVA with pitavastatin, an OATP1B1 substrate, had no clinically relevant effect on the exposure of pitavastatin.

Breast Cancer Resistance Protein (BCRP) Substrates

VNZ and D-IVA are inhibitors of BCRP in vitro. Concomitant use of Alyftrek with BCRP substrates may increase exposure of these substrates; however, this has not been studied clinically. When administered concomitantly with substrates of BCRP, caution and appropriate monitoring should be used.

Hormonal contraceptives

Alyftrek is not expected to have an impact on the efficacy of oral contraceptives. Alyftrek was not evaluated for concomitant use with oral contraceptives. TEZ in combination with IVA and IVA alone have been studied with ethinyl estradiol/norethindrone and were found to have no clinically relevant effect on the exposures of the oral contraceptive. VNZ, TEZ, and D-IVA have low potential to induce or inhibit CYP3A based on in vitro data.

Paediatric population

Interaction studies have only been performed in adults.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no or limited amount of data (less than 300 pregnancy outcomes) in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). Because animal reproduction studies are not always predictive of human response, Alyftrek should be used during pregnancy only if the potential benefits outweigh the potential risks.

Breast-feeding

VNZ and TEZ are excreted into the milk of lactating female rats. The effect of D-IVA has not been evaluated; however, IVA is excreted into the milk of lactating female rats. Exposure in rats of 14C‑VNZ, 14C‑TEZ and 14C-IVA in milk was approximately 0.2, 3.0, and 1.5 times, respectively, the value observed in plasma (based on AUC).

A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Alyftrek 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 VNZ, TEZ, and D-IVA on fertility in humans. VNZ and TEZ had no effects on fertility and reproductive performance indices in male and female rats at doses up to 12.5 mg/kg/day for males (19 times Maximum recommended human dose (MRHD)) and 10 mg/kg/day for females (30 times MRHD) for VNZ and 200 mg/kg/day for males (3 times MRHD) and 100 mg/kg/day for females (3 times MRHD) for TEZ. The effects of D-IVA on fertility have not been evaluated; however, IVA 200 mg/kg/day (13 and 15 times MRHD for females and males, respectively) had an effect on fertility in female and male rats (see section 5.3).

4.7. Effects on ability to drive and use machines

Alyftrek has no or negligible influence on the ability to drive and use machines.

4.8. Undesirable effects

Summary of the safety profile

The safety profile of Alyftrek is based on data from 480 participants aged 12 years and older in two randomized, ivacaftor/tezacaftor/elexacaftor (IVA/TEZ/ELX)-controlled phase 3 studies (studies 121-102 and 121-103) with 52 weeks of treatment duration. In both studies, all subjects participated in a 4-week run-in period with IVA/TEZ/ELX. In studies 121-102 and 121-103, the proportion of people with CF who discontinued Alyftrek prematurely due to adverse events was 3.8%.

Serious adverse drug reactions that occurred with Alyftrek in 2 or more participants (≥ 0.4%) were ALT increased (0.4%) and AST increased (0.4%). The most common (≥ 10%) adverse drug reactions in people with CF treated with Alyftrek were headache (15.8%) and diarrhoea (12.1%).

Tabulated list of adverse reactions

Table 3 shows overall incidence of adverse drug reactions of people with CF treated with Alyftrek. Adverse drug reactions for Alyftrek are ranked under the MedDRA frequency classification: 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).

Table 3: Adverse reactions by preferred term, frequency

System Organ Class (SOC)

Adverse Drug Reactions (Preferred Term)

Frequency for Alyftrek

Nervous system disorders

Headache

very common

Gastrointestinal disorders

Diarrhoea

very common

Hepatobiliary disorders

Alanine aminotransferase increased

common

Aspartate aminotransferase increased

common

Skin and subcutaneous tissue disorders

Rash

common

Investigations

Blood creatine phosphokinase increased

common

Safety data from the following studies were generally consistent with the safety data observed in studies 121-102 and 121-103:

• A 24-week, open-label study (study 121-105, Cohort B1) in 78 people with CF aged 6 to less than 12 years.

Detailed description of selected adverse reactions

Transaminase elevations

In studies 121-102 and 121-103, the incidence of maximum transaminase (ALT or AST) > 8 ×, > 5 ×, or > 3 × the ULN was 1.3%, 2.5%, and 6.0% with Alyftrek. The incidence of adverse reactions of transaminase elevations was 9.0% with Alyftrek. Of the Alyftrek-treated participants, 1.5% discontinued treatment for elevated transaminases.

In study 121-105, Cohort B1, in people with CF aged 6 to less than 12 years, the incidence of maximum transaminase (ALT or AST) >8 ×, > 5 ×, and > 3 × ULN were 0%, 1.3%, and 3.8%, respectively.

Rash events

In studies 121-102 and 121-103, the incidence of rash events (e.g., rash, rash pruritic) was 11.0% with Alyftrek. The rash events were generally mild to moderate in severity. The incidence of rash events was 9.4% in males and 13.0% in females.

A role for hormonal contraceptives in the occurrence of rash cannot be excluded. For people with CF taking hormonal contraceptives who develop rash, consider interrupting Alyftrek and hormonal contraceptives. Following the resolution of rash, consider resuming Alyftrek without the hormonal contraceptives. If rash does not recur, resumption of hormonal contraceptives can be considered.

Increased creatine phosphokinase

In studies 121-102 and 121-103, the incidence of maximum creatine phosphokinase > 5 × the ULN was 7.9% with Alyftrek. Of the Alyftrek-treated participants, 0.2% discontinued treatment for increased creatine phosphokinase.

Paediatric population

The safety data of Alyftrek in study 121-105, Cohort B1 was evaluated in 78 people with CF aged 6 to less than 12 years. The safety profile is generally consistent among adolescents and adult patients.

During study 121‑105, Cohort B1 in people with CF aged 6 to less than 12 years, the incidence of maximum transaminase (ALT or AST) > 8 ×, > 5 ×, and > 3 × ULN was 0.0%, 1.3%, and 3.8%, respectively. No Alyftrek‑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).

Other special populations

The safety profile of Alyftrek was generally similar across all subgroups of patients, including analysis by age, sex, 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:

Yellow Card Scheme

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

4.9. Overdose

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