Alyftrek 125 mg/50 mg/10 mg/ film-coated tablets

Film-coated tablet (tablet) Alyftrek 125 mg/50 mg/10 mg film‑coated tablets Purple, capsule‑shaped tablet debossed with “V10” on one side and plain on the other (15 mm × 7 mm).

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.

5.1 Pharmacodynamic properties Pharmacotherapeutic group: Other respiratory system products, ATC code: R07AX33. Mechanism of action VNZ 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 select mutant forms of CFTR (including *F508del*-CFTR) to increase the amount of CFTR protein delivered to the cell surface compared to either molecule alone. D-IVA potentiates the channel open probability (or gating) of the CFTR protein at the cell surface. The combined effect of VNZ, TEZ and D-IVA is increased quantity and function of CFTR at the cell surface, resulting in increased CFTR activity as measured both by CFTR mediated chloride transport *in vitro* and by sweat chloride (SwCl) in people with CF. CFTR Chloride Transport Assay in Fischer Rat Thyroid (FRT) cells expressing mutant CFTR The chloride transport response of mutant CFTR protein to D-IVA/TEZ/VNZ was determined in Ussing chamber electrophysiology studies using a panel of FRT cell lines transfected with individual *CFTR* mutations. D-IVA/TEZ/VNZ 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 of clinical benefit. 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. Clinical outcomes were consistent with *in vitro* results and indicate that a single responsive allele (including the *F508del* mutation) is sufficient to result in a significant clinical response. Table 4 lists responsive *CFTR* mutations based on clinical data and/or on *in vitro* data in FRT cells indicating that D-IVA/TEZ/VNZ increases chloride transport to at least 10% of normal over baseline. | | | | | | | | | | --- | --- | --- | --- | --- | --- | --- | --- | | **Table 4: List of *CFTR* gene mutations that are responsive to Alyftrek** | | | | | | | | | *1341G→A* | *A72D* | *F508C;S1251N*\* | *H139R* | *L15P* | *Q372H* | *R709Q* | *V1240G* | | *1507\_1515del9* | *C491R* | *F508del* | *H199R* | *L165S* | *Q452P* | *R74Q* | *V1293G* | | *1898+3A→G* | *D110E* | *F575Y* | *H199Y* | *L206W* | *Q493R* | *R74W* | *V201M* | | *2183A->G* | *D110H* | *F587I* | *H609R* | *L320V* | *Q552P* | *R74W;D1270N* \* | *V232D* | | *2752-26A→G* | *D1152H* | *G1047R* | *H620P* | *L333F* | *Q98R* | *R74W;V201M* \* | *V392G* | | *2789+2insA* | *D1270N* | *G1061R* | *H620Q* | *L333H* | *R1048G* | *R74W;V201M;D1270N* \* | *V456A* | | *2789+5G→A* | *D1445N* | *G1069R* | *H939R* | *L346P* | *R1066C* | *R751L* | *V456F* | | *296+28A→G* | *D192G* | *G1123R* | *H939R;H949L* | *L441P* | *R1066H* | *R75L* | *V520F* | | *3041-15T→G* | *D443Y* | *G1244E* | *I1027T* | *L453S* | *R1066L* | *R75Q* | *V562I* | | *3141del9* | *D443Y;G576A;R668C*\* | *G1247R* | *I105N* | *L619S* | *R1066M* | *R792G* | *V603F* | | *3195del6* | *D513G* | *G1249R* | *I1139V* | *L967S* | *R1070Q* | *R933G* | *V754M* | | *3199del6* | *D565G* | *G126D* | *I1234Vdel6aa* | *L997F* | *R1070W* | *S1045Y* | *W1098C* | | *3272-26A→G* | *D579G* | *G1349D* | *I125T* | *M1101K* | *R1162L* | *S108F* | *W1282R* | | *3600G→A* | *D614G* | *G149R* | *I1269N* | *M1101R* | *R117C* | *S1118F* | *W361R* | | *3849+10kbC→T* | *D836Y* | *G178E* | *I1366N* | *M1137V* | *R117C;G576A;R668C* | *S1159F* | *Y1014C* | | *3849+40A→G* | *D924N* | *G178R* | *I1398S* | *M150K* | *R117G* | *S1159P* | *Y1032C* | | *3849+4A→G* | *D979V* | *G194R* | *I148N* | *M152V* | *R117H* | *S1235R* | *Y109N* | | *3850-3T→G* | *D993Y* | *G194V* | *I148T* | *M265R* | *R117L* | *S1251N* | *Y161D* | | *4005+2T→C* | *E116K* | *G27E* | *I175V* | *M952I* | *R117P* | *S1255P* | *Y161S* | | *546insCTA* | *E116Q* | *G27R* | *I331N* | *M952T* | *R1283M* | *S13F* | *Y301C* | | *5T;TG12* | *E193K* | *G314E* | *I336K* | *N1088D* | *R1283S* | *S341P* | *Y563N* | | *5T;TG13* | *E292K* | *G424S* | *I502T* | *N1303I* | *R170H* | *S364P* | *Y569C* | | *621+3A→G* | *E403D* | *G463V* | *I506L* | *N1303K* | *R258G* | *S492F* | *Y913C* | | *711+3A→G* | *E474K* | *G480C* | *I506T* | *N186K* | *R297Q* | *S549I* | | | *A1006E* | *E56K* | *G480S* | *I556V* | *N187K* | *R31C* | *S549N* | | | *A1067P* | *E588V* | *G551A* | *I601F* | *N418S* | *R31L* | *S549R* | | | *A1067T* | *E60K* | *G551D* | *I618T* | *P140S* | *R334L* | *S589N* | | | *A107G* | *E822K* | *G551S* | *I807M* | *P205S* | *R334Q* | *S737F* | | | *A120T* | *E831X* | *G576A* | *I980K* | *P499A* | *R347H* | *S912L* | | | *A234D* | *E92K* | *G576A;R668C* \* | *K1060T* | *P574H* | *R347L* | *S945L* | | | *A309D* | *F1016S* | *G622D* | *K162E* | *P5L* | *R347P* | *S977F* | | | *A349V* | *F1052V* | *G628R* | *K464E* | *P67L* | *R352Q* | *T1036N* | | | *A455E* | *F1074L* | *G85E* | *L1011S* | *P750L* | *R352W* | *T1053I* | | | *A46D* | *F1099L* | *G91R* | *L102R* | *P99L* | *R516G* | *T1086I* | | | *A554E* | *F1107L* | *G970D* | *L1065P* | *Q1100P* | *R516S* | *T1246I* | | | *A559T* | *F191V* | *G970S* | *L1077P* | *Q1291R* | *R553Q* | *T1299I* | | | *A559V* | *F200I* | *H1054D* | *L1324P* | *Q1313K* | *R555G* | *T338I* | | | *A561E* | *F311del* | *H1085P* | *L1335P* | *Q237E* | *R560S* | *T351I* | | | *A613T* | *F311L* | *H1085R* | *L137P* | *Q237H* | *R560T* | *T604I* | | | *A62P* | *F508C* | *H1375P* | *L1480P* | *Q359R* | *R668C* | *V1153E* | | | \* Complex/compound mutations where a single allele of the *CFTR* gene has multiple mutations; these exist independent of the presence of mutations on the other allele. | | | | | | | | Pharmacodynamic effects *Effects on sweat chloride* In study 121-102 (people with CF heterozygous for a *F508del* and a *CFTR* mutation that results in a protein that is not responsive to IVA or TEZ/IVA [minimal function mutation]) the treatment difference of Alyftrek compared to IVA/TEZ/ELX for mean absolute change in SwCl from baseline through week 24 was ‑8.4 mmol/L (95% CI: -10.5, -6.3; *P* < 0.0001). In study 121-103 (people with CF homozygous for the *F508del* mutation, heterozygous for the *F508del* mutation and either a gating or a residual function mutation, or at least one mutation responsive to IVA/TEZ/ELX with no *F508del* mutation), the treatment difference of Alyftrek compared to IVA/TEZ/ELX for mean absolute change in SwCl from baseline through week 24 was ‑2.8 mmol/L (95% CI: ‑4.7, ‑0.9; *P* = 0.0034). In study 121-105, Cohort B1 (people with CF aged 6 to less than 12 years with at least one mutation that is responsive to IVA/TEZ/ELX), the mean absolute change in SwCl from baseline through week 24 was -8.6 mmol/L (95% CI: -11.0, -6.3). Cardiovascular effects *Effect on QT interval* At exposures corresponding up to 6 times over those observed with the VNZ maximum recommended dose, and doses up to 3 times over the TEZ and D-IVA maximum recommended doses, the QT/QTc interval in healthy subjects was not prolonged to any clinically relevant extent. Clinical efficacy and safety The efficacy of Alyftrek in people with CF aged 12 years and older was evaluated in two, phase 3, randomized, double-blind, IVA/TEZ/ELX-controlled studies (studies 121-102 and 121-103). The pharmacokinetic profile, safety, and efficacy of Alyftrek in people with CF aged 6 to less than 12 years are supported with evidence from studies of Alyftrek in people with CF aged 12 years and older (studies 121-102 and 121-103) and additional data from an open‑label, phase 3 study (study 121-105, Cohort B1). *Studies 121-102 and 121-103* Study 121-102 was a 52‑week, randomized, double‑blind, IVA/TEZ/ELX‑controlled study in people with CF heterozygous for *F508del* and a *CFTR* mutation that results in a protein that is not responsive to IVA or TEZ/IVA (minimal function mutation). A total of 398 people with CF aged 12 years and older (mean age 30.8 years) received IVA/TEZ/ELX during a 4‑week run-in period and were then randomized to receive Alyftrek or IVA/TEZ/ELX during the 52‑week treatment period. After the 4‑week run-in, the mean ppFEV1 at baseline was 67.1 percentage points (range: 28.0, 108.6) and the mean SwCl at baseline was 53.9 mmol/L (range: 10.0 mmol/L, 113.5 mmol/L). Study 121-103 was a 52-week, randomized, double-blind, IVA/TEZ/ELX controlled study in people with CF who had one of the following genotypes: homozygous for the *F508del* mutation, heterozygous for the *F508del* mutation and either a gating or a residual function mutation, or at least one mutation responsive to IVA/TEZ/ELX with no *F508del* mutation. A total of 573 people with CF aged 12 years and older (mean age 33.7 years) received IVA/TEZ/ELX during a 4-week run-in period and were then randomized to receive Alyftrek or IVA/TEZ/ELX during the 52-week treatment period. After the 4-week run-in, the mean ppFEV1 at baseline was 66.8 percentage points (range: 36.4, 112.5) and the mean SwCl at baseline was 42.8 mmol/L (range: 10.0 mmol/L, 113.3 mmol/L). In both studies, the primary endpoint evaluated non-inferiority in mean absolute change from baseline in ppFEV1 through week 24. Key secondary endpoints evaluated superiority in mean absolute change from baseline in SwCl through week 24, and the proportion of participants achieving SwCl < 60 mmol/L and SwCl < 30 mmol/L through week 24. In study 121-102, treatment with Alyftrek resulted in an LS mean difference of 0.2 percentage points (1-sided *P* < 0.0001 for non-inferiority; 95% CI: -0.7, 1.1) in absolute change in ppFEV1 from baseline through week 24 compared to IVA/TEZ/ELX. In study 121‑103, treatment with Alyftrek resulted in an LS mean difference of 0.2 percentage points (1‑sided *P* < 0.0001 for non-inferiority; 95% CI: -0.5, 0.9) in absolute change in ppFEV1 from baseline through week 24 compared to IVA/TEZ/ELX. In studies 121-102 and 121-103, mean absolute change from baseline in ppFEV1 through week 24 was maintained through week 52. As the lower bounds of the 95% CI of the LS mean difference in absolute change in ppFEV1 from baseline through week 24 was greater than -3.0 percentage points (the pre‑specified non‑inferiority margin) in study 121-102 and study 121-103, these results demonstrate non‑inferiority of Alyftrek compared to IVA/TEZ/ELX. In studies 121-102 and 121-103, Alyftrek was superior to IVA/TEZ/ELX on all key secondary endpoints. On the first key secondary endpoint, when compared to IVA/TEZ/ELX, treatment with Alyftrek resulted in a reduction of ‑8.4 mmol/L (95% CI: ‑10.5, ‑6.3; *P* < 0.0001) and ‑2.8 mmol/L (95% CI: ‑4.7, ‑0.9; *P* = 0.0034) in SwCl through Week 24, in studies 121-102 and 121-103, respectively. Absolute change from baseline in SwCl through Week 24 was maintained through Week 52 in both trials. On the remaining key secondary endpoints, treatment with Alyftrek resulted in 86% of people with CF achieving a SwCl level below 60 mmol/L through Week 24, compared to 77% of people treated with IVA/TEZ/ELX (odds ratio 2.21; 95% CI: 1.55, 3.15; *P* < 0.0001), and 31% of people with CF achieving a SwCl level below 30 mmol/L through Week 24, compared to 23% of people treated with IVA/TEZ/ELX (odds ratio 2.87; 95% CI: 2.00, 4.12; *P* < 0.0001). Other secondary endpoints (pulmonary exacerbation rate, change in CFQ-R RD score from baseline) demonstrated consistent benefit between Alyftrek and IVA/TEZ/ELX. See Table 5 for a summary of key efficacy outcomes for studies 121-102 and 121-103. | | | | | | | | --- | --- | --- | --- | --- | --- | | **Table 5: Efficacy analyses from study 121-102 and study 121-103** | | | | | | | **Analysis\** | **Statistic** | **Study 121-102** | | **Study 121-103** | | | **Alyftrek** **N = 196** | **IVA/TEZ/ELX** **N = 202** | **Alyftrek** **N = 284** | **IVA/TEZ/ELX** **N = 289** | | **Primary** | | | | | | | Baseline ppFEV1 (percentage points) | Mean (SD) | 67.0 (15.3) | 67.2 (14.6) | 67.2 (14.6) | 66.4 (14.9) | | Absolute change from baseline in ppFEV1 through week 24 (percentage points) | n | 187 | 193 | 268 | 276 | | LS mean (SE) | 0.5 (0.3) | 0.3 (0.3) | 0.2 (0.3) | 0.0 (0.2) | | LS mean difference, 95% CI | 0.2 (-0.7, 1.1) | | 0.2 (-0.5, 0.9) | | | P-value (1-sided) for Non-Inferiority# | < 0.0001 | | < 0.0001 | | | **Key Secondary** | | | | | | | Baseline SwCl (mmol/L) | Mean (SD) | 53.6 (17.0) | 54.3 (18.2) | 43.4 (18.5) | 42.1 (17.9) | | Absolute change from baseline in SwCl through week 24 (mmol/L) | n | 185 | 194 | 270 | 276 | | LS mean (SE) | -7.5 (0.8) | 0.9 (0.8) | -5.1 (0.7) | -2.3 (0.7) | | LS mean difference, 95% CI | -8.4 (-10.5, -6.3) | | -2.8 (-4.7, -0.9) | | | P-value (2-sided) | < 0.0001 | | 0.0034 | | | Proportion of participants with SwCl < 60 mmol/L† through week 24 | n | **465 Alyftrek vs 479 IVA/TEZ/ELX** | | | | | Proportion (%) | 86 Alyftrek vs 77 IVA/TEZ/ELX | | | | | Odds Ratio, 95% CI¶ | 2.21 (1.55, 3.15) | | | | | P-value (2-sided) | < 0.0001 | | | | | Proportion of participants with SwCl < 30 mmol/L§ through week 24 | n | **465 Alyftrek vs 479 IVA/TEZ/ELX** | | | | | Proportion (%) | 31 Alyftrek vs 23 IVA/TEZ/ELX | | | | | Odds Ratio, 95% CI¶ | 2.87 (2.00, 4.12) | | | | | P-value (2-sided) | < 0.0001 | | | | | **Other Secondary** Ϸ | | | | | | | Number of pulmonary exacerbations through week 52 | Number of events | 67 | 90 | 86 | 79 | | Event rate per year | 0.32 | 0.42 | 0.29 | 0.26 | | Rate difference, 95% CI | -0.10 (-0.24, 0.04) | | 0.03 (-0.07, 0.13) | | | Absolute change from baseline in CFQ-R RD score through week 24 (points) | n | 186 | 192 | 268 | 270 | | LS mean (SE) | 0.5 (1.1) | -1.7 (1.0) | -1.2 (0.8) | -1.2 (0.8) | | LS mean difference, 95% CI | 2.3 (-0.6, 5.2) | | -0.1 (-2.3, 2.1) | | | ppFEV1: percent predicted Forced Expiratory Volume in 1 second; CI: Confidence Interval; SE: Standard Error; CFQ‑R RD: Cystic Fibrosis Questionnaire‑Revised (respiratory domain); SwCl: Sweat Chloride Note: Analyses were based on the full analysis set (FAS) unless otherwise noted. FAS was defined as all randomized subjects who carry the intended CFTR allele mutation and received at least 1 dose of study drug. \ A 4-week IVA/TEZ/ELX run-in-period was performed to establish an on-treatment baseline. † SwCl ≥ 60 mmol/L meets the diagnostic threshold for CF as evidence of CFTR dysfunction. § Normal SwCl levels are considered < 30 mmol/L. ¶ Odds ratio > 1 favours Alyftrek. # The pre-specified non-inferiority margin was -3.0 percentage points. Ϸ Not controlled for multiplicity. | | | | | | *Study 121-105* Study 121-105 was multicohort, open‑label study in people with CF with at least one mutation responsive to IVA/TEZ/ELX. Cohort A1 evaluated pharmacokinetic and safety parameters of Alyftrek during a 22‑day treatment period in a total of 17 people with CF aged 6 to less than 12 years of age. Cohort B1 evaluated the safety, tolerability, and efficacy of Alyftrek in a total of 78 people with CF aged 6 to less than 12 years (mean age 9.1 years) during a 24‑week treatment period. In Cohort B1, all participants were on IVA/TEZ/ELX at baseline. The mean ppFEV1 at baseline on IVA/TEZ/ELX was 99.7 percentage points (range: 29.3, 146.0) and the mean SwCl at baseline, on IVA/TEZ/ELX, was 40.4 mmol/L (range: 11.5 mmol/L, 109.5 mmol/L). In study 121-105, Cohort B1, safety and tolerability were the primary endpoints. Efficacy endpoints included absolute change in ppFEV1, absolute change in SwCl, proportion of participants with SwCl of < 60 mmol/L, proportion of participants with SwCl of < 30 mmol/L, absolute change in CFQ-R respiratory domain score, and number of PEx through Week 24. See Table 6 for a summary of efficacy outcomes. | | | | | --- | --- | --- | | **Table 6: Efficacy analyses, study 121-105 (Cohort B1)** | | | | **Analysis** | **Statistic** | **D-IVA/TEZ/VNZ** **N = 78** | | **Secondary Efficacy** | | | | Baseline ppFEV1 | Mean (SD) | 99.7 (15.1) | | Baseline SwCl | Mean (SD) | 40.4 (20.9) | | Absolute change in ppFEV1 from baseline through week 24 (percentage points) | LS mean (95% CI) | 0.0 (-2.0, 1.9) | | Absolute change in SwCl from baseline through week 24 (mmol/L) | LS mean (95% CI) | -8.6 (-11.0, -6.3) | | Proportion of participants with SwCl <60 mmol/L\* through week 24 | Proportion (95% CI) | 95% (87%, 99%) | | Proportion of participants with SwCl <30 mmol/L† through week 24 | Proportion (95% CI) | 53% (41%, 64%) | | Absolute change in CFQ-R Respiratory Domain score from baseline through week 24 (points) | LS mean (95% CI) | 3.9 (1.5, 6.3) | | Number of pulmonary exacerbations through week 24 | Event rate per year | 0.15 | | CI: Confidence Interval; ppFEV1: percent predicted Forced Expiratory Volume in 1 second; CFQ‑R: Cystic Fibrosis Questionnaire‑Revised \* SwCl ≥ 60 mmol/L meets the diagnostic threshold for CF as evidence of CFTR dysfunction. † Normal SwCl levels are considered < 30 mmol/L. | | | The Medicines and Healthcare products Regulatory Agency (MHRA) has deferred the obligation to submit the results of studies with Alyftrek in one or more subset of the paediatric population in cystic fibrosis (see section 4.2 for information on paediatric use).5.2 Pharmacokinetic properties The pharmacokinetics of VNZ, TEZ and D-IVA are similar between healthy adult subjects and people with CF. Following initiation of once-daily dosing of D-IVA/TEZ/VNZ plasma concentrations reach steady state within 20 days for VNZ, within 8 days for TEZ, and within 8 days for D-IVA. Upon dosing D-IVA/TEZ/VNZ to steady state, the accumulation ratio based on AUC is approximately 6.09 for VNZ, 1.92 for TEZ and 1.74 for D-IVA. Key pharmacokinetic parameters for D‑IVA/TEZ/VNZ at steady state in people with CF aged 12 years and older are shown in Table 7. | | | | | | --- | --- | --- | --- | | **Table 7: Mean (SD) pharmacokinetic parameters of VNZ, TEZ and D-IVA at steady state in people with CF aged 12 years and older** | | | | | **Dose** | **Active Substance** | **Cmax (mcg/mL)\** | **AUC0‑24h, (mcg∙h/mL)\** | | D-IVA 250 mg /TEZ 100 mg /VNZ 20 mg | VNZ | 0.812 (0.344) | 18.6 (8.08) | | TEZ | 6.77 (1.24) | 89.5 (28.0) | | D-IVA | 2.33 (0.637) | 39.0 (15.3) | | SD: Standard Deviation; Cmax: maximum observed concentration; AUC0‑24h: Area Under the Concentration versus time curve at steady state. \*Values based on population PK modelling. | | | | Absorption VNZ, TEZ, and D-IVA are absorbed with a median (range) time to maximum concentration (tmax) of approximately 7.80 hours (3.70 to 11.9 hours), 1.60 hours (1.40 to 1.70 hours), and 3.7 hours (2.7 to 11.4 hours), respectively. VNZ exposure (AUC) increases approximately 4‑ to 6‑fold when administered with fat‑containing meals relative to fasted conditions. D-IVA exposure increases approximately 3‑ to 4‑fold when administered with fat-containing meals relative to fasted conditions, while food has no clinically significant effect on the exposure of TEZ (see section 4.2). Distribution VNZ and D-IVA are > 99% bound to plasma protein primarily to albumin, and alpha 1‑acid glycoprotein. TEZ is approximately 99% bound to plasma proteins, primarily to albumin. After oral administration of D-IVA/TEZ/VNZ, the mean (SD) apparent volume of distribution of VNZ, TEZ and D-IVA was 90.4 L (31.3), 123 L (43.2) and 157 L (47.3), respectively. VNZ, TEZ and D-IVA do not partition preferentially into human red blood cells. Biotransformation VNZ is metabolized extensively in humans, mainly by CYP3A4/5. VNZ has no major circulating metabolites. TEZ is metabolized extensively in humans, mainly by CYP3A4/5. Following oral administration of a single dose of 100 mg 14C‑TEZ to healthy male subjects, M1‑TEZ, M2‑TEZ and M5‑TEZ were the three major circulating metabolites of TEZ in humans. M1-TEZ has similar potency to that of TEZ and is considered pharmacologically active. M2‑TEZ is much less pharmacologically active than TEZ or M1‑TEZ and M5‑TEZ is not considered pharmacologically active. Another minor circulating metabolite, M3‑TEZ, is formed by direct glucuronidation of TEZ. D-IVA is primarily metabolized by CYP3A4/5 to form the two major circulating metabolites, M1‑D-IVA and M6‑D-IVA. Relative to IVA, D-IVA exhibited more metabolic stability and formed less M1‑D-IVA, the deuterated-equivalent of M1‑IVA. M1‑D-IVA has approximately one-fifth the potency of D-IVA and is considered pharmacologically active. M6‑D-IVA is the other major metabolite of D-IVA, the deuterated‑equivalent of M6‑IVA, and is not considered pharmacologically active. Elimination After oral administration of D-IVA/TEZ/VNZ, the mean (SD) apparent clearance values of VNZ, TEZ and D-IVA were 1.18 (0.455) L/h, 0.937 (0.338) L/h and 6.52 (2.77) L/h, respectively. The mean (SD) terminal half‑lives of VNZ, TEZ and D-IVA following administration of the D-IVA/TEZ/VNZ fixed‑dose combination tablets are approximately 54.0 (10.1) hours, 92.4 (23.1) hours and 17.3 (2.67) hours, respectively. The mean (SD) effective half-lives of VNZ, TEZ and D-IVA following administration of the D‑IVA/TEZ/VNZ fixed-dose combination tablets are approximately 92.8 (30.2) hours, 22.5 (5.85) hours and 19.2 (8.71) hours, respectively. Excretion Following oral administration of 14C-VNZ alone (91.6%), the majority of radioactivity was eliminated in faeces, primarily as metabolites. Following oral administration of 14C‑TEZ alone, the majority of the dose (72%) was excreted in the faeces (unchanged or as the M2‑TEZ) and about 14% was recovered in urine (mostly as M2‑TEZ), resulting in a mean overall recovery of 86% up to 26 days after the dose. Preclinical data indicate that the majority of 14C-D-IVA and 14C-IVA are excreted in the faeces. Major excreted metabolites of D-IVA were M1-D-IVA and M6-D-IVA and major excreted metabolites for IVA were M1-IVA and M6-IVA. The excretion of D‑IVA in humans is expected to be similar to that of IVA, based on similar structure (deuterated isotopologue) and non-clinical data. After oral administration of 14C-IVA alone, the majority of IVA (87.8%) was eliminated in faeces after metabolic conversion. There was minimal elimination of IVA and its metabolites in urine (only 6.6% of IVA was recovered in the urine). Hepatic impairment D-IVA/TEZ/VNZ has not been studied in subjects with severe hepatic impairment (Child‑Pugh Class C). Following a single dose of D-IVA/TEZ/VNZ, subjects with moderate hepatic impairment had an approximately 30% lower total VNZ exposures, comparable total TEZ exposures, and 20% lower total D-IVA exposures compared to healthy subjects matched for demographics. Renal impairment Urinary excretion of VNZ, TEZ, and D-IVA is negligible (see Elimination). VNZ alone or in combination with TEZ and D-IVA has not been studied in people with CF with severe renal impairment (eGFR less than 30 mL/min) or in people with CF with end‑stage renal disease. Based on population pharmacokinetic (PK) analysis, VNZ exposures were similar in patients with mild (N = 126; eGFR 60 to less than 90 mL/min/1.73 m2) and moderate renal impairment (N = 2; eGFR 30 to less than 60 mL/min/1.73 m2) relative to those with normal renal function (N = 580; eGFR 90 mL/min/1.73 m2 or greater). Based on population PK analysis, exposure of TEZ was similar in patients with mild renal impairment (N = 172; eGFR 60 to less than 90 mL/min/1.73 m2) and moderate renal impairment (N = 8; eGFR 30 to less than 60 mL/min/1.73 m2) relative to those with normal renal function (N = 637; eGFR 90 mL/min/1.73 m2 or greater). Based on population PK analysis, exposure of D-IVA was similar in patients with mild (N = 132; eGFR 60 to less than 90 mL/min/1.73 m2) and moderate renal impairment (N = 2; eGFR 30 to less than 60 mL/min/1.73 m2) relative to those with normal renal function (N = 577; eGFR 90 mL/min/1.73 m2 or greater) (see section 4.2). Race Race had no clinically meaningful effect on VNZ exposure based on population PK analysis in whites (N = 664) and non-whites (N = 44). The non-white races consisted of 9 Black or African Americans, 7 Asians, 7 with multiple racial background, 2 American Indian or Alaska Native, 2 with other ethnic background, and 17 not collected. Very limited PK data indicate comparable exposure of TEZ in whites (N = 652) and non-whites (N = 8). The non-white races consisted of 5 Blacks or African Americans and 3 Native Hawaiians or other Pacific Islanders. Race had no clinically meaningful effect on the PK of D-IVA in whites (N = 670) and non-whites (N = 41) based on a population PK analysis. The non-white races consisted of 18 Black or African Americans, 2 Asians, 3 with multiple racial background, 1 with other ethnic background, and 17 not collected. Gender Based on population PK analysis, there are no clinically relevant differences in exposures of VNZ, TEZ, and D-IVA between males and females. Elderly Clinical studies of D-IVA/TEZ/VNZ 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 (see section 4.2). Paediatric people with CF 6 to less than 18 years of age VNZ, TEZ, and D-IVA exposures observed in phase 3 studies as determined using population PK analysis are presented by age group in Table 8. VNZ, TEZ, and D-IVA exposures in the 6 to less than 18 years of age are within the range observed in adults with CF. | | | | | | | | --- | --- | --- | --- | --- | --- | | **Table 8: Mean (SD) vanzacaftor, tezacaftor and deutivacaftor Exposures by Age Group** | | | | | | | **Age group** | **Weight** | **Dose** | **VNZ** AUC0-24h (mcg∙h/mL) | **TEZ** AUC0-24h (mcg∙h/mL) | **D-IVA** AUC0-24h (mcg∙h/mL) | | 6 to < 12 years | < 40 kg (N = 70) | VNZ 12 mg qd/ TEZ 60 mg qd/ D-IVA150 mg qd | 13.0 (4.90) | 69.1 (20.7) | 30.2 (11.6) | | ≥ 40 kg (N = 8) | VNZ 20 mg qd/ TEZ 100 mg qd/ D-IVA 250 mg qd | 18.6 (7.49) | 101 (33.7) | 48.5 (18.7) | | 12 to < 18 years | - (N = 66) | VNZ 20 mg qd/ TEZ 100 mg qd/ D-IVA 250 mg qd | 15.8 (6.52) | 93.0 (32.5) | 37.1 (15.3) | | ≥ 18 years | - (N = 414) | 19.0 (8.22) | 89.0 (27.2) | 39.3 (15.3) | | SD: Standard Deviation; AUC0-24h: Area Under the Concentration versus time curve at steady state; qd: once daily. | | | | | |5.3 Preclinical safety data Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use. Vanzacaftor Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential. *Fertility and Pregnancy* VNZ was not teratogenic in rats at 10 mg/kg/day and at 40 mg/kg/day in rabbits (approximately 30 and 22 times, respectively, the MRHD based on AUCs of VNZ). VNZ had no effects on male or fertility and early embryonic development in rats at oral doses up to 12.5 mg/kg/day in males and 10 mg/kg/day for females (approximately 19 times for males and 30 times for females the MRHD based on AUC of vanzacaftor). Placental transfer of VNZ was observed in pregnant rats. Tezacaftor Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated-dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development. Placental transfer of TEZ was observed in pregnant rats. Deutivacaftor Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity. D-IVA is a deuterated isotopologue of IVA with an established toxicity profile similar to IVA based on a 13-week single-agent repeat dose toxicity study; therefore, reproductive and developmental toxicity data and carcinogenicity data from IVA are expected to be equivalent to D-IVA. *Fertility and Pregnancy* The effect of D-IVA on fertility and pregnancy has not been evaluated; however, IVA was associated with a reduction in overall fertility index, number of pregnancies, number of corpora lutea and implantation sites, as well as changes in the estrous cycle in females at 200 mg/kg/day dose (approximately 13 times the MRHD based on AUC of IVA). Slight decreases of the seminal vesicle weights were observed in males at 200 mg/kg/day dose (approximately 15 times the MRHD based on AUC of IVA). In a pre- and post-natal development study in pregnant rats at doses above 100 mg/kg/day (approximately 8 times the MRHD), IVA resulted in survival and lactation indices that were 92% and 98% of control values, respectively, as well as reductions in pup body weights. Placental transfer of IVA was observed in pregnant rats and rabbits. *Juvenile animals* Findings of cataracts were observed in juvenile rats dosed from postnatal day 7 through 35 with IVA dose levels of 10 mg/kg/day and higher (0.3 times the MRHD based on systemic exposure of IVA and its metabolites). This finding has not been observed in foetuses derived from rat dams treated with IVA on gestation days 7 to 17, in rat pups exposed to IVA to a certain extent through milk ingestion up to postnatal day 20, in 7‑week‑old rats, or in 3.5‑ to 5‑month‑old dogs treated with IVA. The potential relevance of these findings in humans is unknown. Deutivacaftor/tezacaftor/vanzacaftor Combination repeat‑dose toxicity studies in rats involving the co‑administration of VNZ, TEZ and D-IVA to assess the potential for additive and/or synergistic toxicity did not produce any unexpected toxicities or interactions.

6.1 List of excipients Tablet core Croscarmellose sodium (E468) Hypromellose (E464) Hypromellose acetate succinate Magnesium stearate (E470b) Microcrystalline cellulose (E460(i)) Sodium laurilsulfate (E487) Tablet film coat Carmine (E120) Brilliant Blue FCF aluminium lake (E133) Hydroxypropyl cellulose (E463) Hypromellose (E464) Iron oxide red (E172) Talc (E553b) Titanium dioxide (E171)6.2 Incompatibilities Not applicable.6.3 Shelf life 2 years6.4 Special precautions for storage This medicinal product does not require any special storage conditions.6.5 Nature and contents of container Thermoform blister consisting of PCTFE (polychlorotrifluoroethylene) film laminated to PVC (polyvinyl chloride) film and sealed with a blister foil lidding. Alyftrek Pack size of 56 tablets (4 foil blisters, each with 14 tablets)6.6 Special precautions for disposal and other handling Any unused medicinal product or waste material should be disposed of in accordance with local requirements.