Alyftrek Drug Information

Recommended Laboratory Testing Prior to ALYFTREK Initiation and During Treatment Prior to initiating ALYFTREK, obtain liver function tests (ALT, AST, alkaline phosphatase, and bilirubin) for all patients. Monitor liver function tests every month during the first 6 months of treatment, then every 3 months for the next 12 months, then at least annually thereafter. Consider more frequent monitoring for patients with a history of liver disease, elevated liver function tests at baseline, or a history of elevated liver function tests with drugs containing elexacaftor, tezacaftor, and/or ivacaftor.

Recommended Dosage

The recommended ALYFTREK dosage in adult and pediatric patients aged 6 years and older is provided in Table 1. Administer ALYFTREK orally (swallow the tablets whole) with fat-containing food, once daily, at approximately the same time each day. Examples of meals or snacks that contain fat are those prepared with butter or oils or those containing eggs, peanut butter, cheeses, nuts, whole milk, or meats.

Table 1: Recommended Dosage of ALYFTREK in Adult and Pediatric Patients Table 2 describes the recommended dosage modification for ALYFTREK when used concomitantly with strong or moderate CYP3A inhibitors. Table 2: Dosage Modification for Concomitant Use of ALYFTREK with Strong or

Recommended Dosage for Patients with Hepatic Impairment Severe Hepatic Impairment (Child-Pugh Class C): ALYFTREK should not be used in patients with severe hepatic impairment (HI) (Child-Pugh Class C). Moderate Hepatic Impairment (Child-Pugh Class B): The use of ALYFTREK in patients with moderate HI (Child-Pugh Class B) is not recommended. Use of ALYFTREK should only be considered in patients with moderate HI when there is a clear medical need, and the benefit outweighs the risk.

If used, the recommended dosage in patients with moderate HI is the same as for patients with normal hepatic function. Liver function tests should be closely monitored. Mild Hepatic Impairment (Child-Pugh Class A): The recommended dosage of ALYFTREK in patients with mild HI (Child-Pugh Class A) is the same as in patients with normal hepatic function.

Recommendations Regarding Missed Dose(s) If 6 hours or less have passed since the missed dose, take the missed dose as soon as possible and continue on the original schedule. If more than 6 hours have passed since the missed dose, skip the missed dose, and continue on the original schedule the next day.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The adverse reactions data below are from clinical trials of ALYFTREK in patients 6 years of age and older with CF with at least one responsive CFTR variant who were able to tolerate ELX/TEZ/IVA. Adverse reactions data in patients who previously discontinued or interrupted ELX/TEZ/IVA due to adverse reactions are not available.

Adverse Reactions in Patients Aged 12 Years and Older with CF The safety of ALYFTREK is based on 480 patients with CF aged 12 years and older who have at least one F508del variant or another responsive variant in the CFTR gene in two, 52-week, active-controlled trials (Trials 1 and 2). Patients with a history of prior intolerance to ELX/TEZ/IVA (i.e., patients who discontinued or interrupted treatment due to adverse reactions) were excluded. Trials 1 and 2 were not designed to evaluate meaningful comparisons of the incidence of adverse reactions between the ALYFTREK and ELX/TEZ/IVA treatment groups.

For additional information regarding ELX/TEZ/IVA adverse reactions, refer to ELX/TEZ/IVA Prescribing Information. Table 3: Adverse Reactions Occurring in ≥5% of ALYFTREK-Treated Patients and ≥1% Higher than ELX/TEZ/IVA-Treated Patients Aged 12 Years and Older with CF Who Had at Least One F508del Variant or Responsive Variant in the CFTR Gene (Trials 1 and 2) Adverse events that occurred in ≥5% of ELX/TEZ/IVA-treated patients at a similar or higher incidence than the ALYFTREK-treated patients included: infective pulmonary exacerbation of CF, COVID-19, diarrhea, abdominal pain, pyrexia, nasal congestion, increased sputum, increased blood creatinine phosphokinase, rhinorrhea, hemoptysis, nausea, back pain, arthralgia, constipation, sinusitis, dyspnea, and vomiting. In these trials, 1.5% of ALYFTREK-treated patients and 0.6% of ELX/TEZ/IVA-treated patients discontinued treatment for elevated transaminases.

Table 4 shows the incidence of maximum transaminase (ALT or AST) elevations in Trials 1 and 2. The rashes were generally mild to moderate in severity. A role of hormonal contraceptives in the occurrence of rash cannot be excluded.

Discontinuation due to increased creatinine phosphokinase was 0.2% for ALYFTREK-treated patients and 0.2% for ELX/TEZ/IVA-treated patients. Cases of rhabdomyolysis without renal involvement have been reported in patients who had recently exercised taking a fixed-dose combination drug containing ELX/TEZ/IVA (the same or similar active ingredients as ALYFTREK). Increased Blood Pressure Elevations in mean systolic and diastolic blood pressure have been reported in patients taking a fixed-dose combination drug containing ELX/TEZ/IVA (the same or similar active ingredients as ALYFTREK).

The mean systolic and diastolic blood pressures remained in the normal range from both ALYFTREK and ELX/TEZ/IVA treatment arms. Adverse reactions for these patients were generally similar to those reported in Trial 1 and Trial 2. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Nervous System Disorders: intracranial hypertension Psychiatric Disorders: anxiety, depression, suicidal ideation and behavior, insomnia

Effect of Other Drugs and Grapefruit on ALYFTREK Strong or Moderate CYP3A Inducers Concomitant use of ALYFTREK with strong or moderate CYP3A inducers is not recommended. Vanzacaftor, tezacaftor, and deutivacaftor are substrates of CYP3A. Concomitant use of ALYFTREK with a strong or moderate CYP3A inducer decreases vanzacaftor, tezacaftor, and deutivacaftor exposure which may reduce ALYFTREK effectiveness.

Strong or Moderate CYP3A Inhibitors Reduce the ALYFTREK dosage when used concomitantly with a strong or moderate CYP3A inhibitor. Concomitant use with a strong CYP3A inhibitor increases vanzacaftor, tezacaftor, and deutivacaftor exposure, which may increase the risk of ALYFTREK adverse reactions. Grapefruit Food or drink containing grapefruit should be avoided during treatment with ALYFTREK.

Concomitant use of ALYFTREK with grapefruit juice which contains one or more components that moderately inhibit CYP3A may increase exposure of vanzacaftor, tezacaftor and deutivacaftor.

Effect of ALYFTREK on Other Drugs P-glycoprotein (P-gp) Substrates Unless otherwise recommended in the P-gp substrate Prescribing Information, monitor more frequently for adverse reactions with concomitant use of ALYFTREK with P-gp substrates where minimal concentration changes may lead to serious adverse reactions related to P-gp substrates. Tezacaftor and deutivacaftor (components of ALYFTREK) are P-gp inhibitors. Administration of tezacaftor/ivacaftor increases exposure of P-gp substrates, which may increase the risk of adverse reactions related to these substrates.

Breast Cancer Resistance Protein (BCRP) Substrates Unless otherwise recommended in the BCRP substrate Prescribing Information, monitor more frequently for adverse reactions with concomitant use of ALYFTREK with BCRP substrates where minimal concentration changes may lead to serious adverse reactions related to BCRP substrates. Vanzacaftor (VNZ) and deutivacaftor (D-IVA) (components of ALYFTREK) 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.

CYP2C9 Substrates Use caution when ALYFTREK is used concomitantly with CYP2C9 substrates. Monitor the international normalized ratio (INR) more frequently with concomitant use of ALYFTREK with warfarin. This recommendation is based upon a mechanistic understanding of deutivacaftor pharmacokinetics (it is an inhibitor of CYP2C9 in vitro).

Drugs with No Clinically Significant Interactions with ALYFTREK Ciprofloxacin No clinically relevant effect on the exposure of tezacaftor was observed when tezacaftor/ivacaftor was used concomitantly with ciprofloxacin. Hormonal Contraceptives No clinically significant differences in the pharmacokinetics of ethinyl estradiol/norethindrone containing hormonal contraceptives were observed when used concomitantly with tezacaftor in combination with ivacaftor and ivacaftor alone. No clinically significant differences in the pharmacokinetics of ethinyl estradiol/norethindrone containing hormonal contraceptives are expected when used in combination with ALYFTREK based upon a mechanistic understanding of vanzacaftor, tezacaftor, and deutivacaftor pharmacokinetics; however, this has not been studied clinically.

A role for hormonal contraceptives contributing to rash cannot be excluded. For patients 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.

Pregnancy Risk Summary There are no available data on ALYFTREK use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Although there are no animal reproduction studies with the concomitant administration of vanzacaftor, tezacaftor, and deutivacaftor, separate reproductive and developmental studies were conducted with vanzacaftor and tezacaftor in pregnant rats and rabbits. Deutivacaftor is a deuterated isotopologue of ivacaftor with a toxicity profile similar to ivacaftor.

Reproductive and development studies were conducted with ivacaftor in pregnant rats and rabbits. In animal embryo fetal development (EFD) studies, oral administration of vanzacaftor to pregnant rats and rabbits during organogenesis demonstrated no adverse developmental effects at doses that produced maternal exposures up to approximately 30 times the exposure at the maximum recommended human dose (MRHD) in rats and 22 times the MRHD in rabbits. Oral administration of tezacaftor to pregnant rats and rabbits during organogenesis demonstrated no adverse developmental effects at doses that produced maternal exposures up to approximately 3 times the exposure at the MRHD in rats and 0.2 times the MRHD in rabbits (based on summed AUCs of tezacaftor and the metabolite M1-TEZ).

Oral administration of ivacaftor to pregnant rats and rabbits during organogenesis demonstrated no adverse developmental effects at doses that produced maternal exposures up to approximately 8 and 9 times the exposure at the MRHD, respectively (based on AUC of ivacaftor for rats and rabbits). No adverse developmental effects were observed after oral administration of vanzacaftor, tezacaftor, or ivacaftor to pregnant rats from the period of organogenesis through lactation at doses that produced maternal exposures approximately 18 times, 1 time, and 8 times the exposures at the MRHD, respectively (based on AUCs of vanzacaftor, tezacaftor and M1-TEZ, and ivacaftor) ( see Data ). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is respectively. Vanzacaftor did not cause adverse effects to the fetus at exposures up to 30 times the MRHD (based on AUC for vanzacaftor at maternal doses up to 10 mg/kg/day).

Vanzacaftor did not cause adverse effects to the fetus at exposures up to 22 times the MRHD (based on AUC of vanzacaftor at maternal doses up to 40 mg/kg/day). The high dose of 70 mg/kg/day (71 times the exposure at the MRHD) produced maternal toxicity (i.e., mortality, abortion, decreased mean body weight or body weight gains) and was associated with findings of increased post-implantation loss, decreased live fetuses, decreased fetal body weight, and increased kidney malformations. Placental transfer of vanzacaftor was observed in pregnant rats.

Tezacaftor did not cause adverse effects to the fetus at exposures up to 3 times the MRHD (based on summed AUCs of tezacaftor and M1-TEZ). Maternal toxicity in rats was observed at ≥50 mg/kg/day (approximately ≥1 time the MRHD). Lower fetal body weights were observed in rabbits at a maternally toxic dose that produced exposures approximately 1 time the MRHD (based on summed AUCs of tezacaftor and M1-TEZ at a maternal dose of 50 mg/kg/day).

Tezacaftor had no adverse developmental effects on pups at an exposure of approximately 1 time the MRHD (based on summed AUCs for tezacaftor and M1-TEZ at a maternal dose of 25 mg/kg/day). Decreased fetal body weights and early developmental delays in pinna detachment, eye opening, and righting reflex occurred at a maternally toxic dose (based on maternal weight loss) that produced exposures approximately 2 times the exposure at the MRHD (based on summed AUCs for tezacaftor and M1-TEZ). Placental transfer of tezacaftor was observed in pregnant rats.

Deutivacaftor: Animal reproduction studies have not been conducted with deutivacaftor. Ivacaftor did not cause adverse effects to the fetus at exposures up to 8 times the MRHD for deutivacaftor (based on AUC of ivacaftor in animal studies up to 200 mg/kg/day). Maternal toxicity (i.e., death, decreased food consumption, decreased mean body weight and body weight gain, decreased clinical condition, abortions) was observed at doses greater than or equal to 50 mg/kg/day (approximately 3 times the MRHD).

Ivacaftor had no effects on delivery or growth and development of offspring at exposures up to 8 times the MRHD (based on AUC for ivacaftor at maternal oral doses up to 100 mg/kg/day). Decreased fetal body weights were observed at a maternally toxic dose (200 mg/kg/day, 13 times the exposure at MHRD). Placental transfer of ivacaftor was observed in pregnant rats and rabbits.

Pediatric Use The safety and effectiveness of ALYFTREK for the treatment of CF have been established in pediatric patients aged 6 years and older who have a clinical diagnosis of CF and who have at least one variant in the CFTR gene that is either responsive based on clinical and/or in vitro data or results in production of CFTR protein. Use of ALYFTREK for this indication was supported by evidence from two adequate and well-controlled trials (Trials 1 and 2) in patients with CF aged 12 years and older who had at least one F508del variant or another responsive variant in the CFTR gene and additional pharmacokinetic and safety data in pediatric patients with CF aged 6 to less than 12 years who had at least one F508del variant or another responsive variant in the CFTR gene (Trial 3). In Trial 2, 41 adolescents aged 12 to less than 18 years who were homozygous for F508del variant, heterozygous for F508del variant and either a gating or a residual function variant, or with at least one variant responsive to ELX/TEZ/IVA with no F508del variant.

The efficacy of ALYFTREK in patients aged 6 to less than 12 years for this indication was extrapolated from patients aged 12 years and older with support from population pharmacokinetic analyses showing vanzacaftor, tezacaftor, and deutivacaftor exposure levels in patients aged 6 to less than 12 years to be within the range of exposures observed in patients aged 12 years and older. The overall safety profile of patients in Trial 3 was generally similar to the safety data in adult and pediatric patients 12 years of age and older observed in Trials 1 and 2. There is a risk of cataracts in pediatric patients treated with ALYFTREK.

Perform baseline and follow-up ophthalmological examination in pediatric patients prior to and during treatment with ALYFTREK. The safety and effectiveness of ALYFTREK in patients younger than 6 years of age have not been established. Juvenile Animal Toxicity Data Findings of cataracts were observed in juvenile rats dosed from postnatal Day 7 through 35 with ivacaftor dose levels of 10 mg/kg/day and higher (0.21 times the MRHD based on systemic exposure of ivacaftor and its metabolites).

This finding has not been observed in older animals. Studies were conducted with tezacaftor in juvenile rats starting at postnatal day (PND) 21 and ranging up to PNDs 35 to 49. Findings of convulsions and death were observed in juvenile rats that received a tezacaftor dose level of 100 mg/kg/day (approximately equivalent to 1.9 times the MRHD based on summed AUCs of tezacaftor and its metabolite, M1-TEZ).

A no effect dose level was identified at 30 mg/kg/day (approximately equivalent to 0.8 times the MRHD based on summed AUCs of tezacaftor and its metabolite, M1-TEZ). Findings were dose related and generally more severe when dosing with tezacaftor was initiated earlier in the postnatal period (PND 7, which would be approximately equivalent to a human neonate). Tezacaftor and its metabolite, M1-TEZ, are substrates for P-glycoprotein.

Lower brain levels of P-glycoprotein activity in younger rats resulted in higher brain levels of tezacaftor and M1-TEZ. These findings are not relevant for the indicated pediatric population 6 to 11 years of age, for whom levels of P-glycoprotein activity are equivalent to levels observed in adults.

Treatment of overdosage consists of general supportive measures including monitoring of vital signs and observation of the clinical status.