Dosage & Administration
Prior to initiating ALYFTREK obtain liver function tests (ALT, AST, alkaline phosphatase, and bilirubin) in all patients. Monitor liver function tests every month during the first 6 months of treatment, then every 3 months during the next 12 months, then at least annually thereafter.
| Age | Weight | Once Daily Oral Dosage |
|---|---|---|
| 6 to less than 12 years old | Less than 40 kg | Three tablets of vanzacaftor 4 mg/tezacaftor 20 mg/deutivacaftor 50 mg |
| Greater than or equal to 40 kg | Two tablets of vanzacaftor 10 mg/tezacaftor 50 mg/deutivacaftor 125 mg | |
| 12 years and older | Any Weight | Two tablets of vanzacaftor 10 mg/tezacaftor 50 mg/deutivacaftor 125 mg |
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Alyftrek Prescribing Information
Elevated transaminases have been observed in patients treated with ALYFTREK. Cases of serious and potentially fatal drug-induced liver injury and liver failure were reported in patients who were taking a fixed-dose combination drug containing elexacaftor, tezacaftor, and ivacaftor, which contains the same or similar active ingredients as ALYFTREK. Liver injury has been reported within the first month of therapy and up to 15 months following initiation of elexacaftor/tezacaftor/ivacaftor [see Warnings and Precautions (5.1) and Adverse Reactions (6)].
Assess liver function tests (ALT, AST, alkaline phosphatase, and bilirubin) in all patients prior to initiating ALYFTREK, 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 or elevated liver function tests at baseline [see Dosage and Administration (2.1), Warnings and Precautions (5.1), Adverse Reactions (6), and Use in Specific Populations (8.7)].
Interrupt ALYFTREK for significant elevations in liver function tests or in the event of signs or symptoms of liver injury. Consider referral to a hepatologist. Follow patients closely with clinical and laboratory monitoring until abnormalities resolve. If abnormalities resolve, resume treatment only if the benefit is expected to outweigh the risk. Closer monitoring is advised after resuming ALYFTREK [see Warnings and Precautions (5.1)].
ALYFTREK should not be used in patients with severe hepatic impairment (Child-Pugh Class C). ALYFTREK is not recommended in patients with moderate hepatic impairment (Child-Pugh Class B) and should only be considered when there is a clear medical need, and the benefit outweighs the risk. If used, monitor patients closely [see Dosage and Administration (2.4), Warnings and Precautions (5.1), Adverse Reactions (6), Use in Specific Populations (8.7), and Clinical Pharmacology (12.3)].
ALYFTREK is indicated for the treatment of cystic fibrosis (CF) in patients 6 years of age and older who have at least one F508del mutation or another responsive mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene (see Table 5) [see Clinical Pharmacology (12.1)].
If the patient's genotype is unknown, an FDA-cleared CF mutation test should be used to confirm the presence of at least one indicated mutation.
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 [see Warnings and Precautions (5.1) and Use in Specific Populations (8.7)].
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 [see Clinical Pharmacology (12.3)]. 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.
| Age | Weight | Once Daily Oral Dosage |
|---|---|---|
| 6 to less than 12 years old | Less than 40 kg | Three tablets of vanzacaftor 4 mg/tezacaftor 20 mg/deutivacaftor 50 mg (total dose of vanzacaftor 12 mg/tezacaftor 60 mg/ deutivacaftor 150 mg) |
| Greater than or equal to 40 kg | Two tablets of vanzacaftor 10 mg/tezacaftor 50 mg/deutivacaftor 125 mg (total dose of vanzacaftor 20 mg/tezacaftor 100 mg/ deutivacaftor 250 mg) | |
| 12 years and older | Any weight | Two tablets of vanzacaftor 10 mg/tezacaftor 50 mg/deutivacaftor 125 mg (total dose of vanzacaftor 20 mg/tezacaftor 100 mg/ deutivacaftor 250 mg) |
Dosage Modification for Strong or Moderate CYP3A Inhibitors
Table 2 describes the recommended dosage modification for ALYFTREK when used concomitantly with strong or moderate CYP3A inhibitors [see Warnings and Precautions (5.5)]. Administer ALYFTREK orally (swallow the tablets whole) with fat-containing food, once daily, at approximately the same time each day [see Clinical Pharmacology (12.3)].
| Age | Weight | Moderate CYP3A Inhibitors | Strong CYP3A Inhibitors |
|---|---|---|---|
| 6 to less than 12 years old | Less than 40 kg | Two tablets of vanzacaftor 4 mg/tezacaftor 20 mg/deutivacaftor 50 mg every other day (total dose of vanzacaftor 8 mg/tezacaftor 40 mg/deutivacaftor 100 mg) | Two tablets of vanzacaftor 4 mg/tezacaftor 20 mg/deutivacaftor 50 mg once a week (total dose of vanzacaftor 8 mg/tezacaftor 40 mg/deutivacaftor 100 mg) |
| Greater than or equal to 40 kg | One tablet of vanzacaftor 10 mg/tezacaftor 50 mg/deutivacaftor 125 mg every other day | One tablet of vanzacaftor 10 mg/tezacaftor 50 mg/deutivacaftor 125 mg once a week | |
| 12 years and older | Any weight | One tablet of vanzacaftor 10 mg/tezacaftor 50 mg/deutivacaftor 125 mg every other day | One tablet of vanzacaftor 10 mg/tezacaftor 50 mg/deutivacaftor 125 mg once a week |
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 [see Dosage and Administration (2.1, 2.2)].
- 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. Liver function tests should be closely monitored [see Dosage and Administration (2.1, 2.2)].
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.
Tablets:
- Fixed-dose combination containing vanzacaftor 4 mg (equivalent to 4.24 mg of vanzacaftor calcium dihydrate), tezacaftor 20 mg, and deutivacaftor 50 mg. Each tablet is purple, round-shaped, film-coated, debossed with "V4" on one side and plain on the other.
- Fixed-dose combination containing vanzacaftor 10 mg (equivalent to 10.6 mg of vanzacaftor calcium dihydrate), tezacaftor 50 mg, and deutivacaftor 125 mg. Each tablet is purple, oblong-shaped, film-coated, debossed with "V10" on one side and plain on the other.
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 2% to 4% and 15% to 20%, respectively.
Data
Animal Data
Vanzacaftor: In an EFD study, pregnant rats were administered vanzacaftor at oral doses of 2.5, 5, and 10 mg/kg/day during the period of organogenesis from gestation Days 6-17. 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). In an EFD study, pregnant rabbits were administered vanzacaftor at oral doses of 10, 40, and 70 mg/kg/day during the period of organogenesis from gestation Days 7-20. 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. In a pre- and postnatal development (PPND) study in pregnant rats administered vanzacaftor at oral doses of 2.5, 5, and 10 mg/kg/day from gestation Day 6 through lactation Day 18, vanzacaftor did not cause adverse developmental effects in pups at maternal doses up to 10 mg/kg/day (approximately 18 times the exposure at the MRHD). Placental transfer of vanzacaftor was observed in pregnant rats.
Tezacaftor: In an EFD study, pregnant rats were administered tezacaftor at oral doses of 25, 50, and 100 mg/kg/day during the period of organogenesis from gestation Days 6-17. 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). In an EFD study, pregnant rabbits were administered tezacaftor at oral doses of 10, 25, and 50 mg/kg/day during the period of organogenesis from gestation Days 7-20. Tezacaftor did not cause adverse effects to the fetus at exposures up to 0.2 times the MRHD (based on summed AUCs of tezacaftor and M1-TEZ). 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). In a PPND study, pregnant rats were administered tezacaftor at oral doses of 25, 50, and 100 mg/kg/day from gestation Day 6 through lactation Day 18. 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. However, as a deuterated isotopologue of ivacaftor with a toxicity profile similar to ivacaftor based on a 13-week single-agent repeat dose toxicity study, the reproductive and developmental toxicity data from ivacaftor can inform the developmental and reproductive risks associated with deutivacaftor.
In an EFD study, pregnant rats were administered ivacaftor at oral doses of 50, 100, and 200 mg/kg/day during the period of organogenesis from gestation Days 7-17. 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). In an EFD study, pregnant rabbits were administered ivacaftor at oral doses of 25, 50, and 100 mg/kg/day during the period of organogenesis from gestation Days 7-19. Ivacaftor did not cause adverse effects to the fetus at exposures up to 9 times the MRHD for deutivacaftor (based on AUC of ivacaftor in animal studies). 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). In a PPND study, pregnant rats were administered ivacaftor at oral doses of 50, 100, and 200 mg/kg/day from gestation Day 7 through lactation Day 20. 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.
Lactation
Risk Summary
There are no data on the presence of vanzacaftor, tezacaftor, or deutivacaftor or their metabolites in human milk, the effects on the breastfed infant, or the effects on milk production.
Vanzacaftor and tezacaftor are excreted into the milk of lactating female rats. Deutivacaftor has not been evaluated; however, ivacaftor is excreted into the milk of lactating female rats (see Data). When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for ALYFTREK and any potential adverse effects on the breastfed child from ALYFTREK or from the underlying maternal condition.
Data
The concentration of vanzacaftor, tezacaftor, or deutivacaftor in animal milk does not necessarily predict the concentration of drug in human milk.
Vanzacaftor: Lacteal excretion of vanzacaftor in rats was demonstrated following a single oral dose (10 mg/kg) of 14C-vanzacaftor administered 6 to 10 days postpartum to lactating dams. Exposure of 14C-vanzacaftor in milk was approximately 0.2 times the value observed in plasma (based on AUC0-72h).
Tezacaftor: Lacteal excretion of tezacaftor in rats was demonstrated following a single oral dose (30 mg/kg) of 14C-tezacaftor administered 6 to 10 days postpartum to lactating dams. Exposure of 14C-tezacaftor in milk was approximately 3.0 times higher than in plasma (based on AUC0-72h).
Deutivacaftor: Deutivacaftor has not been evaluated; however, ivacaftor is excreted into the milk of lactating female rats. Lacteal excretion of ivacaftor in rats was demonstrated following a single oral dose (100 mg/kg) of 14C-ivacaftor administered 9 to 10 days postpartum to lactating dams. Exposure of 14C-ivacaftor in milk was approximately 1.5 times higher than in plasma (based on AUC0-24h).
Pediatric Use
The safety and effectiveness of ALYFTREK for the treatment of CF in pediatric patients aged 6 years and older who have at least one F508del mutation or another responsive mutation in the CFTR gene have been established. 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 mutation or another responsive mutation 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 mutation or another responsive mutation in the CFTR gene (Trial 3). In these trials, a total of 145 patients with CF aged 6 to less than 18 years received ALYFTREK including:
- In Trial 1, 26 adolescents aged 12 to less than 18 years who were heterozygous for F508del and a CFTR mutation that is not responsive to ivacaftor or tezacaftor/ivacaftor (minimal function mutation) [see Adverse Reactions (6.1) and Clinical Studies (14)].
- In Trial 2, 41 adolescents aged 12 to less than 18 years who were homozygous for F508del mutation, heterozygous for F508del mutation and either a gating or a residual function mutation, or with at least one mutation responsive to ELX/TEZ/IVA with no F508del mutation [see Adverse Reactions (6.1) and Clinical Studies (14)].
- In Trial 3, 78 pediatric patients with CF aged 6 to less than 12 years (mean age 9.1 years) with at least one mutation that is responsive to ELX/TEZ/IVA [see Adverse Reactions (6.1)]. In Trial 3, patients who weighed less than 40 kg patients received ALYFTREK (vanzacaftor 12 mg/tezacaftor 60 mg/deutivacaftor 150 mg once daily) and patients who weighed 40 kg or more received ALYFTREK (vanzacaftor 20 mg/tezacaftor 100 mg/deutivacaftor 250 mg once daily).
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 [see Clinical Pharmacology (12.3)].
Safety of ALYFTREK in patients aged 6 to less than 12 years for this indication was based on Trial 3. 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 [see Adverse Reactions (6.1)].
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 [see Warnings and Precautions (5.6)].
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 [see Warnings and Precautions (5.6)].
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.
Geriatric Use
Clinical studies of ALYFTREK did not include a sufficient number of patients with CF aged 65 years and older (n=2, 0.4% of patients treated with ALYFTREK in Trials 1 and 2) to determine whether they respond differently from younger adult patients with CF.
Renal Impairment
The recommended ALYFTREK dosage in patients with CF with mild to moderate renal impairment (RI) (eGFR 30 to < 90 mL/min/1.73 m2) is the same in patients with CF with normal kidney function. Use of ALYFTREK in patients with CF with severe RI (eGFR <30 mL/min/1.73 m2) or end-stage renal disease is recommended only if the benefits are expected to outweigh the risks.
No clinically significant differences in the pharmacokinetics of vanzacaftor, tezacaftor, or deutivacaftor were observed in patients with mild to moderate RI (eGFR 30 to <90 mL/min/1.73 m2) [see Clinical Pharmacology (12.3)]. The effect of severe RI (eGFR <30 mL/min/1.73 m2) on vanzacaftor, tezacaftor, or deutivacaftor pharmacokinetics is unknown [see Clinical Pharmacology (12.3)].
Hepatic Impairment
Severe Hepatic Impairment
ALYFTREK should not be used in patients with severe hepatic impairment (HI) (Child-Pugh Class C). ALYFTREK has not been studied in patients with CF with severe HI [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)].
Moderate Hepatic Impairment
The use of ALYFTREK is not recommended in patients with moderate HI (Child-Pugh Class B). Use of ALYFTREK should only be considered in patients with 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 [see Dosage and Administration (2.2), Warnings and Precautions (5.1) and Adverse Reactions (6.1)].
Mild Hepatic Impairment
The recommended dosage of ALYFTREK in patients with mild HI (Child-Pugh Class A) is the same as in patients with normal hepatic function. Liver function tests should be closely monitored [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)].
None.