Vanzacaftor, Tezacaftor, and Deutivacaftor (Monograph)

Brand name: Alyftrek
Drug class: Cystic Fibrosis Transmembrane Conductance Regulator Correctors

Introduction

Vanzacaftor, tezacaftor, and deutivacaftor (vanzacaftor/tezacaftor/deutivacaftor) is a fixed-combination preparation containing 3 drugs that act directly on the cystic fibrosis transmembrane conductance regulator (CFTR) protein; vanzacaftor and tezacaftor are CFTR correctors and deutivacaftor is a CFTR potentiator.

Uses for Vanzacaftor, Tezacaftor, and Deutivacaftor

Vanzacaftor, tezacaftor, and deutivacaftor has the following uses:

Vanzacaftor/tezacaftor/deutivacaftor 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 CFTR gene.

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.

Vanzacaftor, Tezacaftor, and Deutivacaftor Dosage and Administration

General

Vanzacaftor/tezacaftor/deutivacaftor is available in the following dosage form(s) and strength(s):

• Fixed-dose combination tablets containing vanzacaftor 4 mg, tezacaftor 20 mg, and deutivacaftor 50 mg.

• Fixed-dose combination tablets containing vanzacaftor 10 mg, tezacaftor 50 mg, and deutivacaftor 125 mg.

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults and Pediatric Patients ≥6 Years of Age

Dosage and Administration

Select patients for treatment with vanzacaftor/tezacaftor/deutivacaftor based on the presence of at least one F508del mutation or another responsive mutation in the CFTR gene. See manufacturer's prescribing information for a list of mutations responsive to vanzacaftor/tezacaftor/deutivacaftor.

Prior to initiating vanzacaftor/tezacaftor/deutivacaftor, 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.

Administer vanzacaftor/tezacaftor/deutivacaftor orally with fat-containing food, once daily, at approximately the same time each day.

The recommended dosage of vanzacaftor/tezacaftor/deutivacaftor is provided in the following table.

Vanzacaftor/tezacaftor/deutivacaftor should not be used in patients with severe hepatic impairment. Use is also not recommended in patients with moderate hepatic impairment unless the benefit outweighs the risk. If used, no dosage adjustment is recommended; liver function tests should be closely monitored.

See full prescribing information for dosage modifications for concomitant use of vanzacaftor/tezacaftor/deutivacaftor with strong or moderate CYP3A inhibitors.

Cautions for Vanzacaftor, Tezacaftor, and Deutivacaftor

Contraindications

None.

Warnings/Precautions

Drug-induced Liver Injury and Liver Failure

Elevated transaminases have been observed in patients treated with vanzacaftor/tezacaftor/deutivacaftor. Cases of serious and potentially fatal drug-induced liver injury and liver failure have been reported in patients with and without a history of liver disease who were taking a fixed-dose combination drug containing elexacaftor, tezacaftor, and ivacaftor (ELX/TEZ/IVA), which contains the same or similar active ingredients as vanzacaftor/tezacaftor/deutivacaftor. Liver injury has been reported within the first month of therapy and up to 15 months following initiation of ELX/TEZ/IVA.

Assess liver function tests (ALT, AST, alkaline phosphatase, and bilirubin) in all patients prior to initiating vanzacaftor/tezacaftor/deutivacaftor. Assess 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 in patients with a history of liver disease, elevated liver function tests at baseline, or a history of elevated liver function tests with drugs containing ELX, TEZ and/or IVA.

Interrupt vanzacaftor/tezacaftor/deutivacaftor therapy in patients with significant elevations in liver function tests (e.g., ALT or AST >5× the upper limit or normal [ULN] or ALT or AST >3× ULN with bilirubin >2× ULN) or clinical signs or symptoms suggestive of liver injury (e.g., jaundice, right upper quadrant pain, nausea, vomiting, altered mental status, ascites).

Consider referral to a hepatologist and follow patients closely with clinical and laboratory monitoring until abnormalities resolve. If abnormalities resolve and if the benefit is expected to outweigh the risk, resume vanzacaftor/tezacaftor/deutivacaftor treatment with close monitoring.

Vanzacaftor/tezacaftor/deutivacaftor should not be used in patients with severe hepatic impairment (Child-Pugh Class C). The fixed combination 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.

Hypersensitivity Reactions

Hypersensitivity reactions, including cases of anaphylaxis, have been reported in the postmarketing setting of drugs containing ELX, TEZ, and/or IVA (the same or similar active ingredients in vanzacaftor/tezacaftor/deutivacaftor). If signs or symptoms of serious hypersensitivity reactions develop during vanzacaftor/tezacaftor/deutivacaftor treatment, discontinue the fixed combination preparation and institute appropriate therapy. Consider the benefits and risks for the individual patient to determine whether to resume treatment.

Patients who Discontinued or Interrupted Elexacaftor-, Tezacaftor-, or Ivacaftor-containing Drugs Due to Adverse Reactions

There are no available safety data for vanzacaftor/tezacaftor/deutivacaftor in patients who previously discontinued or interrupted treatment with drugs containing elexacaftor, tezacaftor, or ivacaftor due to adverse reactions. Consider the benefits and risks before using vanzacaftor/tezacaftor/deutivacaftor in these patients. If vanzacaftor/tezacaftor/deutivacaftor is used in these patients, closely monitor for adverse reactions as clinically appropriate.

Reduced Effectiveness with Concomitant Use of CYP3A Inducers

Following concomitant use of strong or moderate CYP3A inducers with vanzacaftor/tezacaftor/deutivacaftor, exposures of the drugs were decreased, which may reduce effectiveness. Concomitant use with strong or moderate CYP3A inducers is not recommended.

Adverse Reactions with Concomitant Use of CYP3A Inhibitors

Following concomitant use of strong or moderate CYP3A inhibitors with vanzacaftor/tezacaftor/deutivacaftor, exposures of the drugs were increased, which may increase the risk of adverse reactions. Reduce the vanzacaftor/tezacaftor/deutivacaftor dosage with concomitant use of strong or moderate CYP3A inhibitors.

Cataracts

Cases of non-congenital lens opacities have been reported in pediatric patients treated with drugs containing ivacaftor (which is similar to an active ingredient in vanzacaftor/tezacaftor/deutivacaftor). Although other risk factors were present (such as corticosteroid use, exposure to radiation) in some cases, a possible risk attributable to ivacaftor treatment cannot be excluded. Baseline and follow-up ophthalmological examinations are recommended in pediatric patients treated with vanzacaftor/tezacaftor/deutivacaftor.

Specific Populations

Pregnancy

There are no available data on vanzacaftor/tezacaftor/deutivacaftor 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/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).

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.

Lactation

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. 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 vanzacaftor/tezacaftor/deutivacaftor and any potential adverse effects on the breastfed child from the combination therapy or from the underlying maternal condition.

Pediatric Use

The safety and effectiveness of vanzacaftor/tezacaftor/deutivacaftor for the treatment of CF in pediatric patients 6 years of age and older who have at least one F508del mutation or another responsive mutation in the CFTR gene have been established. Use of vanzacaftor/tezacaftor/deutivacaftor for this indication was supported by evidence from two adequate and well-controlled trials (Trials 1 and 2) in patients 12 years of age and older with CF who had at least one F508del mutation or another responsive mutation in the CFTR gene and additional pharmacokinetic and safety data in pediatric patients 6 to less than 12 years of age with CF 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 6 to less than 18 years of age received vanzacaftor/tezacaftor/deutivacaftor including the following:

• In Trial 1, 26 adolescents 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).

• In Trial 2, 41 adolescents 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.

• In Trial 3, 78 pediatric patients 6 to less than 12 years of age (mean age 9.1 years) with CF and at least one mutation that is responsive to ELX/TEZ/IVA. In Trial 3, patients who weighed less than 40 kg patients received vanzacaftor/tezacaftor/deutivacaftor (vanzacaftor 12 mg/tezacaftor 60 mg/deutivacaftor 150 mg once daily) and patients who weighed 40 kg or more received vanzacaftor/tezacaftor/deutivacaftor (vanzacaftor 20 mg/tezacaftor 100 mg/deutivacaftor 250 mg once daily).

The efficacy of vanzacaftor/tezacaftor/deutivacaftor in patients 6 to less than 12 years of age for this indication was extrapolated from patients 12 years of age and older with support from population pharmacokinetic analyses showing vanzacaftor/tezacaftor/deutivacaftor exposure levels in patients 6 to less than 12 years to be within the range of exposures observed in patients 12 years of age and older.

Safety of vanzacaftor/tezacaftor/deutivacaftor in patients 6 to less than 12 years of age 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.

There is a risk of cataracts in pediatric patients treated with vanzacaftor/tezacaftor/deutivacaftor. Perform baseline and follow-up ophthalmological examination in pediatric patients prior to and during treatment.

The safety and effectiveness of vanzacaftor/tezacaftor/deutivacaftor in patients younger than 6 years of age have not been established.

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 time 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.

Geriatric Use

Clinical studies of vanzacaftor/tezacaftor/deutivacaftor did not include a sufficient number of patients 65 years of age and older with CF to determine whether they respond differently from younger adult patients with CF.

Renal Impairment

The recommended vanzacaftor/tezacaftor/deutivacaftor dosage in patients with CF with mild to moderate renal impairment (eGFR 30 to < 90 mL/min/1.73 m²) is the same as in patients with CF with normal kidney function. Use of vanzacaftor/tezacaftor/deutivacaftor in patients with CF with severe renal impairment (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/deutivacaftor were observed in patients with mild to moderate renal impairment (eGFR 30 to <90 mL/min/1.73 m²). The effect of severe renal impairment (eGFR <30 mL/min/1.73 m²) on vanzacaftor/tezacaftor/deutivacaftor pharmacokinetics is unknown.

Hepatic Impairment

Vanzacaftor/tezacaftor/deutivacaftor should not be used in patients with severe hepatic impairment (Child-Pugh Class C). The fixed-combination preparation has not been studied in patients with CF with severe hepatic impairment.

The use of vanzacaftor/tezacaftor/deutivacaftor is not recommended in patients with moderate hepatic impairment (Child-Pugh Class B). Use of vanzacaftor/tezacaftor/deutivacaftor should only be considered in patients with hepatic impairment when there is a clear medical need, and the benefit outweighs the risk. If used, the recommended dosage in patients with moderate hepatic impairment is the same as for patients with normal hepatic function. Liver function tests should be closely monitored.

The recommended dosage of vanzacaftor/tezacaftor/deutivacaftor in patients with mild hepatic impairment (Child-Pugh Class A) is the same as in patients with normal hepatic function. Liver function tests should be closely monitored.

Common Adverse Effects

Most common adverse reactions to vanzacaftor/tezacaftor/deutivacaftor (≥5% of patients and at a frequency higher than ELX/TEZ/IVA by ≥1%) were cough, nasopharyngitis, upper respiratory tract infection, headache, oropharyngeal pain, influenza, fatigue, increased ALT, rash, increased AST, and sinus congestion.

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

• Strong or moderate CYP3A inducers: Concomitant use with vanzacaftor/tezacaftor/deutivacaftor is not recommended.

• Strong or moderate CYP3A inhibitors: Reduce vanzacaftor/tezacaftor/deutivacaftor dosage with concomitant use. Avoid food or drink containing grapefruit.

Actions

Mechanism of Action

Vanzacaftor and tezacaftor 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. Deutivacaftor potentiates the channel open probability (or gating) of the CFTR protein at the cell surface.

The combined effect of vanzacaftor/tezacaftor/deutivacaftor 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 in patients with CF.

Effects of vanzacaftor/tezacaftor/deutivacaftor on chloride transport for mutant CFTR protein was determined in Ussing chamber electrophysiology studies using a panel of Fischer Rat Thyroid (FRT) cell lines stably expressing CFTR protein from individual mutations. Vanzacaftor/tezacaftor/deutivacaftor increased chloride transport in FRT cells expressing select CFTR mutations.

The threshold that the treatment-induced increase in chloride transport must exceed for the mutant CFTR protein to be considered responsive is ≥10% of normal over baseline. This threshold was used because it is expected to predict 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.

Homozygous and heterozygous N1303K- Human Bronchial Epithelial (HBE) cells showed greater chloride transport in the presence of vanzacaftor/tezacaftor/deutivacaftor than F508del/F508del-HBE cells treated with tezacaftor/ivacaftor, which has shown clinical benefit in people homozygous for F508del.

Advice to Patients

• Advise the patient to read the FDA-approved patient labeling (Medication Guide).

• Inform patients that elevations of transaminases have occurred in patients with CF treated with vanzacaftor/tezacaftor/deutivacaftor and that cases of drug-induced liver injury and failure have been observed with the fixed-dose combination drug containing elexacaftor, tezacaftor, and ivacaftor, which contains the same or similar active ingredients as vanzacaftor/tezacaftor/deutivacaftor.

• Advise all patients that liver function tests should be assessed prior to initiating vanzacaftor/tezacaftor/deutivacaftor, and then assessed every month during the first 6 months of treatment, then every 3 months for the next 12 months, then at least annually thereafter. Inform patients with a history of liver disease or liver function test elevations at baseline that more frequent monitoring may be necessary. Instruct patients to interrupt treatment with vanzacaftor/tezacaftor/deutivacaftor if symptoms of liver injury occur (e.g., jaundice, right upper quadrant pain, nausea, vomiting, altered mental status, ascites) and notify their healthcare provider immediately.

• Inform patients that hypersensitivity reactions including anaphylaxis have been reported in patients who received drugs containing elexacaftor, tezacaftor, and/or ivacaftor (the same or similar active ingredients as vanzacaftor/tezacaftor/deutivacaftor). Instruct patients to discontinue vanzacaftor/tezacaftor/deutivacaftor and notify their healthcare provider if they experience signs and symptoms of a hypersensitivity reaction, including rash, hives, itching, facial swelling, tightness of the chest and wheezing.

• Inform patients that there is no available safety data for vanzacaftor/tezacaftor/deutivacaftor in patients who previously discontinued or interrupted treatment with elexacaftor-, tezacaftor-, or ivacaftor-containing drugs due to adverse reactions. These patients who start treatment with vanzacaftor/tezacaftor/deutivacaftor may require closer and more frequent monitoring.

• Inform patients that certain medications, herbal supplements, or vitamins, when used concomitantly with vanzacaftor/tezacaftor/deutivacaftor, may reduce the effectiveness of the combination drug or increase the risk of adverse reactions. Instruct patients to report all concomitant medications, herbal supplements, or vitamins, to their healthcare providers while taking vanzacaftor/tezacaftor/deutivacaftor.

• Instruct patients to avoid food or drink containing grapefruit when using vanzacaftor/tezacaftor/deutivacaftor.

• Inform patients that abnormality of the eye lens (cataract) has been noted in some pediatric patients receiving drugs containing ivacaftor (which is similar to an active ingredient in vanzacaftor/tezacaftor/deutivacaftor) and baseline and follow-up ophthalmological examinations are needed in pediatric patients receiving vanzacaftor/tezacaftor/deutivacaftor.

• Inform patients that vanzacaftor/tezacaftor/deutivacaftor is best absorbed by the body when taken with food that contains fat. Examples include eggs, butter, peanut butter, whole-milk dairy products (such as whole milk, cheese and yogurt), etc.

• Inform patients of the following if they miss a vanzacaftor/tezacaftor/deutivacaftor dose. If 6 hours or less have passed since the missed dose is usually taken, patients should be instructed to take the prescribed dose with fat-containing food as soon as possible. If more than 6 hours have passed since the missed dose, patients should be instructed to skip the missed dose and continue on the original schedule the next day.

Additional Information

AHFSfirstRelease^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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