Vanzacaftor, Tezacaftor, and Deutivacaftor (Monograph)

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

Introduction

Fixed combination containing vanzacaftor and tezacaftor (cystic fibrosis transmembrane conductance regulator [CFTR] correctors) and deutivacaftor (CFTR potentiator).

Uses for Vanzacaftor, Tezacaftor, and Deutivacaftor

Cystic Fibrosis

Vanzacaftor, tezacaftor, and deutivacaftor combination therapy: Treatment of cystic fibrosis (CF) in patients ≥6 years of age who have at least one F508del mutation or another responsive mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.

Designated an orphan drug by FDA for this use.

If patient’s genotype is unknown, FDA-cleared CF mutation test should be used to confirm presence of at least one F508del mutation or a mutation that is responsive based on clinical response and/or in vitro data.

Current standard of care for treatment of CF is elexacaftor/tezacaftor/ivacaftor combination therapy. Deutivacaftor is a modified form of ivacaftor that allows vanzacaftor/tezacaftor/deutivacaftor to be taken once a day. The 2018 Cystic Fibrosis Foundation pulmonary guideline addresses use of CFTR modulators in patients with CF. Vanzacaftor/tezacaftor/deutivacaftor and elexacaftor/tezacaftor/ivacaftor were approved after publication of guideline, and therefore not addressed.

Vanzacaftor, Tezacaftor, and Deutivacaftor Dosage and Administration

General

Pretreatment Screening

• Obtain liver function tests.

• Obtain baseline ophthalmologic examination in pediatric patients.

Patient Monitoring

• Monitor liver function tests every month during the first 6 months of treatment, every 3 months during the next 12 months, and at least annually thereafter.

• Perform follow-up ophthalmologic examinations in pediatric patients.

Administration

Oral Administration

Administer orally as tablets.

Available in 2 different dosage combinations: 4 mg of vanzacaftor, 20 mg of tezacaftor, and 50 mg of deutivacaftor (4 mg/20 mg/50 mg) and 10 mg of vanzacaftor, 50 mg of tezacaftor, and 125 mg of deutivacaftor (10 mg/50 mg/125 mg).

Swallow tablets whole.

Administer tablets once daily, at same time each day with fat-containing food (e.g., eggs, cheese, nuts, peanut butter, whole milk, meats, or food prepared with butter or oils).

If a dose is missed by ≤6 hours, take dose as soon as possible; take next dose at regularly scheduled time.

If a dose is missed by >6 hours, omit dose; take next dose at regularly scheduled time.

Dosage

Dosage of vanzacaftor calcium dihydrate is expressed in terms of vanzacaftor.

Pediatric Patients

Cystic Fibrosis

Oral

Pediatric patients 6 to <12 years of age: Recommended dosage is weight-based. For patients ≥40 kg, recommended dosage is 2 tablets of vanzacaftor 10 mg/tezacaftor 50 mg/deutivacaftor 125 mg once daily. For patients <40 kg, the recommended dosage is 3 tablets of vanzacaftor 4 mg/tezacaftor 20 mg/deutivacaftor 50 mg once daily.

Pediatric patients ≥12 years of age: Recommended dosage is 2 tablets of vanzacaftor 10 mg/tezacaftor 50 mg/deutivacaftor 125 mg once daily.

Adults

Cystic Fibrosis

Oral

Recommended dosage is 2 tablets of vanzacaftor 10 mg/tezacaftor 50 mg/deutivacaftor 125 mg once daily.

Dosage Modification for Patients Taking CYP3A Inhibitors

Dosage adjustments necessary when co-administered with strong (e.g., ketoconazole, itraconazole, posaconazole, voriconazole, and clarithromycin) or moderate (e.g., fluconazole, erythromycin) CYP3A inhibitors (see Table 1).

Special Populations

Hepatic Impairment

Dosage adjustment is not necessary in patients with mild hepatic impairment; however, liver function tests should be monitored closely in such patients.

Use not recommended in patients with moderate hepatic impairment. If there is clear medical need and expected benefit exceeds potential risk, vanzacaftor/tezacaftor/deutivacaftor should be used with caution at same dose as for patients with normal hepatic function. Monitor liver function tests closely in patients with moderate hepatic impairment.

Should not be used in patients with severe hepatic impairment.

Renal Impairment

Dosage adjustment not necessary in patients with mild or moderate renal impairment.

Use in patients with severe renal impairment or end-stage renal disease (ESRD) is recommended only if expected benefit exceeds potential risk.

Geriatric Patients

No specific dosage recommendations.

Cautions for Vanzacaftor, Tezacaftor, and Deutivacaftor

Contraindications

• None.

Warnings/Precautions

Warnings

Drug-induced Liver Injury and Liver Failure

Elevated transaminases observed. (See Boxed Warning.)

Serious and potentially fatal drug-induced liver injury and liver failure reported in patients with and without history of liver disease.

Assess ALT, AST, alkaline phosphatase, and bilirubin prior to initiating vanzacaftor/tezacaftor/deutivacaftor; continue monitoring every month during the first 6 months of treatment, every 3 months for the next 12 months, then at least annually thereafter. Consider more frequent monitoring in patients with history of liver disease, history of elevated liver function tests with previous use of drugs containing elexacaftor, tezacaftor, and/or ivacaftor, or patients with elevated liver function tests at baseline.

Interrupt treatment if signs (e.g., ALT or AST >5x ULN or ALT or AST 3x ULN with bilirubin >2x ULN) or symptoms of liver injury (e.g., jaundice, right upper quadrant pain, nausea, vomiting, altered mental status, ascites) occur. Consider referral to hepatologist; monitor clinical and laboratory abnormalities until resolved. Resume treatment when abnormalities resolve, and only if benefit expected to outweigh risk; monitor patients closely.

Do not use in patients with severe hepatic impairment; not recommended with moderate hepatic impairment. Should only be considered in patients with moderate hepatic impairment when there is clear medical need and benefit outweighs risk; if used, monitor closely.

Other Warnings and Precautions

Hypersensitivity Reactions

Hypersensitivity reactions, including anaphylaxis, reported.

If signs or symptoms of serious hypersensitivity reactions develop, discontinue therapy and initiate appropriate therapy. Consider benefits and risks when determining whether to resume.

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

No available data on safety of using vanzacaftor/tezacaftor/deutivacaftor in patients who previously discontinued or interrupted treatment with drugs containing elexacaftor, tezacaftor, or ivacaftor due to adverse reactions.

Consider risks and benefits of using vanzacaftor/tezacaftor/deutivacaftor in these patients; if patients proceed with treatment, closely monitor for adverse reactions as clinically appropriate.

Reduced Effectiveness with Concomitant Use of CYP3A Inducers

Concomitant use with strong or moderate CYP3A inducers decreases exposure of vanzacaftor, tezacaftor, and deutivacaftor, which may reduce therapeutic efficacy of the drug.

Concomitant use with strong or moderate CYP3A inducers is not recommended.

Adverse Reactions with Concomitant Use of CYP3A Inhibitors

Concomitant use with strong or moderate CYP3A inhibitors increases exposure of vanzacaftor, tezacaftor, deutivacaftor, which may increase risk of drug-associated adverse reactions.

If used concomitantly with strong or moderate CYP3A inhibitors, reduce dosage of vanzacaftor/tezacaftor/deutivacaftor.

Cataracts

Ocular lens opacities (not congenital in nature) reported in pediatric patients receiving ivacaftor-containing drug regimens.

Baseline and follow-up ophthalmologic examinations recommended in pediatric patients.

Specific Populations

Pregnancy

No adequate data on use of vanzacaftor/tezacaftor/deutivacaftor or individual components in pregnant women. In animal studies, no adverse developmental effects observed after oral administration of vanzacaftor, tezacaftor, or ivacaftor to pregnant rats.

Lactation

Not known whether vanzacaftor/tezacaftor/deutivacaftor or individual components are distributed into human milk, effects on breastfed infant, or effect on milk production. Vanzacaftor, tezacaftor, and ivacaftor are distributed into milk in rats; deutivacaftor not evaluated.

Consider developmental and health benefits of breastfeeding along with mother’s clinical need and any potential adverse effects on breastfed infant from the drugs or from underlying maternal condition.

Pediatric Use

Safety and efficacy established in pediatric patients ≥6 years of age.

Geriatric Use

Clinical studies did not include sufficient numbers of patients ≥65 years of age.

Hepatic Impairment

Vanzacaftor/tezacaftor/deutivacaftor should only be considered in patients with moderate hepatic impairment when there is clear medical need, and benefit outweighs risk. Should not be used in patients with severe hepatic impairment.

Renal Impairment

No clinically significant differences in pharmacokinetics of vanzacaftor, tezacaftor, or deutivacaftor observed in patients with mild to moderate renal impairment. Effect of severe renal impairment on vanzacaftor, tezacaftor, or deutivacaftor pharmacokinetics unknown.

Common Adverse Effects

Most common adverse reactions (≥5%): cough, nasopharyngitis, upper respiratory tract infection, headache, oropharyngeal pain, influenza, fatigue, increased ALT, rash, increased AST, sinus congestion.

Drug Interactions

Vanzacaftor, tezacaftor, and deutivacaftor are substrates of CYP3A.

Deutivacaftor is an inhibitor of CYP2C9 in vitro.

Vanzacaftor and deutivacaftor are P-glycoprotein (P-gp) inhibitors and in vitro inhibitors of breast cancer resistance protein (BCRP).

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Strong or moderate CYP3A inducers: Decreased vanzacaftor, tezacaftor, and deutivacaftor exposure. Concomitant use with strong or moderate CYP3A inducers not recommended.

Strong or moderate CYP3A inhibitors: Increased vanzacaftor, tezacaftor, and deutivacaftor exposure. Reduced dosage recommended.

Concomitant administration of deutivacaftor with warfarin, CYP2C9 substrate, may increase systemic exposure of warfarin. Monitoring recommended (e.g., INR) when concomitant administration of deutivacaftor with warfarin is required. Deutivacaftor may increase exposure of other medications metabolized by CYP2C9; however, not studied clinically.

Drugs Affecting or Affected by Transport Systems

P-gp substrates: Possible increased exposure of P-gp substrate. Use P-gp substrates with narrow therapeutic index concomitantly with caution; monitor more frequently.

BCRP substrates: Possible increased exposure of BCRP substrate; however, not studied clinically. Use BCRP substrates with narrow therapeutic index concomitantly with caution; monitor more frequently.

Specific Drugs

Vanzacaftor, Tezacaftor, and Deutivacaftor Pharmacokinetics

Absorption

Bioavailability

Steady state concentrations of vanzacaftor, tezacaftor, and deutivacaftor achieved within 20, 8, and 8 days, respectively.

Following administration of vanzacaftor, tezacaftor, and deutivacaftor, time to maximum absorption achieved at 7.8, 1.6, and 3.7 hours, respectively.

Food

Exposure of vanzacaftor increased 4- and 6-fold following administration of low-fat and high-fat meal, respectively.

Exposure of deutivacaftor increased 3- and 4-fold following administration of low-fat and high-fat meal, respectively.

Distribution

Plasma Protein Binding

≥99%.

Elimination

Metabolism

Vanzacaftor, tezacaftor, and deutivacaftor metabolized by CYP3A4/5.

Tezacaftor and deutivacaftor active metabolites, M1-TEX and M1-D-IVA, respectively.

Half-life

Vanzacaftor: 92.8 hours.

Tezacaftor: 22.5 hours.

Deutivacaftor: 19.2 hours.

Stability

Storage

Oral

Tablets

Store at 20-25°C; excursions permitted to 15-30°C.

Actions

• Vanzacaftor/tezacaftor/deutivacaftor contains 3 drugs acting directly on cystic fibrosis transmembrane conductance regulator (CFTR) protein; vanzacaftor and tezacaftor are CFTR correctors and deutivacaftor is CFTR potentiator.

• Deutivacaftor is deuterated isotopologue of ivacaftor.

• Vanzacaftor/tezacaftor/deutivacaftor has same mechanism of action as elexacaftor/tezacaftor/ivacaftor.

• Mutations in gene encoding CFTR affect quantity or function of this protein at the cell surface resulting in cystic fibrosis.

• Vanzacaftor and tezacaftor bind to different sites on CFTR protein and have an additive effect in facilitating cellular processing and trafficking of select mutant forms of CFTR (including F508del-CFTR) to increase amount of CFTR protein delivered to the cell surface.

• Deutivacaftor facilitates increased chloride transport by potentiating probability of channel opening (or gating) of CFTR protein at the cell surface.

• Combined effect of vanzacaftor, tezacaftor, and deutivacaftor increases quantity and function of CFTR at the cell surface, resulting in increased chloride transport.

Advice to Patients

• Advise patients 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.

• 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.

• Advise patients to inform their clinician if they are or plan to become pregnant or plan to breast-feed.

• Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.

• Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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.

Fixed combination of vanzacaftor/tezacaftor/deutivacaftor can only be obtained through select specialty pharmacies and distributors.

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