Vanzacaftor, Tezacaftor, And Deutivacaftor

FDA Drug Information • Also known as: Alyftrek

Brand Names: Alyftrek
Dosage Form: TABLET, FILM COATED
Product Type: DRUG FOR FURTHER PROCESSING

⚠ Boxed Warning (Black Box)

WARNING: DRUG-INDUCED LIVER INJURY AND LIVER FAILURE 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) ] . WARNING: DRUG-INDUCED LIVER INJURY AND LIVER FAILURE See full prescribing information for complete boxed warning. Elevated transaminases have been observed in patients treated with ALYFTREK ( 5.1 , 6 ). Cases of serious and potentially fatal drug-induced liver injury and liver failure leading to transplantation and death were reported in patients who were taking ELX/TEZ/IVA, a drug containing the same or similar active ingredients as ALYFTREK ( 5.1 ). Assess liver function tests (ALT, AST, alkaline phosphatase, bilirubin) in all patients prior to initiating ALYFTREK, every month for first 6 months, every 3 months for next 12 months, then at least annually ( 2.1 , 5.1 ). Interrupt ALYFTREK for significant elevations in LFTs or signs or symptoms of liver injury. Follow patients closely with clinical and laboratory monitoring until abnormalities resolve ( 5.1 ). Resume ALYFTREK if abnormalities resolve and only if the benefit is expected to outweigh the risk ( 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) ( 2.4 , 5.1 , 8.7 , 12.3 ).

Description

11 DESCRIPTION ALYFTREK (vanzacaftor, tezacaftor, and deutivacaftor tablets) are fixed-dose combination tablets for oral use available as: 10 mg of vanzacaftor (equivalent to 10.6 mg of vanzacaftor calcium dihydrate), 50 mg of tezacaftor, 125 mg of deutivacaftor or 4 mg of vanzacaftor (equivalent to 4.24 mg of vanzacaftor calcium dihydrate), 20 mg of tezacaftor, 50 mg of deutivacaftor. The tablets contain the following inactive ingredients: croscarmellose sodium, hypromellose, hypromellose acetate succinate, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. The tablet film coating contains Brilliant Blue FCF aluminum lake/FD&C Blue #1, carmine, hydroxypropyl cellulose, hypromellose, iron oxide red, talc, and titanium dioxide. The active ingredients of ALYFTREK are described below. Vanzacaftor Vanzacaftor is provided as a calcium salt. Vanzacaftor calcium dihydrate is a white solid that is practically insoluble in water (< 0.1 mg/mL). Its chemical name is calcium bis((14 S )-8-[3-(2-{dispiro[2.0.2 4 .1 3 ]heptan-7-yl}ethoxy)pyrazol-1-yl]-12,12-dimethyl-2,2,4-trioxo-2λ 6 -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1 11,14 .0 5,10 ]tetracosa-1(23),5,7,9,19,21-hexaen-3-ide) dihydrate. Its molecular formula is C 32 H 38 N 7 O 4 S∙Ca 0.5 ∙H 2 O and its molecular weight is 654.82. Vanzacaftor calcium dihydrate has the following structural formula: Chemical Structure Tezacaftor Tezacaftor is a white to off-white solid that is practically insoluble in water (< 5 microgram/mL). Its chemical name is 1-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)-N-{1-[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl}cyclopropane-1-carboxamide. Its molecular formula is C 26 H 27 N 2 F 3 O 6 and its molecular weight is 520.50. Tezacaftor has the following structural formula: Chemical Structure Deutivacaftor Deutivacaftor is a white to off-white solid that is practically insoluble in water (< 0.1 mg/mL). Pharmacologically, it is a CFTR...

What Is Vanzacaftor, Tezacaftor, And Deutivacaftor Used For?

1 INDICATIONS AND USAGE 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. ALYFTREK is a combination of deutivacaftor, a CFTR potentiator, tezacaftor, and vanzacaftor indicated for the treatment of cystic fibrosis (CF) in patients aged 6 years and older who have at least one F508del mutation or another responsive mutation in the CFTR gene. ( 1 , 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. ( 1 , 12.1 )

Dosage and Administration

2 DOSAGE AND 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. ( 2.1 , 5.1 ) Recommended Dosage for Adult and Pediatric Patients Aged 6 Years and Older (with fat-containing food) ( 2.2 ) 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 Should not be used in patients with severe hepatic impairment. Use not recommended in patients with moderate hepatic impairment unless the benefit outweighs the risk. If used, no dose adjustment is recommended. Liver function tests should be closely monitored. ( 2.4 , 5.1 , 6.1 , 8.7 ) See full prescribing information for dosage modifications for concomitant use of ALYFTREK with strong or moderate CYP3A inhibitors. ( 2.3 , 5.6 , 7.1 ) 2.1 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) ]. 2.2 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. Table 1: Recommended Dosage of ALYFTREK in Adult and Pediatric Patients Aged 6 Years and Older 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...

Side Effects (Adverse Reactions)

6 ADVERSE REACTIONS The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling: Drug-Induced Liver Injury and Liver Failure [see Warnings and Precautions (5.1) ] Hypersensitivity Reactions, Including Anaphylaxis [see Warnings and Precautions (5.2) ] Patients Who Discontinued or Interrupted Elexacaftor-, Tezacaftor-, or Ivacaftor-Containing Drugs Due to Adverse Reactions [see Warnings and Precautions (5.3) ] Intracranial Hypertension [see Warnings and Precautions (5.4) ] Cataracts [see Warnings and Precautions (5.7) ] Most common adverse reactions to ALYFTREK (≥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. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Vertex Pharmaceuticals Incorporated at 1-877-634-8789 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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 mutation 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 mutation or another responsive mutation in the CFTR gene in two, 52-week, active-controlled trials (Trials 1 and 2) [see Clinical Studies (14) ]. In both trials, patients received a fixed-dose combination drug containing elexacaftor, tezacaftor, and ivacaftor (ELX/TEZ/IVA) in a 4-week run-in period and then were subsequently randomized to continue ELX/TEZ/IVA (elexacaftor 200 mg/tezacaftor 100 mg/ivacaftor 150 mg in the morning and ivacaftor 150 mg in the evening) or receive ALYFTREK (vanzacaftor 20 mg/tezacaftor 100 mg/deutivacaftor 250 mg) once daily. 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. In Trial 1 and Trial 2 combined, the proportion of patients who discontinued treatment prematurely due to adverse reactions were 3.8% and 3.7% in ALYFTREK and ELX/TEZ/IVA treatment groups, respectively. Serious adverse reactions that occurred more frequently with ALYFTREK treatment than with ELX/TEZ/IVA treatment that occurred in 2 or more patients (≥0.4%) were influenza (1.5%), increased AST (0.4%), increased GGT (0.4%), depression (0.4%), and syncope (0.4%). 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 Mutation or Responsive Mutation in the CFTR Gene (Trials 1 and 2) Adverse Reactions ALYFTREK N=480 ELX/TEZ/IVA N=491 Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; ELX, elexacaftor; IVA, ivacaftor; TEZ, tezacaftor Cough Cough is composed of several similar terms including productive cough. 120 (25%) 116 (24%) Nasopharyngitis 102 (21%) 95 (19%) Upper respiratory tract infection Upper respiratory tract infection is composed of several similar terms including viral upper respiratory tract...

Drug Interactions

7 DRUG INTERACTIONS Strong or moderate CYP3A inducers : Concomitant use with ALYFTREK is not recommended. ( 5.5 , 7.1 ) Strong or moderate CYP3A inhibitors : Reduce ALYFTREK dosage with concomitant use. Avoid food or drink containing grapefruit. ( 2.3 , 5.6 , 7.1 ) 7.1 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 [see Clinical Pharmacology (12.3) ] which may reduce ALYFTREK effectiveness [see Warnings and Precautions (5.5) ] . Strong or Moderate CYP3A Inhibitors Reduce the ALYFTREK dosage when used concomitantly with a strong or moderate CYP3A inhibitor [see Dosage and Administration (2.3) ] . Vanzacaftor, tezacaftor, and deutivacaftor are CYP3A substrates. Concomitant use with a strong CYP3A inhibitor increases vanzacaftor, tezacaftor, and deutivacaftor exposure [see Clinical Pharmacology (12.3) ] , which may increase the risk of ALYFTREK adverse reactions [see Warnings and Precautions (5.6) ]. Concomitant use with a moderate CYP3A inhibitor is predicted to increase vanzacaftor, tezacaftor, and deutivacaftor exposure [see Clinical Pharmacology (12.3) ] , which may increase the risk of ALYFTREK adverse reactions [see Warnings and Precautions (5.6) ]. 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. 7.2 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 [see Clinical Pharmacology (12.3) ] , which may increase the risk of adverse reactions related to these substrates. Breast Cancer Resistance Protein (BCRP) Substrates Unless otherwise recommended in BCRP substrate Prescribing Information, monitor more frequently for adverse reactions with concomitant use of ALYFTREK with BCRP substrate where minimal concentrations 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 [see Clinical Pharmacology (12.3) ]. CYP2C9...

Contraindications

4 CONTRAINDICATIONS None. None. ( 4 )

Pregnancy and Breastfeeding

8.1 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...

Overdosage

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

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING ALYFTREK (vanzacaftor, tezacaftor, and deutivacaftor) tablets are supplied as follows: Table 10: ALYFTREK Tablets and Package Configuration Strengths Tablet Description Package Configuration NDC 4 mg of vanzacaftor/ 20 mg of tezacaftor / 50 mg of deutivacaftor purple, round-shaped, film-coated, debossed with "V4" on one side and plain on the other 84-count carton containing 4 wallets, each wallet containing 21 tablets in blister packs NDC 51167-135-01 10 mg of vanzacaftor/ 50 mg of tezacaftor / 125 mg of deutivacaftor purple, oblong-shaped, film-coated, debossed with "V10" on one side and plain on the other 56-count carton containing 4 wallets, each wallet containing 14 tablets in blister packs NDC 51167-121-01 Store at 20°C - 25°C (68°F - 77°F); excursions permitted to 15°C - 30°C (59°F - 86°F) [see USP Controlled Room Temperature].

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.