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Elexacaftor, Tezacaftor, And Ivacaftor

Class: Cystic Fibrosis Transmembrane Conductance Regulator Correctors
Chemical Name: N-(1,3-Dimethyl-1H-pyrazole-4-sulfonyl)-6-[3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide
Molecular Formula: C26H34F3N7O4SC26H27F3N2O6C24H28N2O3
CAS Number: 2216712-66-0
Brands: Trikafta

Medically reviewed by Drugs.com on Nov 11, 2019. Written by ASHP.

Introduction

The combination of elexacaftor, tezacaftor, and ivacaftor increases the quantity and function of the cystic fibrosis transmembrane conductance regulator (CFTR) protein at the cell surface, resulting in increased CFTR activity as measured by CFTR mediated chloride transport.

Uses for Elexacaftor, Tezacaftor, And Ivacaftor

Elexacaftor, tezacaftor, and ivacaftor has the following uses:

The combination of elexacaftor, tezacaftor, and ivacaftor is indicated for the treatment of cystic fibrosis (CF) in patients aged 12 years and older who have at least one F508del 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 F508del mutation.

Elexacaftor, Tezacaftor, And Ivacaftor Dosage and Administration

General

The combination of elexacaftor, tezacaftor, and ivacaftor is available in the following dosage form(s) and strength(s):

  • Co-packaged as elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg fixed-dose combination tablets and ivacaftor 150 mg tablets.

Dosage

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

  • The combination of elexacaftor, tezacaftor, and ivacaftor is administered orally.

  • Instruct patients to swallow the tablets whole.

  • Elexacaftor, tezacaftor, and ivacaftor should be taken with fat-containing food. Examples of meals or snacks that contain fat are those prepared with butter or oils or those containing eggs, cheeses, nuts, whole milk, or meats.

Pediatric Patients

Dosage in Pediatric Patients 12 Years of Age and Older
  • The recommended starting dosage is two tablets (each containing elexacaftor 100 mg, tezacaftor 50 mg and ivacaftor 75 mg) taken in the morning and one ivacaftor tablet (containing ivacaftor 150 mg) taken in the evening, approximately 12 hours apart.

  • Should not be used in patients with severe hepatic impairment. Use not recommended in patients with moderate hepatic impairment unless the benefit exceeds the risk. Reduce dose if used in patients with moderate hepatic impairment. Liver function tests should be closely monitored.

  • Reduce dose when co-administered with drugs that are moderate or strong CYP3A inhibitors.

Adults

Dosage in Adults
  • The recommended starting dosage is two tablets (each containing elexacaftor 100 mg, tezacaftor 50 mg and ivacaftor 75 mg) taken in the morning and one ivacaftor tablet (containing ivacaftor 150 mg) taken in the evening, approximately 12 hours apart.

  • Should not be used in patients with severe hepatic impairment. Use not recommended in patients with moderate hepatic impairment unless the benefit exceeds the risk. Reduce dose if used in patients with moderate hepatic impairment. Liver function tests should be closely monitored.

  • Reduce dose when co-administered with drugs that are moderate or strong CYP3A inhibitors.

Cautions for Elexacaftor, Tezacaftor, And Ivacaftor

Contraindications

None.

Warnings/Precautions

Liver Function Test Elevations

Elevated transaminases have been observed in patients with CF treated with elexacaftor, tezacaftor, and ivacaftor. Bilirubin elevations have also been observed with elexacaftor, tezacaftor, and ivacaftor treatment. Assessments of liver function tests (ALT, AST, and bilirubin) are recommended for all patients prior to initiating elexacaftor, tezacaftor, and ivacaftor, every 3 months during the first year of treatment, and annually thereafter. For patients with a history of hepatobiliary disease or liver function test elevations, more frequent monitoring should be considered. In the event of significant elevations in liver function tests, e.g. ALT or AST >5 × the upper limit of normal (ULN) or ALT or AST >3 × ULN with bilirubin >2 × ULN, dosing should be interrupted and laboratory tests closely followed until the abnormalities resolve. Following the resolution of liver function test elevations, consider the benefits and risks of resuming treatment.

Concomitant Use with CYP3A Inducers

Exposure to ivacaftor is significantly decreased and exposure to elexacaftor and tezacaftor is expected to decrease by the concomitant use of strong CYP3A inducers, which may reduce the therapeutic effectiveness of elexacaftor, tezacaftor, and ivacaftor. Therefore, co-administration with strong CYP3A inducers is not recommended.

Concomitant Use with CYP3A Inhibitors

Exposure to elexacaftor, tezacaftor and ivacaftor is increased when co-administered with strong or moderate CYP3A inhibitors. Therefore, the dose of elexacaftor, tezacaftor, and ivacaftor should be reduced when used concomitantly with moderate or strong CYP3A inhibitors.

Cataracts

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

Specific Populations

Pregnancy

Risk Summary: There are limited and incomplete human data from clinical trials on the use of the combination containing elexacaftor, tezacaftor, and ivacaftor or its individual components in pregnant women to inform a drug-associated risk. Although there are no animal reproduction studies with the concomitant administration of elexacaftor, tezacaftor and ivacaftor, separate reproductive and developmental studies were conducted with each active component of elexacaftor, tezacaftor, and ivacaftor in pregnant rats and rabbits.

In animal embryo fetal development (EFD) studies oral administration of elexacaftor to pregnant rats and rabbits during organogenesis demonstrated no teratogenicity or adverse developmental effects at doses that produced maternal exposures up to approximately 2 times the exposure at the maximum recommended human dose (MRHD) in rats and 4 times the MRHD in rabbits [based on summed AUCs of elexacaftor and its metabolite (for rat) and AUC of elexacaftor (for rabbit)]. Oral administration of tezacaftor to pregnant rats and rabbits during organogenesis demonstrated no teratogenicity or 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 M1-TEZ). Oral administration of ivacaftor to pregnant rats and rabbits during organogenesis demonstrated no teratogenicity or adverse developmental effects at doses that produced maternal exposures up to approximately 5 and 14 times the exposure at the MRHD, respectively [based on summed AUCs of ivacaftor and its metabolites (for rat) and AUC of ivacaftor (for rabbit)]. No adverse developmental effects were observed after oral administration of elexacaftor, tezacaftor or ivacaftor to pregnant rats from the period of organogenesis through lactation at doses that produced maternal exposures approximately 1 time, approximately 1 time and 3 times the exposures at the MRHD, respectively [based on summed AUCs of parent and metabolite(s)].

The background risk of major birth defects and miscarriage for the indicated population is unknown. 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.

Animal Data for Elexacaftor: In an EFD study in pregnant rats dosed during the period of organogenesis from gestation Days 6-17, elexacaftor was not teratogenic and did not affect fetal survival at exposures up to 9 times the MRHD (based on summed AUC for elexacaftor and its metabolite at maternal doses up to 40 mg/kg/day). Lower mean fetal body weights were observed at doses ≥25 mg/kg/day that produced maternal exposures ≥4 times the MRHD. In an EFD study in pregnant rabbits dosed during the period of organogenesis from gestation Days 7-20, elexacaftor was not teratogenic at exposures up to 4 times the MRHD (based on AUC of elexacaftor at maternal doses up to 125 mg/kg/day). In a pre- and postnatal development (PPND) study in pregnant rats dosed from gestation Day 6 through lactation Day 18, elexacaftor did not cause developmental defects in pups at maternal doses up to 10 mg/kg/day (approximately 1 time the MRHD based on summed AUCs of elexacaftor and its metabolite). Placental transfer of elexacaftor was observed in pregnant rats.

Animal Data for Tezacaftor: In an EFD study in pregnant rats dosed during the period of organogenesis from gestation Days 6-17 and in pregnant rabbits dosed during the period of organogenesis from gestation Days 7-20, tezacaftor was not teratogenic and did not affect fetal development or survival at exposures up to 3 and 0.2 times, respectively 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 in pregnant rats dosed 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 1 time the exposure at the MRHD (based on summed AUCs for tezacaftor and M1-TEZ at a maternal oral dose of 50 mg/kg/day). Placental transfer of tezacaftor was observed in pregnant rats.

Animal Data for Ivacaftor: In an EFD study in pregnant rats dosed during the period of organogenesis from gestation Days 7-17 and in pregnant rabbits dosed during the period of organogenesis from gestation Days 7-19, ivacaftor was not teratogenic and did not affect fetal survival at exposures up to 5 and 14 times, respectively, the MRHD [based on summed AUCs of ivacaftor and its metabolites (for rat) and AUC of ivacaftor (for rabbit)]. In a PPND study in pregnant rats dosed from gestation Day 7 through lactation Day 20, ivacaftor had no effects on delivery or growth and development of offspring at exposures up to 3 times the MRHD (based on summed AUCs for ivacaftor and its metabolites at maternal oral doses up to 100 mg/kg/day). Decreased fetal body weights were observed at a maternally toxic dose that produced exposures 5 times the MRHD (based on summed AUCs of ivacaftor and its metabolites). Placental transfer of ivacaftor was observed in pregnant rats and rabbits.

Lactation

Risk Summary: There is no information regarding the presence of elexacaftor, tezacaftor, or ivacaftor in human milk, the effects on the breastfed infant, or the effects on milk production. Elexacaftor, tezacaftor, and ivacaftor are excreted into the milk of lactating rats. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for elexacaftor, tezacaftor, and ivacaftor and any potential adverse effects on the breastfed child from elexacaftor, tezacaftor, and ivacaftor or from the underlying maternal condition.

Data for Elexacaftor: Lacteal excretion of elexacaftor in rats was demonstrated following a single oral dose (10 mg/kg) of 14C-elexacaftor administered 6 to 10 days postpartum to lactating dams. Exposure of 14C-elexacaftor in milk was approximately 0.4 times the value observed in plasma (based on AUC0-72h).

Data for 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 times higher than in plasma (based on AUC0-72h).

Data for Ivacaftor: 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 elexacaftor, tezacaftor, and ivacaftor for the treatment of CF in pediatric patients 12 years and older who have at least one F508del mutation in the CFTR gene have been established. Use of elexacaftor, tezacaftor, and ivacaftor for this indication was supported by evidence from two adequate and well-controlled studies in CF patients 12 years and older (Trial 1 and Trial 2). In these trials, a total of 72 adolescents (aged 12 to 17 years) received elexacaftor, tezacaftor, and ivacaftor, including:

  • In Trial 1, 56 adolescents who had an F508del mutation on one allele and a mutation on the second allele that results in either no CFTR protein or a CFTR protein that is not responsive to ivacaftor and tezacaftor/ivacaftor.

  • In Trial 2, 16 adolescents who were homozygous for the F508del mutation.

The safety and effectiveness of elexacaftor, tezacaftor, and ivacaftor in patients with CF younger than 12 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 (0.24 times the MRHD based on systemic exposure of ivacaftor and its metabolites). This finding has not been observed in older animals.

Geriatric Use

Clinical studies of elexacaftor, tezacaftor, and ivacaftor did not include any patients aged 65 years and older.

Renal Impairment

The combination of elexacaftor, tezacaftor, and ivacaftor has not been studied in patients with severe renal impairment or end-stage renal disease. No dosage adjustment is recommended in patients with mild (eGFR 60 to <90 mL/min/1.73 m2) or moderate (eGFR 30 to <60 mL/min/1.73 m2) renal impairment. Use with caution in patients with severe (eGFR <30 mL/min/1.73 m2) renal impairment or end-stage renal disease.

Hepatic Impairment

Patients with severe hepatic impairment (Child-Pugh Class C) should not be treated with elexacaftor, tezacaftor, and ivacaftor. Use of elexacaftor, tezacaftor, and ivacaftor is not recommended in patients with moderate hepatic impairment (Child-Pugh Class B) unless the benefit exceeds the risk. If used in patients with moderate hepatic impairment, elexacaftor, tezacaftor, and ivacaftor should be used with caution and at a reduced dose. Liver function tests should be closely monitored. No dose modification is recommended for patients with mild hepatic impairment (Child-Pugh Class A).

Patients with Severe Lung Dysfunction

Trial 1 included a total of 18 patients receiving elexacaftor, tezacaftor, and ivacaftor with ppFEV1 <40 at baseline. The safety and efficacy in this subgroup were comparable to those observed in the overall population.

Common Adverse Effects

The most common adverse drug reactions to elexacaftor, tezacaftor, and ivacaftor (occurring in ≥5% of patients and at a frequency higher than placebo by ≥1%) were headache, upper respiratory tract infection, abdominal pain, diarrhea, rash, alanine aminotransferase increased, nasal congestion, blood creatine phosphokinase increased, aspartate aminotransferase increased, rhinorrhea, rhinitis, influenza, sinusitis and blood bilirubin increased.

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 CYP3A inducers: Avoid co-administration.

  • Strong or moderate CYP3A inhibitors: Reduce elexacaftor, tezacaftor, and ivacaftor dosage when co-administered. Avoid food or drink containing grapefruit.

Actions

Mechanism of Action

Elexacaftor and tezacaftor bind to different sites on the CFTR protein and have an additive effect in facilitating the cellular processing and trafficking of F508del-CFTR to increase the amount of CFTR protein delivered to the cell surface compared to either molecule alone. Ivacaftor potentiates the channel open probability (or gating) of the CFTR protein at the cell surface.

The combined effect of elexacaftor, tezacaftor and ivacaftor is increased quantity and function of F508del-CFTR at the cell surface, resulting in increased CFTR activity as measured by CFTR mediated chloride transport.

Advice to Patients

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Liver Function Test Elevations and Monitoring

Inform patients that elevation in transaminases has occurred in patients treated with elexacaftor, tezacaftor, and ivacaftor. Elevations in bilirubin have also been observed with elexacaftor, tezacaftor, and ivacaftor treatment. Liver function tests (ALT, AST, and bilirubin) should be assessed prior to initiating elexacaftor, tezacaftor, and ivacaftor, every 3 months during the first year of treatment, and annually thereafter. More frequent monitoring should be considered in patients with a history of hepatobiliary disease or liver function test elevations.

Drug Interactions with CYP3A Inducers and Inhibitors

Ask patients to tell you all the medications they are taking including any herbal supplements or vitamins. Co-administration of elexacaftor, tezacaftor, and ivacaftor with strong CYP3A inducers (e.g., rifampin, St. John's wort) is not recommended, as they may reduce the efficacy of elexacaftor, tezacaftor, and ivacaftor. Dose reduction to two elexacaftor/tezacaftor/ivacaftor tablets twice a week, taken approximately 3 to 4 days apart is recommended when co-administered with strong CYP3A inhibitors, such as ketoconazole. Advise the patient not to take the evening dose of ivacaftor. Dose reduction to two elexacaftor/tezacaftor/ivacaftor tablets and one ivacaftor tablet taken on alternate days is recommended when co-administered with moderate CYP3A inhibitors, such as fluconazole. Advise the patient not to take the evening dose of ivacaftor. Food or drink containing grapefruit should be avoided.

Use in Patients with Hepatic Impairment

The combination of elexacaftor, tezacaftor, and ivacaftor has not been studied in patients with moderate or severe hepatic impairment. Inquire and/or assess whether patients have liver impairment. Patients with severe hepatic impairment (Child-Pugh Class C, score 10-15) should not be treated with elexacaftor, tezacaftor, and ivacaftor. Use of elexacaftor, tezacaftor, and ivacaftor is not recommended in patients with moderate hepatic impairment (Child-Pugh Class B, score 7-9) unless the benefit exceeds the risk. If used in patients with moderate hepatic impairment, elexacaftor, tezacaftor, and ivacaftor should be used with caution and at a reduced dose. Liver function tests should be closely monitored. No dose adjustment is recommended for patients with mild hepatic impairment (Child-Pugh Class A, score 5-6).

Cataracts

Inform patients that abnormality of the eye lens (cataract) has been noted in some children and adolescents receiving ivacaftor-containing regimens. Baseline and follow-up ophthalmological examinations should be performed in pediatric patients initiating treatment with elexacaftor, tezacaftor, and ivacaftor.

Administration

Inform patients that the combination of elexacaftor, tezacaftor, and ivacaftor is best absorbed by the body when taken with food that contains fat. A typical CF diet will satisfy this requirement. Examples include eggs, butter, peanut butter, whole-milk dairy products (such as whole milk, cheese, and yogurt), etc.

Patients should be informed about what to do in the event they miss a dose of elexacaftor/tezacaftor/ivacaftor tablets or ivacaftor tablet:

If 6 hours or less have passed since the missed morning or evening dose is usually taken, patients should be instructed to take the prescribed dose as soon as possible and continue on the regular schedule.

If more than 6 hours have passed since the time the morning dose is usually taken, patients should be instructed to take the morning dose as soon as possible, and not take the evening dose. Patients should take the next scheduled morning dose at the usual time.

If more than 6 hours have passed since the time the evening dose is usually taken, patients should be instructed to not take the missed evening dose. Patients should take the next scheduled morning dose at the usual time.

Patients should be instructed to not take the morning and evening doses at the same time.

Patients should be advised to contact their health care provider if they have questions.

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.

Elexacaftor, Tezacaftor, and Ivacaftor

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Kit

Elexacaftor 100 mg, Tezacaftor 50 mg, and Ivacaftor 75 mg (56 film-coated tablets)

Ivacaftor 150 mg (28 film-coated tablets)

Trikafta (available as blister cards containing 14 fixed-combination tablets and 7 single-entity tablets)

Vertex Pharmaceuticals Incorporated

AHFS Drug Information. © Copyright 2021, Selected Revisions November 11, 2019. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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