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Symdeko

Generic Name: Tezacaftor and Ivacaftor
Class: Cystic Fibrosis Transmembrane Conductance Regulator Correctors
Chemical Name: 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[1-[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)indol-5-yl]cyclopropane-1-carboxamide
Molecular Formula: C26H27F3N2O6C24H28N2O3
CAS Number: 1152311-62-0

Medically reviewed on Feb 19, 2018

Introduction

The combination of tezacaftor and ivacaftor facilitates the delivery of and potentiates cystic fibrosis transmembrane conductance regulator (CFTR) protein to the cell surface, which enhances cellular chloride transport.1

Uses for Symdeko

The combination of tezacaftor/ivacaftor has the following uses:

The combination of tezacaftor and ivacaftor is indicated for the treatment of patients with cystic fibrosis (CF) aged 12 years and older who are homozygous for the F508del mutation or who have at least one mutation in the CFTR gene that is responsive to tezacaftor/ivacaftor based on in vitro data and/or clinical evidence.1

If the patient's genotype is unknown, an FDA-cleared CF mutation test should be used to detect the presence of a CFTR mutation followed by verification with bi-directional sequencing when recommended by the mutation test instructions for use.1

Symdeko Dosage and Administration

General

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

  • Co-packaged as tezacaftor 100 mg/ivacaftor 150 mg fixed-dose combination tablets and ivacaftor 150 mg tablets.1

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

Dosage and Administration
  • Adults and pediatric patients aged 12 years and older: one tablet containing tezacaftor 100 mg/ivacaftor 150 mg in the morning and one tablet containing ivacaftor 150 mg in the evening, approximately 12 hours apart. Tezacaftor and ivacaftor should be taken with fat-containing food.1

  • Reduce dose in patients with moderate and severe hepatic impairment.1 (See Use in Patients with Hepatic Impairment under Advice to Patients.)

  • Reduce dose when co-administered with drugs that are moderate or strong CYP3A inhibitors.1 (See Drug Interactions with CYP3A Inducers and Inhibitors under Advice to Patients.)

Cautions for Symdeko

Contraindications

  • None.1

Warnings/Precautions

Transaminase (AST/ALT) Elevations

Elevated transaminases have been observed in patients with CF treated with tezacaftor and ivacaftor, as well as with ivacaftor monotherapy. Assessments of transaminases (ALT and AST) are recommended for all patients prior to initiating tezacaftor and ivacaftor, every 3 months during the first year of treatment, and annually thereafter. For patients with a history of transaminase elevations, more frequent monitoring should be considered. In the event of significant elevations of transaminases, e.g., patients with ALT or AST >5 × 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 transaminase elevations, consider the benefits and risks of resuming treatment.1

Concomitant Use with CYP3A Inducers

Exposure to ivacaftor is significantly decreased and exposure to tezacaftor may be reduced by the concomitant use of CYP3A inducers, which may reduce the therapeutic effectiveness of tezacaftor and ivacaftor. Therefore, co-administration with strong CYP3A inducers is not recommended.1

Cataracts

Cases of non-congenital lens opacities have been reported in pediatric patients treated with tezacaftor and ivacaftor, as well as with ivacaftor monotherapy. Although other risk factors were present in some cases (such as corticosteroid use, exposure to radiation), a possible risk attributable to treatment with tezacaftor and ivacaftor cannot be excluded. Baseline and follow-up ophthalmological examinations are recommended in pediatric patients initiating treatment with tezacaftor and ivacaftor.1

Specific Populations

Pregnancy

Risk Summary: There are limited and incomplete human data from clinical trials and post-marketing reports on the use of the combination of tezacaftor and ivacaftor or its individual components, tezacaftor and ivacaftor, in pregnant women to inform a drug-associated risk. Although there are no animal reproduction studies with the concomitant administration of tezacaftor and ivacaftor, separate reproductive and developmental studies were conducted with tezacaftor and ivacaftor in pregnant rats and rabbits. In animal reproduction studies, 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 maximum recommended human dose (MRHD) in rats and 0.2 times the MRHD in rabbits (based on summed AUCs for tezacaftor and M1 metabolite). 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 6 and 16 times the exposure at the MRHD, respectively. No adverse developmental effects were observed after oral administration of either tezacaftor or ivacaftor to pregnant rats from the period of organogenesis through lactation at doses that produced maternal exposures approximately 1 and 4 times the exposures at the MRHD, respectively. 1

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.1

Animal Data (Tezacaftor). In an embryo-fetal development study in pregnant rats dosed during the period of organogenesis from gestation Days 6-17, tezacaftor was not teratogenic and did not affect fetal development or survival at exposures up to 3 times the MRHD (based on summed AUCs for tezacaftor and M1 metabolite at maternal oral doses up to 100 mg/kg/day). In an embryo-fetal development study 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 0.2 times the MRHD (based on summed AUCs for tezacaftor and M1 metabolite at maternal oral doses up to 25 mg/kg/day). Lower fetal body weights were observed in rabbits at a maternally toxic dose that produced exposures approximately 0.4 times the MRHD (at a maternal dose of 50 mg/kg/day). In a pre- and postnatal development (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 times the MRHD (based on summed AUCs for tezacaftor and M1 metabolite 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 metabolite at a maternal oral dose of 50 mg/kg/day). Placental transfer of tezacaftor was observed in pregnant rats.1

Animal Data (Ivacaftor):In an embryo-fetal development study in pregnant rats dosed during the period of organogenesis from gestation Days 7-17, ivacaftor was not teratogenic and did not affect fetal survival at exposures up to 6 times the MRHD (based on summed AUCs for ivacaftor and its metabolites at a maternal oral dose of 200 mg/kg/day). In an embryo-fetal development study in pregnant rabbits dosed during the period of organogenesis from gestation Days 7-19, ivacaftor was not teratogenic and did not affect fetal development or survival at exposures up to 16 times the MRHD (on an ivacaftor AUC basis at maternal oral doses up to 100 mg/kg/day). 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 4 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 6 times the MRHD. Placental transfer of ivacaftor was observed in pregnant rats and rabbits.1

Lactation

Risk Summary: There is no information regarding the presence of tezacaftor or ivacaftor in human milk, the effects on the breastfed infant, or the effects on milk production. Both 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 tezacaftor and ivacaftor and any potential adverse effects on the breastfed child from tezacaftor and ivacaftor or from the underlying maternal condition.1

1

Data (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 AUC0-24h).1

Data (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).1

Pediatric Use

Tezacaftor and ivacaftor is indicated for the treatment of CF in pediatric patients aged 12-17 years who are homozygous for the F508del mutation or who have at least one mutation in the CFTR gene that is responsive to tezacaftor/ivacaftor based on in vitro data and/or clinical evidence.1

Clinical trials included the following CF patients:1

  • 12 to 17 years of age who are homozygous for the F508del mutation .1

  • 12 to 17 years of age who are heterozygous for the F508del mutation and a second mutation predicted to be responsive to tezacaftor/ivacaftor.1

The safety and efficacy of tezacaftor and ivacaftor in patients with CF younger than 12 years of age have not been studied.1

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 (0.25 times the MRHD based on systemic exposure of ivacaftor and its metabolites). This finding has not been observed in older animals.1

Geriatric Use

Clinical trials of tezacaftor and ivacaftor did not include sufficient numbers of patients 65 years of age and over to determine whether they respond differently from younger patients.1

Hepatic Impairment

No dose adjustment is necessary for patients with mild hepatic impairment (Child-Pugh Class A). A reduced dose of tezacaftor and ivacaftor is recommended in patients with moderate hepatic impairment (Child-Pugh Class B). There is no experience in patients with severe hepatic impairment (Child-Pugh Class C), but tezacaftor/ivacaftor exposure is expected to be higher than in patients with moderate hepatic impairment. Therefore, use with caution at a reduced dose in patients with severe hepatic impairment after weighing the risks and benefits of treatment.1

Renal Impairment

The combination of tezacaftor and ivacaftor has not been studied in patients with moderate or severe renal impairment or in patients with end-stage renal disease. No dose adjustment is recommended for mild and moderate renal impairment. Caution is recommended in patients with severe renal impairment or end-stage renal disease.1

Patients With Severe Lung Dysfunction

Trial 1 and Trial 2 included a total of 39 tezacaftor and ivacaftor-treated patients with ppFEV1 <40 at baseline (range 30-40); 23 patients in Trial 1 and 16 patients in Trial 2. There were 24 placebo-treated patients in Trial 1, and 15 placebo- and 13 ivacaftor-treated patients in Trial 2, with ppFEV1 <40 at baseline. The safety and efficacy in this subgroup were comparable to the overall results observed in both Trials 1 and 2.1

Common Adverse Effects

The most common adverse drug reactions to tezacaftor and ivacaftor (occurring in ≥3% of patients) were headache, nausea, sinus congestion, and dizziness.1

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:

CYP3A inhibitors: Reduce tezacaftor and ivacaftor dose when co-administered with strong (e.g., ketoconazole) or moderate (e.g., fluconazole) CYP3A inhibitors. Avoid food containing grapefruit or Seville oranges.1

Actions

Mechanism Of Action

Tezacaftor facilitates the cellular processing and trafficking of normal and select mutant forms of CFTR (including F508del-CFTR) to increase the amount of mature CFTR protein delivered to the cell surface. Ivacaftor is a CFTR potentiator that facilitates increased chloride transport by potentiating the channel-open probability (or gating) of the CFTR protein at the cell surface. For ivacaftor to function, CFTR protein must be present at the cell surface. Ivacaftor can potentiate the CFTR protein delivered to the cell surface by tezacaftor, leading to a further enhancement of chloride transport than either agent alone. The combined effect of tezacaftor and ivacaftor is increased quantity and function of CFTR at the cell surface, resulting in increases in chloride transport.1

Table 1 lists responsive CFTR mutations based on (1) a clinical FEV1 response and/or (2) in vitro data in FRT cells, indicating that tezacaftor/ivacaftor increases chloride transport to at least 10% of untreated normal over baseline. CFTR gene mutations that are not responsive to ivacaftor alone are not expected to respond to tezacaftor and ivacaftor except for F508del homozygotes.1

A patient must have two copies of the F508del mutation or at least one copy of a responsive mutation presented in Table 1 to be indicated.

Table 1: List of CFTR Gene Mutations that Produce CFTR Protein and are Responsive to Tezacaftor and Ivacaftor

E56K

R117C

A455E

S945L

R1070W

3272-26A→G

P67L

E193K

F508dela

S977F

F1074L

3849+10kbC→T

R74W

L206W

D579G

F1052V

D1152H

D110E

R347H

711+3A→G

K1060T

D1270N

D110H

R352Q

E831X

A1067T

2789+5G→A

Advice to Patients

Advise the patient to read the FDA-approved patient labeling (Patient Information).1

Transaminase (ALT or AST) Elevations and Monitoring

Inform patients that elevation in liver tests has occurred in patients treated with the combination of tezacaftor and ivacaftor or with ivacaftor alone. Transaminases (ALT and AST) should be assessed prior to initiating the combination of 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 transaminase elevations.1

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 the combination of tezacaftor and ivacaftor with strong CYP3A inducers (e.g., rifampin, St. John's wort) is not recommended, as they may reduce the therapeutic effectiveness of the combination of tezacaftor and ivacaftor. Adjustment of the dose to one tablet of tezacaftor 100 mg/ivacaftor 150 mg 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 150 mg. Dose reduction to one tablet of tezacaftor 100 mg/ivacaftor 150 mg or ivacaftor 150 mg, taken on alternate days in the morning, is recommended when co-administered with moderate CYP3A inhibitors such as fluconazole. Advise the patient not to take the evening dose of ivacaftor 150 mg. Food or drink containing grapefruit or Seville oranges should be avoided.1

Cataracts

Inform patients that abnormality of the eye lens (cataract) has been noted in some children and adolescents receiving the combination of tezacaftor and ivacaftor or with ivacaftor alone. Baseline and follow-up ophthalmological examinations should be performed in pediatric patients initiating treatment with the combination of tezacaftor and ivacaftor.1

Use in Patients with Hepatic Impairment

Inquire and/or assess whether patients have liver impairment. Adjust the dose in patients with moderately impaired hepatic function (Child-Pugh Class B, score 7-9) to one tablet of tezacaftor 100 mg/ivacaftor 150 mg once daily in the morning and advise the patient not to take the evening dose of ivacaftor 150 mg. The combination of tezacaftor and ivacaftor has not been studied in patients with severe hepatic impairment (Child-Pugh Class C, score 10-15); however, exposure is expected to be substantially higher than that observed in patients with moderate hepatic impairment. When benefits are expected to outweigh the risks, tezacaftor and ivacaftor should be used with caution in patients with severe hepatic impairment at a dose of one tablet of tezacaftor 100 mg/ivacaftor 150 mg once daily in the morning or less frequently. Advise the patient not to take the evening dose of ivacaftor 150 mg. No dose adjustment is recommended for patients with mild hepatic impairment (Child-Pugh Class A, score 5-6).1

Administration

Inform patients that the combination of 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, cheese pizza, whole-milk dairy products (such as whole milk, cheese, and yogurt), etc.1

Patients should be informed about what to do in the event they miss a dose of tezacaftor/ivacaftor or ivacaftor:1

  • If 6 hours or less have passed since the time tezacaftor/ivacaftor or ivacaftor is usually taken, patients should be instructed to take the prescribed dose of tezacaftor/ivacaftor or ivacaftor with fat-containing food as soon as possible.1

  • If more than 6 hours have passed since the time tezacaftor/ivacaftor or ivacaftor is usually taken, the missed dose should NOT be taken and the patient should resume the usual dosing schedule.1

  • Patients should be advised to contact their health care provider if they have questions.1

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.

Tezacaftor and Ivacaftor

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Kit

7 tablets, film-coated, Tezacaftor 100 mg/Ivacaftor 150 mg

7 tablets, film-coated, Ivacaftor 150 mg

4 weekly blister cards (14 tablets each) per kit

Symdeko

Vertex Pharmaceuticals Incorporated

AHFS Drug Information. © Copyright 2018, Selected Revisions February 19, 2018. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Vertex Pharmaceuticals Incorporated. SYMDEKO (tezacaftor/ivacaftor) tablets; (ivacaftor) tablets, for oral use prescribing information. 2018 Feb. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=302ae804-37db-44fd-ac2f-3dbdeda9aa4b

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