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Tezacaftor and Ivacaftor Tablets

TABLE OF CONTENTS

1. DESCRIPTION 8. USE IN SPECIFIC POPULATIONS
2. INDICATIONS AND USAGE 9. OVERDOSAGE
3. DOSAGE AND ADMINISTRATION 10. MECHANISM OF ACTION
4. CONTRAINDICATIONS 11. PHARMACODYNAMICS
5. WARNINGS AND PRECAUTIONS 12. PHARMACOKINETICS
6. ADVERSE REACTIONS 13. HOW SUPPLIED/STORAGE AND HANDLING
7. DRUG INTERACTIONS

 

1. DESCRIPTION

SYMDEKO is co-packaged as a tezacaftor/ivacaftor fixed-dose combination tablet and an ivacaftor tablet. Both tablets are for oral administration.

The tezacaftor/ivacaftor fixed-dose combination tablet is available as a yellow, capsule-shaped, film-coated tablet containing 100 mg of tezacaftor, 150 mg of ivacaftor, and the following inactive ingredients: croscarmellose sodium, hypromellose, hypromellose acetate succinate, magnesium stearate, microcrystalline cellulose and sodium lauryl sulfate. The tablet film coat contains HPMC/hypromellose 2910, hydroxypropyl cellulose, iron oxide yellow, talc and titanium dioxide.

The ivacaftor tablet is available as a light blue, capsule-shaped, film-coated tablet containing 150 mg of ivacaftor and the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hypromellose acetate succinate, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. The tablet film coat contains carnauba wax, FD&C Blue #2, PEG 3350, polyvinyl alcohol, talc, and titanium dioxide. The printing ink contains ammonium hydroxide, iron oxide black, propylene glycol, and shellac.

The active ingredients of SYMDEKO are described below.

Tezacaftor

Tezacaftor is a white to off-white powder that is practically insoluble in water (<5 microgram/mL). Its chemical name of tezacaftor 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)-1Hindol-5-yl}cyclopropane-1-carboxamide. Tezacaftor has the following structural formula:

Empirical formula: C26H27N2F3O6 - Molecular weight: 520.50

Ivacaftor

Ivacaftor is a white to off-white powder that is practically insoluble in water (<0.05 microgram/mL). Pharmacologically it is a CFTR potentiator. Its chemical name is N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide. Ivacaftor has the following structural formula:

Empirical formula: C24H28N2O3 - Molecular weight: 392.49

2. INDICATIONS AND USAGE

SYMDEKO 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 cystic fibrosis transmembrane conductance regulator (CFTR) gene that is responsive to tezacaftor/ivacaftor based on in vitro data and/or clinical evidence [see Clinical Pharmacology and Clinical Studies].

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.

3. DOSAGE AND ADMINISTRATION

3.1 Dosing Information in Adults, Adolescents, and Children Ages 12 Years and Older

The recommended dose is one tablet (tezacaftor 100 mg/ivacaftor 150 mg) taken in the morning and one tablet (ivacaftor 150 mg) taken in the evening, approximately 12 hours apart. SYMDEKO is for oral use. Instruct patients to swallow the tablets whole. SYMDEKO should be taken with fat-containing food, such as food recommended in standard nutritional guidelines. 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 [see Clinical Pharmacology].

If 6 hours or less have passed since the missed morning or evening dose, the patient should take the missed dose as soon as possible and continue on the original schedule. If more than 6 hours have passed since the missed morning or evening dose, the patient should not take the missed dose. The next scheduled dose can be taken at the usual time. More than one dose should not be taken at the same time.

3.2 Dose Adjustment for Patients with Hepatic Impairment

For dose adjustment for patients with hepatic impairment, refer to Table 1. Studies have not been conducted in patients with severe hepatic impairment (Child-Pugh Class C), but exposure of tezacaftor and ivacaftor is expected to be higher than in patients with moderate hepatic impairment. Therefore, SYMDEKO should be used with caution at an adjusted dose after weighing the risks and benefits of treatment in these patients [see Use in Specific Populations (8.6), Clinical Pharmacology, and Patient Counseling Information].

Table 1: Dosage Recommendations for Patients with Hepatic Impairment

3.3 Dose Adjustment for Patients Taking Drugs that are CYP3A Inhibitors

The dosing regimen of SYMDEKO should be adjusted when co-administered with moderate and strong CYP3A inhibitors.

When co-administered with moderate inhibitors of CYP3A (e.g., fluconazole, erythromycin), the dosing regimen should be adjusted as in Table 2 [see Drug Interactions (7.2), Clinical Pharmacology, and Patient Counseling Information]. When co-administered with strong inhibitors of CYP3A (e.g., ketoconazole, itraconazole, posaconazole, voriconazole, telithromycin, and clarithromycin), the dosing regimen should be adjusted as in Table 2 [see Drug Interactions (7.2), Clinical Pharmacology, and Patient Counseling Information].

Table 2: Dosing Schedule for Concomitant Use of SYMDEKO with Moderate and Strong CYP3A Inhibitors

*Continue dosing with tezacaftor 100 mg/ivacaftor 150 mg or ivacaftor 150 mg tablets on alternate days.

#Dosing with tezacaftor 100 mg/ivacaftor 150 mg tablets twice a week, taken approximately 3 to 4 days apart.

^The evening dose of ivacaftor 150 mg should not be taken.

Food or drink containing grapefruit or Seville oranges should be avoided during treatment with SYMDEKO [see Drug Interactions (7.2) and Patient Counseling Information].

4. CONTRAINDICATIONS

None.

5. WARNINGS AND PRECAUTIONS

5.1 Transaminase (AST/ALT) Elevations

Elevated transaminases have been observed in patients with CF treated with SYMDEKO, as well as with ivacaftor monotherapy. Assessments of transaminases (ALT and AST) are recommended for all patients prior to initiating SYMDEKO, 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 x upper limit of normal (ULN), or ALT or AST >3 x ULN with bilirubin >2 x 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 [see Adverse Reactions (6)].

5.2 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 SYMDEKO. Therefore, co-administration with strong CYP3A inducers is not recommended [see Drug Interactions (7.1), Clinical Pharmacology, and Patient Counseling Information].

5.3 Cataracts

Cases of non-congenital lens opacities have been reported in pediatric patients treated with SYMDEKO, 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 SYMDEKO cannot be excluded. Baseline and follow-up ophthalmological examinations are recommended in pediatric patients initiating treatment with SYMDEKO [see Use in Specific Populations (8.4) and Patient Counseling Information].

6. ADVERSE REACTIONS

The following adverse reaction is discussed in greater detail in other sections of the label:

 Transaminase Elevations [see Warnings and Precautions (5.1)]

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 overall safety profile of SYMDEKO is based on data from three double-blind, placebo-controlled, Phase 3 clinical trials: 2 parallel-group trials of 12 and 24 week duration and one cross-over design trial of 8 weeks duration. Eligible patients were also able to participate in an open-label extension safety study (up to 96 weeks of SYMDEKO). In the three placebo-controlled Phase 3 trials (Trials 1, 2, and 3), a total of 496 patients with CF aged 12 years and older received at least one dose of SYMDEKO. The proportion of patients who discontinued study drug prematurely due to adverse events was 1.6% for SYMDEKO-treated patients and 2.0% for placebo-treated patients. Serious adverse reactions, whether considered drug-related or not by the investigators, that occurred more frequently in SYMDEKO-treated patients compared to placebo included distal intestinal obstruction syndrome, 3 (0.6%) SYMDEKO-treated subjects vs. 0 placebo. There were no deaths in the placebo controlled trials, and one death in the open label extension study due to respiratory failure and influenza infection in a patient who had discontinued SYMDEKO seven weeks prior.

The safety profile of SYMDEKO was generally similar across all subgroups of patients, including analysis by age, sex, baseline percent predicted FEV1 (ppFEV1), and geographic regions.

Table 3 shows adverse reactions occurring in ≥3% of SYMDEKO-treated patients that also occurred at a higher rate than in the placebo-treated patients in the 12- and 24-week placebo controlled, parallel-group Phase 3 trials (Trials 1 and 3).

Table 3: Incidence of Adverse Drug Reactions in ≥3% of SYMDEKO-Treated Patients and Greater than Placebo

The safety profile for the CF patients enrolled in Trial 2 who were heterozygous for the F508del mutation and a second mutation predicted to be responsive to tezacaftor/ivacaftor was similar to that observed in Trials 1 and 3.

Laboratory abnormalities

Transaminase elevations

During the placebo-controlled Phase 3 trials, the incidence of maximum transaminase (ALT or AST) >8, >5, or >3 x the upper limit of normal (ULN) was similar between SYMDEKO-treated patients and placebo-treated patients; 0.2%, 1.0%, and 3.4% in SYMDEKO-treated patients, and 0.4%, 1.0%, and 3.4% in placebo-treated patients. One patient (0.2%) on SYMDEKO and 2 patients (0.4%) on placebo permanently discontinued treatment for elevated transaminases. No SYMDEKO-treated patients experienced a transaminase elevation >3 x ULN associated with elevated total bilirubin >2 x ULN.

7. DRUG INTERACTIONS

Potential for other drugs to affect tezacaftor/ivacaftor

7.1 Inducers of CYP3A

Tezacaftor and ivacaftor are substrates of CYP3A (ivacaftor is a sensitive substrate of CYP3A). Concomitant use of CYP3A inducers may result in reduced exposures and thus reduced SYMDEKO efficacy. Co-administration of ivacaftor with rifampin, a strong CYP3A inducer, significantly decreased ivacaftor exposure (area under the curve [AUC]) by 89%. Tezacaftor exposures can also be expected to decrease significantly during co-administration with strong CYP3A inducers. Therefore, co-administration of SYMDEKO with strong CYP3A inducers is not recommended [see Warnings and Precautions (5.2), Clinical Pharmacology, and Patient Counseling Information].

Examples of strong CYP3A inducers include:

 rifampin, rifabutin, phenobarbital, carbamazepine, phenytoin, and St. John’s wort (Hypericum perforatum)

7.2 Inhibitors of CYP3A

Co-administration with itraconazole, a strong CYP3A inhibitor, increased tezacaftor exposure (AUC) by 4.0-fold and ivacaftor by 15.6-fold. When co-administered with strong CYP3A inhibitors, the dosing regimen of SYMDEKO should be adjusted [see Dosage and Administration (3.3), Clinical Pharmacology, and Patient Counseling Information].

Examples of strong CYP3A inhibitors include:

 ketoconazole, itraconazole, posaconazole, and voriconazole

 telithromycin and clarithromycin

Co-administration of fluconazole increased ivacaftor exposure (AUC) by 3.0-fold. Simulation suggested co-administration with fluconazole, a moderate CYP3A inhibitor, may increase tezacaftor exposure (AUC) by approximately 2.0-fold. When co-administered with moderate CYP3A inhibitors, the dosing regimen of SYMDEKO should be adjusted [see Dosage and Administration (3.3), Clinical Pharmacology, and Patient Counseling Information].

Examples of moderate CYP3A inhibitors include:

 fluconazole

 erythromycin

Co-administration of SYMDEKO with grapefruit juice, which contains one or more components that moderately inhibit CYP3A, may increase exposure of tezacaftor and ivacaftor; therefore, food or drink containing grapefruit or Seville oranges should be avoided during treatment with SYMDEKO [see Dosage and Administration (3.3), Clinical Pharmacology, and Patient Counseling Information].

7.3 Ciprofloxacin

Co-administration of SYMDEKO with ciprofloxacin had no significant effect on the exposure of tezacaftor or ivacaftor. Therefore, no dose adjustment is necessary during concomitant administration of SYMDEKO with ciprofloxacin [see Clinical Pharmacology].

Potential for tezacaftor/ivacaftor to affect other drugs

7.4 CYP3A Substrates

Co-administration of SYMDEKO with midazolam (oral), a sensitive CYP3A substrate, did not affect midazolam exposure. No dose adjustment of CYP3A substrates is required when co-administered with SYMDEKO [see Clinical Pharmacology].

7.5 Digoxin and Other P-gp Substrates

Co-administration of SYMDEKO with digoxin, a sensitive P-gp substrate, increased digoxin exposure by 1.3-fold consistent with weak inhibition of P-gp by ivacaftor. Administration of SYMDEKO may increase systemic exposure of medicinal products that are sensitive substrates of P-gp, which may increase or prolong their therapeutic effect and adverse reactions. When used concomitantly with digoxin or other substrates of P-gp with a narrow therapeutic index such as cyclosporine, everolimus, sirolimus, and tacrolimus, caution and appropriate monitoring should be used [see Clinical Pharmacology].

7.6 Hormonal Contraceptives

SYMDEKO has been studied with an ethinyl estradiol/ norethindrone oral contraceptive and was found to have no significant effect on the exposures of the hormonal contraceptive. SYMDEKO is not expected to modify the efficacy of hormonal contraceptives [see Clinical Pharmacology].

8. USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

There are limited and incomplete human data from clinical trials and post-marketing reports on the use of SYMDEKO 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 (see Data).

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.

Data

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 time 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.

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.

8.2 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 (see Data). The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for SYMDEKO and any potential adverse effects on the breastfed child from SYMDEKO or from the underlying maternal condition.

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).

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).

8.4 Pediatric

Use SYMDEKO is indicated for the treatment of CF in pediatric patients ages 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 [see Clinical Pharmacology and Clinical Studies]. Clinical trials included the following CF patients:

 12 to 17 years of age who are homozygous for the F508del mutation [see Adverse Reactions (6) and Clinical Studies].

 12 to 17 years of age who are heterozygous for the F508del mutation and a second mutation predicted to be responsive to tezacaftor/ivacaftor [see Adverse Reactions (6) and Clinical Studies].

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

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.

8.5 Geriatric Use

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

8.6 Hepatic Impairment

No dose adjustment is necessary for patients with mild hepatic impairment (Child-Pugh Class A). A reduced dose of SYMDEKO 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 [see Dosage and Administration (3.2), Clinical Pharmacology, and Patient Counseling Information].

8.7 Renal Impairment

SYMDEKO 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 [Clinical Pharmacology].

8.8 Patients with Severe Lung Dysfunction

Trial 1 and Trial 2 included a total of 39 SYMDEKO-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.

9. OVERDOSAGE

No specific antidote is available for overdose with SYMDEKO. Treatment of overdose consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient.

10. 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.

CFTR Chloride Transport Assay in Fisher Rat Thyroid (FRT) cells expressing mutant CFTR

The chloride transport response of mutant CFTR protein to tezacaftor/ivacaftor was determined in Ussing chamber electrophysiology studies using a panel of FRT cell lines transfected with individual CFTR mutations. The FRT assay was conducted in ivacaftor-responsive mutations and F508del. Tezacaftor/ivacaftor increased chloride transport in FRT cells expressing CFTR mutations that result in CFTR protein being delivered to the cell surface.

The minimum response threshold was designated as a net increase of at least 10% of untreated normal over baseline. The tezacaftor/ivacaftor incubation resulted in either similar or increased chloride transport compared to ivacaftor alone. In vitro data may not accurately predict added clinical benefit of SYMDEKO (tezacaftor/ivacaftor combination) over KALYDECO (ivacaftor) alone for individual mutations. In addition, the magnitude of the net change over baseline in CFTR-mediated chloride transport is not correlated with the magnitude of clinical response for individual mutations.

Figure 1: Net Change Over Baseline (% of untreated normal) in CFTR-Mediated Chloride Transport Following Addition of SYMDEKO (tezacaftor/Ivacaftor combination) in FRT Cells Expressing Mutant CFTR proteins (Ussing Chamber Electrophysiology Data)

*Clinical data exist for these mutations [see Clinical Studies].

#F508del represents data from one allele. A patient must have two copies of F508del mutation to be indicated for tezacaftor/ivacaftor (see Table 4).

Splice mutations cannot be studied in the FRT assay and are not included in Figure 1.

Table 4 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 SYMDEKO except for F508del homozygotes.

Table 4: List of CFTR Gene Mutations that Produce CFTR Protein and are Responsive to SYMDEKO

*A patient must have two copies of the F508del mutation or at least one copy of a responsive mutation presented in Table 4 to be indicated.

11. PHARMACODYNAMICS

Effects on Sweat Chloride

In Trial 1 (patients homozygous for the F508del mutation), the treatment difference between SYMDEKO and placebo in mean absolute change from baseline in sweat chloride through Week 24 was -10.1 mmol/L (95% CI: -11.4, -8.8).

In Trial 2 (patients heterozygous for the F508del mutation and a second mutation predicted to be responsive to tezacaftor/ivacaftor), the treatment difference in mean absolute change from baseline in sweat chloride through Week 8 was -9.5 mmol/L (95% CI: -11.7, -7.3) between SYMDEKO and placebo, and -4.5 mmol/L (95% CI: -6.7, -2.3) between ivacaftor and placebo.

Cardiac Electrophysiology

At a dose 3 times the maximum approved recommended dose, tezacaftor does not prolong the QT interval to any clinically relevant extent.

In a separate study of ivacaftor evaluating doses up to 3 times the maximum approved recommended dose, ivacaftor does not prolong the QT interval to any clinically relevant extent.

12. PHARMACOKINETICS

The pharmacokinetics of tezacaftor and ivacaftor are similar between healthy adult volunteers and patients with CF. Following once-daily dosing of tezacaftor and twice-daily dosing of ivacaftor in patients with CF, plasma concentrations of tezacaftor and ivacaftor reach steady-state within 8 days and within 3 to 5 days, respectively, after starting treatment. At steady-state, the accumulation ratio is approximately 1.5 for tezacaftor and 2.2 for ivacaftor. Exposures of tezacaftor (administered alone or in combination with ivacaftor) increase in an approximately dose-proportional manner with increasing doses from 10 mg to 300 mg once daily. Key pharmacokinetic parameters for tezacaftor and ivacaftor at steady state are shown in Table 5.

Table 5: Mean (SD) Pharmacokinetic Parameters of Tezacaftor and Ivacaftor at Steady State in Patients with CF

*AUC0-24h for tezacaftor and AUC0-12h for ivacaftor

Absorption

After a single dose in healthy subjects in the fed state, tezacaftor was absorbed with a median (range) time to maximum concentration (tmax) of approximately 4.0 hours (2 to 6 hours). The median (range) tmax of ivacaftor was approximately 6.0 hours (3 to 10 hours) in the fed state.

When a single dose of tezacaftor/ivacaftor was administered with fat-containing foods, tezacaftor exposure was similar and ivacaftor exposure was approximately 3 times higher than when taken in a fasting state.

Distribution

Tezacaftor is approximately 99% bound to plasma proteins, primarily to albumin. Ivacaftor is approximately 99% bound to plasma proteins, primarily to alpha 1-acid glycoprotein and albumin. After oral administration of tezacaftor 100 mg once daily/ivacaftor 150 mg every 12 hours in patients with CF in the fed state, the mean (±SD) for apparent volume of distribution of tezacaftor and ivacaftor was 271 (157) L and 206 (82.9) L, respectively. Neither tezacaftor nor ivacaftor partition preferentially into human red blood cells.

Elimination

After oral administration of tezacaftor 100 mg once daily/ivacaftor 150 mg every 12 hours in patients with CF in the fed state, the mean (±SD) for apparent clearance values of tezacaftor and ivacaftor were 1.31 (0.41) and 15.7 (6.38) L/h, respectively. After steady-state dosing of tezacaftor in combination with ivacaftor in CF patients, the effective half-lives of tezacaftor and ivacaftor were approximately 15.0 (3.44) and 13.7 (6.06) hours, respectively.

Metabolism

Tezacaftor is metabolized extensively in humans. In vitro data suggested that tezacaftor is metabolized mainly by CYP3A4 and CYP3A5. Following oral administration of a single dose of 100 mg 14C-tezacaftor to healthy male subjects, M1, M2, and M5 were the 3 major circulating metabolites of tezacaftor in humans. M1 has the similar potency to that of tezacaftor and is considered pharmacologically active. M2 is much less pharmacologically active than tezacaftor or M1, and M5 is not considered pharmacologically active. Another minor circulating metabolite, M3, is formed by direct glucuronidation of tezacaftor.

Ivacaftor is also metabolized extensively in humans. In vitro and in vivo data indicate that ivacaftor is metabolized primarily by CYP3A4 and CYP3A5. M1 and M6 are the two major metabolites of ivacaftor in humans. M1 has approximately one-sixth the potency of ivacaftor and is considered pharmacologically active. M6 is not considered pharmacologically active.

Excretion

Following oral administration of 14C-tezacaftor, the majority of the dose (72%) was excreted in the feces (unchanged or as the M2 metabolite) and about 14% was recovered in urine (mostly as M2 metabolite), resulting in a mean overall recovery of 86% up to 21 days after the dose. Less than 1% of the administrated dose was excreted in urine as unchanged tezacaftor, showing that renal excretion is not the major pathway of tezacaftor elimination in humans.

Following oral administration of ivacaftor alone, the majority of ivacaftor (87.8%) is eliminated in the feces after metabolic conversion. There was minimal elimination of ivacaftor and its metabolites in urine (only 6.6% of total radioactivity was recovered in the urine), and there was negligible urinary excretion of ivacaftor as unchanged drug.

Specific populations

Pediatric patients 12 to less than 18 years of age

The following conclusions about exposures between adults and the pediatric population are based on population PK analyses:

Following oral administration of SYMDEKO tablets, tezacaftor 100 mg once daily / ivacaftor 150 mg every 12 hours, the mean (±SD) AUCss was 97.3 (35.7) mcg·h/mL and 11.4 (5.46) mcg·h/mL, respectively for tezacaftor and ivacaftor, similar to the mean AUCss in adult patients administered SYMDEKO tablets, tezacaftor 100 mg once daily/ivacaftor 150 mg every 12 hours.

Patients with Hepatic Impairment

Following multiple doses of tezacaftor and ivacaftor for 10 days, subjects with moderately impaired hepatic function (Child-Pugh Class B, score 7 to 9) had an approximately 36% increase in AUC and a 10% increase in Cmax for tezacaftor, and a 1.5-fold increase in ivacaftor AUC compared with healthy subjects matched for demographics. In a separate study, subjects with moderately impaired hepatic function (Child-Pugh Class B, score 7-9) had similar ivacaftor Cmax, but an approximately 2.0-fold increase in ivacaftor AUC0-∞ compared with healthy subjects matched for demographics.

Pharmacokinetic studies have not been conducted in patients with mild (Child-Pugh Class A, score 5 to 6) or severe hepatic impairment (Child-Pugh Class C, score 10 to 15) receiving SYMDEKO. The magnitude of increase in exposure in patients with severe hepatic impairment is unknown, but is expected to be higher than that observed in patients with moderate hepatic impairment [see Dosage and Administration (3.2), Use in Specific Populations (8.6), and Patient Counseling Information].

Patients with Renal Impairment

SYMDEKO has not been studied in patients with moderate or severe renal impairment (creatinine clearance ≤30 mL/min) or in patients with end-stage renal disease. In a human pharmacokinetic study with tezacaftor alone, there was minimal elimination of tezacaftor and its metabolites in urine (only 13.7% of total radioactivity was recovered in the urine with 0.79% as unchanged drug).

In a human pharmacokinetic study with ivacaftor alone, there was minimal elimination of ivacaftor and its metabolites in urine (only 6.6% of total radioactivity was recovered in the urine).

In population pharmacokinetic analysis, data from 665 patients on tezacaftor or tezacaftor in combination with ivacaftor in Phase 2/3 clinical trials indicated that mild renal impairment (N=147; eGFR 60 to less than 90 mL/min/1.73 m2) and moderate renal impairment (N=7; eGFR 30 to less than 60 mL/min/1.73 m2) did not affect the clearance of tezacaftor significantly [see Use in Specific Populations (8.7)].

Male and Female Patients

The pharmacokinetic parameters of tezacaftor and ivacaftor are similar in males and females.

Drug Interactions Studies

Drug interaction studies were performed with SYMDEKO and other drugs likely to be co-administered or drugs commonly used as probes for pharmacokinetic interaction studies [see Drug Interactions (7)].

Potential for Tezacaftor/Ivacaftor to Affect Other Drugs

Clinical studies (with rosiglitazone and desipramine – see Table 6) showed that ivacaftor is not an inhibitor of CYP2C8 or CYP2D6. Based on in vitro results, ivacaftor has the potential to inhibit CYP3A and P-gp, and may also inhibit CYP2C9. In vitro, ivacaftor was not an inducer of CYP isozymes. Ivacaftor is not an inhibitor of transporters OATP1B1, OATP1B3, OCT1, OCT2, OAT1, or OAT3.

Based on in vitro results, tezacaftor has a low potential to inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Tezacaftor has a low potential to induce CYP3A, but it is not an inducer of CYP1A2 and CYP2B6. Tezacaftor has a low potential to inhibit transporters P-gp, BCRP, OATP1B1, OATP1B3, OCT2, OAT1, or OAT3.

Clinical studies with midazolam showed that SYMDEKO is not an inhibitor of CYP3A. Co-administration of SYMDEKO with digoxin, a sensitive P-gp substrate, increased digoxin exposure by 1.3-fold. Co administration of SYMDEKO with an ethinyl estradiol/ norethindrone oral contraceptive had no significant effect on the exposures of the hormonal contraceptives.

The effects of tezacaftor and ivacaftor (or ivacaftor alone) on the exposure of co-administered drugs are shown in Table 6 [see Drug Interactions (7)].

Potential for Other Drugs to Affect Tezacaftor/Ivacaftor

In vitro studies showed that ivacaftor and tezacaftor were substrates of CYP3A enzymes (i.e., CYP3A4 and CYP3A5). Exposure to ivacaftor and tezacaftor will be reduced by concomitant CYP3A inducers and increased by concomitant CYP3A inhibitors.

In vitro studies showed that tezacaftor is a substrate for the uptake transporter OATP1B1, and efflux transporters P-gp and BCRP. Tezacaftor is not a substrate for OATP1B3. In vitro studies showed that ivacaftor is not a substrate for OATP1B1, OATP1B3, or P-gp.

The effects of co-administered drugs on the exposure of tezacaftor and ivacaftor (or ivacaftor alone) are shown in Table 7 [see Dosage and Administration (3.3) and Drug Interactions (7)].

Table 6: Impact of Tezacaftor/Ivacaftor or Ivacaftor on Other Drugs

↑ = increase, ↓ = decrease, ↔ = no change. CI = Confidence interval; TEZ = tezacaftor; IVA = ivacaftor; PK = Pharmacokinetics

Table 7: Impact of Other Drugs on Tezacaftor/Ivacaftor or Ivacaftor

↑ = increase, ↓ = decrease, ↔ = no change. CI = Confidence interval; TEZ = tezacaftor; IVA = ivacaftor; PK = Pharmacokinetics

*Effect is not clinically significant – no dose adjustment is necessary

13. HOW SUPPLIED/STORAGE AND HANDLING

How Supplied:

SYMDEKO is co-packaged as a tezacaftor/ivacaftor fixed-dose combination tablet and an ivacaftor tablet. The tezacaftor/ivacaftor fixed dose combination tablets are supplied as yellow, capsule-shaped tablets containing 100 mg of tezacaftor and 150 mg of ivacaftor. Each tablet is debossed with “V100” on one side and plain on the other. Ivacaftor tablets are supplied as light blue, film-coated, capsule-shaped tablets containing 150 mg of ivacaftor. Each tablet is printed with the characters “V150” on one side and plain on the other. SYMDEKO is supplied as:

56-count tablet carton containing a 4-week supply (4 weekly wallets, each with 14 tablets) NDC 51167-661-01

Storage and Handling:

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

Rx only

Rev 02/18