Data from FDA - Curated by EPG Health - Last updated 04 March 2018

Indication(s)

1 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 (12.1) and Clinical Studies (14)]. 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. SYMDEKO is a combination of tezacaftor and ivacaftor, 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. (12.1, 14) 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.

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Advisory information

contraindications
4 CONTRAINDICATIONS None. None. (4)
Adverse reactions
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)] The most common adverse drug reactions to SYMDEKO (occurring in ≥3% of patients) were headache, nausea, sinus congestion, and dizziness. (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 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 Adverse Reactions (Preferred Term) SYMDEKO N=334 n (%) Placebo N=343 n (%) Headache 49 (15) 44 (13) Nausea 29 (9) 24 (7) Sinus congestion 13 (4) 6 (2) Dizziness 12 (4) 8 (2) 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 × 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 × ULN associated with elevated total bilirubin >2 × ULN.

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION Adults and pediatric patients ages 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. SYMDEKO should be taken with fat-containing food. (2.1, 12.3) Reduce dose in patients with moderate and severe hepatic impairment. (2.2, 8.6, 12.3) Reduce dose when co-administered with drugs that are moderate or strong CYP3A inhibitors. (2.3, 7.2, 12.3) 2.1 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 (12.3)]. 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. 2.2 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 (12.3), and Patient Counseling Information (17)]. Table 1: Dosage Recommendations for Patients with Hepatic Impairment Morning Evening Mild (Child-Pugh Class A) No dose adjustment No dose adjustment Moderate (Child-Pugh Class B) One tablet of tezacaftor 100 mg/ivacaftor 150 mg once daily No ivacaftor 150 mg dose Severe (Child-Pugh Class C) One tablet of tezacaftor 100 mg/ivacaftor 150 mg once daily (or less frequently) 2.3 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 (12.3), and Patient Counseling Information (17)]. 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 (12.3), and Patient Counseling Information (17)]. Table 2: Dosing Schedule for Concomitant Use of SYMDEKO with Moderate and Strong CYP3A Inhibitors Moderate CYP3A Inhibitors Day 1 Day 2 Day 3 Day 4Continue dosing with tezacaftor 100 mg/ivacaftor 150 mg or ivacaftor 150 mg tablets on alternate days. Morning Dose Tezacaftor 100 mg/ivacaftor 150 mg tablet ✓ - ✓ - Ivacaftor 150 mg tablet - ✓ - ✓ Evening Dose Ivacaftor 150 mg tablet - - - - Strong CYP3A Inhibitors Day 1 Day 2 and Day 3 Day 4Dosing with tezacaftor 100 mg/ivacaftor 150 mg tablets twice a week, taken approximately 3 to 4 days apart. Morning Dose Tezacaftor 100 mg/ivacaftor 150 mg tablet ✓ - ✓ Evening DoseThe evening dose of ivacaftor 150 mg should not be taken. Ivacaftor 150 mg tablet - - - Food or drink containing grapefruit or Seville oranges should be avoided during treatment with SYMDEKO [see Drug Interactions (7.2) and Patient Counseling Information (17)].
Use in special populations
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 (12.1) and Clinical Studies (14)]. 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 (14)]. 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 (14)]. 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 (2.2), Clinical Pharmacology (12.3), and Patient Counseling Information (17)]. 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 (12.3)]. 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.

Interactions

7 DRUG INTERACTIONS Potential for other drugs to affect tezacaftor/ivacaftor CYP3A inhibitors: Reduce SYMDEKO dose when co-administered with strong (e.g., ketoconazole) or moderate (e.g., fluconazole) CYP3A inhibitors. Avoid food containing grapefruit or Seville oranges. (2.3, 7.2, 12.3) 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 (12.3), and Patient Counseling Information (17)]. 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 (2.3), Clinical Pharmacology (12.3), and Patient Counseling Information (17)]. 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 (2.3), Clinical Pharmacology (12.3), and Patient Counseling Information (17)]. 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 (2.3), Clinical Pharmacology (12.3), and Patient Counseling Information (17)]. 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 (12.3)]. 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 (12.3)]. 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 (12.3)]. 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 (12.3)].

More information

Category Value
Authorisation number NDA210491
Orphan designation No
Product NDC 51167-661
Date Last Revised 12-02-2018
Type HUMAN PRESCRIPTION DRUG
RXCUI 1999388
Storage and handling Store at 20-25ºC (68-77ºF); excursions permitted to 15-30ºC (59-86ºF) [see USP Controlled Room Temperature].
Marketing authorisation holder Vertex Pharmaceuticals Incorporated