SYMDEKO

1 Dosing Considerations SYMDEKO should only be administered to patients who have a mutation in the CFTR gene that is responsive to SYMDEKO. If the patient’s genotype is unknown, an accurate and validated genotyping method should be performed to confirm the presence of an indicated mutation [see Action and Clinical Pharmacology (10) and Clinical Trials (14)].

2 Recommended Dose and Dosage Adjustment Adults, adolescents, and children aged 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 with fat-containing food.

3)]. Hepatic impairment A dose reduction to 1 tablet of tezacaftor/ivacaftor in the morning is recommended for patients with moderate hepatic impairment (Child-Pugh Class B). Studies have not been conducted in patients with severe hepatic impairment (Child-Pugh Class C), but exposure is expected to be higher than in patients with moderate hepatic impairment.

Therefore, use with caution after weighing the risks and benefits of treatment and reduce the dose accordingly in these patients. For dose adjustment for patients with hepatic impairment, refer to Table 1.

Table 1:

Dosing 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 with fat-containing food No ivacaftor 150 mg dose Severe (Child-Pugh Class C) Starting dose: One tablet of tezacaftor 100 mg/ivacaftor 150 mg once daily with fat- containing food.

If required dosing intervals should be lengthened to reduce the dosage further, according to clinical response and tolerability. Renal impairment No dose adjustment is recommended for mild and moderate renal impairment. 3)]. 3)]. , fluconazole, erythromycin), the dose should be adjusted as in Table 2.

3)].

Table 2:

Dosing schedule for concomitant use of Tezacaftor/Ivacaftor or Ivacaftor with moderate CYP3A inhibitors Moderate CYP3A inhibitors Day 1 Day 2 Day 3 Day 4* Morning Dose Tezacaftor 100 mg/ ivacaftor 150 mg tablet  -  - Ivacaftor 150 mg tablet -  -  Evening Dose^ Ivacaftor 150 mg tablet - - - - *Continue dosing with tezacaftor 100 mg/ivacaftor 150 mg or ivacaftor 150 mg tablets on alternate days.

1 Adverse Reaction Overview The safety profile of SYMDEKO is based on pooled data from three double-blind, placebo-controlled, Phase 3 clinical trials (2 parallel-group trials of 12 and 24 weeks 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. The 12-week parallel arm study was terminated following the planned interim analysis since the pre-specified futility criteria had been met. In the three placebo-controlled Phase 3 trials, a total of 496 patients with CF aged 12 years and older received at least one dose of SYMDEKO.

0% for placebo-treated patients. 6%) SYMDEKO-treated subjects vs. 0 placebo-treated patients. The most common adverse drug reactions experienced by patients who received SYMDEKO in the pooled, placebo-controlled phase 3 studies were headache (14%) and nasopharyngitis (12%).

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. 2 Clinical Trial Adverse Reactions Because clinical trials are conducted under very specific conditions, the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug.

Adverse reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates. The incidence of adverse reactions below is based on pooled data from three double-blind, placebo-controlled, Phase 3 clinical trials.

Table 4 shows adverse reactions occurring in ≥3% of SYMDEKO-treated patients and at a frequency higher than placebo by ≥1%. 4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data Laboratory Abnormalities Transaminase elevations During the placebo-controlled Phase 3 trials (up to 24 weeks), the incidence of maximum transaminase (ALT or AST) >8, >5, or >3 x ULN was similar between SYMDEKO-treated patients and placebo-treated patients.

2)]. Due caution should be exercised when driving or operating a vehicle or potentially dangerous machinery. Patients experiencing dizziness should be advised not to drive or operate machines until symptoms abate. 3)]. Elevated transaminase (AST/ALT) levels Elevated transaminases have been observed in CF patients treated with SYMDEKO, as well as with ivacaftor monotherapy.

, patients with ALT AST >5 x 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. 4)]. 3)]. 2)]. Monitoring and Laboratory Tests Effect on liver function tests Elevated transaminases have been observed in CF patients 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.

, patients with ALT or AST >5 x 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. 4)]. , abdominal pain, anorexia, jaundice, dark urine, pale stools, pruritus).

Ophthalmologic Cataracts Cases of non-congenital lens opacities without impact on vision 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 and 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 Non-Clinical Toxicology (16)]. 3)]. Sexual Health Fertility Tezacaftor had no effects on fertility and reproductive performance indices in male and female rats at doses up to 100 mg/kg/day (approximately 3 times the maximum recommended human dose [MRHD] based on summed area under the curve (AUCs) of tezacaftor and M1-TEZ).

SYMDEKO is contraindicated in patients who are hypersensitive to tezacaftor, ivacaftor or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see Dosage Forms, Strengths, Composition and Packaging (6).