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 1001 patients in three double-blind, placebo-controlled, clinical trials: two 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 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 reactions 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 patients 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 FEV

Table 5 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 trials (Trials 1 and 3).

The safety data from the following trials are similar to that observed in Trials 1 and 3:

The following adverse reactions have been identified during post approval use of SYMDEKO. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

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

Examples of strong CYP3A inducers include:

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

Examples of strong CYP3A inhibitors include:

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

Examples of moderate CYP3A inhibitors include:

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 should be avoided during treatment with SYMDEKO

Co-administration of SYMDEKO with ciprofloxacin had no significant effect on the exposure of tezacaftor or ivacaftor. Therefore, no dosage adjustment is necessary during concomitant administration of SYMDEKO with ciprofloxacin

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

Ivacaftor may inhibit CYP2C9; therefore, monitoring of the international normalized ratio (INR) during co-administration of SYMDEKO with warfarin is recommended. Other medicinal products for which exposure may be increased by SYMDEKO include glimepiride and glipizide; these medicinal products should be used with caution

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

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