Forzinity Drug Information

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 practice. In the FORZINITY clinical development program, 12 male patients aged 12 to 35 years with genetically-confirmed Barth syndrome received treatment with daily subcutaneous injections of 40 mg FORZINITY. Eleven of these 12 patients were Caucasian. Patients first participated in a double-blind, placebo-controlled crossover trial where they were randomized to one of two sequences: 12 weeks of FORZINITY in Period 1 then a 4-week washout followed by 12 weeks of placebo in Period 2 or 12 weeks of placebo in Period 1 then a 4-week washout followed by 12 weeks of FORZINITY in Period 2 Ten patients completed the randomized trial and entered the open-label extension period where they received FORZINITY once daily.

Eight of these patients received FORZINITY for 168 weeks, three of whom received FORZINITY for a total of 192 weeks. Adverse reactions occurring more commonly on FORZINITY than on placebo include injection site reactions such as injection site erythema, pain, induration, pruritus, bruising, and urticaria (Table 2). Table 2: Summary of Adverse Drug Reactions in the Placebo-Controlled Crossover Study, Barth Safety Population Combined (Periods 1 and 2) Elamipretide Placebo N=12 N=12 n (%) n (%) Any local administration reaction 12 8 Injection site erythema 12 3 Injection site induration 8 2 Injection site pruritus 8 2 Injection site pain 9 5 Injection site bruising 3 0 Injection site urticaria 3 0 Injection site hemorrhage 0 1 Eosinophilia Increases in absolute eosinophil counts were noted frequently in studies where duration of administration of FORZINITY was 30 days or greater. Eosinophil counts generally peaked around 90 days after initial exposure (mean increase from baseline ~0.5 to 0.6 × 10 3 /uL) and returned to baseline levels after 6 to 12 months of continuous exposure or after discontinuation of FORZINITY. The elevation in eosinophils was not associated with clinical manifestations or changes in other laboratory parameters.

Pregnancy Risk Summary Barth Syndrome is a rare, X-linked, recessive, genetic disorder and is not likely to affect females. Therefore, there are no data with FORZINITY use in pregnant women to evaluate for a drug-related risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. In animal reproduction studies, no adverse developmental outcomes occurred at any dose tested (see Data ). FORZINITY contains benzyl alcohol as a preservative.

Because benzyl alcohol is rapidly metabolized by a pregnant woman, benzyl alcohol exposure in the fetus is unlikely. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

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 In pregnant rats, once-daily intravenous infusion of elamipretide during the period of organogenesis did not result in embryo-fetal developmental toxicity at doses tested up to 10 mg/kg/day, approximately 4 times the clinical exposure at the maximum recommended human dose (MRHD) of 40 mg/day, based on area under the concentration-time curve (AUC). In pregnant rabbits, intravenous infusion with elamipretide once daily during the period of organogenesis (GD 7 to GD 19) did not result in embryo-fetal developmental toxicity at doses tested up to 50 mg/kg/day, approximately 10 times the clinical exposure at the MRHD, based on AUC. In a pre- and postnatal study in rats, elamipretide was subcutaneously administered at doses of 0, 5, 10 or 15 mg/kg/day throughout pregnancy and lactation (GD 6 to Lactation Day 20). No adverse developmental effects were observed at doses up to 15 mg/kg/day, approximately 6-times the clinical exposure at the MRHD, based on AUC.

Pediatric Use The safety and effectiveness of FORZINITY to improve muscle strength have been established in pediatric patients with Barth syndrome weighing at least 30 kg. Use of FORZINITY for this indication is supported by improvement in knee extensor muscle strength, an intermediate clinical endpoint, observed in an open-label extension study of FORZINITY that included seven pediatric patients aged 12 years and older. . The safety and effectiveness of FORZINITY have not been established in pediatric patients weighing less than 30 kg. FORZINITY is not approved for use in neonates.

Serious adverse reactions, including fatal reactions, of new onset or worsening metabolic acidosis that progressed to neurotoxicity, and in some cases gasping syndrome, have been reported in low-birth weight neonates and preterm neonates who received BA containing drugs intravenously (FORZINITY is not approved for intravenous use) . Gasping syndrome is a life-threatening condition in neonates caused by BA toxicity that is characterized by new onset or worsening metabolic acidosis with gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and gasping respirations followed by death. In reported cases, BA in amounts of 99 to 234 mg/kg/day produced blood BA levels of 6.6 to 14.9 mg/dL, but the minimum amount of BA at which gasping syndrome may occur in neonates is not known (FORZINITY contains 20 mg of BA per mL) .

Serious hypersensitivity to elamipretide or any of the excipients in FORZINITY. Serious hypersensitivity to any of the ingredients

There were no reports of overdose during clinical trials with FORZINITY. Symptoms and signs of overdose are likely to be histamine-related (e.g., decreased blood pressure, presyncope) and should be managed according to standard of care. Interrupt treatment with FORZINITY if there is suspicion of overdose.