Trofinetide

Plasma concentrations of OATP1B1 and OATP1B3 substrates may be increased if given concomitantly with trofinetide. Avoid the concomitant use of trofinetide with OATP1B1 and OATP1B3 substrates for which a small change in substrate plasma concentration may lead to serious toxicities.

Trofinetide is a weak CYP3A4 inhibitor; therefore, plasma concentrations of CYP3A4 substrates may be increased if given concomitantly with trofinetide. Closely monitor when trofinetide is used in combination with orally administered CYP3A4 sensitive substrates for which a small change in substrate plasma concentration may lead to serious toxicities.

No dedicated clinical study has been conducted to evaluate the pharmacokinetics of trofinetide in subjects with renal impairment. Since the drug is eliminated mainly through the kidney, administration of trofinetide to patients with moderate or severe renal impairment is not recommended.

Risk Summary

There are no adequate data on the developmental risks associated with the use of trofinetide in pregnant women. No adverse developmental effects were observed following oral administration of trofinetide to pregnant animals at doses associated with plasma exposures below those used clinically [see Animal Data].

The estimated 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

Oral administration of trofinetide (0, 150, 450, or 1000 mg/kg twice daily; 0, 300, 900, or 2000 mg/kg/day) to pregnant rats during the period of organogenesis resulted in no adverse effects on embryofetal development. At the highest dose tested, plasma exposure (AUC) was less than that in humans at the maximum recommended human dose (MRHD) of 12,000 mg twice daily (24,000 mg/day).

Oral administration of trofinetide (0, 75, 150, or 300 mg/kg twice daily; 0, 150, 300, or 600 mg/kg/day) to pregnant rabbits during the period of organogenesis resulted in no adverse effects on embryofetal development. At the highest dose tested, plasma exposure (AUC) was less than that in humans at the MRHD.

Oral administration of trofinetide (0, 150, 450, or 1000 mg/kg twice daily; 0, 300, 900, or 2000 mg/kg/day) to rats throughout pregnancy and lactation resulted in no adverse effects on pre- and postnatal development. At the highest dose tested, plasma exposure (AUC) was less than that in humans at the MRHD.

There is no information regarding the presence of trofinetide or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for trofinetide and any potential adverse effects on the breastfed infant from trofinetide or from the underlying maternal condition.

Carcinogenesis

Studies to evaluate the carcinogenic potential of trofinetide have not been conducted.

Mutagenesis

Trofinetide was negative in in vitro (bacterial reverse mutation, chromosomal aberration in Chinese hamster ovary cells) and in vivo (mouse micronucleus) assays.

Impairment of Fertility

Oral administration of trofinetide (0, 150, 450, or 1000 mg/kg twice daily; 0, 300, 900, or 2000 mg/kg/day) to male and female rats prior to and throughout mating and continuing in females through gestation day 7 resulted in no adverse effects on fertility or reproductive function. Plasma exposures at the highest dose tested were less than that in humans at the maximum recommended human dose of 12,000 mg/dose (24,000 mg/day).

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 controlled and uncontrolled trials in patients with Rett syndrome, 260 patients ages 2 to 40 years were treated with trofinetide, including 109 patients treated for more than 6 months, 69 patients treated for more than 1 year, and 4 patients treated for more than 2 years.

Adult and Pediatric Patients With Rett Syndrome 5 Years of Age and Older

The safety of trofinetide was evaluated in a randomized, double-blind, placebo-controlled, 12-week study of patients with Rett syndrome (Study 1). In Study 1, 93 patients received trofinetide and 94 patients received placebo. All patients were female, 92% were White, and the mean age was 11 years (range 5 to 20 years).

Adverse Reactions Leading to Discontinuation of Treatment

Eighteen patients (19%) receiving trofinetide had adverse reactions that led to withdrawal from the study. The most common adverse reaction leading to discontinuation of treatment with trofinetide was diarrhea (15%).

Common Adverse Reactions

Adverse reactions that occurred in Study 1 in at least 5% of patients treated with trofinetide and were at least 2% more frequent than in patients on placebo are presented in the following table.

Adverse Reactions in at Least 5% of Patients Treated With Trofinetide and at Least 2% Greater than Placebo in Study 1:

Pediatric Patients With Rett Syndrome 2 to 4 Years of Age

In an open-label study in pediatric patients 2 to 4 years of age with Rett syndrome, a total of 13 patients received trofinetide for at least 12 weeks and 9 patients received trofinetide for at least 6 months. Adverse reactions in pediatric patients 2 to 4 years of age treated with trofinetide were similar to those reported in adult and pediatric patients 5 years of age and older with Rett syndrome in Study 1.