Daybue Drug Information

and DAYBUE STIX are indicated for the treatment of Rett syndrome in adults and pediatric patients 2 years of age and older. DAYBUE and DAYBUE STIX are indicated for the treatment of Rett syndrome in adults and pediatric patients 2 years of age and older.

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 DAYBUE, including 112 patients treated for more than 6 months, 92 patients treated for more than 1 year, and 44 patients treated for more than 2 years. The safety of DAYBUE STIX has been established from an adequate, well-controlled study, and open-label studies of DAYBUE . Below is a display of the adverse reactions of DAYBUE in these studies.

Adult and Pediatric Patients with Rett Syndrome 5 Years of Age and Older The safety of DAYBUE 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 DAYBUE 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 DAYBUE had adverse reactions that led to withdrawal from the study. The most common adverse reaction leading to discontinuation of treatment with DAYBUE was diarrhea (15%). Common Adverse Reactions Adverse reactions that occurred in Study 1 in at least 5% of patients treated with DAYBUE and were at least 2% more frequent than in patients on placebo are presented in Table 5. Table 5 Adverse Reactions in at Least 5% of Patients Treated with DAYBUE and at Least 2% Greater than Placebo in Study 1 Adverse Reaction DAYBUE (N=93) % Placebo (N=94) % Diarrhea 82 20 Vomiting 29 12 Fever 9 4 Seizure 9 6 Anxiety 8 1 Decreased appetite 8 2 Fatigue 8 2 Nasopharyngitis 5 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 (N=15), a total of 13 patients received DAYBUE for at least 12 weeks and 10 patients received DAYBUE for at least 12 months.

Adverse reactions in pediatric patients 2 to 4 years of age treated with DAYBUE were similar to those reported in adult and pediatric patients 5 years of age and older with Rett syndrome in Study 1.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of DAYBUE. 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. Aspiration and aspiration pneumonia secondary to vomiting .

Effect of

DAYBUE and DAYBUE STIX on Other Drugs CYP3A and/or P-gp Substrates Closely monitor patients when DAYBUE or DAYBUE STIX is administered concomitantly with sensitive CYP3A and/or P-gp substrates where minimal increases in the plasma concentration of these substrates may lead to serious adverse reactions. Trofinetide, a weak inhibitor of CYP3A and an inhibitor of P-gp, increased the plasma concentrations of CYP3A and/or P-gp substrates , which may increase the risk of adverse reactions associated with these substrates.

Pregnancy Risk Summary There are no adequate data on the developmental risks associated with the use of DAYBUE or DAYBUE STIX 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 . 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.

Pediatric Use The safety and effectiveness of DAYBUE and DAYBUE STIX for the treatment of Rett syndrome have been established in pediatric patients aged 2 years and older. The safety and effectiveness of DAYBUE for the treatment of Rett syndrome in pediatric patients 5 years of age and older was established in a randomized, double-blind, placebo-controlled, 12-week study (Study 1), which included 108 pediatric patients age 5 to less than 12 years of age and 47 pediatric patients age 12 to less than 17 years of age. Use of DAYBUE or DAYBUE STIX in patients 2 to 4 years of age is supported by evidence from Study 1 and pharmacokinetic and safety data in 15 pediatric patients 2 to 4 years of age treated with DAYBUE . Safety and effectiveness in pediatric patients less than 2 years of age have not been established.

Juvenile Animal Data Oral administration of trofinetide (0, 150, 300, or 1000 mg/kg twice daily; 0, 300, 600, or 2000 mg/kg/day) to rats from postnatal day (PND) 13-14 through 28 weeks of age resulted in no adverse effects on growth or neurobehavioral function. Plasma exposures at the highest dose tested were similar to those in pediatric patients at recommended doses. Oral administration of trofinetide (0, 150, 300, or 1000 mg/kg twice daily; 0, 300, 600, or 2000 mg/kg/day) to juvenile rats for 10 weeks beginning on PND 13-14 resulted in no adverse effects on sexual maturation or reproductive function.

Plasma exposures at the highest dose tested were similar to those in pediatric patients at recommended doses.