Trofinetide

DAYBUE 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. ( 1 )

Oral solution: 200 mg/mL of a pink to red, strawberry flavored solution. For oral solution: 5,000 mg, 6,000 mg, or 8,000 mg of white, off-white to pinkish powder with strawberry flavor, packaged in individual packets. Oral solution: 200 mg/mL ( 3 ) For oral solution: 5,000 mg, 6,000 mg, or 8,000 mg per packet ( 3 )

None. None. ( 4 )

Diarrhea: Most patients experience diarrhea during treatment with DAYBUE. Advise patients to stop laxatives before starting DAYBUE or DAYBUE STIX. If diarrhea occurs, patients should start antidiarrheal treatment, increase oral fluids, and notify their healthcare provider. Interrupt, reduce dose, or discontinue DAYBUE or DAYBUE STIX if severe diarrhea occurs or if dehydration is suspected. ( 2.4 , 5.1 ) Weight Loss: Weight loss may occur in patients treated with DAYBUE or DAYBUE STIX. Monitor weight and interrupt, reduce dose, or discontinue DAYBUE or DAYBUE STIX if significant weight loss occurs. ( 2.4 , 5.2 ) Vomiting: Aspiration and aspiration pneumonia have occurred after vomiting in patients treated with DAYBUE. Interrupt, reduce dose, or discontinue DAYBUE or DAYBUE STIX if vomiting is severe or occurs despite medical management. ( 2.5 , 5.3 )

5.1 Diarrhea In Study 1 [see Clinical Studies (14) ] and in long-term studies, 85% of patients treated with DAYBUE experienced diarrhea. In those treated with DAYBUE, 49% either had persistent diarrhea or recurrence after resolution despite dose interruptions, reductions, or concomitant antidiarrheal therapy. Diarrhea severity was of mild or moderate severity in 96% of cases. In Study 1, antidiarrheal medication was used in 51% of patients treated with DAYBUE. Advise patients to stop laxatives before starting DAYBUE or DAYBUE STIX. If diarrhea occurs, patients should notify their healthcare provider, consider starting antidiarrheal treatment, and monitor hydration status and increase oral fluids, if needed. Interrupt, reduce dose, or discontinue DAYBUE or DAYBUE STIX if severe diarrhea occurs or if dehydration is suspected [see Dosage and Administration (2.4) ] .

5.2 Weight Loss In Study 1, 12% of patients treated with DAYBUE experienced weight loss of greater than 7% from baseline, compared to 4% of patients who received placebo. In long-term studies, 2.2% of patients discontinued treatment with DAYBUE due to weight loss. Monitor weight and interrupt, reduce dose, or discontinue DAYBUE or DAYBUE STIX if significant weight loss occurs [see Dosage and Administration (2.4) ] .

5.3 Vomiting In Study 1, vomiting occurred in 29% of patients treated with DAYBUE and in 12% of patients who received placebo [see Adverse Reactions (6.1) ]. Patients with Rett syndrome are at risk for aspiration and aspiration pneumonia. Aspiration and aspiration pneumonia have been reported following vomiting in patients being treated with DAYBUE. Interrupt, reduce dose, or discontinue DAYBUE or DAYBUE STIX if vomiting is severe or occurs despite medical management [see Dosage and Administration (2.5) ] .

The following clinically significant adverse reactions are described elsewhere in labeling: Diarrhea [see Warnings and Precautions (5.1) ] Weight Loss [see Warnings and Precautions (5.2) ] Vomiting [see Warnings and Precautions (5.3) ] The most common adverse reactions (that occurred in at least 10% of DAYBUE-treated patients and at least 2% greater than in placebo) were diarrhea and vomiting. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Acadia Pharmaceuticals Inc. at 1-844-422-2342 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 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 [see Clinical Studies (14) ] . 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) [see Clinical Studies (14) ] . 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.

6.2 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 [see Warnings and Precautions (5.3) ] .

Orally administered CYP3A and/or P-gp sensitive substrates for which a small change in substrate plasma concentration may lead to serious adverse reactions: closely monitor for adverse reactions with concomitant use. ( 7.1 )

7.1 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 [see Clinical Pharmacology (12.3) ] , which may increase the risk of adverse reactions associated with these substrates.

Severe renal impairment: DAYBUE and DAYBUE STIX are not recommended. ( 8.6 )

8.1 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 [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.

8.2 Lactation Risk Summary 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 DAYBUE or DAYBUE STIX and any potential adverse effects on the breastfed infant from the treatment or from the underlying maternal condition.

8.4 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 [see Adverse Reactions (6.1) and Clinical Studies (14) ]. 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 [see Dosage and Administration (2.1) , Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , and Clinical Studies (14) ] . 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.

8.5 Geriatric Use Clinical studies of DAYBUE did not include patients 65 years of age and older to determine whether or not they respond differently from younger patients. This drug is known to be substantially excreted by the kidney. Because elderly patients are more likely to have decreased renal function, it may be useful to monitor renal function.

8.6 Renal Impairment Mild renal impairment is not expected to impact the exposure of trofinetide; therefore, dosage adjustment is not necessary. Dosage adjustment of DAYBUE or DAYBUE STIX is recommended in patients with moderate renal impairment (adult: eGFR 30 to 59 mL/min; pediatric: eGFR 30 to 59 mL/min/1.73 m 2 ) [see Dosage and Administration (2.6) , Clinical Pharmacology (12.3) ] . Administration of DAYBUE or DAYBUE STIX to patients with severe renal impairment (eGFR less than 30 mL/min for adults or less than 30 mL/min/1.73 m 2 for pediatrics) is not recommended .

The mechanism by which trofinetide exerts therapeutic effects in patients with Rett syndrome is unknown.