Trofinetide

1 INDICATIONS AND USAGE 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 )

2 DOSAGE AND ADMINISTRATION Recommended dosage is twice daily, morning and evening, according to patient weight. DAYBUE or DAYBUE STIX can be given with or without food. ( 2.1 ) Patient Weight Recommended Dosage 9 kg to less than 12 kg 5,000 mg twice daily 12 kg to less than 20 kg 6,000 mg twice daily 20 kg to less than 35 kg 8,000 mg twice daily 35 kg to less than 50 kg 10,000 mg twice daily 50 kg or more 12,000 mg twice daily Can be given orally or via gastrostomy (G) tube; doses administered via gastrojejunal (GJ) tubes must be administered through the G-port. ( 2.1 ) See Full Prescribing Information for instruction on dissolving DAYBUE STIX for oral solution powder. ( 2.3 ) See Full Prescribing Information for dosage recommendations in patients with renal impairment. ( 2.6 , 8.6 ) 2.1 Recommended Dosage The recommended dosage of DAYBUE or DAYBUE STIX is based on patient weight as shown in Table 1 . Administer DAYBUE or DAYBUE STIX orally or via gastrostomy (G) tube twice daily, in the morning and evening, with or without food. Doses administered via gastrojejunal (GJ) tubes must be administered through the G-port. Table 1 Recommended Dosage of DAYBUE or DAYBUE STIX in Patients 2 Years of Age and Older Patient Weight Recommended Dosage 9 kg to less than 12 kg 5,000 mg twice daily 12 kg to less than 20 kg 6,000 mg twice daily 20 kg to less than 35 kg 8,000 mg twice daily 35 kg to less than 50 kg 10,000 mg twice daily 50 kg or more 12,000 mg twice daily 2.2 DAYBUE Oral Solution Preparation Table 2 includes the volume of DAYBUE oral solution to administer for the corresponding recommended dosage [see Dosage and Administration (2.1 , 2.6) ] . A calibrated measuring device, such as an oral syringe or oral dosing cup, should be obtained from the pharmacy to measure and deliver the prescribed dose accurately. A household measuring cup, teaspoon, or tablespoon is not an adequate measuring device. Table 2 Recommended Volume of DAYBUE Oral Solution for Administration Dosage DAYBUE Oral Solution Volume 2,500 mg twice daily Dosage for patients with moderate renal impairment [see Dosage and Administration (2.6) ] 12.5 mL twice daily 3,000 mg twice daily 15 mL twice daily 4,000 mg twice daily 20 mL twice daily 5,000 mg twice daily 25 mL twice daily 6,000 mg twice daily 30 mL twice daily 8,000 mg twice daily 40 mL twice daily 10,000 mg twice daily 50 mL twice daily 12,000 mg twice daily 60 mL twice daily Discard any unused DAYBUE oral solution after 14 days of first opening the bottle [see How Supplied/Storage and Handling (16.2) ] . 2.3 DAYBUE STIX for Oral Solution Preparation Prior to administration, DAYBUE STIX for oral solution powder must be dissolved in a cold to room temperature water or water-based beverage (juice, tea, lemonade, limeade, or liquid hydration). Preparation of DAYBUE STIX Determine the correct dosage as shown in Table 1 or Table 4 (for patients with moderate renal impairment). Select the appropriate packet strength and number of packets required for each dose, as shown in Table 3 . Determine the appropriate volume of liquid within the recommended volume range as shown in Table 3 , based on individual patient factors (e.g., age, palatability). Measure the volume of liquid determined in Step 3 by using a calibrated measuring device obtained from the pharmacy. Empty the entire contents of the DAYBUE STIX packet(s) into the measured liquid. Do not attempt to use partial packets to prepare a dose. Stir until the powder is completely dissolved. Administer the prepared oral solution immediately; do not store for future use. Discard any prepared oral solution that is not immediately administered. Table 3 Preparation Instructions for DAYBUE STIX for Oral Solution Powder Dose DAYBUE STIX Packet(s) Needed to Prepare Each Dose Volume of Liquid Required to Dissolve Entire Dose Liquid types include water or water-based beverage. , Volume should be selected within the recommended range based on individual patient factors. 5,000 mg One 5,000 mg packet 15 mL to 60 mL 6,000 mg One 6,000 mg packet 15 mL to 60 mL 8,000 mg One 8,000 mg packet 25 mL to 120 mL 10,000 mg Two 5,000 mg packets 30 mL to 120 mL (each packet requires 15 mL to 60 mL) 12,000 mg Two 6,000 mg packets 30 mL to 120 mL (each packet requires 15 mL to 60 mL) 2.4 Dose Modification for Diarrhea or Weight Loss Advise patients to stop laxatives before starting DAYBUE or DAYBUE STIX. Interrupt, reduce dose, or discontinue DAYBUE or DAYBUE STIX if severe diarrhea occurs, if dehydration is suspected, or if significant weight loss occurs [see Warnings and Precautions (5.1 , 5.2) ]. 2.5 Dose Modification for Vomiting After Administration If vomiting occurs after DAYBUE or DAYBUE STIX administration, an additional dose should not be taken. Instead, continue with the next scheduled dose. Interrupt, reduce dose, or discontinue DAYBUE or DAYBUE STIX if vomiting is severe or occurs despite medical management [see Warnings and Precautions (5.3) ] . 2.6 Dosage Recommendations in Patients with Renal Impairment No dosage adjustment is recommended for patients with mild renal impairment (estimated glomerular filtration rate [eGFR] 60 to 89 mL/min for adult patients or 60 to 89 mL/min/1.73 m 2 for pediatric patients). The recommended dosage of DAYBUE or DAYBUE STIX for patients with moderate renal impairment (eGFR 30 to 59 mL/min for adult patients or 30 to 59 mL/min/1.73 m 2 for pediatric patients) is described in Table 4 [see Use in Specific Populations (8.6) , Clinical Pharmacology (12.3) ]. DAYBUE and DAYBUE STIX are not recommended for patients with severe renal impairment (eGFR less than 30 mL/min for adult patients or less than 30 mL/min/1.73 m 2 for pediatric patients). For patients with moderate renal impairment who require a dose less than 5,000 mg, DAYBUE oral solution is recommended. Do not attempt to use partial packets of DAYBUE STIX to prepare a dose. Table 4 Recommended Dosage of DAYBUE or DAYBUE STIX in Patients with Moderate Renal Impairment Patient Weight Recommended Dosage 9 kg to less than 12 kg 2,500 mg twice daily Use DAYBUE oral solution to administer this dosage. 12 kg to less than 20 kg 3,000 mg twice daily 20 kg to less than 35 kg 4,000 mg twice daily 35 kg to less than 50 kg 5,000 mg twice daily 50 kg or more 6,000 mg twice daily 2.7 Missed Dose If a dose of DAYBUE or DAYBUE STIX is missed, the next dose should be taken as scheduled. Doses should not be doubled.

6 ADVERSE REACTIONS 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 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. 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, a total of 13 patients received DAYBUE for at least 12 weeks and 9 patients received DAYBUE for at least 6 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) ] .

12.3 Pharmacokinetics DAYBUE STIX for oral solution demonstrated comparable bioavailability to DAYBUE oral solution in adult healthy subjects under fasted state. Trofinetide exhibits linear kinetics with no time- or dose-dependent effect on pharmacokinetic parameters. Systemic exposure to trofinetide was dose-proportional across the studied dose range. Minimal to no accumulation was observed following multiple-dose administration. Absorption The time to maximum drug concentration (T max ) is about 2 to 3 hours after administration. Based on the mass balance study, at least 84% of the administered dose was absorbed following oral administration of 12,000 mg trofinetide. Effect of Food Coadministration of trofinetide with a high-fat meal had no impact on the total exposure (AUC 0-inf ) of trofinetide and reduced the peak plasma concentration (C max ) by approximately 20% [see Dosage and Administration (2.1) ] . Distribution Following oral administration, the apparent volume of distribution of trofinetide in adult healthy subjects was approximately 80 L. Trofinetide protein binding in human plasma is less than 6%. Elimination The effective elimination half-life of orally administered trofinetide in healthy subjects is about 1.5 hours. Metabolism Trofinetide is not significantly metabolized by CYP450 enzymes. Hepatic metabolism is not a significant route of trofinetide elimination. Excretion Trofinetide is primarily excreted unchanged (approximately 80% of the dose) in urine, with minor excretion in feces. Specific Populations Pediatric Patients The drug exposure of trofinetide in pediatric patients ages 2 to 4 years of age is similar to children older than 4 years and adults when following the recommended dosage [see Dosage and Administration (2.1) ] . Patients with Renal Impairment Based on population PK analysis of clinical trials data, patients with mild renal impairment (eGFR 60 to 89 mL/min/1.73 m 2 ) showed no significant impact on the exposure of trofinetide compared to patients with normal renal function. Based on a renal impairment study in adult subjects, the effect of moderate renal impairment (eGFR 30 to 59 mL/min) increases the exposure (AUC 0-inf ) of trofinetide approximately 80% compared to patients with normal renal function administered the same dose [see Dosage and Administration (2.6) ] . The effect of severe renal impairment on the exposure of trofinetide has not been investigated [see Use in Specific Populations (8.6) ] . Patients with Hepatic Impairment The pharmacokinetics in patients with hepatic impairment have not been studied. However, hepatic impairment is not expected to impact the exposure of trofinetide because hepatic metabolism is not a significant route of trofinetide elimination. Drug Interaction Studies Clinical Studies CYP3A and/or P-gp Substrates: Coadministration of trofinetide 12,000 mg twice daily with 4 mg of loperamide (a moderately sensitive CYP3A substrate and a P-gp substrate) increased the AUC of loperamide by 1.73-fold and the C max by 1.95-fold [see Drug Interactions (7.1) ] . Administration of trofinetide 2 hours prior to loperamide increased the AUC of loperamide by 1.22-fold and the C max by 1.44-fold. In Vitro Trofinetide is not a substrate of CYP450 enzymes, uridine diphosphate glucuronosyltransferase (UGT), or major drug transporters. Cytochrome P450 (CYP450) Enzymes: Trofinetide inhibits CYP3A [see Drug Interactions (7.1) ] . Trofinetide inhibits CYP1A2, 2B6, 2C8, 2C19, and 2D6, but is not expected to result in clinically significant drug interactions. Trofinetide does not inhibit CYP2C9. UDP-Glucuronosyltransferase (UGT): Trofinetide inhibits UGT enzymes, UGT1A9, 2B7, and 2B15. Transporter Systems: Trofinetide inhibits P-gp [see Drug Interactions (7.1) ] , BCRP, and BSEP. Trofinetide inhibits OAT1, OCT2, OATP1B1, OATP1B3, MATE1, and MATE2-K, but is not expected to result in clinically significant drug interactions. Trofinetide does not inhibit OAT3.