Trofinetide

DAYBUE oral solution and DAYBUE STIX for oral solution contain the active moiety trofinetide. The chemical name of trofinetide is (2S)-2-{[(2S)-1-(2-aminoacetyl)-2-methylpyrrolidine-2-carbonyl]amino}pentanedioic acid (IUPAC). The molecular formula of trofinetide is C 13 H 21 N 3 O 6 and its molecular weight is 315.33 g/mol. The chemical structure is shown below. Trofinetide is a white to off-white solid and is freely soluble in water. DAYBUE oral solution is pink to red in color and contains 1 g of trofinetide in each 5 mL of solution (200 mg/mL). The oral solution also contains FD&C Red No. 40, maltitol, methylparaben sodium, propylparaben sodium, purified water, strawberry flavor, and sucralose as inactive ingredients. DAYBUE STIX for oral solution is a white, off-white to pinkish powder to be dissolved in a cold to room temperature water or water-based beverage before administration and contains 5,000 mg, 6,000 mg, or 8,000 mg of trofinetide in each packet. The for oral solution powder contains natural strawberry flavor and sucralose as inactive ingredients. Chemical Structure

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 )

16.1 How Supplied DAYBUE (trofinetide) 200 mg/mL oral solution is a pink to red, strawberry flavored solution supplied in a round high-density polyethylene (HDPE) multi-dose bottle with a child-resistant closure containing 450 mL of oral solution (NDC 63090-660-01). DAYBUE STIX (trofinetide) for oral solution is a white, off-white to pinkish powder with a strawberry flavor supplied in multi-layer aluminum packets as follows: Package Configuration and NDC Number Strength Individual Packet Carton of 60 Packets 5,000 mg 63090-663-01 63090-663-60 6,000 mg 63090-664-01 63090-664-60 8,000 mg 63090-665-01 63090-665-60 16.2 Storage and Handling DAYBUE Oral Solution Store DAYBUE in an upright position refrigerated at 2°C to 8°C (36°F to 46°F). Do not freeze. Keep the child-resistant cap tightly closed. Discard any unused DAYBUE oral solution after 14 days of first opening the bottle. DAYBUE STIX for Oral Solution Store DAYBUE STIX packets at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature].

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.

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) ] .

Advise the caregiver or patient to read the FDA-approved patient labeling (Patient Information). Preparation and Administration Advise the caregiver or patient that DAYBUE or DAYBUE STIX may be given orally or via gastrostomy (G) tube; doses administered via gastrojejunal (GJ) tubes must be administered through the G-port. DAYBUE or DAYBUE STIX may be taken with or without food [see Dosage and Administration (2.1) ]. Instruct the caregiver or patient to obtain a calibrated measuring device, such as an oral syringe or oral dosing cup, from the pharmacy. A household measuring cup, teaspoon, or tablespoon is not an adequate measuring device [see Dosage and Administration (2.2 , 2.3) ] . DAYBUE Oral Solution Instruct the caregiver or patient to discard any unused DAYBUE oral solution after 14 days from first opening the bottle. DAYBUE STIX for Oral Solution Advise the caregiver or patient that 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) prior to administration [see Dosage and Administration (2.3) ] . Instruct the caregiver or patient on how much water or water-based beverage is needed to dissolve the contents of DAYBUE STIX packet(s). Instruct the caregiver or patient to administer the prepared oral solution immediately and not to store for future use. Any prepared oral solution not administered must be discarded. Instruct patients to not attempt to use partial packets to prepare a dose. Diarrhea Advise the caregiver or patient that DAYBUE or DAYBUE STIX can cause diarrhea. Instruct the patient to stop taking 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 [see Warnings and Precautions (5.1) ] . Weight Loss Inform the caregiver or patient that DAYBUE or DAYBUE STIX may cause weight loss and to notify their healthcare provider if weight loss occurs [see Warnings and Precautions (5.2) ] . Vomiting Advise the caregiver or patient that DAYBUE or DAYBUE STIX can cause vomiting and if vomiting occurs after DAYBUE or DAYBUE STIX administration, do not take an additional dose, but continue with the next scheduled dose [see Dosage and Administration (2.5) ] . Instruct patients to notify their healthcare provider if vomiting does not stop despite medical management [see Warnings and Precautions (5.3) ] . Storage DAYBUE Oral Solution Keep bottles of DAYBUE upright and refrigerated before and after opening. Do not freeze [see How Supplied/Storage and Handling (16.2) ] .

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.

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).

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.

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.

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.

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) ] .