USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Severe renal impairment: DAYBUE and DAYBUE STIX are not recommended. (8.6). 8.1 Pregnancy. Risk SummaryThere 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 to 4% and 15 to 20%, respectively.. Data. Animal DataOral 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 SummaryThere 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 mothers 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 years and older. The safety and effectiveness of DAYBUE for the treatment of Rett syndrome in pediatric patients years of age and older was established in randomized, double-blind, placebo-controlled, 12-week study (Study 1), which included 108 pediatric patients age 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 to years of age is supported by evidence from Study and pharmacokinetic and safety data in 15 pediatric patients to 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 years of age have not been established.. Juvenile Animal DataOral 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 m2) [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 m2 for pediatrics) is not recommended.

ADVERSE REACTIONS SECTION.

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)] 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. 6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 to 40 years were treated with DAYBUE, including 112 patients treated for more than months, 92 patients treated for more than year, and 44 patients treated for more than 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 display of the adverse reactions of DAYBUE in these studies.. Adult and Pediatric Patients with Rett Syndrome Years of Age and OlderThe safety of DAYBUE was evaluated in 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 to 20 years).. Adverse Reactions Leading to Discontinuation of TreatmentEighteen 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 ReactionsAdverse reactions that occurred in Study 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 Adverse Reactions in at Least 5% of Patients Treated with DAYBUE and at Least 2% Greater than Placebo in Study 1Adverse ReactionDAYBUE(N=93)%Placebo (N=94)% Diarrhea8220 Vomiting2912 Fever94 Seizure96 Anxiety81 Decreased appetite82 Fatigue82 Nasopharyngitis51. Pediatric Patients with Rett Syndrome to Years of AgeIn an open-label study in pediatric patients to years of age with Rett syndrome (N=15), 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 to years of age treated with DAYBUE were similar to those reported in adult and pediatric patients years of age and older with Rett syndrome in Study 1.. 6.2Postmarketing Experience. The following adverse reactions have been identified during postapproval use of DAYBUE. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Aspiration and aspiration pneumonia secondary to vomiting [see Warnings and Precautions (5.3)].

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisStudies to evaluate the carcinogenic potential of trofinetide have not been conducted.. MutagenesisTrofinetide was negative in in vitro (bacterial reverse mutation, chromosomal aberration in Chinese hamster ovary cells) and in vivo (mouse micronucleus) assays.. Impairment of FertilityOral 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 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 PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. The mechanism by which trofinetide exerts therapeutic effects in patients with Rett syndrome is unknown. 12.2 Pharmacodynamics. Cardiac ElectrophysiologyAt the maximum recommended dose in healthy adult subjects, trofinetide does not prolong the QT interval to any clinically relevant extent. 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.. AbsorptionThe time to maximum drug concentration (Tmax) is about to 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 FoodCoadministration of trofinetide with high-fat meal had no impact on the total exposure (AUC0-inf) of trofinetide and reduced the peak plasma concentration (Cmax) by approximately 20% [see Dosage and Administration (2.1)].. DistributionFollowing 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%.. EliminationThe effective elimination half-life of orally administered trofinetide in healthy subjects is about 1.5 hours.. MetabolismTrofinetide is not significantly metabolized by CYP450 enzymes. Hepatic metabolism is not significant route of trofinetide elimination. ExcretionTrofinetide is primarily excreted unchanged (approximately 80% of the dose) in urine, with minor excretion in feces.. Specific Populations. Pediatric PatientsThe drug exposure of trofinetide in pediatric patients ages to years of age is similar to children older than years and adults when following the recommended dosage [see Dosage and Administration (2.1)].. Patients with Renal ImpairmentBased on population PK analysis of clinical trials data, patients with mild renal impairment (eGFR 60 to 89 mL/min/1.73 m2) showed no significant impact on the exposure of trofinetide compared to patients with normal renal function. Based on renal impairment study in adult subjects, the effect of moderate renal impairment (eGFR 30 to 59 mL/min) increases the exposure (AUC0-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 ImpairmentThe 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 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 mg of loperamide (a moderately sensitive CYP3A substrate and P-gp substrate) increased the AUC of loperamide by 1.73-fold and the Cmax by 1.95-fold [see Drug Interactions (7.1)]. Administration of trofinetide hours prior to loperamide increased the AUC of loperamide by 1.22-fold and the Cmax by 1.44-fold.. In VitroTrofinetide is not 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.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. DAYBUE STIXThe effectiveness of DAYBUE STIX has been established from an adequate and well-controlled study of DAYBUE for the treatment of Rett syndrome and demonstration of similar pharmacokinetics between DAYBUE STIX for oral solution and DAYBUE oral solution [see Clinical Pharmacology (12.3)]. Presented below is display of the efficacy results of the adequate and well-controlled study of DAYBUE in patients with Rett syndrome. DAYBUEThe efficacy of DAYBUE for the treatment of Rett syndrome was established in 12-week randomized, double-blind, placebo-controlled study in patients with Rett syndrome to 20 years of age (Study 1; NCT04181723). Patients (N=187) had diagnosis of typical Rett syndrome according to the Rett Syndrome Diagnostic Criteria with documented disease-causing mutation in the MECP2 gene. Patients were randomized to receive DAYBUE (N=93) or matching placebo (N=94) for 12 weeks. The DAYBUE dosage was based on patient weight to achieve similar exposure in all patients [see Dosage and Administration (2.1)].The co-primary efficacy measures were change from baseline after 12 weeks of treatment in the total score of the Rett Syndrome Behaviour Questionnaire (RSBQ) and the Clinical Global Impression-Improvement (CGI-I) score. The RSBQ is 45-text rating scale completed by the caregiver that assesses range of symptoms of Rett syndrome (breathing, hand movements or stereotypies, repetitive behaviors, night-time behaviors, vocalizations, facial expressions, eye gaze, and mood). Each text is scored as (not true), (somewhat or sometimes true), or (very true or often true), with maximum possible score of 90 points. Lower scores reflect lesser severity in signs and symptoms of Rett syndrome. The CGI-I is rated by clinicians to assess whether patient has improved or worsened on 7-point scale (1=very much improved to 7=very much worse) in which decrease in score indicates improvement.Treatment with DAYBUE demonstrated statistically significant difference in favor of DAYBUE as compared to placebo on the co-primary efficacy endpoints, the change from baseline in RSBQ total score, and the CGI-I score at week 12 (Table 6, Figure 1, and Figure 2).Table Summary of Study Efficacy ResultsMean Baseline Score (SE)Mean Week 12 Score (SE)LS Mean Change from Baseline to Week 12 (SE)DAYBUE-Placebo Treatment Difference, LS Mean (95% CI)Difference in LS mean from the mixed-effect model for repeated measure analysis p-valueCI=confidence interval; LS mean=least-squares mean; SE=standard errorRSBQDAYBUE43.7 (1.21)39.9 (1.38)-4.9 (0.94)-3.2 (-5.7, -0.6)0.018Placebo44.5 (1.26)42.8 (1.42)-1.7 (0.90)CGI-IDAYBUE--3.5 (0.08)---0.3(-0.5, -0.1)0.003Placebo--3.8 (0.06)Figure 1Change From Baseline in RSBQ Total Score in Study 1Figure 2Distribution of CGI-I Scores for Patients Completing Study 1. Figure 1. Figure 2.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 to 40 years were treated with DAYBUE, including 112 patients treated for more than months, 92 patients treated for more than year, and 44 patients treated for more than 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 display of the adverse reactions of DAYBUE in these studies.. Adult and Pediatric Patients with Rett Syndrome Years of Age and OlderThe safety of DAYBUE was evaluated in 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 to 20 years).. Adverse Reactions Leading to Discontinuation of TreatmentEighteen 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 ReactionsAdverse reactions that occurred in Study 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 Adverse Reactions in at Least 5% of Patients Treated with DAYBUE and at Least 2% Greater than Placebo in Study 1Adverse ReactionDAYBUE(N=93)%Placebo (N=94)% Diarrhea8220 Vomiting2912 Fever94 Seizure96 Anxiety81 Decreased appetite82 Fatigue82 Nasopharyngitis51. Pediatric Patients with Rett Syndrome to Years of AgeIn an open-label study in pediatric patients to years of age with Rett syndrome (N=15), 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 to years of age treated with DAYBUE were similar to those reported in adult and pediatric patients years of age and older with Rett syndrome in Study 1.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. None.. None. (4).

DESCRIPTION SECTION.

11 DESCRIPTION. 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]aminopentanedioic acid (IUPAC). The molecular formula of trofinetide is C13H21N3O6 and its molecular weight is 315.33 g/mol. The chemical structure is shown below.Trofinetide is white to off-white solid and is freely soluble in water.DAYBUE oral solution is pink to red in color and contains g of trofinetide in each 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 white, off-white to pinkish powder to be dissolved in 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.

DOSAGE & ADMINISTRATION SECTION.

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 WeightRecommended Dosage9 kg to less than 12 kg5,000 mg twice daily12 kg to less than 20 kg6,000 mg twice daily20 kg to less than 35 kg8,000 mg twice daily35 kg to less than 50 kg10,000 mg twice daily50 kg or more12,000 mg twice dailyCan 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). 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). 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). 2.1Recommended 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 Recommended Dosage of DAYBUE or DAYBUE STIX in Patients Years of Age and OlderPatient WeightRecommended Dosage9 kg to less than 12 kg5,000 mg twice daily12 kg to less than 20 kg6,000 mg twice daily20 kg to less than 35 kg8,000 mg twice daily35 kg to less than 50 kg10,000 mg twice daily50 kg or more12,000 mg twice daily. 2.2DAYBUE Oral Solution Preparation. Table includes the volume of DAYBUE oral solution to administer for the corresponding recommended dosage [see Dosage and Administration (2.1, 2.6)]. 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. household measuring cup, teaspoon, or tablespoon is not an adequate measuring device.Table Recommended Volume of DAYBUE Oral Solution for AdministrationDosageDAYBUE Oral Solution Volume2,500 mg twice dailyDosage for patients with moderate renal impairment [see Dosage and Administration (2.6)] 12.5 mL twice daily3,000 mg twice daily 15 mL twice daily4,000 mg twice daily 20 mL twice daily5,000 mg twice daily25 mL twice daily6,000 mg twice daily30 mL twice daily8,000 mg twice daily40 mL twice daily10,000 mg twice daily50 mL twice daily12,000 mg twice daily60 mL twice dailyDiscard any unused DAYBUE oral solution after 14 days of first opening the bottle [see How Supplied/Storage and Handling (16.2)].. 2.3DAYBUE STIX for Oral Solution Preparation. Prior to administration, DAYBUE STIX for oral solution powder must be dissolved in cold to room temperature water or water-based beverage (juice, tea, lemonade, limeade, or liquid hydration).. Preparation of DAYBUE STIXDetermine the correct dosage as shown in Table or Table (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 by using 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 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 Preparation Instructions for DAYBUE STIX for Oral Solution PowderDoseDAYBUE STIX Packet(s) Needed to Prepare Each DoseVolume of Liquid Required to Dissolve Entire DoseLiquid types include water or water-based beverage. Volume should be selected within the recommended range based on individual patient factors. 5,000 mgOne 5,000 mg packet15 mL to 60 mL6,000 mgOne 6,000 mg packet15 mL to 60 mL8,000 mgOne 8,000 mg packet25 mL to 120 mL10,000 mgTwo 5,000 mg packets30 mL to 120 mL(each packet requires 15 mL to 60 mL)12,000 mgTwo 6,000 mg packets30 mL to 120 mL(each packet requires 15 mL to 60 mL). Determine the correct dosage as shown in Table or Table (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 by using 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 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.. 2.4Dose 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)]. 2.5Dose 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 m2 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 m2 for pediatric patients) is described in Table [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 m2 for pediatric patients).For patients with moderate renal impairment who require dose less than 5,000 mg, DAYBUE oral solution is recommended. Do not attempt to use partial packets of DAYBUE STIX to prepare dose.Table Recommended Dosage of DAYBUE or DAYBUE STIX in Patients with Moderate Renal ImpairmentPatient WeightRecommended Dosage9 kg to less than 12 kg2,500 mg twice dailyUse DAYBUE oral solution to administer this dosage. 12 kg to less than 20 kg3,000 mg twice daily 20 kg to less than 35 kg4,000 mg twice daily 35 kg to less than 50 kg5,000 mg twice daily50 kg or more6,000 mg twice daily. 2.7Missed Dose. If dose of DAYBUE or DAYBUE STIX is missed, the next dose should be taken as scheduled. Doses should not be doubled.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Oral solution: 200 mg/mL of 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). Oral solution: 200 mg/mL (3). For oral solution: 5,000 mg, 6,000 mg, or 8,000 mg per packet (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Orally administered CYP3A and/or P-gp sensitive substrates for which small change in substrate plasma concentration may lead to serious adverse reactions: closely monitor for adverse reactions with concomitant use. (7.1). Orally administered CYP3A and/or P-gp sensitive substrates for which small change in substrate plasma concentration may lead to serious adverse reactions: closely monitor for adverse reactions with concomitant use. (7.1). 7.1Effect of DAYBUE and DAYBUE STIX on Other Drugs. CYP3A and/or P-gp SubstratesClosely 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, 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.

GERIATRIC USE SECTION.

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.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. 16.1 How Supplied. DAYBUE (trofinetide) 200 mg/mL oral solution is pink to red, strawberry flavored solution supplied in round high-density polyethylene (HDPE) multi-dose bottle with child-resistant closure containing 450 mL of oral solution (NDC 63090-660-01). DAYBUE STIX (trofinetide) for oral solution is white, off-white to pinkish powder with strawberry flavor supplied in multi-layer aluminum packets as follows:Package Configuration and NDC NumberStrengthIndividual PacketCarton of 60 Packets5,000 mg63090-663-0163090-663-606,000 mg63090-664-0163090-664-608,000 mg63090-665-0163090-665-60. 16.2 Storage and Handling. DAYBUE Oral SolutionStore DAYBUE in an upright position refrigerated at 2C to 8C (36F to 46F). 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 SolutionStore DAYBUE STIX packets at 20C to 25C (68F to 77F); excursions permitted between 15C and 30C (59F and 86F) [see USP Controlled Room Temperature].

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. DAYBUE and DAYBUE STIX are indicated for the treatment of Rett syndrome in adults and pediatric patients years of age and older.. DAYBUE and DAYBUE STIX are indicated for the treatment of Rett syndrome in adults and pediatric patients years of age and older. (1).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the caregiver or patient to read the FDA-approved patient labeling (Patient Information).. Preparation and AdministrationAdvise 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 calibrated measuring device, such as an oral syringe or oral dosing cup, from the pharmacy. household measuring cup, teaspoon, or tablespoon is not an adequate measuring device [see Dosage and Administration (2.2, 2.3)].. DAYBUE Oral SolutionInstruct the caregiver or patient to discard any unused DAYBUE oral solution after 14 days from first opening the bottle.. DAYBUE STIX for Oral SolutionAdvise the caregiver or patient that DAYBUE STIX for oral solution powder must be dissolved in 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 dose.. DiarrheaAdvise 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 LossInform 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)].. VomitingAdvise 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 SolutionKeep bottles of DAYBUE upright and refrigerated before and after opening. Do not freeze [see How Supplied/Storage and Handling (16.2)].

LACTATION SECTION.

8.2 Lactation. Risk SummaryThere 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 mothers 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.

MECHANISM OF ACTION SECTION.

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

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisStudies to evaluate the carcinogenic potential of trofinetide have not been conducted.. MutagenesisTrofinetide was negative in in vitro (bacterial reverse mutation, chromosomal aberration in Chinese hamster ovary cells) and in vivo (mouse micronucleus) assays.. Impairment of FertilityOral 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 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).

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 450 ML ORAL SOLUTION BOTTLE LABEL. NDC 63090-660-01450 mL Rx onlyDaybue(TM)(trofinetide)oral solution200 mg/mLRecommended Dosage:See prescribing information.For oral or G-tube administration only.. PRINCIPAL DISPLAY PANEL 450 ML ORAL SOLUTION BOTTLE LABEL.

PEDIATRIC USE SECTION.

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 years and older. The safety and effectiveness of DAYBUE for the treatment of Rett syndrome in pediatric patients years of age and older was established in randomized, double-blind, placebo-controlled, 12-week study (Study 1), which included 108 pediatric patients age 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 to years of age is supported by evidence from Study and pharmacokinetic and safety data in 15 pediatric patients to 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 years of age have not been established.. Juvenile Animal DataOral 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.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Cardiac ElectrophysiologyAt the maximum recommended dose in healthy adult subjects, trofinetide does not prolong the QT interval to any clinically relevant extent.

PHARMACOKINETICS SECTION.

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.. AbsorptionThe time to maximum drug concentration (Tmax) is about to 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 FoodCoadministration of trofinetide with high-fat meal had no impact on the total exposure (AUC0-inf) of trofinetide and reduced the peak plasma concentration (Cmax) by approximately 20% [see Dosage and Administration (2.1)].. DistributionFollowing 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%.. EliminationThe effective elimination half-life of orally administered trofinetide in healthy subjects is about 1.5 hours.. MetabolismTrofinetide is not significantly metabolized by CYP450 enzymes. Hepatic metabolism is not significant route of trofinetide elimination. ExcretionTrofinetide is primarily excreted unchanged (approximately 80% of the dose) in urine, with minor excretion in feces.. Specific Populations. Pediatric PatientsThe drug exposure of trofinetide in pediatric patients ages to years of age is similar to children older than years and adults when following the recommended dosage [see Dosage and Administration (2.1)].. Patients with Renal ImpairmentBased on population PK analysis of clinical trials data, patients with mild renal impairment (eGFR 60 to 89 mL/min/1.73 m2) showed no significant impact on the exposure of trofinetide compared to patients with normal renal function. Based on renal impairment study in adult subjects, the effect of moderate renal impairment (eGFR 30 to 59 mL/min) increases the exposure (AUC0-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 ImpairmentThe 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 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 mg of loperamide (a moderately sensitive CYP3A substrate and P-gp substrate) increased the AUC of loperamide by 1.73-fold and the Cmax by 1.95-fold [see Drug Interactions (7.1)]. Administration of trofinetide hours prior to loperamide increased the AUC of loperamide by 1.22-fold and the Cmax by 1.44-fold.. In VitroTrofinetide is not 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.

POSTMARKETING EXPERIENCE SECTION.

6.2Postmarketing Experience. The following adverse reactions have been identified during postapproval use of DAYBUE. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Aspiration and aspiration pneumonia secondary to vomiting [see Warnings and Precautions (5.3)].

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryThere 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 to 4% and 15 to 20%, respectively.. Data. Animal DataOral 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.

RECENT MAJOR CHANGES SECTION.

Dosage and Administration (2.1, 2.2, 2.3, 2.6)12/2025.

RENAL IMPAIRMENT SUBSECTION.

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 m2) [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 m2 for pediatrics) is not recommended.

SPL PATIENT PACKAGE INSERT SECTION.

PATIENT INFORMATIONDAYBUE(R) (day-BYOO)(trofinetide)oral solutionDAYBUE(R) STIX (day-BYOO STIX)(trofinetide)for oral solutionThis Patient Information has been approved by the U.S. Food and Drug AdministrationIssued: 12/2025What is DAYBUE or DAYBUE STIXDAYBUE or DAYBUE STIX are prescription medicines used to treat Rett syndrome in adults and children years of age and older.It is not known if DAYBUE or DAYBUE STIX is safe and effective in children under years of age. Before taking DAYBUE or DAYBUE STIX, tell your healthcare provider about all of your medical conditions, including if you:have kidney problems.are pregnant or plan to become pregnant. It is not known if DAYBUE or DAYBUE STIX will harm your unborn baby.are breastfeeding or plan to breastfeed. It is not known if DAYBUE or DAYBUE STIX passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby while taking DAYBUE or DAYBUE STIX.Tell your healthcare provider about all of the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.Taking DAYBUE or DAYBUE STIX with certain medicines may affect the way other medicines work and can cause serious side effects.Know the medicines you take. Keep list of them to show your healthcare provider and pharmacist when you get new medicine.How should take DAYBUE or DAYBUE STIXTake DAYBUE or DAYBUE STIX exactly as your healthcare provider tells you to take it.If you have kidney problems, talk to your healthcare provider about the right dose of DAYBUE or DAYBUE STIX.If you take laxatives, stop taking them before starting treatment with DAYBUE or DAYBUE STIX.DAYBUE or DAYBUE STIX may be given by mouth or through gastrostomy (G) tube. If DAYBUE or DAYBUE STIX is given through gastrojejunal (GJ) tube, the G-port must be used.DAYBUE or DAYBUE STIX may be taken with or without food.Your pharmacist should provide an oral syringe or dosing cup that is needed to measure your prescribed dose of DAYBUE or the amount of liquid to mix with DAYBUE STIX powder. household measuring cup, teaspoon, or tablespoon is not an adequate measuring device. If you are taking DAYBUE oral solution: Throw away any unused DAYBUE oral solution after 14 days of first opening the bottle.If you are taking DAYBUE STIX for oral solution: Open each packet only when you are ready to use it.DAYBUE STIX powder must be dissolved in cold to room temperature water or water-based beverage (juice, tea, lemonade, or liquid hydration).Your healthcare provider will tell you how much cold to room temperature water or water-based beverage to use to dissolve the powder in each packet.Empty the entire contents of the DAYBUE STIX packets needed for your prescribed dose into the measured liquid. Do not attempt to use part of packet.Stir until the powder is completely dissolved.After the powder is dissolved, take the prepared oral solution right away. Do not store for future use.Throw away any prepared oral solution that was not taken.Your healthcare provider may change your dose or stop treatment with DAYBUE or DAYBUE STIX if needed.If you vomit after taking dose of DAYBUE or DAYBUE STIX, do not take another dose to make up for that dose. Wait and take the next dose at your usual time. Call your healthcare provider if your vomiting does not stop.If you miss dose of DAYBUE or DAYBUE STIX, skip that dose and take your next dose at your usual time. Do not take doses to make up the missed dose.What are the possible side effects of DAYBUE or DAYBUE STIXDAYBUE or DAYBUE STIX may cause side effects, including: Diarrhea. Diarrhea is common side effect of DAYBUE or DAYBUE STIX that can sometimes be severe. Diarrhea may cause you to lose too much water from your body (dehydration). Tell your healthcare provider if you have diarrhea while taking DAYBUE or DAYBUE STIX. Your healthcare provider may ask you to increase the amount you drink or take antidiarrheal medicine as needed.Weight loss. DAYBUE or DAYBUE STIX can cause weight loss. Tell your healthcare provider if you notice you are losing weight at any time during treatment with DAYBUE or DAYBUE STIX. Vomiting. Vomiting is common side effect of DAYBUE or DAYBUE STIX. Sometimes vomit can get into your lungs (aspiration), which could cause an infection (aspiration pneumonia). Tell your healthcare provider if you have severe vomiting or if vomiting happens often.The most common side effects of DAYBUE or DAYBUE STIX include diarrhea and vomiting.These are not all the possible side effects of DAYBUE or DAYBUE STIX. Tell your healthcare provider if you have any side effects that bother you or do not go away. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store DAYBUE or DAYBUE STIXDAYBUE oral solution: Store DAYBUE oral solution bottle in the refrigerator between 36F to 46F (2C to 8C). Do not freeze.Keep DAYBUE oral solution bottle in an upright position.Keep the child-resistant cap on the bottle tightly closed.DAYBUE STIX for oral solution: Store DAYBUE STIX for oral solution powder packets at room temperature between 68F to 77F (20C to 25C).Keep DAYBUE, DAYBUE STIX, and all medicines out of the reach of children.General information about the safe and effective use of DAYBUE or DAYBUE STIX.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use DAYBUE or DAYBUE STIX for condition for which it was not prescribed. Do not give DAYBUE or DAYBUE STIX to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about DAYBUE or DAYBUE STIX that is written for health professionals.What are the ingredients in DAYBUE or DAYBUE STIXActive ingredient: trofinetide DAYBUE oral solution inactive ingredients: FD&C Red No. 40, maltitol, methylparaben sodium, propylparaben sodium, purified water, strawberry flavor, and sucralose. DAYBUE STIX for oral solution inactive ingredients: natural strawberry flavor and sucralose. Marketed by Acadia Pharmaceuticals Inc., San Diego, CA 92130 USADAYBUE is registered trademark of Acadia Pharmaceuticals Inc.(C)2025 Acadia Pharmaceuticals Inc. All rights reserved.For more information, go to www.daybue.com or call 1-844-422-2342.. DAYBUE or DAYBUE STIX are prescription medicines used to treat Rett syndrome in adults and children years of age and older.. have kidney problems.. are pregnant or plan to become pregnant. It is not known if DAYBUE or DAYBUE STIX will harm your unborn baby.. are breastfeeding or plan to breastfeed. It is not known if DAYBUE or DAYBUE STIX passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby while taking DAYBUE or DAYBUE STIX.. Take DAYBUE or DAYBUE STIX exactly as your healthcare provider tells you to take it.. If you have kidney problems, talk to your healthcare provider about the right dose of DAYBUE or DAYBUE STIX.. If you take laxatives, stop taking them before starting treatment with DAYBUE or DAYBUE STIX.. DAYBUE or DAYBUE STIX may be given by mouth or through gastrostomy (G) tube. If DAYBUE or DAYBUE STIX is given through gastrojejunal (GJ) tube, the G-port must be used.. DAYBUE or DAYBUE STIX may be taken with or without food.. Your pharmacist should provide an oral syringe or dosing cup that is needed to measure your prescribed dose of DAYBUE or the amount of liquid to mix with DAYBUE STIX powder. household measuring cup, teaspoon, or tablespoon is not an adequate measuring device. If you are taking DAYBUE oral solution: Throw away any unused DAYBUE oral solution after 14 days of first opening the bottle.. Throw away any unused DAYBUE oral solution after 14 days of first opening the bottle.. If you are taking DAYBUE STIX for oral solution: Open each packet only when you are ready to use it.DAYBUE STIX powder must be dissolved in cold to room temperature water or water-based beverage (juice, tea, lemonade, or liquid hydration).Your healthcare provider will tell you how much cold to room temperature water or water-based beverage to use to dissolve the powder in each packet.Empty the entire contents of the DAYBUE STIX packets needed for your prescribed dose into the measured liquid. Do not attempt to use part of packet.Stir until the powder is completely dissolved.After the powder is dissolved, take the prepared oral solution right away. Do not store for future use.Throw away any prepared oral solution that was not taken.. Open each packet only when you are ready to use it.. DAYBUE STIX powder must be dissolved in cold to room temperature water or water-based beverage (juice, tea, lemonade, or liquid hydration).. Your healthcare provider will tell you how much cold to room temperature water or water-based beverage to use to dissolve the powder in each packet.. Empty the entire contents of the DAYBUE STIX packets needed for your prescribed dose into the measured liquid. Do not attempt to use part of packet.. Stir until the powder is completely dissolved.. After the powder is dissolved, take the prepared oral solution right away. Do not store for future use.. Throw away any prepared oral solution that was not taken.. Your healthcare provider may change your dose or stop treatment with DAYBUE or DAYBUE STIX if needed.. If you vomit after taking dose of DAYBUE or DAYBUE STIX, do not take another dose to make up for that dose. Wait and take the next dose at your usual time. Call your healthcare provider if your vomiting does not stop.. If you miss dose of DAYBUE or DAYBUE STIX, skip that dose and take your next dose at your usual time. Do not take doses to make up the missed dose.. Diarrhea. Diarrhea is common side effect of DAYBUE or DAYBUE STIX that can sometimes be severe. Diarrhea may cause you to lose too much water from your body (dehydration). Tell your healthcare provider if you have diarrhea while taking DAYBUE or DAYBUE STIX. Your healthcare provider may ask you to increase the amount you drink or take antidiarrheal medicine as needed.. Weight loss. DAYBUE or DAYBUE STIX can cause weight loss. Tell your healthcare provider if you notice you are losing weight at any time during treatment with DAYBUE or DAYBUE STIX. Vomiting. Vomiting is common side effect of DAYBUE or DAYBUE STIX. Sometimes vomit can get into your lungs (aspiration), which could cause an infection (aspiration pneumonia). Tell your healthcare provider if you have severe vomiting or if vomiting happens often.. DAYBUE oral solution: Store DAYBUE oral solution bottle in the refrigerator between 36F to 46F (2C to 8C). Do not freeze.Keep DAYBUE oral solution bottle in an upright position.Keep the child-resistant cap on the bottle tightly closed.. Store DAYBUE oral solution bottle in the refrigerator between 36F to 46F (2C to 8C). Do not freeze.. Keep DAYBUE oral solution bottle in an upright position.. Keep the child-resistant cap on the bottle tightly closed.. DAYBUE STIX for oral solution: Store DAYBUE STIX for oral solution powder packets at room temperature between 68F to 77F (20C to 25C).. Store DAYBUE STIX for oral solution powder packets at room temperature between 68F to 77F (20C to 25C).

SPL UNCLASSIFIED SECTION.

2.1Recommended 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 Recommended Dosage of DAYBUE or DAYBUE STIX in Patients Years of Age and OlderPatient WeightRecommended Dosage9 kg to less than 12 kg5,000 mg twice daily12 kg to less than 20 kg6,000 mg twice daily20 kg to less than 35 kg8,000 mg twice daily35 kg to less than 50 kg10,000 mg twice daily50 kg or more12,000 mg twice daily.

STORAGE AND HANDLING SECTION.

16.2 Storage and Handling. DAYBUE Oral SolutionStore DAYBUE in an upright position refrigerated at 2C to 8C (36F to 46F). 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 SolutionStore DAYBUE STIX packets at 20C to 25C (68F to 77F); excursions permitted between 15C and 30C (59F and 86F) [see USP Controlled Room Temperature].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. 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). 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). 5.1Diarrhea. In Study [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)].. 5.2Weight 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)].. 5.3Vomiting. 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)].