Daybue patient education
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Dosage & administration
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Daybue prescribing information
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.
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 )
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.
| 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 |
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.
| 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) ] .
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.
| 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) |
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) ].
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) ] .
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.
| 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 |
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.
DOSAGE FORMS AND STRENGTHS
Oral solution: 200 mg/mL of a pink to red, strawberry flavored solution.
For oral solution: 5,000 mg, 6,000 mg, or 8,000 mg of white, off-white to pinkish powder with strawberry flavor, packaged in individual packets.
USE IN SPECIFIC POPULATIONS
Severe renal impairment: DAYBUE and DAYBUE STIX are not recommended. (8.6 )
Pregnancy
Risk Summary
There are no adequate data on the developmental risks associated with the use of DAYBUE or DAYBUE STIX in pregnant women. No adverse developmental effects were observed following oral administration of trofinetide to pregnant animals at doses associated with plasma exposures below those used clinically [see Animal Data ] .
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Data
Animal Data
Oral administration of trofinetide (0, 150, 450, or 1000 mg/kg twice daily; 0, 300, 900, or 2000 mg/kg/day) to pregnant rats during the period of organogenesis resulted in no adverse effects on embryofetal development. At the highest dose tested, plasma exposure (AUC) was less than that in humans at the maximum recommended human dose (MRHD) of 12,000 mg twice daily (24,000 mg/day).
Oral administration of trofinetide (0, 75, 150, or 300 mg/kg twice daily; 0, 150, 300, or 600 mg/kg/day) to pregnant rabbits during the period of organogenesis resulted in no adverse effects on embryofetal development. At the highest dose tested, plasma exposure (AUC) was less than that in humans at the MRHD.
Oral administration of trofinetide (0, 150, 450, or 1000 mg/kg twice daily; 0, 300, 900, or 2000 mg/kg/day) to rats throughout pregnancy and lactation resulted in no adverse effects on pre- and postnatal development. At the highest dose tested, plasma exposure (AUC) was less than that in humans at the MRHD.
Lactation
Risk Summary
There is no information regarding the presence of trofinetide or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for DAYBUE or DAYBUE STIX and any potential adverse effects on the breastfed infant from the treatment or from the underlying maternal condition.
Pediatric Use
The safety and effectiveness of DAYBUE and DAYBUE STIX for the treatment of Rett syndrome have been established in pediatric patients aged 2 years and older. The safety and effectiveness of DAYBUE for the treatment of Rett syndrome in pediatric patients 5 years of age and older was established in a randomized, double-blind, placebo-controlled, 12-week study (Study 1), which included 108 pediatric patients age 5 to less than 12 years of age and 47 pediatric patients age 12 to less than 17 years of age [see Adverse Reactions (6.1) and Clinical Studies (14) ]. Use of DAYBUE or DAYBUE STIX in patients 2 to 4 years of age is supported by evidence from Study 1 and pharmacokinetic and safety data in 13 pediatric patients 2 to 4 years of age treated with DAYBUE for 12 weeks [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.
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.
Renal Impairment
Mild renal impairment is not expected to impact the exposure of trofinetide; therefore, dosage adjustment is not necessary. Dosage adjustment of DAYBUE or DAYBUE STIX is recommended in patients with moderate renal impairment (adult: eGFR 30 to 59 mL/min; pediatric: eGFR 30 to 59 mL/min/1.73 m 2 ) [see Dosage and Administration (2.6) , Clinical Pharmacology (12.3) ] . Administration of DAYBUE or DAYBUE STIX to patients with severe renal impairment (eGFR less than 30 mL/min for adults or less than 30 mL/min/1.73 m 2 for pediatrics) is not recommended .
CONTRAINDICATIONS
None.
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
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) ] .
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) ] .
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) ] .
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) ]
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 .
| 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.
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) ] .
DRUG INTERACTIONS
- 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 )
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.
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]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.
CLINICAL PHARMACOLOGY
Mechanism of Action
The mechanism by which trofinetide exerts therapeutic effects in patients with Rett syndrome is unknown.
Pharmacodynamics
Cardiac Electrophysiology
At the maximum recommended dose in healthy adult subjects, trofinetide does not prolong the QT interval to any clinically relevant extent .
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.
NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility
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).
CLINICAL STUDIES
DAYBUE STIX
The 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 a display of the efficacy results of the adequate and well-controlled study of DAYBUE in patients with Rett syndrome.
DAYBUE
The efficacy of DAYBUE for the treatment of Rett syndrome was established in a 12-week randomized, double-blind, placebo-controlled study in patients with Rett syndrome 5 to 20 years of age (Study 1; NCT04181723).
Patients (N=187) had a diagnosis of typical Rett syndrome according to the Rett Syndrome Diagnostic Criteria with a 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 a 45-item rating scale completed by the caregiver that assesses a range of symptoms of Rett syndrome (breathing, hand movements or stereotypies, repetitive behaviors, night-time behaviors, vocalizations, facial expressions, eye gaze, and mood). Each item is scored as 0 (not true), 1 (somewhat or sometimes true), or 2 (very true or often true), with a 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 a patient has improved or worsened on a 7-point scale (1=very much improved to 7=very much worse) in which a decrease in score indicates improvement.
Treatment with DAYBUE demonstrated a 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 ).
| Mean 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-value | ||
|---|---|---|---|---|---|---|
| CI=confidence interval; LS mean=least-squares mean; SE=standard error | ||||||
| RSBQ | DAYBUE | 43.7 (1.21) | 39.9 (1.38) | -4.9 (0.94) | -3.2 (-5.7, -0.6) | 0.018 |
| Placebo | 44.5 (1.26) | 42.8 (1.42) | -1.7 (0.90) | |||
| CGI-I | DAYBUE | -- | 3.5 (0.08) | -- | -0.3 (-0.5, -0.1) | 0.003 |
| Placebo | -- | 3.8 (0.06) | ||||
Figure 1 Change From Baseline in RSBQ Total Score in Study 1
Figure 2 Distribution of CGI-I Scores for Patients Completing Study 1
HOW SUPPLIED/STORAGE AND HANDLING
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 |
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].
Mechanism of Action
The mechanism by which trofinetide exerts therapeutic effects in patients with Rett syndrome is unknown.
