Drug Detail:Daybue (Trofinetide)
Drug Class: Miscellaneous central nervous system agents
Highlights of Prescribing Information
DAYBUE™ (trofinetide) oral solution
Initial U.S. Approval: 2023
Indications and Usage for Daybue Oral Solution
DAYBUE is indicated for the treatment of Rett syndrome in adults and pediatric patients 2 years of age and older. (1)
Daybue Oral Solution Dosage and Administration
- Recommended dosage is twice daily, morning and evening, according to patient weight. DAYBUE can be given with or without food. (2.1)
| Patient Weight | DAYBUE Dosage | DAYBUE Volume |
|---|---|---|
| 9 kg to less than 12 kg | 5,000 mg twice daily | 25 mL twice daily |
| 12 kg to less than 20 kg | 6,000 mg twice daily | 30 mL twice daily |
| 20 kg to less than 35 kg | 8,000 mg twice daily | 40 mL twice daily |
| 35 kg to less than 50 kg | 10,000 mg twice daily | 50 mL twice daily |
| 50 kg or more | 12,000 mg twice daily | 60 mL twice daily |
- Can be given orally or via gastrostomy (G) tube; doses administered via gastrojejunal (GJ) tubes must be administered through the G-port. (2.2)
Dosage Forms and Strengths
- Oral solution: 200 mg/mL (3)
Contraindications
None. (4)
Warnings and Precautions
- Diarrhea: Most patients experience diarrhea during treatment with DAYBUE. Advise patients to stop laxatives before starting DAYBUE. If diarrhea occurs, patients should start antidiarrheal treatment, increase oral fluids, and notify their healthcare provider. Interrupt, reduce dose, or discontinue DAYBUE if severe diarrhea occurs or if dehydration is suspected. (2.4, 5.1)
- Weight Loss: Weight loss may occur in patients treated with DAYBUE. Monitor weight and interrupt, reduce dose, or discontinue DAYBUE if significant weight loss occurs. (5.2)
Adverse Reactions/Side Effects
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.
Drug Interactions
- Orally administered CYP3A4 sensitive substrates for which a small change in substrate plasma concentration may lead to serious toxicities: closely monitor for adverse reactions with concomitant use. (7.1)
- OATP1B1 and OATP1B3 substrates for which a small change in substrate plasma concentration may lead to serious toxicities: avoid concomitant use. (7.1)
Use In Specific Populations
Moderate to severe renal impairment: DAYBUE is not recommended. (8.6)
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
Revised: 3/2023
Full Prescribing Information
1. Indications and Usage for Daybue Oral Solution
DAYBUE is indicated for the treatment of Rett syndrome in adults and pediatric patients 2 years of age and older.
2. Daybue Oral Solution Dosage and Administration
2.1 Dosing Information
Administer DAYBUE orally twice daily, in the morning and evening, according to patient weight as shown in Table 1. DAYBUE can be taken with or without food.
| Patient Weight | DAYBUE Dosage | DAYBUE Volume |
|---|---|---|
| 9 kg to less than 12 kg | 5,000 mg twice daily | 25 mL twice daily |
| 12 kg to less than 20 kg | 6,000 mg twice daily | 30 mL twice daily |
| 20 kg to less than 35 kg | 8,000 mg twice daily | 40 mL twice daily |
| 35 kg to less than 50 kg | 10,000 mg twice daily | 50 mL twice daily |
| 50 kg or more | 12,000 mg twice daily | 60 mL twice daily |
2.2 Administration Information
Administer DAYBUE orally or via gastrostomy (G) tube; doses administered via gastrojejunal (GJ) tubes must be administered through the G-port.
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 is not an adequate measuring device.
Discard any unused DAYBUE oral solution after 14 days of first opening the bottle [see How Supplied/Storage and Handling (16.2)].
3. Dosage Forms and Strengths
Trofinetide oral solution: 200 mg/mL of a pink to red, strawberry flavored solution.
5. Warnings and Precautions
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. 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 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 if significant weight loss occurs.
6. Adverse Reactions/Side Effects
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)]
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
In controlled and uncontrolled trials in patients with Rett syndrome, 260 patients ages 2 to 40 years were treated with DAYBUE, including 109 patients treated for more than 6 months, 69 patients treated for more than 1 year, and 4 patients treated for more than 2 years.
7. Drug Interactions
7.1 Effect of DAYBUE on Other Drugs
Trofinetide is a weak CYP3A4 inhibitor; therefore, plasma concentrations of CYP3A4 substrates may be increased if given concomitantly with DAYBUE [see Clinical Pharmacology (12.3)]. Closely monitor when DAYBUE is used in combination with orally administered CYP3A4 sensitive substrates for which a small change in substrate plasma concentration may lead to serious toxicities.
Plasma concentrations of OATP1B1 and OATP1B3 substrates may be increased if given concomitantly with DAYBUE [see Clinical Pharmacology (12.3)]. Avoid the concomitant use of DAYBUE with OATP1B1 and OATP1B3 substrates for which a small change in substrate plasma concentration may lead to serious toxicities.
8. Use In Specific Populations
8.1 Pregnancy
Data
Animal Data
Oral administration of trofinetide (0, 150, 450, or 1000 mg/kg twice daily; 0, 300, 900, or 2000 mg/kg/day) to pregnant rats during the period of organogenesis resulted in no adverse effects on embryofetal development. At the highest dose tested, plasma exposure (AUC) was less than that in humans at the maximum recommended human dose (MRHD) of 12,000 mg twice daily (24,000 mg/day).
Oral administration of trofinetide (0, 75, 150, or 300 mg/kg twice daily; 0, 150, 300, or 600 mg/kg/day) to pregnant rabbits during the period of organogenesis resulted in no adverse effects on embryofetal development. At the highest dose tested, plasma exposure (AUC) was less than that in humans at the MRHD.
Oral administration of trofinetide (0, 150, 450, or 1000 mg/kg twice daily; 0, 300, 900, or 2000 mg/kg/day) to rats throughout pregnancy and lactation resulted in no adverse effects on pre- and postnatal development. At the highest dose tested, plasma exposure (AUC) was less than that in humans at the MRHD.
8.4 Pediatric Use
The safety and effectiveness of DAYBUE 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 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.
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.
11. Daybue Oral Solution Description
Trofinetide is designated chemically as (2S)-2-{[(2S)-1-(2-aminoacetyl)-2-methylpyrrolidine-2-carbonyl]amino}pentanedioic acid (IUPAC). Its empirical formula is C13H21N3O6 and its molecular weight is 315.33 g/mol. The chemical structure is:
Trofinetide is a white to off-white solid and is freely soluble in water.
DAYBUE is a pink to red, oral solution with each 5 mL containing 1 g of trofinetide (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.
12. Daybue Oral Solution - Clinical Pharmacology
12.1 Mechanism of Action
The mechanism by which trofinetide exerts therapeutic effects in patients with Rett syndrome is unknown.
12.3 Pharmacokinetics
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.
14. Clinical Studies
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 3, 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)* | 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
16. How is Daybue Oral Solution supplied
17. Patient Counseling Information
Advise the caregiver or patient to read the FDA-approved patient labeling (Patient Information).
| PATIENT INFORMATION DAYBUE™ (day-BYOO) (trofinetide) oral solution |
|
|---|---|
| This Patient Information has been approved by the U.S. Food and Drug Administration | Approved 3/2023 |
What is DAYBUE?
|
|
Before taking DAYBUE, tell your healthcare provider about all of your medical conditions, including if you:
Taking DAYBUE with certain medicines may affect the way other medicines work and can cause serious side effects. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. |
|
How should I take DAYBUE?
|
|
| What are the possible side effects of DAYBUE?
DAYBUE may cause side effects, including:
These are not all the possible side effects of DAYBUE. 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 I store DAYBUE?
|
|
| General information about the safe and effective use of DAYBUE.
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use DAYBUE for a condition for which it was not prescribed. Do not give DAYBUE 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 that is written for health professionals. |
|
| What are the ingredients in DAYBUE?
Active ingredient: trofinetide Inactive ingredients: FD&C Red No. 40, maltitol, methylparaben sodium, propylparaben sodium, purified water, strawberry flavor, and sucralose. Marketed by Acadia Pharmaceuticals Inc., San Diego, CA 92130 USA DAYBUE is a trademark of Acadia Pharmaceuticals Inc. ©2023 Acadia Pharmaceuticals Inc. All rights reserved. For more information, go to www.daybue.com or call 1-844-422-2342. |
|
| DAYBUE
trofinetide solution |
||||||||||||||||||||
|
||||||||||||||||||||
|
||||||||||||||||||||
|
||||||||||||||||||||
|
||||||||||||||||||||
|
||||||||||||||||||||
|
||||||||||||||||||||
| Labeler - Acadia Pharmaceuticals Inc. (963571302) |
