Daybue

PATIENT INFORMATION

DAYBUE™
(day-BYOO)
(trofinetide) oral solution

What is DAYBUE?

• DAYBUE is a prescription medicine used to treat Rett syndrome in adults and children 2 years of age and older.
• It is not known if DAYBUE is safe and effective in children under 2 years of age.

Before taking DAYBUE, 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 will harm your unborn baby.
• are breastfeeding or plan to breastfeed. It is not known if DAYBUE passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby while taking DAYBUE.

Tell your healthcare provider about all of the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

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?

• Take DAYBUE exactly as your healthcare provider tells you to take it.
• If you take laxatives, stop taking them before starting treatment with DAYBUE.
• Your healthcare provider may change your dose or stop treatment with DAYBUE if needed.
• Your pharmacist should provide an oral syringe or dosing cup that is needed to measure your prescribed dose. Do not use a household measuring cup.
• DAYBUE may be taken by mouth or given through a gastrostomy (G) tube. If DAYBUE is given through a gastrojujenal (GJ) tube, the G-port must be used
• DAYBUE may be taken with or without food.
• Throw away any unused DAYBUE after 14 days of first opening the bottle.
• If you vomit after taking a dose of DAYBUE, do not take another dose to make up for that dose. Wait and take the next dose at your usual time.
• If you miss a dose of DAYBUE, skip that dose and take your next dose at your usual time. Do not take 2 doses to make up the missed dose.

What are the possible side effects of DAYBUE?

DAYBUE may cause side effects, including:

• Diarrhea. Diarrhea is a common side effect of DAYBUE 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. Your healthcare provider may ask you to increase the amount you drink or take anti-diarrheal medicine as needed.
• Weight loss. DAYBUE can cause weight loss. Tell your healthcare provider if you notice you are losing weight at any time during treatment with DAYBUE.

The most common side effects of DAYBUE include diarrhea and vomiting.

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?

• Store DAYBUE in the refrigerator between 36°F to 46°F (2°C to 8°C). Do not freeze.
• Keep DAYBUE in an upright position.
• Keep the child-resistant cap tightly closed.

Keep DAYBUE and all medicines out of the reach of children.

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.

This Patient Information has been approved by the U.S. Food and Drug Administration.

DESCRIPTION

Trofinetide is designated chemically as (2S)-2-{[(2S)-1-(2-aminoacetyl)-2-methylpyrrolidine-2carbonyl]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.

 

INDICATIONS

DAYBUE is indicated for the treatment of Rett syndrome in adults and pediatric patients 2 years of age and older.

 

DOSAGE AND ADMINISTRATION

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.

Table 1 Recommended Dosage of DAYBUE in Patients 2 Years of Age and Older

 

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

 

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].

Missed Dose Or Vomiting After Administration

If a dose of DAYBUE is missed, the next dose should be taken as scheduled. Doses should not be doubled.

If vomiting occurs after DAYBUE administration, an additional dose should not be taken. Instead, continue with the next scheduled dose.

Dose Modification For Diarrhea Or Weight Loss

Advise patients to stop laxatives before starting DAYBUE. Interrupt, reduce the dosage, or discontinue DAYBUE if severe diarrhea occurs, if dehydration is suspected, or if significant weight loss occurs [see WARNINGS AND PRECAUTIONS].

SIDE EFFECTS

The following clinically significant adverse reactions are described elsewhere in labeling:

• Diarrhea [see WARNINGS AND PRECAUTIONS]
• Weight Loss [see WARNINGS AND PRECAUTIONS]

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.

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]. 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 2.

Table 2 Adverse Reactions in at Least 5% of Patients Treated With DAYBUE and at Least 2% Greater than Placebo in Study 1

 

Adverse Reaction	DAYBUE (N=93) %	Placebo (N=94) %
Diarrhea	82	20
Vomiting	29	12
Fever	9	4
Seizure	9	6
Anxiety	8	1
Decreased appetite	8	2
Fatigue	8	2
Nasopharyngitis	5	1

 

Pediatric Patients With Rett Syndrome 2 To 4 Years Of Age

In an open-label study in pediatric patients 2 to 4 years of age with Rett syndrome, a total of 13 patients received DAYBUE for at least 12 weeks and 9 patients received DAYBUE for at least 6 months. Adverse reactions in pediatric patients 2 to 4 years of age treated with DAYBUE were similar to those reported in adult and pediatric patients 5 years of age and older with Rett syndrome in Study 1.

 

DRUG INTERACTIONS

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]. 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]. 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.

 

WARNINGS

Included as part of the “PRECAUTIONS” Section

 

PRECAUTIONS

Diarrhea

In Study 1 [see Clinical Studies] 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].

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.

Patient Counseling Information

Advise the caregiver or patient to read the FDA-approved patient labeling (PATIENT INFORMATION).

DAYBUE Administration

Advise the caregiver or patient that DAYBUE may be given orally or via gastrostomy (G) tube; doses administered via gastrojejunal (GJ) tubes must be administered through the G-port. DAYBUE may be taken with or without food [see DOSAGE AND ADMINISTRATION].

Instruct the caregiver or patient to obtain a calibrated measuring device, such as an oral syringe or oral dosing cup, from the pharmacy to measure and deliver the prescribed dose accurately. A household measuring cup is not an adequate measuring device.

Instruct the caregiver or patient to discard any unused DAYBUE after 14 days of first opening the bottle.

Diarrhea

Advise the caregiver or patient that DAYBUE can cause diarrhea. Instruct the patient to stop taking 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 [see WARNINGS AND PRECAUTIONS].

Weight Loss

Inform the caregiver or patient that DAYBUE may cause weight loss and to notify their healthcare provider if weight loss occurs [see WARNINGS AND PRECAUTIONS].

Vomiting

Advise the caregiver or patient that DAYBUE can cause vomiting and if vomiting occurs after DAYBUE administration, do not take an additional dose, but continue with the next scheduled dose.

Storage

Keep bottles of DAYBUE oral solution upright and refrigerated before and after opening. Do not freeze [see HOW SUPPLIED].

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).

 

Use In Specific Populations

Pregnancy

Risk Summary

There are no adequate data on the developmental risks associated with the use of DAYBUE 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 and any potential adverse effects on the breastfed infant from DAYBUE or from the underlying maternal condition.

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 and Clinical Studies]. 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, ADVERSE REACTIONS, CLINICAL PHARMACOLOGY , and Clinical Studies].

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

No dedicated clinical study has been conducted to evaluate the pharmacokinetics of DAYBUE in subjects with renal impairment. Since the drug is eliminated mainly through the kidney, administration of DAYBUE to patients with moderate or severe renal impairment is not recommended.

OVERDOSE

No Information Provided

CONTRAINDICATIONS

None.

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, DAYBUE does not prolong the QT interval to any clinically relevant extent.

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.

Absorption

The time to maximum drug concentration (Tmax) 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 DAYBUE with a 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].

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

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 recommend dosage [see DOSAGE AND ADMINISTRATION].

The pharmacokinetics in patients with renal impairment have not been studied [see Use In Specific Populations].

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

In Vitro

Trofinetide is not a substrate of CYP450 enzymes, uridine diphosphate glucuronosyltransferase (UGT), or major drug transporters. Therefore, coadministration of drugs that are inducers or inhibitors of CYP450, UGT, or major drug transporters will not significantly affect the systemic exposure of trofinetide.

Trofinetide is a weak CYP3A4 inhibitor. Using physiologically based pharmacokinetic modeling, coadministration of trofinetide with orally administered midazolam, a sensitive CYP3A4 substrate, was predicted to increase the AUC of midazolam by approximately 1.33-fold [see DRUG INTERACTIONS]. No inhibition on CYP450 enzymes, CYP1A2, 2C8, 2C9, 2C19, and 2D6, is expected at therapeutic systemic concentrations based on the in vitro assays and the static mechanistic models. Time-dependent inhibition on CYP2B6 was inconclusive based on in vitro data. DAYBUE inhibits UGT enzymes, UGT1A9, 2B7, and 2B15, in vitro.

No inhibition was observed at therapeutic systemic concentrations on P-gp, BCRP, BSEP, OAT1, OAT3, OCT2, MATE1, and MATE2-K, based on the in vitro assays. Trofinetide inhibits OATP1B1 and OATP1B3 in vitro [see DRUG INTERACTIONS].

In Vivo

There have been no in vivo assessments of drug interactions with trofinetide.

 

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].

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).

Table 3 Summary of Study 1 Efficacy Results

 

		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)a	p-value
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)
CI=confidence interval; LS mean=least-squares mean; SE=standard error a Difference in LS mean from the mixed-effect model for repeated measure analysis

 

Figure 1 Change From Baseline in RSBQ Total Score in Study 1

 

 

Figure 2 Distribution of CGI-I Scores for Patients Completing Study 1