PRINCIPAL DISPLAY PANEL - 450 mL Bottle Carton

NDC 63090-660-01

Daybue™
(trofinetide)
oral solution

200 mg/mL

Recommended Dosage:
See prescribing information.

For oral or G-tube administration only.

450 mL

Rx only

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

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.

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 inTable 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.

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.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

DAYBUE (trofinetide) 200 mg/mL oral solution is a pink to red, strawberry flavored solution supplied in a nominal 500 mL round high-density polyethylene (HDPE) multi-dose bottle with a child-resistant closure containing 450 mL of oral solution (NDC 63090-660-01).

16.2 Storage and Handling

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.

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 Electrophysiology

At the maximum recommended dose in healthy adult subjects, DAYBUE does not prolong the QT interval to any clinically relevant extent.

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.

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 (2.2)].

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 recommended dosage [see Dosage and Administration (2.1)].

The pharmacokinetics in patients with renal impairment have not been studied [see Use in Specific Populations (8.6)].

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 (7.1)]. 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 (7.1)].

In Vivo

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

13 NONCLINICAL TOXICOLOGY

13.1 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).

17 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 (2.1, 2.2)].

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 (5.1)].

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 (5.2)].

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/Storage and Handling (16.2)].