Description for Daybue
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:
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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.
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.
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 3.
Table 3 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.
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 for Daybue
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.
Warnings for Daybue
Included as part of the PRECAUTIONS section.
Precautions for Daybue
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 (2.3)].
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 [see Dosage and Administration (2.3)].
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 if vomiting is severe or occurs despite medical management [see Dosage and Administration (2.4)].
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 Pharmacology for Daybue
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 (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 between 60-89 mL/min/1.73 m2) 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 (AUC0-inf) of trofinetide approximately 80% compared to patients with normal renal function administered the same dose [see Dosage and Administration (2.5)]. 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
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.
Patient Information for Daybue
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 [see Warnings and Precautions (5.3)]. Instruct patients to notify their healthcare provider if vomiting does not stop despite medical management.
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)].
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