Trofinetide (Monograph)

Drug class: Central Nervous System Agents, Miscellaneous

Medically reviewed by Drugs.com on Feb 10, 2024. Written by ASHP.

Introduction

Synthetic analog of glycine–proline–glutamate, the N-terminal tripeptide of insulin-like growth factor-1 (IGF-1).

Uses for Trofinetide

Rett Syndrome

Treatment of Rett syndrome in adults and pediatric patients ≥2 years of age ; designated an orphan drug by FDA for this use.

Current consensus recommendations for the treatment of Rett syndrome focus on supportive care measures for progressive multisystem symptoms; specific role for trofinetide not yet established.

Trofinetide Dosage and Administration

General

Patient Monitoring

• Monitor for significant weight loss.

• Monitor for severe diarrhea and/or dehydration.

Other General Considerations

• Because trofinetide can cause diarrhea, advise patients to discontinue laxatives before starting trofinetide.

Administration

Administer orally.

Available as a 200 mg/mL oral solution.

May administer through a G tube. If given through a GJ tube, must administer through the G-port.

Manufacturer recommends obtaining a calibrated measuring device (e.g., oral syringe, oral dosing cup) from the pharmacy for accurate dosing and administration of the prescribed dose.

If dose is missed, skip the missed dose and take the next regularly scheduled dose. If dose is vomited, do not take an additional dose.

Oral Administration

Administer with or without food.

May administer through a gastrostomy (G) tube. Doses administered through a gastrojejunal (GJ) tube must be given through the G-port.

Dosage

Pediatric Patients

Rett Syndrome

Oral

Patients ≥2 years of age: weight-based dosage (see Table 1) given twice daily in the morning and evening.

Adults

Rett Syndrome

Oral

Weight-based dosage (see Table 1) given twice daily in the morning and evening.

Dosage Modification for Toxicity

Dosage interruption, reduction, or discontinuation of trofinetide recommended if severe diarrhea or significant weight loss occurs or if dehydration suspected.

Special Populations

Hepatic Impairment

No specific dosage recommendations.

Renal Impairment

No specific dosage recommendations; administration to patients with moderate or severe renal impairment not recommended.

Geriatric Patients

No specific dosage recommendations.

Related/similar drugs

Daybue

Cautions for Trofinetide

Contraindications

• None.

Warnings/Precautions

Diarrhea

Diarrhea reported in most patients taking trofinetide; most cases mild to moderate in severity.

Advise patients to discontinue laxatives before initiation of trofinetide. Advise patients to notify their healthcare provider if diarrhea develops during treatment and to consider starting antidiarrheals; monitor hydration status and increase oral fluid intake if needed. If severe diarrhea or suspected dehydration occurs, trofinetide dosage interruption, reduction, or discontinuation recommended.

Weight Loss

Weight loss of >7% from baseline reported.

Monitor patient weight during treatment. If significant weight loss occurs, trofinetide dosage interruption, reduction, or discontinuation recommended.

Specific Populations

Pregnancy

No adequate data in pregnant women to assess for drug-associated developmental risk.

Lactation

Not known if trofinetide or metabolites are present in human milk. Effects on the breastfed infant and effects on milk production not known. Consider developmental and health benefits of breastfeeding in addition to the mother's clinical need for the drug, the potential for adverse effects on the breastfed infant from the drug, and the potential for adverse effects on the infant from the untreated maternal condition.

Pediatric Use

Safety and efficacy of trofinetide for the treatment of Rett syndrome established in pediatric patients ≥2 years of age.

Geriatric Use

No patients ≥65 years of age included in clinical studies of trofinetide to assess differences in response compared to younger adult patients. Renal function monitoring may be useful in geriatric patients, as trofinetide is eliminated renally.

Hepatic Impairment

Pharmacokinetics not evaluated in hepatic impairment; however, hepatic impairment not expected to affect trofinetide exposure, since hepatic metabolism is not a significant route of trofinetide elimination.

Renal Impairment

Pharmacokinetics not evaluated in renal impairment. Because trofinetide primarily undergoes renal elimination, trofinetide not recommended in patients with moderate or severe renal impairment.

Common Adverse Effects

Adverse reactions (≥10%) of patients receiving trofinetide (with a ≥2% higher incidence than placebo) included diarrhea and vomiting.

Drug Interactions

Trofinetide weakly inhibits CYP3A4 in vitro. Not expected to inhibit CYP1A2, 2C8, 2C9, 2C19, or 2D6 at therapeutic concentrations. Unclear whether trofinetide inhibits CYP2B6 based on in vitro data. In vitro, trofinetide is an inhibitor of uridine diphosphate-glucuronosyltransferase (UGT) enzymes UGT1A9, 2B7, and 2B15. Not an inhibitor of P-gp, breast cancer resistance protein (BCRP), bile salt export pump (BSEP), organic anion transporter (OAT) 1, OAT3, organic cation transporter (OCT) 2, multidrug and toxin extrusion (MATE) 1, or MATE2-K, but does inhibit organic anion transporter polypeptide (OATP) 1B1 and OATP1B3 in vitro.

Not a substrate of CYP isoenzymes in vitro. Not a substrate of the major drug transporters or UGT. Because trofinetide is not a substrate of CYP isoenzymes, major drug transporters, or UGT, the concomitant use of inducers or inhibitors of these systems does not have a significant impact on trofinetide exposure.

Drugs Metabolized by Hepatic Microsomal Enzymes

Concomitant use with a CYP3A4 substrate may increase plasma exposures of the CYP3A4 substrate. Monitor patients closely when used concomitantly with orally administered sensitive CYP3A4 substrates that can cause serious toxicities when there are minor changes in substrate plasma concentrations.

Drugs Affected by Transport Proteins

Concomitant use with an OATP1B1 or OATP1B3 substrate may increase plasma concentrations of the substrate. Avoid concomitant use of trofinetide with substrates of OATP1B1 or OATP1B3 for which small changes in the plasma concentrations of the substrate could result in serious toxicities.

Specific Drugs

Trofinetide Pharmacokinetics

Absorption

Bioavailability

Dose-proportional exposure, with little to no accumulation following repeated dosing.

Following oral administration, peak plasma concentrations of trofinetide achieved within 2—3 hours.

Following oral administration of 12,000 mg of trofinetide, at least 84% of the dose is absorbed.

Food

Administration with a high-fat meal had no impact on trofinetide exposure but decreased peak plasma concentrations of trofinetide by approximately 20%.

Special Populations

At recommended dosage, systemic exposure of trofinetide observed in pediatric patients 2—4 years of age similar to that observed in children and adults ≥4 years of age.

Distribution

Extent

Not known if trofinetide or its metabolites excreted into milk.

Plasma Protein Binding

<6%.

Elimination

Metabolism

Not significantly metabolized by CYP isoenzymes and not significantly eliminated via hepatic metabolism.

Elimination Route

Primarily excreted as unchanged drug in the urine (approximately 80%); excreted minimally in the feces.

Half-life

Approximately 1.5 hours.

Stability

Storage

Oral

Oral solution

2—8°C; do not freeze. Discard any remaining trofinetide solution 14 days after opening the bottle.

Actions

• Synthetic analog of glycine–proline–glutamate, the N-terminal tripeptide of insulin-like growth factor-1 (IGF-1).

• Not known how trofinetide exerts therapeutic effects in patients with Rett syndrome.

Advice to Patients

• Advise caregivers and patients that trofinetide may be taken with or without food.

• Advise caregivers and patients that a calibrated measuring device, such as an oral syringe or oral dosing cup, should be obtained from the pharmacy to measure and administer doses accurately.

• Instruct caregivers and patients to refrigerate trofinetide oral solution and to discard any remaining trofinetide 14 days after first opening the bottle.

• Advise caregivers and patients that because trofinetide can cause diarrhea, laxatives should be stopped before starting trofinetide. Instruct caregivers and patients to inform their healthcare provider if diarrhea occurs and to consider starting antidiarrheals. Hydration status should be monitored and oral fluid intake increased if necessary.

• Inform the caregiver or patient that trofinetide may cause weight loss; patients should notify their healthcare provider if weight loss occurs.

• Advise patients and caregivers that trofinetide may cause vomiting; if vomiting occurs after administration, an additional dose should not be taken and the next dose should be administered at the normal scheduled time.

• Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.

• Advise women to inform their clinician if they are or plan to become pregnant or plan to breastfeed.

• Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Trofinetide is obtained through designated specialty pharmacies. Contact manufacturer or consult the drug website ([Web]) for specific availability information.

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