Trofinetide is an oral analog of the amino-terminal tripeptide of insulin-like growth factor 1 (IGF-1) indicated for the treatment of Rett syndrome in adults and pediatric patients 2 years and older. The efficacy of trofinetide for the treatment of Rett syndrome was demonstrated in a randomized, double-blind, placebo-controlled trial in patients 5 to 20 years (n = 187), in which trofinetide was compared to placebo over 12 weeks. Trofinetide significantly reduced Rett Syndrome Behaviour Questionnaire (RSBQ) scores, suggesting lesser severity in signs and symptoms of Rett syndrome with trofinetide treatment [trofinetide-placebo treatment difference -3.2 (95% CI, -5.7 to -0.6); p = 0.018]. Trofinetide also significantly reduced Clinical Global Impression-Improvement (CGI-I) scores, suggesting improvement with trofinetide treatment [trofinetide-placebo treatment difference -0.3 (95% CI, -0.5 to -0.1); p = 0.003]. Diarrhea, vomiting, and weight loss are the most common adverse effects reported with trofinetide, and interruption, dose reduction, or discontinuation of trofinetide is necessary if severe diarrhea, dehydration, or weight loss occurs.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
-Ensure laxatives are discontinued before trofinetide initiation. Interrupt, reduce the dosage, or discontinue trofinetide if severe diarrhea occurs, if dehydration is suspected, or if significant weight loss occurs.
Oral Liquid Formulations
-Administer without regard to meals.
-Measure and administer the oral solution using a calibrated measuring device.
-A gastrostomy tube may be used for administration. Doses administered via gastrojejunal (GJ) tubes must be administered through the G-port.
-Storage: Discard any unused solution after 14 days of first opening the bottle.
-Missed dose or vomiting after administration: If a dose is missed, administer the next dose as scheduled. Do not double doses. If vomiting occurs after trofinetide administration, do not administer an additional dose; continue with the next scheduled dose.
Central nervous system or psychiatric adverse effects reported during a clinical trial with trofinetide (n = 93) vs. placebo (n = 94) include anxiety (8% vs. 1%), fever (9% vs. 4%), and seizures (9% vs 6%).
Diarrhea was reported in 82% of subjects treated with trofinetide (n = 93) compared to 20% of subjects given placebo (n = 94) during a clinical trial. In long-term studies, 85% of trofinetide-treated subjects experienced diarrhea. In those treated with trofinetide, 49% either had persistent diarrhea or recurrence after resolution despite dose interruptions, reductions, or concomitant antidiarrheal therapy. Diarrhea severity was of mild to moderate severity in 96% of cases. Antidiarrheal medication was used in 51% of subjects treated with trofinetide. The most common adverse reaction leading to discontinuation of treatment with trofinetide was diarrhea (15%). Ensure laxatives are discontinued before starting trofinetide. If diarrhea occurs, consider starting antidiarrheal treatment, and monitor hydration status and increase oral fluids, if needed. Interrupt, reduce dose, or discontinue trofinetide if severe diarrhea occurs or if dehydration is suspected. Other gastrointestinal adverse effects reported during a clinical trial with trofinetide (n = 93) vs. placebo (n = 94) include vomiting (29% vs. 12%) and anorexia (8% vs. 2%). If vomiting occurs after trofinetide administration, do not administer an additional dose; continue with the next schedule dose. Resume treatment with the next scheduled dose.
Weight loss of more than 7% from baseline was reported in 12% of subjects treated with trofinetide (n = 93) compared to 4% of subjects given placebo (n = 94) during a clinical trial. In long-term studies, 2.2% of subjects discontinued trofinetide because of weight loss. Monitor weight and interrupt, reduce the dosage, or discontinue trofinetide if significant weight loss occurs.
Fatigue was reported in 8% of subjects treated with trofinetide (n = 93) compared to 2% of subjects given placebo (n = 94) during a clinical trial.
Naso-pharyngitis was reported in 5% of subjects treated with trofinetide (n = 93) compared to 1% of subjects given placebo (n = 94) during a clinical trial.
Diarrhea is commonly reported with trofinetide use. Ensure laxatives are discontinued before starting trofinetide. If diarrhea occurs, consider starting antidiarrheal treatment, and monitor hydration status and increase oral fluids, if needed. Interrupt, reduce dose, or discontinue trofinetide if severe diarrhea occurs or if dehydration is suspected.
Avoid trofinetide use in persons with moderate or severe renal impairment or renal failure since the drug is eliminated mainly through the kidney. Trofinetide has not been studied in persons with renal impairment.
There are no adequate data on the developmental risk associated with trofinetide use during human pregnancy. In animal studies, oral administration of trofinetide during the period of organogenesis or throughout pregnancy and lactation resulted in no adverse effects on embryo-fetal development or pre- and postnatal development at plasma exposures lower than those used clinically.
Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for trofinetide and any potential adverse effects on the breast-fed infant from trofinetide or the underlying maternal condition. There are no data on the presence of trofinetide or its metabolites in human milk, the effects on the breast-fed infant, or the effects on milk production.
For the treatment of Rett syndrome:
Oral dosage:
Adults weighing 50 kg or more: 12,000 mg PO twice daily.
Adults weighing 35 to 49 kg: 10,000 mg PO twice daily.
Children and Adolescents 2 to 17 years weighing 50 kg or more: 12,000 mg PO twice daily.
Children and Adolescents 2 to 17 years weighing 35 to 49 kg: 10,000 mg PO twice daily.
Children and Adolescents 2 to 17 years weighing 20 to 34 kg: 8,000 mg PO twice daily.
Children 2 to 12 years weighing 12 to 19 kg: 6,000 mg PO twice daily.
Children 2 to 12 years weighing 9 to 11 kg: 5,000 mg PO twice daily.
Maximum Dosage Limits:
-Adults
weighing 50 kg or more: 24,000 mg/day PO.
weighing 35 to 49 kg: 20,000 mg/day PO.
-Geriatric
weighing 50 kg or more: 24,000 mg/day PO.
weighing 35 to 49 kg: 20,000 mg/day PO.
-Adolescents
weighing 50 kg or more: 24,000 mg/day PO.
weighing 35 to 49 kg: 20,000 mg/day PO.
weighing 20 to 34 kg: 16,000 mg/day PO.
-Children
2 to 12 years weighing 50 kg or more: 24,000 mg/day PO.
2 to 12 years weighing 35 to 49 kg: 20,000 mg/day PO.
2 to 12 years weighing 20 to 34 kg: 16,000 mg/day PO.
2 to 12 years weighing 12 to 19 kg: 12,000 mg/day PO.
2 to 12 years weighing 9 to 11 kg: 10,000 mg/day PO.
1 to 2 years: Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
No dosage adjustment is needed in persons with mild renal impairment. Use in persons with moderate or severe renal impairment is not recommended.
*non-FDA-approved indication
Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Consider a reduced dose of dihydrocodeine with frequent monitoring for respiratory depression and sedation if concurrent use of trofinetide is necessary. If trofinetide is discontinued, consider increasing the dihydrocodeine dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Concomitant use of dihydrocodeine with trofinetide may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If trofinetide is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Trofinetide is a weak inhibitor of CYP3A, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
Acetaminophen; Codeine: (Moderate) Concomitant use of codeine with trofinetide may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of trofinetide could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If trofinetide is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Trofinetide is a weak inhibitor of CYP3A.
Acetaminophen; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of trofinetide is necessary. Hydrocodone is a CYP3A substrate, and coadministration with CYP3A inhibitors like trofinetide can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If trofinetide is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Acetaminophen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of trofinetide is necessary. If trofinetide is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A substrate, and coadministration with weak CYP3A inhibitors like trofinetide can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If trofinetide is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Alfentanil: (Moderate) Consider a reduced dose of alfentanil with frequent monitoring for respiratory depression and sedation if concurrent use of trofinetide is necessary. If trofinetide is discontinued, consider increasing the alfentanil dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Alfentanil is a sensitive CYP3A substrate, and coadministration with CYP3A inhibitors like trofinetide can increase alfentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of alfentanil. If trofinetide is discontinued, alfentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to alfentanil.
Alprazolam: (Major) Avoid coadministration of alprazolam and trofinetide due to the potential for elevated alprazolam concentrations, which may cause prolonged sedation and respiratory depression. If coadministration is necessary, consider reducing the dose of alprazolam as clinically appropriate and monitor for an increase in alprazolam-related adverse reactions. Lorazepam, oxazepam, or temazepam may be safer alternatives if a benzodiazepine must be administered in combination with trofinetide, as these benzodiazepines are not oxidatively metabolized. Alprazolam is a CYP3A substrate and trofinetide is a weak CYP3A inhibitor. Coadministration with another weak CYP3A inhibitor increased alprazolam maximum concentration by 82%, decreased clearance by 42%, and increased half-life by 16%.
Amlodipine; Atorvastatin: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with trofinetide is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is an OATP1B1/3 substrate; trofinetide is an OATP1B1/3 inhibitor.
Aripiprazole: (Moderate) Monitor for aripiprazole-related adverse reactions during concomitant use of trofinetide. Patients receiving both a CYP2D6 inhibitor plus trofinetide may require an aripiprazole dosage adjustment. Dosing recommendations vary based on aripiprazole dosage form, CYP2D6 inhibitor strength, and CYP2D6 metabolizer status. See prescribing information for details. Concomitant use may increase aripiprazole exposure and risk for side effects. Aripiprazole is a CYP3A and CYP2D6 substrate; trofinetide is a weak CYP3A inhibitor.
Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of codeine with trofinetide may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of trofinetide could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If trofinetide is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Trofinetide is a weak inhibitor of CYP3A.
Aspirin, ASA; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of trofinetide is necessary. If trofinetide is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A substrate, and coadministration with weak CYP3A inhibitors like trofinetide can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If trofinetide is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Atogepant: (Major) Limit the dose of atogepant to 10 or 30 mg PO once daily for episodic migraine or 30 mg PO once daily for chronic migraine if coadministered with trofinetide. Concurrent use may increase atogepant exposure and the risk of adverse effects. Atogepant is a substrate of OATP1B1 and OATP1B3 and trofinetide is an OATP inhibitor. Coadministration with an OATP1B1/3 inhibitor resulted in a 2.85-fold increase in atogepant overall exposure and a 2.23-fold increase in atogepant peak concentration.
Atorvastatin: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with trofinetide is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is an OATP1B1/3 substrate; trofinetide is an OATP1B1/3 inhibitor.
Benzhydrocodone; Acetaminophen: (Moderate) Consider a reduced dose of benzhydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of trofinetide is necessary. Benzhydrocodone is a prodrug for hydrocodone. Hydrocodone is a CYP3A substrate, and coadministration with weak CYP3A inhibitors like trofinetide can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of benzhydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If trofinetide is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to benzhydrocodone.
Brincidofovir: (Moderate) Postpone the administration of trofinetide for at least three hours after brincidofovir administration and increase monitoring for brincidofovir-related adverse reactions (i.e., elevated hepatic enzymes and bilirubin, diarrhea, other gastrointestinal adverse events) if concomitant use of brincidofovir and trofinetide is necessary. Brincidofovir is an OATP1B1/3 substrate and trofinetide is an OATP1B1/3 inhibitor. In a drug interaction study, the mean AUC and Cmax of brincidofovir increased by 374% and 269%, respectively, when administered with another OATP1B1/3 inhibitor.
Bupivacaine; Lidocaine: (Moderate) Monitor for lidocaine toxicity if coadministration with trofinetide is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP3A substrate and trofinetide is a weak CYP3A inhibitor.
Buprenorphine: (Moderate) Concomitant use of buprenorphine and trofinetide can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when trofinetide is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping trofinetide, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If trofinetide is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A and trofinetide is a CYP3A inhibitor.
Buprenorphine; Naloxone: (Moderate) Concomitant use of buprenorphine and trofinetide can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when trofinetide is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping trofinetide, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If trofinetide is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A and trofinetide is a CYP3A inhibitor.
Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Concomitant use of codeine with trofinetide may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of trofinetide could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If trofinetide is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Trofinetide is a weak inhibitor of CYP3A.
Butalbital; Aspirin; Caffeine; Codeine: (Moderate) Concomitant use of codeine with trofinetide may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of trofinetide could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If trofinetide is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Trofinetide is a weak inhibitor of CYP3A.
Carbamazepine: (Moderate) Monitor carbamazepine concentrations closely during coadministration of trofinetide; carbamazepine dose adjustments may be needed. Concomitant use may increase carbamazepine concentrations. Carbamazepine is a CYP3A substrate and trofinetide is a CYP3A inhibitor.
Celecoxib; Tramadol: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with trofinetide is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of trofinetide, a weak CYP3A inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
Chlorpheniramine; Codeine: (Moderate) Concomitant use of codeine with trofinetide may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of trofinetide could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If trofinetide is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Trofinetide is a weak inhibitor of CYP3A.
Chlorpheniramine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of trofinetide is necessary. Hydrocodone is a CYP3A substrate, and coadministration with CYP3A inhibitors like trofinetide can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If trofinetide is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Cisapride: (Major) Avoid concomitant use of cisapride and trofinetide; use increases cisapride exposure and the risk for adverse effects such as QT/QTc prolongation and torsade de pointes (TdP). Cisapride is a CYP3A substrate and trofinetide is a weak CYP3A inhibitor. Concomitant use of cisapride with CYP3A inhibitors is disallowed under the Propulsid Limited Access Program.
Clozapine: (Moderate) Consider a clozapine dose reduction if coadministered with trofinetide and monitor for adverse reactions. If trofinetide is discontinued, monitor for lack of clozapine effect and increase dose if necessary. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is partially metabolized by CYP3A. Trofinetide is a weak CYP3A inhibitor.
Codeine: (Moderate) Concomitant use of codeine with trofinetide may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of trofinetide could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If trofinetide is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Trofinetide is a weak inhibitor of CYP3A.
Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with trofinetide may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of trofinetide could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If trofinetide is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Trofinetide is a weak inhibitor of CYP3A.
Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of codeine with trofinetide may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of trofinetide could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If trofinetide is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Trofinetide is a weak inhibitor of CYP3A.
Codeine; Phenylephrine; Promethazine: (Moderate) Concomitant use of codeine with trofinetide may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of trofinetide could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If trofinetide is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Trofinetide is a weak inhibitor of CYP3A.
Codeine; Promethazine: (Moderate) Concomitant use of codeine with trofinetide may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of trofinetide could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If trofinetide is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Trofinetide is a weak inhibitor of CYP3A.
Cyclosporine: (Moderate) Closely monitor cyclosporine whole blood trough concentrations as appropriate and watch for cyclosporine-related adverse reactions if coadministration with trofinetide is necessary. The dose of cyclosporine may need to be adjusted. Concurrent use may increase cyclosporine exposure causing an increased risk for cyclosporine-related adverse events. Cyclosporine is a CYP3A substrate and trofinetide is a weak CYP3A inhibitor.
Diazepam: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with trofinetide is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP3A substrate and trofinetide is a CYP3A inhibitor.
Disopyramide: (Moderate) Monitor for an increase in disopyramide-related adverse reactions if coadministration with trofinetide is necessary as concurrent use may increase disopyramide exposure. Disopyramide is a CYP3A substrate and trofinetide is a weak CYP3A inhibitor. Although specific drug interaction studies have not been done for disopyramide, cases of life-threatening interactions have been reported when disopyramide was coadministered with moderate and strong CYP3A inhibitors.
Dofetilide: (Moderate) Monitor for an increase in dofetilide-related adverse reactions, including QT prolongation, if coadministration with trofinetide is necessary as concurrent use may increase dofetilide exposure. Trofinetide is a weak CYP3A inhibitor. Dofetilide is a minor CYP3A substrate; however, because there is a linear relationship between dofetilide plasma concentration and QTc, concomitant administration of CYP3A inhibitors may increase the risk of arrhythmia (torsade de pointes).
Elagolix: (Contraindicated) Coadministration of elagolix with trofinetide is contraindicated as concurrent use may increase elagolix exposure. Elagolix is a substrate of OATP1B1 and trofinetide is a strong OATP1B1 inhibitor.
Elagolix; Estradiol; Norethindrone acetate: (Contraindicated) Coadministration of elagolix with trofinetide is contraindicated as concurrent use may increase elagolix exposure. Elagolix is a substrate of OATP1B1 and trofinetide is a strong OATP1B1 inhibitor.
Elbasvir; Grazoprevir: (Contraindicated) Concomitant use of grazoprevir and trofinetide is contraindicated due to the potential for increased grazoprevir exposure. Grazoprevir is a substrate of OATP1B1/3; trofinetide is an inhibitor of OATP1B1/3.
Eliglustat: (Major) Coadministration of eliglustat and trofinetide is not recommended in poor CYP2D6 metabolizers (PMs). In extensive CYP2D6 metabolizers (EM) with mild hepatic impairment, coadministration of these agents requires dosage reduction of eliglustat to 84 mg PO once daily. Eliglustat is a CYP3A and CYP2D6 substrate; trofinetide is a weak CYP3A inhibitor. Because CYP3A plays a significant role in the metabolism of eliglustat in CYP2D6 PMs, coadministration of eliglustat with CYP3A inhibitors may increase eliglustat exposure and the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias).
Eluxadoline: (Major) Reduce the dose of eluxadoline to 75 mg twice daily and monitor for eluxadoline-related adverse effects including decreased mental and physical acuity if coadministered with trofinetide. Coadministration may increase exposure of eluxadoline. Eluxadoline is an OATP1B1 substrate and trofinetide is a an OATP1B1 inhibitor. Coadministration with another OATP1B1 inhibitor increased the exposure of eluxadoline by 4.4-fold.
Ezetimibe; Simvastatin: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with trofinetide is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is an OATP1B1 substrate; trofinetide is an OATP1B1 inhibitor.
Felodipine: (Moderate) Concurrent use of felodipine and trofinetide should be approached with caution and conservative dosing of felodipine due to the potential for significant increases in felodipine exposure. Monitor for evidence of increased felodipine effects including decreased blood pressure and increased heart rate. Felodipine is a sensitive CYP3A substrate and trofinetide is a weak CYP3A inhibitor. Concurrent use of another weak CYP3A inhibitor increased felodipine AUC and Cmax by approximately 50%.
Fentanyl: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of trofinetide is necessary. If trofinetide is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A substrate, and coadministration with CYP3A inhibitors like trofinetide can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If trofinetide is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Finerenone: (Moderate) Monitor serum potassium during initiation or dose adjustment of either finerenone or trofinetide; a finerenone dosage reduction may be necessary. Concomitant use may increase finerenone exposure and the risk of hyperkalemia. Finerenone is a CYP3A substrate and trofinetide is a weak CYP3A inhibitor. Coadministration with another weak CYP3A inhibitor increased overall exposure to finerenone by 21%.
Flibanserin: (Moderate) The concomitant use of flibanserin and multiple weak CYP3A inhibitors, including trofinetide, may increase flibanserin concentrations, which may increase the risk of flibanserin-induced adverse reactions. Therefore, patients should be monitored for hypotension, syncope, somnolence, or other adverse reactions, and the potential outcomes of combination therapy with multiple weak CYP3A inhibitors and flibanserin should be discussed with the patient.
Fluvastatin: (Moderate) Monitor for an increase in fluvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with trofinetide is necessary. Concomitant use may increase fluvastatin exposure. Fluvastatin is a substrate of OATP1B3; trofinetide is an inhibitor of OATP1B3.
Glecaprevir; Pibrentasvir: (Moderate) Monitor for an increase in glecaprevir-related adverse reactions if coadministration with trofinetide is necessary. Concomitant use may increase glecaprevir exposure. Glecaprevir is an OATP1B1/3 substrate; trofinetide is an OATP1B1/3 inhibitor.
Glyburide: (Moderate) Monitor for an increase in glyburide-related adverse reactions, such as hypoglycemia, if coadministration with trofinetide is necessary. Concomitant use may increase glyburide exposure. Glyburide is a substrate of OATP1B1/3; trofinetide is an OATP1B1/3 inhibitor.
Glyburide; Metformin: (Moderate) Monitor for an increase in glyburide-related adverse reactions, such as hypoglycemia, if coadministration with trofinetide is necessary. Concomitant use may increase glyburide exposure. Glyburide is a substrate of OATP1B1/3; trofinetide is an OATP1B1/3 inhibitor.
Homatropine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of trofinetide is necessary. Hydrocodone is a CYP3A substrate, and coadministration with CYP3A inhibitors like trofinetide can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If trofinetide is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of trofinetide is necessary. Hydrocodone is a CYP3A substrate, and coadministration with CYP3A inhibitors like trofinetide can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If trofinetide is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydrocodone; Ibuprofen: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of trofinetide is necessary. Hydrocodone is a CYP3A substrate, and coadministration with CYP3A inhibitors like trofinetide can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If trofinetide is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Ibuprofen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of trofinetide is necessary. If trofinetide is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A substrate, and coadministration with weak CYP3A inhibitors like trofinetide can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If trofinetide is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Isradipine: (Minor) Monitor for an increase in isradipine-related adverse reactions including hypotension if coadministration with trofinetide is necessary. Concomitant use may increase isradipine exposure. Isradipine is a CYP3A substrate and trofinetide is a weak CYP3A inhibitor.
Ixabepilone: (Moderate) Monitor for ixabepilone toxicity and reduce the ixabepilone dose as needed if concurrent use of trofinetide is necessary. Concomitant use may increase ixabepilone exposure and the risk of adverse reactions. Ixabepilone is a CYP3A substrate and trofinetide is a weak CYP3A inhibitor.
Lemborexant: (Major) Limit the dose of lemborexant to 5 mg PO once daily if coadministered with trofinetide as concomitant use may increase lemborexant exposure and the risk of adverse effects. Lemborexant is a CYP3A substrate; trofinetide is a weak CYP3A inhibitor. Coadministration with a weak CYP3A inhibitor is predicted to increase lemborexant exposure by less than 2-fold.
Letermovir: (Moderate) Monitor for an increase in letermovir-related adverse reactions if coadministration with trofinetide is necessary. Concomitant use may increase letermovir exposure. Letermovir is a substrate of OATP1B1/3; trofinetide is an OATP1B1/3 inhibitor.
Lidocaine: (Moderate) Monitor for lidocaine toxicity if coadministration with trofinetide is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP3A substrate and trofinetide is a weak CYP3A inhibitor.
Lidocaine; Epinephrine: (Moderate) Monitor for lidocaine toxicity if coadministration with trofinetide is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP3A substrate and trofinetide is a weak CYP3A inhibitor.
Lidocaine; Prilocaine: (Moderate) Monitor for lidocaine toxicity if coadministration with trofinetide is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP3A substrate and trofinetide is a weak CYP3A inhibitor.
Lomitapide: (Major) Decrease the dose of lomitapide by one-half not to exceed 30 mg/day PO if coadministration with trofinetide is necessary. Concomitant use may significantly increase the serum concentration of lomitapide. Trofinetide is a weak CYP3A inhibitor; the exposure to lomitapide is increased by approximately 2-fold in the presence of weak CYP3A inhibitors.
Lonafarnib: (Major) Avoid coadministration of lonafarnib and trofinetide; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. If coadministration is unavoidable, reduce to or continue lonafarnib at a dosage of 115 mg/m2 and closely monitor patients for lonafarnib-related adverse reactions. Resume previous lonafarnib dosage 14 days after discontinuing trofinetide. Lonafarnib is a sensitive CYP3A substrate and trofinetide is a weak CYP3A inhibitor.
Maraviroc: (Moderate) Monitor for an increase in maraviroc-related adverse reactions if coadministration with trofinetide is necessary. Concomitant use may increase maraviroc exposure. Maraviroc is an OATP1B1 substrate; trofinetide is an OATP1B1 inhibitor.
Mefloquine: (Moderate) Use mefloquine with caution if coadministration with trofinetide is necessary as concurrent use may increase mefloquine exposure and mefloquine-related adverse events. Mefloquine is a substrate of CYP3A and trofinetide is a weak CYP3A inhibitor.
Meperidine: (Moderate) Consider a reduced dose of meperidine with frequent monitoring for respiratory depression and sedation if concurrent use of trofinetide is necessary. If trofinetide is discontinued, meperidine plasma concentrations can decrease resulting in reduced efficacy and potential withdrawal syndrome in a patient who has developed physical dependence to meperidine. Meperidine is a substrate of CYP3A and trofinetide is a weak CYP3A inhibitor. Concomitant use with trofinetide can increase meperidine exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of meperidine.
Methadone: (Moderate) Consider a reduced dose of methadone with frequent monitoring for respiratory depression and sedation if concurrent use of trofinetide is necessary. If trofinetide is discontinued, methadone plasma concentrations can decrease resulting in reduced efficacy and potential withdrawal syndrome in a patient who has developed physical dependence to methadone. Methadone is a substrate of CYP3A, CYP2B6, CYP2C19, CYP2C9, and CYP2D6; trofinetide is a weak CYP3A inhibitor. Concomitant use with trofinetide can increase methadone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of methadone.
Midazolam: (Moderate) Use caution when midazolam is coadministered with trofinetide. Concurrent use may increase midazolam exposure leading to prolonged sedation. Midazolam is a sensitive CYP3A substrate and trofinetide is a weak CYP3A inhibitor.
Momelotinib: (Moderate) Monitor for an increase in momelotinib-related adverse reactions if coadministration with trofinetide is necessary. Concomitant use may increase momelotinib exposure. Momelotinib is an OATP1B1/3 substrate; trofinetide is an OATP1B1/3 inhibitor. Coadministration with another OATP1B1/1B3 inhibitor increased momelotinib exposure by 57%; exposure of its active M21 metabolite increased by 12%.
Nanoparticle Albumin-Bound Sirolimus: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 during concomitant use of trofinetide. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and trofinetide is a weak CYP3A inhibitor.
Nimodipine: (Moderate) Monitor blood pressure and reduce the dose of nimodipine as clinically appropriate if coadministration with trofinetide is necessary. Concurrent use may increase nimodipine exposure. Nimodipine is a CYP3A substrate and trofinetide is a weak CYP3A inhibitor.
Nisoldipine: (Major) Avoid coadministration of nisoldipine with trofinetide due to increased plasma concentrations of nisoldipine. If coadministration is unavoidable, monitor blood pressure closely during concurrent use of these medications. Nisoldipine is a CYP3A substrate and trofinetide is a CYP3A inhibitor. Coadministration with another CYP3A inhibitor increased the AUC of nisoldipine by 30% to 45%.
Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of trofinetide is necessary. If trofinetide is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A substrate, and coadministration with weak CYP3A inhibitors like trofinetide can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If trofinetide is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Pimozide: (Major) Avoid concomitant use of pimozide and trofinetide. Concomitant use may result in elevated pimozide concentrations resulting in QT prolongation, ventricular arrhythmias, and sudden death. Pimozide is CYP3A substrate, and trofinetide is a weak CYP3A inhibitor.
Pitavastatin: (Moderate) Monitor for an increase in pitavastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with trofinetide is necessary. Concomitant use may increase pitavastatin exposure. Pitavastatin is an OATP1B1 substrate; trofinetide is an OATP1B1 inhibitor.
Pravastatin: (Moderate) Monitor for an increase in pravastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with trofinetide is necessary. Concomitant use may increase pravastatin exposure. Pravastatin is an OATP1B1/3 substrate; trofinetide is an OATP1B1/3 inhibitor.
Propafenone: (Moderate) Monitor for increased propafenone toxicity if coadministered with trofinetide; concurrent use may increase propafenone exposure and therefore increase the risk of proarrhythmias. Avoid simultaneous use of propafenone and trofinetide with a CYP2D6 inhibitor or in patients with CYP2D6 deficiency. Propafenone is a CYP3A and CYP2D6 substrate; trofinetide is a weak CYP3A inhibitor.
Resmetirom: (Major) Avoid concomitant use of resmetirom and trofinetide due to the risk for increased resmetirom exposure which may increase the risk for resmetirom-related adverse effects. Resmetirom is an OATP1B1/3 substrate and trofinetide is an OATP1B1/3 inhibitor.
Revefenacin: (Major) Avoid concomitant use of revefenacin and trofinetide. Concomitant use may increase exposure to the active metabolite of revefenacin and the risk for anticholinergic adverse effects. The active metabolite of revefenacin is a substrate of OATP1B1/3; trofinetide is an inhibitor of OATP1B1/3.
Rosuvastatin: (Moderate) Monitor for an increase in rosuvastatin-related adverse reactions, including myopathy and rhabdomyolysis, during concomitant use with trofinetide. Concurrent use may increase rosuvastatin exposure. Rosuvastatin is a substrate of the drug transporter OATP1B1/3 and trofinetide is an OATP1B1/3 inhibitor.
Rosuvastatin; Ezetimibe: (Moderate) Monitor for an increase in rosuvastatin-related adverse reactions, including myopathy and rhabdomyolysis, during concomitant use with trofinetide. Concurrent use may increase rosuvastatin exposure. Rosuvastatin is a substrate of the drug transporter OATP1B1/3 and trofinetide is an OATP1B1/3 inhibitor.
Simvastatin: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with trofinetide is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is an OATP1B1 substrate; trofinetide is an OATP1B1 inhibitor.
Sirolimus: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of trofinetide. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and trofinetide is a weak CYP3A inhibitor.
Sodium Phenylbutyrate: (Major) Avoid coadministration of sodium phenylbutyrate; taurursodiol and trofinetide. Concomitant use may increase plasma concentrations of sodium phenylbutyrate; taurursodiol. Sodium phenylbutyrate; taurursodiol is an OATP1B3 substrate and trofinetide is an OATP1B3 inhibitor.
Sodium Phenylbutyrate; Taurursodiol: (Major) Avoid coadministration of sodium phenylbutyrate; taurursodiol and trofinetide. Concomitant use may increase plasma concentrations of sodium phenylbutyrate; taurursodiol. Sodium phenylbutyrate; taurursodiol is an OATP1B3 substrate and trofinetide is an OATP1B3 inhibitor. (Moderate) Avoid coadministration of sodium phenylbutyrate; taurursodiol and trofinetide. Concomitant use may increase plasma concentrations of sodium phenylbutyrate; taurursodiol. Sodium phenylbutyrate; taurursodiol is an OATP1B3 substrate and trofinetide is an OATP1B3 inhibitor.
Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) Avoid concomitant use of voxilaprevir and trofinetide. Concomitant use may increase voxilaprevir exposure and the risk of voxilaprevir-related adverse reactions. Voxilaprevir is a substrate of OATP1B1/3; trofinetide is an OATP1B1/3 inhibitor.
Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if trofinetide must be administered. Consider a reduced dose of sufentanil injection with frequent monitoring for respiratory depression and sedation if concurrent use of trofinetide is necessary. If trofinetide is discontinued, consider increasing the sufentanil injection dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Sufentanil is a CYP3A substrate, and coadministration with a weak CYP3A inhibitor like trofinetide can increase sufentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of sufentanil. If trofinetide is discontinued, sufentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to sufentanil.
Tacrolimus: (Moderate) Monitor tacrolimus serum concentrations as appropriate and watch for tacrolimus-related adverse reactions if coadministration with trofinetide is necessary. The dose of tacrolimus may need to be reduced. Tacrolimus is a sensitive CYP3A substrate with a narrow therapeutic range; trofinetide is a weak CYP3A inhibitor.
Tramadol: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with trofinetide is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of trofinetide, a weak CYP3A inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
Tramadol; Acetaminophen: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with trofinetide is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of trofinetide, a weak CYP3A inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
Triazolam: (Moderate) Monitor for signs of triazolam toxicity during coadministration with trofinetide. Coadministration may increase the exposure of triazolam. Triazolam is a sensitive CYP3A substrate and trofinetide is a weak CYP3A inhibitor.
Ubrogepant: (Major) Limit the initial and second dose of ubrogepant to 50 mg if coadministered with trofinetide. Concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a CYP3A substrate; trofinetide is a weak CYP3A inhibitor.
Vinorelbine: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with trofinetide is necessary. Vinorelbine is a CYP3A substrate and trofinetide is a weak CYP3A inhibitor.
Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with trofinetide is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. The R-enantiomer of warfarin is a CYP3A substrate and trofinetide is a weak CYP3A inhibitor. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Zavegepant: (Major) Avoid concomitant use of zavegepant and trofinetide. Concomitant use may increase zavegepant exposure and the risk for zavegepant-related adverse effects. Zavegepant is an OATP1B3 substrate and trofinetide is an OATP1B3 inhibitor. Concomitant use with another OATP1B3 inhibitor increased zavegepant overall exposure by 2.3-fold.
The mechanism by which trofinetide exerts its effects in persons with Rett syndrome is unknown. Trofinetide is an analog of the amino-terminal tripeptide of insulin-like growth factor 1 (IGF-1). Trofinetide may improve disease symptoms by normalizing neuron and glial cell dysfunction due to anti-inflammatory and trophic effects as well as normalizing protein synthesis, dendritic morphology, and neuronal signaling and enhancing antioxidant response.
Trofinetide is administered orally. The mean apparent Vd of trofinetide in healthy adults is approximately 80 L. Plasma protein binding of trofinetide is less than 6%. Trofinetide does not undergo significant hepatic metabolism. Trofinetide is excreted mostly unchanged in urine (approximately 80% of the dose), with minor excretion in the feces. The effective elimination half-life of trofinetide is approximately 1.5 hours.
Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: CYP3A4, OATP1B1, OATP1B3, UGT1A9, UGT2B7, UGT2B15
Trofinetide is a weak CYP3A4 inhibitor. Trofinetide inhibits OATP1B1, OATP1B3, UGT1A9, UGT2B7, and UGT2B15 in vitro.
-Route-Specific Pharmacokinetics
Oral Route
The time to maximum concentration (Tmax) of trofinetide is approximately 2 to 3 hours. Approximately 84% of the administered dose was absorbed after oral administration of trofinetide 12,000 mg. Coadministration of trofinetide with a high-fat meal reduced the trofinetide peak plasma concentration (Cmax) by approximately 20% and had no impact on the total exposure (AUC). Trofinetide exhibits linear kinetics with no time- or dose-dependent effects on pharmacokinetic parameters. Drug exposure is dose-proportional within the studied dose range. Minimal to no accumulation was observed after multiple dose administration.
-Special Populations
Hepatic Impairment
The pharmacokinetics of trofinetide in persons 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.
Renal Impairment
The effect of renal impairment on the pharmacokinetics of trofinetide has not been studied.
Pediatrics
The drug exposure of trofinetide in pediatric subjects ages 2 to 4 years is similar to children older than 4 years and adults when following the recommended dosage.