FDA Approves FINTEPLA (Fenfluramine) for Seizures Associated with Dravet Syndrome in Patients 2 Years of Age and Older
On June 25, 2020, the U.S. Food and Drug Administration (FDA) approved FINTEPLA (fenfluramine) for the treatment of seizures associated with Dravet syndrome in patients 2 years of age and older. The approved recommended dosage of FINTEPLA is 0.1 mg/kg twice daily, which can be increased weekly based on efficacy and tolerability. FINTEPLA is a solution to be administered orally and may be taking with or without food. The maximum recommended maintenance dosage if FINTEPLA 0.35 mg/kg twice daily (maximum daily dosage of 26 mg) in patients not on concomitant stiripentol. In patients taking concomitant stiripentol and clobazam, the maximum recommended maintenance dosage of 0.2 mg/kg twice daily (maximum daily dosage of 17 mg).
There is an association between serotonergic drugs with 5-HT2B receptor agonist activity, including fenfluramine (the active ingredient in FINTEPLA), and valvular heart disease and pulmonary arterial hypertension. Echocardiogram assessments are required before, during, and after treatment with FINTEPLA. The benefits versus the risks of initiating or continuing FINTEPLA must be considered, based on echocardiogram findings. Because of the risks of valvular heart disease and pulmonary arterial hypertension, FINTEPLA is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the FINTEPLA REMS.
FINTEPLA is contraindicated in patients with hypersensitivity to fenfluramine or any of the excipients in FINTEPLA and concomitant use of, or within 14 days of the administration, of monoamine oxidase inhibitors (MAOIs).
Prior to starting treatment with FINTEPLA, obtain an echocardiogram assessment to evaluate for valvular heart disease and pulmonary arterial hypertension. Obtain an echocardiogram assessment every 6 months during treatment with FINTEPLA, and 3 to 6 months after the final dose of FINTEPLA. When discontinuing FINTEPLA, the dose should be decreased gradually. As with all antiepileptic drugs, abrupt discontinuation should be avoided when possible to minimize the risk of increased seizure frequency and status epilepticus.
Additional information regarding dosage and administration, including the recommended titration schedule, as well as warnings and precautions about valvular heart disease, pulmonary arterial hypertension, decreased appetite and decreased weight, somnolence, sedation, and lethargy, suicidal behavior and ideation, withdrawal of antiepileptic drugs, serotonin syndrome, increase in blood pressure, and glaucoma can be found in the full prescribing information linked below.
Mechanism of Action (MOA) and Pharmacokinetics (PK)
MOA: The mechanisms by which fenfluramine exerts its therapeutic effects in the treatment of seizures associated with Dravet syndrome are unknown. Fenfluramine and the metabolite, norfenfluramine, increase extracellular levels of serotonin through interaction with serotonin transporter proteins, and exhibit agonist activity at serotonin 5HT-2 receptors.
General PK: The steady-state Cmax and AUC of fenfluramine is slightly greater than dose proportional over the dose range of fenfluramine 13 to 51.8 mg twice daily (1 to 4 times the maximum recommended dose). In pediatric patients who received FINTEPLA 0.7 mg/kg/day, up to a total daily dose of fenfluramine 26 mg, the geometric mean steady-state fenfluramine (CV%) Cmax is 68 (41%) ng/mL and AUC0-24 is 1390 (44%) ng*h/mL.
Absorption: Fenfluramine steady state Tmax is 4 to 5 hours, and the absolute bioavailability of fenfluramine is approximately 68-74%.
Distribution: The geometric mean (CV%) apparent volume of distribution of fenfluramine is 11.9 (16.5%) L/kg following oral administration of FINTEPLA in healthy subjects. Protein binding of fenfluramine is 50% and is independent of concentration in vitro.
Elimination: The elimination half-life of fenfluramine was 20 hours and the geometric mean (CV%) clearance is 24.8 (29%) L/h, following oral administration of FINTEPLA in healthy subjects.
Metabolism: Over 75% of fenfluramine is metabolized to norfenfluramine primarily by CYP1A2, CYP2B6, and CYP2D6, and to a minor extent by CYP2C9, CYP2C19, and CYP3A4/5. Norfenfluramine is then deaminated and oxidized to form inactive metabolites.
Excretion: Greater than 90% of an orally administered dose of fenfluramine is excreted in the urine as fenfluramine, norfenfluramine, or other metabolites with fenfluramine and norfenfluramine accounting for less than 25% of the total; less than 5% is found in feces.
Drug Interactions
Stiripentol Plus Clobazam: If FINTEPLA is coadministered with stiripentol plus clobazam, the maximum recommended maintenance dosage of FINTEPLA is reduced to 0.2 mg/kg twice daily (maximum daily dosage of 17 mg). Coadministration of FINTEPLA with stiripentol plus clobazam, with or without valproate, increases fenfluramine plasma concentrations and decreases its metabolite, norfenfluramine.
Strong CYP1A2 and CYP2B6 Inducers: Consider an increase in FINTEPLA dosage when coadministered with rifampin or a strong CYP1A2 and CYP2B6 inducer; however, do not exceed the maximum daily dosage. Coadministration with rifampin or a strong CYP1A2 and CYP2B6 inducer will decrease fenfluramine plasma concentrations.
Effects of Serotonin Receptor Antagonists: If cyproheptadine or potent 5-HT1A, 5-HT1D, 5-HT2A, or 5-HT2C serotonin receptor antagonists are coadministered with FINTEPLA, patients should be monitored appropriately. Cyproheptadine and potent 5-HT1A, 5-HT1D, 5-HT2A, and 5-HT2C serotonin receptor antagonists may decrease the efficacy of FINTEPLA.
Serotonergic Drugs: FINTEPLA is contraindicated with concomitant use and within 14 days of the administration of MAOIs. Use FINTEPLA with caution in patients taking other medications that increase serotonin. Concomitant administration of FINTEPLA and drugs (e.g., SSRIs, SNRIs, TCAs, MAO inhibitors, trazodone, etc.), over-the-counter medications (e.g., dextromethorphan), or herbal supplements (e.g., St. John’s wort) that increase serotonin may increase the risk of serotonin syndrome.
Use in Specific Populations
The effect of age (2 to 50 years), sex, and race had no clinically meaningful effect on the pharmacokinetics of fenfluramine.
Renal Impairment: Administration of FINTEPLA to patients with moderate or severe renal impairment is not recommended.
Hepatic Impairment: Administration of FINTEPLA to patients with hepatic impairment is not recommended.
Efficacy and Safety
Efficacy of FINTEPLA was demonstrated in two randomized, double-blind, placebo-controlled trials in patients 2 to 18 years of age diagnosed with Dravet syndrome. Additional information regarding efficacy trial(s) can be found in the full prescribing information linked below.
The most common adverse reactions (incidence ≥ 10% and greater than placebo) were decreased appetite; somnolence, sedation, lethargy; diarrhea; constipation; abnormal echocardiogram; fatigue, malaise, asthenia; ataxia, balance disorder, gait disturbance; blood pressure increased; drooling, salivary hypersecretion; pyrexia; upper respiratory tract infection; vomiting; decreased weight; fall; status epilepticus.
Full prescribing information is available at https://go.usa.gov/xwMpA.
Visit Drugs@FDA at http://go.usa.gov/cMsjT for prescribing and patient information, approval letters, reviews and other information for FDA-approved drug products, which are often available shortly following approval.
A non-comprehensive list of examples of clinical substrates, inhibitors and inducers for metabolic and transporter system related interactions may be found at https://go.usa.gov/xXY9C.
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at https://www.fda.gov/safety/medwatch/default.htm, by faxing (1-800-FDA-0178), or by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).
The Office of Clinical Pharmacology (OCP) is pleased to offer the e-mail subscription service Clinical Pharmacology Corner. This is a free service from FDA to provide occasional updates from OCP regarding newly approved therapies, new regulatory and scholarly publications, upcoming events and other items of interest. Subscribe today at https://updates.fda.gov/subscriptionmanagement (note: this link does not work with Internet Explorer) and select Clinical Pharmacology Corner under Drugs.
We always welcome your thoughts regarding the format, content, and utility of this communication. Comments may be sent via email to [email protected].
This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.