Fintepla Drug Information

FINTEPLA is indicated for the treatment of seizures associated with Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS) in patients 2 years of age and older.

Assessments Prior to Initiating FINTEPLA Prior to starting treatment with FINTEPLA, obtain an echocardiogram assessment to evaluate for valvular heart disease and pulmonary arterial hypertension.

Dosing Information FINTEPLA is to be administered orally and may be taken with or without food. Dravet Syndrome The initial starting and maintenance dosage for patients with Dravet syndrome is 0.1 mg/kg twice daily, which can be increased weekly based on efficacy and tolerability. Table 1 provides the recommended titration schedule, if needed.

Patients with Dravet syndrome not on concomitant stiripentol who are tolerating FINTEPLA at 0.1 mg/kg twice daily and require further reduction of seizures may benefit from a dosage increase up to a maximum recommended maintenance dosage of 0.35 mg/kg twice daily (maximum daily dosage of 26 mg). Patients with Dravet syndrome taking concomitant stiripentol plus clobazam who are tolerating FINTEPLA at 0.1 mg/kg twice daily and require further reduction of seizures may benefit from a dosage increase up to a maximum recommended maintenance dosage of 0.2 mg/kg twice daily (maximum daily dosage of 17 mg). Lennox-Gastaut Syndrome The initial starting dosage for patients with Lennox-Gastaut syndrome is 0.1 mg/kg twice daily, which should be increased weekly based on tolerability.

Table 1 provides the recommended titration schedule. Patients with Lennox-Gastaut syndrome not on concomitant stiripentol who are tolerating FINTEPLA should be titrated to the recommended maintenance dosage of 0.35 mg/kg twice daily (maximum daily dosage of 26 mg). Patients with Lennox-Gastaut syndrome taking concomitant stiripentol plus clobazam who are tolerating FINTEPLA should be titrated to the recommended maintenance dosage of 0.2 mg/kg twice daily (maximum daily dosage of 17 mg).

Table 1: FINTEPLA Recommended Titration Schedule For patients not on concomitant stiripentol in whom a more rapid titration is warranted, the dose may be increased every 4 days.

Dosage Modifications for Patients with Concomitant Use of Strong CYP1A2 or CYP2D6 Inhibitors (DS and LGS) For patients with concomitant use of FINTEPLA with a strong CYP1A2 or CYP2D6 inhibitor, a maximum total daily dosage of 20 mg without concomitant stiripentol and 17 mg with concomitant stiripentol plus clobazam is recommended.

Dosage Modifications for Patients with Severe Renal Impairment (DS and LGS) For patients with severe renal impairment (estimated glomerular filtration rate (eGFR) 15 to 29 mL/min/1.73m 2 ), a maximum total daily dosage of 20 mg without concomitant stiripentol and 17 mg with concomitant stiripentol plus clobazam is recommended.

Dosage Modifications for Patients with Mild, Moderate, and Severe Hepatic Impairment (DS and LGS) See Table 2 for dosage adjustments and recommendations for patients with hepatic impairment.

Assessments During and After Administration of FINTEPLA

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.

Administration Instructions

A calibrated measuring device (either a 3 mL or 6 mL oral syringe) will be provided by the pharmacy and is recommended to measure and administer the prescribed dose accurately. A household teaspoon or tablespoon is not an adequate measuring device and should not be used. Discard any unused FINTEPLA oral solution remaining after 3 months of first opening the bottle or the "Discard After" date on the bottle, whichever is sooner.

FINTEPLA is compatible with commercially available gastric and nasogastric feeding tubes.

Discontinuation 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.

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. Dravet Syndrome In placebo-controlled trials of patients with DS taking concomitant standard of care AEDs, 122 patients were treated with FINTEPLA and 84 patients received placebo. All patients were receiving at least one other AED.

The most frequent adverse reaction leading to discontinuation in the patients treated with any dose of FINTEPLA was somnolence (3%). The most common adverse reactions that occurred in patients treated with FINTEPLA (incidence at least 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. Table 4 lists the adverse reactions that were reported in 5% or more of patients treated with FINTEPLA and at a rate greater than those on placebo during the titration and maintenance phases of Study 1 and Study 2.

Table 4: Adverse Reactions in 5% or More of Patients Treated with FINTEPLA and Greater Than Placebo in Placebo-Controlled Trials for Dravet Syndrome Lennox-Gastaut Syndrome In the placebo-controlled trial of patients with LGS taking concomitant standard of care AEDs (Study 3), 176 patients were treated with FINTEPLA and 87 patients received placebo. The duration of treatment in this trial was 16 weeks. The most frequent adverse reactions leading to discontinuation in the patients treated with any dose of FINTEPLA were seizure (2%) and somnolence (2%).

Table 5: Adverse Reactions in 5% or More of Patients Treated with FINTEPLA and Greater Than Placebo in the Placebo-Controlled Trial for Lennox Gastaut Syndrome 8 3 6 Echocardiographic Safety Assessments of Valvular Heart Disease and Pulmonary Arterial Hypertension Valvular heart disease and pulmonary arterial hypertension were evaluated in the placebo- controlled and open-label extension studies via echocardiography for up to 3 years in duration for 341 DS patients and 263 LGS patients. Screening for valvular heart disease assessed for mild or greater aortic regurgitation or moderate or greater mitral regurgitation, and assessed for additional characteristics of VHD (e.g., valve thickening or restrictive valve motion). In these clinical studies, two patients with LGS exhibited mild aortic regurgitation (AR) but neither patient had any cardiac signs or symptoms or evidence of valvular structural changes.

Neither patient had VHD. The rates of mild AR are consistent with those seen in the screening period prior to treatment (3 patients in LGS and 1 patient in DS clinical trials).

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of FINTEPLA. 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. Psychiatric disorders: aggression

Effect of Other Drugs on FINTEPLA Stiripentol Plus Clobazam Coadministration of FINTEPLA with stiripentol plus clobazam, with or without valproate, increases fenfluramine plasma concentrations. If FINTEPLA is coadministered with stiripentol plus clobazam, the maximum daily dosage of FINTEPLA is 0.2 mg/kg twice daily (maximum daily dosage of 17 mg). Strong CYP1A2, CYP2B6, or CYP3A Inducers Coadministration of FINTEPLA with strong CYP1A2, CYP2B6, or CYP3A inducers will decrease fenfluramine plasma concentrations, which may lower the efficacy of FINTEPLA.

It is recommended to avoid coadministration of strong CYP1A2, CYP2B6 or CYP3A inducers. If coadministration of a strong CYP1A2, CYP2B6, or CYP3A inducer with FINTEPLA is necessary, monitor the patient for reduced efficacy and consider increasing the dosage of FINTEPLA as needed; however, do not exceed the maximum daily dosage of FINTEPLA. If a strong CYP1A2, CYP2B6, or CYP3A inducer is discontinued during maintenance treatment with FINTEPLA, consider gradual reduction in the FINTEPLA dosage to the dose administered prior to initiating the inducer.

Strong CYP1A2 or CYP2D6 Inhibitors Coadministration of FINTEPLA with strong CYP1A2 or CYP2D6 inhibitors will increase fenfluramine plasma concentrations. If FINTEPLA is coadministered with strong CYP1A2 or CYP2D6 inhibitors, the maximum daily dosage of FINTEPLA is 20 mg. If a strong CYP1A2 or CYP2D6 inhibitor is discontinued during maintenance treatment with FINTEPLA, consider gradual increase in the FINTEPLA dosage to the dose recommended without CYP1A2 or CYP2D6 inhibitors; however, do not exceed the maximum daily dosage of FINTEPLA.

If FINTEPLA is coadministered with stiripentol and a strong CYP1A2 or CYP2D6 inhibitor, do not exceed the maximum daily dosage of FINTEPLA of 17 mg.

Effects of Serotonin Receptor Antagonists Cyproheptadine and potent 5-HT1A, 5-HT1D, 5-HT2A, and 5-HT2C serotonin receptor antagonists may decrease the efficacy of FINTEPLA. 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.

Serotonergic Drugs

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. Concomitant use of FINTEPLA is contraindicated within 14 days of taking MAOIs.

Use FINTEPLA with caution in patients taking other medications that increase serotonin.

Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as FINTEPLA, during pregnancy. Encourage women who are taking FINTEPLA during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling the toll-free number 1-888-233-2334 or visiting http://www.aedpregnancyregistry.org. Risk Summary There are no data on FINTEPLA use in pregnant women.

Available data from epidemiologic studies with fenfluramine or dexfenfluramine are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. FINTEPLA can cause decreased appetite and decreased weight; monitor for adequate weight gain during pregnancy. In animal studies, administration of fenfluramine throughout organogenesis (rat and rabbit) or throughout gestation and lactation (rat) resulted in adverse effects on development (fetal malformations, embryofetal and offspring mortality and growth impairment) in the presence of maternal toxicity at clinically relevant maternal plasma levels of fenfluramine and its major active metabolite (see Data ).

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is respectively. Clinical Considerations Disease-associated Maternal and/or Embryofetal Risk Epilepsy, with or without exposure to antiepileptic drugs, has been associated with several adverse outcomes during pregnancy, including preeclampsia, preterm labor, antepartum and postpartum hemorrhage, placental abruption, poor fetal growth, prematurity, fetal death, and maternal mortality.

The risk of maternal or fetal injury may be greatest for patients with untreated or poorly controlled convulsive seizures. Women with epilepsy who become pregnant should not abruptly discontinue antiepileptic drugs, including FINTEPLA, due to the risk of status epilepticus or severe seizures, which may be life-threatening. Data Animal Data Oral administration of fenfluramine mg/kg/day to pregnant rats during organogenesis resulted in decreased fetal body weights and marked increases in fetal malformations (external, visceral, and skeletal) at the highest dose tested, which was associated with maternal toxicity.

At the no-effect dose (8.6 mg/kg/day) for adverse effects on embryofetal development in rats, maternal plasma exposures (AUC) of fenfluramine and norfenfluramine (the major metabolite) were approximately 2 and 5 times, respectively, those in humans at the maximum recommended human dose (MRHD) of 26 mg/day. Oral administration of fenfluramine mg/kg/day to pregnant rabbits throughout organogenesis resulted in increased embryofetal mortality at all doses and increases in fetal malformations (external and skeletal) at the highest dose tested, which was associated with maternal toxicity. A no-adverse-effect dose for adverse effects on embryofetal development in rabbits was not identified.

At the lowest dose tested in rabbits (4.3 mg/kg/day), maternal plasma exposures of fenfluramine and norfenfluramine were lower than those in humans at the MRHD. Oral administration of fenfluramine mg/kg/day to female rats throughout gestation and lactation resulted in marked increases in stillborn pups and neonatal offspring deaths at the highest dose tested and delayed growth and reflex development during the pre- weaning period at all doses. Maternal body weight gain was decreased at all doses during pregnancy and at the two highest doses during lactation.

A no-effect dose for adverse effects on pre- and postnatal development in rats was not determined. At the lowest dose tested in rats (4.3 mg/kg/day), maternal plasma exposures of fenfluramine and norfenfluramine were approximately 0.5 and 3 times, respectively, those in humans at the MRHD.

Pediatric Use The safety and effectiveness of FINTEPLA for the treatment of seizures associated with DS and LGS have been established in patients 2 years of age and older. Use of FINTEPLA for the treatment of seizures associated with DS in patients 2 years of age and older is supported by two randomized, double-blind, placebo-controlled trials in 202 patients 2 to 18 years of age. FINTEPLA can cause decreases in appetite and weight.

The growth of pediatric patients treated with FINTEPLA should be carefully monitored. Safety and effectiveness in patients less than 2 years of age have not been established. Juvenile Animal Data Oral administration of fenfluramine mg/kg/day to young rats for 10 weeks starting on postnatal day 7 resulted in reduced body weight and neurobehavioral changes (decreased locomotor activity and learning and memory deficits) at all doses tested.

Neurobehavioral effects persisted after dosing was discontinued. Bone size was decreased at the mid and high doses; brain size was decreased at the highest dose. Partial or complete recovery was seen for these endpoints.

A no-effect dose for postnatal developmental toxicity was not identified. The lowest dose tested (3.0 mg/kg/day) was associated with plasma fenfluramine exposures (AUC) less than that in humans at the maximum recommended human dose (MRHD) of 26 mg/day and norfenfluramine (metabolite) exposures (AUC) approximately 2 times that in humans at the MRHD.

FINTEPLA is contraindicated in patients with: Hypersensitivity to fenfluramine or any of the excipients in FINTEPLA Concomitant use, or within 14 days of the administration, of monoamine oxidase inhibitors because of an increased risk of serotonin syndrome Hypersensitivity to fenfluramine or any of the excipients in FINTEPLA Within 14 days of the administration of monoamine oxidase inhibitors due to an increased risk of serotonin syndrome

Overdose has not been observed in the FINTEPLA clinical trial program. However, overdose of fenfluramine, the active ingredient in FINTEPLA, has been reported at higher doses than those included in the clinical trial program. Some of the cases were fatal.

Events reported after overdose include mydriasis, tachycardia, flushing, tremors/twitching/muscle spasms, agitation/restlessness/anxiety, increased muscle tone/rigor/opisthotonos, respiratory distress or failure, and seizure. Seizure, coma, and cardiorespiratory arrest were reported in most of the fatal overdoses. There is no available specific antidote to the overdose reactions of FINTEPLA.

In the event of overdose, standard medical practice for the management of drug overdosage should be used. An adequate airway, oxygenation, and ventilation should be ensured; monitoring of cardiac rhythm and vital sign measurement is recommended. A certified poison control center should be contacted for updated information on the management of overdose with FINTEPLA.