Dosage & Administration
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Fintepla Prescribing Information
FINTEPLA can cause valvular heart disease and pulmonary arterial hypertension [see Warnings and Precautions (5.1)].
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 [see Dosage and Administration (2.1, 2.6) and Warnings and Precautions (5.1)].
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 [see Warnings and Precautions (5.2)].
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 [see Dosage and Administration (2.6) and Warnings and Precautions (5.1)].
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) [see Drug Interactions (7.1)].
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) [see Drug Interactions (7.1)].
| Without concomitant stiripentol * | With concomitant stiripentol plus clobazam | |||
|---|---|---|---|---|
| Weight-based Dosage | Maximum Total Daily Dosage † | Weight-based Dosage | Maximum Total Daily Dosage † | |
| ||||
| Initial Dosage ‡ | 0.1 mg/kg twice daily | 26 mg | 0.1 mg/kg twice daily | 17 mg |
| Day 7 | 0.2 mg/kg twice daily | 26 mg | 0.15 mg/kg twice daily | 17 mg |
| Day 14 § | 0.35 mg/kg twice daily | 26 mg | 0.2 mg/kg twice daily | 17 mg |
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 [see Drug Interactions (7.1)].
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/1.73m2), a maximum total daily dosage of 20 mg without concomitant stiripentol and 17 mg with concomitant stiripentol plus clobazam is recommended [see Use in Specific Populations (8.6)].
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 [see Use in Specific Populations (8.7)].
| Hepatic Impairment Classification | Without concomitant stiripentol * | With concomitant stiripentol plus clobazam |
|---|---|---|
| Maximum total daily dosage | Maximum total daily dosage | |
| ||
| Mild (Child-Pugh A) | 20 mg | 13 mg * |
| Moderate (Child-Pugh B) | 20 mg | Use not recommended |
| Severe (Child-Pugh C) | 17 mg | Use not recommended |
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 [see Warnings and Precautions (5.1)].
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[see How Supplied/Storage and Handling (16.1)]. 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 [see Warnings and Precautions (5.6)].
Oral solution: 2.2 mg/mL fenfluramine as a clear, colorless, cherry flavored liquid.
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 [see Warnings and Precautions (5.3)]; 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).
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. 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 2 to 4% and 15 to 20%, respectively.
Data
Animal Data
Oral administration of fenfluramine (0, 4.5, 8.6, or 34.6 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 (0, 4.3, 8.6, 13.0 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 (0, 4.3, 8,6, or 34.6 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.
Lactation
Risk Summary
There are no data on the presence of fenfluramine or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production.
The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for FINTEPLA and any potential adverse effects on the breastfed infant from FINTEPLA or from the underlying maternal condition.
Females and Males of Reproductive Potential
Infertility
In animal studies, oral administration of fenfluramine resulted in adverse reproductive effects in males and females at clinically relevant doses in the presence of parental toxicity [see Nonclinical Toxicology (13.1)].
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. Use of FINTEPLA for the treatment of seizures associated with LGS is supported by a randomized, double-blind, placebo-controlled study in 263 patients aged 2 to 35 years, including 187 patients less than 18 years [see Boxed Warning, Warnings and Precautions (5), Adverse Reaction (6.1), and Clinical Studies (14)].
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 (0, 3.0, 7,8, or 17.3 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.
Geriatric Use
Clinical studies of FINTEPLA for the treatment of DS or LGS did not include patients 65 years of age and over to determine whether they respond differently from younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
Renal Impairment
In patients with estimated glomerular filtration rate (eGFR) 15 to 29 mL/min/1.73m2, do not exceed the maximum daily dosage of FINTEPLA of 20 mg. In patients with eGFR 15 to 29 ml/min/1.73m2 and concomitant stiripentol use, do not exceed the maximum daily dosage of FINTEPLA of 17 mg [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)]. FINTEPLA has not been studied in patients with eGFR < 15 mL/min/1.73m2.
Hepatic Impairment
Combined molar exposures of fenfluramine and norfenfluramine were increased in subjects with various degrees of hepatic impairment (Child-Pugh Class A, B, and C), necessitating a dosage adjustment in these patients [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)].
FINTEPLA is contraindicated in patients with:
- Hypersensitivity to fenfluramine or any of the excipients in FINTEPLA [see Description (11)]
- Concomitant use, or within 14 days of the administration, of monoamine oxidase inhibitors because of an increased risk of serotonin syndrome [see Warnings and Precautions (5.7)]