Highlights

See Patient counseling information and medication guide available in the DAILYMED drug label information.

Indications and usage

Fenfluramine is indicated for the treatment of seizures associated with Dravet syndrome and Lennox-Gastaut syndrome in patients 2 years of age and older.

Dosage and administration

Assessments before initiating fenfluramine

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

Dosing information

Fenfluramine is to be administered orally and may be taken with or without food.

Dravet syndrome.

Patients with Dravet syndrome taking concomitant stiripentol plus clobazam who are tolerating fenfluramine 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.

Table 1. Fenfluramine Recommended Titration Schedule*

Dosage modifications for patients with concomitant use of strong CYP1A2 or CYP2D6 inhibitors (Dravet syndrome and Lennox-Gastaut syndrome)

For patients with concomitant use of fenfluramine 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 (Dravet syndrome and Lennox-Gastaut syndrome)

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.

Dosage modifications for patients with mild, moderate, and severe hepatic impairment (Dravet syndrome and Lennox-Gastaut syndrome)

See Table 2 for dosage adjustments and recommendations for patients with hepatic impairment.

Table 2. Fenfluramine Dosage Modifications and Recommendations for Patients with Hepatic Impairment

Assessments during and after administration of fenfluramine

To evaluate for valvular heart disease and pulmonary arterial hypertension, obtain an echocardiogram assessment every 6 months during treatment with fenfluramine, and 3 to 6 months after the final dose of fenfluramine.

Administration instructions

A calibrated measuring device (either a 3 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 fenfluramine oral solution remaining after 3 months of first opening the bottle or the "Discard After" date on the bottle, whichever is sooner.

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

Discontinuation of fenfluramine

When discontinuing fenfluramine, the dose should be decreased gradually. As with all antiseizure medications, abrupt discontinuation should be avoided when possible to minimize the risk of increased seizure frequency and status epilepticus.

Dosage forms and strengths

Oral solution. 2.2 mg/mL fenfluramine as a clear, colorless, cherry-flavored liquid.

Contraindications

Fenfluramine is contraindicated in patients with:

Warnings and precautions

Valvular heart disease and pulmonary arterial hypertension

Fenfluramine can cause valvular heart disease and pulmonary arterial hypertension. There is a known association between serotonergic drugs with 5-HT2B receptor agonist activity, including fenfluramine (the active ingredient in fenfluramine), and valvular heart disease and pulmonary arterial hypertension. Although no patients receiving fenfluramine developed valvular heart disease or pulmonary arterial hypertension in clinical trials for Dravet syndrome and Lennox-Gastaut syndrome of up to 3 years in duration, cases of valvular heart disease and pulmonary arterial hypertension have been reported during use of fenfluramine in the postmarketing setting.

Because of this risk, cardiac monitoring is required before starting treatment, during treatment, and after treatment with fenfluramine concludes. Cardiac monitoring via echocardiogram can identify evidence of valvular heart disease and pulmonary arterial hypertension prior to a patient becoming symptomatic, aiding in early detection of these conditions.

Monitoring. Before starting treatment, patients must undergo an echocardiogram to evaluate for valvular heart disease and pulmonary arterial hypertension.

Echocardiograms should be repeated every 6 months, and once 3 to 6 months post-treatment with fenfluramine.

The prescriber must consider the benefits versus the risks of initiating or continuing treatment with fenfluramine if any of the following signs are observed via ECHO:

Fenfluramine is available only through a restricted program under a risk evaluation and mitigation strategy.

Fenfluramine risk evaluation and mitigation strategy program

Fenfluramine is available only through a restricted distribution program called the fenfluramine risk evaluation and mitigation strategy program because of the risk of valvular heart disease and pulmonary arterial hypertension.

Notable requirements of the fenfluramine risk evaluation and mitigation strategy program include:

Further information is available at www.FinteplaREMS.com or by telephone at 1-877-964-3649.

Decreased appetite and decreased weight

Fenfluramine can cause decreases in appetite and weight. In placebo-controlled studies for Dravet syndrome (Study 1 and Study 2 combined), approximately 37% of patients treated with fenfluramine reported, as an adverse reaction, decreased appetite, and approximately 9% reported decreased weight, as compared to 8% and 1%, respectively, of patients on placebo. In the placebo-controlled study for Lennox-Gastaut syndrome (Study 3), approximately 28% of patients treated with fenfluramine reported, as an adverse reaction, decreased appetite, and approximately 5% reported decreased weight, as compared to 15% and 2%, respectively, of patients on placebo. By the end of the controlled studies, 19% (Studies 1 and 2 combined) of patients with Dravet syndrome and 7% (Study 3) of patients with Lennox-Gastaut syndrome treated with fenfluramine had a measured decrease in weight of 7% or greater from their baseline weight, compared to 2% (Study 1 and 2) and 0% (Study 3) of patients on placebo. This measured decrease in weight appeared to be dose-related. In the controlled studies for Dravet syndrome, 26% of patients on fenfluramine 0.7 mg/kg/day (Study 1), 19% of patients on fenfluramine 0.4 mg/kg/day in combination with stiripentol (Study 2), and 13% of patients taking fenfluramine 0.2 mg/kg/day (Study 1) experienced at least a 7% decrease in weight from baseline. In the controlled study for Lennox-Gastaut syndrome, 9% of patients on fenfluramine 0.7 mg/kg/day (Study 3) and 6% of patients on fenfluramine 0.2 mg/kg/day (Study 3) experienced at least a 7% decrease in weight from baseline. Approximately half of the patients with Lennox-Gastaut syndrome and most patients with Dravet syndrome resumed the expected measured increases in weight during the open-label extension studies. Given the frequency of these adverse reactions, the growth of pediatric patients treated with fenfluramine should be carefully monitored. Weight should be monitored regularly during treatment with fenfluramine, and dose modifications should be considered if a decrease in weight is observed.

Somnolence, sedation, and lethargy

Fenfluramine can cause somnolence, sedation, and lethargy. In controlled studies for Dravet syndrome (Study 1 and Study 2 combined), the incidence of somnolence, sedation, and lethargy was 25% in patients treated with fenfluramine, compared with 11% of patients on placebo. In the controlled study for Lennox-Gastaut syndrome (Study 3), the incidence of somnolence, sedation, and lethargy was 19% in patients treated with fenfluramine, compared with 16% of patients on placebo. In general, these effects may diminish with continued treatment.

Other central nervous system depressants, including alcohol, could potentiate these effects of fenfluramine. Prescribers should monitor patients for somnolence and sedation and should advise patients not to drive or operate machinery until they have gained sufficient experience on fenfluramine to gauge whether it adversely affects their ability to drive or operate machinery.

Suicidal behavior and ideation

Antiseizure medications, including fenfluramine, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with an antiseizure medication for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, or any unusual changes in mood or behavior.

Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different antiseizure medications that did not include fenfluramine showed that patients randomized to one of the antiseizure medications had approximately twice the risk (adjusted relative risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 antiseizure medication-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.

The increased risk of suicidal thoughts or behavior with antiseizure medications was observed as early as 1 week after starting drug treatment with antiseizure medications and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.

The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with antiseizure medications of varying mechanisms of action and across a range of indications suggests that the risk applies to all antiseizure medications used for any indication. The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed. Table 3 shows absolute and relative risk by indication for all evaluated antiseizure medications.

Table 3. Risk of Suicidal Thoughts or Behaviors by Indication for Antiepileptic Drugs in the Pooled Analysis

The relative risk for suicidal thoughts or behavior was higher in clinical trials in patients with epilepsy than in clinical trials in patients with psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.

Anyone considering prescribing fenfluramine or any other antiseizure medication must balance the risk of suicidal thoughts or behaviors with the risk of untreated illness. Epilepsy and many other illnesses for which antiseizure medications are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

Withdrawal of antiseizure medications

As with most antiseizure medications, fenfluramine should generally be withdrawn gradually because of the risk of increased seizure frequency and status epilepticus. If withdrawal is needed because of a serious adverse reaction, rapid discontinuation can be considered.

Serotonin syndrome

Serotonin syndrome, a potentially life-threatening condition, may occur with fenfluramine, particularly with concomitant administration of fenfluramine with other serotonergic drugs, including, but not limited to, selective serotonin-norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors, tricyclic antidepressants, bupropion, triptans, dietary supplements (eg, St. John's Wort, tryptophan), drugs that impair metabolism of serotonin (including monoamine oxidase inhibitors, which are contraindicated with fenfluramine), dextromethorphan, lithium, tramadol, and antipsychotics with serotonergic agonist activity. Patients should be monitored for the emergence of signs and symptoms of serotonin syndrome, which include mental status changes (eg, agitation, hallucinations, coma), autonomic instability (eg, tachycardia, labile blood pressure, hyperthermia), neuromuscular signs (eg, hyperreflexia, incoordination), and/or gastrointestinal symptoms (eg, nausea, vomiting, diarrhea). If serotonin syndrome is suspected, treatment with fenfluramine should be stopped immediately, and symptomatic treatment should be started.

Increase in blood pressure

Fenfluramine can cause an increase in blood pressure. Rare cases of significant elevation in blood pressure, including hypertensive crisis, have been reported in adult patients treated with fenfluramine, including patients without a history of hypertension. In clinical trials of up to 3 years in duration, no pediatric or adult patient receiving fenfluramine developed a hypertensive crisis. Monitor blood pressure in patients treated with fenfluramine.

Glaucoma

Fenfluramine can cause mydriasis and can precipitate angle closure glaucoma. Consider discontinuing treatment with fenfluramine in patients with acute decreases in visual acuity or ocular pain.

Adverse reactions

The following clinically significant adverse reactions are described elsewhere in the labeling:

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.

In controlled and uncontrolled trials in patients with Dravet syndrome, 341 patients were treated with fenfluramine, including 312 patients treated for more than 6 months, 284 patients treated for more than 1 year, and 138 patients treated for more than 2 years.

In controlled and uncontrolled trials in patients with Lennox-Gastaut syndrome, 262 patients were treated with fenfluramine, including 219 patients treated for more than 6 months, 172 patients treated for more than 1 year, and 127 patients treated for more than 2 years.

Dravet syndrome. In placebo-controlled trials of patients with Dravet syndrome taking concomitant standard of care antiseizure medications, 122 patients were treated with fenfluramine and 84 patients received placebo. The duration of treatment in these trials was 16 weeks (Study 1) or 17 weeks (Study 2).

In Study 1 and Study 2, the mean age was 9 years (range 2 to 19 years), and approximately 46% of patients were female and 74% were White. All patients were receiving at least one other antiseizure medication.

In Study 1 and Study 2, the rates of discontinuation as a result of any adverse reaction were 13%, 0%, and 7% for patients treated with fenfluramine 0.7 mg/kg/day, 0.2 mg/kg/day, and 0.4 mg/kg/day in combination with stiripentol, respectively, compared to 6% for patients on placebo. The most frequent adverse reaction leading to discontinuation in the patients treated with any dose of fenfluramine was somnolence (3%).

The most common adverse reactions that occurred in patients treated with fenfluramine (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 fenfluramine 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 Fenfluramine and Greater Than Placebo in Placebo-Controlled Trials for Dravet Syndrome (Study 1 and 2)

Lennox-Gastaut syndrome. In the placebo-controlled trial of patients with Lennox-Gastaut syndrome taking concomitant standard of care antiseizure medications (Study 3), 176 patients were treated with fenfluramine, and 87 patients received placebo. The duration of treatment in this trial was 16 weeks. The mean age was 13.7 years (range 2 to 35 years), and 29% of patients were at least 18 years of age, 45% of patients were female, and 79% were White. All patients were receiving at least one other antiseizure medication.

The rates of discontinuation as a result of any adverse reaction were 6% and 5% for patients treated with fenfluramine 0.7 mg/kg/day and 0.2 mg/kg/day, respectively, compared to 1% for patients on placebo. The most frequent adverse reactions leading to discontinuation in the patients treated with any dose of fenfluramine were seizure (2%) and somnolence (2%).

The common adverse reactions that occurred in patients treated with fenfluramine (incidence at least 10% and greater than placebo) were diarrhea, decreased appetite, fatigue, somnolence, and vomiting.

Table 5 lists the adverse reactions that were reported in 5% or more of patients treated with fenfluramine and at a rate greater than those on placebo during the titration and maintenance phases of Study 3.

Table 5. Adverse Reactions in 5% or More of Patients Treated with Fenfluramine and Greater Than Placebo in the Placebo-Controlled Trial for Lennox Gastaut Syndrome (Study 3)

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 patients with Dravet syndrome and 263 patients with Lennox-Gastaut syndrome. Screening for valvular heart disease assessed for mild or greater aortic regurgitation or moderate or greater mitral regurgitation, and assessed for additional characteristics of valvular heart disease (eg, valve thickening or restrictive valve motion).

In these clinical studies, two patients with Lennox-Gastaut syndrome exhibited mild aortic regurgitation, but neither patient had any cardiac signs or symptoms or evidence of valvular structural changes. Neither patient had valvular heart disease. The rates of mild aortic regurgitation are consistent with those seen in the screening period prior to treatment (three patients in Lennox-Gastaut syndrome and one patient in Dravet syndrome clinical trials).

Postmarketing experience

The following adverse reactions have been identified during postapproval use of fenfluramine. 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.

Drug interactions

Effect of other drugs on fenfluramine

Stiripentol plus clobazam. Coadministration of fenfluramine with stiripentol plus clobazam, with or without valproate, increases fenfluramine plasma concentrations. If fenfluramine is coadministered with stiripentol plus clobazam, the maximum daily dosage of fenfluramine is 0.2 mg/kg twice daily (maximum daily dosage of 17 mg).

Strong CYP1A2, CYP2B6, or CYP3A inducers. Coadministration of fenfluramine with strong CYP1A2, CYP2B6, or CYP3A inducers will decrease fenfluramine plasma concentrations, which may lower the efficacy of fenfluramine.

It is recommended to avoid coadministration of strong CYP1A2, CYP2B6, or CYP3A inducers. If coadministration of a strong CYP1A2, CYP2B6, or CYP3A inducer with fenfluramine is necessary, monitor the patient for reduced efficacy and consider increasing the fenfluramine dosage as needed; however, do not exceed the maximum daily dosage of fenfluramine.

If a strong CYP1A2, CYP2B6, or CYP3A inducer is discontinued during maintenance treatment with fenfluramine, consider a gradual reduction in the fenfluramine dosage to the dose administered prior to initiating the inducer.

Strong CYP1A2 or CYP2D6 inhibitors. Coadministration of fenfluramine with strong CYP1A2 or CYP2D6 inhibitors will increase fenfluramine plasma concentrations. If fenfluramine is coadministered with strong CYP1A2 or CYP2D6 inhibitors, the maximum daily dosage of fenfluramine is 20 mg.

If a strong CYP1A2 or CYP2D6 inhibitor is discontinued during maintenance treatment with fenfluramine, consider a gradual increase in the fenfluramine dosage to the dose recommended without CYP1A2 or CYP2D6 inhibitors; however, do not exceed the maximum daily dosage of fenfluramine.

If fenfluramine is coadministered with stiripentol and a strong CYP1A2 or CYP2D6 inhibitor, do not exceed the maximum daily dosage of fenfluramine 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 fenfluramine. If cyproheptadine or potent 5-HT1A, 5-HT1D, 5-HT2A, or 5-HT2C serotonin receptor antagonists are coadministered with fenfluramine, patients should be monitored appropriately.

Serotonergic drugs

Concomitant administration of fenfluramine and drugs (eg, SSRIs, SNRIs, TCAs, MAO inhibitors, trazodone, etc.), over-the-counter medications (eg, dextromethorphan), or herbal supplements (eg, St. John's Wort) that increase serotonin may increase the risk of serotonin syndrome. Concomitant use of fenfluramine is contraindicated within 14 days of taking MAOIs. Use fenfluramine with caution in patients taking other medications that increase serotonin.

Use in specific populations

Pregnancy

Pregnancy exposure registry. There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiseizure medications, such as fenfluramine, during pregnancy. Encourage women who are taking fenfluramine 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 www.aedpregnancyregistry.org.

Risk summary. There are no data on fenfluramine 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. Fenfluramine 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).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defects, 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 two and five 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 three 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 fenfluramine and any potential adverse effects on the breastfed infant from fenfluramine 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.

Pediatric use

The safety and effectiveness of fenfluramine for the treatment of seizures associated with Dravet syndrome and Lennox-Gastaut syndrome have been established in patients 2 years of age and older.

Use of fenfluramine for the treatment of seizures associated with Dravet syndrome 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 fenfluramine for the treatment of seizures associated with Lennox-Gastaut syndrome 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.

Fenfluramine can cause decreases in appetite and weight. The growth of pediatric patients treated with fenfluramine 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 two times that in humans at the MRHD.

Geriatric use

Clinical studies of fenfluramine for the treatment of Dravet syndrome or Lennox-Gastaut syndrome 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 fenfluramine 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 fenfluramine of 17 mg. Fenfluramine 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.

Overdosage

Overdose has not been observed in the fenfluramine clinical trial program. However, overdose of fenfluramine, the active ingredient in fenfluramine, 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, or muscle spasms; agitation, restlessness, or anxiety; increased muscle tone, rigor, or 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 fenfluramine. 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 fenfluramine.

Clinical pharmacology

Mechanism of action

The precise mechanism by which fenfluramine exerts its therapeutic effects in the treatment of seizures associated with Dravet syndrome and Lennox-Gastaut syndrome is unknown. Fenfluramine and the metabolite, norfenfluramine, exhibit agonist activity at serotonin 5-HT2 receptors. There is an association between serotonergic drugs with 5-HT2B receptor agonist activity, including fenfluramine and norfenfluramine, and valvular heart disease and pulmonary arterial hypertension.

Pharmacodynamics

Cardiac electrophysiology. At a dose four times the maximum recommended dose, fenfluramine did not prolong the QT interval when tested in an adult population.

Pharmacokinetics

The pharmacokinetics of fenfluramine and norfenfluramine were studied in healthy subjects, in pediatric patients with Dravet syndrome, and in pediatric and adult patients with Lennox-Gastaut syndrome. The steady-state systemic exposure (C_max and AUC) of fenfluramine was slightly greater than dose proportional over the dose range of 13 to 51.8 mg twice-daily fenfluramine (ie, one to four times the maximum recommended dose). In pediatric patients with Dravet syndrome who received fenfluramine 0.7 mg/kg/day, up to a total daily dose of 26 mg fenfluramine, the geometric mean steady-state fenfluramine (coefficient of variation) C_max was 68.0 (41%) ng/mL and AUC_0-24h was 1390 (44%) ng*h/mL.

Absorption. Fenfluramine has a time to maximum plasma concentration (T_max) of 3 to 5 hours at steady state. The absolute bioavailability of fenfluramine is approximately 68% to 74%. There was no effect of food on the pharmacokinetics of fenfluramine or norfenfluramine.

Distribution. The geometric mean (CV%) apparent volume of distribution (Vz/F) of fenfluramine is 11.9 (16.5%) L/kg following oral administration of fenfluramine in healthy subjects. Fenfluramine is 50% bound to human plasma proteins in vitro, and binding is independent of drug concentrations.

Elimination. The elimination half-life of fenfluramine was 20 hours, and the geometric mean (CV%) clearance (CL/F) was 24.8 (29%) L/h, following oral administration of fenfluramine in healthy subjects.

Metabolism. Over 75% of fenfluramine is metabolized to norfenfluramine prior to elimination, primarily by CYP1A2, CYP2B6, and CYP2D6. Other CYP enzymes involved to a minor extent are CYP2C9, CYP2C19, and CYP3A4/5. Both fenfluramine and norfenfluramine are pharmacologically active. Norfenfluramine is further deaminated and oxidized to form inactive metabolites.

Excretion. Most of an orally administered dose of fenfluramine (greater than 90%) 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.

Specific populations. The effect of age (range: 2 to 50 years), sex, and race had no clinically meaningful effect on the pharmacokinetics of fenfluramine.

Patients with renal impairment. In a dedicated clinical study comparing the pharmacokinetics of a single dose of 0.35 mg/kg fenfluramine in subjects with severe renal impairment (eGFR < 30 mL/min/1.73m2 determined by MDRD) and matched healthy volunteers, C_max and AUC_0-inf of fenfluramine increased by 20% and 88%, respectively, and C_max and AUC_0-inf of norfenfluramine increased by 13% and 21%, respectively in subjects with severe renal impairment. Fenfluramine has not been studied in patients with eGFR < 15 mL/min/1.73m2 (determined by MDRD). It is not known if fenfluramine or norfenfluramine is dialyzable.

Patients with hepatic impairment. In a study comparing the pharmacokinetics of a single dose of 0.35 mg/kg fenfluramine in subjects with mild, moderate, or severe hepatic impairment (Child-Pugh Class A, B, or C) and subjects with normal liver function, AUC0-t of fenfluramine increased by 95%, 113%, and 185% in subjects with mild, moderate, and severe hepatic impairment, respectively. C_max of fenfluramine increased by 19%, 16%, and 29% in subjects with mild, moderate, and severe hepatic impairment, respectively. AUC0-t of norfenfluramine increased by 18% in mild hepatic impairment, 4% in moderate hepatic impairment, and decreased by 11% in severe hepatic impairment. C_max of norfenfluramine decreased by 21%, 36%, and 45% in subjects with mild, moderate, and severe hepatic impairment, respectively. Combined molar AUC0-t of fenfluramine and norfenfluramine increased by 55%, 56%, and 82% in subjects with mild, moderate, and severe hepatic impairment, respectively. Combined molar C_max of fenfluramine and norfenfluramine increased by 7.5%, 1.3%, and 8% in subjects with mild, moderate, and severe hepatic impairment, respectively. The maximum daily dosage of fenfluramine should be reduced in patients with mild hepatic impairment with/without stiripentol plus clobazam. The maximum daily dosage of fenfluramine should be reduced in patients with moderate or severe hepatic impairment without stiripentol plus clobazam.

Drug interaction studies.

Clinical studies. Effect of a single dose of stiripentol, clobazam, and valproic acid combination:

Coadministration of a single 0.7 mg/kg dose of fenfluramine, with a single dose of a stiripentol, clobazam, and valproic acid combination in healthy volunteers, increased the AUC_0-inf of fenfluramine by 69% and the C_max by 18%, and decreased the AUC0-72 hours of norfenfluramine by 41% and the C_max by 42%, as compared to fenfluramine administered alone.

Effect of steady state stiripentol plus clobazam, with or without valproate. Fenfluramine pharmacokinetic data were collected from patients after receiving multiple fenfluramine administrations in Study 1 as well as Study 2. Population pharmacokinetic modeling and simulation were used to assess the effect of stiripentol plus clobazam with or without valproate on fenfluramine pharmacokinetics. The effect of stiripentol plus clobazam, with or without valproate, on fenfluramine pharmacokinetics is greater when fenfluramine is at steady-state than for the first dose of fenfluramine. At steady state in the patient population, the coadministration of 0.1 mg/kg twice daily (0.2 mg/kg/day), maximum 17 mg/day, of fenfluramine with stiripentol plus clobazam with or without valproate, is expected to result in a 166% increase in fenfluramine AUC_0-24 and a 38% decrease in norfenfluramine AUC_0-24, as compared to 0.2 mg/kg/day, maximum 26 mg/day, fenfluramine dose administered alone.

Effect of steady state cannabidiol. Coadministration of a single 0.35 mg/kg dose of fenfluramine with repeated doses of cannabidiol increased the AUC_0-inf of fenfluramine by 59% and the C_max by 10%, and decreased the AUC_0-inf of norfenfluramine by 22% and the C_max by 33%, as compared to fenfluramine administered alone. This interaction is not expected to be clinically significant.

Effect of strong CYP1A2 or CYP2D6 inhibitors. Coadministration of a single 0.35 mg/kg dose of fenfluramine with fluvoxamine (a strong CYP1A2 inhibitor) at steady state (50 mg once daily) in healthy volunteers increased the AUC0- inf of fenfluramine by 102% and the Cmax by 22%, and decreased the AUC_0-inf of norfenfluramine by 22% and the C_max by 44%, as compared to fenfluramine administered alone.

Coadministration of a single 0.35 mg/kg dose of fenfluramine with paroxetine (a strong CYP2D6 inhibitor) at steady state (30 mg once daily) in healthy volunteers increased the AUC_0-inf of fenfluramine by 81% and the C_max by 13%, and decreased the AUC_0-inf of norfenfluramine by 13% and the C_max by 29%, as compared to fenfluramine administered alone.

Effect of strong CYP1A2, CYP2B6, or CYP3A inducers. Coadministration of a single 0.35 mg/kg dose of fenfluramine with rifampin (a CYP1A2, CYP2B6, and CYP3A inducer) at steady state (600 mg once daily) in healthy volunteers decreased the AUC_0-inf of fenfluramine by 58% and the C_max by 40%, and decreased the AUC_0-inf of norfenfluramine by 50%, and increased the C_max of norfenfluramine by 13%, as compared to fenfluramine administered alone.

Effect of fenfluramine on other drugs. Coadministration of a single 0.7 mg/kg dose of fenfluramine, with a single dose of a stiripentol, clobazam, and valproic acid combination, did not affect the pharmacokinetics of stiripentol, nor the pharmacokinetics of clobazam or its N‑desmethyl-metabolite norclobazam, nor the pharmacokinetics of valproic acid, as compared to the stiripentol, clobazam, and valproic acid combination alone. Coadministration of a single 0.35 mg/kg dose of fenfluramine, with repeated doses of cannabidiol, did not affect the pharmacokinetics of cannabidiol, as compared to cannabidiol alone.

In vitro studies. Fenfluramine is primarily metabolized by CYP1A2, CYP2B6, and CYP2D6 in vitro. Other CYP enzymes involved to a minor extent are CYP2C9, CYP2C19, and CYP3A4/5.

Effect of fenfluramine and norfenfluramine on CYP substrates. Fenfluramine and norfenfluramine are not inhibitors or inducers of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4 at clinically relevant concentrations.

Effect of transporters on fenfluramine and norfenfluramine. Fenfluramine and norfenfluramine are not substrates of the P-g, BCRP, OAT1, OAT3, OCT2, MATE1, or MATE2-K transporters.

Effect of fenfluramine on transporters. Fenfluramine and norfenfluramine are not inhibitors of P-gp, BCRP, OAT1B1, OATP1B3, OAT1, OAT3, OCT2, MATE1, or MATE2-K transporters.

Nonclinical toxicology

Carcinogenesis, mutagenesis, and impairment of fertility

Carcinogenesis. Oral administration of fenfluramine to Tg.rasH2 mice (0, 4.3, 13.0, 34.6, or 51.8 mg/kg/day) for 26 weeks and to male and female rats (0, 0.9, 2.2, or 6.9 mg/kg/day) for 89 and 97 weeks, respectively, resulted in no evidence of drug-induced tumors in either species. In rats, plasma exposures (AUC) of fenfluramine and norfenfluramine (the major metabolite) at the highest dose tested were approximately five and 11 times, respectively, those in humans at the maximum recommended human dose (MRHD) of 26 mg/day.

Mutagenesis. Fenfluramine was negative in an in vitro bacterial mutation (Ames) assay and an in vivo micronucleus and comet assay in rats.

Impairment of fertility. Oral administration of fenfluramine (0, 3.0, 6.9, or 17.3 mg/kg/day) to male and female rats prior to and throughout mating and continuing in females to day 7 of gestation resulted in a decrease in fertility and increases in abnormal sperm and epithelial vacuolation of the epididymis at the highest dose tested and altered estrous cyclicity, decreased corpora lutea and implantations, and increased embryolethality at the mid and high dose. These doses were associated with parental toxicity. The no-effect doses for adverse effects on fertility and reproductive performance in rats (6.9 and 3.0 mg/kg/day in males and females, respectively) were associated with plasma fenfluramine exposures (AUC) approximately three and 0.6 times, respectively, and norfenfluramine exposures approximately five and three times, respectively, those in humans at the MRHD.

Clinical studies

Dravet syndrome

The effectiveness of fenfluramine for the treatment of seizures associated with Dravet syndrome in patients 2 years of age and older was established in two randomized, double-blind, placebo-controlled trials in patients 2 to 18 years of age.

Study 1 (N=117) compared a 0.7 mg/kg/day and a 0.2 mg/kg/day dose of fenfluramine with placebo in patients who were not receiving stiripentol (NCT02682927 and NCT02826863). Study 2 (N=85) compared a 0.4 mg/kg/day dose of fenfluramine with placebo in patients who were receiving stiripentol and either clobazam, valproate, or both (NCT02926898). In both studies, patients had a clinical diagnosis of Dravet syndrome and were inadequately controlled on at least one antiseizure medication or other antiseizure treatment, including vagal nerve stimulation or a ketogenic diet. Both trials had a 6-week baseline period, during which patients were required to have a minimum of six convulsive seizures while on stable antiseizure medication therapy. Convulsive seizures included tonic, clonic, generalized tonic-clonic, tonic-atonic, secondarily generalized tonic-clonic, hemiclonic, and focal with observable motor signs. The baseline period was followed by randomization into a 2-week (Study 1) or 3-week (Study 2) titration period and a subsequent 12-week maintenance period, where the dose of fenfluramine remained stable.

In Study 1, 98% of patients were taking between one and four concomitant antiseizure medications. The most frequently used concomitant antiseizure medications (in at least 25% of patients) were valproate (61%), clobazam (59%), and topiramate (25%). In Study 2, 100% of patients were taking between two and four concomitant antiseizure medications. The most frequently used concomitant antiseizure medications (in at least 25% of patients) were stiripentol (100%), clobazam (94%), and valproate (89%).

The primary efficacy endpoint in both studies was the change from baseline in the frequency of convulsive seizures per 28 days during the combined 14-week (Study 1) or 15-week (Study 2) titration and maintenance periods (ie, treatment period). The median longest interval between convulsive seizures was also assessed.

In Study 1 and Study 2, the reduction in convulsive seizure frequency per 28 days was statistically significantly greater for all dose groups of fenfluramine compared to placebo. A reduction in convulsive seizures was observed within 3 to 4 weeks of starting fenfluramine, and the effect remained generally consistent over the 14- or 15-week treatment period.

See Table 6 and Figures 1, 2, and 3 in the DAILYMED drug label information for data regarding seizure response in patients with Dravet syndrome treated with fenfluramine compared to placebo.

Lennox-Gastaut syndrome

The effectiveness of fenfluramine for the treatment of seizures associated with Lennox-Gastaut syndrome in patients 2 years of age and older was established in a randomized, double-blind, placebo-controlled study in 263 patients 2 to 35 years of age (Study 3; NCT03355209).

Study 3 compared a 0.7 mg/kg/day and a 0.2 mg/kg/day dose of fenfluramine with placebo. Patients had a diagnosis of Lennox-Gastaut syndrome and were inadequately controlled on at least one antiseizure medication, with or without vagal nerve stimulation and/or ketogenic diet. The study had a 4-week baseline period, during which patients were required to have a minimum of eight drop seizures while on stable antiseizure medication therapy. Drop seizures were generalized tonic-clonic, secondarily generalized tonic-clonic, tonic, atonic, or tonic-atonic seizures that were confirmed to result in drops. The baseline period was followed by randomization into a 2-week titration period and a subsequent 12-week maintenance period, where the dose of fenfluramine remained stable.

In Study 3, 99% of patients were taking between one and four concomitant antiseizure medications. The most frequently used concomitant antiseizure medications (in at least 25% of patients) were clobazam (45%), lamotrigine (34%), and valproate (56%).

The primary efficacy endpoint in Study 3 was the median percent change from baseline in the frequency of drop seizures per 28 days during the combined 14-week titration and maintenance periods (ie, treatment period). The proportion of patients who achieve improvement (minimally, much, or very much improved) in the Clinical Global Impression of Change (CGI-I) as assessed by the principal investigator was a secondary endpoint.

In Study 3, the median percent change from baseline (reduction) in the frequency of drop seizures per 28 days was significantly greater for the 0.7 mg/kg/day dose group of fenfluramine compared with placebo. A reduction in drop seizures was observed within 2 weeks of initiating treatment with fenfluramine, and the effect remained generally consistent over the 14-week treatment period.

The median percent reduction from baseline in drop seizure frequency per 28 days for the lower dose of fenfluramine (0.2 mg/kg/day) did not reach statistical significance compared to placebo.

See Table 7 and Figure 4 in the DAILYMED drug label information for data regarding seizure response in patients with Lennox-Gastaut syndrome treated with fenfluramine compared to placebo.

How supplied/storage and handling

How supplied

Fenfluramine oral solution is a clear, colorless, cherry-flavored liquid containing 2.2 mg/mL fenfluramine and is supplied in a white plastic bottle with a child-resistant closure as follows:

Before dispensing, the pharmacist will insert a press-in bottle adapter into the dispensing bottle. The pharmacy will provide 3 or 6 mL calibrated oral dosing syringes.

Storage and handling

Store fenfluramine at room temperature between 20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C to 30°C (59°F to 86°F).

Do not refrigerate or freeze. Store the bottle and syringe together.

Discard any unused portion 3 months after first opening the bottle or the "Discard After" date on the bottle, whichever is sooner.

Patient counseling information

Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).

Administration information. Advise patients who are prescribed fenfluramine to use the oral dosing syringes provided by the pharmacy. Instruct patients to discard any unused fenfluramine 3 months after first opening the bottle or if the "discard after" date on the dispensing bottle has passed, whichever is sooner.

Valvular heart disease and pulmonary arterial hypertension. Advise patients that cardiac monitoring must be performed using echocardiography to monitor for serious heart valve changes or high blood pressure in the arteries of the lungs.

Fenfluramine risk evaluation and mitigation strategy program. Fenfluramine is available only through a restricted program called the fenfluramine risk evaluation and mitigation strategy program. Inform the patient of the following notable requirements:

Fenfluramine is only prescribed by certified health care providers and only dispensed from certified pharmacies participating in the program. Therefore, provide patients with the telephone number and website for information on how to obtain the product.

Decreased appetite and decreased weight. Advise patients that decreased appetite is frequent during treatment with fenfluramine, which can cause a decrease in weight.

Somnolence, sedation, and lethargy. Inform patients that fenfluramine can cause somnolence, sedation, and lethargy. Caution patients about operating hazardous machinery, including motor vehicles, until they are reasonably certain that fenfluramine does not affect them adversely (eg, impair judgment, thinking, or motor skills).

Suicidal thinking and behavior. Counsel patients, their caregivers, and their families that antiseizure medications may increase the risk of suicidal thoughts and behavior and advise them to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts of self-harm. Instruct patients, caregivers, and families to report behaviors of concern immediately to healthcare providers.

Withdrawal of antiseizure medications. Advise patients not to discontinue use of fenfluramine without consulting their healthcare provider. Fenfluramine should normally be gradually withdrawn to reduce the potential for increased seizure frequency and status epilepticus.

Serotonin syndrome. Inform patients about the risk of serotonin syndrome, which can be life-threatening. Advise patients on the signs and symptoms of serotonin syndrome and that certain over-the-counter medications and herbal supplements can increase this risk.

Increase in blood pressure. Inform patients that fenfluramine can cause an increase in blood pressure.

Glaucoma. Inform patients that fenfluramine can cause mydriasis and can precipitate angle closure glaucoma. Instruct patients to contact their healthcare provider if they have any acute decreases in visual acuity or ocular pain.

Pregnancy registry. Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during fenfluramine therapy. Encourage women who are taking fenfluramine to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiseizure medications during pregnancy.

Medication guide

See the Medication guide section of the DAILYMED drug label information.

Acknowledgement

This article was excerpted from U.S. FDA Drug Labeling information available on the DailyMed website.