AHFS Class:

• Anticonvulsants, Miscellaneous 28:12.92

Generic Name(s):

• Fenfluramine hydrochloride

Chemical Name:

• N-ethyl-α-methyl-3-(trifluoromethyl) phenethylamine hydrochloride

Molecular Formula:

• C₁₂H₁₆F₃N

Fenfluramine hydrochloride, an amphetamine derivative with serotonergic effects, is an anticonvulsant agent.1,5,6,7,13

Seizure Disorders

Seizures Associated with Dravet Syndrome

Fenfluramine hydrochloride oral solution is used for the treatment of seizures associated with Dravet syndrome in patients 2 years of age or older.1,3,4 Fenfluramine is designated an orphan drug by FDA for use in this condition.2

Dravet syndrome (also known as severe myoclonic epilepsy of infancy) is a rare and severe type of epilepsy characterized by early onset of multiple refractory seizure types, frequent episodes of status epilepticus, and developmental delay with cognitive and psychomotor impairment.4,9,10,15 Up to 85% of patients have mutations in the SCN1A gene encoding the voltage-gated sodium channel.4,9,10 Seizures in patients with Dravet syndrome are generally refractory to current anticonvulsant drug options; certain anticonvulsants (e.g., carbamazepine, oxcarbazepine, lamotrigine, phenytoin, vigabatrin) may exacerbate the condition and should be avoided.4,9,10 Although evidence from controlled studies is limited,14,15 experts generally recommend initial treatment with either clobazam† or valproic acid†, followed by a combination of both drugs; however, adequate seizure control is rarely achieved with these drugs alone, and most patients will require additional anticonvulsant agents.10,14 Complete seizure freedom is typically not achievable; therefore, treatment is generally aimed at reducing the frequency of the most problematic seizures (e.g., convulsive seizures, status epilepticus) while minimizing adverse effects of anticonvulsant therapy.10,14 (See Dravet Syndrome under Uses: Epilepsy Syndromes, in the Anticonvulsants General Statement 28:12.)

The current indication for fenfluramine is based principally on 2 randomized, double-blind, placebo-controlled studies in patients 2-18 years of age with Dravet syndrome who had inadequately controlled seizures despite therapy with at least one anticonvulsant or other antiseizure therapy (e.g., vagal nerve stimulation, ketogenic diet).1,3,4 Patients experiencing at least 6 convulsive seizures during a 6-week baseline period were randomized to receive fenfluramine or placebo in addition to their existing treatment regimen.1,3,4 The first study compared fenfluramine dosages of 0.2 and 0.7 mg/kg daily with placebo in patients who were not receiving stiripentol; the second study compared fenfluramine 0.4 mg/kg daily with placebo in patients who were receiving stiripentol in addition to either clobazam or valproate (or both).1 Dosage of fenfluramine was titrated over the course of 2 or 3 weeks depending on the study and maintained at the target dosage for 12 weeks.1 The primary efficacy outcome of both studies was the percent change from baseline in monthly (e.g., over 28 days) frequency of convulsive seizures (i.e., tonic, clonic, generalized tonic-clonic, tonic-atonic, secondarily generalized tonic-clonic, hemiclonic, focal with observable motor signs) during the treatment period.1,3,4

In both studies, fenfluramine (at all dosages evaluated) substantially reduced convulsive seizure frequency compared with placebo (median reductions relative to placebo of 31.7, 59.5, and 70% with dosages of 0.2, 0.4, and 0.7 mg/kg daily, respectively).1 Seizure freedom was achieved in 3 of 40 patients (8%) in the fenfluramine 0.7 mg/kg daily group, in 3 of 38 patients (8%) in the fenfluramine 0.2 mg/kg daily group, and in 1 of 43 patients (2%) in the fenfluramine 0.4 mg/kg daily group compared with no patients in any of the placebo groups.1 The treatment effect was observed within 3-4 weeks of initiating fenfluramine and generally maintained over the 14- or 15-week treatment period.1 Across both studies, a greater proportion of fenfluramine-treated patients had reductions in seizure frequency of 50% or greater compared with those receiving placebo.1 In addition, patients receiving fenfluramine had a longer interval between convulsive seizures compared with those receiving placebo.1

General

Because of the risk of valvular heart disease and pulmonary arterial hypertension, regular echocardiographic evaluations should be performed during fenfluramine therapy.1 An echocardiogram should be obtained prior to initiating therapy, every 6 months during treatment, and then once 3-6 months after the drug is discontinued.1 (See Valvular Heart Disease and Pulmonary Arterial Hypertension under Warnings/Precautions: Warnings, in Cautions.)

Fenfluramine should be withdrawn gradually to minimize the potential for increased seizure frequency and status epilepticus.1 (See Discontinuance of Therapy under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Patients receiving therapy with an anticonvulsant, including fenfluramine, for any indication should be closely monitored for the emergence or worsening of depression, suicidal thoughts or behavior (suicidality), or any unusual changes in mood or behavior.1 (See Suicidality Risk under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Restricted Distribution Program

Because of the risk of valvular heart disease and pulmonary arterial hypertension, fenfluramine is available only through a restricted distribution program called the Fintepla Risk Evaluation and Mitigation Strategy (REMS) program.1 Clinicians and patients must enroll in the Fintepla REMS program and comply with all requirements, including educational and monitoring components.1 Pharmacies must be certified by enrolling in the program and must only dispense to patients who are authorized to receive the drug.1

Additional information about the Fintepla REMS program is available at [Web] or 1-877-964-3649.1

Administration

Fenfluramine is administered orally twice daily as an oral solution.1 The drug may be administered with or without food.1

A calibrated measuring device (i.e., either a 3- or 6-mL oral dosing syringe) should be used to measure and administer the prescribed dose of fenfluramine oral solution; a household teaspoon or tablespoon is not an adequate measuring device.1 Any unused portions of the oral solution should be discarded 3 months after the bottle is first opened or if the “discard after” date has passed, whichever is sooner.1

Fenfluramine oral solution is compatible with commercially available gastric and nasogastric feeding tubes.1

Dosage

Dosage of fenfluramine hydrochloride is expressed in terms of fenfluramine.1

The initial starting and maintenance dosage of fenfluramine for the treatment of seizures associated with Dravet syndrome in adults and pediatric patients 2 years of age or older is 0.1 mg/kg twice daily.1 Dosage may be increased weekly based on efficacy and tolerability.1

If dosage titration is necessary in patients not receiving concomitant stiripentol, the manufacturer recommends an increase to 0.2 mg/kg twice daily on day 7, and then to 0.35 mg/kg twice daily on day 14 if further increase is needed; the maximum total daily dosage is 26 mg in these patients.1 For patients not receiving concomitant stiripentol in whom a more rapid titration is warranted, the dose may be increased every 4 days.1

If dosage titration of fenfluramine is necessary in patients receiving stiripentol and clobazam concomitantly, the manufacturer recommends an increase to 0.15 mg/kg twice daily on day 7, and then to 0.2 mg/kg twice daily on day 14 if further increase is needed; the maximum total daily dosage is 17 mg in these patients.1

Contraindications

Fenfluramine is contraindicated in patients with hypersensitivity to fenfluramine or any excipients in the preparation.1

Fenfluramine is contraindicated during or within 14 days of administration of monoamine oxidase (MAO) inhibitors due to increased risk of serotonin syndrome.1 (See Serotonin Syndrome under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Warnings/Precautions

Warnings

Valvular Heart Disease and Pulmonary Arterial Hypertension

Serotonergic drugs with 5-HT_2B receptor agonist activity, including fenfluramine, have been associated with valvular heart disease and pulmonary arterial hypertension (PAH).1,11,13 Fenfluramine was previously approved and used as an appetite suppressant to treat obesity in adults, but was voluntarily withdrawn from the US market by the manufacturer in November 1997 following reports of cardiac valvulopathy and primary pulmonary hypertension associated with the drug.7,11,13 The dosages of fenfluramine used in these individuals were generally higher than those used in patients with epilepsy.7,8,13 No cases of valvular heart disease or PAH have been reported to date in patients with Dravet syndrome receiving fenfluramine in clinical studies of up to 3 years' duration.1,3,8 However, precautions are required when fenfluramine is used to minimize the potential for these risks.1

Prior to initiating fenfluramine therapy, patients must have an echocardiogram performed to evaluate for valvular heart disease and PAH.1 Echocardiograms should be repeated every 6 months during therapy, and then once 3-6 months after the drug is discontinued.1 Echocardiographic assessments can identify evidence of valvulopathy or PAH prior to the development of symptoms, and thereby assist in early detection of these conditions.1 If the echocardiogram reveals any evidence of valvular heart disease or PAH, the benefits versus risks of initiating or continuing treatment with fenfluramine should be considered.1 Fenfluramine is available only through a restricted distribution program to mitigate the risk of valvular heart disease and PAH.1 (See Restricted Distribution Program under Dosage and Administration: General.)

Other Warnings and Precautions

Decreased Appetite and Weight Loss

Fenfluramine can cause decreased appetite and weight loss.1 In the principal efficacy studies of the drug in patients with Dravet syndrome, decreased appetite (37 versus 8%) and decreased weight (9 versus 1%) were reported more frequently in patients receiving fenfluramine than in those receiving placebo.1 By the end of the controlled studies, 19% of patients treated with fenfluramine had a measured decrease in weight of 7% or greater from their baseline weight compared with 2% of patients treated with placebo.1 The effects of the drug on weight appeared to be dose related.1

The patient's weight should be monitored regularly during therapy and dosage modifications should be considered if a decrease in weight occurs.1 In addition, growth rate in pediatric patients should be carefully monitored.1

Somnolence and Sedation

Fenfluramine can cause somnolence, sedation, and lethargy.1 In the principal efficacy studies, 25% of patients who received fenfluramine reported these adverse effects compared with 11% of those who received placebo.1 Such effects may diminish with continued treatment.1

Other CNS depressants, including alcohol, may potentiate these effects of fenfluramine.1 Patients should be monitored for somnolence and sedation and should be advised not to drive or operate machinery until they have gained sufficient experience with the drug.1

Suicidality Risk

The risk of suicidality (suicidal behavior or ideation) is increased in patients receiving anticonvulsants for any indication.1 An analysis of 199 placebo-controlled studies involving 11 different anticonvulsants in patients with epilepsy, psychiatric disorders, and other conditions found that patients receiving anticonvulsants had approximately twice the risk of suicidal behavior or ideation (0.43%) compared with patients receiving placebo (0.24%).1 This increased suicidality risk was consistent among anticonvulsants with varying mechanisms of actions and across a range of indications, and was observed as early as 1 week after beginning therapy.1 Because most of these studies did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior with anticonvulsant treatment beyond 24 weeks is not known.1 Although patients treated with an anticonvulsant for epilepsy, psychiatric disorders, and other conditions were all found to have an increased suicidality risk compared with those receiving placebo, the relative risk was higher for patients with epilepsy compared with those receiving anticonvulsants for other conditions.1

Clinicians who prescribe fenfluramine or any other anticonvulsant should balance the risk of suicidality with the risk of untreated illness.1 Epilepsy and many other illnesses for which anticonvulsants are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior.1 All patients treated with an anticonvulsant for any indication should be closely monitored for the emergence or worsening of suicidal thoughts and behavior.1 If any such symptoms emerge during anticonvulsant therapy, the clinician should consider whether they may be related to the illness being treated.1 (See Advice to Patients.)

Discontinuance of Therapy

As with most anticonvulsant agents, fenfluramine therapy should be withdrawn gradually to reduce the risk of increased seizure frequency and status epilepticus.1 Rapid discontinuance of the drug may be considered for safety concerns (e.g., occurrence of a serious adverse event).1

Serotonin Syndrome

Potentially life-threatening serotonin syndrome may occur with fenfluramine, particularly when used concomitantly with other serotonergic drugs including, but not limited to, selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs), selective serotonin-reuptake inhibitors (SSRIs), tricyclic antidepressants, bupropion, serotonin (5-hydroxytryptamine; 5-HT) type 1 receptor agonists (“triptans”), dietary supplements (e.g., St. John's wort, tryptophan), drugs that impair metabolism of serotonin (e.g., monoamine oxidase [MAO] inhibitors), dextromethorphan, lithium, tramadol, and antipsychotic agents with serotonergic agonist activity.1 (See Cautions: Contraindications.)

Patients should be monitored for the emergence of signs and symptoms of serotonin syndrome, which may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination), and/or GI symptoms (e.g., nausea, vomiting, diarrhea).1 If serotonin syndrome is suspected, fenfluramine should be discontinued immediately and symptomatic treatment should be initiated. 1

Increased Blood Pressure

Fenfluramine can cause an increase in blood pressure.1 Substantial elevations in blood pressure, including hypertensive crisis, have been reported rarely in adults receiving fenfluramine, including those without a history of hypertension.1 Hypertensive crisis has not been reported in any patient receiving fenfluramine in clinical trials of up to 3 years' duration.1

Blood pressure should be monitored in patients receiving fenfluramine.1

Glaucoma

Fenfluramine can cause mydriasis and precipitate angle closure glaucoma.1 Discontinuance of therapy should be considered in patients with acute decreases in visual acuity or ocular pain.1

Abuse Potential and Dependence

Fenfluramine is subject to control under the Federal Controlled Substances Act of 1970 as a schedule IV (C-IV) drug.1

Specific Populations

Pregnancy

There are no adequate human or animal data on the developmental risks associated with the use of fenfluramine in pregnant women.1

Women who are pregnant while receiving fenfluramine should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry at 888-233-2334 or [Web].1

Lactation

It is not known whether fenfluramine or its metabolites are distributed into milk, or if the drug affects milk production or the breast-fed infant.1 The benefits of breast-feeding should be considered along with the importance of fenfluramine to the woman and any potential adverse effects on the breast-fed infant from the drug or underlying maternal condition.1

Pediatric Use

Safety and efficacy of fenfluramine in pediatric patients younger than 2 years of age have not been established.1

Geriatric Use

Clinical studies of fenfluramine for the treatment of Dravet syndrome did not include patients 65 years of age and over to determine whether they respond differently from younger patients.1 In general, dosage selection in geriatric patients 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.1

Hepatic Impairment

Use of fenfluramine in patients with hepatic impairment is not recommended.1

Renal Impairment

Use of fenfluramine in patients with moderate or severe renal impairment is not recommended.1

Common Adverse Effects

Adverse effects reported in at least 10% of patients with Dravet syndrome receiving fenfluramine in clinical trials and more frequently than placebo include decreased appetite, somnolence, sedation, lethargy, diarrhea, constipation, abnormal echocardiogram, fatigue, malaise, asthenia, ataxia, balance disorder, gait disturbance, increased blood pressure, drooling, salivary hypersecretion, pyrexia, upper respiratory tract infection, vomiting, decreased weight, falls, and status epilepticus.1,3

Fenfluramine is metabolized principally by cytochrome P-450 (CYP) isoenzymes 1A2, 2B6, and 2D6, and to a lesser extent by CYP2C9, 2C19, and 3A4/5.1

Fenfluramine does not inhibit or induce CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4 at clinically relevant concentrations.1

Fenfluramine and its active metabolite (norfenfluramine) are not inhibitors of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transport proteins (OATP) 1B1 or OATP1B3, organic anion transporters (OAT) 1 or OAT3, organic cation transporter (OCT) 2, or multidrug and toxin extrusion transporters (MATE) 1 and MATE2K.1

Fenfluramine and norfenfluramine are not substrates of P-gp, BCRP, OAT1, OAT3, OCT2, MATE1, or MATE2K transporters.1

Drugs Affecting Hepatic Microsomal Enzymes

Potent Inducers of CYP1A2 or CYP2B6

Concomitant use of fenfluramine with potent inducers of CYP1A2 or CYP2B6 such as rifampin may decrease plasma concentrations of fenfluramine and decrease efficacy of the drug.1 An increase in the dosage of fenfluramine (without exceeding the maximum recommended dosage) should be considered if the drug is used concomitantly with a potent CYP1A2 or CYP2B6 inducer.1

CNS Depressants

Concomitant use of fenfluramine and CNS depressants (including alcohol) can increase the risk of somnolence and sedation.1

Anticonvulsants

Stiripentol, Clobazam, and Valproate

Coadministration of fenfluramine with stiripentol, clobazam, and valproate in healthy individuals resulted in increased systemic exposure and peak plasma concentrations of fenfluramine by 69 and 18%, respectively; systemic exposure and peak plasma concentrations of norfenfluramine were decreased by 41 and 42%, respectively.1,12 The pharmacokinetics of stiripentol, clobazam (and its norclobazam metabolite), and valproate do not appear to be affected by fenfluramine.1,12

Population pharmacokinetic modeling and simulation were used to assess the effect of stiripentol plus clobazam with or without valproate on the pharmacokinetics of fenfluramine in patients with Dravet syndrome.1 Based on this analysis, the addition of fenfluramine to an existing regimen of stiripentol plus clobazam with or without valproate is expected to increase systemic exposure of fenfluramine by up to 42% after the first dose.1 The effect on fenfluramine pharmacokinetics is greater at steady state concentrations (expected increase of 166% in fenfluramine exposure and decrease of 38% in norfenfluramine exposure).1

If fenfluramine is administered concomitantly with stiripentol and clobazam, dosage of fenfluramine should be reduced; the manufacturer recommends a maximum daily dosage of 0.2 mg/kg twice daily (maximum 17 mg daily) when fenfluramine is used concomitantly with stiripentol and clobazam.1,12

Cannabidiol

Coadministration of fenfluramine with cannabidiol resulted in increased systemic exposure and peak plasma concentrations of fenfluramine by 59 and 10%, respectively; systemic exposure and peak plasma concentrations of norfenfluramine were decreased by 22 and 33%, respectively.1 The pharmacokinetics of cannabidiol do not appear to be affected by fenfluramine.1

Serotonergic Drugs

Concomitant use of fenfluramine and drugs that increase serotonin, including selective serotonin-norepinephrine reuptake inhibitors (SNRIs), selective serotonin-reuptake inhibitors (SSRIs), tricyclic antidepressants, bupropion, serotonin (5-hydroxytryptamine; 5-HT) type 1 receptor agonists (“triptans”), dietary supplements (e.g., St. John's wort, tryptophan), drugs that impair metabolism of serotonin (e.g., monoamine oxidase [MAO] inhibitors), dextromethorphan, lithium, tramadol, and antipsychotic agents with serotonergic activity, may increase the risk of serotonin syndrome.1

Concomitant use of fenfluramine and MAO inhibitors is contraindicated.1 Fenfluramine should be used with caution in patients receiving other serotonergic drugs.1 Such patients should be monitored for the emergence of signs and symptoms of serotonin syndrome.1 If serotonin syndrome is suspected, fenfluramine should be discontinued immediately and symptomatic treatment should be initiated.1 (See Serotonin Syndrome under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Description

Fenfluramine, an amphetamine derivative, is an anticonvulsant agent.1,5,6,7,13 The mechanism by which fenfluramine exerts its anticonvulsant effects is not known, but presumed to involve the serotonergic system.1,5 Fenfluramine and its norfenfluramine metabolite increase extracellular levels of serotonin by inhibiting the reuptake of serotonin and exhibiting agonist activity at serotonin type 2 (5-hydroxytryptamine [5-HT₂]) receptors.1,5,7 Norfenfluramine shows greater affinity and agonist activity at the 5-HT₂ receptor than fenfluramine.5,13 Other mechanisms also may be involved; there is some evidence indicating that fenfluramine modulates sigma-1 receptors, which have been associated with neuroprotection.5,6

Systemic exposure of fenfluramine increases in a slightly greater than dose-proportional manner over the dosage range of 13-51.8 mg twice daily.1 Following oral administration, peak plasma concentrations of the drug are achieved within 4-5 hours.1 Absolute bioavailability of fenfluramine is approximately 68-74%.1 Fenfluramine is 50% bound to plasma proteins.1 Fenfluramine is metabolized to norfenfluramine (pharmacologically active metabolite), principally by cytochrome P-450 (CYP) isoenzymes 1A2, 2B6, and 2D6, and to a lesser extent by CYP2C9, 2C19, and 3A4/5.1 Norfenfluramine is then deaminated and oxidized to inactive metabolites.1 The majority of an administered dose (more than 90%) is eliminated in urine as fenfluramine, norfenfluramine, or other metabolites; less than 5% is found in feces.1 The elimination half-life of fenfluramine is 20 hours.1

Advice to Patients

Importance of advising patients to read the FDA-approved patient labeling (medication guide and instructions for use).1

Importance of advising patients to use the oral dosing syringes provided by the pharmacy.1

Risk of 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.1

Fenfluramine is available only through a restricted program called the Fintepla REMS program.1 Importance of providing patients with the telephone number and website for information on how to obtain the drug.1 Importance of informing patients that they must enroll in the REMS program and comply with ongoing monitoring requirements.1

Importance of advising patients that decreased appetite is frequent during treatment with fenfluramine, which can cause a decrease in weight.1

Importance of informing patients that fenfluramine can cause somnolence, sedation, and lethargy.1 Importance of advising patients not to engage in hazardous activities requiring mental alertness, such as operating a motor vehicle or other dangerous machinery, until the effects of the drug are known.1

Anticonvulsants, including fenfluramine, may increase the risk of suicidal thoughts or behavior.1 Importance of patients, caregivers, and family members being alert to and immediately reporting emergence or worsening of depression, any unusual changes in mood or behavior, or emergence of suicidal thoughts, behavior, or thoughts of self harm.1

Importance of advising patients not to discontinue fenfluramine therapy without consulting with their clinician.1 The drug should be gradually withdrawn to minimize the risk of increased seizure frequency and status epilepticus.1

Risk of serotonin syndrome, which can be life-threatening.1 Importance of advising patients of the signs and symptoms of serotonin syndrome and that certain over-the-counter (OTC) medications and herbal supplements can increase this risk.1

Importance of informing patients that fenfluramine can increase blood pressure.1

Importance of informing patients that fenfluramine can cause mydriasis and precipitate angle closure glaucoma.1 Instruct patients to contact their clinician if they experience any acute decreases in visual acuity or ocular pain.1

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, vitamins, herbal supplements, as well as any concomitant illnesses.1

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 Importance of clinicians informing women about the existence of and encouraging enrollment in the North American Antiepileptic Drug Pregnancy Registry.1 (See Pregnancy under Warnings/Precautions: Specific Populations, in Cautions.)

Additional Information

Overview^® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

1. Zogenix. Fintepla^® (fenfluramine) oral solution prescribing information. Emeryville, CA; 2020 Jun.

2. US Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed 2020 Jul 17. [Web]

3. Lagae L, Sullivan J, Knupp K et al. Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: a randomised, double-blind, placebo-controlled trial. Lancet . 2019; 394:2243-2254. [PubMed 31862249]

4. Nabbout R, Mistry A, Zuberi S et al. Fenfluramine for Treatment-Resistant Seizures in Patients With Dravet Syndrome Receiving Stiripentol-Inclusive Regimens: A Randomized Clinical Trial. JAMA Neurol . 2019; [PubMedCentral][PubMed 31790543]

5. Martin P, de Witte PAM, Maurice T et al. Fenfluramine acts as a positive modulator of sigma-1 receptors. Epilepsy Behav . 2020; 105:106989. [PubMed 32169824]

6. Rodríguez-Muñoz M, Sánchez-Blázquez P, Garzón J. Fenfluramine diminishes NMDA receptor-mediated seizures via its mixed activity at serotonin 5HT2A and type 1 sigma receptors. Oncotarget . 2018; 9:23373-23389. [PubMedCentral][PubMed 29805740]

7. Schoonjans AS, Marchau F, Paelinck BP et al. Cardiovascular safety of low-dose fenfluramine in Dravet syndrome: a review of its benefit-risk profile in a new patient population. Curr Med Res Opin . 2017; 33:1773-1781. [PubMed 28704161]

8. Schoonjans A, Paelinck BP, Marchau F et al. Low-dose fenfluramine significantly reduces seizure frequency in Dravet syndrome: a prospective study of a new cohort of patients. Eur J Neurol . 2017; 24:309-314. [PubMedCentral][PubMed 27790834]

9. Gataullina S, Dulac O. From genotype to phenotype in Dravet disease. Seizure . 2017; 44:58-64. [PubMed 27817982]

10. Wirrell EC, Laux L, Donner E et al. Optimizing the Diagnosis and Management of Dravet Syndrome: Recommendations From a North American Consensus Panel. Pediatr Neurol . 2017; 68:18-34.e3. [PubMed 28284397]

11. Centers for Disease Control and Prevention. Cardiac valvulopathy associated with exposure to fenfluramine or dexfenfluramine: U.S. Department of Health and Human Services interim public health recommendations, November 1997. MMWR Morb Mortal Wkly Rep. 1997; 46:1061-6. [Web]

12. Boyd B, Smith S, Gammaitoni A et al. A phase I, randomized, open-label, single-dose, 3-period crossover study to evaluate the drug-drug interaction between ZX008 (fenfluramine HCl oral solution) and a regimen of stiripentol, clobazam, and valproate in healthy subjects. Int J Clin Pharmacol Ther . 2019; 57:11-19. [PubMedCentral][PubMed 30336805]

13. Polster T. Individualized treatment approaches: Fenfluramine, a novel antiepileptic medication for the treatment of seizures in Dravet syndrome. Epilepsy Behav . 2019; 91:99-102. [PubMed 30269941]

14. Wirrell EC. Treatment of Dravet Syndrome. Can J Neurol Sci . 2016; 43 Suppl 3:S13-8. [PubMed 27264138]

15. Brigo F, Igwe SC, Bragazzi NL. Antiepileptic drugs for the treatment of infants with severe myoclonic epilepsy. Cochrane Database Syst Rev . 2017; 5:CD010483. [PubMed 28521067]