Fenfluramine (Monograph)

Brand name: Fintepla
Drug class: Anticonvulsants, Miscellaneous
Chemical name: N-ethyl-α-methyl-3-(trifluoromethyl) phenethylamine hydrochloride
Molecular formula: C₁₂H₁₆F₃N
CAS number: 458-24-2

Introduction

Anticonvulsant; amphetamine derivative with serotonergic effects.

Uses for Fenfluramine

Seizure Disorders

Treatment of seizures associated with Dravet syndrome in patients ≥2 years of age. Designated an orphan drug by FDA for use in this condition.

Fenfluramine Dosage and Administration

General

• Perform echocardiogram prior to initiating therapy, every 6 months during treatment, and then once 3–6 months after the drug is discontinued. (See Boxed Warning.)

• Avoid abrupt discontinuance; withdraw gradually to minimize potential for increased seizure frequency and status epilepticus. (See Discontinuance of Therapy under Cautions.)

• Closely monitor for emergence or worsening of depression, suicidal thoughts or behavior (suicidality), or any unusual changes in mood or behavior. (See Suicidality Risk under Cautions.)

Restricted Distribution Program

• Available only through a restricted distribution program (Fintepla REMS program).

• Clinicians and patients must enroll in the program and comply with all requirements. Pharmacies must also enroll in the program and must only dispense to patients who are authorized to receive the drug.

• Additional information available at [Web] or 1-877-964-3649.

Administration

Oral Administration

Administer orally twice daily as an oral solution. May administer with or without food.

Use a calibrated measuring device (i.e., either a 3- or 6-mL oral dosing syringe) to measure and administer the prescribed dose; a household teaspoon or tablespoon is not an adequate measuring device. Discard any unused portions 3 months after the bottle is first opened or if the “discard after” date has passed, whichever is sooner.

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

Dosage

Available as fenfluramine hydrochloride; dosage expressed in terms of fenfluramine.

Pediatric Patients

Seizure Disorders

Seizures Associated with Dravet Syndrome

Oral

Pediatric patients ≥2 years of age: Initial starting and maintenance dosage is 0.1 mg/kg twice daily.

May increase dosage weekly based on efficacy and tolerability.

Dosage titration schedule in patients not receiving concomitant stiripentol: 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 up to a maximum total daily dosage of 26 mg. (See Prescribing Limits under Dosage and Administration.) If more rapid titration is warranted, may increase dosage every 4 days.

Dosage titration schedule in patients receiving stiripentol and clobazam concomitantly: 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 up to a maximum total daily dosage of 17 mg. (See Prescribing Limits under Dosage and Administration.)

Adults

Seizure Disorders

Seizures Associated with Dravet Syndrome

Oral

Initial starting and maintenance dosage is 0.1 mg/kg twice daily.

May increase dosage weekly based on efficacy and tolerability.

Dosage titration schedule in patients not receiving concomitant stiripentol: 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 up to a maximum total daily dosage of 26 mg. If more rapid titration is warranted, may increase dosage every 4 days.

Dosage titration schedule in patients receiving stiripentol and clobazam concomitantly: 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 up to a maximum total daily dosage of 17 mg.

Prescribing Limits

Pediatric Patients

Seizure Disorders

Seizures Associated with Dravet Syndrome

Oral

Patients not receiving concomitant stiripentol: Maximum total daily dosage of 26 mg.

Patients receiving concomitant stiripentol and clobazam: Maximum total daily dosage of 17 mg.

Adults

Seizure Disorders

Dravet Syndrome

Oral

Patients not receiving concomitant stiripentol: Maximum total daily dosage of 26 mg.

Patients receiving concomitant stiripentol and clobazam: Maximum total daily dosage of 17 mg.

Special Populations

Hepatic Impairment

Use not recommended in patients with hepatic impairment.

Renal Impairment

Use not recommended in patients with moderate or severe renal impairment.

Geriatric Patients

Select dosage carefully, usually starting at the low end of dosing range.

Related/similar drugs

Banzel, clonazepam, lamotrigine, Mounjaro, topiramate, Lamictal, semaglutide

Cautions for Fenfluramine

Contraindications

• Hypersensitivity to fenfluramine or any excipients in the preparation.

• Patients receiving MAO inhibitors concomitantly (or within 14 days). (See Serotonin Syndrome under Cautions.)

Warnings/Precautions

Warnings

Valvular Heart Disease and Pulmonary Arterial Hypertension

Potential risk of valvular heart disease and PAH. (See Boxed Warning.) Fenfluramine was previously approved as an appetite suppressant to treat adult obesity, but was withdrawn from the US market in November 1997 following reports of cardiac valvulopathy and PAH associated with the drug. Dosages used in the management of obesity are generally higher than those used in patients with epilepsy. No cases reported in clinical trials of up to 3 years in patients with Dravet syndrome. However, precautions are required when the drug is used because of these potential risks.

Monitor cardiac function (with echocardiogram) prior to initiating therapy, every 6 months during therapy, and once 3–6 months after the drug is discontinued. If echocardiogram reveals any evidence of valvular heart disease or PAH, consider benefits versus risks of initiating or continuing fenfluramine therapy.

General Precautions

Decreased Appetite and Weight Loss

Decreased appetite and weight loss reported. Effects on weight appear to be dose related.

Monitor patient's weight regularly during treatment; consider dosage modification if decreased weight occurs. Carefully monitor growth in pediatric patients.

Somnolence and Sedation

Fenfluramine can cause somnolence, sedation, and lethargy. Such effects may diminish with continued treatment. Concomitant use of other CNS depressants, including alcohol, may potentiate these effects.

Monitor patients for somnolence and sedation. Advise patients not to drive or operate machinery until they have gained sufficient experience with the drug.

Suicidality Risk

Increased risk of suicidality (suicidal behavior or ideation) observed in an analysis of studies using various anticonvulsants in patients with epilepsy, psychiatric disorders, and other conditions; risk in patients receiving anticonvulsants (0.43%) was approximately twice that in patients receiving placebo (0.24%). Increased suicidality risk was observed as early as 1 week after initiation of anticonvulsant therapy; because most studies were ≤24 weeks' duration, risk of treatment beyond 24 weeks not known. Risk was higher for patients with epilepsy compared with those receiving anticonvulsants for other conditions.

Balance risk of suicidality with risk of untreated illness. Epilepsy and other illnesses treated with anticonvulsants are themselves associated with morbidity and mortality and an increased risk of suicidality.

Monitor all patients receiving anticonvulsants for suicidal thoughts and behavior. If suicidal thoughts or behavior emerges during anticonvulsant therapy, consider whether these symptoms may be related to the illness itself. (See Advice to Patients.)

Discontinuance of Therapy

Abrupt withdrawal may increase seizure frequency and risk of status epilepticus. Withdraw gradually unless safety concerns require more rapid withdrawal.

Serotonin Syndrome

Risk of potentially life-threatening serotonin syndrome, particularly with concurrent use of other serotonergic drugs including, but not limited to, SNRIs, SSRIs, tricyclic antidepressants, bupropion, 5-HT type 1 receptor agonists (“triptans”), dietary supplements (e.g., St. John’s wort, tryptophan), drugs that impair metabolism of serotonin (e.g., MAO inhibitors), dextromethorphan, lithium, tramadol, and antipsychotic agents with serotonergic agonist activity. (See Contraindications under Cautions.)

Manifestations may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile BP, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or GI symptoms (e.g., nausea, vomiting, diarrhea). If serotonin syndrome is suspected, discontinue fenfluramine immediately and initiate symptomatic treatment.

Increased BP

Fenfluramine may increase BP. Substantial elevation in BP, including hypertensive crisis, reported rarely in adults receiving fenfluramine, including those without a history of hypertension. No cases of hypertensive crisis reported in clinical trials of up to 3 years in patients with Dravet syndrome.

Monitor BP during treatment.

Abuse Potential and Dependence

Fenfluramine is subject to control as a schedule IV (C-IV) drug.

Specific Populations

Pregnancy

No adequate human or animal data.

North American Antiepileptic Drug (NAAED) Pregnancy Registry at 888-233-2334 or [Web].

Lactation

Not known whether fenfluramine is distributed into milk, affects milk production, or affects the breast-fed infant. Consider known benefits of breast-feeding and importance of fenfluramine to the woman; also consider potential adverse effects on the breast-fed infant from the drug or underlying maternal condition.

Pediatric Use

Safety and efficacy not established in pediatric patients <2 years of age.

Geriatric Use

No experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.

Hepatic Impairment

Use not recommended in patients with hepatic impairment.

Renal Impairment

Use not recommended in patients with moderate or severe renal impairment.

Common Adverse Effects

Decreased appetite, somnolence, sedation, lethargy, diarrhea, constipation, abnormal echocardiogram, fatigue, malaise, asthenia, ataxia, balance disorder, gait disturbance, increased BP, drooling, salivary hypersecretion, pyrexia, upper respiratory tract infection, vomiting, decreased weight, falls, status epilepticus.

Drug Interactions

Metabolized principally by CYP isoenzymes 1A2, 2B6, and 2D6, and to a lesser extent by CYP2C9, 2C19, and 3A4/5.

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

Does not inhibit 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 or MATE2K.

Not a substrate of P-gp, BCRP, OAT1, OAT3, OCT2, MATE1, or MATE2K.

Drugs Affecting Hepatic Microsomal Enzymes

Potent inducers of CYP1A2 or CYP2B6: May decrease plasma concentrations of fenfluramine and decrease efficacy of the drug. Consider an increase in fenfluramine dosage if used concomitantly (without exceeding maximum recommended dosage).

Specific Drugs

Fenfluramine Pharmacokinetics

Absorption

Bioavailability

Absolute bioavailability approximately 68–74%.

Food

No effect of food on pharmacokinetics of fenfluramine or norfenfluramine.

Plasma Concentrations

Peak plasma concentrations achieved in about 4–5 hours at steady state.

Systemic exposure is slightly greater than dose proportional over dosage range of 13–51.8 mg twice daily.

Distribution

Extent

Not known whether distributed into human milk.

Plasma Protein Binding

50% bound to human plasma proteins independent of drug concentrations.

Elimination

Metabolism

More than 75% is metabolized to norfenfluramine, principally by CYP1A2, CYP2B6, and CYP2D6.

Norfenfluramine is deaminated and oxidized to inactive metabolites.

Elimination Route

Principally excreted in urine as fenfluramine, norfenfluramine, or other metabolites; less than 5% excreted in feces.

Half-life

Elimination half-life of approximately 20 hours.

Stability

Storage

Oral

Solution

20–25°C (may be exposed to 15–30°C); do not refrigerate or freeze.

Store bottle and syringe together. Discard unused portions 3 months after bottle is first opened or after the “discard after” date, whichever is sooner.

Actions

• Amphetamine derivative with serotonergic effects.

• Mechanism of anticonvulsant activity not known, but is thought to be mediated by its serotonergic effects. Fenfluramine and its norfenfluramine metabolite increase extracellular levels of serotonin by inhibiting reuptake of serotonin and exhibiting agonist activity at serotonin type 2 (5-hydroxytryptamine [5-HT₂]) receptors.

• Additional mechanisms may be involved; there is some evidence that fenfluramine interacts with sigma-1 receptors, which have been associated with neuroprotection.

Advice to Patients

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

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

• 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 BP in the arteries of the lungs.

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

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

• Importance of informing patients that fenfluramine can cause somnolence, sedation, and lethargy. 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.

• Anticonvulsants, including fenfluramine, may increase the risk of suicidal thoughts or behavior. 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.

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

• Risk of serotonin syndrome, which can be life-threatening. 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.

• Importance of informing patients that fenfluramine can increase BP.

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

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

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed. Importance of clinicians informing women about the existence of and encouraging enrollment in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. (See Pregnancy under Cautions.)

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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

Distribution of fenfluramine is restricted. (See Restricted Distribution Program under Dosage and Administration.)

Reload page with references included

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