Fenfluramine: Drug information

For additional information see "Fenfluramine: Pediatric drug information" and "Fenfluramine: Patient drug information"

For abbreviations, symbols, and age group definitions show table

ALERT: US Boxed Warning

Valvular heart disease and pulmonary arterial hypertension

Fenfluramine can cause valvular heart disease and pulmonary arterial hypertension. Echocardiogram assessments are required before, during, and after treatment with fenfluramine. The benefits vs the risks of initiating or continuing fenfluramine must be considered, based on echocardiogram findings. Because of the risks of valvular heart disease and pulmonary arterial hypertension, fenfluramine is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the FINTEPLA REMS.

Brand Names: US

Fintepla

Pharmacologic Category

Antiseizure Agent, Miscellaneous;
Serotonin 5HT-2 Receptor Agonist

Dosing: Adult

Dravet syndrome–associated seizures

Dravet syndrome–associated seizures:

Patients not taking stiripentol plus clobazam : Oral: Initial: 0.1 mg/kg twice daily; may increase based on response and tolerability after 7 days to 0.2 mg/kg twice daily; may further increase based on response and tolerability after 7 days to 0.35 mg/kg twice daily. Maximum dose: 26 mg/day. Note: If a more rapid titration is warranted, the dose may be increased every 4 days (only in patients not receiving concomitant stiripentol plus clobazam).

Patients taking stiripentol plus clobazam: Oral: Initial: 0.1 mg/kg twice daily; may increase based on response and tolerability after 7 days to 0.15 mg/kg twice daily; may further increase based on response and tolerability after 7 days to 0.2 mg/kg twice daily. Maximum dose: 17 mg/day.

Lennox-Gastaut syndrome–associated seizures

Lennox-Gastaut syndrome–associated seizures:

Patients not taking stiripentol plus clobazam: Oral: Initial: 0.1 mg/kg twice daily; Day 7: Increase as tolerated to 0.2 mg/kg twice daily; Day 14: Increase as tolerated to 0.35 mg/kg twice daily. Maximum dose: 26 mg/day. Note: If a more rapid titration is warranted, the dose may be increased every 4 days (only in patients not receiving concomitant stiripentol plus clobazam).

Patients taking stiripentol plus clobazam: Oral: Initial: 0.1 mg/kg twice daily; Day 7: Increase as tolerated to 0.15 mg/kg twice daily; Day 14: Increase as tolerated to 0.2 mg/kg twice daily. Maximum dose: 17 mg/day.

Discontinuation of therapy: Withdraw gradually to minimize the potential of increased seizure frequency.

Dosage adjustment for concomitant therapy : Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

eGFR ≥30 mL/minute/1.73 m²: No dosage adjustments are necessary.

eGFR 15 to 29 mL/minute/1.73 m²:

Patients not taking stiripentol plus clobazam: Maximum dose: 20 mg/day.

Patients taking stiripentol plus clobazam: Maximum dose: 17 mg/day.

eGFR <15 mL/minute/1.73 m²: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Dosing: Liver Impairment: Adult

Mild impairment (Child-Pugh class A):

Patients not taking stiripentol plus clobazam: Maximum dose: 20 mg/day.

Patients taking stiripentol plus clobazam: Maximum dose: 13 mg/day.

Moderate impairment (Child-Pugh class B):

Patients not taking stiripentol plus clobazam: Maximum dose: 20 mg/day.

Patients taking stiripentol plus clobazam: Use is not recommended.

Severe impairment (Child-Pugh class C):

Patients not taking stiripentol plus clobazam: Maximum dose: 17 mg/day.

Patients taking stiripentol plus clobazam: Use is not recommended.

Dosing: Older Adult

Refer to adult dosing.

Dosing: Pediatric

(For additional information see "Fenfluramine: Pediatric drug information")

Note: Prior to initiation, obtain an echocardiogram assessment to rule out valvular heart disease and pulmonary arterial hypertension.

Dravet syndrome–associated seizures

Dravet syndrome–associated seizures:

Children ≥2 years and Adolescents:

Patients not taking stiripentol: Oral: Initial: 0.1 mg/kg/dose twice daily; may increase based on response and tolerability after 7 days to 0.2 mg/kg/dose twice daily; may further increase based on response and tolerability after 7 days to 0.35 mg/kg/dose twice daily. Maximum daily dose: 26 mg/day. Note: If a more rapid titration is warranted, the dose may be increased every 4 days (only in patients not receiving concomitant stiripentol).

Patients taking stiripentol: Oral: Initial: 0.1 mg/kg/dose twice daily; may increase based on response and tolerability after 7 days to 0.15 mg/kg/dose twice daily; may further increase based on response and tolerability after 7 days to 0.2 mg/kg/dose twice daily. Maximum daily dose: 17 mg/day.

Lennox-Gastaut syndrome–associated seizures

Lennox- Gastaut syndrome–associated seizures:

Children ≥2 years and Adolescents:

Patients not taking stiripentol: Oral: Initial: 0.1 mg/kg/dose twice daily for 1 week; on day 7, increase as tolerated to 0.2 mg/kg/dose twice daily for 1 week; then on day 14 increase as tolerated to the recommended maintenance dose of 0.35 mg/kg/dose twice daily. Maximum daily dose: 26 mg/day. Note: If a more rapid titration is warranted, the dose may be increased every 4 days (only in patients not receiving concomitant stiripentol).

Patients taking stiripentol: Oral: Initial: 0.1 mg/kg/dose twice daily for 1 week; on day 7, increase as tolerated to 0.15 mg/kg/dose twice daily for 1 week; then on day 14 increase as tolerated to the recommended maintenance dose of 0.35 mg/kg/dose twice daily. Maximum daily dose: 17 mg/day.

Discontinuation of therapy: Gradually decrease the dose to discontinue; abrupt discontinuation may result in increased seizure frequency or status epilepticus.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Pediatric

Children ≥2 years and Adolescents:

eGFR ≥30 mL/minute/1.73 m²: No dosage adjustments are necessary.

eGFR 15 to 29 mL/minute/1.73 m²:

Patients not receiving stiripentol: Maximum daily dose: 20 mg/day.

Patients receiving stiripentol: Maximum daily dose: 17 mg/day.

eGFR <15 mL/minute/1.73 m²: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Dosing: Liver Impairment: Pediatric

Children ≥2 years and Adolescents: Mild to severe impairment: Use is not recommended.

Adverse Reactions (Significant): Considerations

Blood pressure increased

Increased blood pressure has been reported; hypertensive crisis has also been observed in adults receiving fenfluramine, including patients without a history of hypertension; there were no cases of hypertensive crisis in patients receiving fenfluramine for Dravet syndrome or Lennox-Gastaut syndrome in trials up to 3 years duration.

Pulmonary arterial hypertension

Pulmonary hypertension (arterial) has been associated with fenfluramine when previously marketed at higher doses for weight loss in adults (and withdrawn from the market in 1997). In current trials of fenfluramine for Dravet syndrome or Lennox-Gastaut syndrome up to 3 years duration, there were no reports of pulmonary arterial hypertension (PAH) in patients receiving fenfluramine (Ref).

Mechanism: Unclear; however, serotonin receptor 5HT-2 agonist activity promotes both vasoconstriction and remodeling of pulmonary vasculature, resulting in a thickening of the medial layer and a narrowing of the lumen of the pulmonary artery (Ref).

Onset: Delayed; based on a retrospective trial of previous case reports of PAH associated with fenfluramine-derivatives for weight loss, the median onset of symptoms was 4.5 years in patients with a median duration of therapy of 6 months (Ref).

Risk factors:

Based on previous data when fenfluramine was used as an appetite suppressant for weight loss:

• Family history of pulmonary hypertension (Ref)

• Duration of use (>3 to 6 months) (Ref)

Serotonin syndrome

Serotonin syndrome may occur, particularly when used in combination with other serotonergic agents or agents that impair metabolism of serotonin. The diagnosis of serotonin syndrome is made based on the Hunter Serotonin Toxicity Criteria (Ref) and may result in a spectrum of symptoms, such as anxiety, agitation, confusion, delirium, hyperreflexia, muscle rigidity, myoclonus, tachycardia, tachypnea, and tremor. Severe cases may cause hyperthermia, significant autonomic instability (ie, rapid and severe changes in blood pressure and pulse), coma, and seizures (Ref).

Mechanism: Dose-related; overstimulation of serotonin receptors by serotonergic agents (Ref).

Onset: Rapid; onset of serotonin syndrome is typically within hours of exposure but delays of ≥24 hours have been reported (Ref).

Risk factors:

• Concurrent use of drugs that increase serotonin synthesis, block serotonin reuptake, and/or impair serotonin metabolism

Valvular heart disease

Fenfluramine has been associated with valvular heart disease when previously marketed at higher doses for weight loss in adults, and this concern led to its withdrawal from the US market in 1997 (Ref). In current trials in patients receiving fenfluramine for Dravet syndrome, trace aortic insufficiency and mitral valve insufficiency, considered to be within the normal physiologic range, have commonly been observed; no cases of valvular heart disease were observed in studies for Dravet syndrome or Lennox-Gastaut syndrome up to 3 years duration (Ref).

Mechanism: Dose-related; likely due to activation of serotonin 5HT-_2Breceptors; 5HT-_2Breceptors are abundantly expressed on aortic and mitral valves, and these receptors are known to stimulate mitogenesis (Ref).

Onset: Varied; cases have been reported within months to years after drug discontinuation (Ref).

Risk factors:

Based on previous data when fenfluramine was used as an appetite suppressant for weight loss:

• High doses (Ref)

• Duration of use (≥3 months) (Ref)

• Coadministration with other medications known to be 5HT-_2Breceptor agonists (Ref)

Weight loss

Fenfluramine causes decreased appetite and significant weight loss (≥7% from baseline); during open-label extension studies, approximately half of patients resumed expected measured increases in weight.

Mechanism: Dose-related (likely); as a derivative of amphetamine, it is believed the anorectic effect is mediated through its serotonergic effects, leading to increased 5-HT in the brain and resulting in decreased appetite (Ref).

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in children, adolescents, and adults and may include rates with concurrent antiseizure medications.

>10%:

Cardiovascular: Aortic insufficiency (18% to 23%; including aortic regurgitation) (Lagae 2020) (table 1), increased blood pressure (8% to 13%) (table 2), mitral valve insufficiency (18% to 23%; including mitral regurgitation and mitral stenosis) (Ennezat 2021; Lagae 2020) (table 3)

**Fenfluramine: Adverse Reaction: Aortic Insufficiency**
Drug (Fenfluramine)	Placebo	Dose	Indication	Number of Patients (Fenfluramine)	Number of Patients (Placebo)	Source	Comments
23%	13%	0.7 mg/kg/day	Dravet syndrome	40	40	Lagae 2020	Trace and within the normal physiological range
18%	13%	0.2 mg/kg/day	Dravet syndrome	39	40	Lagae 2020	Trace and within the normal physiological range

**Fenfluramine: Adverse Reaction:** **Increased Blood Pressure**
Drug (Fenfluramine)	Placebo	Dose	Indication	Number of Patients (Fenfluramine)	Number of Patients (Placebo)
13%	5%	0.2 mg/kg/day	Dravet syndrome	39	84
8%	5%	0.7 mg/kg/day	Dravet syndrome	40	84

**Fenfluramine: Adverse Reaction:** **Mitral Valve Insufficiency**
Drug (Fenfluramine)	Placebo	Dose	Indication	Number of Patients (Fenfluramine)	Number of Patients (Placebo)	Source	Comments
23%	13%	0.7 mg/kg/day	Dravet syndrome	40	40	Lagae 2020	Trace and within the normal physiological range
18%	13%	0.2 mg/kg/day	Dravet syndrome	39	40	Lagae 2020	Trace and within the normal physiological range

Endocrine & metabolic: Weight loss (2% to 13%) (table 4)

**Fenfluramine: Adverse Reaction:** **Weight Loss**
Drug (Fenfluramine)	Placebo	Dose	Indication	Number of Patients (Fenfluramine)	Number of Patients (Placebo)
13%	1%	0.2 mg/kg/day	Dravet syndrome	39	84
5%	1%	0.7 mg/kg/day	Dravet syndrome	40	84
8%	2%	0.7 mg/kg/day	Lennox-Gastaut syndrome	87	87
2%	2%	0.2 mg/kg/day	Lennox-Gastaut syndrome	89	87

Gastrointestinal: Decreased appetite (20% to 38%) (table 5), diarrhea (11% to 31%), sialorrhea (≤13%), vomiting (8% to 14%)

**Fenfluramine: Adverse Reaction:** **Decreased Appetite**
Drug (Fenfluramine)	Placebo	Dose	Indication	Number of Patients (Fenfluramine)	Number of Patients (Placebo)
38%	8%	0.7 mg/kg/day	Dravet syndrome	40	84
23%	8%	0.2 mg/kg/day	Dravet syndrome	39	84
36%	12%	0.7 mg/kg/day	Lennox-Gastaut syndrome	87	87
20%	12%	0.2 mg/kg/day	Lennox-Gastaut syndrome	89	87

Nervous system: Asthenia (≤24%), drooling (≤13%), drowsiness (≤26%), fatigue (≤24%), lethargy (≤26%), malaise (≤24%), sedated state (≤26%)

Respiratory: Upper respiratory tract infection (7% to 21%)

Miscellaneous: Fever (15%)

1% to 10%:

Cardiovascular: Increased heart rate (3% to 5%)

Dermatologic: Skin rash (8%)

Endocrine & metabolic: Dehydration (5%), increased serum prolactin (5%)

Gastrointestinal: Constipation (3% to 10%), gastroenteritis (3% to 8%)

Genitourinary: Urinary incontinence (3% to 5%), urinary tract infection (5%)

Hematologic & oncologic: Bruise (5%)

Nervous system: Abnormal behavior (8%; stereotypy: 5%), abnormal gait (≤10%), ataxia (≤10%), balance impairment (≤10%), chills (5%), falling (10%), headache (8%), hypoactivity (5%), hypotonia (8%), insomnia (5%), irritability (3% to 8%), mood changes (negativism: 5%), status epilepticus (3%), tremor (3%)

Respiratory: Rhinitis (3% to 8%)

Frequency not defined:

Cardiovascular: Heart valve disease (when previously marketed at higher doses for weight loss in adults), hypertensive crisis

Respiratory: Pulmonary hypertension (arterial; when previously marketed at higher doses for weight loss in adults)

Postmarketing: Nervous system: Aggressive behavior

Contraindications

Hypersensitivity to fenfluramine or any component of the formulation; concomitant use with or within 14 days of monoamine oxidase inhibitors.

Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Warnings/Precautions

Concerns related to adverse effects:

• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery, driving).

• Ocular effects: May cause mild pupillary dilation, which, in susceptible individuals, can lead to an episode of angle-closure glaucoma. Consider discontinuing fenfluramine in patients with acute decreases in visual acuity or ocular pain.

• Suicidal ideation: Pooled analysis of trials involving various antiseizure medications (regardless of indication) showed an increased risk of suicidal thoughts/behavior (incidence rate: 0.43% treated patients compared to 0.24% of patients receiving placebo); risk observed as early as 1 week after initiation and continued through duration of trials (most trials ≤24 weeks). Monitor all patients for notable changes in behavior that might indicate suicidal thoughts or depression; notify health care provider immediately if symptoms occur.

Other warnings/precautions:

• REMS program:Counsel patients about the risks, signs and symptoms, and required monitoring for valvular heart disease and pulmonary arterial hypertension.

• Withdrawal: Antiseizure medications should not be discontinued abruptly because of the possibility of increasing seizure frequency; therapy should be withdrawn gradually to minimize the potential of increased seizure frequency, unless safety concerns require a more rapid withdrawal.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Oral, as hydrochloride:

Fintepla: 2.2 mg/mL (30 mL, 360 mL) [gluten free; contains ethylparaben, methylparaben; cherry flavor]

Generic Equivalent Available: US

Pricing: US

Solution (Fintepla Oral)

2.2 mg/mL (per mL): $66.02

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Administration: Adult

Oral: Administer with or without food using the provided calibrated oral syringe (3 mL or 6 mL); do not use a household teaspoon or tablespoon (overdosage may occur).

Enteral: May be administered via gastric and nasogastric feeding tubes.

Administration: Pediatric

Oral: May be administered without regard to meals using provided oral syringe; do not use a household teaspoon (overdosage may occur). May also be administered via gastric or nasogastric tube.

Medication Guide and/or Vaccine Information Statement (VIS)

An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:

Fintepla: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/212102s013lbl.pdf#page=30

Use: Labeled Indications

Dravet syndrome–associated seizures: Treatment of seizures associated with Dravet syndrome in patients ≥2 years of age.

Lennox-Gastaut syndrome–associated seizures: Treatment of seizures associated with Lennox-Gastaut syndrome in patients ≥2 years of age.

Metabolism/Transport Effects

Substrate of CYP1A2 (Major with inducers), CYP1A2 (Minor with inhibitors), CYP2B6 (Major with inducers), CYP2B6 (Minor with inhibitors), CYP2C19 (Minor), CYP2C9 (Minor), CYP2D6 (Minor), CYP3A4 (Minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential;

Drug Interactions

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.

Acrivastine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Alcohol (Ethyl): CNS Depressants may increase CNS depressant effects of Alcohol (Ethyl). Risk C: Monitor

Alizapride: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Amisulpride (Oral): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Articaine: May increase CNS depressant effects of CNS Depressants. Management: Consider reducing the dose of articaine if possible when used in patients who are also receiving CNS depressants. Monitor for excessive CNS depressant effects with any combined use. Risk D: Consider Therapy Modification

Azelastine (Nasal): May increase CNS depressant effects of CNS Depressants. Risk X: Avoid

Benperidol: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Blonanserin: CNS Depressants may increase CNS depressant effects of Blonanserin. Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Risk D: Consider Therapy Modification

Brexanolone: CNS Depressants may increase CNS depressant effects of Brexanolone. Risk C: Monitor

Brimonidine (Topical): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Broccoli: May decrease serum concentration of CYP1A2 Substrates (High risk with Inducers). Risk C: Monitor

Bromopride: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Bromperidol: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid

Buclizine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Buprenorphine: CNS Depressants may increase CNS depressant effects of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants. Risk D: Consider Therapy Modification

BusPIRone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Cannabidiol: May increase CNS depressant effects of Fenfluramine. Cannabidiol may increase serum concentration of Fenfluramine. Risk C: Monitor

Cannabinoid-Containing Products: CNS Depressants may increase CNS depressant effects of Cannabinoid-Containing Products. Risk C: Monitor

Cannabis: May decrease serum concentration of CYP1A2 Substrates (High risk with Inducers). Risk C: Monitor

Cetirizine (Systemic): May increase CNS depressant effects of CNS Depressants. Management: Consider avoiding this combination if possible. If required, monitor for excessive sedation or CNS depression, limit the dose and duration of combination therapy, and consider CNS depressant dose reductions. Risk D: Consider Therapy Modification

Chloral Hydrate/Chloral Betaine: CNS Depressants may increase CNS depressant effects of Chloral Hydrate/Chloral Betaine. Management: Consider alternatives to the use of chloral hydrate or chloral betaine and additional CNS depressants. If combined, consider a dose reduction of either agent and monitor closely for enhanced CNS depressive effects. Risk D: Consider Therapy Modification

Chlormethiazole: May increase CNS depressant effects of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Risk D: Consider Therapy Modification

Chlorphenesin Carbamate: May increase adverse/toxic effects of CNS Depressants. Risk C: Monitor

CloBAZam: May increase serum concentration of Fenfluramine. Management: Limit the fenfluramine dose to a maximum daily dosage of 0.2 mg/kg twice daily (17 mg/day) when used in combination with stiripentol and clobazam. Risk D: Consider Therapy Modification

CNS Depressants: May increase adverse/toxic effects of CNS Depressants. Risk C: Monitor

CYP1A2 Inhibitors (Strong): May increase serum concentration of Fenfluramine. Management: Limit fenfluramine dose to 20 mg/day without concurrent stiripentol or to 17 mg/day with concomitant stiripentol and clobazam when used with a strong CYP1A2 inhibitor. Risk D: Consider Therapy Modification

CYP2D6 Inhibitors (Strong): May increase serum concentration of Fenfluramine. Management: Limit fenfluramine dose to 20 mg/day without concurrent stiripentol or to 17 mg/day with concomitant stiripentol and clobazam when used with a strong CYP2D6 inhibitor. Risk D: Consider Therapy Modification

CYP3A4 Inducers (Strong): May decrease serum concentration of Fenfluramine. Management: Avoid concurrent use of strong CYP3A4 inducers with fenfluramine when possible. If combined use cannot be avoided, consider increasing the fenfluramine dose, but do not exceed the fenfluramine maximum daily dose. Risk D: Consider Therapy Modification

Cyproheptadine: May decrease therapeutic effects of Fenfluramine. Fenfluramine may increase CNS depressant effects of Cyproheptadine. Risk C: Monitor

Dantrolene: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Daridorexant: May increase CNS depressant effects of CNS Depressants. Management: Dose reduction of daridorexant and/or any other CNS depressant may be necessary. Use of daridorexant with alcohol is not recommended, and the use of daridorexant with any other drug to treat insomnia is not recommended. Risk D: Consider Therapy Modification

DexmedeTOMIDine: CNS Depressants may increase CNS depressant effects of DexmedeTOMIDine. Management: Monitor for increased CNS depression during coadministration of dexmedetomidine and CNS depressants, and consider dose reductions of either agent to avoid excessive CNS depression. Risk D: Consider Therapy Modification

Difelikefalin: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Difenoxin: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Dihydralazine: CNS Depressants may increase hypotensive effects of Dihydralazine. Risk C: Monitor

Dimethindene (Topical): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Dothiepin: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Doxylamine: CNS Depressants may increase CNS depressant effects of Doxylamine. Risk C: Monitor

DroPERidol: May increase CNS depressant effects of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Risk D: Consider Therapy Modification

Emedastine (Systemic): May increase CNS depressant effects of CNS Depressants. Management: Consider avoiding this combination if possible. If required, monitor for excessive sedation or CNS depression, limit the dose and duration of combination therapy, and consider CNS depressant dose reductions. Risk C: Monitor

Entacapone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Esketamine (Nasal): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Fexinidazole: May decrease serum concentration of CYP2B6 Substrates (High risk with Inducers). Management: Avoid concomitant use of fexinidazole and CYP2B6 substrates when possible. If combined, monitor for reduced efficacy of the CYP2B6 substrate. Risk D: Consider Therapy Modification

Flunarizine: CNS Depressants may increase CNS depressant effects of Flunarizine. Risk X: Avoid

Flunitrazepam: CNS Depressants may increase CNS depressant effects of Flunitrazepam. Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Risk D: Consider Therapy Modification

HydrOXYzine: May increase CNS depressant effects of CNS Depressants. Management: Consider a decrease in the CNS depressant dose, as appropriate, when used together with hydroxyzine. Increase monitoring of signs/symptoms of CNS depression in any patient receiving hydroxyzine together with another CNS depressant. Risk D: Consider Therapy Modification

Inhalational Anesthetics: Fenfluramine may increase hypotensive effects of Inhalational Anesthetics. Risk C: Monitor

Ixabepilone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Kava Kava: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Ketotifen (Systemic): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Kratom: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid

Lemborexant: May increase CNS depressant effects of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Risk D: Consider Therapy Modification

Levocetirizine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Linezolid: Fenfluramine may increase serotonergic effects of Linezolid. This could result in serotonin syndrome. Risk X: Avoid

Lisuride: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Lofepramine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Lofexidine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Loxapine: CNS Depressants may increase CNS depressant effects of Loxapine. Management: Consider reducing the dose of CNS depressants administered concomitantly with loxapine due to an increased risk of respiratory depression, sedation, hypotension, and syncope. Risk D: Consider Therapy Modification

Magnesium Sulfate: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Melitracen [INT]: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Mequitazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Metergoline: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Methotrimeprazine: CNS Depressants may increase CNS depressant effects of Methotrimeprazine. Methotrimeprazine may increase CNS depressant effects of CNS Depressants. Management: Reduce the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Risk D: Consider Therapy Modification

Methoxyflurane: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Methylene Blue: Fenfluramine may increase serotonergic effects of Methylene Blue. This could result in serotonin syndrome. Risk X: Avoid

Metoclopramide: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

MetyroSINE: CNS Depressants may increase sedative effects of MetyroSINE. Risk C: Monitor

Minocycline (Systemic): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Monoamine Oxidase Inhibitors (Antidepressant): Fenfluramine may increase serotonergic effects of Monoamine Oxidase Inhibitors (Antidepressant). This could result in serotonin syndrome. Risk X: Avoid

Monoamine Oxidase Inhibitors (Type B): Fenfluramine may increase serotonergic effects of Monoamine Oxidase Inhibitors (Type B). This could result in serotonin syndrome. Risk X: Avoid

Moxonidine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Nabilone: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid

Nalfurafine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Noscapine: CNS Depressants may increase adverse/toxic effects of Noscapine. Risk X: Avoid

Olopatadine (Nasal): May increase CNS depressant effects of CNS Depressants. Risk X: Avoid

Opicapone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Opioid Agonists: CNS Depressants may increase CNS depressant effects of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider Therapy Modification

Opipramol: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Orphenadrine: CNS Depressants may increase CNS depressant effects of Orphenadrine. Risk X: Avoid

Oxomemazine: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid

Oxybate Salt Products: CNS Depressants may increase CNS depressant effects of Oxybate Salt Products. Management: Consider alternatives to this combination when possible. If combined, dose reduction or discontinuation of one or more CNS depressants (including the oxybate salt product) should be considered. Interrupt oxybate salt treatment during short-term opioid use Risk D: Consider Therapy Modification

OxyCODONE: CNS Depressants may increase CNS depressant effects of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider Therapy Modification

Paliperidone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Paraldehyde: CNS Depressants may increase CNS depressant effects of Paraldehyde. Risk X: Avoid

Perampanel: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Periciazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Pipamperone: May increase adverse/toxic effects of CNS Depressants. Risk C: Monitor

Piribedil: CNS Depressants may increase CNS depressant effects of Piribedil. Risk C: Monitor

Pizotifen: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Pramipexole: CNS Depressants may increase sedative effects of Pramipexole. Risk C: Monitor

Procarbazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

RifAMPin: May decrease serum concentration of Fenfluramine. Management: Avoid concurrent use of rifampin with fenfluramine when possible. If combined use cannot be avoided, consider increasing the fenfluramine dose, but do not exceed the fenfluramine maximum daily dose. Risk D: Consider Therapy Modification

Rilmenidine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Ropeginterferon Alfa-2b: CNS Depressants may increase adverse/toxic effects of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased. Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania). Risk D: Consider Therapy Modification

ROPINIRole: CNS Depressants may increase sedative effects of ROPINIRole. Risk C: Monitor

Rotigotine: CNS Depressants may increase sedative effects of Rotigotine. Risk C: Monitor

Serotonergic Agents (High Risk): Fenfluramine may increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Risk C: Monitor

Serotonergic Agents (Moderate Risk, Miscellaneous): Fenfluramine may increase serotonergic effects of Serotonergic Agents (Moderate Risk, Miscellaneous). This could result in serotonin syndrome. Risk C: Monitor

Stiripentol: May increase serum concentration of Fenfluramine. Management: If coadministered with stiripentol and clobazam, initate fenfluramine at 0.1 mg/kg twice daily, then on day 7 increase fenfluramine to 0.15 mg/kg twice daily, and on day 14 increase fenfluramine to 0.2 mg/kg twice daily. Max dose 17 mg/day. Risk D: Consider Therapy Modification

Suvorexant: CNS Depressants may increase CNS depressant effects of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Risk D: Consider Therapy Modification

Thalidomide: CNS Depressants may increase CNS depressant effects of Thalidomide. Risk X: Avoid

Trimeprazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Valerian: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Zolpidem: CNS Depressants may increase CNS depressant effects of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Risk D: Consider Therapy Modification

Zuranolone: May increase CNS depressant effects of CNS Depressants. Management: Consider alternatives to the use of zuranolone with other CNS depressants or alcohol. If combined, consider a zuranolone dose reduction and monitor patients closely for increased CNS depressant effects. Risk D: Consider Therapy Modification

Reproductive Considerations

Contraception is recommended when treating patients with Dravet syndrome or Lennox-Gastaut syndrome who could become pregnant (Wirrell 2024). Manage epilepsy in patients who could become pregnant based on a shared decision-making process that optimizes seizure control and considers the possibility of pregnancy during treatment (Pack 2024). Regularly discuss age-specific and developmental needs, including pregnancy planning and contraceptive options during the patient’s reproductive lifespan (ACOG 2020; NICE 2022).

Pregnancy Considerations

Outcome data related to inadvertent maternal use of fenfluramine in pregnancy are available from previous reports when used to treat obesity (Jones 2002; Vial 1992). Fenfluramine is associated with an increased risk of pulmonary arterial hypertension, which has also been reported following exposure in pregnancy (Bonnin 2005).

Data collection to monitor pregnancy and infant outcomes following exposure to antiseizure drugs is ongoing. Patients exposed to fenfluramine during pregnancy are encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry (888-233-2334 or http://www.aedpregnancyregistry.org).

Breastfeeding Considerations

It is not known if fenfluramine is present in breast milk.

According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother.

Monitoring Parameters

Echocardiogram to evaluate for valvular heart disease and pulmonary arterial hypertension (baseline, every 6 months during treatment, 3 to 6 months after discontinuing); weight (baseline, then regularly during treatment); growth in pediatric patients (regularly during treatment); BP (baseline, then periodically during treatment); signs/symptoms of serotonin syndrome, such as mental status changes (eg, agitation, hallucinations, delirium, coma), autonomic instability (eg, tachycardia, labile BP, diaphoresis), neuromuscular changes (eg, tremor, rigidity, myoclonus), GI symptoms (eg, nausea, vomiting, diarrhea), and/or seizures.

Mechanism of Action

The mechanisms by which fenfluramine exerts its therapeutic effects in the treatment of seizures associated with Dravet syndrome and Lennox-Gastaut syndrome are unknown. Fenfluramine and the metabolite, norfenfluramine, increase extracellular levels of serotonin through interaction with serotonin transporter proteins, and exhibit agonist activity at serotonin 5HT-2 receptors.

Pharmacokinetics (Adult Data Unless Noted)

Note: Pharmacokinetic parameters in pediatric patients are reported to be similar to those in healthy adult subjects.

Distribution: V_z/F: 11.9 L/kg.

Protein binding: 50%.

Metabolism: 75% is metabolized primarily by CYP1A2, CYP2B6, and CYP2D6 to active metabolite norfenfluramine; CYP2C9, CYP2C19, and CYP2D6 are involved to a minor extent. Norfenfluramine is deaminated and oxidized to inactive metabolites.

Bioavailability: ~68% to 74%.

Half-life elimination: 20 hours.

Time to peak: 3 to 5 hours.

Excretion: Urine: >90% (<25% as unchanged drug or active metabolite); feces: <5%.

Pharmacokinetics: Additional Considerations (Adult Data Unless Noted)

Altered kidney function: In patients with severe renal impairment (eGFR <30 mL/minute/1.73 m², C_max and AUC of fenfluramine increased by 20% and 88%, respectively, and C_max and AUC of norfenfluramine increased by 13% and 21%, respectively, following a single 0.35 mg/kg dose. Has not been studied in eGFR <15 mL/minute/1.73 m².

Hepatic function impairment: In patients with mild, moderate, or severe hepatic impairment (Child-Pugh class A, B, and C), AUC of fenfluramine increased by 95%, 113%, and 185%, respectively, and C_max of fenfluramine increased by 19%, 16%, and 29%, respectively, compared to patients with normal hepatic function, following a single 0.35 mg/kg/dose. AUC of norfenfluramine increased by 18% in mild hepatic impairment and 4% in moderate hepatic impairment, but decreased by 11% in severe hepatic impairment and C_max of norfenfluramine decreased by 21%, 36%, and 45% in patients with mild, moderate, and severe hepatic impairment, respectively, compared to patients with normal hepatic function, following a single 0.35 mg/kg/dose. The combined molar AUC of fenfluramine and norfenfluramine increased by 55%, 56%, and 82%, and the combined molar C_max of fenfluramine and norfenfluramine increased by 7.5%, 1.3%, and 8% in patients with mild, moderate, and severe hepatic impairment, respectively, compared to patients with normal hepatic function, following a single 0.35 mg/kg/dose.

Brand Names: International

International Brand Names by Country

For country code abbreviations (show table)

(AT) Austria: Fintepla;
(CZ) Czech Republic: Fintepla;
(DE) Germany: Fintepla;
(ES) Spain: Fintepla;
(FI) Finland: Fintepla;
(FR) France: Fenfluramine;
(GB) United Kingdom: Fintepla;
(HU) Hungary: Fintepla;
(IE) Ireland: Fintepla;
(IT) Italy: Fintepla;
(JP) Japan: Fintepla;
(MX) Mexico: Fintepla;
(NL) Netherlands: Fintepla;
(NO) Norway: Fintepla;
(PL) Poland: Fintepla;
(PR) Puerto Rico: Fintepla;
(PT) Portugal: Fintepla;
(RO) Romania: Fintepla;
(SE) Sweden: Fintepla;
(SK) Slovakia: Fintepla

Abenhaim L, Moride Y, Brenot F, et al. Appetite-suppressant drugs and the risk of primary pulmonary hypertension. International Primary Pulmonary Hypertension Study Group. N Engl J Med. 1996;335(9):609-616. doi:10.1056/NEJM199608293350901 [PubMed 8692238]
American College of Obstetricians and Gynecologists (ACOG). Gynecologic management of adolescents and young women with seizure disorders: ACOG committee opinion, number 806. Obstet Gynecol. 2020;135(5):e213-e220. doi:10.1097/AOG.0000000000003827 [PubMed 32332416]
Andrejak M, Tribouilloy C. Drug-induced valvular heart disease: an update. Arch Cardiovasc Dis. 2013;106(5):333-339. doi:10.1016/j.acvd.2013.02.003 [PubMed 23769407]
Bartlett D. Drug-induced serotonin syndrome. Crit Care Nurse. 2017;37(1):49-54. doi:10.4037/ccn2017169 [PubMed 28148614]
Bonnin M, Mercier FJ, Sitbon O, et al. Severe pulmonary hypertension during pregnancy: mode of delivery and anesthetic management of 15 consecutive cases. Anesthesiology. 2005;102(6):1133-1137. doi:10.1097/00000542-200506000-00012 [PubMed 15915025]
Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med. 2005;352(11):1112-1120. doi:10.1056/NEJMra041867. Erratum in: N Engl J Med. 2007;356(23):2437. Erratum in: N Engl J Med. 2009;361(17):1714. [PubMed 15784664]
Dempsie Y, MacLean MR. Pulmonary hypertension: therapeutic targets within the serotonin system. Br J Pharmacol. 2008;155(4):455-462. doi:10.1038/bjp.2008.241 [PubMed 18536742]
Dunkley EJ, Isbister GK, Sibbritt D, Dawson AH, Whyte IM. The Hunter Serotonin Toxicity Criteria: Simple and accurate diagnostic decision rules for serotonin toxicity. QJM. 2003;96(9):635-642. doi:10.1093/qjmed/hcg109 [PubMed 12925718]
Fintepla (fenfluramine) [prescribing information]. Smyrna, GA: UCB Inc; April 2025.
Jones KL, Johnson KA, Dick LM, Felix RJ, Kao KK, Chambers CD. Pregnancy outcomes after first trimester exposure to phentermine/fenfluramine. Teratology. 2002;65(3):125-130. doi:10.1002/tera.10023 [PubMed 11877776]
Lagae L, Sullivan J, Knupp K, et al; FAiRE DS Study Group. Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: a randomised, double-blind, placebo-controlled trial. Lancet. 2019;394(10216):2243-2254. doi:10.1016/S0140-6736(19)32500-0 [PubMed 31862249]
National Institute for Health and Care Excellence (NICE). Epilepsies in children, young people and adults. https://www.nice.org.uk/guidance/ng217. Published April 27, 2022. Accessed June 19, 2024.
Pack AM, Oskoui M, Williams Roberson S, et al. Teratogenesis, perinatal, and neurodevelopmental outcomes after in utero exposure to antiseizure medication: practice guideline from the AAN, AES, and SMFM. Neurology. 2024;102(11):e209279. doi:10.1212/WNL.0000000000209279 [PubMed 38748979]
Rothman RB, Baumann MH. Serotonergic drugs and valvular heart disease. Expert Opin Drug Saf. 2009;8(3):317-329. doi:10.1517/14740330902931524 [PubMed 19505264]
Sachdev M, Miller WC, Ryan T, Jollis JG. Effect of fenfluramine-derivative diet pills on cardiac valves: a meta-analysis of observational studies. Am Heart J. 2002;144(6):1065-1073. doi:10.1067/mhj.2002.126733 [PubMed 12486432]
Schoonjans AS, Lagae L, Ceulemans B. Low-dose fenfluramine in the treatment of neurologic disorders: experience in Dravet syndrome. Ther Adv Neurol Disord. 2015;8(6):328-338. doi:10.1177/1756285615607726 [PubMed 26600876]
Souza R, Humbert M, Sztrymf B, et al. Pulmonary arterial hypertension associated with fenfluramine exposure: report of 109 cases. Eur Respir J. 2008;31(2):343-348. doi:10.1183/09031936.00104807. Erratum in: Eur Respir J. 2008;31(4):912. [PubMed 17959632]
Sun-Edelstein C, Tepper SJ, Shapiro RE. Drug-induced serotonin syndrome: a review. Expert Opin Drug Saf. 2008;7(5):587-596. doi:10.1517/14740338.7.5.587 [PubMed 18759711]
Vial T, Robert E, Carlier P, Bertolotti E, Brun A. First-trimester in utero exposure to anorectics: a French collaborative study with special reference to dexfenfluramine. Int J Risk Saf Med. 1992;3(4):207-214. doi:10.3233/JRS-1992-3404 [PubMed 23511002]
Wirrell EC, Lagae L, Scheffer IE, Cross JH, Specchio N, Strzelczyk A. Practical considerations for the use of fenfluramine to manage patients with Dravet syndrome or Lennox-Gastaut syndrome in clinical practice. Epilepsia Open. 2024;9(5):1643-1657. doi:10.1002/epi4.12998 [PubMed 38962968]

Topic 128557 Version 142.0

خرید پکیج

Fenfluramine: Drug information