FENFLURAMINE

Clinical safety rating: caution

Comprehensive clinical and safety monograph for FENFLURAMINE (FENFLURAMINE).

How it works

Fenfluramine is a serotonin-releasing agent and serotonin receptor agonist. It increases extracellular serotonin levels by promoting release from presynaptic neurons and inhibiting reuptake, leading to appetite suppression. Its antiseizure effect in Dravet syndrome is thought to be mediated via 5-HT2 receptor activation, enhancing inhibitory neurotransmission.

What the body does with it

Metabolism	Primarily metabolized by CYP2C9 and CYP1A2 to active metabolite norfenfluramine; minor metabolism by CYP3A4 and CYP2D6.
Excretion	Renal excretion of unchanged drug accounts for <1% of the administered dose; fenfluramine is extensively metabolized, with metabolites primarily excreted renally. Approximately 60–70% of the dose appears in urine as metabolites (including norfenfluramine and other dealkylated products) within 72 hours, and about 5–10% is eliminated in feces via biliary excretion.
Half-life	Terminal elimination half-life of fenfluramine is approximately 20 hours (range 13–30 hours) for the parent drug, while its active metabolite norfenfluramine has a longer half-life of approximately 30–34 hours. This extended half-life supports twice-daily dosing but contributes to accumulation with repeated administration.
Protein binding	Approximately 34–40% bound to plasma proteins, primarily albumin.
Volume of Distribution	Volume of distribution is approximately 10–15 L/kg, indicating extensive distribution into tissues. High Vd reflects significant uptake into tissues, including brain, which correlates with its central anorectic and serotonergic activity.
Bioavailability	Oral bioavailability is approximately 70–80% due to first-pass metabolism. The absolute bioavailability is about 70% in adults; food does not significantly alter overall absorption.
Onset of Action	Orally: Onset of clinical effect (appetite suppression) occurs within 1–2 hours after oral administration, with peak plasma concentrations reached at 1.5–4 hours. For Dravet syndrome (as fenfluramine hydrochloride), onset of seizure reduction may be observed within 2–4 weeks of initiating therapy.
Duration of Action	Duration of appetite-suppressant effect is approximately 12–20 hours following a single oral dose, allowing twice-daily dosing. For antiseizure effects in Dravet syndrome, the duration of action supports a 12-hour dosing interval, with sustained efficacy over time.

Classification & Brands

Dosing & administration

25 mg orally three times daily, titrated to a maximum of 400 mg daily in divided doses.

Dosage form	SOLUTION
Renal impairment	GFR 30-89 mL/min: no adjustment required; GFR 15-29 mL/min: reduce dose by 50%; GFR <15 mL/min or dialysis: contraindicated.
Liver impairment	Child-Pugh A: no adjustment; Child-Pugh B: reduce dose by 50%; Child-Pugh C: avoid use.
Pediatric use	Weight-based: 0.5-2 mg/kg/day orally divided every 8 hours, maximum 80 mg/day; use only for Dravet syndrome in patients aged 2-18 years.
Geriatric use	Start at 12.5 mg twice daily; caution due to increased risk of valvular heart disease and pulmonary hypertension.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for FENFLURAMINE (FENFLURAMINE).

Breastfeeding	Excreted in breast milk. M/P ratio not determined. Due to potential for infant toxicity (serotonin effects, including increased crying, sleep disturbances), advise against breastfeeding during therapy. Consider alternative medications.
Teratogenic Risk	First trimester: Limited human data; animal studies show increased risk of cardiovascular malformations at high doses. Second/third trimester: Risk of persistent pulmonary hypertension of the newborn (PPHN) and serotonin syndrome-like withdrawal in neonates. Avoid in pregnancy unless benefit outweighs risk.

Warnings & precautions

■ FDA Black Box Warning

Valvular heart disease and pulmonary hypertension: Fenfluramine is associated with increased risk of cardiac valvulopathy and pulmonary hypertension, especially with long-term use or high doses.

Side Effect Profile

Serious Effects

Absolute Contraindications

History of valvular heart disease, pulmonary hypertension, within 14 days of MAOIs, hypersensitivity to fenfluramine, concurrent use of other serotonergic drugs (risk of serotonin syndrome), and patients with unrepaired congenital heart disease.

Clinical Precautions

Precautions

Cardiac valvulopathy, pulmonary hypertension, serotonin syndrome (especially with serotonergic drugs), CNS depression (avoid concurrent alcohol), glaucoma, and potential for abuse. Monitor echocardiograms before and during treatment.

Clinical Tips & Counseling

Drug interactions

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FENFLURAMINE

Clinical safety rating: caution

Comprehensive clinical and safety monograph for FENFLURAMINE (FENFLURAMINE).

How it works

What the body does with it

Metabolism	Primarily metabolized by CYP2C9 and CYP1A2 to active metabolite norfenfluramine; minor metabolism by CYP3A4 and CYP2D6.
Excretion	Renal excretion of unchanged drug accounts for <1% of the administered dose; fenfluramine is extensively metabolized, with metabolites primarily excreted renally. Approximately 60–70% of the dose appears in urine as metabolites (including norfenfluramine and other dealkylated products) within 72 hours, and about 5–10% is eliminated in feces via biliary excretion.
Half-life	Terminal elimination half-life of fenfluramine is approximately 20 hours (range 13–30 hours) for the parent drug, while its active metabolite norfenfluramine has a longer half-life of approximately 30–34 hours. This extended half-life supports twice-daily dosing but contributes to accumulation with repeated administration.
Protein binding	Approximately 34–40% bound to plasma proteins, primarily albumin.
Volume of Distribution	Volume of distribution is approximately 10–15 L/kg, indicating extensive distribution into tissues. High Vd reflects significant uptake into tissues, including brain, which correlates with its central anorectic and serotonergic activity.
Bioavailability	Oral bioavailability is approximately 70–80% due to first-pass metabolism. The absolute bioavailability is about 70% in adults; food does not significantly alter overall absorption.
Onset of Action	Orally: Onset of clinical effect (appetite suppression) occurs within 1–2 hours after oral administration, with peak plasma concentrations reached at 1.5–4 hours. For Dravet syndrome (as fenfluramine hydrochloride), onset of seizure reduction may be observed within 2–4 weeks of initiating therapy.
Duration of Action	Duration of appetite-suppressant effect is approximately 12–20 hours following a single oral dose, allowing twice-daily dosing. For antiseizure effects in Dravet syndrome, the duration of action supports a 12-hour dosing interval, with sustained efficacy over time.

Classification & Brands

Dosing & administration

25 mg orally three times daily, titrated to a maximum of 400 mg daily in divided doses.

Dosage form	SOLUTION
Renal impairment	GFR 30-89 mL/min: no adjustment required; GFR 15-29 mL/min: reduce dose by 50%; GFR <15 mL/min or dialysis: contraindicated.
Liver impairment	Child-Pugh A: no adjustment; Child-Pugh B: reduce dose by 50%; Child-Pugh C: avoid use.
Pediatric use	Weight-based: 0.5-2 mg/kg/day orally divided every 8 hours, maximum 80 mg/day; use only for Dravet syndrome in patients aged 2-18 years.
Geriatric use	Start at 12.5 mg twice daily; caution due to increased risk of valvular heart disease and pulmonary hypertension.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for FENFLURAMINE (FENFLURAMINE).

Breastfeeding	Excreted in breast milk. M/P ratio not determined. Due to potential for infant toxicity (serotonin effects, including increased crying, sleep disturbances), advise against breastfeeding during therapy. Consider alternative medications.
Teratogenic Risk	First trimester: Limited human data; animal studies show increased risk of cardiovascular malformations at high doses. Second/third trimester: Risk of persistent pulmonary hypertension of the newborn (PPHN) and serotonin syndrome-like withdrawal in neonates. Avoid in pregnancy unless benefit outweighs risk.

Warnings & precautions

■ FDA Black Box Warning

Valvular heart disease and pulmonary hypertension: Fenfluramine is associated with increased risk of cardiac valvulopathy and pulmonary hypertension, especially with long-term use or high doses.