fenfluramine (Rx)

Brand and Other Names:Fintepla
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

oral solution, Schedule IV

  • 2.2mg/mL

Seizures

Indicated for treatment of seizures associated with Dravet syndrome

Without concomitant stiripentol

  • Initial dose: 0.1 mg/kg PO BID; not to exceed 26 mg/day
  • May be increased weekly based on efficacy and tolerability
  • On Day 7: May increase dose up to 0.2 mg/kg PO BID (maximum of 26 mg/day)
  • On Day14: May increase dose up to 0.35 mg/kg PO BID (maximum of 26 mg/day)
  • In whom a more rapid titration is warranted, may increase dose every 4 days

With concomitant stiripentol and clobazam

  • Initial dose: 0.1 mg/kg PO BID; not to exceed 17 mg/day
  • May be increased weekly based on efficacy and tolerability
  • On Day 7: May increase dose up to 0.15 mg/kg PO BID (maximum of 17 mg/day)
  • On Day14: May increase dose up to 0.2 mg/kg PO BID (maximum of 17 mg/day)

Dosage Modifications

Renal impairment

  • Moderate-to-severe: Not recommended

Hepatic impairment

  • All severities: Not recommended

Dosing Considerations

Assessment during and after administration

  • Obtain echocardiogram (ECHO) every 6 months during treatment, and 3-6 months after final dose

Discontinuing fenfluramine

  • Gradually decrease dose
  • Avoid abrupt discontinuation when possible to minimize the risk of increased seizure frequency and status epilepticus

Dosage Forms & Strengths

oral solution, Schedule IV

  • 2.2mg/mL

Seizures

<2 years: Safety and efficacy not established

≥2 years

  • Indicated for treatment of seizures associated with Dravet syndrome in patients aged 2 years and older

  • Without concomitant stiripentol
    • Initial dose: 0.1 mg/kg PO BID; not to exceed 26 mg/day
    • May be increased weekly based on efficacy and tolerability
    • On Day 7: May increase dose up to 0.2 mg/kg PO BID (maximum of 26 mg/day)
    • On Day14: May increase dose up to 0.35 mg/kg PO BID (maximum of 26 mg/day)
    • In whom a more rapid titration is warranted, may increase dose every 4 days
  • With concomitant stiripentol and clobazam
    • Initial dose: 0.1 mg/kg PO BID; not to exceed 17 mg/day
    • May be increased weekly based on efficacy and tolerability
    • On Day 7: May increase dose up to 0.15 mg/kg PO BID (maximum of 17 mg/day)
    • On Day14: May increase dose up to 0.2 mg/kg PO BID (maximum of 17 mg/day)

Dosage Modifications

Renal impairment

  • Moderate-to-severe: Not recommended

Hepatic impairment

  • All severities: Not recommended

Dosing Considerations

Assessment during and after administration

  • Obtain echocardiogram (ECHO) every 6 months during treatment, and 3-6 months after final dose
  • Carefully monitor growth of children and adolescents
  • Monitor weight regularly during treatment; dose modifications should be considered if a decrease in weight is observed

Discontinuing fenfluramine

  • Gradually decrease dose
  • Avoid abrupt discontinuation when possible to minimize the risk of increased seizure frequency and status epilepticus
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Interactions

Interaction Checker

and fenfluramine

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    No Interactions Found
    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

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            Adverse Effects

            >10%

            • Decreased appetite (23-49%)
            • Diarrhea (15-31%)
            • Fatigue, malaise, asthenia (15-30%)
            • Somnolence, sedation, lethargy (23-26%)
            • Abnormal ECHO (9-23%)
            • Pyrexia (15-21%)
            • Upper respiratory tract infection (7-21%)
            • Trace of mitral or aortic valve regurgitation (14-16%)
            • Blood pressure increased (8-13%)
            • Drooling, salivary hypersecretion (8-13%)
            • Weight decreased (5-13%)
            • Status epilepticus (3-12%)

            1-10%

            • Fall (10%)
            • Ataxia, balance disorder, gait disturbance (7-10%)
            • Vomiting (5-10%)
            • Constipation (3-10%)
            • Decreased blood glucose (9%)
            • Abnormal behavior (8-9%)
            • Ear infection (3-9%)
            • Irritability (3-9%)
            • Tremor (3-9%)
            • Bronchitis (3-9%)
            • Hypotonia (8%)
            • Headache (8%)
            • Rash (5-8%)
            • Rhinitis (3-8%)
            • Gastroenteritis (2-8%)
            • Blood prolactin increased (5%)
            • Decreased activity (5%)
            • Dehydration (5%)
            • Stereotypy (5%)
            • Contusion (5%)
            • Eczema (5%)
            • Enuresis (5%)
            • Laryngitis (5%)
            • Negativism (5%)
            • Urinary tract infection (5%)
            • Viral infection (5%)
            • Croup (3-5%)
            • Increased heart rate (3-5%)
            • Urinary incontinence (3-5%)
            • Chills (2-5%)
            • Insomnia (2-5%)
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            Warnings

            Black Box Warnings

            Valvular heart disease and pulmonary arterial hypertension

            • There is an association between serotonergic drugs with 5-HT2B receptor agonist activity, including fenfluramine (the active ingredient), and valvular heart disease and pulmonary arterial hypertension
            • ECHO assessments are required before, during, and after treatment
            • Consider the benefits versus the risks of initiating or continuing fenfluramine based on ECHO findings
            • Owing to the risks of valvular heart disease and pulmonary arterial hypertension, fenfluramine is available only through a restricted program called the Fintepla REMS program

            Contraindications

            Hypersensitivity to fenfluramine or any of the excipients

            Concomitant use of, or within 14 days of, the administration of monoamine oxidase inhibitors (MAOIs)

            Cautions

            Owing to the association between serotonergic drugs with 5-HT2B receptor agonist activity, fenfluramine, pulmonary arterial hypertension, and valvular heart disease, cardiac monitoring is required before initiating treatment, during treatment, and after completion of fenfluramine

            May decrease appetite and weight; monitor weight regularly during treatment and modify dose if a decrease in weight is observed

            May cause somnolence, sedation, and lethargy; other CNS depressants, including alcohol, could potentiate these effects

            Advise patients not to drive or operate machinery until they have gained sufficient experience on fenfluramine

            Antiepileptic drugs (AEDs) increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication; monitor for the emergence or worsening of depression, suicidal thoughts or behavior, or any unusual changes in mood or behavior

            As with most AEDs, fenfluramine should be withdrawn gradually because of the risk of increased seizure frequency and status epilepticus; if withdrawal is needed owing to serious adverse reaction, rapid discontinuation can be considered

            Serotonin syndrome may occur, particularly with coadministration of fenfluramine with other serotonergic drugs, including, but not limited to, selective serotonin-norepinephrine reuptake inhibitors (SNRIs), selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), bupropion, triptans, dietary supplements (eg, St. John’s Wort, tryptophan), drugs that impair metabolism of serotonin (MAOIs, which are contraindicated with fenfluramine), dextromethorphan, lithium, tramadol, and antipsychotics with serotonergic agonist activity

            Significant elevation in blood pressure, including hypertensive crisis, has been reported; monitor blood pressure during treatment

            May cause mydriasis and can precipitate angle-closure glaucoma; discontinue therapy in patients with acute decrease in visual acuity or ocular pain

            Fintepla REMS program

            • Further information is available at http://www.FinteplaREMS.com or by telephone at 1-877-964-3649
            • Prescribers
              • Must be certified by enrolling in the program
              • Must counsel patients receiving fenfluramine about the risk of valvular heart disease and pulmonary arterial hypertension, signs and symptoms of valvular heart disease and pulmonary arterial hypertension, cardiac monitoring via ECHO during treatment, and cardiac monitoring after treatment
            • Patients
              • Must enroll in the REMS program and comply with ongoing monitoring requirements
            • Pharmacies, wholesalers, and distributers
              • Must be certified by enrolling in the REMS program and must only dispense to patients who are authorized to receive treatment
              • Wholesalers and distributers must only distribute to certified pharmacies

            Drug interaction overview

            • Stiripentol plus clobazam
              • Coadministration with stiripentol plus clobazam, with or without valproate, inhibits the metabolism of fenfluramine, thereby increasing fenfluramine plasma concentrations and decreasing its metabolite, norfenfluramine
              • Dose adjustment is required for patients taking stiripentol plus clobazam
            • Strong CYP1A2 and CYP2B6 inducers
              • Coadministration with rifampin or strong CYP1A2 and CYP2B6 inducers decreases fenfluramine plasma levels and effects
              • Consider increasing fenfluramine dosage when coadministered with rifampin or a strong CYP1A2 and CYP2B6 inducer; do not exceed the maximum daily dosage
            • Serotonin receptor antagonists
              • Monitor appropriately when coadministered with cyproheptadine or potent 5-HT1A, 5-HT1D, 5-HT2A, or 5-HT2C serotonin receptor antagonists
              • Cyproheptadine and potent 5-HT1A, 5-HT1D, 5-HT2A, and 5-HT2C serotonin receptor antagonists may decrease the efficacy of fenfluramine
            • Serotonergic drugs
              • Coadministration with MAOIs is contraindicated
              • Use with caution in patients taking medications that increase serotonin
              • Coadministration with drugs (eg, SSRIs) that increase serotonin may increase the risk of serotonin syndrome
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            Pregnancy & Lactation

            Pregnancy

            There are adequate human or animal data on the developmental risks associated with the use in pregnant females

            Pregnancy exposure registry

            • Registry monitors pregnancy outcomes in females exposed to AEDs, such as fenfluramine during pregnancy
            • Encourage females who are taking fenfluramine during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling the toll-free number 1-888-233-2334 or visiting http://www.aedpregnancyregistry.org

            Lactation

            No data available on the presence of fenfluramine or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            Mechanism of action for the treatment of seizures associated with Dravet syndrome is 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

            Absorption

            Peak plasma concentration (steady-state): 68 ng/mL

            AUC (steady-state): 1390 ng⋅hr/mL

            Peak plasma time (steady-state): 4-5 hr

            Absolute bioavailability: ~68-74%

            Distribution

            Vd: 11.9 L/kg

            Protein bound: 50%

            Metabolism

            Primarily metabolized by CYP1A2, CYP2B6, and CYP2D6

            Minor extent are CYP2C9, CYP2C19, and CYP3A4/5

            Norfenfluramine is then deaminated and oxidized to form inactive metabolites

            Elimination

            Half-life: 20 hr

            Clearance: 24.8 L/hr

            Excretion

            • Urine: >90% as fenfluramine; <25% of total (norfenfluramine, or other metabolites)
            • Feces: <5%
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            Administration

            Oral Administration

            Use a calibrated measuring device (either a 3- or 6-mL oral syringe) provided by the pharmacy to measure and administer the prescribed dose accurately; do not use a household teaspoon or tablespoon

            Also compatible with commercially available gastric and nasogastric feeding tubes

            Storage

            Unopened bottle

            • Store at room temperature (20-25ºC [68-77ºF]); excursions permitted to 15-30ºC (59-86ºF)
            • Do not refrigerate or freeze
            • Store the bottle and syringe together

            Opened bottle

            • Discard any unused portion 3 months after first opening the bottle or the “Discard After” date on the bottle, whichever is sooner
            • Do not refrigerate or freeze
            • Store the bottle and syringe together
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            Images

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            Formulary

            FormularyPatient Discounts

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            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
            QL Quantity Limits
            Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
            ST Step Therapy
            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
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            Drugs that have restrictions other than prior authorization, quantity limits, and step therapy associated with each prescription.
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.