There is an association between serotonergic drugs with 5-HT2B receptor agonist activity, including fenfluramine, and 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.
Dravet syndrome: Children ≥2 years and Adolescents: Oral: Initial: 0.1 mg/kg/dose twice daily; may increase based on clinical response and tolerability after 7 days to 0.2 mg/kg/dose twice daily. After 7 days, if not receiving concurrent stiripentol, may further increase to 0.35 mg/kg/dose twice daily; maximum dose: 13 mg/dose twice daily; may increase dose every 4 days if more rapid titration is warranted. For dosing in patients receiving concurrent stiripentol or other interacting drugs, consult drug interactions database.
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.
Children ≥2 years and Adolescents:
Mild impairment: No dosage adjustments are provided in the manufacturer's labeling.
Moderate to severe impairment: Use is not recommended.
Children ≥2 years and Adolescents: Mild to severe impairment: Use is not recommended.
(For additional information see "Fenfluramine: Drug information")
Dravet syndrome–associated seizures: 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. If not on stiripentol, increase to 0.35 mg/kg twice daily. Maximum dose: 26 mg/day. If receiving concurrent stiripentol, may increase to 0.2 mg/kg twice daily. Maximum dose: 17 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).
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.
Mild impairment: There are no dosage adjustments provided in the manufacturer's labeling.
Moderate to severe impairment: Use is not recommended.
Use is not recommended in patients with hepatic impairment.
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]
No
C-IV
An FDA-approved patient medication guide, which is available with the product information at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/212102s000lbl.pdf#page=23, must be dispensed with this medication.
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.
Oral: Administer with or without food using the provided calibrated oral syringe (3 mL or 6 mL).
Enteral: May be administered via gastric and nasogastric feeding tubes.
Store between 20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C to 30°C (59°F to 86°F). Do not refrigerate or freeze. Store the bottle and syringe together. Discard any unused portion 3 months after first opening the bottle or the “Discard After” date on the bottle, whichever is sooner.
Treatment of seizures associated with Dravet syndrome (FDA approved in ages ≥2 years).
Increased blood pressure is common with therapy; hypertensive crisis has also been observed rarely 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 in trials up to 3 years duration.
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 up to 3 years duration, there were no reports of pulmonary arterial hypertension (PAH) in children and young adults 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 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:
• Concomitant use of drugs that increase serotonin synthesis, block serotonin reuptake, and/or impair serotonin metabolism (eg, monoamine oxidase inhibitors [MAOIs]). Of note, concomitant use of some serotonergic agents, such as MAOIs, is contraindicated.
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 up to 3 years duration (Ref).
Mechanism: Dose-related; likely due to activation of serotonin 5HT-2B receptors; 5HT-2B receptors 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-2B receptor agonists (Ref)
Fenfluramine commonly causes decreased appetite and significant weight loss (≥7% from baseline) in children and adolescents receiving fenfluramine for Dravet syndrome; however, most patients resumed expected growth-associated weight gain by the end of the 3-year open-label extension study.
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).
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>10%:
Cardiovascular: Aortic insufficiency (18% to 23%) (Lagae 2020) (table 1) , increased blood pressure (8% to 13%) (table 2) , mitral valve insufficiency (18% to 23%) (Lagae 2020) (table 3)
Drug (Fenfluramine) |
Placebo |
Dose |
Number of Patients (Fenfluramine) |
Number of Patients (Placebo) |
Source |
Comments |
---|---|---|---|---|---|---|
23% |
13% |
0.7 mg/kg/day |
40 |
40 |
Lagae 2020 |
Trace and within the normal physiological range |
18% |
13% |
0.2 mg/kg/day |
39 |
40 |
Lagae 2020 |
Drug (Fenfluramine) |
Placebo |
Dose |
Number of Patients (Fenfluramine) |
Number of Patients (Placebo) |
---|---|---|---|---|
13% |
5% |
0.2 mg/kg/day |
39 |
84 |
8% |
5% |
0.7 mg/kg/day |
40 |
84 |
Drug (Fenfluramine) |
Placebo |
Dose |
Number of Patients (Fenfluramine) |
Number of Patients (Placebo) |
Source |
Comments |
---|---|---|---|---|---|---|
23% |
13% |
0.7 mg/kg/day |
40 |
40 |
Lagae 2020 |
Trace and within the normal physiological range |
18% |
13% |
0.2 mg/kg/day |
39 |
40 |
Lagae 2020 |
Endocrine & metabolic: Weight loss (5% to 13%, dose-related) (table 4)
Drug (Fenfluramine) |
Placebo |
Dose |
Number of Patients (Fenfluramine) |
Number of Patients (Placebo) |
---|---|---|---|---|
13% |
1% |
0.2 mg/kg/day |
39 |
84 |
5% |
1% |
0.7 mg/kg/day |
40 |
84 |
Gastrointestinal: Decreased appetite (23% to 38%) (table 5) , diarrhea (15% to 31%), sialorrhea
Drug (Fenfluramine) |
Placebo |
Dose |
Number of Patients (Fenfluramine) |
Number of Patients (Placebo) |
---|---|---|---|---|
38% |
8% |
0.7 mg/kg/day |
40 |
84 |
23% |
8% |
0.2 mg/kg/day |
39 |
84 |
Nervous system: Drooling, drowsiness, fatigue, lethargy, malaise, sedated state
Neuromuscular & skeletal: Asthenia
Respiratory: Upper respiratory tract infection (5% to 21%)
Miscellaneous: Fever (5% to 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%), vomiting (5% to 10%)
Genitourinary: Urinary incontinence (3% to 5%), urinary tract infection (5%)
Hematologic & oncologic: Bruise (5%)
Nervous system: Abnormal behavior (8%; stereotypy: 5%), abnormal gait, ataxia, balance impairment, chills (5%), falling (10%), headache (8%), hypoactivity (5%), hypotonia (8%), insomnia (5%), irritability (3%), mood changes (negativism: 5%), status epilepticus (3%)
Neuromuscular & skeletal: Tremor (3%)
Otic: Otic infection (3% to 8%)
Respiratory: Bronchitis (3%), croup (3% to 5%), 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)
Hypersensitivity to fenfluramine or any component of the formulation; concomitant use with or within 14 days of monoamine oxidase inhibitors.
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.
Disease-related concerns:
• Hepatic impairment: Use is not recommended in patients with hepatic impairment.
• Renal impairment: Use is not recommended in moderate or severe renal impairment.
Other warnings/precautions:
• REMS program: [US Boxed Warning]: Fenfluramine is available only through a restricted Risk Evaluation and Mitigation Strategy (REMS) program. Prescribers and pharmacies must enroll in the Fintepla REMS program; enrollment and additional information are available at 1-877-964-3649 or at www.FinteplaREMS.com. 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.
Substrate of CYP1A2 (major), CYP2B6 (major), CYP2C19 (minor), CYP2C9 (minor), CYP2D6 (minor), CYP3A4 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy
Alizapride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Azelastine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Blonanserin: CNS Depressants may enhance the CNS depressant effect 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 enhance the CNS depressant effect of Brexanolone. Risk C: Monitor therapy
Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Broccoli: May decrease the serum concentration of CYP1A2 Substrates (High risk with Inducers). Risk C: Monitor therapy
Bromopride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Buprenorphine: CNS Depressants may enhance the CNS depressant effect 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
Cannabinoid-Containing Products: CNS Depressants may enhance the CNS depressant effect of Cannabinoid-Containing Products. Risk C: Monitor therapy
Cannabis: May decrease the serum concentration of CYP1A2 Substrates (High risk with Inducers). Risk C: Monitor therapy
Chlormethiazole: May enhance the CNS depressant effect 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 enhance the adverse/toxic effect of CNS Depressants. Risk C: Monitor therapy
CloBAZam: May increase the 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 enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapy
Cyproheptadine: Fenfluramine may enhance the CNS depressant effect of Cyproheptadine. Cyproheptadine may diminish the therapeutic effect of Fenfluramine. Risk C: Monitor therapy
Daridorexant: May enhance the CNS depressant effect 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
Difelikefalin: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Doxylamine: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended. Risk C: Monitor therapy
Droperidol: May enhance the CNS depressant effect 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
Esketamine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Fexinidazole: May decrease the 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
Flunitrazepam: CNS Depressants may enhance the CNS depressant effect 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 enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Kava Kava: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Kratom: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Lemborexant: May enhance the CNS depressant effect 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
Linezolid: Fenfluramine may enhance the serotonergic effect of Linezolid. This could result in serotonin syndrome. Risk X: Avoid combination
Lisuride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Lorcaserin (Withdrawn From US Market): May enhance the serotonergic effect of Serotonergic Agents (Moderate Risk, Miscellaneous). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Lumacaftor and Ivacaftor: May decrease the serum concentration of CYP2B6 Substrates (High risk with Inducers). Risk C: Monitor therapy
Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect 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
Methylene Blue: Fenfluramine may enhance the serotonergic effect of Methylene Blue. This could result in serotonin syndrome. Risk X: Avoid combination
Metoclopramide: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Risk C: Monitor therapy
Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Monoamine Oxidase Inhibitors (Antidepressant): Fenfluramine may enhance the serotonergic effect of Monoamine Oxidase Inhibitors (Antidepressant). This could result in serotonin syndrome. Risk X: Avoid combination
Monoamine Oxidase Inhibitors (Type B): Fenfluramine may enhance the serotonergic effect of Monoamine Oxidase Inhibitors (Type B). This could result in serotonin syndrome. Risk X: Avoid combination
Olopatadine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Opioid Agonists: CNS Depressants may enhance the CNS depressant effect 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
Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Risk X: Avoid combination
Oxitriptan: May enhance the serotonergic effect of Serotonergic Agents (Moderate Risk, Miscellaneous). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Oxybate Salt Products: CNS Depressants may enhance the CNS depressant effect 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 enhance the CNS depressant effect 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
Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Risk X: Avoid combination
Perampanel: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Risk C: Monitor therapy
Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Risk C: Monitor therapy
RifAMPin: May decrease the serum concentration of Fenfluramine. Management: Consider increasing the fenfluramine dose when used together with rifampin, but do not exceed the fenfluramine maximum daily dosage [0.35 mg/kg twice daily (26 mg/day)]. Risk C: Monitor therapy
Ropeginterferon Alfa-2b: CNS Depressants may enhance the adverse/toxic effect 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 enhance the sedative effect of ROPINIRole. Risk C: Monitor therapy
Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Risk C: Monitor therapy
Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Risk C: Monitor therapy
Serotonergic Agents (High Risk): Fenfluramine may enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Risk C: Monitor therapy
Serotonergic Agents (Moderate Risk, Miscellaneous): Fenfluramine may enhance the serotonergic effect of Serotonergic Agents (Moderate Risk, Miscellaneous). This could result in serotonin syndrome. Risk C: Monitor therapy
Stiripentol: May increase the 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
Suvorexant: CNS Depressants may enhance the CNS depressant effect 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 enhance the CNS depressant effect of Thalidomide. Risk X: Avoid combination
Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Valerian: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Zolpidem: CNS Depressants may enhance the CNS depressant effect 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
Information related to inadvertent maternal use of fenfluramine in pregnancy is 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).
Echocardiogram (baseline and every 6 months during therapy; 3 to 6 months following discontinuation); growth and weight; blood pressure; vision or eye changes; seizure frequency, duration, and severity; signs and symptoms of serotonin syndrome in patients receiving concomitant serotonergic agents (eg, mental status changes, hyperthermia, tachycardia, hyperreflexia, GI symptoms); emergence or worsening depression and suicidality (eg, suicidal thoughts, depression, behavioral changes).
The mechanisms by which fenfluramine exerts its therapeutic effects in the treatment of seizures associated with Dravet 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.
Note: Pharmacokinetic parameters in pediatric patients are reported to be similar to those in healthy adult subjects.
Distribution: Vz/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: 4 to 5 hours.
Excretion: Urine: >90% (<25% as unchanged drug or active metabolite); feces: <5%.
Solution (Fintepla Oral)
2.2 mg/mL (per mL): $55.98
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