Ponderax

Uses

Ponderax is fenfluramine is a phenethylamine that is structurally similar to serotonin. Due to its ability to increase extracellular serotonin levels, modulate serotonergic and other neurologic receptors, and control neurotransmission, it is effective in treating pharmacoresistant seizures.

Ponderax is indicated for the treatment of seizures in Dravet syndrome patients aged two years and older.

Ponderax is also used to associated treatment for these conditions: Seizures

How Ponderax works

Dravet syndrome is a complex pediatric encephalopathy characterized by recurrent pharmacoresistant seizures of variable type, delayed development, and in many cases, impairment in speech, language, gait, and other neurocognitive functions. Despite substantial variation in presentation and severity, roughly 80% of patients with Dravet syndrome have mutations in the SCN1A gene, which encodes the alpha subunit of a voltage-gated sodium channel (Na_v1.1). This channel is predominantly localized in inhibitory GABAergic interneurons as well as in excitatory pyramidal neurons; it is thought that dysfunction of neurotransmission regulation results in the seizures and other corresponding symptoms of Dravet syndrome.

Various in vitro and in vivo studies have demonstrated that fenfluramine is capable of acting as an agonist of multiple serotonin receptors including 5-HT_1A, 5-HT_1D, 5-HT_2A, 5-HT_2B, and 5-HT_2C, as well as a σ1 receptor antagonist. This is at least partly because fenfluramine, as well as its active metabolite norfenfluramine, can act on sodium-dependent serotonin transporters (SERTs) to reverse transport direction and thereby increase extracellular serotonin levels. However, work in animal models of Dravet syndrome suggest that only the modulation of 5-HT_1D, 5-HT_2C, σ1, and possibly 5-HT_2A receptors of fenfluramine result in the anti-epileptiform activity. Interestingly, 5-HT_2B receptor agonism, which had previously been associated with cardiac valvulopathy, is not anticipated to have any therapeutic value in Dravet syndrome.

Although the exact mechanism by which stimulation/inhibition of various receptors leads to the observed therapeutic benefit is unclear, it is hypothesized to be two-fold. Stimulation of 5-HT_1D and 5-HT_2C may result in increased GABAergic neurotransmission, while σ1 receptor antagonism may help to modulate responses to N-methyl-D-aspartate (NMDA).

Toxicity

Overdosage of fenfluramine has been reported; in overdose cases, symptoms include agitation, anxiety, restlessness, twitching, tremors/muscle spasms, flushing, tachycardia, mydriasis, increased muscle tone, respiratory distress/failure, seizure, and coma. Some overdosage cases proved fatal, and in most fatal cases, patients experienced seizures, coma, and cardiorespiratory arrest.

There is currently no standard practice for managing fenfluramine overdose. Symptomatic management, including ensuring proper ventilation and monitoring of both cardiac and respiratory functions is recommended.

Food Interaction

• Take with or without food. The absorption is unaffected by food.

[Moderate] GENERALLY AVOID: Alcohol may potentiate the central nervous system and cardiovascular effects of centrally-acting appetite suppressants.

In one study, concurrent administration of methamphetamine (30 mg intravenously) and ethanol (1 gm

This increases cardiac work and myocardial oxygen consumption, which may lead to more adverse cardiovascular effects than either agent alone.

Subjective effects of ethanol were diminished in the eight study subjects, but those of methamphetamine were not affected.

The pharmacokinetics of methamphetamine were also unaffected except for a decrease in the apparent volume of distribution at steady state.

MANAGEMENT: Concomitant use of centrally-acting appetite suppressants and alcohol should be avoided if possible, especially in patients with a history of cardiovascular disease.

Patients should be counselled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

Ponderax Hypertension interaction

[Moderate] Ponderax can cause an increase in blood pressure.

Exercise care when using this agent in hypertensive patients.

It is recommended to monitor blood pressure in patients treated with fenfluramine.

Ponderax Drug Interaction

Major: buspirone, buspirone, duloxetine, duloxetine, desvenlafaxine, desvenlafaxine, fluoxetine, fluoxetineModerate: aripiprazole, aripiprazole, lorazepam, lorazepam, celecoxib, celecoxib, divalproex sodium, divalproex sodium, acetaminophen / hydrocodone, acetaminophen / hydrocodone, diazepam, diazepam

Ponderax Disease Interaction

Major: cardiac disease, pulmonary diseaseModerate: suicidal tendency, bipolar disorders, psychotic disorders, alcoholism, anorexia, hypertension, liver impairment, renal dysfunction, visual disturbance

Volume of Distribution

Ponderax has an apparent volume of distribution of 11.9 L/kg with a coefficient of variation of 16.5% following oral administration in healthy subjects.

Elimination Route

Ponderax has a steady-state T_max of between four and five hours and an absolute bioavailability of approximately 68-74%. Ponderax administered to pediatric patients at 0.7 mg/kg/day up to 26 mg resulted in a mean C_max of 68.0 ng/mL with a coefficient of variation of 41%; similarly the AUC_0-24 was 1390 (44%) ng*h/mL.

Half Life

Ponderax has an elimination half-life of 20 hours in healthy subjects.

Clearance

Ponderax has a mean clearance of 24.8 L/h with a coefficient of variation of 29% in healthy subjects.

Elimination Route

Over 90% of fenfluramine is excreted in urine and less than 5% in feces; unchanged fenfluramine and the major active metabolite norfenfluramine account for less than 25% of the recovered amount.

Innovators Monograph

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