Adifax
Adifax Uses, Dosage, Side Effects, Food Interaction and all others data.
Dravet syndrome is a pediatric encephalopathy that typically manifests within the first year of life following exposure to elevated temperatures. It is characterized by recurrent pharmacoresistant seizures, which increase in frequency and severity with disease progression. Concomitantly with these seizures, patients typically display delayed development and neurocognitive impairment. Adifax is a serotonergic phenethylamine originally used as an appetite suppressant until concerns regarding cardiotoxicity in obese patients lead to its withdrawal from the market in 1997. Through its ability to modulate neurotransmission, fenfluramine has reemerged as an effective therapy against pharmacoresistant seizures, such as those involved in Dravet syndrome.
Adifax was granted initial FDA approval in 1973 prior to its withdrawal; it was granted a new FDA approval on June 25, 2020, for treatment of Dravet syndrome patients through the restricted FINTEPLA REMS program. It is currently sold under the name FINTEPLA® by Zogenix INC.
Adifax increases extracellular serotonin levels, and also acts as both a serotonergic 5-HT2 receptor agonist and σ1 receptor antagonist. These activities, through an incompletely understood mechanism, lead to anti-epileptiform activity and therapeutic benefit. This modulation has other effects such as decreased appetite, weight loss, sedation, lethargy, increased blood pressure, and mood alteration including possible suicidal ideation. There is a risk of glaucoma and potentially fatal serotonin syndrome. Adifax should be gradually withdrawn following treatment alteration or cessation.
| Trade Name | Adifax |
| Availability | Prescription only |
| Generic | Fenfluramine |
| Fenfluramine Other Names | Fenfluramina, Fenfluramine, Fenfluraminum |
| Related Drugs | topiramate, phentermine, Topamax, semaglutide, Wegovy, Saxenda, liraglutide, cannabidiol, clobazam, Epidiolex |
| Type | |
| Formula | C12H16F3N |
| Weight | Average: 231.2573 Monoisotopic: 231.123484132 |
| Protein binding | Fenfluramine is 50% bound to plasma proteins independent of plasma drug concentration. |
| Groups | Approved, Illicit, Investigational, Withdrawn |
| Therapeutic Class | |
| Manufacturer | |
| Available Country | |
| Last Updated: | September 19, 2023 at 7:00 am |
Uses
Adifax 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.
Adifax is indicated for the treatment of seizures in Dravet syndrome patients aged two years and older.
Adifax is also used to associated treatment for these conditions: Seizures
How Adifax 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 (Nav1.1). 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-HT1A, 5-HT1D, 5-HT2A, 5-HT2B, and 5-HT2C, 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-HT1D, 5-HT2C, σ1, and possibly 5-HT2A receptors of fenfluramine result in the anti-epileptiform activity. Interestingly, 5-HT2B 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-HT1D and 5-HT2C 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. 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.
MANAGEMENT: Concomitant use of centrally-acting appetite suppressants and alcohol should be avoided if possible, especially in patients with a history of cardiovascular disease.
Adifax Hypertension interaction
[Moderate] Adifax 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.
Adifax 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
Volume of Distribution
Adifax 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
Adifax has a steady-state Tmax of between four and five hours and an absolute bioavailability of approximately 68-74%. Adifax administered to pediatric patients at 0.7 mg/kg/day up to 26 mg resulted in a mean Cmax of 68.0 ng/mL with a coefficient of variation of 41%; similarly the AUC0-24 was 1390 (44%) ng*h/mL.
Half Life
Adifax has an elimination half-life of 20 hours in healthy subjects.
Clearance
Adifax 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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