Fenfluramine
Fenfluramine, sold under the brand name Fintepla, is a medication used for the treatment of seizures associated with Dravet syndrome in people age two and older.
The most common adverse reactions include decreased appetite; drowsiness, sedation and lethargy; diarrhea; constipation; abnormal echocardiogram; fatigue or lack of energy; ataxia, balance disorder, gait disturbance ; increased blood pressure; drooling, salivary hypersecretion ; pyrexia ; upper respiratory tract infection; vomiting; decreased weight; risk of falls; and status epilepticus.
Medical uses
In the United States fenfluramine is indicated for the treatment of seizures associated with Dravet syndrome in people age two and older.Dravet syndrome is a life-threatening, rare and chronic form of epilepsy. It is often characterized by severe and unrelenting seizures despite medical treatment.
Adverse effects
The U.S. Food and Drug Administration fenfluramine labeling includes a boxed warning stating the drug is associated with valvular heart disease and pulmonary arterial hypertension. Because of the risks of VHD and PAH, fenfluramine is available only through a restricted drug distribution program, under a risk evaluation and mitigation strategy. The fenfluramine REMS requires health care professionals who prescribe fenfluramine and pharmacies that dispense fenfluramine to be specially certified in the fenfluramine REMS and that patients be enrolled in the REMS. As part of the REMS requirements, prescribers and patients must adhere to the required cardiac monitoring with echocardiograms to receive fenfluramine.At higher therapeutic doses, headache, diarrhea, dizziness, dry mouth, erectile dysfunction, anxiety, insomnia, irritability, lethargy, and stimulation have been reported with fenfluramine.
There have been reports associating chronic fenfluramine treatment with emotional instability, cognitive deficits, depression, psychosis, exacerbation of pre-existing psychosis, and sleep disturbances. It has been suggested that some of these effects may be mediated by serotonergic neurotoxicity/depletion of serotonin with chronic administration and/or activation of serotonin 5-HT2A receptors.
Heart valve disease
The distinctive valvular abnormality seen with fenfluramine is a thickening of the leaflet and chordae tendineae. One mechanism used to explain this phenomenon involves heart valve serotonin receptors, which are thought to help regulate growth. Since fenfluramine and its active metabolite norfenfluramine stimulate serotonin receptors, this may have led to the valvular abnormalities found in patients using fenfluramine. In particular norfenfluramine is a potent inhibitor of the re-uptake of 5-HT into nerve terminals. Fenfluramine and its active metabolite norfenfluramine affect the 5-HT2B receptors, which are plentiful in human cardiac valves. The suggested mechanism by which fenfluramine causes damage is through over or inappropriate stimulation of these receptors leading to inappropriate valve cell division. Supporting this idea is the fact that this valve abnormality has also occurred in patients using other drugs that act on 5-HT2B receptors.According to a study of 5,743 former users conducted by a plaintiff's expert cardiologist, damage to the heart valve continued long after stopping the medication. Of the users tested, 20% of women, and 12% of men were affected. For all ex-users, there was a 7-fold increase of chances of needing surgery for faulty heart valves caused by the drug.
Overdose
In overdose, fenfluramine can cause serotonin syndrome and rapidly result in death.Pharmacology
Pharmacodynamics
Fenfluramine acts primarily as a serotonin releasing agent. It increases the level of serotonin, a neurotransmitter that regulates mood, appetite and other functions. Fenfluramine causes the release of serotonin by disrupting vesicular storage of the neurotransmitter, and reversing serotonin transporter function. The drug also acts as a norepinephrine releasing agent to a lesser extent, particularly via its active metabolite norfenfluramine. At high concentrations, norfenfluramine, though not fenfluramine, also acts as a dopamine releasing agent, and so fenfluramine may do this at very high doses as well. In addition to monoamine release, while fenfluramine binds only very weakly to the serotonin 5-HT2 receptors, norfenfluramine binds to and activates the serotonin 5-HT2B and 5-HT2C receptors with high affinity and the serotonin 5-HT2A receptor with moderate affinity. The result of the increased serotonergic and noradrenergic neurotransmission is a feeling of fullness and reduced appetite.The combination of fenfluramine with phentermine, a norepinephrine–dopamine releasing agent acting primarily on norepinephrine, results in a well-balanced serotonin–norepinephrine releasing agent with weaker effects of dopamine release.
| Drug | Type | Ref | |||
| Fenfluramine | 739 | >10,000 | 79.3–108 | ||
| -Fenfluramine | 302 | >10,000 | 51.7 | ||
| -Fenfluramine | >10,000 | >10,000 | 147 | ||
| Norfenfluramine | 168–170 | 1,900–1,925 | 104 | ||
| Phentermine | 39.4 | 262 | 3,511 |
Pharmacokinetics
The elimination half-life of fenfluramine has been reported as ranging from 13 to 30 hours. The mean elimination half-lives of its enantiomers have been found to be 19 hours for dexfenfluramine and 25 hours for levfenfluramine. Norfenfluramine, the major active metabolite of fenfluramine, has an elimination half-life that is about 1.5 to 2 times as long as that of fenfluramine, with mean values of 34 hours for dexnorfenfluramine and 50 hours for levnorfenfluramine.Chemistry
Fenfluramine is a substituted amphetamine and is also known as 3-trifluoromethyl-N-ethylamphetamine. It is a racemic mixture of two enantiomers, dexfenfluramine and levofenfluramine. Some analogues of fenfluramine include norfenfluramine, benfluorex, flucetorex, and fludorex.History
Fenfluramine was developed in the early 1960s and was introduced in France in 1963. Approximately 50 million Europeans were treated with fenfluramine for appetite suppression between 1963 and 1996. Fenfluramine was approved in the United States in 1973. The combination of fenfluramine and phentermine was proposed in 1984. Approximately 5 million people in the United States were given fenfluramine or dexfenfluramine with or without phentermine between 1996 and 1998.In the early 1990s, French researchers reported an association of fenfluramine with primary pulmonary hypertension and dyspnea in a small sample of patients. Fenfluramine was withdrawn from the U.S. market in 1997 after reports of heart valve disease and continued findings of pulmonary hypertension, including a condition known as cardiac fibrosis. It was subsequently withdrawn from other markets around the world. It was banned in India in 1998.
Fenfluramine was an appetite suppressant which was used to treat obesity. It was used both on its own and, in combination with phentermine, as part of the anti-obesity medication Fen-Phen.
In June 2020, fenfluramine was approved for medical use in the United States with an indication to treat Dravet syndrome.
The effectiveness of fenfluramine for the treatment of seizures associated with Dravet syndrome was demonstrated in two clinical studies in 202 subjects between ages two and eighteen. The studies measured the change from baseline in the frequency of convulsive seizures. In both studies, subjects treated with fenfluramine had significantly greater reductions in the frequency of convulsive seizures during the trials than subjects who received placebo. These reductions were seen within 3–4 weeks, and remained generally consistent over the 14- to 15-week treatment periods.
The U.S. Food and Drug Administration granted the application for fenfluramine priority review and orphan drug designations. The FDA granted approval of Fintepla to Zogenix, Inc.