Fenfluramine

Source: Wikipedia, the free encyclopedia.
Fenfluramine
Ball-and-stick models of fenfluramine, showing the dextro isomer above and the levo isomer below
Clinical data
Trade namesSeizures: Fintepla
Appetite suppressant: Pondimin, Ponderax, Ponderal, others
Other namesZX008; 3-Trifluoromethyl-N-ethylamphetamine
AHFS/Drugs.comProfessional Drug Facts
MedlinePlusa620045
License data
Pregnancy
category
  • AU: B2
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Elimination half-life13–30 hours[5]
Identifiers
  • (RS)-N-Ethyl- 1-[3-(trifluoromethyl)phenyl]propan-2-amine
JSmol)
ChiralityRacemic mixture
  • CCNC(C)Cc1cccc(C(F)(F)F)c1
  • InChI=1S/C12H16F3N/c1-3-16-9(2)7-10-5-4-6-11(8-10)12(13,14)15/h4-6,8-9,16H,3,7H2,1-2H3 checkY
  • Key:DBGIVFWFUFKIQN-UHFFFAOYSA-N checkY
  (verify)

Fenfluramine, sold under the brand name Fintepla, is a

cardiovascular toxicity before being repurposed for new indications.[8][9] Fenfluramine was used for weight loss both alone under the brand name Pondimin and in combination with phentermine commonly known as fen-phen.[8][10][11]

positive modulator.[12][13][14] Its mechanism of action in the treatment of seizures is unknown,[6] but may involve increased activation of certain serotonin receptors and the σ1 receptor.[13][9][15]

Fenfluramine was developed in the early 1960s and was first introduced for medical use as an appetite suppressant in

withdrawn from the United States market in 1997.[8][16] Subsequently, it was repurposed for the treatment of seizures and was reintroduced in the United States and the European Union in 2020.[7][3][9] Fenfluramine was previously a schedule IV controlled substance in the United States.[7] However, the substance has since no-longer been subject to control pursuant to rule-making issued on 23 December 2022.[17]

Medical uses

Seizures

Fenfluramine is indicated for the treatment of seizures associated with Dravet syndrome and Lennox–Gastaut syndrome in people age two and older.[6][7][3]

Dravet syndrome is a life-threatening, rare and chronic form of epilepsy.[7] It is often characterized by severe and unrelenting seizures despite medical treatment.[7]

Obesity

Fenfluramine was formerly used as an

withdrawn for this use due to cardiovascular toxicity.[8]

Adverse effects

The most common adverse reactions in people with seizures include decreased appetite; drowsiness, sedation and lethargy; diarrhea; constipation; abnormal echocardiogram; fatigue or lack of energy; ataxia (lack of coordination), balance disorder, gait disturbance (trouble with walking); increased blood pressure; drooling, salivary hypersecretion (saliva overproduction); pyrexia (fever); upper respiratory tract infection; vomiting; decreased weight; risk of falls; and status epilepticus.[7]

The U.S. Food and Drug Administration (FDA) fenfluramine labeling includes a boxed warning stating the drug is associated with valvular heart disease (VHD) and pulmonary arterial hypertension (PAH).[7] 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 (REMS).[7] 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.[7] As part of the REMS requirements, prescribers and patients must adhere to the required cardiac monitoring with echocardiograms to receive fenfluramine.[7]

At higher therapeutic doses,

CNS stimulation have been reported with fenfluramine.[5]

There have been reports associating chronic fenfluramine treatment with

sleep disturbances.[5][18] 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.[18][19][20][21]

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.[22] 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.[23][24]

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.[25] 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.[25]

Overdose

In

overdose, fenfluramine can cause serotonin syndrome and rapidly result in death.[8][26]

Pharmacology

Pharmacodynamics

Fenfluramine acts primarily as a

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.[27][28]

Fenfluramine, phentermine, and monoamine release (
EC50
Tooltip Half-maximal effective concentration, nM)
Drug NETooltip Norepinephrine DATooltip Dopamine 5-HTTooltip Serotonin Type Ref
Fenfluramine 739 >10,000 79.3–108 SRATooltip Serotonin–norepinephrine releasing agent [32][27][28]
  D-Fenfluramine 302 >10,000 51.7 SNRATooltip Serotonin–norepinephrine releasing agent [32][27]
  
L-Fenfluramine
 >10,000 >10,000 147 SRA [27][33]
Norfenfluramine 168–170 1,900–1,925 104 SNRA [27][28]
Phentermine 39.4 262 3,511 NDRATooltip Norepinephrine–dopamine releasing agent [32]

Fenfluramine was identified as a

positive modulator of the σ1 receptor in 2020 and this action may be involved in its therapeutic benefits in the treatment of seizures.[13][14]

Pharmacokinetics

The

elimination half-life of fenfluramine has been reported as ranging from 13 to 30 hours.[5] The mean elimination half-lives of its enantiomers have been found to be 19 hours for dexfenfluramine and 25 hours for levfenfluramine.[8] 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.[8]

Chemistry

Fenfluramine is a substituted amphetamine and is also known as 3-trifluoromethyl-N-ethylamphetamine.[8] It is a racemic mixture of two enantiomers, dexfenfluramine and levofenfluramine.[8] 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.[8] Approximately 50 million Europeans were treated with fenfluramine for appetite suppression between 1963 and 1996.[8] Fenfluramine was approved in the United States in 1973.[8] The combination of fenfluramine and phentermine was proposed in 1984.[8] Approximately 5 million people in the United States were given fenfluramine or dexfenfluramine with or without phentermine between 1996 and 1998.[8]

In the early 1990s, French researchers reported an association of fenfluramine with primary

dyspnea in a small sample of patients.[8] Fenfluramine was withdrawn from the U.S. market in 1997 after reports of heart valve disease[34][16] and continued findings of pulmonary hypertension, including a condition known as cardiac fibrosis.[35] It was subsequently withdrawn from other markets around the world. It was banned in India in 1998.[36]

Fenfluramine was an appetite suppressant which was used to treat obesity.[8] It was used both on its own and, in combination with phentermine, as part of the anti-obesity medication Fen-Phen.[8]

In June 2020, fenfluramine was approved for medical use in the United States with an indication to treat Dravet syndrome.[7][37]

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.[7] The studies measured the change from baseline in the frequency of convulsive seizures.[7] 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 (inactive treatment).[7] These reductions were seen within 3–4 weeks, and remained generally consistent over the 14- to 15-week treatment periods.[7]

The U.S. Food and Drug Administration (FDA) granted the application for fenfluramine priority review and orphan drug designations.[7][38][39] The FDA granted approval of Fintepla to Zogenix, Inc.[7]

On 15 October 2020, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Fintepla, intended for the treatment of seizures associated with Dravet syndrome.[40] Fenfluramine was approved for medical use in the European Union in December 2020.[3]

Society and culture

Legal status

Fenfluramine is a prescription medication in the US. Fenfluramine was removed from Schedule IV of the Controlled Substances Act in December 2022.[41]

Recreational use

Unlike various other amphetamine derivatives, fenfluramine is reported to be

lysergic acid diethylamide (LSD).[44][45]
Indirect (via induction of serotonin release) and/or direct activation of the 5-HT2A receptor would be expected to be responsible for the psychedelic effects of the drug at sufficient doses.

References

  1. FDA
    . Retrieved 22 Oct 2023.
  2. ^ Anvisa (2023-07-24). "RDC Nº 804 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 804 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 2023-07-25). Archived from the original on 2023-08-27. Retrieved 2023-08-27.
  3. ^ a b c d e "Fintepla EPAR". European Medicines Agency. 13 October 2020. Retrieved 8 January 2021.
  4. ^ "Fintepla Product information". Union Register of medicinal products. Retrieved 3 March 2023.
  5. ^
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  6. ^ a b c d "FINTEPLA (fenfluramine) oral solution" (PDF). Zogenix Inc. U.S. Food and Drug Administration. March 2022.
  7. ^ a b c d e f g h i j k l m n o p q r "FDA Approves New Therapy for Dravet Syndrome". U.S. Food and Drug Administration (FDA) (Press release). 25 June 2020. Retrieved 25 June 2020. Public Domain This article incorporates text from this source, which is in the public domain.
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  11. ^ Kolata, Gina (September 23, 1997). "How Fen-Phen, A Diet 'Miracle,' Rose and Fell". New York Times. NY, NY, USA.
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  17. ^ "Schedules of Controlled Substances: Removal of Fenfluramine From Control". U.S. Federal Register. 23 December 2022.
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  29. ^ Nestler EJ (2001). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience. McGraw-Hill.
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    S2CID 15573624
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  35. ^ "FDA Announces Withdrawal Fenfluramine and Dexfenfluramine (Fen-Phen)". U.S. Food and Drug Administration. 15 September 1997. Archived from the original on 19 July 2013.
  36. ^ "Drugs banned in India". Central Drugs Standard Control Organization, Dte.GHS, Ministry of Health and Family Welfare, Government of India. Archived from the original on 2015-02-21. Retrieved 2013-09-17.
  37. ^ "FDA Approves FINTEPLA (fenfluramine) for the Treatment of Seizures Associated with Dravet Syndrome" (Press release). Zogenix Inc. 25 June 2020. Retrieved 25 June 2020 – via GlobeNewswire.
  38. ^ "Fenfluramine Orphan Drug Designations and Approvals". U.S. Food and Drug Administration (FDA). 24 December 1999. Retrieved 25 June 2020.
  39. ^ "Fenfluramine Orphan Drug Designations and Approvals". U.S. Food and Drug Administration (FDA). 24 December 1999. Retrieved 25 June 2020.
  40. ^ "Fintepla: Pending EC decision". European Medicines Agency (EMA). 16 October 2020. Archived from the original on 21 October 2020. Retrieved 16 October 2020. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  41. DEA
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  43. ^ Competitive problems in the drug industry: hearings before Subcommittee on Monopoly and Anticompetitive Activities of the Select Committee on Small Business, United States Senate, Ninetieth Congress, first session. U.S. Government Printing Office. 1976. pp. 2–. {{cite book}}: |work= ignored (help)
  44. ^
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  45. ISBN 978-3-642-66709-1
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Further reading

External links
Retrieved from "https://en.wikipedia.org/w/index.php?title=Fenfluramine&oldid=1217514750"