Fenfluramine/phentermine: Difference between revisions

{{Short description|Drug combination prescribed for weight loss; later withdrawn from market}}

| verifiedrevid = 445087358

| image = Fenfluramine and phentermine.svg

| image2 = Fenphen3D.png

| class1 = [[Serotonin|Serotoninergic]]

| class2 = [[Adrenergic]], [[dopaminergic]], serotoninergic

| legal_CA = <!-- / Schedule I, II, III, IV, V, VI, VII, VIII -->

| legal_UK = <!-- GSL / P / POM / CD / Class A, B, C -->

| legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V -->

| CAS_number = 159089-37-9

The [[medication|drug]] combination '''fenfluramine/phentermine''', usually called '''fen-phen''', was an anti-[[obesity]] treatment in the early 1990s that utilized two [[anorectic]]s. [[Fenfluramine]] was marketed by American Home Products (later known as [[Wyeth]]) as ''Pondimin'', but was shown to cause potentially fatal [[pulmonary hypertension]] and [[heart valve]] problems, which eventually led to its withdrawal in 1997 and legal damages of over $13 billion.<ref name=PowerfulMedicines>Avorn J. (2004). ''Powerful Medicines'', pp. 71-84. Alfred A. Knopf.</ref> [[Phentermine]] was not shown to have harmful effects.<ref name=PowerfulMedicines/>

Fenfluramine acts as a [[serotonin releasing agent]],<ref>[[Eric J. Nestler|Nestler, Eric J.]] "Molecular Neuropharmacology: A Foundation for Clinical Neuroscience" McGraw-Hill, 2001.</ref> phentermine as primarily a [[norepinephrine releasing agent]]. Phentermine also induces the release of serotonin and dopamine, although to a far lesser extent than it induces the release of norepinephrine.<ref name=Phen01>{{cite journal | vauthors = Rothman RB, Baumann MH, Dersch CM, Romero DV, Rice KC, Carroll FI, Partilla JS | title = Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin | journal = Synapse | volume = 39 | issue = 1 | pages = 32–41 | date = January 2001 | pmid = 11071707 | doi = 10.1002/1098-2396(20010101)39:1<32::AID-SYN5>3.0.CO;2-3 | s2cid = 15573624 }}</ref>

== History ==

[[Fenfluramine]] as a single drug was first introduced in the 1970s, but was not popular because it only temporarily reduced weight.<ref name=PowerfulMedicines/> A 1984 study found a weight loss of 7.5&nbsp;kg on average in 24 weeks, as compared to 4.4&nbsp;kg under placebo.<ref name="Weintraub1984">{{cite journal | vauthors = Weintraub M, Hasday JD, Mushlin AI, Lockwood DH | title = A double-blind clinical trial in weight control. Use of fenfluramine and phentermine alone and in combination | journal = Archives of Internal Medicine | volume = 144 | issue = 6 | pages = 1143–8 | date = June 1984 | pmid = 6375610 | doi = 10.1001/archinte.144.6.1143 }}</ref> It sold modestly until the 1990s, when it was combined with [[phentermine]] and heavily marketed.<ref name=PowerfulMedicines/>

=== Testing on children in New York City ===

The [[New York Psychiatric Institute]], associated with [[Columbia University]], the [[Research Foundation of the City University of New York]], and [[Mount Sinai Hospital (Manhattan)|Mount Sinai Medical Center]] tested fenfluramine intravenously on more than 100 Black and Hispanic boys between the ages of 6 and 10, with delinquent older brothers, to test the theory that delinquent behavior could be predicted by [[serotonin]] levels. These studies were conducted before the drug was pulled from the market in September 1997. In 1998, [[CNN]] reported that these organizations were under "evaluation" by the Office for Protection from Research Risks, an arm of the [[National Institutes of Health]].<ref>{{Cite news |date=April 14, 1998 |title=Groups say children subjected to unethical medical tests |work=CNN |url=http://www.cnn.com/US/9804/14/child.experiments/ |access-date=September 23, 2023}}</ref> An article in Nature reports that these tests were published as a study in ''[[Archives of General Psychiatry]]'' in 1997 and that "The New York trial, funded largely by the Lowenstein Foundation, with some support from the [[National Institute of Mental Health]], was halted in 1995, two years before the drug was withdrawn."<ref>{{Cite news |last=Wadman |first=Meredith |date=April 1, 1998 |title=Row erupts over child aggression study |work=Nature |url=https://www.nature.com/articles/33760 |access-date=September 23, 2023}}</ref> In 1999 [[the New York Times]] reported that the [[Mount Sinai School of Medicine]] and the Research Foundation of the City University of New York were officially faulted by Federal research-ethics officials for conducting these tests. The article reports that the yearlong investigation found no misconduct by New York State Psychiatric Institute for these tests. This article reports the number of children involved in the study as 150, and states that none were harmed.<ref>{{Cite news |last=Bernstein |first=Nina |date=June 12, 1999 |title=2 Institutions Faulted for Tests on Children |pages=21 |work=The New York Times |url=https://www.nytimes.com/1999/06/12/nyregion/2-institutions-faulted-for-tests-on-children.html|access-date=September 23, 2023}}</ref>

===Harm and litigation===

A similar drug, [[aminorex]], had caused severe lung damage and "provided reason to worry that similar drugs ... could increase the risk of a rare but often fatal lung disease, pulmonary hypertension."<ref name=PowerfulMedicines/> In 1994, Wyeth official Fred Wilson expressed concerns about fenfluramine's labeling containing only four cases of pulmonary hypertension when a total of 41 had been observed, but no action was taken until 1996.<ref name=PowerfulMedicines/> In 1995, Wyeth introduced [[dexfenfluramine]] (the [[Levorotation and dextrorotation|dextro]] isomer, marketed as ''Redux''), which it hoped would cause fewer adverse effects. However, the medical officer of the [[Food and Drug Administration]] (FDA), [[Leo Lutwak]], insisted upon a [[black box warning]] of pulmonary hypertension risks. After Lutwak refused to approve the drug, the FDA management had James Milton Bilstad, FDA Senior Drug Evaluator, sign it and approved the drug with no black box warning for marketing in 1996.<ref name=PowerfulMedicines/> European regulators required a major warning of pulmonary hypertension risks.<ref name=PowerfulMedicines/>

In 1996, a 30-year-old woman developed heart problems after a month of using fenfluramine/phentermine; when she died in February 1997, the ''[[Boston Herald]]'' devoted a front-page article to her.<ref>{{cite news |first=Ed |last=Hayward |name-list-style=vanc |title=Diet to Death |newspaper=Boston Herald |page=1 |date=6 May 1997 |access-date=3 September 2009 |url=https://pqasb.pqarchiver.com/bostonherald/access/11667452.html?dids=11667452:11667452&FMT=CITE&FMTS=CITE:FT&type=current&date=May+6%2C+1997&author=ED+HAYWARD&pub=Boston+Herald&edition=&startpage=001&desc=Diet+to+Death+Woman+killed+by+fen%2Fphen%2C+suit+alleges |archive-date=15 June 2011 |archive-url=https://web.archive.org/web/20110615093215/http://pqasb.pqarchiver.com/bostonherald/access/11667452.html?dids=11667452:11667452&FMT=CITE&FMTS=CITE:FT&type=current&date=May+6%2C+1997&author=ED+HAYWARD&pub=Boston+Herald&edition=&startpage=001&desc=Diet+to+Death+Woman+killed+by+fen%2Fphen%2C+suit+alleges |url-status=dead }}</ref> In August 1997 a paper in the ''[[New England Journal of Medicine]]'' (NEJM) from the [[Mayo Clinic]] discussed clinical findings in 24 people who had taken fen-phen. The authors noted that their findings suggested a possible correlation between [[mitral valve]] dysfunction and the use of these anorectic agents.<ref name="Connolly">{{cite journal | vauthors = Connolly HM, Crary JL, McGoon MD, Hensrud DD, Edwards BS, Edwards WD, Schaff HV | title = Valvular heart disease associated with fenfluramine-phentermine | journal = The New England Journal of Medicine | volume = 337 | issue = 9 | pages = 581–8 | date = August 1997 | pmid = 9271479 | doi = 10.1056/NEJM199708283370901 | doi-access = free }}</ref> The FDA alerted medical practitioners that it had received nine additional reports of the same type, and requested all health care professionals to report any such cases to the agency’s [[MedWatch]] program, or to their respective pharmaceutical manufacturers. The FDA subsequently received over a hundred additional reports of [[valvular heart disease]] in people taking fen-phen, fenfluramine alone or dexfenfluramine alone.<ref name="FDA">{{cite journal | title = Cardiac valvulopathy associated with exposure to fenfluramine or dexfenfluramine: U.S. Department of Health and Human Services interim public health recommendations, November 1997 | journal = MMWR. Morbidity and Mortality Weekly Report | volume = 46 | issue = 45 | pages = 1061–6 | date = November 1997 | pmid = 9385873 | url = https://www.cdc.gov/mmwr/preview/mmwrhtml/00049815.htm | author1 = Centers for Disease Control Prevention (CDC) }}</ref> The FDA requested that the manufacturers of fenfluramine and dexfenfluramine stress the potential risk to the heart in the drugs' labeling and in package inserts.<ref>{{Cite web|url=https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm180082.htm|title="Fen-Phen" Update (Fenfluramine, Phentermine, Dexfenfluramine)|website=[[Food and Drug Administration]]|date=2009-11-04|access-date=2019-04-19|archive-url=https://web.archive.org/web/20091104225050/https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm180082.htm|archive-date=2009-11-04}}</ref> The FDA continued to receive reports in 1997 of valvular heart disease in people who had taken these drugs. This disease typically involves the [[aortic valve|aortic]] and mitral valves.

After reports of valvular heart disease and pulmonary hypertension, primarily in women who had been undergoing treatment with fen-phen or (dex)fenfluramine, the FDA requested its withdrawal from the market in September 1997.<ref name="FDA" /><ref>{{cite news|title=Press release: FDA Announces Withdrawal Fenfluramine and Dexfenfluramine (Fen-Phen)|url=https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm179871.htm|work=FDA|date=September 15, 1997|archive-url=https://web.archive.org/web/20091104225047/https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm179871.htm|archive-date=4 November 2009}}</ref> The action was based on findings from doctors who had evaluated people taking these two drugs with [[echocardiogram]]s, a procedure that can test the functioning of heart valves. The findings indicated that approximately 30 percent of people who had taken the combination for up to 24 months had abnormal echocardiograms, even though they had no symptoms. This percentage of abnormal test results was much higher than would be expected from a sample of the population who had not been exposed to either fenfluramine or dexfenfluramine.<ref name="Connolly" /><ref name=2003rev>{{cite journal | vauthors = Weigle DS | title = Pharmacological therapy of obesity: past, present, and future | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 88 | issue = 6 | pages = 2462–9 | date = June 2003 | pmid = 12788841 | doi = 10.1210/jc.2003-030151 | doi-access = free }}</ref> Follow-up studies showed that for people who took the combination for 3 months or less, the rate of heart valve complications was less than 3%.<ref name=2003rev/>

=== Aftermath ===

Upon the release of the information regarding fen-phen's cardiac risks, the [[Association of Trial Lawyers of America]] formed a large trial lawyer group to seek damages from American Home Products, the distributor of fenfluramine and dexfenfluramine.<ref name=NEWSWEEK>[http://www.newsweek.com/1997/09/28/after-fen-phen.html "After Fen-Phen"], Karen Springen and Geoffrey Cowley, ''[[Newsweek]]'', September 29, 1997</ref>

Fen-phen is no longer widely available. In April 2005, ''[[American Lawyer]]'' magazine ran a cover story on the wave of fen-phen litigation, reporting that more than 50,000 [[product liability]] lawsuits had been filed by alleged fen-phen victims. Total liability was estimated to be as high as $14 billion. Wyeth was still in negotiations with injured parties in February 2005, offering settlements of $5,000 to $200,000 to some of those who had sued, and stating they might offer more to those who were most seriously injured.<ref name="NYTimes_2-17-05">[https://query.nytimes.com/gst/fullpage.html?res=9505E7D6133AF934A25751C0A9639C8B63 New York Times: Fen-Phen Case Lawyers Say They'll Reject Wyeth Offer], Feb. 17, 2005.</ref> One plaintiff's attorney said that "the payments [were] not going to be large enough to cover medical expenses."<ref name="six">{{cite news | url = https://www.nytimes.com/1999/10/08/business/fen-phen-maker-to-pay-billions-in-settlement-of-diet-injury-cases.html?pagewanted=all | work=The New York Times | title=Fen-Phen Maker to Pay Billions In Settlement of Diet-Injury Cases | first=David J. | last=Morrow | name-list-style = vanc | date=8 October 1999}}</ref> Thousands of injured persons rejected these offers.<ref name="NYTimes_2-17-05" /> At the time, Wyeth announced it had set aside $21.1 billion (U.S.) to cover the cost of the lawsuits.<ref name="NYTimes_2-17-05" />

== Possible uses ==

===Obesity===

In 1984, researchers at the [[University of Rochester Medical Center]] reported that they had performed a double-blind, controlled clinical trial comparing phentermine alone, fenfluramine alone, a combination of phentermine and fenfluramine, and placebo, for weight loss in humans. Weight loss in those receiving the fen-phen combination was significantly greater (8.4±1.1&nbsp;kg) than in those receiving placebo (4.4±0.9&nbsp;kg) and equivalent to that of those receiving fenfluramine (7.5±1.2&nbsp;kg) or phentermine alone (10.0±1.2&nbsp;kg). This amounts to an additional weight loss of 4±2&nbsp;kg over the course of 24 weeks. Adverse effects were less frequent with the combination regimen than with the other active (non-placebo) treatments. The authors felt that combining fenfluramine and phentermine capitalized on their [[pharmacodynamics|pharmacodynamic]] differences, resulting in equivalent weight loss, fewer adverse effects, and better appetite control.<ref name="Weintraub1984" />

===Addiction remission===

The term fen-phen was defined/termed/labeled in 1994 when Pietr Hitzig and Richard B. Rothman reported that this combination could presumptively remit alcohol and cocaine craving. The authors suggested that other combined dopamine and [[serotonin agonist]]s or [[Precursor (chemistry)|precursors]] might share this therapeutic potential.<ref name="hitzig94">{{cite journal | vauthors = Hitzig P | title = Combined serotonin and dopamine indirect agonists correct alcohol craving and alcohol-associated neuroses | journal = Journal of Substance Abuse Treatment | volume = 11 | issue = 5 | pages = 489–90 | year = 1994 | pmid = 7869471 | doi = 10.1016/0740-5472(94)90103-1 | url = https://sites.google.com/site/pietrhitzig/Home/reference-manager/reference-manager/1640_Hitzig.pdf?revision=6 }}{{Dead link|date=April 2024 |bot=InternetArchiveBot |fix-attempted=yes }}</ref><ref>{{cite journal | vauthors = Rothman RB, Gendron T, Hitzig P | title = Hypothesis that mesolimbic dopamine (DA) plays a key role in mediating the reinforcing effects of drugs of abuse as well as the rewarding effects of ingestive behaviors | journal = Journal of Substance Abuse Treatment | volume = 11 | issue = 3 | pages = 273–5 | year = 1994 | pmid = 8072057 | doi = 10.1016/0740-5472(94)90086-8 | doi-access = free }}</ref> Subsequent experiments in rats supported these preliminary reports.<ref>{{cite journal | vauthors = Yu YL, Fisher H, Sekowski A, Wagner GC | title = Amphetamine and fenfluramine suppress ethanol intake in ethanol-dependent rats | journal = Alcohol | volume = 14 | issue = 1 | pages = 45–8 | year = 1997 | pmid = 9014023 | doi = 10.1016/s0741-8329(96)00110-3 }}</ref><ref>{{cite journal | vauthors = Glatz AC, Ehrlich M, Bae RS, Clarke MJ, Quinlan PA, Brown EC, Rada P, Hoebel BG | display-authors = 6 | title = Inhibition of cocaine self-administration by fluoxetine or D-fenfluramine combined with phentermine | journal = Pharmacology, Biochemistry, and Behavior | volume = 71 | issue = 1–2 | pages = 197–204 | year = 2002 | pmid = 11812523 | doi = 10.1016/S0091-3057(01)00657-8 | s2cid = 188983 }}</ref> In 2006 it was confirmed that the combination of phentermine and the serotonin precursor [[5-hydroxytryptophan]] (5-HTP), in place of fenfluramine, significantly decreased alcohol withdrawal seizures in rats.<ref>{{cite journal | vauthors = Halladay AK, Wagner GC, Sekowski A, Rothman RB, Baumann MH, Fisher H | title = Alterations in alcohol consumption, withdrawal seizures, and monoamine transmission in rats treated with phentermine and 5-hydroxy-L-tryptophan | journal = Synapse | volume = 59 | issue = 5 | pages = 277–89 | date = April 2006 | pmid = 16416445 | doi = 10.1002/syn.20239 | s2cid = 30453212 }}</ref>

Intramural [[National Institutes of Health]] (NIH) double-blind protocols to demonstrate the efficacy of fen-phen in alcohol and cocaine addiction were designed,<ref>{{Cite web|url=https://accounts.google.com/v3/signin/identifier?continue=https%3A%2F%2Fsites.google.com%2Fsite%2Fsites%2Fsystem%2Ferrors%2FWebspaceNotFound%3Fpath%3D%2Fpietrhitzig%2FHome%2Freference-manager%2Freference-manager%2FNIDA_DIR_266.pdf&followup=https%3A%2F%2Fsites.google.com%2Fsite%2Fsites%2Fsystem%2Ferrors%2FWebspaceNotFound%3Fpath%3D%2Fpietrhitzig%2FHome%2Freference-manager%2Freference-manager%2FNIDA_DIR_266.pdf&ifkv=AXo7B7VAYjwZEx9QrHsuCP5m1nHhPyx1sFFCtiA_fI6uP2yF6omCwJ35c_FyR9h8ylndPNzDNp1Vag&passive=1209600&service=jotspot&flowName=WebLiteSignIn&flowEntry=ServiceLogin&dsh=S-620330648%3A1692526259458220|title=Google Sites: Sign-in|website=accounts.google.com|accessdate=20 August 2023}}</ref> but never performed.

==Adverse effects of serotonin==

The findings on fen-phen, specifically fenfluramine, causing valvular heart disease and pulmonary hypertension prompted a renewed interest in the deleterious effects of systemic serotonin. It had already been known for decades that two of the major side-effects of the [[carcinoid syndrome]], in which excessive serotonin is produced endogenously, are valvular disease and pulmonary hypertension. Several centers were able to note a relationship to an excessive activation of the serotonin receptor subtype [[5-HT2B receptor|5-HT_2B]].<ref>{{cite journal | vauthors = Rothman RB, Baumann MH, Savage JE, Rauser L, McBride A, Hufeisen SJ, Roth BL | title = Evidence for possible involvement of 5-HT(2B) receptors in the cardiac valvulopathy associated with fenfluramine and other serotonergic medications | journal = Circulation | volume = 102 | issue = 23 | pages = 2836–41 | date = December 2000 | pmid = 11104741 | doi = 10.1161/01.CIR.102.23.2836 | doi-access = free }}</ref><ref>{{cite journal|author3-link=Bryan Roth | vauthors = Hutcheson JD, Setola V, Roth BL, Merryman WD | title = Serotonin receptors and heart valve disease--it was meant 2B | journal = Pharmacology & Therapeutics | volume = 132 | issue = 2 | pages = 146–57 | date = November 2011 | pmid = 21440001 | pmc = 3179857 | doi = 10.1016/j.pharmthera.2011.03.008 }}</ref>

==See also==

* [[Semaglutide]], another weight-loss drug that gained mass popularity

== References ==

{{reflist|2}}

*''[[Frontline (U.S. TV series)|Frontline]]'': [https://www.pbs.org/wgbh/pages/frontline/shows/prescription/interviews/lutwak.html Dangerous prescriptions] – Interview with Leo Lutwak, in which he discusses the side effects of fenfluramine (Pondimin), its successor dexfenfluramine (Redux), and the fen-phen combination.

*[https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm072820.htm U.S. FDA fen-phen information]

* {{cite journal | vauthors = Tellier P | title = Fenfluramines, idiopathic pulmonary primary hypertension and cardiac valve disorders: facts and artifacts | journal = Annales de Médecine Interne | volume = 152 | issue = 7 | pages = 429–36 | date = November 2001 | pmid = 11965083 }}

{{DEFAULTSORT:Fenfluramine phentermine}}

[[Category:Combination anti-obesity drugs]]

[[Category:Withdrawn anti-obesity drugs]]