SEROTONERGIC AGENTS FOR OBESITY

NOTE--Fenfluramine and dexfenfluramine (Redux) were removed from the US market in 1997

Combined use of d,l-fenfluramine (Pondimin) with phentermine (Ionamin)

  1. Produce anorexic effect through augmentation of catecholaminergic neurotransmission (phentermine) and serotonergic transmission (fenfluramine)
  2. Only one long-term controlled study; this showed some modest sustained effect over 3.5y of use, though only small # of pts stayed in study that long (Clin. Pharm. Ther. 51: 581-646, 1992)
  1. 121 obese pts. given 6wks intensive behavior modification and diet and exercise instruction, then randomized to receive 60mg d,l-fenfluramine + 15mg phenterming resin vs. placebo; all adjunctive modalities continued throughout study
  2. During initial 28wks, double-blind tx took place, sig. greater wt loss with phen-fen than placebo (14.3 vs. 4.6kg); weight loss plateud after about 18wks and was maintained for the subsequent 10
  3. After 28wk tx period, all pts remaining in trial were tx'd either continuously or intermittently with phen-fen for another 70 wks; during this period, the continuous-therapy group regained avg. 3kg
  4. Then for another yr, doses were tweaked to approach goal of 120% of ideal body weight with minimal side effects
  5. Then (3y after start of study) the 51 pts remaining in the study were randomized to active drugs vs. placebo for another 34 wks; active drug group regained avg. 4kg during this period; placebo group regained sig. more; at end of this period, active tx group had los avg. 7kg from baseline vs. 2kg in placebo group
  6. Then all meds discontinued and pts followed for another 20wks. 48 pts completed study; pts who had been receiving drugs regained avg. of 2.7kg over 20wks
  1. Side effects: diarrhea, dry mouth (fenfluramine); insomnia, nervousness, constipation, elevated BP (phentermine); some anecdotal reports of exacerbation of depression or mania with either or in combination during tx or withdrawal; some reports of short-term memory loss during tx; very low potential for abuse per JAMA rvw
  2. Contraindications and cautions
  1. Arrhythmias or other cardiovascular disease or any severe systemic disease
  2. Caution with DM (may reduce blood glucose)
  3. Caution with HTN (may reduce BP)
  4. Don't use in pts with glaucoma
  5. Don't use concurrently with MAOI's OR SSRI's (unclear if risk with SSRI's theoretical risk of "serotonin syndrome"
  6. Note risk of primary pulmonary hypertension (see below)
  7. Risk of valvular disease
  1. Case series from Mayo clinic of 24 women presenting with valvular heart disease while on phen-fen (Connolly et al., "Valvular Heart Disease Associated with Fenfluramin-Phentermine", in press for NEJM as of 7/97)
  2. Mean age 43 +/- 8y; mean duration of phen-fen 12 +/- 7mos
  3. Abnormalities included MR, TR, AR; 8pts had pulmonary HTN. 5 had required surgery as of publication
  4. 5 of the pts had been on sertraline or fluoxetine concurrently with phen-fen
  5. Presented with sx, e.g. SOBOE, or a murmur on exam
  6. Histopathologic findings in those undergoing valvular bx were "indistinguishable" from those seen in ergotamine-related valvular disease and in carcinoid
  1. Low potential for abuse according to JAMA review

Dexfenfluramine (the d-isomer of fenfluramine)

  1. Stimulates serotonin release and inhibits its uptake; metabolite also has serotonergic activity
  2. Metabolized in liver and metabolite excreted in urine
  3. 822 obese pts given dexfenfluramine 15mg BID vs. placebo x 12mos, also had calorie-restricted diet; dex group lost avg. 9.8kg vs. 7.2kg with placebo (sig.); most weight loss occurred in 1st 6mos; sig. diff in weight loss between groups disappeared 2mos after discontinuation of drug (Lancet 2:1142, 1989; followup reported in Int. J. Obes. 14 (suppl. 2):48, 1991; cited in JAMA rvw)
  4. 60 obese pts given diet + dexfenfluramine vs. placebo; dex group lost avg. 9.7kg vs. 4.9kg with placebo; no diff. in wt. loss between groups 5 mos after discontinuation of tx
  5. No direct comparisons to phen-fen
  6. Side effects: drowsiness, diarrhea, dry mouth; some anecdotal reports of depression during tx or withdrawal
  7. Association with primary pulmonary hypertension (International Primary Pulmonary Hypertension Study, NEJM 335:609. 1996)
  1. Multinational case-control study of 95 European cases of PPH and 355 age- and sex-matched controls
  2. Use of any anorexigen (90% of these were using dexfenfluramine or d,l-fenfluramine) for any length of time ass'd with RR 10 for PPH; use for >3mo ass'd with RR 20 (increased risk of PPH from 1-2/million/yr to 18/million/yr)
  3. No evidence that it's reversible with discontinuation
  4. No sig. association between PPH and obesity