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Phentermine combined with fenfluramine ("Phen/Fen Diet"): How well did this combination work? (written in 1995)


The information below was written before fenfluramine was withdrawn from the market because of its association with valvular heart disease. This information is provided to give some perspective on the use of this combination and what went wrong.

Most people have heard of combining phentermine with fenfluramine ("phen/fen diet") in an attempt to control weight. Michael Weintraub, et al in a series of studies (Long-term weight control Study I , II, III, IV, V, VI, & VII in Clin Pharmacol Ther; May 1992) studied these medications in individuals over a period of 210 weeks. Both medications are anorexics (appetite suppressants) that help diminish appetite by different mechanisms of action. Phentermine is a stimulant acting through noradrenergic and dopaminergic pathways resulting in decreased appetite and less frequent eating. Fenfluramine acts through serotonergic mechanisms resulting in a feeling of increased satiety. Phentermine may produce "mild" side effects such as nervousness, irritability, insomnia, agitation, dizziness, dry mouth, constipation, elevated blood pressure, and rapid or irregular heartbeats.

Fenfluramine may produce somewhat opposite effects with drowsiness, sedation, diarrhea, and depression. Both medications can lead to serious side effects, with fenfluramine being associated with primary pulmonary hypertension, a life-threatening complication. Furthermore, in July 1997, a new complication (valvular heart disease) was found to be associated with the use of "phen/fen". The thinking was that by combining these two medications, one could take advantage of their different pharmacologic actions and get, in essence, better effectiveness while (hopefully) minimizing the "mild" side effects. The results of the studies are summarized below.

Patient participation

Patients were 18 to 60 years of age and weighed between 130% and 180% of their ideal body weights according to the 1983 Metropolitan Life Insurance Tables. The patients were in good health, not taking any long-term medications, and did not have hypertension (high blood pressure), diabetes, or other chronic diseases.


Phentermine resin (15 mg) combined with Fenfluramine (60 mg).

Behavior therapy

Active and ongoing behavior therapy with professionals trained in behavior modification techniques was an integral part of the study.

Caloric restriction

All individuals received individualized dietary counseling by dieticians to help limit calorie consumption to between 1500-1800 kcal per day for men and between 1000-1200 kcal per day for women.


The participants in the study were started on graded exercise programs to expend at least an extra 300 kcal three times per week over their usual daily activities.

Medical monitoring

All participants were seen by physicians at regular intervals during the study, with periodic laboratory and electrocardiographic monitoring.

Results at 34 weeks

Placebo patients (no medication but all other components as noted above): 4.6 kg (~10 lb.) average weight loss.

Medication patients: (medication and all other components as noted above): 14.2 kg (~30 lb.) average weight loss.

The study continued

Between weeks 34 and 104, all patients were placed on medication (including the placebo treated patients). During this two-year time frame, 31% of the patients left the study and about 50% of these (or about 15% overall) left the study because of medication-related side effects. During this time, behavioral and dietary therapy, along with exercise and medical monitoring, were ongoing. Some patients were placed on intermittent medication (during October to January and April to June), while others (25% of the remaining group) who did not lose more than 10% of their initial weight were placed on an augmented dose (30 mg) of phentermine combined with fenfluramine (60 mg).

Results at 104 weeks (83 of the 121 people who started the study):

  • Continuous Medication(39% of remaining participants): 12.6 kg.(~27 lb.) average weight loss
  • Intermittent Medication (39% of remaining participants): 11.5 kg (~25 lb.) average weight loss

  • Augmented Medication group (22% of remaining participants): 6.5 kg (~ 14 lb.) average weight loss.

  • Average weight loss of the 83 participants making it to week 104: 10.8 kg (~23 lb.) weight loss

The study continued

Between weeks 104 and 156, attempts were made to optimize response to the medication by adjusting the dosages in order to achieve a body weight of 120% or less of ideal body weight. At the end of 156 weeks, 59 patients out of 121 remained in the study. The dosages and results after 156 weeks are as shown:

Group I (Phentermine 15 mg and fenfluramine 30 mg) [2 participants out of 59 remaining]:

Weight change from week 0: -14.1 kg

From week 104: +7.6 kg

Group II (Phentermine 15 mg and fenfluramine 60 mg) [14 participants out of 59 remaining]:

Weight change from week 0: -10.9 kg

From week 104: +2.7 kg

Group III (Phentermine 15 mg and fenfluramine 60 mg but medication used intermittently weeks 104-156) [7 participants out of 59 remaining]:

Weight change from week 0: -8.8 kg

From week 104: +4.0 kg

Group IV (Phentermine 30 mg and fenfluramine 60 mg) [9 participants out of 59 remaining]:

Weight change from week 0: -7.7 kg

From week 104: +3.8 kg

Group V (Phentermine 30 mg and fenfluramine 60 mg in the morning and additional fenfluramine 30 mg in the evening) [8 participants out of 59 remaining]:

Weight change from week 0: -10.5 kg

From week 104: +3.0 kg

Group VI (Phentermine 30 mg and fenfluramine 60 mg in the morning and additional fenfluramine 60 mg in the evening) [19 participants out of 59 remaining]:

Weight change from week 0: -8.4 kg

From week 104: +4.0 kg

In other words, all groups continued to gain weight (on average), although all remaining individuals were on medication. The average weight of the remaining group of 59 was 9.4 kg (~21 lbs) less than when they started the study 156 weeks before.

The study continued

The remaining participants were again randomized to either receive daily doses of phentermine 15 mg combined with fenfluramine 60 mg or placebo. Behavior modification, dietary instruction, exercise, and physician visits continued for both groups. Both groups continued to gain weight, but the medication group gained weight slower (4.4 kg gain between weeks 156 and 190) than the placebo group (6.9 kg gain between weeks 156 and 190). Overall, the remaining participants (51 of the initial 121 that started) weighed, on average, 4.1 kg (~9 lbs.) less than when they started the study 190 weeks before.

And the study continued

Between 190 and 210 weeks, all participants were tapered off their medications. The behavior modification, dietary instruction, physician monitoring, and exercise were continued. At the end of the study, the remaining 48 participants were, on average, 1.4 kg (~3 lbs) less than when they started the study. However, 7 of the remaining participants were 10% or more below their initial body weights.


1) Medication (phentermine + fenfluramine) in a program combining behavior modification, dietary instruction, exercise, and medical monitoring will assist with weight loss to a moderate degree, with the greatest weight loss occurring within the first year and the weight gradually returning toward baseline despite continued intervention.

2) The average weight loss with the medication protocol (program) peaked at 14 kg at week 34.

3) Patients who were treated only with dietary instruction, behavior modification, exercise intervention, and physician monitoring lost an average of 4.6 kg at week 34.

4) All patients received ongoing dietary instruction, behavior modification, physician monitoring and exercise intervention. Although the total weight loss was small at week 210 (~3 lbs in the participants who continued), the natural history of obesity is to gain 1 to 2% of body weight per year and thus there was some measure of success from this program.

5) There was no evidence that the body weight control mechanism was reset to a lower level from long-term use of medication.

6) The effect of using medication without concomitant dietary, behavioral, exercise intervention, and physician monitoring is unknown.

(1997) Cardiac problems related to dexfenfluramine and phentermine combined with fenfluramine ("Phen/Fen")

Since the initial report on the valvular heart disease problems associated with dexfenfluramine (brand name REDUX) and the use of "phen/fen," many people are confused and frightened. Valvular heart disease refers to abnormalities of one of the four valves (aortic, mitral, pulmonic, and tricuspid) that are inside the heart and direct the flow of blood. These valves, which are normally smooth and composed of connective tissue, open and close in response to the pumping action of the heart. If one of the valves malfunctions, it can lead to insufficient blood flow to the body or result in a "back pressure," which may result in fluid accumulating in the lungs or lower portions of the body. Symptoms of valvular heart disease can vary from no symptoms in the early stages to chest pain, shortness of breath, or swelling in the legs as the disease progresses.

If an individual was on these medications for any length of time, there is concern. Many studies have been performed with conflicting results. The largest controlled study (that is, having echocardiograms done before, during, and after treatment with fenfluramine or dexfenfluramine and phentermine or mazindol) was published in July, 1999 (OR 1999;7:313-322). In that study, 16.5% of the individuals developed valvular heart disease. The average use of the medications was 17 months in this study. Other, less well-controlled studies have shown an incidence of valvular heart disease of 22% for individuals who utilized the medications (dexfenfluramine or fenfluramine either alone or in combination with other medications, such as phentermine) for less than 6 months. The incidence increased to 35 % of all individuals who utilized the medications for more than 6 months. Overall, there may be upwards of a million Americans afflicted with valvular heart disease related to these medications.

What to do?

If you have taken any fenfluramine or dexfenfluramine, you should undergo a thorough examination by your physician with particular attention to the pulmonary and cardiac examination. You should undergo a specialized test called an echocardiogram if any of the following are present:

-- A new heart murmur (extra heart sound) discovered on examination.

-- New cardiac symptoms, such as shortness of breath, chest pain, or leg swelling develop.

-- You are anticipating undergoing a medical or dental procedure that may result in bacteria entering your bloodstream, which could result in bacterial endocarditis (infection of the heart valves).

-- You have taken the medications for 3 months or longer since the majority of heart valve problems cannot be heard on physical examination.

There are many medical and dental procedures that can result in bacteria getting into the bloodstream. Physicians and dentists routinely give antibiotics to prevent patients with valvular heart disease (such as rheumatic fever-related heart disease or someone with an artificial heart valve) from developing endocarditis. The reason for the third recommendation (above) is that individuals who were on the medications and who were determined by echocardiogram to have significant valvular heart disease confirmed by echocardiogram, fully 83% had normal physical examinations (no clinical history or physical finding to suggest such disease being present)!

What about studies that state there is no increased incidence of valvular heart disease in people treated with Redux?

Unfortunately, each published study has had errors that have accounted for the benign results. For example, a study sponsored by the manufacturer of Redux (American Home Products) was presented at a meeting of the American College of Cardiology in Atlanta on March 31, 1998. That study, which was only 77 days long, compared placebo pills with regular Redux and a sustained release Redux in looking at the incidence of valvular heart disease. The results are as follows:

Aortic Valve Leakage (>mild)
Mitral Valve Leakage
(> moderate)
Total % with Heart Valve Problems (may have more than one valve involved)
Placebo Group
3.6 %
1.2 %
4.5 %
Regular Redux
5 %
1.7 %
6.5 %
Sustained Release Redux
5.8 %
1.8 %
7.3 %

Dexfenfluramine and fenfluramine withdrawn from market (written Sept 16, 1997)

On September 15, 1997, the U.S. Food and Drug Administration (FDA) announced the withdrawal of dexfenfluramine (brand name REDUX) and fenfluramine (brand name Pondimin) from the market. The section on "what will happen in the future" was updated in 2004.

What was found?

It was reported in March, 1997 ( U.S. data) and a few years back (European literature) that unusual heart valve abnormalities, which resulted in "leaky" heart valves, were being detected in individuals on fenfluramine and/or dexfenfluramine used in association with phentermine ("phen/fen"). In July 1997, the Mayo Clinic released the results of a study that was subsequently published in the New England Journal of Medicine (August 28, 1997). Since then, many more cases have been reported to the FDA's MedWatch Program. Most of the reported cases involve the aortic and/or mitral valve. Several studies were then undertaken in an attempt to determine the incidence of these abnormalities. The studies appear to indicate that up to 32% of individuals who were on dexfenfluramine or fenfluramine with or without phentermine may be afflicted with these leaky heart valves. For comparison, the incidence of these abnormalities in the general and obese population is just over 1%. These finding prompted the FDA to ask American Home Products/Wyeth-Ayerst and Interneuron Pharmaceuticals to withdraw these medications from the market.

What were the dosages and length of use of the medications in the studies?

In the patients who have been reported to MedWatch, the average age was 44.9 years, but the range in age was from 22 to 67. The average weight was 200 lbs. The average dose of fenfluramine was 56 mg/day, with a range of 10 to 120 mg per day. The average duration of treatment was 11.9 months, but with a range of as little as 1 month and as long as 39 months.

In five separate studies undertaken in asymptomatic individuals, the doses of fenfluramine were between 20 and 60 mg per day with a length of treatment of 6 to 24 months. Of note is that the incidence of cardiac valvular lesions in the asymptomatic patients was remarkably similar in all five centers (the incidence in the center that studied individuals after being on medication for six months was about the same as the center that tested individuals after being on the medications 24 months).

What were the symptoms?

Of the patients that were reported to MedWatch, 61% had shortness of breath, while 24% were asymptomatic but were noted to have a new heart murmur (unusual heart sound) during physical examination. Fifteen percent of the patients' murmurs were found by routine screening with echocardiograms. As noted above, in the five studies that prompted the recall, none of the patients exhibited any symptoms.

Should I be concerned?

Yes. You must stop your medications and seek medical advice as soon as possible. Remember, the preliminary findings are that over 30% of asymptomatic individuals who have used these medications are afflicted. If you do have leaky heart valves, your heart must work harder than usual to pump the blood through your body. This may result in premature heart failure or other heart problems.

If I do have valvular damage, what will happen to me?

In the years that have passed since the recall, it appears that about 30% of individuals with mild to moderate heart valve abnormalities have the abnormalities improve or resolve on their own. In most people, the condition appears to stabilize, but in some, leakage of the valves worsens. If you have heart valve abnormalities, you probably should receive antibiotics prior to any dental, urologic, or gynecologic procedure to prevent infection of the heart valves since these procedures can increase the chances of bacteria getting into your bloodstream. You will need long term medical follow-up, which you should discuss with your treating physician.

Updated: 27 December 2011

Copyright © 1996 -2011 Michael D. Myers, M.D., Inc.
All rights reserved.

Disclaimer Statement

The above information is for general purposes only and should not be construed as definitive or binding medical advice, diagnosis or treatment. Because each person is medically different, individuals should consult their own personal physicians for specific information and/or treatment recommendations.