Web site: June 1999
Prescriber Update: No.18:13-18
Medsafe Editorial Team
Evidence now favours a causal connection between dexfenfluramine (Adifax™)
and fenfluramine (Ponderax™) when used alone and the development of heart valve
abnormalities on echocardiography. Both medicines were withdrawn in 1997. The
incidence, severity and likelihood of progression of the valve abnormalities is
The risk appears to be minimal with use < 3 months; most abnormalities were reported as mild. The risk is presently not quantifiable, but appears to increase with duration of use.
The major consequence of concern is the development of endocarditis in the damaged valve. As a large number of patients have been exposed to these medications since Ponderax first became available in 1966, and the development of endocarditis is preventable, guidelines have been drawn up in consultation with the Cardiac Society of Australia and New Zealand:
ACC has advised that patients suffering heart valve abnormalities as a consequence of taking dexfenfluramine or fenfluramine would fit the criteria of medical misadventure.
Dexfenfluramine or fenfluramine
may cause valvular abnormalities
The risk increases with duration of use
With short term use abnormalities are mild
More than 25,000 may have used dexfenfluramine or fenfluramine
Clinical examination recommended if use ≥ 3 months; echocardiography if signs or symptoms of abnormalities
Report significant heart murmurs to CARM
ACC may cover investigational costs
No other weight loss medication implicated
Consumer leaflet available
Two recently published controlled studies have provided evidence that dexfenfluramine (Adifax™ capsules) and fenfluramine (Ponderax™ tablets and Pacaps™) when used alone can cause heart valve abnormalities.1,2 Earlier evidence from an uncontrolled case series3 suggested an association of severe valvular abnormalities with combination therapy using dexfenfluramine or fenfluramine with phentermine.
One study1 retrospectively examined general practice records in the United Kingdom from the time before any data on the association between dexfenfluramine and fenfluramine and valvular abnormalities had been published. The notes were examined for entries recording newly diagnosed idiopathic valvular abnormalities on ausculatation. New murmurs were recorded in 5 out of 6532 recipients of dexfenfluramine and 6 out of 2371 recipients of fenfluramine. None of those who had received phentermine alone (862) or those in the obese control group (9281) were recorded as having newly diagnosed murmurs. For dexfenfluramine or fenfluramine the 5-year cumulative incidence of valvular abnormality was 7.1 (95% CI 3.6-17.8) per 10,000 subjects for 1-3 months use and 35.0 (16.4-76.2) per 10,000 subjects for > 4 months use. It should be noted that because there had not been a systematic review of patients to identify cases, this study may underestimate the actual rate of occurrence.
In the other retrospective study2 echocardiograms were conducted on untreated obese controls and patients who had been included in one of three studies where therapies were fenfluramine plus phentermine, dexfenfluramine plus phentermine or dexfenfluramine alone. The background rate of cardiac valve abnormalities was 1.3% among controls and 22.7% among treated obese patients. The rate was less for those given dexfenfluramine alone (12.8%) than for those given combination treatment. It is not clear from the study what proportion of these cases had a clinically significant abnormality. These results are subject to significant confounding by duration of treatment, as the group who received single agent treatment had been treated for a shorter time (4.9 ± 3.2 months) compared with dexfenfluramine plus phentermine (9.0 ± 2.2 months) and fenfluramine plus phentermine (26.5 ± 9.1 months). In some studies risk of valve abnormality increased with duration of use.
A third study4 conducted echocardiography on patients who had been treated with dexfenfluramine for an average of 71-72 days. The study demonstrated that aortic or mitral regurgitation (or both) was present in 4.5% of controls and 6.9% of patients treated with dexfenfluramine. Although higher rates of aortic and mitral valve regurgitation were found among those who had received active treatment, the authors commented that "the degree of regurgitation in most affected patients was considered physiologic, trace or mild."
A single published case report where the patient was followed for 2 years suggests that the valve abnormalities associated with dexfenfluramine or fenfluramine may be partially reversible.5
While these studies may appear reassuring in terms of severity, the first published material3 of an association between these agents and valve abnormalities was of a case series of patients, aged 44 ± 8 years, some of whom required surgical intervention or medical treatment for heart failure. The patients had been treated with fenfluramine and phentermine for 12.3 ± 7.1 months.
From the data available it is difficult to estimate the rate of valvular abnormalities with dexfenfluramine or fenfluramine over and above the background rate of 1-4% reported in several studies. The increase in risk, above background, of clinically significant abnormalities appears to be close to zero for use for less than 3 months. The risk probably increases with duration of use and may be as high as 30% in some users.
Fenfluramine has been available in New Zealand since 1966 and dexfenfluramine since 1993. Both medicines were removed from the market in September 1997. At the time of withdrawal the recommended duration of use was limited to 3 months, and use with another anorexiant was contraindicated. The distributor has estimated that the average duration of use of Adifax in Australia at the time of its withdrawal from the market was 45 days. Using this figure, together with data on the volume of use in New Zealand, it is estimated that around 25,000 New Zealanders used Ponderax or Adifax in the 10 years from September 1987 to September 1997.6 No usage data are available for the previous 20 years, but fenfluramine is known to have been widely used in the 1970s.
It is not clear whether the minor abnormalities found in most studies will progress to become clinically significant. Because of the potential for valve abnormalities to place patients at increased risk of bacterial endocarditis which may produce serious health consequences, Medsafe has, on the recommendation of the Medicines Adverse Reactions Committee, consulted with the Cardiac Society of Australia and New Zealand and drawn up guidelines for checking individuals for evidence of cardiac valve disease. The guidelines cover all individuals who have received either dexfenfluramine or fenfluramine since the launch of fenfluramine in New Zealand in 1966.
Please report to the Centre for Adverse Reactions Monitoring (CARM) all cases where a patient exposed to dexfenfluramine or fenfluramine has been advised that they require antibiotic prophylaxis because of valve abnormalities.
ACC has advised that patients suffering heart valve abnormalities as a consequence of taking dexfenfluramine or fenfluramine would fit the criteria of medical misadventure. At the time of the initial assessment, general practitioners should fill out a claim form clearly labelled "medical misadventure" which details the patients exposure to the medication. The ACC will make a minimum contribution of $26 towards the cost of the initial visit. The patient should forward the claim to ACC to seek prior approval before proceeding with further investigations, such as echocardiography.
No association has been made between other weight loss medication and valvular abnormalities. It appears that the mechanism of occurrence of valvular heart disease relates to the elevation of serotonin levels by dexfenfluramine and fenfluramine. Evidence suggests that phentermine used alone does not cause valvular damage. It is unlikely that orlistat (Xenical) will be associated with anything of this nature because it does not act systemically and the mode of its action is completely different from that of dexfenfluramine or fenfluramine.
A consumer leaflet has been prepared to provide information to help people identify whether or not they have taken dexfenfluramine or fenfluramine and to direct them to their general practitioner for initial assessment. Copies of the leaflet have been sent to pharmacies, general practitioners, dietitians etc. for distribution to consumers. The leaflet is available on this web site. Additional printed copies of the leaflet are available - phone 04 496 2277, fax 03 479 0979, e-mail email@example.com or post an order to the Ministry of Health, c/- Wickliffe Ltd, PO Box 932, Dunedin. A toll-free telephone line (0800 931 139) has also been set up to advise consumers of this issue.