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Valvular Abnormalities with Dexfenfluramine and Fenfluramine

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Prescriber Update 18: 13-18
June 1999

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 Both medicines were withdrawn in 1997.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 poorly defined.
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:

Patients who took dexfenfluramine or fenfluramine for < 3 months need not be examined
Those who took either or both agents for ≥ 3 months should be examined by a GP for evidence of a heart murmur or other abnormal cardiac signs
If a murmur or other abnormality is found, or the heart cannot be examined due to obesity, refer the patient to a cardiologist for echocardiography
Until a cardiologist is able to advise on the risk of endocarditis, appropriate prophylactic antibiotics should be given to patients requiring dental or other surgical procedures that put them at risk of endocarditis, and
Practitioners should send an adverse reaction report for valve abnormalities requiring antibiotic prophylaxis in patients exposed to these medicines to the Centre for Adverse Reactions Monitoring.

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

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 series³suggested an association of severe valvular abnormalities with combination therapy using dexfenfluramine or fenfluramine with phentermine.

The risk increases with duration of use

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.

With short term use abnormalities are mild

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.

More than 25,000 may have used dexfenfluramine or fenfluramine

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.

Clinical examination recommended if use ≥ 3 months; echocardiography if signs or symptoms of abnormalities

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.

Those who took dexfenfluramine or fenfluramine for < 3 months need not be examined for evidence of valvular heart disease unless they have a personal concern about the risk.
Those who took dexfenfluramine or fenfluramine for ≥ 3 months, and those uncertain of the duration of use, should be given a physical examination for a heart murmur.
Those who have taken weight loss medication but cannot identify whether it was dexfenfluramine, fenfluramine or another agent, should also be given a physical examination.
There is no need for urgency in conducting this screening procedure. It will be sufficient for patients to be examined on their next visit to the surgery. A special visit need not be arranged, unless the patient is symptomatic.
If there is a heart murmur or some other abnormal physical sign (such as elevated pulse rate or enlarged heart) the patient should be referred to a cardiologist for echocardiography.
If it is impossible to hear the heart sounds adequately due to obesity, the patient should be referred for an echocardiogram.
Advise patients with a murmur that they may be at risk of developing endocarditis and that they should have an echocardiogram to determine whether a valve abnormality exists and to ascertain its severity.
Until fully assessed by a specialist, all patients referred for echocardiography should be treated with antibiotic prophylaxis for dental and surgical procedures that are associated with a risk of endocarditis.
The cardiologist will advise whether on-going antibiotic prophylaxis is required.
Repeat examinations are not considered necessary in patients in whom no abnormality is detected, because use of dexfenfluramine and fenfluramine in New Zealand ceased more than 18 months ago.

Report significant heart murmurs to CARM

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 may cover investigational costs

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 other weight loss medication implicated

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.

Consumer leaflet available

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 pubs@health.govt.nz 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.

Adifax/Ponderax packages

References

Jick H, Vasilakis C, Weinrauch LA, Meier CR, Jick SS, Derby LE. A population-based study of appetite-suppressant drugs and the risk of cardiac-valve regurgitation. NEJM 1998;339:719-24.
Khan MA, Herzog CA, St Peter JV, et al. The prevalence of cardiac valvular insufficiency assessed by transthoracic echocardiography in obese patients treated with appetite-suppressant drugs. NEJM 1998;339:713-8.
Connolly HM, Crary JL, McGoon MD, et al. Valvular heart disease associated with fenfluramine-phentermine. NEJM 1997;337:581-88.
Weissman NJ, Tighe JF, Gottdiener JS, Gwynne JT, for the Sustained-Release Dexfenfluramine Study Group. An assessment of heart-valve abnormalities in obese patients taking dexfenfluramine, sustained release dexfenfluramine or placebo. NEJM 1998;339:725-32.
Cannistra LB, Cannistra AJ. Regression of multivalvular regurgitation after the cessation of fenfluramine and phentermine treatment. NEJM 1998;339:771.
Based on data supplied by Servier Laboratories (Australia) Pty Ltd and IMS, January 1999.