September 1996

ANOREXIANT ALERT!!

A Dear Health Care Professional letter was recently issued from Wyeth-Ayerst regarding the incidence of primary pulmonary hypertension (PPH) associated with dexfenfluramine use. The potential risk of PPH is now calculated to be between 23 and 46 cases per million patients per year, twice that previously estimated. The recent manufacturers letter was prompted by the re-analysis of data from the International Primary Pulmonary Hypertension Study (IPPHS), a case-controlled, international study recently published in New England Journal of Medicine [NEJM 335(9): 609-616] that examined the risk of PPH with appetite-suppressant drugs. As dexfenfluramine was recently added to the KUMC Formulary, prescribers and patients should be familiar with this recent information. A short review of the article and a monograph on dexfenfluramine is provided below.

Appetite-Suppressant Drugs and the Risk of Primary Pulmonary Hypertension

In a case controlled, international study, 95 patients with PPH and 355 controls were enrolled to examine the relationship between anorexigen use and PPH risk. Although the case patients and the control patients took a similar number of drugs (4.4 ± 4.5 vs. 4.3 ± 4.4), the use of appetite-suppressant drugs was higher in the case patients (31.6% vs. 7.3%). Overall, the odds ratio for PPH risk was 6.3 with anorexigen use but was 23.1 if these drugs were used for greater than 3 months. The most commonly used anorexigens in this study by case patients were dexfenfluramine (18.9%) or fenfluramine (6.3%).

This article raises important issues regarding anorexiant prescribing. As dexfenfluramine has recently been added to the KUMC Formulary, it is important that patients are counseled regarding PPH risk, that dexfenfluramine is prescribed within its indications, and that patients are closely monitored in follow up visits. Dexfenfluramine should not be prescribed for cosmetic weight loss and is indicated for use only in those patients who have a body mass index (BMI) of at least 30kg/m² or 27 kg/m² (which is approximately 20% over desirable weight) in the presence of other risk factors (e.g., hypertension, diabetes, or hyperlipidemia). A full monograph on dexfenfluramine follows.

FORMULARY ADDITION

Dexfenfluramine (Redux ®) C-IV

15 mg Capsules; Wyeth-Ayerst Laboratories

Pharmacology and Indications

Dexfenfluramine is indicated for the management of obesity in combination with a reduced calorie diet. Dexfenfluramine is recommended for obese patients with an initial body mass index >= 30 kg/m² or >= 27 kg/m² in the presence of other risk factors (e.g., hypertension, diabetes, hyperlipidemia). Dexfenfluramine is an isomer of fenfluramine, which is a sympathomimetic amine. Dexfenfluramine is a potent and selective serotonergic agonist that promotes the release and inhibits the reuptake of serotonin. The action of dexfenfluramine in treating obesity is primarily via decreased caloric intake as a result of increased serotonin levels in brain synapses.

Pharmacokinetics

Dexfenfluramine is completely absorbed after oral dosing, with a systemic bioavailability of about 68% due to first pass metabolism by the liver. Peak plasma levels of dexfenfluramine are reached within four hours of oral administration. The half-life is approximately 13 to 24 hours. Steady-state levels are reached within four to eight days. Excretion is largely renal with 7% to 19% of the dose excreted as the unchanged drug, 4% to 11% as the active metabolite, and the remainder as inactive metabolites.

Clinical Efficacy

Dexfenfluramine has been studied in numerous short term, monotherapy studies (three to six months). Dexfenfluramine 15 mg to 30 mg twice daily has produced mean weight losses ranging from about three to ten kg and has generally produced greater weight loss than placebo.

Chronic therapy with appetite suppressants may be required in the treatment of obesity in some patients. Several long-term studies have been initiated to evaluate whether dexfenfluramine may be a candidate for long-term use.

Dexfenfluramine was evaluated in an international, multi center, placebo-controlled, double-blind study (INDEX) enrolling 822 obese patients. Male and female patients whose weight exceeded 120% of ideal body weight (as listed in the 1983 Metropolitan Life Insurance Company tables for medium frame) were randomized to either dexfenfluramine 15 mg twice daily or placebo. In combination with a reduced calorie diet, significant weight loss occurred in both groups during the first six months of the study, although the dexfenfluramine-treated patients had a higher cumulative mean weight loss. Dexfenfluramine-treated patients tended to maintain a stable weight during the second six months of the study, while the patients treated with placebo tended to regain weight.

Adverse Reactions

Adverse effects reported with dexfenfluramine in clinical trials have been transient in most cases and have resolved with continued treatment. These effects include: drowsiness, fatigue, abdominal discomfort, nausea, constipation, diarrhea, dry mouth, thirst, polyuria, vertigo, dizziness, insomnia, headache, depression, anxiety, paresthesia, and mood disorders. Side effects occur less frequently when dexfenfluramine is administered as 15 mg twice daily rather than 30 mg once daily. Depression may occur if dexfenfluramine is rapidly withdrawn.

In short term, pre-marketing clinical studies, there was no evidence of addictive or drug-seeking behavior. However, as with any weight-loss agent, the potential exists for misuse of dexfenfluramine in inappropriate patient populations (e.g., patients with anorexia nervosa or bulimia).

Use of anorectic for longer than three months is associated with an increase in the risk of primary pulmonary hypertension (PPH). The company has recently changed their package insert to reflect an increase in the occurrence of PPH while taking dexfenfluramine. The risk of PPH is estimated to be 23-46 cases per million for persons using the drug longer than three months. The risk for PPH was 23 times higher for patients using anorexigens for three or more months as compared to non-users. Therapy should be discontinued in patients who develop new, unexplained symptoms of dyspnea, angina pectoris, syncope, or lower extremity edema. These patients should be evaluated for the etiology of these symptoms and the possible presence of pulmonary hypertension.

Contraindications and Drug Interactions

Dexfenfluramine is contraindicated in patients with hypersensitivity to dexfenfluramine or related compounds and in patients with diagnosed pulmonary hypertension. Dexfenfluramine is also contraindicated in patients receiving monoamine oxidase inhibitors (MAO). At least 14 days should elapse between discontinuation of a MAO inhibitor and initiation of treatment with dexfenfluramine. At least three weeks should elapse between discontinuation of dexfenfluramine and initiation of treatment with a MAO inhibitor. Dexfenfluramine should be used in caution in patients with glaucoma.

Dexfenfluramine should not be taken in combination with other serotonergic medications (See table 1). There have been reports of serious, sometimes fatal reactions. The appropriate interval between administration of these agents and dexfenfluramine has not been established. Serotonin syndrome has been reported with concomitant use of selective serotonin reuptake inhibitors, agents for migraine therapy (sumatriptan succinate and dihydroergotamine), and buspirone. Presenting symptoms of this syndrome may include excitement, hypomania, restlessness, loss of consciousness, confusion, disorientation, anxiety, agitation, motor weakness, myoclonus, tremor, hyperreflexia, ataxia, incoordination, hyperthermia, shivering, pupillary dilation, emesis, and tachycardia.

False positive urine drug tests for amphetamines by ELISA have been observed. Gas chromatography/mass spectroscopy can distinguish a positive urine drug test caused by dexfenfluramine from true-positive drug tests.

Prescribing Regulations

Dexfenfluramine is structurally similar to the classic sympathomimetic amines and a controlled substance. The Kansas Board of Healing Arts statute and regulation dealing with Short Term Treatment of Obesity does apply, i.e.:

1) 30 days limit per prescription

2) 90 days total per year

3) Intent or purpose written in prescriber=s own hand writing

4) No refills (new prescription each time)

KUMC also requires the prescription be written on a green KUMC prescription form.

There are some studies at KUMC that use dexfenfluramine in combination with another anorectic drug (a noradrenergic agent or a serotonergic agent), but the manufacturer recommends it only as monotherapy.

Conclusions

Dexfenfluramine appears to increase short-term weight loss when used in combination with caloric restriction and patient counseling. All patients receiving this medication should be followed according to a weight reduction protocol.

Dexfenfluramine carries a KUMC Cost Code Index of C.

TABLE 1

Adapted from: American Family Physician,October 1995, page 1477

Return to PharmKey Home Page