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Primary Pulmonary Hypertension
A 2-year, international (5 country), case-control (epidemiological) study identified 95 primary pulmonary hypertension (PPH) cases; 20 of these had been exposed to anorexigens in the past, and 9 of the 20 had been exposed to anorexigens for longer than three months. In this study, the use of anorexigens for longer than 3 months was associated with an increase in the risk of developing PPH (odds ratio = 9.1, 95% confidence interval = 2.6-31.5). This increased risk of PPH was concentrated in persons who had used the drugs within the preceding year; there was no significant increase in risk for persons who had taken the drugs more than 1 year ago or for persons who had used these agents for 3 months or less. In the general population, the yearly occurrence of PPH is estimated to be about 1-2 cases per 1,000,000 persons. Therefore, the case-control study indicated an estimated risk associated with the long-term use of anorexigen drugs of about 18 cases per million persons exposed per year. According to the case-control study, obesity itself (body mass index ³30 kg/m2) was also associated with an increase of about two-fold in the risk of developing PPH.
PPH is a serious condition; the 4-year survival rate has been reported to be 55%.
The initial symptom of pulmonary hypertension is generally dyspnea. Other initial symptoms include: angina pectoris, syncope, or lower extremity edema. Patients should be advised to report immediately any deterioration in exercise tolerance. Treatment 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.
Neurochemical Findings in Animals
Dexfenfluramine and its active metabolite d-norfenfluramine are believed to reduce food intake through interactions with the serotoninergic neurotransmitter system. In animals, doses of dexfenfluramine that result in brain concentrations approximately 10 times those observed in humans produce prolonged reductions (weeks to months) in brain serotonin concentrations following cessation of dexfenfluramine treatment. These reductions in brain serotonin concentrations are accompanied by correlate observations of diminished visualization of serotoninergic neurons by immunohistochemical techniques and decreased numbers of serotonin transporters. Some investigators have interpreted these results as surrogate indicators of neurotoxicity; others have interpreted these results as an extension of the pharmacology of serotonin reuptake inhibitors. Resolution of differences in the interpretation of the animal findings may occur with further research.
Changes in brain serotonin concentrations following acute, high-dose dexfenfluramine administration have been noted in all animal species and with all routes of drug administration tested. Prolonged reductions in brain serotonin concentrations in rats have been observed following acute, but not escalating, dose regimens. In mice, 2 years of drug administration at a dose producing at least 12 times the human brain level of dexfenfluramine produced no change in brain serotonin concentrations or serotonin transporter number. Changes in brain serotonin concentrations generally have been found to be reversible; however, the dose and brain concentration of dexfenfluramine and d-norfenfluramine may affect reversibility. Persistent reductions in brain serotonin concentrations and neuronal serotonin immunoreactivity were observed in three squirrel monkeys 14-17 months after a 4-day, 10 mg/kg/day subcutaneous dose regimen of dexfenfluramine; the effects of lower doses or different dose regimens were not reported in this study. In a separate study, other squirrel monkeys given this high-dose regimen achieved brain concentrations of dexfenfluramine approximately 35 times those of obese patients taking normal therapeutic doses.
Studies employing experimental techniques that are independent of serotonin content (e.g., retrograde transport, silver staining, glial fibrillary acidic protein content) could not detect neuronal damage at doses of dexfenfluramine in animals producing decreased brain serotonin concentrations. The observed neuro-chemical changes were not associated with persistent changes in animal behavior. The relevance of the animal findings to humans is not known.
Because of dexfenfluramine's potential to produce mild-to-moderate drowsiness, the patient's individual response should be assessed before engaging in activities requiring alertness. Dexfenfluramine may potentiate the sedative effects of alcohol or other drugs with CNS action.
If the patient develops any symptoms of intolerance, e.g., nausea and vomiting, the dosage should be reduced, or the drug discontinued.
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). See INDICATIONS AND USAGE for recommended prescribing guidelines.
Information for the Patient
Patients should be informed that false-positive urine drug tests for amphetamines have been observed for up to 24 hours following a 30-mg dose (2 capsules) of dexfenfluramine. See Drug/Laboratory Test Interactions below.
The safety and efficacy of dexfenfluramine in combination with other weight-loss agents have not been studied; therefore, concomitant use is not recommended.
Use in Patients with Concomitant Illness
Weight loss has been associated with a reduction in hyperglycemia in obese diabetic patients, a reduction of blood pressure in obese hypertensive patients, and an improvement in the lipid profile in obese hyperlipidemic patients. Therefore, when dexfenfluramine is used for the management of obesity associated with hypertension, diabetes, or dyslipidemia, there may be changes in these conditions and the medications used to treat them should be monitored, and adjusted, if necessary.
Drug/Laboratory Test Interactions
False-positive urine drug tests for amphetamines by ELISA have been observed for up to 24 hours following a 30-mg dose (2 capsules) of dexfenfluramine. Patients should be informed of this possible false-positive laboratory finding when undergoing urine drug screenings. Gas chromatography/mass spectroscopy can distinguish false-positive urine drug tests caused by dexfenfluramine from true-positive drug tests. See Information for Patients above.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
Carcinogenicity studies in rats and mice have not shown a carcinogenic potential for dexfenfluramine at doses up to 12 mg/kg and 27 mg/kg, respectively. These doses are 4.8 and 5.8 times the daily human dose (calculated on a body surface area [mg/m2] basis). When given to pregnant rats, dexfenfluramine caused a significant reduction in the number of fetuses and live young.
Dexfenfluramine has no detectable mutagenic activity as determined by the Ames test, gene conversion-DNA repair test, evaluation of the clastogenic effect on cultures of human lymphocytes, mouse lymphoma cell mutation test, and the micronucleus test in the mouse.
Teratogenic Effects: Pregnancy Category C: Dexfenfluramine produced dose-related effects on reproduction and fertility in rats. In a three-generation fertility and reproduction study, administration of dexfenfluramine to female rats at 2.5 and 5 times the human daily dose (calculated on a body surface area [mg/m2] basis) caused significant reductions in body weight and weight gain throughout pregnancy; the number of placental implantations and fetuses was reduced, there was a reduced number of live young, and delayed ossification was seen in the fetuses. No significant treatment-related adverse effects or abnormalities were observed in second- and third-generation rats.
Teratogenicity studies were conducted in rats and rabbits. Neither study showed any treatment-related embryotoxicity or teratogenicity at doses up to 10 times the daily human dose (calculated on a body surface area [mg/m2] basis). There are no adequate and well-controlled studies of dexfenfluramine in pregnant women. Dexfenfluramine is not recommended for pregnant women.
Dexfenfluramine is excreted in rat milk. It is not known whether dexfenfluramine is excreted in human milk. Therefore, dexfenfluramine should not be administered to a nursing woman.
Use in Other Populations
Pediatric Use: Safety and effectiveness of dexfenfluramine in pediatric patients have not been established.
Geriatric Use: As with all CNS-active medications, caution should be exercised in treating elderly patients with dexfenfluramine. Clinical studies of dexfenfluramine did not include sufficient numbers of patients aged 65 or older to determine whether they respond differently than younger patients. Pharmacokinetics in elderly patients are discussed in CLINICAL PHARMACOLOGY.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 12/8/2004
Additional Redux Information
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You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.
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