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The action of dexfenfluramine hydrochloride in treating obesity is primarily via decreased caloric intake associated with increased serotonin levels in brain synapses. Dexfenfluramine hydrochloride is a serotonin reuptake inhibitor and releasing agent. In vitro studies have confirmed the dual serotoninergic mechanism of action of dexfenfluramine by demonstrating that the drug inhibits serotonin reuptake by axon terminals and causes the release of serotonin from synaptosomes. In animals, the reduced caloric intake and the loss in body weight elicited by dexfenfluramine is associated with release of serotonin from presynaptic axon terminals in the brain, inhibition of neuronal serotonin reuptake, and therefore, an increase of serotonin receptor activation. This results in an enhancement of serotoninergic transmission in the centers of feeding behavior, located in the ventro-medial nucleus of the hypothalamus. In rats, enhanced serotoninergic transmission induced by dexfenfluramine selectively suppressed appetite for carbohydrates which resulted in reduction of food consumption when the dietary carbohydrate to protein ratio was high. Unlike amphetamines and other serotonin-active agonists and antagonists, dexfenfluramine neither enhances nor suppresses dopamine-mediated neurotransmission.
In clinical trials, dexfenfluramine treatment in conjunction with a reduced-calorie diet is associated with a reduction in appetite and may slow gastric emptying. These and other actions may contribute to the reduction in caloric consumption associated with dexfenfluramine. In one clinical trial, dexfenfluramine was shown to preferentially decrease carbohydrate consumption at meals and to manage carbohydrate craving between meals by decreasing the consumption of snack foods with a high carbohydrate content in patients who frequently snack on such foods.
Pharmacokinetics and Metabolism
Systemic Bioavailability: Dexfenfluramine is completely absorbed after oral dosing, with a systemic bioavailability of about 68% because of first pass metabolism by the liver. In studies in which patients received a single 30-mg oral dose of dexfenfluramine, mean peak plasma concentrations of dexfenfluramine ranged between 11 and 41 ng/mL in individual patients after 1.5 to 8.0 hours. The average terminal elimination half-life of plasma dexfenfluramine ranged from 17 to 20 hours, and the average total body clearance of dexfenfluramine was 691.9 mL/min. In man, following doses of 15 mg dexfenfluramine twice a day for 15 days, mean maximal plasma dexfenfluramine concentrations ranging from 15 to 92 ng/mL were observed, and steady-state plasma levels were achieved 8 days after the initial dose. The average steady-state plasma concentrations were somewhat lower than predicted by single-dose pharmacokinetics and the average time to steady-state was longer than the predicted 4 to 5 days. The major active metabolite, d-norfenfluramine, accumulated to maximal plasma concentrations of about 26 ng/mL, with steady-state plasma levels occurring at about 9 days. The d-norfenfluramine plasma half-life is estimated to be 32 hours. After reaching steady-state levels, there was no evidence of increasing concentrations of dexfenfluramine or d-norfenfluramine in plasma during 12 months of dosing. Following administration of single 30-mg, 40-mg, and 60-mg doses of dexfenfluramine to healthy volunteers, dexfenfluramine Cmax values of 25 ng/mL, 33 ng/mL, and 51 ng/mL and area-under-the-curve0-t values of 144 ng·hr/mL, 191 ng·hr/mL, and 275 ng·hr/mL, respectively, were found. In a dose response study of dexfenfluramine involving obese patients treated for 12 weeks, dexfenfluramine Cmin values of 24 ng/mL at a dose of 15 mg twice daily and 58 ng/mL at a dose of 30 mg twice daily were observed. These data suggest that plasma concentrations of dexfenfluramine increase in proportion to the administered dose.
Protein Binding and Distribution: At a dexfenfluramine plasma concentration of 100 ng/mL, 36% is bound to plasma proteins. Dexfenfluramine is distributed into body tissue in non-obese subjects, with a volume of distribution of 839 L.
Metabolism: Dexfenfluramine is metabolized in the liver. The first steps in the metabolism of dexfenfluramine are dealkylation, resulting in formation of the active metabolite, d-norfenfluramine and deamination to an inactive d-hydroxy derivative. In a study of drug metabolism using radiolabeled dexfenfluramine, levofenfluramine and d,l-fenfluramine in two healthy subjects, 92% of the administered radioactivity was found in urine and 1% in feces over 6 days. Fenfluramine accounted for 7% to 19% and norfenfluramine accounted for 4% to 11% of the urine radioactivity. Other metabolites (inactive) included 1-(m-trifluoromethylphenyl)-1,2-propane diol (21 to 38%), m-trifluoromethyl benzoic acid (7 to 22%), m-trifluoromethyl hippuric acid (<1 to 11%), and 1-(m-trifluoromethylphenyl)-propan-2-ol (2 to 4%).
Renal Disease and Liver Disease: Specific studies in patients with renal and hepatic impairment have not been conducted.
Obese Patients: In obese patients who received a single 30-mg dose, a mean peak plasma dexfenfluramine concentration of about 22.3 ng/mL is reached after about 5.2 hours. In a parallel-group, multiple-dose pharmacokinetic study of dexfenfluramine (15 mg twice daily) there were no significant differences in steady-state pharmacokinetic parameters between obese and non-obese subjects.
Age: The pharmacokinetics of a single 30-mg dose of dexfenfluramine in eight elderly patients, ranging from 66 to 83 years of age, have been examined in one study. The mean maximal plasma concentration was 21.8 ng/mL, and ranged from 9.7 to 33.0 ng/mL in individual patients. Time to maximal plasma concentration was about 5 hours and ranged from 3 hours to 10 hours. Area-under-the-curve to infinity was 615 ng·hr/mL and ranged from 16 to 1205 ng·hr/mL. Mean (±SD) steady-state plasma concentrations of dexfenfluramine and d-norfenfluramine after six months of treatment (15 mg twice daily) in 18 obese patients over 60 years old were 27.3 (±16.3) ng/mL and 14.0 (±7.4) ng/mL, respectively, compared to values of 24.1 (±15.9) and 15.6 (±11.2), respectively, in 268 patients under 60 years old. In a cohort of these patients followed through 12 months of treatment (15 mg twice daily) mean (±SD) steady-state plasma concentrations of dexfenfluramine and d-norfenfluramine in 17 obese patients over 60 years old were 32.9 (±16.8) ng/mL and 18.0 (±8.0) ng/mL, respectively, compared to values of 23.9 (±12.9) and 14.4 (±8.2), respectively, in 186 obese patients under 60 years old.
Observational epidemiologic studies have established a relationship between obesity and the risks for cardiovascular disease, non-insulin dependent diabetes mellitus (NIDDM), certain forms of cancer, gallstones, certain respiratory disorders, and an increase in overall mortality. These studies suggest that weight loss, if maintained, may produce health benefits for some patients with chronic obesity who may also be at risk for other diseases.
The long-term effects of dexfenfluramine on the morbidity and mortality associated with obesity have not been established. Short-term (<4 months), placebo-controlled, double-blind studies have provided evidence that dexfenfluramine does not adversely affect glycemia, lipid profile, or blood pressure control in obese patients. Some short-term studies have suggested that weight loss with dexfenfluramine may be associated with a reduction in hyperglycemia in obese diabetic patients, a reduction in blood pressure in obese hypertensive patients, and improvement in the lipid profile in obese hyperlipidemic patients.
Dexfenfluramine has been shown to be effective in reducing excess body weight in obese patients. In 16 of 17 double-blind, placebo-controlled trials, of various treatment durations and with different design features, where all patients were on reduced-calorie diets, dexfenfluramine-treated patients lost statistically significantly more weight on average than those treated with placebo. In these studies, weight loss was evident within 4 weeks of initiating treatment, even in some patients where reduced-calorie diet alone had failed to induce a significant weight loss.
In the INDEX study, a one-year, double-blind, placebo-controlled trial of obese patients, dexfenfluramine, in conjunction with a reduced-calorie diet, produced a significant reduction in weight during the first 4 to 6 months. This response was maintained during continuation of therapy (up to 12 months of treatment). The percentage of patients who achieved various levels of weight loss at 1 year are shown below.
Last reviewed on RxList: 12/8/2004
This monograph has been modified to include the generic and brand name in many instances.
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