Redux (dexfenfluramine hydrochloride capsules), an anti-obesity drug, is a serotonin reuptake inhibitor and releasing agent. Redux is available for oral administration in white, opaque, hard-gelatin capsules. The active ingredient is dexfenfluramine hydrochloride. Each capsule contains 15 mg dexfenfluramine hydrochloride. Inactive ingredients include: lactose, gelatin capsule, corn starch, microcrystalline cellulose, talc, titanium dioxide, magnesium stearate, colloidal silicon dioxide, and edible ink.

Dexfenfluramine hydrochloride, a white to off-white crystalline powder, is designated chemically as (S)-N-ethyl-alpha-methyl-3-(trifluoromethyl) benzeneethanamine hydrochloride and has a molecular weight of 267.7. Its empirical formula is C₁₂H₁₆F₃N·HCl. Dexfenfluramine is freely soluble in water, alcohol, chloroform, and methanol The pKa of dexfenfluramine hydrochloride is 10.

Dexfenfluramine is indicated for the management of obesity including weight loss and maintenance of weight loss in patients on a reduced calorie diet. Dexfenfluramine hydrochloride is recommended for obese patients with an initial body mass index ³30 kg/m², or ³27 kg/m² in the presence of other risk factors (e.g., hypertension, diabetes, hyperlipidemia).

The safety and effectiveness of dexfenfluramine beyond 1 year have not been determined at this time.

Below is a chart of Body Mass Index (BMI) based on various heights and weights.

BMI is calculated by taking the patient's weight, in kg, divided by the patient's height, in meters, squared. Metric conversions are as follows: pounds ÷ 2.2 = kg; inches x 0.0254 = meters.

TABLE 1 - BODY MASS INDEX (BMI), kg/m²

Patients with BMI values ³30 may be candidates for dexfenfluramine therapy.

Patients with BMI values of 27-29 may be candidates for dexfenfluramine therapy if they also have a concomitant risk factor (e.g., hypertension, diabetes, hyperlipidemia).

The usual dosage is one 15-mg capsule twice daily, with meals. Doses above 30 mg per day are not recommended.

Analysis of numerous variables has indicated that about 60% of patients who lose at least 4 pounds in the first 4 weeks of treatment with dexfenfluramine in combination with a reduced-calorie diet lose at least 10% of their initial body weight by the end of 1 year of treatment. If a patient has not lost at least 4 pounds in the first 4 weeks of treatment, the physician should consider reevaluation of therapy which may include discontinuation of dexfenfluramine.

The safety and effectiveness of dexfenfluramine beyond 1 year have not been determined at this time.

Infrequently, symptoms (e.g., abdominal pain, anxiety, asthenia, delusion, depression, diarrhea, dizziness, hypertension, insomnia, nausea and vomiting) have occurred within several days following cessation of dexfenfluramine. If the physician notes such symptoms, clinical judgment should guide the treatment, which may include tapering the dose (15 mg once daily) for 2 weeks prior to complete discontinuation.

Redux (dexfenfluramine hydrochloride capsules) 15 mg, is supplied in number 3, white, opaque, hard-gelatin capsules. Each capsule is marked with "Redux" and three black vertical bands.

Storage: Store at room temperature, between 15°C and 30°C (59°F and 86°F).

Commonly Observed

The most commonly observed, treatment-emergent adverse events associated with the use of dexfenfluramine in double-blind, placebo-controlled clinical trials were diarrhea (17.5%), dry mouth (12.5%), and somnolence (7.1%). These and other commonly observed adverse reactions were generally mild and transient. (Commonly observed is defined as incidence of 5% or greater and incidence in dexfenfluramine group at least twice that of placebo group, as derived from the Table 3 below.)

Associated with Discontinuation of Treatment

Seven percent of the 1159 patients who received dexfenfluramine in double-blind, placebo-controlled clinical trials discontinued treatment because of an adverse event. The most common adverse events resulting in discontinuation included asthenia, insomnia, headache, and depression. Five percent of the 1138 placebo-treated patients discontinued because of an adverse event.

Incidence in Controlled Clinical Trials

The following Table 3 lists treatment-emergent adverse events from several double-blind, placebo-controlled trials that occurred at a frequency of 2% or more among patients treated with dexfenfluramine and occurred at least as frequently as the placebo group, regardless of relationship to study medication.

Other Events Observed in Controlled Clinical Trials

The events below are classified within body system categories and enumerated in order of decreasing frequency using the following definitions. Frequent adverse events are those occurring in more than 1/100 patients but were not described above because the frequency in dexfenfluramine-treated patients was less than that in placebo-treated patients or they occurred at a rate less than 2%. Infrequent adverse events are those occurring in 1/100 to 1/1000 patients, while rare adverse events are those occurring in only one patient during placebo-controlled clinical trials.

Body as a whole:

Frequent: infection, flu syndrome, pain,back pain, fever, allergic reaction.

Infrequent: malaise, neck pain, chest pain, generalized edema, stress, face edema, neoplasm, pelvic pain.

Rare: adenoma, immune system disorder, neck rigidity, suicide attempt.

Cardiovascular System:

Frequent: hypertension, angina pectoris, palpitation, vasodilation, migraine.

Infrequent: cardiovascular disorder, tachycardia, postural hypotension, hypotension, peripheral vascular disorder, syncope, arrhythmia, extrasystoles, hemorrhage, thrombophlebitis, varicose vein.

Rare: heart block, pulmonary embolus, thrombosis.

Gastrointestinal system:

Frequent: constipation, nausea, dyspepsia, increased appetite, rectal disorder, gastritis, gastroenteritis, flatulence.

Infrequent: colitis, eructation, gastrointestinal hemorrhage, enteritis, peptic ulcer, hepatitis, hepatomegaly.

Rare: appendicitis, cholelithiasis, fecal incontinence, melena, mouth ulceration, pancreatitis, rectal hemorrhage, sialoadenitis.

Endocrine:

Infrequent: goiter, diabetes mellitus, thyroid disorder.

Rare: hypothyroidism.

Hemic and lymphatic system:

Infrequent: anemia, lymphedema.

Rare: coagulation disorder, lymphadenopathy, polycythemia, thrombocythemia.

Metabolic and nutritional:

Infrequent: edema, gout, hypoglycemia, hypokalemia.

Rare: hyperglycemia, hyperkalemia, hyperlipemia, hyperuricemia.

Musculoskeletal system:

Frequent: arthralgia, myalgia, arthritis.

Infrequent: leg cramps, joint disorder, bone disorder, tenosynovitis, myasthenia, rheumatoid arthritis.

Rare: bursitis, tetany.

Nervous system:

Frequent: nervousness, anxiety, increased libido, hypertonia, paresthesia.

Infrequent: tremor, amnesia, euphoria, decreased libido, incoordination, neuralgia, speech disorder, ataxia, hypokinesia, sleep disorder, abnormal gait, agitation, confusion, depersonalization, diplopia, hostility, hyperesthesia, hyperkinesia, peripheral neuritis.

Rare: apathy, dementia, hallucinations, hypotonia, neuritis, neurosis, paralysis.

Respiratory system:

Frequent: rhinitis, sinusitis. Infrequent: asthma, dyspnea, epistaxis, laryngitis.

Rare: apnea, hyperventilation.

Skin and appendages:

Frequent: sweating, alopecia, urticaria, pruritus.

Infrequent: skin disorder, fungal dermatitis, hirsutism, eczema, psoriasis.

Rare: skin hypertrophy.

Special senses:

Frequent: taste perversion, amblyopia.

Infrequent: abnormal vision, conjunctivitis, eye disorder, glaucoma, tinnitus, vestibular disorder, dry eyes, mydriasis.

Rare: abnormality of accommodation, anisocoria, lacrimation disorder, miosis, parosmia, retinal disorder.

Urogenital system:

Frequent: menstrual disorder, urinary tract infection, nocturia, dysmenorrhea.

Infrequent: amenorrhea, dysuria, oliguria, albuminuria, breast pain, kidney calculus, kidney pain.

Rare: spontaneous abortion, threatened abortion, breast neoplasm, endometrial disorder, female lactation, hematuria, impotence, mastitis, nephritis, prostatic disorder, testis disorder, urinary incontinence, urinary retention, uterine hemorrhage.

In controlled clinical trials, there has been no consistent pattern of laboratory abnormalities in patients treated with dexfenfluramine.

Post-introduction Reports

Voluntary reports of adverse events temporally associated with dexfenfluramine that have been received since market introduction in countries other than the US, for which the association with the drug is unknown, and which are not included in descriptions of adverse events elsewhere in this labeling, include the following:

Body as a whole: anaphylaxis, congenital anomaly, eventration, hypothermia, laryngeal edema, peritonitis, reaction aggravation, retroperitoneal fibrosis, scleroderma, sudden death.

Cardiovascular system: pulmonary hypertension (see WARNINGS), atrial fibrillation, cardiomyopathy, cerebral vasculitis, ECG abnormal, heart arrest, heart failure, myocardial infarction, myocarditis, shock, tachycardia, ventricular fibrillation, ventricular tachycardia.

Digestive system: dysphagia, gastrointestinal disorder, tongue disorder. Endocrine system--diabetic coma.

Gastrointestinal system: hepatic failure, jaundice, liver damage.

Hemic and lymphatic system: agranulocytosis, antinuclear antibody present, bone marrow depression, ecchymosis, hemolytic anemia, pancytopenia.

Metabolic and nutritional: dehydration, elevated lipases, increased prolactin, thyroid disease, weight increase.

Musculoskeletal: myopathy.

Nervous system: antisocial reaction, apathy, cerebellar ataxia, cerebrovascular accident (including cerebral hemorrhage, cerebral infarction, cerebral ischemia and cochlear infarction), choreoathetosis, convulsions, decreased reflexes, delirium, drug dependence, dyslexia, encephalopathy, grand mal convulsions, Guillain-Barré syndrome, hemiplegia, hypoesthesia, manic-depressive psychosis, manic reaction, memory loss, meningism, meningitis, neuropathy, papilledema, paraplegia, personality disorder, reflexes increased, retrobulbar neuritis, schizophrenic reaction, stupor, subdural hematoma, twitch, withdrawal syndrome.

Respiratory system: pulmonary hypertension (see WARNINGS), diffuse interstitial pneumonitis, dyspnea, hiccup, lung edema.

Skin and appendages: angioedema, bullous eruption, erythema multiforme, lower extremity purpura, purpura annularis telangiectodes, Stevens-Johnson syndrome (erythema multiforme major).

Special Senses: ophthalmoplegia, photophobia, transitory deafness, visual field defects.

Urogenital system: breast enlargement, carcinoma (breast), carcinoma (cervix), ejaculation abnormal, gynecomastia, hypomenorrhea, kidney failure, placenta previa, urinary tract disorder.

Adverse Events Occurring After Discontinuation

In controlled clinical trials and/or in post-marketing reports, symptoms have been reported within a few days after discontinuation of dexfenfluramine. These include one or more of the following: abdominal pain, anxiety, asthenia, delusion, depression, diarrhea, dizziness, hypertension, insomnia, nausea and vomiting.

DRUG ABUSE AND DEPENDENCE

Controlled Substance Class

Dexfenfluramine is a controlled substance in Schedule IV.

Abuse and Physical and Psychological Dependence

Dexfenfluramine is not an amphetamine or a stimulant. There is no evidence of addictive or drug-seeking behavior in pre-marketing clinical studies. Dexfenfluramine was inactive in rat and monkey self-administration, drug-discrimination, and place-preference models of abuse potential.

In patients receiving nonselective monoamine oxidase inhibitors (MAOIs) (e.g., selegiline hydrochloride) in combination with serotoninergic agents (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline, venlafaxine), there have been reports of serious, sometimes fatal, reactions. Because dexfenfluramine is a serotonin releaser and reuptake inhibitor, dexfenfluramine should not be used concomitantly with a MAO inhibitor (see CONTRAINDICATIONS).

At least 14 days should elapse between discontinuation of a MAO inhibitor and initiation of treatment with dexfenfluramine. At least 3 weeks should elapse between discontinuation of dexfenfluramine and initiation of treatment with a MAO inhibitor.

A rare, but serious, constellation of symptoms, termed "serotonin syndrome," has been reported with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and agents for migraine therapy, such as Imitrex (sumatriptan succinate) and dihydroergotamine. The syndrome requires immediate medical attention and may include one or more of the following symptoms: excitement, hypomania, restlessness, loss of consciousness, confusion, disorientation, anxiety, agitation, motor weakness, myoclonus, tremor, hemiballismus, hyperreflexia, ataxia, dysarthria, incoordination, hyperthermia, shivering, pupillary dilation, diaphoresis, emesis, and tachycardia. Dexfenfluramine should not be administered with other serotoninergic agents. The appropriate interval between administration of these agents and dexfenfluramine has not been established. The use of dexfenfluramine with other CNS-active drugs has not been systematically evaluated; consequently, caution is advised if dexfenfluramine and such drugs are prescribed concurrently.

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.

Miscellaneous

Organic causes of obesity (e.g., hypothyroidism) should be excluded before prescribing dexfenfluramine. Dexfenfluramine should be used with caution in patients with glaucoma.

General

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.

Misuse Potential

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.

Combination Therapy

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.

Pregnancy

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.

Nursing Mothers

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.

Human Experience

Post-marketing experience in Europe over 10 years (August 1984 through December 1994) in an estimated 10 million patients provided reports of 66 instances of overdose (maximum dose per body mass of 54 mg/kg, maximum total dose of 1800 mg), including eight children 6 years of age or under. Three deaths have occurred in association with dexfenfluramine overdosage. One patient with a history of suicide attempts ingested 1800 mg dexfenfluramine and 20 to 30 capsules of Tranxene (clorazepate), one patient was found dead, assumed to have consumed approximately 1500 mg of dexfenfluramine, and the third patient consumed dexfenfluramine (quantity unknown) and several other drugs in an apparent suicide. The second patient had post-mortem levels of dexfenfluramine of 3300 ng/mL, and positive levels for amphetamines and cannabinoids. The exact causes of death were unknown. In 23 other cases of dexfenfluramine overdose, plasma drug levels were determined; the maximum reported plasma drug level for dexfenfluramine was 778 ng/mL (with d-norfenfluramine 37 ng/mL); the maximum d-norfenfluramine level was 371 ng/mL (with dexfenfluramine 483 ng/mL).

Symptoms associated with overdosage consisted mainly of agitation, drowsiness, mydriasis, sweating, shivering, nausea, and vomiting. Other symptoms observed with dexfenfluramine overdose and not noted under ADVERSE REACTIONS include cold sensation, excitation, nystagmus, garrulousness, delusions, bladder tenesmus, chattering teeth, abnormal reflexes, facial myoclonus, trismus, tonic-clonic seizures, impairment of consciousness, coma (stage 2-4), sinus bradycardia, repolarization abnormalities, right anterior hemiblock, polypnea, diffuse bronchial rales, and flushing.

Animal Experience

Significant acute toxicity occurred at oral doses greater than 40, 70, and 75 mg/kg in rats, mice, and guinea pigs, respectively. A dose of 40 mg/kg is approximately 31 times greater than the effective anorectic dose tn rats.

Management of Overdose

General supportive measures for oral drug overdose should be instituted. Measures that have been used in dexfenfluramine overdose cases include aspiration of gastric contents, gastric lavage with activated charcoal, osmotic diuresis, forced acid diuresis, and careful monitoring of CNS or respiratory depression. The effectiveness of dialysis is not known. Patients should be followed closely until there is no further evidence of drug-related CNS effects. No specific therapy for dexfenfluramine overdose is known.

Dexfenfluramine is contraindicated in patients with diagnosed pulmonary hypertension (see WARNINGS). Dexfenfluramine is contraindicated in patients receiving monoamine oxidase inhibitors (see DRUG INTERACTIONS). Dexfenfluramine is contraindicated in patients with hypersensitivity to dexfenfluramine, fenfluramine, or related compounds.

Pharmacologic Actions

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 C_max values of 25 ng/mL, 33 ng/mL, and 51 ng/mL and area-under-the-curve_0-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 C_min 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.

CLINICAL STUDIES

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.

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 WARNINGS, PRECAUTIONS and CONTRAINDICATIONS.