CLINICAL PHARMACOLOGY

Diethylpropion hydrochloride is a sympathomimetic amine with some pharmacologic activity similar to that of the prototype drugs of this class used in obesity, the amphetamines. Actions include some central nervous system stimulation and elevation of blood pressure. Tolerance has been demonstrated with all drugs of this class in which these phenomena have been looked for.

Drugs of this class used in obesity are commonly known as "anorectics" or "anorexigenics." It has not been established, however, that the action of such drugs in treating obesity is primarily one of appetite suppression. For example, other central nervous system actions or metabolic effects may be involved.

Adult obese subjects instructed in dietary management and treated with "anorectic" drugs lose more weight on the average than those treated with placebo and diet, as determined in relatively short-term clinical trials.

The magnitude of increased weight loss of drug-treated patients over placebo- treated patients averages some fraction of a pound a week. However, individual weight loss may vary substantially from patient to patient. The rate of weight loss is greatest in the first weeks of therapy for both drug and placebo subjects and tends to decrease in succeeding weeks. The possible origins of the increased weight loss due to the various drug effects are not established. The amount of weight loss associated with the use of an "anorectic" drug varies from trial to trial, and the increased weight loss appears to be related in part to variables other than the drug prescribed, such as the physician/investigator relationship, the population treated, and the diet prescribed. Studies do not permit conclusions as to the relative importance of the drug and non-drug factors on weight loss.

The natural history of obesity is measured in years, whereas most studies cited are restricted to a few weeks duration; thus, the total impact of drug- induced weight loss over that of diet alone is unknown.

Diethylpropion is rapidly absorbed from the GI tract after oral administration and is extensively metabolized through a complex pathway of biotransformation involving N-dealkylation and reduction. Many of these metabolites are biologically active and may participate in the therapeutic action of diethylpropion hydrochloride extended release tablets, 75 mg. Due to the varying lipid solubilities of these metabolites, their circulating levels are affected by urinary pH. Diethylpropion and/or its active metabolites are believed to cross the blood-brain barrier and the placenta.

Diethylpropion and its metabolites are excreted mainly by the kidney. It has been reported that between 75-106% of the dose is recovered in the urine within 48 hours after dosing. Using a phosphorescence assay that is specific for basic compounds containing benzoyl group, the plasma half-life of the aminoketone metabolites is estimated to be between 4 to 6 hours.

The controlled-release characteristics of diethylpropion hydrochloride extended release tablets, 75 mg have been demonstrated by studies in humans in which plasma levels of diethylpropion-related materials were measured by phosphorescence analysis. Plasma levels obtained with the diethylpropion hydrochloride extended release tablets, 75 mg formulation administered once daily indicated a more gradual release than the immediate-release formulation (three 25 mg tablets given in a single dose).

Diethylpropion hydrochloride extended release tablets, 75 mg have not been shown superior in effectiveness to the same dosage of the immediate-release formulation (one 25 mg tablet three times daily). After administration of a single dose of diethylpropion hydrochloride extended release tablets, 75 mg (one 75 mg extended release tablet) or diethylpropion hydrochloride solution (75 mg dose) in a cross-over study using normal human subjects, the amount of parent compound and its active metabolites recovered in the urine within 48 hours for the two dosage forms were not statistically different.

PRECAUTIONS

General

Caution is to be exercised in prescribing diethylpropion hydrochloride extended release tablets, 75 mg for patients with hypertension or with symptomatic cardiovascular disease, including arrhythmias. Diethylpropion hydrochloride extended release tablets, 75 mg should not be administered to patients with severe hypertension.

Reports suggest that diethylpropion hydrochloride may increase convulsions in some epileptics. Therefore, epileptics receiving diethylpropion hydrochloride extended release tablets, 75 mg should be carefully monitored. Titration of dose or discontinuance of diethylpropion hydrochloride extended release tablets, 75 mg may be necessary.

The least amount feasible should be prescribed or dispensed at one time in order to minimize the possibility of overdosage.

Information for Patient

The patient should be cautioned about concomitant use of alcohol or other CNS- active drugs and diethylpropion hydrochloride extended release tablets, 75 mg (SeeWARNINGS). The patient should be advised to observe caution when driving or engaging in any potentially hazardous activity.

Laboratory Tests

None

Drug Interactions

Because diethylpropion hydrochloride extended release tablets, 75 mg are monoamines, hypertension may result when either agent is used with monoamine oxidase (MAO) inhibitors (SeeCONTRAINDICATIONS).

Efficacy of diethylpropion with other anorectic agents has not been studied and the combined use may have the potential for serious cardiac problems; therefore, the concomitant use with other anorectic agents is contraindicated.

Antidiabetic drug requirements (i.e., insulin) may be altered. Concurrent use with general anesthetics may result in arrhythmias. The pressor effects of diethylpropion and those of other drugs may be additive when the drugs are used concomitantly; conversely, diethylpropion may interfere with antihypertensive drugs (i.e., guanethidine, a-methyldopa). Concurrent use of phenothiazines may antagonize the anorectic effect of diethylpropion.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

No long-term animal studies have been done to evaluate diethylpropion hydrochloride for carcinogenicity. Mutagenicity studies have not been conducted. Animal reproduction studies have revealed no evidence of impairment of fertility (SeePregnancy).

Pregnancy

**Teratogenic Effects: Pregnancy Category B.**Reproduction studies have been performed in rats at doses up to 1.6 times the human dose (based on mg/m2) and have revealed no evidence of impaired fertility or harm to the fetus due to diethylpropion hydrochloride. There are, however, no adequate and well- controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Spontaneous reports of congenital malformations have been recorded in humans, but no causal relationship to diethylpropion has been established.

**Non-Teratogenic Effects.**Abuse with diethylpropion hydrochloride during pregnancy may result in withdrawal symptoms in the human neonate.

Nursing Mothers

Since diethylpropion hydrochloride and/or its metabolites have been shown to be excreted in human milk, caution should be exercised when diethylpropion hydrochloride extended release tablets, 75 mg are administered to a nursing woman.

Geriatric Use

Clinical studies of diethylpropion hydrochloride extended release tablets, 75 mg did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Pediatric Use

Since safety and effectiveness in pediatric patients below the age of 16 have not been established, diethylpropion hydrochloride extended release tablets, 75 mg is not recommended for use in pediatric patients 16 years of age and under.

Storage

Store at 20 to 25°C (68 to 77°F) [See USP Controlled Room Temperature]. Keep tightly closed and protect from excessive heat.