PHENDIMETRAZINE TARTRATE TABLETS, USP

OVERVIEW

Phendimetrazine tartrate, as the dextro isomer, has the chemical name of (2S.3S)-3, 4-Dimethyl-2-phenylmorpholine L-(*)-tartrate (1.1). Its molecular weight is 341.36.

Phendimetrazine tartrate is a white, odorless crystalline powder. It is freely soluble in water; sparingly soluble in warm alcohol, insoluble in chloroform, acetone, ether and benzene.

Each tablet, for oral administration, contains 35mg of phendimetrazine tartrate. In addition, each tablet contains the following inactive ingredients: Lactose USP, Magnesium Stearate NF, Colloidal Silicon Dioxide, Microcrystalline Cellulose NF, Starch NF (Modified Corn Starch).

CLINICAL PHARMACOLOGY

Phendimetrazine tartrate is a phenylalkylamine sympathomimetic amine with pharmacological activity similar to the prototype drugs of this class used in obesity, the amphetamines. Actions include central nervous system stimulation and elevation of blood pressure. Tachyphylaxis and 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. 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 is only a fraction of a pound a week. 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 proof to variables other than the drug prescribed, such as the physician-investigator, 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 the studies cited are restricted to a low weeks duration, thus the total impact of drug-induced weight loss over that of diet alone must be considered clinically limited.

[BZK - The limited length of the studies makes judgement of effectiveness over long periods uncertain. It simply has not been tested.]

ADVERSE REACTIONS

Cardiovascular: Palpitation, tachycardia, elevation of blood pressure.

Central Nervous System: overstimulation, restlessness, dizziness, insomnia, tremor, headache, psychotic state, agitation, flushing, sweating, blurring of vision.

Gastrointestinal: Dryness of the mouth, diarrhea, constipation, nausea, stomach pain.

Genitourinary: Changes in libido, urinary frequency, dysuria.

DRUG ABUSE AND DEPENDENCE

Phendimetrazine tartrate is classified as a Schedule III controlled substance.

Dependence

Phendimetrazine Tartrate is related chemically and pharmacologically to the amphetamines. Amphetamines and related stimulant drugs have been extensively abused, and the possibility of abuse of phendimetrazine should be kept in mind when evaluating the desirability of including a drug as part of a weight reduction program. Abuse of amphetamines and related drugs may be associated with intense psychological dependence and severe social dysfunction. There are, reports of patients who have increased the dosage to many times that recommended. Abrupt cessation following prolonged high dosage administration results in extreme fatigue and mental depression. Changes are also noted on the sleep EEG. Manifestations of chronic intoxication is psychosis, often clinically indistinguishable from schizophrenia.

WARNINGS

Tolerance to the anorectic effect usually develops within a few weeks. When this occurs the recommended dose should not be exceeded in an attempt to increase the effect rather, the drug should be discontinued.

Use of phendimetrazine within 14 days following the administration of monoamine oxidase inhibitors may result in a hypertensive crisis. Abrupt cessation of administration following prolonged high dosage results in extreme fatigue and depression. Because of the effect on the central nervous system phendimetrazine tartrate may impair the ability of the patient to engage in potentially hazardous activities such as operating machinery or driving a motor vehicle. The patient should therefore be cautioned accordingly.

PRECAUTIONS

Caution is to be exercised in prescribing phendimetrazine for patients with even mild hypertension. Insulin requirements in diabetes mellitus may be altered in association with the use of phendimetrazine and the concomitant dietary regimen.

Phendimetrazine may decrease the hypotensive effect of guanethidine. The least amount feasible should be prescribed or dispensed at one time in order to minimize the possibility of overdosage.

Phendimetrazine tartrate 35 mg Yellow and Speckled tablets contain FD& C Yellow #5 (tartrazine) which may cause allergic type reactions (including bronchial asthma) in certain susceptible persons, although the overall incidence of FD& C Yellow #5 (tartrazine) sensitivity in the general population is low. It is frequently seen in patients who also have aspirin hypersensitivity.

Usage In Pregnancy

Safe use in pregnancy has not been established. Until more information is available, phendimetrazine tartrate should not be taken by women who are or may become pregnant unless, in the opinion of the physician, the potential benefits outweigh the possible hazards.

Usage In Children

Phendimetrazine tartrate is not recommended for use in Children Under 12 years of age.

OVERDOSAGE

Acute overdosage of phendimetrazine tartrate may manifest itself by the following signs and symptoms: unusual restlessness, confusion, belligerance, hallucinations, and panic states. Fatigue and depression usually follow the central stimulation. Cardiovascular effects include arrhythmias, hypertension, or hypotension and circulatory collapse. Gastrointestinal symptoms include nausea, vomiting, diarrhea, and abdominal cramps. Poisoning may result in convulsions, coma and death.

The management of overdosage is largely symptomatic. It includes sedation with a barbiturate. If hypertension is marked, the use of a nitrate or rapid-acting alpha receptor-blocking agent should be considered. Experience with hemodialysis or peritoneal dialysis is inadequate to permit recommendations for its use.

CONTRAINDICATIONS

Known hypersensitivity or idiosyncratic reactions to sympathomimetics. Advanced arteriosclerosis, symptomatic cardiovascular disease, moderate and severe hypertension, hyperthyroidism, glaucoma.

Highly nervous or agitated patients. Patients with a history of drug abuse. Patients taking other CNS stimulants, including monamine oxidase inhibitors.

Anorectics
Stereotypies
Neurotoxicity
VTA/glutamate
CNS stimulants
Self-medication
Appetite suppressants
Phendimetrazine (Bontril, Obex)

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