Pondimin (fenfluramine - removed from us market) (fenfluramine hydrochloride) is an anorectic drug for oral administration. Immediate release tablets containing 20 mg fenfluramine hydrochloride are orange, scored, compressed tablets engraved AHR and 6447.
Inactive Ingredients: (fenfluramine - removed from us market) Corn Starch, FD&C Yellow 6, Magnesium Stearate, Microcrystalline Cellulose, Silicon Dioxide, Sodium Lauryl Sulfate.
Fenfluramine HCl has the following chemical name: N-ethyl-alpha-methyl-3-(trifluoromethyl) benzeneethanamine hydrochloride.
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 trials.
The average magnitude of increased weight loss of drug-treated patients over placebo-treated 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 average 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 few weeks duration; thus, the total impact of drug-induced weight loss over that of diet alone must be considered clinically limited.
DOSAGE AND ADMINISTRATION
The usual dose is one 20 mg tablet three times daily before meals. Depending on the degree of effectiveness and side effects, the dosage may be increased at weekly intervals by one tablet (20 mg) daily until a maximum dosage of two tablets three times daily is attained. Total dosage of fenfluramine should not exceed 120 mg per day.
Pondimin (fenfluramine - removed from us market) is available in 20 mg orange, scored, compressed tablets monogrammed AHR and 6447, in bottles of 100 and 500.
Tablet, Uncoated - Oral - 20 mg
100's Pondimin, AH Robins 00031-6447-63 500's Pondimin, AH Robins 00031-6447-70
Store at controlled room temperature, between 15°C and 30°C (59°F and 86°F).
Dispense in well-closed container.
The most common adverse reactions of fenfluramine are drowsiness, diarrhea, and dry mouth. Less frequent adverse reactions reported in association with fenfluramine are:
Central nervous system: Dizziness; confusion; incoordination; headache; elevated mood; depression; anxiety, nervousness, or tension; insomnia; weakness or fatigue; increased or decreased libido; agitation, dysarthria.
Gastrointestinal: Constipation; abdominal pain; nausea.
Autonomic: Sweating; chills; blurred vision.
Genitourinary: Dysuria; urinary frequency.
Skin: Rash; urticaria; burning sensation.
Miscellaneous: Eye irritation; myalgia; fever; chest pain; bad taste.
Drug Abuse and Dependence
Pondimin (fenfluramine hydrochloride) is a controlled substance in Schedule IV. Fenfluramine is related chemically to the amphetamines, although it differs somewhat pharmacologically. The amphetamines and related stimulant drugs have been extensively abused and can produce tolerance and severe psychological dependence, as well as other adverse organic and mental changes. In this regard, there has been a report of abuse of fenfluramine by subjects with a history of abuse of other drugs. Abuse of 80 to 400 milligrams of the drug has been reported to be associated with euphoria, derealization, and perceptual changes. Fenfluramine did not produce signs of dependence in animals and appears to produce sedation more often than CNS stimulation at therapeutic doses. Its abuse potential appears qualitatively different from that of amphetamines. The possibility that fenfluramine may induce dependence should be kept in mind when evaluating the desirability of including the drug in the weight reduction programs of individual patients.
Fenfluramine may increase slightly the effect of antihypertensive drugs, e.g., guanethidine, methyldopa, reserpine.
Other CNS depressant drugs should be used with caution in patients taking fenfluramine, since the effects may be additive.
When tolerance to the "anorectic" effect develops, the maximum recommended dose should not be exceeded in an attempt to increase the effect; rather, the drug should be discontinued.
Fenfluramine differs in its pharmacological profile from other "anorectic" drugs with which the prescribing practitioner may be familiar. Correspondingly, there are possible adverse effects not associated with other "anorectics"; such effects include those of diarrhea, sedation, and depression. The possibility of these effects should be weighed against the possible advantage of decreased central nervous system stimulation and/or abuse potential.
There have been four cases of pulmonary hypertension reported in association with fenfluramine use. Two cases were apparently reversible after discontinuation of fenfluramine, but evidence of pulmonary hypertension recurred in one of these patients upon rechallenge with fenfluramine. A third patient was initially improved with nifedipine treatment, but was noted to have increased pulmonary arterial pressure again at a four month follow up visit. Finally, an irreversible and fatal case of pulmonary hypertension has been reported in a patient who had seven 1-month courses of fenfluramine in the twelve years prior to death. Patients taking fenfluramine should be advised to report immediately any deterioration in exercise tolerance.
Use only with caution in hypertension, with monitoring of blood pressure, since evidence is insufficient to rule out a possible adverse effect on blood pressure in some hypertensive patients. The drug is not recommended in severely hypertensive patients. The drug is not recommended for patients with symptomatic cardiovascular disease including arrhythmias.
Caution should be exercised in prescribing fenfluramine for patients with a history of mental depression. Further depression of mood may become evident while the patient is on fenfluramine or following withdrawal of fenfluramine. Symptoms of depression occurring immediately following abrupt withdrawal can be readily controlled by reinstituting Fenfluramine HCl, followed by a gradual tapering off of the daily dose.
Information for the Patient
Fenfluramine may impair the ability of the patient to engage in potentially hazardous activities such as operating machinery or driving a motor vehicle (see ADVERSE REACTIONS); the patient should be cautioned accordingly. Patient should also be advised to avoid alcoholic beverages while taking Fenfluramine HCl.
No carcinogenic studies or mutagenic studies have been undertaken with this drug.
Pregnancy Category C
Fenfluramine HCl was shown to produce a questionable embryotoxic effect in rats and a reduced conception rate when given in a dose of 20 times the human dose. However, additional reproduction studies in rats, rabbits, mice, and monkeys at doses up to, respectively, 5 times, 20 times, 1 time, and 5 times the human dose yielded negative results.
There are no adequate and well-controlled studies in pregnant women. Fenfluramine HCl should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Labor and Delivery
The effect of fenfluramine during labor or delivery on the mother and the fetus is unknown. The effect on later growth, development, and functional maturation of the child is unknown.
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when fenfluramine is administered to a nursing mother.
Safety and effectiveness in children below the age of 12 years has not been established.
Signs and Symptoms
Only limited data have been reported concerning clinical effects and management of overdosage of fenfluramine.
Agitation and drowsiness, confusion, flushing, tremor (or shivering), fever, sweating, abdominal pain, hyperventilation, and dilated non-reactive pupils seem frequent in fenfluramine overdosage. Reflexes may be either exaggerated or depressed and some patients may have rotary nystagmus. Tachycardia may be present, but blood pressure may be normal or only slightly elevated. Convulsions, coma, and ventricular extrasystoles, culminating in ventricular fibrillation, and cardiac arrest, may occur at higher dosages.
Less than 5 mg/kg are toxic to humans. Five-ten mg/kg may produce coma and convulsions. Reported single overdoses have ranged from 300 to 2000 mg; the lowest reported fatal dose was a few hundred mg in a small child, and the highest reported nonfatal dose was 1800 mg in an adult. Most deaths were apparently due to respiratory failure and cardiac arrest.
Toxic effects will appear within 30 to 60 minutes and may progress rapidly to potentially fatal complications in 90 to 240 minutes. Symptoms may persist for extended periods depending upon the dose ingested.
After overdosage, only a small percentage of the drug is excreted in the urine. Forced acid diuresis has been recommended only in extreme cases in which the patient survives the early hours of intoxication but fails to show decisive improvement from other measures. Hemodialysis and peritoneal dialysis are of theoretical advantage but have not been used clinically.
Reportedly the treatment of fenfluramine intoxication should include:
Gastric Lavage: (but not drug-induced emesis because the patient may become unconscious at a very early stage.)In the event that gastric lavage is not feasible due to trismus, consult an anesthesiologist for endotracheal intubation after administration of muscle relaxants; only then gastric evacuation should be t.i.d. Administration of activated charcoal after emesis or lavage may reduce absorption of drug.
Drug Therapy: Diazepam or phenobarbital for convulsions or muscular hyperactivity. In the presence of extreme tachycardia: propranolol; in the presence of ventricular extrasystoles: lidocaine; in the presence of hyperpyrexia: chlorpromazine.
Since fenfluramine has been shown to have a slight lowering effect on blood sugar in some patients, the theoretical possibility of hypoglycemia should be borne in mind although this effect has not been reported in cases of clinical overdosage.
Fenfluramine is contraindicated in patients with glaucoma or with hypersensitivity to fenfluramine or other sympathomimetic amines. Do not administer fenfluramine during or within 14 days following the administration of monoamine oxidase inhibitors, since hypertensive crises may result. Patients with a history of drug abuse should not receive this drug.
Fenfluramine should also generally be avoided in patients with psychotic illness. There have been reports of schizophrenic patients who have become agitated, delusional, and assaultive.
A fatal cardiac arrest has been reported shortly after the induction of anesthesia in a patient who had been taking fenfluramine prior to surgery. Fenfluramine may have a catecholamine-depleting effect when administered for prolonged periods of time; therefore, potent anesthetic agents should be administered with caution to patients taking fenfluramine. If general anesthesia cannot be avoided, full cardiac monitoring and facilities for instant resuscitative measures are a minimum necessity.
Fenfluramine is a sympathomimetic amine, the pharmacologic activity of which differs somewhat from that of the prototype drugs of this class used in obesity, the amphetamines, in appearing to produce more central nervous system depression than stimulation.
The mechanism of action of Fenfluramine HCl is unclear but may be related to brain levels (or turnover rates) of serotonin or to increased glucose utilization. The antiappetite effects of Fenfluramine HCl are suppressed by serotonin-blocking drugs and by drugs that lower brain levels of the amine. Furthermore, decreased serotonin levels produced by selective brain lesions suppress the action of Fenfluramine HCl.
In a study of 20 normal males, fenfluramine increased glucose utilization, resulting in decreased blood glucose levels. Experimental work in animals suggested that increased glucose utilization activated the satiety center and decreased the activity of the feeding center. Perhaps by this mechanism Fenfluramine HCl inhibits appetite. The relationship between glucose utilization and serotonin has not been clarified.
Fenfluramine is well-absorbed from the gastrointestinal tract, and a maximal anorectic effect is generally seen after 2 to 4 hours. In man, fenfluramine is de-ethylated to norfenfluramine which is subsequently oxidized to m-trifluoromethyl benzoic acid and excreted as the glycine conjugate, m-trifluoromethylhippuric acid. Other compounds found in the urine include unchanged fenfluramine and norfenfluramine.
The rate of excretion of fenfluramine is pH dependent, with much smaller amounts appearing in an alkaline than in an acid urine.
The half-life of fenfluramine is said to be about 20 hours, compared with 5 hours for amphetamines; however, if urinary excretion is rapid and the pH maintained in the acidic range (below pH 5), half-life can be reduced to 11 hours. Fenfluramine and norfenfluramine reach steady state concentrations in plasma within 3 to 4 days following chronic dosage.
The greatest weight loss is seen in those patients who maintain the highest levels of Fenfluramine HCl. A 2-to-3-kg weight loss over 6 weeks is associated with a plasma level of 0.1 mcg/ml (or 10 mcg/100 ml).
Fenfluramine is widely distributed in almost all body tissues. It is soluble in lipids and crosses the blood-brain barrier. Fenfluramine crosses the placenta readily in monkeys.
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