General Information: Diethylpropion is an oral, sympathomimetic amine that is used as an anorexiant agent. It is structurally and chemically related to the amphetamines. The pharmacologic effects of diethylpropion are also similar to amphetamines. Diethylpropion is utilized in the short-term (up to 12 weeks) management of obesity. Clinical trials report greater weight loss in adult obese subjects treated with dietary management and anorexiants versus patients treated with diet and placebo alone. Weight loss is generally greatest in the first weeks of therapy and decreases in succeeding weeks. Diethylpropion is recommended for short term treatment of obesity; however, longer periods of therapy, up to 25 weeks, may be safely and successfully utilized without the development of tolerance or drug dependence. Diethylpropion was approved by the FDA in 1959 and is available in both immediate-release and sustained-release tablets. It is only indicated for use as monotherapy.
Mechanism of Action: Diethylpropion is a sympathomimetic amine that possesses pharmacological properties similar to amphetamine. Although the exact mechanism of action has not been established, it is thought that appetite suppression is produced by a stimulant effect on the satiety center in the hypothalamic and limbic regions of the brain. Secondary actions include CNS stimulation and blood pressure elevation. Diethylpropion acts primarily on adrenergic pathways to increase the release of norepinephrine from nerve terminals and inhibit its reuptake; therefore, it is considered an indirect-acting sympathomimetic. There is evidence that diethylpropion may also provide some direct stimulation of the nerve terminal to produce the pharmacologic response.
Pharmacokinetics: Diethylpropion is administered orally. Diethylpropion is metabolized through a complex mechanism of N-dealkylation and reduction. N-dealkylation is thought to be responsible for metabolizing 45—55% of the dose whereas reduction accounts for 20—25% of the metabolic processes. Many of the diethylpropion metabolites are active. Diethylpropion and/or its metabolites are believed to cross the blood-brain-barrier and the placenta.
Diethylpropion and its metabolites are excreted primarily by the kidneys. Within 48 hours after dosing, over 75% of the dose is recovered in the urine, 3—6% as unchanged drug, and 64—67% as metabolites. The plasma half-life of the diethylpropion metabolites is approximately 4—8 hours.
Route-Specific Pharmacokinetics: Oral Route: The 75 mg sustained-release tablet has more gradual release characteristics than three 25 mg tablets given in a single dose, based on studies of plasma levels obtained with each dosage form. Diethylpropion is rapidly absorbed from the GI tract.
Indications: Diethylpropion is indicated in the treatment of obesity as a short-term adjunct in a regimen of caloric restriction in patients with an initial body mass index(BMI) of 30 or greater and who have not responded to a weight-reducing regimen of diet and exercise alone.
Contraindications and Precautions: Your health care provider needs to know if you have any of these conditions: heart or blood pressure conditions; glaucoma; are receiving or have received MAOIs within the last two weeks; hyperthyroidism; neurological or psychiatric conditions; are breast-feeding, pregnant, or trying to become pregnant; or a history of substance abuse as diethylpropion is chemically and pharmacologically related to the amphetamine family of sympathomimetic adrenergic agonists.
Patients with anorexia nervosa should not receive anorexiants, since this could worsen the patient's nutritional status. Further, diethylpropion should not be prescribed to patients who have been treated with anorexiant drugs in the preceding 12 months.
Due to its vasopressor effects, diethylpropion is contraindicated in patients with advanced arteriosclerosis, severe hypertension, or pulmonary hypertension. Diethylpropion is not recommended in patients with cardiac arrhythmias, heart murmur, or valvular heart disease. Valvular heart disease is associated with the use of some anorectic agents such as fenfluramine and dexfenfluramine. Cardiac valvulopathy has been very rarely reported with diethylpropion monotherapy, but the causal relationship remains uncertain. Possible contributing factors include use for extended periods of time, higher than recommended dose, and/or use in combination with other anorectic drugs. Baseline cardiac evaluation should be considered to detect preexisting valvular heart diseases or pulmonary hypertension prior to initiation of diethylpropion treatment. Echocardiogram during and after treatment could be useful for detecting any valvular disorders which may occur. In a case-control epidemiological study, the use of anorectic agents, including diethylpropion, was associated with an increased risk of developing pulmonary hypertension, a rare, but often fatal disorder. The use of anorectic agents for longer than 3 months was associated with a 23-fold increase in the risk of developing pulmonary hypertension.1 Increased risk of pulmonary hypertension with repeated courses of therapy cannot be excluded. The onset or aggravation of exertional dyspnea, or unexplained symptoms of angina pectoris, syncope, or lower extremity edema suggest the possibility of occurrence of pulmonary hypertension. Under these circumstances, diethylpropion should be immediately discontinued, and the patient should be evaluated for the possible presence of pulmonary hypertension. The potential risk of possible serious adverse effects such as valvular heart disease and pulmonary hypertension should be assessed carefully against the potential benefit of weight loss.
Because diethylpropion is a sympathomimetic agent, its use is contraindicated in patients with glaucoma.
Diethylpropion is contraindicated in patients receiving MAOI therapy, or within 14 days following the administration of a MAOI since hypertensive crisis may occur.
Diethylpropion is contraindicated in thyroid disease patients with hyperthyroidism, since sympathomimetic stimulation may induce cardiac arrhythmias or other side effects.
Diethylpropion is contraindicated in patients with a history of substance abuse. Diethylpropion is chemically and pharmacologically related to the amphetamines, which have been extensively abused. Physiological dependence can occur with diethylpropion. Abrupt discontinuation of prolonged high dose diethylpropion therapy can result in extreme fatigue and mental depression as well as changes in sleep EEG. If tolerance develops, the recommended dose should not be exceeded in an attempt to increase the effect; rather, the drug should be discontinued.
Diethylpropion is contraindicated in patients in an agitated state. Diethylpropion should be used cautiously in patients with psychosis or mania. Amphetamine-like agents have been shown to aggravate these conditions.
Safety and effectiveness of diethylpropion in children have not been established. Diethylpropion is not recommended for neonates, infants, children and adolescents under 16 years of age.
Reports suggest that diethylpropion may increase the risk of seizures in some epileptic patients. Patients with a seizure disorder receiving diethylpropion should be closely monitored.
Diethylpropion is classified as FDA pregnancy risk category B.2 Diethylpropion and/or its metabolites are thought to cross the placental barrier. Animal data reveal no harmful effects during pregnancy. Spontaneous reports of congenital malformation have been reported in humans, but no causal relationship to diethylpropion has been established. No adequate, well controlled studies exist in pregnant women, however, diethylpropion is not approved for use pregnant women.
Diethylpropion hydrochloride and its metabolites have been shown to be excreted into breast milk. However, it is unknown if diethylpropion or its metabolites will cause harm to the nursing infant.2 Because of the potential for adverse effects in the nursing infants, breast-feeding while taking diethylpropion should be avoided. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.
The use of inhalational anesthetics during surgery may sensitize the myocardium to the effects of sympathomimetic drugs. Because of this, and its effects on blood pressure, diethylpropion should be discontinued several days prior to surgery.
Adequate numbers of geriatric patients were not included in diethylpropion clinical trials to determine if their response would be different from younger patients, although differences have not been seen. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range due to potential decreased hepatic, renal, or cardiac function, concomitant disease or other drug therapy. Diethylpropion is known to be substantially excreted by the kidney. Because elderly patients are more likely to have renal impairment or renal failure, care should be taken in dose selection and monitoring.
Pregnancy: Diethylpropion is classified as FDA pregnancy risk category B.2 Diethylpropion and/or its metabolites are thought to cross the placental barrier. Animal data reveal no harmful effects during pregnancy. Spontaneous reports of congenital malformation have been reported in humans, but no causal relationship to diethylpropion has been established. No adequate, well controlled studies exist in pregnant women, however, diethylpropion is not approved for use pregnant women.
Breast-feeding: Diethylpropion hydrochloride and its metabolites have been shown to be excreted into breast milk. However, it is unknown if diethylpropion or its metabolites will cause harm to the nursing infant.2 Because of the potential for adverse effects in the nursing infants, breast-feeding while taking diethylpropion should be avoided. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.
Atomoxetine, an inhibitor of norepinephrine reuptake used for treatment of ADHD, has been shown to increase heart rate and blood pressure.10 Diethylpropion also inhibits norepinephrine reuptake. The combination of atomoxetine with diethylpropion should be used extremely cautiously, if at all, due to the potential for serious increases in blood pressure and/or heart rate. If these agents must be used concomitantly, consider monitoring blood pressure and heart rate at baseline and regularly throughout treatment.
Interactions between sympathomimetics and MAOIs can be severe. Monoamine oxidase inhibitors (MAOIs) or other drugs that possess MAO-inhibiting activity such as furazolidone13, linezolid 14, or procarbazine 15, can prolong and intensify the cardiac stimulation and vasopressor effects of diethylpropion. In the presence of MAOIs, diethylpropion and other drugs that cause release of norepinephrine induce severe cardiovascular and cerebrovascular responses. Cases have been documented where seizures and pyrexia have occurred. Diethylpropion should not be administered during, or within 14 days following the use of most MAOIs, or drugs with MAO-inhibiting activity.3 Rasagiline is a selective MAO-B inhibitor at manufacturer recommended doses; therefore, serious reactions with sympathomimetics are not ordinarily expected.16 However, because a case of elevated blood pressure occurred during use of rasagiline and a sympathomimetic ophthalmic preparation, caution is advised when rasagiline is administered with sympathomimetics.
Phentermine and diethylpropion have a similar mechanism of action. When phentermine was given with fluoxetine, adrenergic excess and dyskinesia were observed.21 Thus, diethylpropion may interact with fluoxetine similarly. It is unclear, however, if all SSRIs would be affected as fluoxetine has the longest half-life of the group.
Adverse Reactions/Side Effects: Most adverse reactions associated with diethylpropion therapy are centrally-mediated; however, central nervous system adverse reactions associated with diethylpropion therapy are less common than with amphetamine, and they are generally less severe than those symptoms attributed to amphetamine. Central nervous system adverse reactions noted to occur with diethylpropion therapy include anxiety, depression, dizziness, drowsiness, dyskinesia, dysphoria, euphoria, headache, insomnia, jitteriness, nervousness, overstimulation, restlessness, and tremor.2 In one controlled trial assessing the long-term safety and efficacy of diethylpropion in obese patients, the following CNS effects occurred more frequently with active treatment than placebo: insomnia (16.1—52.7% vs 9.1—21.9%), headache (9.7—33.3% vs 4.5—25%), dizziness (9.7—13.9% vs 4.5—9.4%), and tremor (6.4—8.3% vs <= 6.2%).33 Psychosis associated with diethylpropion therapy has been reported with therapeutic as well as high doses, but is more common in previous abusers of stimulant medications. Hallucinations have occurred rarely following high doses of the drug. Several cases of toxic psychosis have been reported following excessive use of the drug and some have been reported in which the recommended dose appears not to have been exceeded. Psychosis abated after the drug was discontinued. Seizures may occur in epileptic patients receiving diethylpropion. Psychological dependence may occur with diethylpropion, but is much less common than with other amphetamine-like agents such as dextroamphetamine and phentermine. The low abuse potential of diethylpropion is related to the lower incidence of euphoria as compared to other amphetamine-like drugs. Prolonged use of diethylpropion may result in physiological dependence leading to a withdrawal syndrome (e.g., extreme fatigue, depression) on cessation of therapy.2 It is advised to avoid abrupt discontinuation of therapy.
Cardiovascular or cerebrovascular adverse effects which have occurred during diethylpropion therapy include hypertension, precordial pain, palpitations, ECG changes, cardiac arrhythmias (including ventricular arrhythmias and sinus tachycardia), and stroke. A reflex sinus bradycardia is common, though usually not clinically significant. There is one case of torsade de pointes occurring in a patient on a restricted calorie diet and receiving diethylpropion in combination with a thiazide diuretic.34 Valvular heart disease associated with the use of some anorectic agents such as fenfluramine and dexfenfluramine has been reported. Cardiac valvulopathy has been very rarely reported with diethylpropion monotherapy, but the causal relationship remains uncertain.2 Possible contributing factors include use for extended periods of time, higher than recommended dose, and/or use in combination with other anorectic drugs.
Tolerance is common with the entire class of amphetamine-like drugs. Tolerance to the anorexiant effects of diethylpropion may develop within a few weeks of starting therapy. Higher doses may be required to produce the same response; however, the maximum recommended dose should not be exceeded in an attempt to increase the effect; instead, the drug should be discontinued.2 The long term pharmacologic benefit of diethylpropion may be maintained by utilizing pulse dosing. Once the weight loss appears to slow or stop, the drug is held for several weeks and is then restarted.
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