Phendimetrazine

/HUMAN EXPOSURE STUDIES/ Phendimetrazine is an anorectic agent which recently has been detected in three medical examiner's cases. In one instance death was attributed to this drug. In the one instance where death was attributed to this substance, the blood concentration was 300 ng/ml.

Concurrent use /of other CNS stimulation-producing medications or thyroid hormones with appetite suppressants/ may increase the CNS stimulant effects of either these medications or the appetite suppressant. /Appetite suppressants, sympathomimetic/

The sympathomimetic effects of appetite suppressants /when used with monoamine oxidase (MAO) inhibitors, including furazolidone, procarbazine , and selegiline/ may be potentiated, possibly resulting in a hypertensive crisis; concurrent use is contraindicated; appetite suppressant should not be administered during or within 14 days following the administration of and MAO inhibitor. /Appetite suppressants, sympathomimetic/

Vasopressant effect may be potentiated; if necessary to administer a pressor amine agent to a patient who has recently received an appetite suppressant, initiating pressor therapy in reduced dosage and monitoring blood pressure at frequent intervals are recommended. /Appetite suppressants, sympathomimetic/

Anorectic effects of the appetite suppressant may be antagonized /when use with phenothiazines/. /Appetite suppressants, sympathomimetic/

For more Interactions (Complete) data for PHENDIMETRAZINE (10 total), please visit the HSDB record page.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 390(SRC), determined from a structure estimation method(2), indicates that phendimetrazine is expected to have moderate mobility in soil(SRC). The pKa of phendimetrazine is 7.3(3), indicating that this compound will partially exist in cation form in the environment and cations generally adsorb more strongly to organic carbon and clay than their neutral counterparts(4). Volatilization of phendimetrazine from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 2.7X10-8 atm-cu m/mole(SRC), using a fragment constant estimation method(5). Phendimetrazine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 3.2X10-3 mm Hg(SRC), determined from a fragment constant method(6). Biodegradation data were not available for phendimetrazine(SRC, 2005).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 390(SRC), determined from a structure estimation method(2), indicates that phendimetrazine is not expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 2.7X10-8 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). The pKa of phendimetrazine is 7.3(5), indicating that this compound will partially exist in cation form in the environment and cations generally adsorb more strongly to organic carbon and clay than their neutral counterparts and do not volatilize(6). Hydrolysis is not expected to be an important environmental fate process since this compound lacks functional groups that hydrolyze under environmental conditions. According to a classification scheme(7), an estimated BCF of 4.1(SRC), from an estimated log Kow of 1.70(8) and a regression-derived equation(9), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation data were not available for phendimetrazine(SRC, 2005).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), phendimetrazine, which has an estimated vapor pressure of 3.2X10-3 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), will exist solely in the vapor phase in the ambient atmosphere. Vapor-phase phendimetrazine is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 0.9 hours(SRC), calculated from its rate constant of 1.5X10-10 cu cm/molecule-sec at 25 °C (SRC) that was derived using a structure estimation method(3). Phendimetrazine does not contain chromophores that absorb at wavelengths >290 nm and therefore is not expected to be susceptible to direct photolysis by sunlight(SRC).

IDENTIFICATION: Phendimetrazine tartrate is an antiobesity drug. Indications: Appetite suppressant (anorectic). Misuse: Performance enhancement and relief of fatigue Abuse: Abuse either orally or by injection is extremely common. HUMAN EXPOSURE: Main risks and target organs: Acute central nervous system stimulation, cardiotoxicity causing tachycardia, arrhythmias, hypertension and cardiovascular collapse. High risk of dependency and abuse. Summary of clinical effects: Cardiovascular: Palpitation, chest pain, tachycardia, arrhythmias and hypertension are common; cardiovascular collapse can occur in severe poisoning. Myocardial ischemia, infarction and ventricular dysfunction are described. Central Nervous System (CNS): Stimulation of CNS, tremor, restlessness, agitation, insomnia, increased motor activity, headache, convulsions, coma and hyperreflexia are described. Stroke and cerebral vasculitis have been observed. Gastrointestinal: Vomiting, diarrhea and cramps may occur. Genitourinary: Increased bladder sphincter tone may cause dysuria, hesitancy and acute urinary retention. Renal failure can result secondary to dehydration or rhabdomyolysis. Renal ischemia may be noted. Dermatologic: Skin is usually pale and diaphoretic, but mucous membranes appear dry. Endocrine: Transient hyperthyroxinemia may be noted. Metabolism: Increased metabolic and muscular activity may result in hyperventilation and hyperthermia. Weight loss is common with chronic use. Fluid/Electrolyte: Hypo- and hyperkalemia have been reported. Dehydration is common. Musculoskeletal: Fasciculations and rigidity may be noted. Rhabdomyolysis is an important consequence of severe poisoning. Psychiatric: Agitation, confusion, mood elevation, increased wakefulness, talkativeness, irritability and panic attacks are typical. Chronic abuse can cause delusions and paranoia. A withdrawal syndrome occurs after abrupt cessation following chronic use. Contraindications: Anorexia, insomnia, psychopathic personality disorders, suicidal tendencies, Tourette syndrome and other disorders, hyperthyroidism, narrow angle glaucoma, diabetes mellitis and cardiovascular diseases such as angina, hypertension and arrythmias. It interacts with several other CNS stimulant drugs. Routes of exposure: Oral: Readily absorbed from the gastro-intestinal tract and buccal mucosa. It is resistant to metabolism by monoamine oxidase. Inhalation: Rapidly absorbed by inhalation and is abused by this route. Absorption by route of exposure: Rapidly absorbed after oral ingestion. Peak plasma levels occur within 1 to 3 hours, varying with the degree of physical activity and the amount of food in the stomach. Absorption is usually complete by 4 to 6 hours. Sustained release preparations are available as resin-bound, rather than soluble, salts. These compounds display reduced peak blood levels compared with standard preparations, but total amount absorbed and time to peak levels remain similar. Distribution by route of exposure: Concentrated in the kidney, lungs, cerebrospinal fluid and brain. They are highly lipid soluble and readily cross the blood-brain barrier. Protein binding and volume of distribution varies widely. Biological half-life by route of exposure: Under normal conditions, about 30% is excreted unchanged in the urine but this excretion is highly variable and is dependent on urinary pH. When the urinary pH is acidic (pH 5.5 to 6.0), elimination is predominantly by urinary excretion with approximately 60% of a dose of being excreted unchanged by the kidney within 48 hours. When the urinary pH is alkaline (pH 7.5 to 8.0), elimination is predominantly by deamination (less than 7% excreted unchanged in the urine); the half-life ranging from 16 to 31 hours. Metabolism: The major metabolic pathway involves deamination by cytochrome P450 to para-hydroxy compound and phenylacetone; this latter compound is subsequently oxidized to benzoic acid and excreted as glucuronide or glycine (hippuric acid) conjugate. Elimination and excretion: Normally 5 to 30% of a therapeutic dose is excreted unchanged in the urine by 24 hours, but the actual amount of urinary excretion and metabolism is highly pH dependent. Mode of action: It appears to exert most or all of its effect in the CNS by causing release of biogenic amines, especially norepinephrine and dopamine, from storage sites in nerve terminals. It may also slow down catecholamine metabolism by inhibiting monoamine oxidase. Human data: Adults: The toxic dose varies considerably due to individual variations and the development of tolerance. Children: Children appear to be more susceptible than adults and are less likely to have developed tolerance. Teratogenicity: It generally does not appear to be a human teratogen. Mild withdrawal symptoms may be observed in the newborn, but the few studies of infant follow-up have not shown long term sequelae, although more studies of this nature are needed. Illicit maternal use or abuse presents a significant risk to the fetus and newborn, including intrauterine growth retardation, premature delivery and the potential for increased maternal, fetal and neonatal morbidity. These poor outcomes are probably multifactorial in origin, involving multiple drug use, life-styles and poor maternal health. However, cerebral injuries occurring in newborns exposed in utero appear to be directly related to the vasoconstrictive properties. Intelligence, psychological function, growth, and physical health were all within the normal range at eight years, but those children exposed throughout pregnancy tended to be more aggressive. Interactions: Acetazolamide: administration may increase serum concentration. Alcohol: may increase serum concentration. Ascorbic acid: lowering urinary pH, may enhance excretion. Furazolidone: may induce a hypertensive response in patients taking furazolidone. Guanethidine: inhibits the antihypertensive response to guanethidine. Haloperidol: limited evidence indicates that haloperidol may inhibit the effects but the clinical importance of this interaction is not established. Lithium carbonate: isolated case reports indicate that lithium may inhibit the effects. Monoamine oxidase inhibitor: severe hypertensive reactions have followed the administration to patients taking monoamine oxidase inhibitors. Norepinephrine: amphetamine abuse may enhance the pressor response to norepinephrine. Phenothiazines: may inhibit the antipsychotic effect of phenothiazines, and phenothiazines may inhibit the anorectic effect .Sodium bicarbonate: large doses of sodium bicarbonate inhibit the elimination thus increasing the effect. Tricyclic antidepressants: theoretically increases the effect, but clinical evidence is lacking. Clinical effects: Acute poisoning: Ingestion: Effects are most marked on the central nervous system, cardiovascular system, and muscles. The triad of hyperactivity, hyperpyrexia, and hypertension is characteristic of acute amphetamine overdosage. Agitation, confusion, headache, delirium, and hallucination, can be followed by coma, intracranial hemorrhage, stroke, and death. Chest pain, palpitation, hypertension, tachycardia, atrial and ventricular arrhythmia, and myocardial infarction can occur. Muscle contraction, bruxism (jaw-grinding), trismus (jaw clenching), fasciculation, rhabdomyolysis, are seen leading to renal failure; and flushing, sweating, and hyperpyrexia can all occur. Hyperpyrexia can cause disseminated intravascular coagulation. Inhalation: The clinical effects are similar to those after ingestion, but occur more rapidly. Parenteral exposure: Intravenous injection is a common mode of administration. The euphoria produced is more intense, leading to a rush or flash which is compared to sexual orgasm. Other clinical effects are similar to those observed after ingestion, but occur more rapidly. Chronic poisoning: Ingestion: Tolerance to the euphoric effects and CNS stimulation induced develops rapidly, leading abusers to use larger and larger amounts to attain and sustain the desired affect. Habitual use or chronic abuse usually results in toxic psychosis classically characterized by paranoia, delusions and hallucinations, which are usually visual, tactile or olfactory in nature, in contrast to the typical auditory hallucinations of schizophrenia. The individual may act on the delusions, resulting in bizarre violent behavior, hostility and aggression, sometimes leading to suicidal or homicidal actions. Dyskinesia, compulsive behavior and impaired performance are common in chronic abusers. The chronic abuser presents as a restless, garrulous, tremulous individual who is suspicious and anxious. Course, prognosis, cause of death: Symptoms and signs give a clinical guide to the severity of intoxication as follows: Mild toxicity: restlessness, irritability, insomnia, tremor, hyperreflexia, sweating, dilated pupils, flushing; Moderate toxicity: hyperactivity, confusion, hypertension, tachypnoea, tachycardia, mild fever, sweating; Severe toxicity: delirium, mania, self-injury, marked hypertension, tachycardia, arrhythmia, hyperpyrexia, convulsion, coma, circulatory collapse. Death can be due to intracranial hemorrhage, acute heart failure or arrhythmia, hyperpyrexia, rhabdomyolysis and consequent hyperkalemia or renal failure, and to violence related to the psychiatric effects. Systematic description of clinical effects: Cardiovascular: Cardiovascular symptoms of acute poisoning include palpitation and chest pain. Tachycardia and hypertension are common. One third of patients reported had a blood pressure greater than 140/90 mmHg, and nearly two-thirds had a pulse rate above 100 beats per minute. Severe poisoning can cause acute myocardial ischemia, myocardial infarction, and left ventricular failure. These probably result from vasospasm, perhaps at sites of existing atherosclerosis. In at least one case, thrombus was demonstrated initially. Chronic oral abuse can cause a chronic cardiomyopathy; an acute cardiomyopathy has also been described. Hypertensive stroke is a well-recognized complication of poisoning. Intra-arterial injection can cause severe burning pain, vasospasm and gangrene. Respiratory: Pulmonary fibrosis, right ventricular hypertrophy and pulmonary hypertension are frequently found at post-mortem examination. Pulmonary function tests usually are normal except for the carbon monoxide diffusing capacity. Respiratory complications are sometimes caused by fillers or adulterants used in injections by chronic users. These can cause multiple microemboli to the lung, which can lead to restrictive lung disease. Neurological: Central nervous system (CNS): Main symptoms include agitation, confusion, delirium, hallucinations, dizziness, dyskinesia, hyperactivity, muscle fasciculation and rigidity, rigors, tics, tremors, seizures and coma. Both occlusive and hemorrhagic strokes have been reported after abuse. Patients with underlying arteriovenous malformations may be at particular risk. Stroke can occur after oral, intravenous, or nasal administration. Severe headache beginning within minutes of ingestion is usually the first symptom. In more than half the cases, hypertension which is sometimes extreme, accompanies other symptoms. A Cerebral vasculitis has also been observed. Dystonia and dyskinesia can occur, even with therapeutic dosages. Psychiatric effects, particularly euphoria and excitement, are the motives for abuse. Paranoia and a psychiatric syndrome indistinguishable from schizophrenia are sequelae of chronic use. Autonomic nervous system: Stimulation of alpha-adrenergic receptors produces mydriasis, increased metabolic rate, diaphoresis, increased sphincter tone, peripheral vasoconstriction and decreased gastrointestinal motility. Stimulation of beta-adrenergic receptors produces increased heart rate and contractility, increased automaticity and dilatation of bronchioles. Skeletal and smooth muscle: Myalgia, muscle tenderness, muscle contractions, and rhabdomyolysis, leading to fever, circulatory collapse, and myoglobinuric renal failure, can occur. Gastrointestinal: Most common symptoms are nausea, vomiting, diarrhea, and abdominal cramps. Anorexia may be severe. Epigastric pain and hematemesis have been described after intravenous use. Hepatic: Hepatitis and fatal acute hepatic necrosis have been described. Urinary: Renal: Renal failure, secondary to dehydration or rhabdomyolysis may be observed. Other: Increased bladder sphincter tone may cause dysuria, hesitancy and acute urinary retention. This effect may be a direct result of peripheral alpha-agonist activity. Endocrine and reproductive systems: Transient hyperthyroxinemia may result from heavy use. Dermatological: Skin is usually pale and diaphoretic, but mucous membranes appear dry. Chronic users may display skin lesion, abscesses, ulcers, cellulitis or necrotizing angiitis due to physical insult to skin, or dermatologic signs of dietary deficiencies, such as cheilosis, purpura. Eye, ear, nose, throat: local effects: Mydriasis may be noted. Diffuse hair loss may be noted. Chronic users may display signs of dietary deficiencies. Hematological: Disseminated intravascular coagulation is an important consequence of severe poisoning. Idiopathic thrombocytopenic purpura may occur. Fluid and electrolyte disturbance: Increase metabolic and muscular activity may result in dehydration. Special risks: Is passed into breast milk and measurable amounts can be detected in breast-fed infant's urine. Therefore lactating mothers are advised not to take or use the drug. /Phendimetrazine tartrate/

Using a structure estimation method based on molecular connectivity indices(1), the Koc of phendimetrazine can be estimated to be 390(SRC). According to a classification scheme(2), this estimated Koc value suggests that phendimetrazine is expected to have moderate mobility in soil. The pKa of phendimetrazine is 7.3(4), indicating that this compound will partially exist in the cation form in the environment and cations generally adsorb more strongly to organic carbon and clay than their neutral counterparts(5).

/HUMAN EXPOSURE STUDIES/ Phendimetrazine is an anorectic agent which recently has been detected in three medical examiner's cases. In one instance death was attributed to this drug. In the one instance where death was attributed to this substance, the blood concentration was 300 ng/ml.

/SIGNS AND SYMPTOMS/ Manifestations of overdose are similar to those of other drugs in the sympathomimetic class. Clinical effects include tremor, fever, tachycardia, hypertension, altered mental status, confusion, seizures, hallucinations , dysrhythmias , cardiovascular collapse, and death.

/SIGNS AND SYMPTOMS/ Adverse effects of treatment include the potential for drug abuse and habituation, serious worsening of hypertension (although in some patients blood pressure may actually fall, presumably as a consequence of weight loss), sleep disturbances, palpitations, dry mouth, and depression (particularly with fenfluramine) /Amphetamine like drugs/

Benchmark Dataset for the Liver Toxicity Knowledge Base (LTKB)

phendimetrazine

Bontril®

Antiobesity agents

Not Applicable

no-DILI-concern

An estimated BCF of 4.1 was calculated for phendimetrazine(SRC), using an estimated log Kow of 1.70(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).

The Henry's Law constant for phendimetrazine is estimated as 2.7X10-8 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that phendimetrazine is expected to be essentially nonvolatile from water surfaces(2). Phendimetrazine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 3.2X10-3 mm Hg at 25 °C(SRC), determined from a fragment constant method(3).

Phendimetrazine is contraindicated in patients with hyperthyroidism, moderate to severe hypertension, advanced arteriosclerosis, symptomatic cardiovascular disease, glaucoma, or known hypersensitivity or idiosyncrasy to sympathomimetic amines. The drug is also contraindicated in patients in agitate states or those who are highly nervous, have a history of drug abuse, or are receiving CNS stimulants. Phendimetrazine is contraindicated during or within 14 days of administration of monoamine oxidase (MAO) inhibitors since hypertensive crisis could result.

The rate constant for the vapor-phase reaction of phendimetrazine with photochemically-produced hydroxyl radicals has been estimated as 1.5X10-10 cu cm/molecule-sec at 25 °C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 0.9 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). Phendimetrazine is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(3). Phendimetrazine does not contain chromophores that absorb at wavelengths >290 nm and therefore is not expected to be susceptible to direct photolysis by sunlight(SRC).

Schedules of controlled substances are established by section 202 of the Controlled Substances Act (21 U.S.C. 812). Unless specifically excepted or unless listed in another schedule, any material, compound, mixture, or preparation which contains any quantity of the following substances having a stimulant effect on the central nervous system, including its salts, isomers (whether optical, position, or geometric), and salts of such isomers whenever the existence of such salts, isomers, and salts of isomers is possible within the specific chemical designation: Benzphetamine, Schedule III, DEA Code #: 1615.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl phendimetrazine tartrate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Phendimetrazine Tartrate/

Phendimetrazine is an effective and widely prescribed appetite suppressant.

Appetite suppressant for the short-term (a few weeks) management of obesity

MEDICATION

Oral: Capsules, extended-release: 105 mg Adipost (C-III), (Jones Pharma), Bontril Slow-Release (C-III), (Amarin), Melflat-105 Unicelles (C-III), (Numark), Phendimetrazine Tartrate Capsules LA (C-III), (Hyrex), Prelu-2 (C-III; with povidone), (Roxane), X-Trozine LA (C-III), (Shire). Tablets: 35 mg Brontril PDM (C-III; scored), (Amarin), Obezine (C-III; scored), (Western Research), Obezine Caplets (C-III; scored), (Western Reserch). /Phendimetrazine tartrate/

Bontril(R) Plegine(R): Capsules and tablets, 35 mg. Controlled-released capsules, 105 mg. /Phendimetrazine tartrate/

Antapentan /hydrochloride/

While data on phendimetrazine were not available (SRC, 2005), the literature suggests that some pharmaceutically active compounds originating from human and veterinary therapy are not eliminated completely in municipal sewage treatment plants and are therefore discharged into receiving waters(1). Wastewater treatment processes often were not designed to remove them from the effluent(2). Another concern is that selected organic waste compounds may be degrading to new and more persistent compounds that may be released instead of or in addition to the parent compound(2). Studies have indicated that several polar pharmaceutically active compounds can leach through subsoils into aquifers(1).