Akinestat

• As an adjunct in the therapy of all forms of parkinsonism (idiopathic, postencephalitic, arteriosclerotic)
• Control of extrapyramidal disorders secondary to neuroleptic drug therapy (e.g., phenothiazines)

Drug-induced Extrapyramidal Symptoms

Oral: One tablet one to three times daily.

Parkinson's Disease: Oral: The usual beginning dose is one tablet three or four times daily. The dosage should be individualized with the dose titrated upward to a maximum of 8 tablets (16 mg) per 24 hours.

1) Hypersensitivity to biperiden 2) Narrow angle glaucoma 3) Bowel obstruction 4) Megacolon

WARNINGS

Isolated instances of mental confusion, euphoria, agitation and disturbed behavior have been reported in susceptible patients. Also, the central anticholinergic syndrome can occur as an adverse reaction to properly prescribed anticholinergic medication, although it is more frequently due to overdosage. It may also result from concomitant administration of an anticholinergic agent and a drug that has secondary anticholinergic actions (see PRECAUTIONS - DRUG INTERACTIONS and OVERDOSAGE sections). Caution should be observed in patients with manifest glaucoma, though no prohibitive rise in intraocular pressure has been noted following either oral or parenteral administration. Patients with prostatism, epilepsy or cardiac arrhythmia should be given this drug with caution.

Occasionally, drowsiness may occur, and patients who drive a car or operate any other potentially dangerous machinery should be warned of this possibility. As with other drugs action on the central nervous system, the consumption of alcohol should be avoided during Akinestat (biperiden) therapy.

PRECAUTIONS

Pregnancy

Pregnancy Category C

Animal reproduction studies have not been conducted with Akinestat (biperiden). It is also not known whether Akinestat (biperiden) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Akinestat (biperiden) should be given to a pregnant woman only if clearly needed.

Nursing Mothers

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 Akinestat (biperiden) is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in children have not been established.

Atropine-like side effects such as dry mouth; blurred vision; drowsiness; euphoria or disorientation; urinary retention; postural hypotension; constipation; agitation; disturbed behavior may been seen. A case of generalized choreic movements has been reported in a Parkinson's disease patient when biperiden was added to carbidopa/levodopa. A reduction in rapid eye movement (REM) sleep, characterized by increased REM latency and decreased percentage of REM sleep, has been reported. There usually are no significant changes in blood pressure or heart rate in patients who have been given the parenteral form of Akinestat (biperiden). Mild transient postural hypotension and bradycardia may occur. These side effects can be minimized or avoided by slow intravenous administration. No local tissue reactions have been reported following intramuscular injection. If gastric irritation occurs following oral administration, it can be avoided by administering the drug during or after meals.

The central anticholinergic syndrome can occur as an adverse reaction to properly prescribed anticholinergic medication. See OVERDOSAGE section for signs and symptoms of the central anticholinergic syndrome, and for treatment.

Signs and Symptoms

Overdosage with Akinestat (biperiden) produces typical central symptoms of atropine intoxication (the central anticholinergic syndrome). Correct diagnosis depends upon recognition of the peripheral signs of parasympathetic blockade including dilated and sluggish pupils; warm, dry skin; facial flushing;decreased secretions of the mouth, pharynx, nose, and bronchi; foul-smelling breath; elevated temperature, tachycardia, cardiac arrhythmias, decreased bowel sounds, and urinary retention. Neuropsychiatric signs such as delirium, disorientation, anxiety, hallucinations, illusions, confusion, incoherence, agitation, hyperactivity, ataxia, loss of memory, paranoia, combativeness, and seizures may be present. The condition can progress to stupor, coma, paralysis, and cardiac and respiratory arrest and death.

Treatment

Treatment of acute overdose revolves around symptomatic and supportive therapy. If Akinestat (biperiden) was administered orally, gastric lavage or other measures to limit absorption should be instituted. A small dose of diazepam or a short acting barbiturate may be administered if CNS excitation is observed. Phenothiazines are contraindicated because the toxicity may be intensified due to their antimuscarinic action, causing coma. Respiratory support, artificial respiration or vasopressor agents may be necessary. Hyperpyrexia must be reversed, fluid volume replaced and acid-base balance maintained. Urinary catheterization may be necessary.

Routine use of physostigmine for overdose is controversial. Delirium, hallucinations, coma, and supraventricular tachycardia (not ventricular tachycardias or conduction defects) seem to respond. If indicated, 1 mg (half this amount for the children or elderly) may be given intramuscularly or by slow intravenous infusion. If there is no response within 20 minutes, and additional 1 mg dose may be given; this may be repeated until a total of 4 mg has been administered, a reversal of the toxic effects occur or excessive cholinergic signs are seen. Frequent monitoring of clinical signs should be done. Since physostigmine is rapidly destroyed, additional injections may be required every one or two hours to maintain control. The relapse intervals tend to lengthen as the toxic anticholinergic agent is metabolized, so the patient should be carefully observed for 8 to 12 hours following the last relapse.

Toxicity in Animals

The LD₅₀ of biperiden in the white mouse is 545 mg/kg orally, 195 mg/kg subcutaneously, and 56 mg/kg intravenously. The acute oral toxicity (LD₅₀) in rats is 750 mg/kg. The intraperitoneal toxicity (LD₅₀) of biperiden lactate in rats was 270 mg/kg and the intravenous toxicity (LD₅₀) in dogs was 222 mg/kg. In dogs under general anesthesia, respiratory arrest occurred at 33 mg/kg (intravenous) and circulatory standstill at 45 mg/kg (intravenous). The oral LD₅₀in dogs is 340 mg/kg. Chronic toxicity studies in both rat and dog have been reported.