Each AKINETON tablet for oral administration contains
2 mg biperiden hydrochloride. Other ingredients may include corn syrup, lactose,
magnesium stearate, potato starch and talc. AKINETON is an anticholinergic
agent. Biperiden is α-5-Norbornen-2-yl-α-phenyl-1-piperidinepropanol.
It is a white, crystalline, odorless powder, slightly soluble in water and
alcohol. It is stable in air at normal temperatures. Biperiden may be represented
by the following structural formula:
AKINETON is a weak peripheral anticholinergic agent.
It has, therefore, some antisecretory, antispasmodic and mydriatic effects.
In addition, AKINETON possesses nicotinolytic activity. Parkinsonism is
thought to result from an imbalance between the excitatory (cholinergic) and
inhibitory (dopaminergic) systems in the corpus striatum. The mechanism of
action of centrally active anticholinergic drugs such as AKINETON is considered
to relate to competitive antagonism of acetylcholine at cholinergic receptors
in the corpus striatum, which then restores the balance.
The parenteral form of AKINETON is an effective and reliable agent
for the treatment of acute episodes of extrapyramidal disturbances sometimes
seen during treatment with neuroleptic agents. Akathisia, akinesia, dyskinetic
tremors, rigor, oculogyric crisis, spasmodic torticollis, and profuse sweating
are markedly reduced or eliminated. With parenteral AKINETON, these drug-induced
disturbances are rapidly brought under control. Subsequently, this can usually
be maintained with oral doses which may be given with tranquilizer therapy
in psychotic and other conditions requiring an uninterrupted therapeutic program.
Pharmacokinetics and Metabolism
Only limited pharmacokinetic studies of biperiden
in humans are available. The serum concentration at 1 to 1.5 hours following
a single, 4 mg oral dose was 4-5 ng/mL. Plasma levels (0.1-0.2 ng/mL) could
be determined up to 48 hours after dosing. Six hours after an oral dose of
250 mg/kg in rats, 87% of the drug had been absorbed. The metabolism of AKINETON
is also incompletely understood, but does involve hydroxylation. In normal
volunteers a single 10 mg intravenous dose of biperiden seemed to cause a
transient rise in plasma cortisol and prolactin. No change in GH, LH, FSH,
or TSH levels were seen. Biperiden lactate (10 mg/mL) was not irritating
to the tissue of rabbits when injected intramuscularly (1.0 mL) into the sacrospinalis
muscles and intradermally (0.25 mL) and subcutaneously (0.5 mL) into
the shaved abdominal skin.
INDICATIONS AND USAGE
As an adjunct in the therapy of all forms of parkinsonism (idiopathic,
Control of extrapyramidal disorders secondary to neuroleptic drug therapy
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.
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 AKINETON therapy.
The central anticholinergic syndrome can occur when
anticholinergic agents such as AKINETON are administered concomitantly with
drugs that have secondary anticholinergic actions, e.g., certain narcotic
analgesics such as meperidine, the phenothiazines and other antipsychotics,
tricyclic antidepressants, certain antiarrhythmics such as the quinidine salts,
and antihistamines. See OVERDOSAGE section
for signs and symptoms of the central anticholinergic syndrome, and for treatment.
Pregnancy Category C
Animal reproduction studies have not been conducted
with AKINETON. It is also not known whether AKINETON can cause fetal harm
when administered to a pregnant woman or can affect reproduction capacity.
AKINETON should be given to a pregnant woman only if clearly needed.
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 AKINETON is administered to a nursing woman.
Safety and effectiveness in children have not been
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 AKINETON. 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
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 AKINETON 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 of acute overdose revolves around symptomatic
and supportive therapy. If AKINETON 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.
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.
DOSAGE AND ADMINISTRATION
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.
AKINETON (biperiden hydrochloride) Tablets, 2 mg each,
white, embossed on one face with a triangle, bisected on the reverse and imprinted
with the number "11."
Bottles of 100 –
NDC # 49884-693-01
Store at 25°C (77°F); excursions permitted
to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Dispense
in tight, light-resistant container as defined in USP.