Akineton

I N S T R U C T I O N for medical use of the medicinal product Akineton (AKINETON®)

Composition:

Active substance: biperiden;

1 ml of solution contains 5 mg of biperiden lactate, corresponding to 3.88 mg of biperiden base;

Excipients: sodium lactate, water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear, colorless solution.

Pharmacotherapeutic group. Antiparkinson agents. Anticholinergic agents. Tertiary amines. Biperiden. ATC code N04A A02.

Pharmacological properties.

Pharmacodynamics.

Biperiden is an anticholinergic agent with predominantly central action. Its peripheral effect is weak compared to that of atropine. Biperiden competitively binds to peripheral and central muscarinic receptors (mainly M1).

In animal studies, biperiden affected parkinsonism-like symptoms (tremor, rigidity) induced by centrally acting cholinergic agents.

Thus, Akineton influences conditions associated with cholinergic hyperactivity in the central nervous system (CNS), such as Parkinson's syndrome as an extrapyramidal symptom of dopamine deficiency due to neuronal degeneration, as well as other symptoms caused by neuroleptics, which can also be attributed to disturbances in dopaminergic neurotransmission in the basal ganglia, resulting in an imbalance between dopaminergic and cholinergic functions. Relatively increased cholinergic activity can be pharmacologically suppressed by anticholinergic agents such as Akineton.

Pharmacokinetics.

Distribution

The plasma protein binding of biperiden is 95%. The apparent volume of distribution of biperiden is 24 ± 4.1 L/kg. Biperiden readily penetrates tissues and has a tissue distribution half-life of 0.6 hours, with a ratio of total volume of distribution to central volume of distribution of 9.6.

There is no information available regarding passage of biperiden through the placenta.

Biotransformation

Biperiden is almost completely metabolized. Unchanged biperiden is not detected in urine. The main metabolite of biperiden is formed via hydroxylation of the bicycloheptane ring (60%); additionally, partial hydroxylation of the piperidine ring occurs (40%).

Multiple metabolites (as hydroxylated products and their conjugates) are excreted in a 50:50 ratio in urine and feces, respectively.

Elimination

The terminal half-life in plasma after a single injection of biperiden lactate in young healthy volunteers is approximately 24 hours, and plasma clearance is 11.6 mL/min/kg.

Elderly patients

Bioavailability and elimination

Since liver mass, hepatic blood flow, and liver enzyme activity may decrease with age, a reduced rate of hepatic metabolism of biperiden may occur in elderly patients, resulting in higher bioavailability and reduced elimination rate compared to younger patients. In a comparative study, elderly patients showed 3−5 times higher AUC values and elimination half-lives twice as long as those in younger volunteers.

Pharmacokinetic data in patients with hepatic or renal impairment are not available.

Preclinical safety data

Chronic toxicity

Chronic toxicity studies in rats and dogs did not reveal signs of organ toxicity.

Mutagenic and carcinogenic potential

In vivo and in vitro studies with biperiden did not show mutagenic or clastogenic effects. Long-term animal studies on the carcinogenic potential of biperiden have not been conducted.

Reproductive toxicity

Biperiden has not been sufficiently studied regarding its reproductive toxicity in animals.

Studies on effects on fertility, fetal and postnatal development are lacking. Embryotoxicity studies did not reveal signs of teratogenic potential or other embryotoxic characteristics when the drug was administered within the therapeutic dose range.

There is no experience with the use of the medicinal product in women during pregnancy and breastfeeding.

Clinical characteristics.

Indications.

Parkinson's syndrome: treatment of symptoms of Parkinson's disease, such as rigidity and tremor.

Extrapyramidal symptoms caused by neuroleptics or pharmacologically similar agents.

Nicotine or organophosphorus poisoning.

Contraindications.

Hypersensitivity to biperiden lactate or to any of the excipients.

Untreated closed-angle glaucoma.

Mechanical gastrointestinal obstruction.

Megacolon.

Gastrointestinal obstruction.

Interaction with other medicinal products and other forms of interaction.

Concomitant use of Akineton with other anticholinergic agents, such as psychotropic drugs, antihistamines, anti-Parkinsonian agents, and spasmolytics, may enhance central and peripheral adverse effects.

Concomitant administration of quinidine may enhance anticholinergic cardiovascular effects (particularly disturbances in atrioventricular conduction).

Concomitant use of Akineton with levodopa may enhance dyskinesia.

Generalized choreiform movements have been observed in patients with Parkinson's disease when biperiden was administered concomitantly with levodopa/carbidopa preparations.

Tardive dyskinesia induced by neuroleptics may be exacerbated by Akineton. Sometimes, parkinsonism symptoms associated with tardive dyskinesia may be so severe that treatment with anticholinergic agents becomes necessary.

Alcohol effects may be potentiated during treatment with Akineton; therefore, alcohol consumption should be avoided.

Akineton reduces the effect of metoclopramide and other agents with similar action on the gastrointestinal tract.

Anticholinergic agents may enhance central nervous system-related adverse effects of pethidine.

Special precautions for use.

Anticholinergic drugs with central action, such as biperiden, may increase susceptibility to epileptic seizures. Akineton should be used with caution in patients with an increased predisposition to seizures (see section "Adverse reactions").

In case of urinary retention, the patient should empty the bladder before each biperiden injection. In individual cases, biperiden may cause difficulty in urination, particularly in patients with prostatic hyperplasia, and less frequently—urinary retention.

During therapy with Akineton, intraocular pressure should be monitored regularly (see section "Adverse reactions"). The medicinal product should also be used with caution in patients with glaucoma.

Akineton may be administered to patients with myasthenia gravis only with extreme caution.

Akineton should be used with caution in patients with conditions that may lead to tachycardia.

If marked dry mouth occurs, it can be alleviated by frequently drinking small amounts of fluid or chewing sugar-free gum.

Precautions for special patient groups

The medicinal product should be used with caution in elderly patients, particularly those with symptoms of organic brain damage. Elderly patients, especially those with cerebrovascular or degenerative cerebral disorders, often exhibit increased sensitivity to the active substance at therapeutic doses.

Memory impairment may occur during treatment with Akineton (see section "Adverse reactions").

There have been isolated reports of misuse and dependence on biperiden, associated with mood improvement and euphoric effects, which were observed rarely.

Except in cases of life-threatening complications, abrupt discontinuation of the medicinal product should be avoided due to the risk of excessive rebound effects.

This medicinal product contains less than 1 mmol (23 mg) of sodium per dose, i.e., it is practically sodium-free.

Use during pregnancy or breastfeeding.

Pregnancy

Since there is no experience with the use of Akineton during pregnancy, the drug should be prescribed only after careful assessment of the benefit-risk ratio.

Breastfeeding

Anticholinergic medicinal products may suppress lactation. Given the chemical structure of the active substance, biperiden is expected to pass into breast milk; therefore, breastfeeding should be discontinued.

Fertility

There are no data available on the effect of Akineton on fertility.

Ability to affect reaction speed when driving or operating machinery.

Due to adverse effects on the central and peripheral nervous systems, such as fatigue, dizziness, and drowsiness, even when used correctly, this drug may impair reaction speed to such an extent that, regardless of any limitations caused by the underlying disease, the ability to participate actively in road traffic or to work with electrical tools, engine-powered tools, or other machinery may be further impaired. This is particularly evident when the drug is used concomitantly with other centrally acting agents, anticholinergic drugs, and especially with alcohol.

Patients taking this medicinal product should refrain from engaging in potentially hazardous activities requiring rapid mental and motor responses.

Method of Administration and Dosage

The dosage of biperiden should be individually adjusted.

Parkinsonism syndrome

At the beginning of treatment and in severe cases, 10–20 mg of biperiden lactate (2–4 ml of injection solution) may be administered intramuscularly or slowly intravenously, dividing the dose into several injections throughout the day.

Extrapyramidal symptoms induced by medicinal products

Adults may be given a single dose of 2.5–5 mg of biperiden lactate (0.5–1 ml of injection solution) administered intramuscularly or slowly intravenously. If necessary, this dose may be repeated after 30 minutes. The maximum total daily dose is 10–20 mg of biperiden lactate (2–4 ml of injection solution).

Children under 1 year of age may be given 1 mg of biperiden lactate (corresponding to 0.2 ml of injection solution); children aged 1 to 6 years – 2 mg of biperiden lactate (corresponding to 0.4 ml of injection solution); and children aged 6 to 10 years – 3 mg of biperiden lactate (corresponding to 0.6 ml of injection solution).

Nicotine poisoning

Intramuscular administration of 5–10 mg of biperiden lactate (1–2 ml of injection solution). In emergency cases, in addition to standard measures, intravenous administration of 5 mg of biperiden lactate (1 ml of injection solution) is advisable.

Poisoning with organophosphorus compounds

In cases of poisoning with organophosphorus compounds, the dosage of the drug Akineton is determined individually. Depending on the toxic manifestations of poisoning, 5 mg of biperiden lactate may be repeatedly administered intravenously until the symptoms of poisoning disappear. If symptoms resolve during injection, administration should be discontinued.

Geriatric patients

The drug should be used with caution. The lowest possible initial dose should be used, and then gradually increased according to the patient's response (see section "Pharmacokinetics").

Patients with hepatic or renal impairment

Pharmacokinetic data in patients with hepatic or renal impairment are lacking. Therefore, the drug should be used with caution. Treatment should be initiated with the lowest possible dose and gradually increased depending on the patient's response.

Method of administration

For adults, the injection solution should be administered intramuscularly or slowly intravenously. For children and adolescents (up to 18 years of age), the injection solution may be administered slowly intravenously. If symptoms resolve during injection, administration should be discontinued. Any unused solution remaining after opening the ampoule should be discarded.

Duration of treatment

The duration of treatment depends on the type and severity of the condition and may vary from short-term use to long-term treatment with the drug, or until treatment can be continued with an oral formulation or discontinued. Treatment with this medicinal product should not be abruptly discontinued; it should be tapered gradually.

Children

Experience with the use of biperiden in children and adolescents (up to 18 years of age) is limited. The drug has been more frequently prescribed for a limited period in cases of drug-induced dystonia (e.g., caused by neuroleptics, metoclopramide, or similar medicinal products), which may occur as an adverse effect or symptom of intoxication.

Overdose

Symptoms of overdose are similar to those of atropine toxicity with peripheral anticholinergic signs: dilated pupils with slow reaction to light (mydriasis), dry mucous membranes, facial flushing, increased heart rate, atony of the bladder and intestines, elevated body temperature, and central nervous system disturbances (such as agitation, delirium, disorientation, confusion, and/or hallucinations). In severe intoxications, there is a risk of circulatory collapse and central respiratory paralysis.

Treatment: administration of acetylcholinesterase inhibitors, particularly physostigmine, which can penetrate into the cerebrospinal fluid and thus affect centrally mediated symptoms (and/or physostigmine salicylate if the physostigmine test is positive). If necessary – supportive measures for cardiovascular and respiratory function (artificial oxygenation), antipyretics (in case of elevated body temperature), and bladder catheterization – depending on the type of symptoms.

Side effects

Side effects may occur especially at the beginning of treatment and when the dosage is increased too rapidly. CNS stimulation is often observed in patients with symptoms of cerebral dysfunction and may require dose reduction.

The frequency of adverse reactions is defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare (< 1/10000), frequency not known (cannot be estimated from the available data).

Infections and infestations

Frequency not known: mumps.

Immune system disorders

Very rare: hypersensitivity.

Psychiatric disorders

Rare: with high-dose administration – agitation, excitement, fear, confusion, delirium, hallucinations, insomnia.

Very rare: nervousness, euphoria.

Nervous system disorders

Rare: fatigue, dizziness, memory impairment.

Very rare: headache, dyskinesia, ataxia, speech disorders, increased susceptibility to epileptic seizures and convulsions.

Eye disorders

Very rare: accommodation disorders, mydriasis, photophobia. Closed-angle glaucoma may occur (intraocular pressure should be monitored).

Cardiac disorders

Rare: tachycardia.

Very rare: bradycardia. Following parenteral administration, a drop in blood pressure may occur.

Gastrointestinal disorders

Rare: dry mouth, nausea, gastric discomfort.

Very rare: constipation.

Skin and subcutaneous tissue disorders

Very rare: decreased sweating, allergic rash.

Musculoskeletal and connective tissue disorders

Rare: muscle spasms.

Renal and urinary disorders

Very rare: dysuria, especially in patients with benign prostatic hyperplasia (dose reduction is required), urinary retention.

General disorders and administration site reactions

Rare: somnolence.

Description of selected adverse reactions

There have been reports of a temporary reduction in the rapid eye movement (REM) sleep phase, characterized by an increased time required to reach this phase and a decreased duration of this phase as a percentage of total sleep time.

Children

The safety profile in children is similar to that in adults.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, should report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 5 years.

Storage conditions. Store in the original packaging, protected from light, at a temperature not exceeding 25 °C, in a place inaccessible to children.

Incompatibilities.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

Packaging. 1 ml in a 2 ml ampoule made of colourless hydrolytic glass type 1 with a constriction and a white mark on the upper part of the ampoule. The ampoules are packed in strips of 5 in a deep-drawn film (either in open form or sealed with paper or PVC or foil) and placed in a cardboard box.

Prescription status. Prescription only.

Manufacturer. Sirtone Pharmaceuticals S.p.A.

Manufacturer's address and location of operation.

Piazza 20 Settembre, 2, 22079 Villa Guardia (Como), Italy.