Akineton

CHARACTERISTICS OF THE MEDICINAL PRODUCT

1. NAME OF THE MEDICINAL PRODUCT

Akineton, 2 mg, tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

1 tablet contains 2 mg of biperiden hydrochloride, which corresponds to 1.8 mg of biperiden.
Excipient with known effect: anhydrous lactose.
Full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Tablet

4. CLINICAL PARTICULARS

4.1 Therapeutic Indications

• Treatment of muscle stiffness, tremors, and movement retardation in Parkinson's disease.
• Treatment of motor disorders in extrapyramidal syndromes: parkinsonian and dystonic, caused by neuroleptics and similarly acting medicinal products, e.g., early dyskinesias, akathisia, and parkinsonian symptoms.
• Treatment of other extrapyramidal movement disorders, including generalized and segmental dystonia, e.g., Meige's syndrome, blepharospasm, or spasmodic torticollis.

4.2 Posology and Method of Administration

Dosage
The dosage is determined individually.
The duration of treatment depends on the type and course of the disease.
Treatment should be started with the smallest effective dose, and then gradually increased
to achieve the most beneficial dose for the patient, depending on the therapeutic effect and adverse reactions.
Parkinson's disease
The recommended initial dose for the treatment of Parkinson's disease is 2 times half a tablet per day (2 mg
of biperiden hydrochloride per day). The dose may be increased by 2 mg per day. The maintenance dose is half to 2 tablets, administered 3 or 4 times a day (corresponding to 3 to 16 mg of biperiden hydrochloride per day). The maximum daily dose is 16 mg of biperiden hydrochloride (corresponding to 8 tablets per day).
Extrapyramidal symptoms caused by other medicinal products
In the treatment of extrapyramidal symptoms caused by other medicinal products, in combination therapy with neuroleptics, half to 2 tablets are used, 1 to 4 times a day (corresponding to 1 to 16 mg of biperiden hydrochloride per day), depending on the severity of symptoms.
Other extrapyramidal movement disorders
Dose adjustment should be done slowly, through gradual, weekly increases in the initial dose of 2 mg, until the maximum tolerated daily dose is reached, which may be several times higher than the maximum daily doses used in other indications.
Children and adolescents (from 3 to 15 years old)
In the treatment of extrapyramidal symptoms caused by other medicines, in combination therapy with neuroleptics, half to 1 tablet is administered 1 to 3 times a day (corresponding to 1 to 6 mg of biperiden hydrochloride per day).
Note:
In situations where rapid action is necessary, the medicinal product should be used in the form of an injection.
Method of administration
Akineton tablets can be divided. It is recommended to take them during or after a meal, with a sufficient amount of liquid.
The risk of adverse reactions from the gastrointestinal tract is lower if the medicinal product is taken immediately after a meal.
The duration of treatment depends on the type and course of the disease. Treatment may be short-term, e.g., in the treatment of extrapyramidal symptoms caused by other medicinal products (especially in children), or long-term (e.g., in the treatment of Parkinson's disease).
Sudden discontinuation of the medicinal product should be avoided. In the case of planned termination of treatment with biperiden, the dose of the medicinal product should be gradually reduced.

4.3 Contraindications

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
• Narrow-angle glaucoma.
• Mechanical obstruction of the gastrointestinal tract.
• Megacolon (colonic impaction).
• Intestinal obstruction.

4.4 Special Warnings and Precautions for Use

At the beginning of treatment and when the dose is increased too quickly, adverse reactions occur.
Particular caution is recommended when using in elderly patients, especially those with organic damage to the central nervous system of vascular origin or due to degeneration, due to the frequent, excessive sensitivity even to therapeutic doses of the medicinal product in these patient groups.
Except in life-threatening situations, sudden discontinuation of the medicinal product should be avoided, due to the risk of relapse of the disease.
Anticholinergic drugs acting centrally, such as biperiden, may increase the risk of seizures. In patients with an increased predisposition to neurological disorders, biperiden should be used with caution (see section 4.8).
In individual cases, especially in patients with prostatic hyperplasia, biperiden may cause urinary disorders, most often urinary retention.
Patients with urinary retention should empty their bladder before each use of the medicinal product.
Particular caution should be exercised when using biperiden in the case of prostatic hyperplasia with residual urine retention, urinary retention, myasthenia, in the case of diseases that may lead to severe tachycardia, and in pregnant women (see section 4.6).
Regular monitoring of intraocular pressure is recommended (see section 4.8).
Cases of abuse of the medicinal product Akineton have been observed. This phenomenon may be caused by the occasionally observed effect of mood enhancement and transient euphoria.
If excessive dryness of the mouth occurs, it can be alleviated by frequently drinking small amounts of liquid or chewing sugar-free gum.
Children and adolescents
Experience with the use of biperiden in children is limited and mainly concerns short-term use in the case of movement disorders caused by other medicines, e.g., neuroleptics, metoclopramide, or similarly acting medicinal products.
The medicinal product should not be used in patients with rare hereditary galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.

4.5 Interaction with Other Medicinal Products and Other Forms of Interaction

The use of biperiden with other medicinal products acting anticholinergically, e.g., psychotropic drugs, first-generation antihistamines, drugs used in Parkinson's disease, and antispasmodics, may increase the risk of adverse reactions in the central and peripheral nervous system.
When co-administered with quinidine, an increase in anticholinergic action on the cardiovascular system (in particular on atrioventricular conduction) may occur.
Concomitant use of levodopa and biperiden may increase dyskinesias. In patients with Parkinson's disease, when biperiden and levodopa or carbidopa products are administered concomitantly, overall movement disorders have been observed, characterized by choreoathetoid movements.
Biperiden may increase late dyskinesias caused by neuroleptics. However, in cases where parkinsonian symptoms coexisting with tardive dyskinesia are very severe, continuation of anticholinergic treatment is justified.
Due to the possibility of increased alcohol effects, alcohol consumption should be avoided during treatment with biperiden.
Anticholinergic drugs such as biperiden reduce the effectiveness of metoclopramide and similarly acting drugs on the gastrointestinal tract.
Anticholinergic drugs may increase the adverse effects of pethidine on the central nervous system.

4.6 Fertility, Pregnancy, and Lactation

Pregnancy
There are no data indicating that the use of biperiden may be associated with teratogenic effects.
However, due to the lack of experience with the use of biperiden during pregnancy, particular caution should be exercised, especially in the first trimester. There are no data on placental transfer. The medicinal product may be used during pregnancy only in cases where, in the doctor's opinion, the benefit to the mother outweighs the potential risk to the fetus.
Breast-feeding
Anticholinergic drugs may inhibit lactation.
Biperiden passes into breast milk, reaching the same concentration as in plasma. During treatment with biperiden, it is recommended to discontinue breast-feeding.

4.7 Effects on Ability to Drive and Use Machines

Akineton may have a significant impact on the ability to drive and use machines.
Even with proper use of the medicinal product, the adverse effects of biperiden on the central and peripheral nervous system, such as fatigue, dizziness, and lethargy, regardless of the limitations caused by the underlying disease requiring treatment, may reduce concentration and reaction speed, posing a risk to patients driving vehicles and operating machines. These symptoms are more pronounced if biperiden is used concomitantly with other drugs affecting the central nervous system, anticholinergic agents, and especially alcohol.

4.8 Adverse Reactions

For the assessment of the frequency of adverse reactions, the following classification was used:
Very common
(≥1/10)
Common
(≥1/100 to <1>Uncommon
(≥1/1000 to <1>Rare
(≥1/10 000 to <1>Very rare
(<1>Not known
(frequency cannot be estimated from the available data)
Adverse reactions may occur mainly at the beginning of treatment and in the case of too rapid dose increases. Due to the lack of data on the number of people taking the medicinal product, it is not possible to precisely determine the percentage of spontaneously reported adverse reactions.
Infections and infestations
Unknown: parotitis.
Immune system disorders
Very rare: hypersensitivity.
Psychiatric disorders
Rare: in the case of higher doses, excitement, agitation, anxiety, disorientation, delirium, hallucinations, insomnia.
Central nervous system stimulation is common in patients with brain function disorders and may require dose reduction. Transient shortening of REM sleep (the phase of sleep in which rapid eye movements occur) has been observed, consisting of prolonged time to reach this phase and a percentage decrease in the share of this phase in total sleep.
Very rare: nervousness, euphoria.
Nervous system disorders
Rare: fatigue, dizziness, memory disorders.
Very rare: headache, dyskinesias, ataxia, and speech disorders, increased susceptibility to seizures and epileptic fits.
Eye disorders
Very rare: accommodation disorders, mydriasis with increased sensitivity to light. Glaucoma with closed-angle glaucoma may occur (intraocular pressure should be regularly monitored).
Cardiac disorders
Rare: tachycardia.
Very rare: bradycardia.
Gastrointestinal disorders
Rare: dryness of the oral mucosa, nausea, gastrointestinal disorders.
Very rare: constipation.
Skin and subcutaneous tissue disorders
Very rare: decreased sweating, allergic rash.
Musculoskeletal and connective tissue disorders
Rare: muscle tremors.
Renal and urinary disorders
Very rare: urinary disorders, especially in patients with prostatic hyperplasia (dose reduction is recommended), less frequently: urinary retention.
General disorders and administration site conditions
Rare: somnolence.
Reporting of suspected adverse reactions
After the medicinal product has been placed on the market, it is important to report any suspected adverse reactions. This allows for continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Department of Adverse Reaction Monitoring of the Office for Registration of Medicinal Products, Medical Devices, and Biocidal Products, Al. Jerozolimskie 181C, 02-222 Warsaw, Tel.: +48 22 49 21 301, Fax: +48 22 49 21 309, e-mail: website: https://smz.ezdrowie.gov.pl
Adverse reactions can also be reported to the marketing authorization holder.

4.9 Overdose

Symptoms
Peripheral anticholinergic symptoms (dilated, "lazy" pupils; dryness of mucous membranes, facial flushing, accelerated heart rate, intestinal and bladder atony, increased body temperature, especially in children), central nervous system disorders (excitement, delirium, confusion, impaired consciousness and/or hallucinations). In the case of severe poisoning, there is a risk of cardiovascular collapse and respiratory arrest.
Procedure in case of overdose
As an antidote, acetylcholinesterase inhibitors are recommended, including, in exceptional cases, physostigmine, which reduces central symptoms (e.g., physostigmine salicylate in the case of a positive physostigmine test). Depending on the severity of symptoms, it may be necessary to support circulation and respiration (oxygen therapy), reduce body temperature in the case of fever, and catheterize the bladder.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: drugs used in Parkinson's disease, ATC code: N04AA02
Biperiden is an anticholinergic drug with a strong effect on the central nervous system.
Compared to atropine, it has a weak anticholinergic effect on the peripheral nervous system.
Biperiden competes with peripheral and central muscarinic receptors (especially M receptors).
Animal studies have shown the effect of biperiden on parkinsonism symptoms caused by centrally acting cholinergic drugs (tremors, muscle stiffness).

5.2 Pharmacokinetic Properties

After oral administration of 4 mg to six study participants (20-33 years old), biperiden hydrochloride was rapidly absorbed, within 27 minutes, reaching a maximum plasma concentration of 5.1 ng/ml after 1.5 hours (mean values). According to other studies, the maximum plasma concentration was 1.01-6.53 and (or) 3.2-5.0 ng/ml and was reached after 0.5-2 hours.
In a comparative study, 10 young, healthy individuals (24 ± 4.7 years old) and 8 elderly patients with Parkinson's disease (77.4 ± 4.8 years old) were administered 4 mg of biperiden orally, and then after 7 days, 2 mg of biperiden twice a day for 6 days. The plasma concentration of biperiden was measured on days 1 and 15. The maximum plasma concentration in young individuals was

• on day 1, 4.3 ± 2.6 ng/ml (after 0.9 hours), and on day 15, 2.5 ± 1.4 ng/ml (after 0.8 hours). It should be noted that on day 15, before blood collection, the study participants were administered 2 mg of biperiden. The maximum plasma concentration of 7.2 ± 4.4 and 4.2 ± 2.2 ng/ml in elderly patients was observed after 1.6 ± 0.7 and 1.6 ± 0.3 hours, respectively.

The elimination half-life in plasma was determined after a single oral administration of 4 mg of biperiden hydrochloride (2 x 2 mg of biperiden hydrochloride) between 12 and 21 hours in young individuals and 30.2 ± 6.4 hours in elderly patients.
With multiple administrations (2 x 2 mg of biperiden hydrochloride for 6 days), the steady-state concentration was 24.5 ± 8.8 hours in younger individuals and 38.5 ± 12.2 hours in elderly patients.
A bioavailability study conducted in 1990 in 16 individuals (male, 20-34 years old) showed the following values after a single administration of 4 mg of biperiden hydrochloride in the form of 2 tablets of the medicinal product Akineton and, for comparison, in the form of an oral aqueous solution of biperiden:

Mean values with confidence interval.
c[ng/ml]

Akineton

Tablets

Biperiden

Solution

2.5

x
xo
o
o
x

1.5

o
x
o
o
x

0.5

x
o
ox

0 1 2 3 4 6 8 t [h]

Fig.: Mean values of biperiden plasma concentration over time after a single administration of 2 tablets of the medicinal product Akineton and (or) 0.92 ml of biperiden solution, corresponding to 4 mg of biperiden hydrochloride, n = 16.
Biperiden binds to plasma proteins in 94% in women and 93% in men.
The apparent volume of distribution is 24 ± 4.1 l/kg.
Biperiden is almost completely metabolized, and no unchanged compound has been detected in urine. The main metabolite is formed as a result of hydroxylation in the bicycloheptane ring (60%) and partial hydroxylation in the piperidine ring (40%). Numerous metabolites (hydroxylated compounds and their conjugation products) are excreted in equal amounts in urine and feces.
Plasma clearance is 11.6 ± 0.8 ml/min/kg body weight.
There are no data on pharmacokinetics in patients with liver and kidney failure.
There are no data on placental transfer.
Biperiden passes into breast milk, reaching the same concentration as in plasma. Since the metabolism in newborns has not been studied and pharmacological and toxic effects cannot be excluded, during treatment with biperiden, it is recommended to discontinue breast-feeding (see section 5.3 "Toxic effects on reproduction").

5.3 Preclinical Safety Data

Acute toxicity
See section 4.9 "Overdose".
Chronic toxicity
Studies on chronic toxicity conducted in rats and dogs did not reveal any organ toxicity.
Genotoxicity and carcinogenicity
In vitro and in vivo studies have not shown any effect of biperiden on the occurrence of genetic mutations and chromosomal aberrations.
Long-term carcinogenicity studies in animals are not available.
Toxic effects on reproduction
Available studies in animals on toxic effects on reproduction do not reveal any particular risk to fertility, fetal development, or postnatal development.
Studies on embryotoxicity did not reveal any risk of developmental anomalies or other embryotoxicity within the therapeutic dose range.
There are no data on the safety of the medicinal product during pregnancy and breast-feeding.

6. PHARMACEUTICAL PARTICULARS

6.1 List of Excipients

Corn starch
Potato starch
Anhydrous lactose
Calcium hydrogen phosphate dihydrate
Microcrystalline cellulose
Copovidone (K 28)
Talc
Magnesium stearate
Purified water

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

5 years

6.4 Special Precautions for Storage

There are no special recommendations for the storage of the medicinal product.

6.5 Nature and Contents of Container

PVC/Aluminum blisters in a cardboard box.
The package contains 50 tablets (5 blisters of 10 tablets each).

6.6 Special Precautions for Disposal and Preparation of the Medicinal Product for Administration

Administration
Without special requirements.
Any unused medicinal product or waste material should be disposed of in accordance with local regulations.

7. MARKETING AUTHORIZATION HOLDER

RESPONSIBLE FOR BATCH RELEASE

Desma GmbH, Peter-Sander-Str. 41b, 55252 Mainz-Kastel, Germany

8. MARKETING AUTHORIZATION NUMBER

Marketing authorization number: R/1932

9. DATE OF FIRST MARKETING AUTHORIZATION

AND DATE OF LAST RENEWAL

Date of first marketing authorization: 31.12.1977
Date of last renewal: 12.06.2014

10. DATE OF REVISION OF THE TEXT

OF THE SUMMARY OF PRODUCT CHARACTERISTICS

• 15.04.2024