Cyclopol

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CYCLODOL (Cyclodol)

Composition:

Active substance: trihexyphenidyl;

1 tablet contains trihexyphenidyl hydrochloride (calculated as 100 % dry substance) 2 mg or 5 mg;

Excipients: lactose monohydrate, microcrystalline cellulose, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: 2 mg and 5 mg tablets – round, flat-faced, bevelled edges, with a score line, white in colour.

Pharmacotherapeutic group. Antiparkinson agents. Anticholinergic agents. Trihexyphenidyl. ATC Code N04AA01.

Pharmacological properties.

Pharmacodynamics.

Cyclodol is a centrally-acting anticholinergic agent that disrupts the balance between dopamine and acetylcholine in the central nervous system (CNS).

In the central nervous system, trihexyphenidyl reduces cholinergic effects caused by dopamine deficiency. The drug exerts a pronounced central N-cholinoblocking effect as well as a peripheral M-cholinoblocking effect.

In parkinsonism, Cyclodol, like other cholinolytic agents, reduces tremor. The drug has a lesser effect on muscular rigidity and bradykinesia. Due to its cholinoblocking action, the drug reduces salivation, sweating, and sebum production. The spasmolytic effect of the drug is also associated with its anticholinergic activity and direct myotropic influence.

Pharmacokinetics.

After oral administration, the drug is rapidly absorbed and penetrates the blood-brain barrier. The mean elimination half-life is 6–10 hours. There is no data available on the distribution, plasma protein binding, metabolism, and clearance of trihexyphenidyl, changes in drug elimination in case of hepatic or renal impairment (including during hemodialysis), or on placental and breast milk penetration.

Clinical characteristics.

Indications.

Monotherapy and combination therapy (with levodopa) for Parkinsonism of various origins.

Additional indications for Cyclopol, 5 mg tablets: extrapyramidal symptoms caused by neuroleptics or drugs with similar effects; Parkinson's disease; Little's disease; spastic paralyses associated with lesions of the extrapyramidal system; in some cases reduces muscle tone and improves movements in pyramidal paresis.

Contraindications.

• Hypersensitivity to trihexyphenidyl or any other component of the drug;
• glaucoma;
• urinary retention;
• benign prostatic hyperplasia with impaired urine flow, prostatic adenoma;
• obstructive gastrointestinal disorders (pyloric or duodenal stenosis, achalasia, etc.);
• paralytic ileus, intestinal atony, atonic constipation, mechanical intestinal obstruction, megacolon;
• tachyarrhythmia, including atrial fibrillation;
• cardiac diseases in decompensated stage.

Interaction with other medicinal products and other forms of interactions.

Cannabinoids, barbiturates, opiates, alcohol, and other CNS depressants − possible additive effects with trihexyphenidyl, increased sedative effect. Potential for abuse exists.

Phenothiazines (including chlorpromazine), clozapine, antihistamines (including diphenhydramine, diprazine), disopyramide, nefopam, amantadine: possible enhancement of anticholinergic side effects.

MAO inhibitors, tricyclic antidepressants with anticholinergic effects: due to additive effects, possible enhancement of anticholinergic effects of trihexyphenidyl, including dry mouth, difficulty initiating urination, urinary retention, blurred vision, acute glaucoma, constipation, paralytic intestinal obstruction, especially in elderly patients. Anticholinergic drugs should be used with caution in patients receiving tricyclic antidepressants or MAO inhibitors. If a patient is already taking antidepressants, trihexyphenidyl should be initiated at a reduced dose, and the patient's condition should be monitored regularly.

Tranquilizers: increased risk of developing tardive dyskinesia when used concomitantly with anticholinergic drugs; therefore, the use of anticholinergic drugs such as trihexyphenidyl for the prevention of drug-induced Parkinsonism during tranquilizer therapy is not recommended. Dyskinesia caused by tranquilizers is exacerbated by concomitant use of trihexyphenidyl.

Metoclopramide, domperidone: trihexyphenidyl reduces the gastrointestinal effects of these drugs.

Other antiparkinsonian agents (e.g., levodopa): absorption and systemic concentrations of levodopa may be reduced when used with trihexyphenidyl; therefore, dosage adjustment may be necessary. Since this combination may enhance drug-induced dyskinesias, especially at the beginning of treatment, the usual dose of trihexyphenidyl or levodopa may need to be reduced during combination therapy.

Parasympathomimetics: effects of trihexyphenidyl may antagonize the effects of parasympathomimetics.

Antiarrhythmic anticholinergic drugs (e.g., quinidine): enhanced anticholinergic effect on cardiac function (inhibition of atrioventricular conduction).

Reserpine: antiparkinsonian effect of trihexyphenidyl is reduced, leading to worsening of parkinsonism symptoms.

Special precautions for use

Since trihexyphenidyl may, in some cases, be prescribed for an indefinite duration, patients should remain under careful medical supervision throughout the entire treatment period.

It should be remembered that abrupt discontinuation or rapid dose reduction of the drug may lead to exacerbation of parkinsonian symptoms and development of potentially fatal neuroleptic malignant syndrome [hyperpyrexia, muscle rigidity, altered mental status, signs of autonomic dysfunction (fluctuations in blood pressure, diaphoresis, tachycardia, cardiac arrhythmia)]. Therefore, except in cases where discontinuation is required for life-threatening reasons, abrupt cessation of the drug should be avoided.

It is important to remember that drug dependence may develop in patients taking trihexyphenidyl, and that trihexyphenidyl may be subject to abuse due to its euphoric and/or hallucinogenic properties, usually when taken at doses higher than recommended.

Before initiating trihexyphenidyl therapy, gonioscopy is recommended in patients, and intraocular pressure should be carefully monitored throughout treatment, since the use of anticholinergic drugs may provoke the development of closed-angle glaucoma, increased intraocular pressure, and blindness. If blurred vision occurs during therapy, closed-angle glaucoma must be considered in the differential diagnosis.

Since anticholinergic drugs may cause psychiatric symptoms such as confusion, delirium, and hallucinations, trihexyphenidyl should be used with particular caution in elderly patients. Dose selection in patients aged 60 years and older should be carried out especially carefully (due to a higher risk of increased sensitivity and development of adverse reactions). A dose reduced by half is usually sufficient to achieve the desired therapeutic effect.

Trihexyphenidyl may trigger or worsen symptoms of tardive dyskinesia; therefore, its use is not recommended in patients with tardive dyskinesia unless they also have concomitant Parkinson's disease.

The use of trihexyphenidyl has been associated with clinical worsening of myasthenia gravis; therefore, the drug should be avoided or used with extreme caution in patients with myasthenia.

Trihexyphenidyl should also be prescribed with caution:

• when concomitant use with other anticholinergic drugs is necessary; combining two anticholinergic antiparkinsonian agents should be avoided, as this may increase adverse effects without enhancing therapeutic efficacy;
• in patients with neuropsychiatric disorders or autonomic neuropathy (possible worsening of disease symptoms);
• in patients with benign prostatic hyperplasia without impaired urine flow;
• in conditions that may be exacerbated by tachycardia, including arterial hypertension, heart disease, atherosclerosis, and hyperthyroidism;
• in high ambient temperatures, including at the workplace (risk of heat stroke due to inhibition of sweat gland activity); in hyperthermia, especially in elderly or debilitated patients − hyperthermia may be intensified;
• in patients with significant hepatic dysfunction or severe renal disease (risk of adverse effects due to reduced drug elimination);
• in patients with chronic alcoholism.

With prolonged treatment, the intensity of adverse reactions caused by the anticholinergic activity of trihexyphenidyl significantly decreases.

The use of the drug is contraindicated in patients with carbohydrate intolerance disorders such as congenital galactosemia, glucose-galactose malabsorption syndrome, or lactase deficiency due to the presence of lactose in the formulation.

The recommended doses of the drug should not be exceeded. Alcohol consumption should be avoided during treatment.

Use during pregnancy or breastfeeding.

The drug should not be used during pregnancy.

Since there are no data on the excretion of trihexyphenidyl into breast milk, breastfeeding should be discontinued if treatment with the drug is necessary.

Ability to affect reaction speed when driving or operating machinery.

During treatment, patients should refrain from driving or operating machinery, as the drug may impair the ability to concentrate and slow psychomotor reactions.

Dosage and Administration

The dosage of the drug should be individually adjusted, starting with the lowest dose and gradually increasing it to the minimum effective dose.

For Parkinsonism syndromes: The initial dose is 1 mg of trihexyphenidyl hydrochloride per day (the 1 mg dosage form of Cyclopol is not used). This dose should be gradually increased every 3–5 days by 1–2 mg per day until the optimal therapeutic effect is achieved. The maintenance dose is 6–16 mg per day, divided into 3–5 doses. The maximum daily dose is 20 mg.

For the treatment of drug-induced extrapyramidal disorders: Administer 2–16 mg of trihexyphenidyl hydrochloride per day, depending on the severity of symptoms. The maximum daily dose is 20 mg.

For anticholinergic therapy of other extrapyramidal disorders: The dosage should be gradually adjusted by increasing the initial dose of 2 mg of trihexyphenidyl hydrochloride daily until reaching the minimum effective maintenance dose, which may exceed the maximum dose used for other indications. The maximum daily dose is 50 mg.

For children aged 5 to 17 years: Cyclopol is indicated only for the treatment of extrapyramidal dystonias. The maximum daily dose is 40 mg of trihexyphenidyl hydrochloride.

The drug can be taken independently of meals. The tablet should be taken with sufficient fluid (150–200 ml). In cases of hypersalivation observed prior to treatment initiation, trihexyphenidyl should be taken after meals. If dry mouth develops during treatment, Cyclopol should be taken before meals (provided nausea does not occur).

Discontinuation of therapy should be gradual, with the dose of trihexyphenidyl reduced over 1–2 weeks until complete withdrawal. Abrupt discontinuation may lead to sudden worsening of the patient's condition due to exacerbation of disease symptoms.

The duration of treatment is determined individually by the physician in each case.

Children.

The drug may be used in children aged 5 years and older only for the treatment of extrapyramidal dystonias.

Overdose.

Administration of trihexyphenidyl in high doses may lead to dangerous poisoning.

Symptoms. Signs of intoxication with anticholinergic agents include facial flushing, dryness of the skin and mucous membranes, mydriasis, accommodation paralysis, difficulty in swallowing, elevated body temperature, arterial hypertension, cardiac arrhythmias (including tachycardia), rapid breathing, nausea, and vomiting. Skin rash may appear on the face and/or upper part of the trunk. Severe intoxication may manifest as generalized muscle weakness, urinary retention, and decreased intestinal peristalsis.

Central nervous system (CNS) stimulation symptoms include delirium, disorientation, restlessness, hallucinations, incoherence, confusion (loss) of consciousness, excitement, hyperactivity, ataxia, paranoid reactions, aggression, and occasionally seizures. This may progress to CNS depression, cardiovascular and respiratory failure, coma, and fatal outcome.

Treatment should be initiated as soon as possible. Airway patency must be ensured. Hemodialysis and hemoperfusion are indicated only within the first hours after poisoning. Antiarrhythmic agents are not recommended in case of arrhythmias. Diazepam may be administered to control agitation and seizures, but the risk of CNS depression should be considered. Hypoxia and acidosis should be corrected. Administration of sodium bicarbonate or sodium lactate is necessary to manage cardiovascular complications.

Physostigmine may be used to treat various symptoms of intoxication (delirium, coma, extrapyramidal disorders), tachyarrhythmias, frequent ventricular extrasystoles, and various conduction blocks. Administer 2–8 mg of physostigmine by infusion under ECG monitoring. In case of physostigmine overdose (half-life 20–40 minutes), atropine is the antidote of choice, with 0.5 mg of atropine counteracting 1 mg of physostigmine.

Adverse Reactions.

Nervous System and Psychiatric Disorders: weakness, headache, dizziness, sleep disturbances, including somnolence, irritability, nausea, vomiting. Exacerbation of myasthenia is possible.

At doses higher than recommended, or in patients with increased sensitivity, restlessness, nervousness, excitement, euphoria, cognitive dysfunction such as confusion, impairment of immediate and short-term memory, insomnia, delirium, hallucinations, paranoid reactions may occur, especially in elderly patients and patients with atherosclerosis.

Cases of dyskinesia in the form of involuntary chorea-like movements of the face, lips, body, and limbs have been reported (particularly in patients receiving levodopa preparations). Development of psychiatric disorders may require discontinuation of treatment. Cases of abuse of trihexyphenidyl due to its euphoric and hallucinogenic properties have been reported.

Effects due to anticholinergic activity: dryness of skin and mucous membranes, including dryness of the oral mucosa with possible development of dysphagia, sensation of thirst, decreased sweating, hyperthermia, flushing, tachycardia, reduced bronchial secretion, constipation, urinary disturbances, including difficulty initiating urination, urinary retention. Possible accommodation disorders (including cycloplegia), mydriasis, visual disturbances (blurred vision), photophobia, increased intraocular pressure, development of angle-closure glaucoma (in some cases leading to blindness).

Cases of paradoxical sinus bradycardia have been reported, isolated cases of purulent parotitis secondary to excessive dryness of the mouth, dilatation of the colon, intestinal obstruction.

Immune System: hypersensitivity reactions, including skin rash.

Upon abrupt discontinuation of treatment, exacerbation of parkinsonism symptoms and development of neuroleptic malignant syndrome have been reported.

In pediatric practice, the following adverse reactions have been observed: hyperkinesia, psychosis, memory impairment, weight loss, restlessness, chorea, sleep disturbances.

Most of these symptoms resolve during continued treatment or can be eliminated by reducing the dose or increasing the intervals between drug administration.

Shelf Life. 5 years. Do not use after the expiry date stated on the packaging.

Storage Conditions. In the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.

Packaging.

Tablets 2 mg: 10 tablets per blister, 4 blisters per pack.

Tablets 5 mg: 10 tablets per blister, 4 blisters per pack.

Prescription Category. Prescription only.

Manufacturer. Public Joint-Stock Company "Scientific and Production Center "Borshchagovskiy Chemical and Pharmaceutical Plant".

Manufacturer's Name and Address of Business Location.

17 Miru Street, Kyiv, 03134, Ukraine.