Clophelin-zn

INSTRUCTION FOR MEDICAL USE of the medicinal product CLOFELINE-ZN (CLOPHELIN-ZN)

Composition:

Active substance: clonidine;

1 tablet contains clonidine hydrochloride 0.15 mg;

Excipients: lactose monohydrate; corn starch; magnesium stearate.

Pharmaceutical form. Tablets.

Main physico-chemical properties: white or white with a yellowish tint tablets, cylindrical in shape with flat surfaces and beveled edges.

Pharmacotherapeutic group. Antihypertensive agents. Central-acting antiadrenergic agents. Imidazoline receptor agonists. ATC code C02AC01.

Pharmacological Properties.

Pharmacodynamics.

Clopheline-ZN is an antihypertensive agent acting at the level of neurohumoral regulation of vascular tone.

After crossing the blood-brain barrier, clonidine selectively stimulates α₂-adrenergic receptors in the nuclei of the vasomotor center of the medulla oblongata, thereby inhibiting sympathetic impulses from the central nervous system, resulting in vasodilation and reduction of arterial blood pressure. The decrease in sympathetic activity is accompanied by reduced levels of catecholamines (particularly norepinephrine) in plasma and urine. However, clonidine does not directly affect catecholamine synthesis; instead, it inhibits the release of norepinephrine from nerve endings via a negative feedback mechanism due to stimulation of central α₂-adrenergic receptors.

Clonidine is an agonist of imidazoline receptors.

Administration of clonidine leads to a reduction in heart rate, systolic and diastolic arterial pressure, as well as systemic vascular resistance. Cardiac output and stroke volume are slightly reduced.

Clonidine exerts sedative and moderate analgesic effects. Due to its central action, it can alleviate somatic and vegetative symptoms of opioid and alcohol withdrawal. Clonidine reduces intraocular pressure by decreasing aqueous humor secretion and improving its outflow. Prolonged use is accompanied by fluid retention in the body.

Pharmacokinetics.

After oral administration, the antihypertensive effect begins within 30–60 minutes. Maximum effect develops within 2–4 hours and lasts approximately 5–12 hours. The duration of action in some patients may extend to 24–36 hours. It is well absorbed from the gastrointestinal tract, independent of food intake, with peak plasma concentration reached within 1.5–2.5 hours. Bioavailability during prolonged use is approximately 65%. Plasma protein binding ranges from 20% to 40%. Approximately 50% of the absorbed dose is metabolized in the liver. Elimination half-life is 12–16 hours with normal renal function, increasing up to 41 hours in cases of impaired renal function. Clonidine readily crosses histohematogenous barriers, including the blood-brain and placental barriers, and penetrates into breast milk. It is excreted by the kidneys (40–60%) and via the intestine (20%). It is practically not removed during hemodialysis (up to 5%).

Clinical characteristics.

Indications.

Hypertensive crisis (except hypertensive crisis in pheochromocytoma).

Rarely possible use for treatment of arterial hypertension (as part of combination therapy).

Opioid withdrawal syndrome (as part of combination therapy).

Contraindications.

Increased individual sensitivity to clonidine or to any of the excipients; arterial hypotension, cardiogenic shock, conduction disorders (atrioventricular (AV) block II and III degree), pronounced bradycardia, sick sinus syndrome, severe ischemic heart disease, recent myocardial infarction, cerebrovascular disorders, pronounced atherosclerosis of cerebral vessels, severe peripheral circulatory disorders, peripheral arterial obstructive diseases (including Raynaud's syndrome), depressive states (including in history), concomitant use of tricyclic antidepressants, renal dysfunction, alcohol intake.

Interaction with other medicinal products and other types of interactions.

When used concomitantly with drugs that depress the central nervous system (tranquilizers, hypnotics, medicinal products containing alcohol), an enhanced sedative effect is possible, mutual potentiation of CNS depressant effects, and development of depressive disorders. The antihypertensive effect of clonidine is reduced by corticosteroids, tricyclic antidepressants, anorexigenic agents (except fenfluramine), sympathomimetics, nonsteroidal anti-inflammatory drugs, and calcium antagonists; increased by anesthetics, vasodilators, diuretics, antihistamines. β-adrenoblockers, calcium channel blockers, and cardiac glycosides increase the risk of bradycardia or (in individual cases) lead to development of AV block. Cases of severe bradycardia have been reported with concomitant use of clonidine and diltiazem, leading to hospitalization and need for cardiac pacing. With simultaneous use of clonidine and atenolol, propranolol, additive antihypertensive effect, sedative action, and dry mouth may develop. Hormonal contraceptives taken orally may enhance the sedative effect of the drug. Clonidine may reduce the efficacy of levodopa and piribedil in patients with Parkinson's disease. Clonidine may increase cyclosporine concentration and blood glucose levels due to reduced insulin secretion, which should be considered during concomitant use with insulin. Do not prescribe together with α-adrenoblockers, as the effect of α1-adrenoblockers may be unpredictable when used concomitantly with clonidine. Nonselective α-adrenoblockers (including phentolamine, tolazoline), as well as drugs with α2-adrenoceptor blocking properties (e.g., mirtazapine), may cause dose-dependent antagonistic reduction of the α2-mediated antihypertensive effect of clonidine. When using drugs with α-adrenoceptor blocking properties (chlorpromazine, haloperidol), orthostatic reactions may be provoked or intensified, antihypertensive effect reduced, and risk of rebound arterial hypertension upon abrupt discontinuation of clonidine increased.

It is not recommended to prescribe simultaneously with antiarrhythmic agents, phenothiazine derivatives, narcotic analgesics, noradrenaline, reserpine, cardiac glycosides, oral hypoglycemic agents, antacids, angiotensin-converting enzyme inhibitors.

Cases of acute delirium have been reported with concomitant use of fluphenazine and clonidine. Symptoms disappeared after discontinuation of clonidine and reappeared upon resumption of its use.

Special precautions for use.

During treatment with Clonidine-Zn, consumption of alcoholic beverages is prohibited.

Sudden discontinuation of the drug may lead to withdrawal syndrome due to increased plasma catecholamine levels: elevated blood pressure, anxiety, headache, nausea; therefore, discontinuation of the drug should be carried out only gradually over 1–2 weeks, taking into account concomitant therapy with other medicinal products. Withdrawal syndrome may appear 18–72 hours after the last dose of clonidine. In case of withdrawal syndrome, immediately resume the drug and subsequently discontinue it gradually, replacing it with other antihypertensive agents. Cases of hypertensive encephalopathy, cerebrovascular disorders, and fatal outcomes have been reported after abrupt discontinuation of clonidine.

The likelihood of such a reaction upon discontinuation of clonidine increases with high-dose therapy or continued concomitant therapy with β-blockers; therefore, special caution is recommended in such cases. To prevent withdrawal syndrome, the drug should not be prescribed to patients who do not have conditions for its regular use.

If temporary discontinuation of therapy is required during combined use of clonidine and a β-adrenoceptor blocker, the β-adrenoceptor blocker should be discontinued first to prevent sympathetic hyperreactivity, followed by gradual discontinuation of Clonidine-Zn, especially if it was used in high doses.

Use clonidine with caution in patients with diabetes mellitus, as it may mask symptoms of hypoglycemia and reduce insulin secretion.

Use with caution in elderly patients – increased sensitivity to the drug is possible. Transient increase in growth hormone concentration may occur.

Use of clonidine may lead to reduced and suppressed salivation, promoting development of caries, periodontosis, and oral candidiasis.

During clonidine therapy, regular monitoring of blood pressure is recommended. Caution should be exercised during prolonged physical exertion, especially in upright position, in hot weather due to risk of orthostatic reactions.

Clonidine, the active substance of Clonidine-Zn, and its metabolites are intensively excreted in urine. Dosage should be individually adjusted according to individual antihypertensive response, which may vary significantly in patients with renal insufficiency; therefore, such patients require careful monitoring. Since only minimal amounts of clonidine are removed during routine hemodialysis, no additional dose of clonidine is required after dialysis.

The drug should be used with caution in patients with mild to moderate bradyarrhythmias, such as sinus bradycardia, polyneuropathy, or constipation.

Patients with known history of depression should be carefully monitored during prolonged clonidine therapy, as reports of further depressive episodes during oral treatment in such patients are periodically received.

As with therapy using other antihypertensive drugs, patients with heart failure should be monitored particularly carefully during clonidine use.

There is insufficient data on the safety of clonidine use in children and adolescents; therefore, it cannot be recommended for use in this population.

Serious adverse events, including sudden death, have been reported with concomitant use of clonidine and methylphenidate. The safety of methylphenidate use in combination with clonidine has not been systematically evaluated.

The blood pressure reduction induced by clonidine may be further enhanced by concomitant use with other antihypertensive agents. This may be therapeutically utilized when using other antihypertensive agents such as diuretics, vasodilators, β-receptor blockers, calcium antagonists, and ACE inhibitors, but the effect of α-blockers is unpredictable.

Patients should be warned that the sedative effect of the drug is enhanced when used concomitantly with barbiturates or other sedative drugs.

Therapeutic effect of clonidine is not expected in arterial hypertension caused by pheochromocytoma.

A weakly positive Coombs' test reaction may develop.

Patients wearing contact lenses should be advised that reduced lacrimal gland secretion may occur during treatment.

The medicinal product contains lactose. If a patient has diagnosed intolerance to certain sugars, consultation with a physician is required before taking this medicinal product.

Use during pregnancy or breastfeeding.

The drug is contraindicated during pregnancy. If use is necessary during lactation, breastfeeding should be discontinued.

Ability to influence reaction rate when driving or operating machinery.

During therapy with the drug, potentially hazardous activities requiring increased attention, rapid mental and motor reactions should be avoided.

Method of administration and dosage.

Administer orally to adults, independent of food intake. The drug is effective in low doses. Dosage should be strictly individually adjusted. The duration of treatment is determined individually by the physician depending on disease course, achieved clinical effect, and drug tolerability. Discontinuation of the drug should always be gradual over 1–2 weeks.

Arterial hypertension. Initial dose is usually 0.075 mg (clonidine preparations of other strengths) 2–3 times daily. If necessary, the dose should be gradually increased to a maximum daily dose of 0.9 mg (6 tablets). The usual effective therapeutic dose is 0.15 mg (1 tablet) 2–3 times daily. Maximum single dose is 0.3 mg (2 tablets). In exceptional cases, daily dose may be increased up to 1.2 mg (8 tablets) – only under physician supervision in hospital conditions.

Elderly patients, especially with manifestations of cerebrovascular disease, should be treated with caution; at the beginning of therapy, use clonidine in another dosage form allowing administration of 0.0375 mg 3 times daily.

Hypertensive crisis. Administer sublingually 0.15–0.3 mg (1–2 tablets) (in absence of pronounced dry mouth).

Withdrawal syndrome. Administer in hospital conditions 0.15–0.3 mg (1–2 tablets) 3 times daily with 6–8 hour intervals for 5–7 days. In case of adverse effects, single doses should be gradually reduced over 2–3 days, after which, if necessary, the drug should be discontinued.

Children.

The drug is contraindicated for use in pediatric practice.

Overdose.

Symptoms. Drowsiness, sedative state, including coma, miosis (pronounced pupillary constriction), bradycardia, intractable vomiting, xerostomia, respiratory depression (up to apnea), impaired consciousness, collapse, decreased or increased blood pressure (especially in adolescents), symptomatic arterial hypotension, orthostatic reactions, QRS complex widening, hypothermia, possible slowing of AV conduction and early repolarization syndrome. Paradoxical increase in blood pressure may occur due to stimulation of peripheral α1-adrenoceptors (usually at doses exceeding 10 mg).

Treatment. Discontinue the drug and provide symptomatic therapy (in case of severe arterial hypotension – fluid infusion and/or sympathomimetic inotropes (dopamine or mesaton); in case of pronounced CNS depression or apnea – intravenous naloxone 2–4 mg, repeated if necessary; gastric lavage and/or activated charcoal administration – if needed). For symptomatic bradycardia, administer atropine sulfate. Tolazoline may be used as a specific antidote: 1 mg tolazoline intravenously or 50 mg orally neutralizes the effect of 0.6 mg clonidine. Hemodialysis is ineffective.

Adverse Reactions

Central nervous system: Sedation, increased fatigue, drowsiness, slowed mental and motor reaction speed, anxiety, agitation, nervousness, depression, vivid or nightmares, dizziness, asthenia, weakness, transient confusion, perception disturbances, hallucinations (including visual, auditory), delusions, delirium, headache, paresthesia, tremor, sleep disorders, including insomnia.

Cardiovascular system: Bradycardia, tachycardia, orthostatic hypotension, "hemitonogenic crisis" – sudden short-term decrease in arterial pressure followed by a sharp increase at the beginning of treatment, congestive heart failure, ECG changes (sinus node block, nodal bradycardia, high-degree AV block, arrhythmias, including bradyarrhythmia), palpitations, syncope. Cases of sinus bradycardia and AV block have been reported both with concomitant use of cardiac glycosides and without them, Raynaud's syndrome (pallor, cold extremities).

Gastrointestinal system: Dry mouth, decreased appetite, nausea, vomiting, constipation, reduced gastric secretion, anorexia, abdominal pain, pseudo-obstruction of the large intestine, pain in salivary glands, including parotid gland, parotitis, mild transient disturbances in liver function tests, hepatitis.

Skin and subcutaneous tissue: Pallor/hyperemia of the skin, urticaria, angioneurotic edema, alopecia.

Musculoskeletal system: Intermittent calf muscle cramps, myalgia, arthralgia.

Allergic reactions: Hypersensitivity reactions, including skin rash, pruritus, itching; very rarely – sublingual administration (in hypertensive crisis) – mucosal swelling, breathing difficulty.

Respiratory system: Dryness of nasal mucosa, breathing difficulties.

Eye disorders: Accommodation disorders, blurred vision, decreased tear production, dry eyes, burning sensation in eyes.

Other: Thrombocytopenia, hyperglycemia, transient increase in glucose and creatine phosphokinase levels in blood serum, sodium and water retention manifested as lower limb edema, weight gain, nasal congestion, nocturia, urinary disorders and retention, erectile dysfunction, decreased libido, reduced potency, gynecomastia in males, fever, malaise, weakly positive Coombs test, increased sensitivity to alcohol. Upon abrupt discontinuation – withdrawal syndrome (sudden increase in arterial pressure (5–20%), angina, anxiety or tension state, nervousness, headache, nausea, hypersalivation, vomiting, severe palpitations, hand and finger tremors, sweating, stomach spasms, sleep disturbances).

Reporting of suspected adverse reactions

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

Shelf life

4 years.

Storage conditions

Store in original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging

10 tablets per blister; 3 blisters per cardboard box.

Prescription status

Prescription only.

Manufacturer

Limited Liability Company "Kharkiv Pharmaceutical Enterprise "Zdorov'ya Narodu".

Manufacturer's address and location of business activity

41 Kuлиkovska Street, Kharkiv, Kharkiv Oblast, 61002, Ukraine.