Verapamil hydrochloride

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT VERAPAMIL HYDROCHLORIDE (VERAPAMIL HYDROCHLORIDE)

Composition:

Active substance: verapamil hydrochloride;

One tablet contains 80 mg of verapamil hydrochloride;

Excipients: maize starch, monohydrate lactose, copovidone, magnesium stearate.

Film-coating: hypromellose, monohydrate lactose, titanium dioxide (E 171), polyethylene glycol, triacetin.

Medicinal form. Film-coated tablets.

Main physico-chemical characteristics: white, round, biconvex film-coated tablets. In cross-section, two layers of different structure are visible.

Pharmacotherapeutic group. Selective calcium antagonists with predominant effect on the heart. Phenylalkylamine derivatives. ATC Code C08D A01.

Pharmacological properties.

Pharmacodynamics.

Verapamil hydrochloride is a selective class I L-type calcium channel blocker with antianginal and antihypertensive effects. It blocks potential-dependent calcium channels and inhibits the influx of calcium ions into cells, particularly into cardiomyocytes and vascular smooth muscle cells, without altering the calcium concentration in the blood.

The antianginal effect of the drug is achieved by reducing the tone of coronary and peripheral arterial vessels, improving myocardial blood supply, including in ischemic areas; it reduces myocardial oxygen demand by decreasing myocardial contractility and increasing coronary blood flow. The antianginal effect is also due to peripheral vasodilatory action, which reduces afterload and myocardial oxygen demand.

Verapamil hydrochloride belongs to class IV antiarrhythmic agents. The antiarrhythmic effect is due to blockade of calcium channels in the cardiac conduction system cells (sinoatrial and atrioventricular nodes), resulting in slowed automaticity of P-cells in the sinus node and ectopic foci in the atria, as well as reduced conduction velocity through the atrioventricular node. Consequently, the effective refractory period in the sinoatrial and atrioventricular nodes is prolonged, sinus rhythm is slowed, and heart rate is reduced.

The antihypertensive effect of verapamil hydrochloride is due to relaxation of vascular smooth muscle, reduction of total peripheral vascular resistance and arterial pressure, usually without development of postural hypotension or reflex tachycardia; bradycardia (heart rate less than 50 beats per minute) occurs rarely.

Pharmacokinetics.

After oral administration, more than 90% of the administered dose of verapamil hydrochloride is absorbed in the small intestine. The drug undergoes extensive first-pass metabolism primarily in the liver, resulting in a bioavailability of 20–35%. Maximum plasma concentration of verapamil hydrochloride is reached within 1–2 hours after administration.

The degree of blood pressure reduction is independent of the plasma concentration of verapamil hydrochloride.

Approximately 90% of the drug is bound to plasma proteins.

Verapamil hydrochloride crosses the placenta and is excreted in breast milk. The mean elimination half-life is 2.8–7.4 hours after the first dose and 4.5–12 hours during chronic administration. In elderly patients, the elimination half-life may be prolonged.

Recent data indicate no significant difference in verapamil pharmacokinetics between individuals with healthy kidneys and patients with end-stage renal failure.

In patients with hepatic impairment, the elimination half-life is prolonged to 14–16 hours, the volume of distribution is increased, and plasma clearance is approximately 30% of normal. Therefore, the dose for such patients should be reduced to one-third of the usual daily dose. The drug is excreted predominantly by the kidneys (70%), and partially via the intestine.

Clinical characteristics.

Indications.

• Arterial hypertension.
• Ischemic heart disease, including stable exertional angina, unstable angina (progressive angina, rest angina), vasospastic angina (variant angina, Prinzmetal's angina), post-infarction angina in patients without heart failure, if β-blockers are not indicated.
• Arrhythmias: paroxysmal supraventricular tachycardia, atrial fibrillation/flutter with rapid atrioventricular conduction (except in Wolff-Parkinson-White syndrome WPW).

Contraindications.

• Hypersensitivity to verapamil hydrochloride or to any of the excipients of the medicinal product.
• Cardiogenic shock.
• Acute phase of myocardial infarction with complications (bradycardia < 50 beats/min, arterial hypotension (systolic pressure below 90 mm Hg), left ventricular failure).
• Severe conduction disorders: sinoatrial and atrioventricular (AV) block of grade II–III

(except in patients with a permanent pacemaker).

• Sick sinus syndrome (except in patients with a permanent pacemaker).
• Heart failure with reduced ejection fraction below 35 % and/or pulmonary artery pressure above 20 mm Hg (unless secondary supraventricular tachycardia is unresponsive to verapamil therapy).
• Atrial fibrillation/flutter in the presence of accessory conduction pathways (in the context of WPW and LGL (Lown-Ganong-Levine) syndromes). In such patients, administration of verapamil hydrochloride carries a risk of ventricular tachyarrhythmias, including ventricular fibrillation.
• Concomitant use of intravenous β-adrenergic blockers (except in intensive care settings).
• Use in combination with ivabradine (see "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

In vitro metabolism studies of verapamil hydrochloride have shown that it is metabolized by cytochrome P450 CYP3A4, CYP1A2, CYP2C8, CYP2C9, and CYP2C18. Verapamil hydrochloride is an inhibitor of CYP3A4 enzymes and P-glycoproteins (P-gp). Clinically significant interactions have been reported with CYP3A4 inhibitors, which are associated with increased plasma levels of verapamil hydrochloride, whereas CYP3A4 inducers cause decreased plasma levels of verapamil hydrochloride; therefore, monitoring for interactions with other medicinal products is necessary. Concomitant administration of verapamil and drugs primarily metabolized by CYP3A4 or being substrates of P-gp may lead to increased concentrations of these drugs, potentially enhancing or prolonging both therapeutic and adverse effects of the concomitant drug.

Potential interactions related to pharmacokinetics

Antihypertensive agents (e.g., vasodilators, ACE inhibitors, diuretics, α-blockers, prazosin, and terazosin): verapamil hydrochloride potentiates their effects.

Quinidine: reduced quinidine clearance (~35%) upon oral administration. Risk of arterial hypotension, and pulmonary edema in patients with hypertrophic obstructive cardiomyopathy. Therefore, co-administration of both drugs should be avoided. Combination of verapamil with antiarrhythmic agents may result in additive cardiovascular effects (e.g., AV block, bradycardia, hypotension, heart failure).

Flecainide: significant mutual myocardial depressant effects, slowed atrioventricular conduction, and prolonged repolarization.

Theophylline: reduced oral and systemic clearance by ~20%, and by 11% in smokers. Elevated serum theophylline levels may increase the risk of adverse effects.

Carbamazepine: increased AUC of carbamazepine (~46%) in patients with refractory partial epilepsy; increased carbamazepine levels, which may lead to adverse effects such as diplopia, headache, ataxia, or dizziness.

Phenytoin: decreased plasma concentration of verapamil.

Imipramine: increased AUC (~15%) of imipramine without affecting the active metabolite desipramine.

Dantrolene: concomitant use of verapamil with intravenous dantrolene may lead to hypotension, myocardial depression, and hyperkalemia; therefore, this combination should be avoided.

Glibenclamide: increased Cmax of glibenclamide by 28%.

Colchicine: increased AUC (~2-fold) and Cmax (~1.3-fold) of colchicine. Combined use of these drugs is not recommended. Colchicine is a substrate for both CYP3A and the efflux transporter P-glycoprotein (P-gp). Verapamil is known to inhibit CYP3A and P-gp. When verapamil and colchicine are administered together, inhibition of P-gp and/or CYP3A by verapamil may enhance the effects of colchicine; therefore, combined use is not recommended.

Erythromycin, clarithromycin, telithromycin: mutual inhibition increases plasma levels of verapamil hydrochloride and macrolides.

Rifampicin: possible reduction in antihypertensive effect. Decreased AUC (~97%), Cmax (~94%), and oral bioavailability (~92%) of verapamil.

Doxorubicin (oral): concomitant administration of doxorubicin and verapamil (oral) increases AUC (~104%) and Cmax (~61%) of doxorubicin in patients with small cell lung cancer. In patients with progressive tumor stage, no significant changes in doxorubicin pharmacokinetics were observed with concomitant intravenous verapamil administration.

Phenobarbital: increases oral clearance of verapamil hydrochloride fivefold.

Buspirone: increases AUC and Cmax by 3–4 times.

Midazolam: increases AUC threefold and Cmax twofold.

Verapamil may increase plasma concentrations of β-blockers, potentially leading to additive cardiovascular effects (e.g., AV block, bradycardia, hypotension, heart failure).

Intravenous β-blockers should not be administered to patients receiving verapamil.

Metoprolol: increased AUC (~32.5%) and Cmax (~41%) of metoprolol in patients with angina (see section "Special precautions").

Propranolol: increased AUC (~65%) and Cmax (~94%) of propranolol in patients with angina (see section "Special precautions").

Digoxin: increased Cmax (~44%), C12h (~53%), Css (~44%), and AUC (~50%) of digoxin in healthy volunteers. Dose reduction of digoxin is recommended (see section "Special precautions").

Digitoxin: decreased digitoxin clearance (~27%) and extrarenal clearance (~29%).

Cimetidine: increases AUC of R-verapamil hydrochloride (~25%) and S-verapamil (~40%), with corresponding reduction in clearance of R- and S-verapamil.

Cyclosporine: increases AUC, Cmax, and Css of cyclosporine by approximately 45%.

Everolimus: increases AUC (~3.5-fold) and Cmax (~2.3-fold) of everolimus. Increases Ctrough of verapamil hydrochloride (~2.3-fold). Precise therapeutic drug monitoring and dose adjustment of everolimus may be necessary.

Sirolimus: increases AUC (~2.2-fold) of sirolimus and AUC (~1.5-fold) of S-verapamil. Therapeutic drug monitoring and dose adjustment of sirolimus may be required.

Tacrolimus: possible increase in plasma levels of this drug.

HMG-CoA reductase inhibitors (statins: simvastatin, atorvastatin, lovastatin): statin therapy should be initiated at the lowest possible doses and gradually increased. If statins are to be prescribed to a patient already receiving verapamil hydrochloride, dose reduction should be considered and dosing adjusted according to plasma cholesterol levels.

Atorvastatin: possible increase in atorvastatin plasma levels. Atorvastatin increases AUC of verapamil hydrochloride by ~43%. Although direct in vivo clinical data are lacking, verapamil has a strong potential to significantly affect the pharmacokinetics of atorvastatin, as well as simvastatin or lovastatin. Caution is advised when combining atorvastatin with verapamil.

Lo vastatin: possible increase in plasma levels of lovastatin. Increased AUC (~63%) and Cmax (~32%) of verapamil hydrochloride.

Simvastatin: increased AUC of simvastatin ~2.6-fold, Cmax of simvastatin ~4.6-fold.

Fluvastatin, pravastatin, and rosuvastatin: not metabolized by the CYP3A4 system and therefore practically do not interact with verapamil hydrochloride.

Almotriptan: increased AUC (~20%) and Cmax (~24%) of almotriptan.

Sulfinpyrazone: increases oral clearance of verapamil hydrochloride threefold and bioavailability by 60%. Possible reduction in antihypertensive effect.

Dabigatran: verapamil hydrochloride in immediate-release tablets increases Cmax (up to 180%) and AUC (up to 150%) of dabigatran. No significant interaction was observed when verapamil was administered 2 hours after dabigatran etexilate (increase in Cmax by ~10% and AUC by ~20%). Risk of bleeding is increased; therefore, careful clinical monitoring is recommended, especially in case of bleeding or in patients with mild to moderate renal impairment. Dose reduction of dabigatran may be necessary when co-administered with oral verapamil hydrochloride (see dabigatran prescribing information for dosing recommendations).

Other direct oral anticoagulants (DOACs): increased absorption of DOACs, as they are P-gp substrates. Additionally, reduced elimination of DOACs metabolized by CYP3A4 may lead to increased systemic bioavailability of DOACs.

According to some data, bleeding risk is increased, especially in patients with additional risk factors. Dose reduction of DOACs may be necessary when used with oral verapamil (see prescribing information for DOACs regarding dosing recommendations).

Ivabradine: concomitant use with ivabradine is contraindicated due to additive effects in reducing heart rate by verapamil hydrochloride (see "Contraindications").

Grapefruit juice: increases AUC of R-verapamil (~49%) and S-verapamil (~37%), increases Cmax of R-verapamil (~75%) and S-verapamil (~51%) without changing elimination half-life or renal clearance. Consumption of grapefruit juice with verapamil hydrochloride should be avoided.

Hypericum perforatum (St. John's wort): decreases AUC of R-verapamil (~78%) and S-verapamil (~80%) with corresponding reduction in Cmax.

Metformin: concomitant administration of verapamil with metformin may reduce metformin efficacy.

Other interactions

Antiviral agents (e.g., ritonavir, indinavir): possible increase in plasma concentration of verapamil hydrochloride. Therefore, verapamil hydrochloride should be used with caution in this combination or its dose should be reduced.

Lithium: increased neurotoxicity of lithium has been reported with concomitant use of verapamil hydrochloride and lithium, with or without increased plasma lithium levels. However, in patients on stable oral lithium doses, addition of verapamil hydrochloride led to decreased plasma lithium levels. Patients receiving both drugs should be closely monitored.

Neuromuscular blocking agents: clinical data and animal studies indicate that verapamil hydrochloride may potentiate the activity of neuromuscular blocking agents (curare-like and depolarizing). Dose reduction of verapamil hydrochloride and/or the neuromuscular blocking agent may be necessary when used concomitantly.

Acetylsalicylic acid: increased risk of bleeding.

Ethanol: verapamil hydrochloride delays ethanol metabolism and increases its plasma levels, thereby enhancing ethanol's effects.

β-adrenergic blockers: increased mutual suppressive effects on sinoatrial node automaticity, AV conduction, and myocardial contractility, thereby increasing the risk of severe arterial hypotension, AV and SA (sinoatrial) block, bradycardia, and heart failure, especially with high-dose β-blockers or intravenous administration.

Patients with signs of chronic heart failure, severe cardiomyopathy, or recent myocardial infarction constitute a special risk group. Combined therapy with verapamil hydrochloride and β-blockers should be administered only when clearly indicated and under strict medical supervision.

Disopyramide (rhythmilen): should not be used concomitantly; disopyramide administration should be discontinued 48 hours before starting verapamil hydrochloride and may be resumed no earlier than 24 hours after stopping verapamil hydrochloride.

Calcium salts and vitamin D: the pharmacological effect of verapamil hydrochloride is likely diminished.

Contrast media: possible potentiation of the suppressive effects of verapamil hydrochloride on sinoatrial node automaticity, AV conduction, and myocardial contractility.

Special precautions for use.

Acute myocardial infarction

The drug should be used with caution in patients with acute myocardial infarction complicated by bradycardia, severe arterial hypotension, or left ventricular dysfunction.

Heart block/AV block I degree/bradycardia/asystole

Verapamil hydrochloride affects the atrioventricular and sinoatrial nodes and prolongs atrioventricular conduction time.

Verapamil hydrochloride affects both the atrioventricular and sinoatrial nodes and may occasionally provoke the development of second- or third-degree AV block, bradycardia, or asystole. These effects are more likely to occur in patients with sick sinus syndrome (sinoatrial nodal disease), which is more commonly observed in elderly patients.

Use with caution in patients with first-degree AV block, due to the potential development of second- or third-degree AV block or unifascicular, bifascicular, or trifascicular bundle branch block, which may necessitate discontinuation of subsequent verapamil hydrochloride doses and initiation of appropriate therapy if required.

Asystole in patients without sick sinus syndrome is usually transient (lasting several seconds or less), with spontaneous return to atrioventricular or normal sinus rhythm. If this phenomenon is not rapidly self-limiting, appropriate therapy should be initiated immediately (see section "Adverse reactions").

The effects of verapamil and β-adrenergic blockers or other drugs on cardiac conduction and myocardial contractility may be additive; therefore, caution is required when they are used concomitantly, particularly with intravenous formulations.

Antiarrhythmic agents, β-adrenergic blockers

Potential for mutual enhancement of cardiovascular effects (increased incidence of high-degree atrioventricular block, marked reduction in heart rate, onset of heart failure, significant decrease in arterial blood pressure). Symptomatic bradycardia (36 beats/min) with an atrial escape rhythm was observed in patients receiving concomitant therapy with timolol eye drops (a β-adrenergic blocker) during treatment with verapamil hydrochloride.

Digoxin

When verapamil hydrochloride is administered concomitantly with digoxin, the digoxin dose should be reduced (see section "Interaction with other medicinal products and other forms of interaction").

Heart failure

Verapamil may affect left ventricular contractility. This effect is generally mild and not clinically significant. However, pre-existing heart failure may be exacerbated or progress. Therefore, heart failure must be adequately compensated prior to initiating verapamil therapy in patients with an ejection fraction greater than 35% (e.g., with digitalis preparations) and carefully monitored throughout the treatment period.

HMG-CoA reductase inhibitors (statins)

See section "Interaction with other medicinal products and other forms of interaction".

Neuromuscular transmission disorders

Verapamil hydrochloride should be used with caution in patients with neuromuscular transmission disorders such as myasthenia gravis, Lambert-Eaton syndrome, or progressive Duchenne muscular dystrophy.

In patients with atrial fibrillation/flutter and accessory pathways (e.g., Wolff-Parkinson-White syndrome), rare enhancement of conduction via the abnormal pathway may occur, potentially leading to increased ventricular tachycardia.

Hepatic impairment

Since verapamil is extensively metabolized in the liver, careful dose titration is required in patients with hepatic disease.

Verapamil hydrochloride should be administered with caution to patients with impaired liver function (a dose reduction to 30% of the usual daily dose is recommended).

Renal impairment

Although data from confirmed comparative studies indicate that renal impairment does not affect the pharmacokinetics of verapamil hydrochloride in patients with end-stage renal disease, there have been several reports suggesting that verapamil hydrochloride should be used with caution and under close monitoring in patients with renal impairment. Verapamil hydrochloride is not removed by hemodialysis.

When prescribing verapamil hydrochloride, it should be considered that elderly individuals may have increased sensitivity to the drug's effects, even at usual doses.

The medicinal product contains lactose; therefore, it should not be administered to patients with rare hereditary forms of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.

One tablet of Verapamil Hydrochloride contains 40 mg of lactose monohydrate and should therefore be used with caution in patients with diabetes mellitus.

Use during pregnancy and breastfeeding.

Well-controlled and clearly documented data on the use of the drug in pregnant women are lacking. Therefore, the drug should be used during pregnancy only if clearly needed.

Verapamil hydrochloride crosses the placenta and is detectable in umbilical cord blood.

The uterine muscle-relaxing properties of verapamil should be considered during treatment.

Verapamil hydrochloride and its metabolites are excreted into breast milk. The amount of verapamil hydrochloride transferred to the newborn is low (0.1–1% of the dose taken by the mother); therefore, use of verapamil hydrochloride may be compatible with breastfeeding. However, the risk to the newborn cannot be excluded. Due to the potential for serious adverse reactions in breastfed infants, verapamil hydrochloride should be used during breastfeeding only if clearly necessary for the mother.

Effect on ability to drive vehicles or operate machinery.

Due to the antihypertensive effect of verapamil hydrochloride and possible drowsiness, the ability to drive vehicles, operate machinery, or work under hazardous conditions may be impaired, depending on individual response. This is particularly relevant during the initial phase of treatment, dose escalation, change of antihypertensive medication, or concomitant use of the drug with alcohol. Verapamil hydrochloride may increase plasma alcohol levels and slow its elimination, thereby potentiating the effects of alcohol.

Method of Administration and Dosage

Dosages should be individually adjusted for each patient.

Tablets should be swallowed whole, not chewed, crushed, divided, or chewed; taken with sufficient liquid (e.g., one glass of water, and under no circumstances grapefruit juice). It is best to take them during or immediately after a meal.

Adults and adolescents with body weight above 50 kg

Ischemic heart disease, paroxysmal supraventricular tachycardia, atrial flutter/fibrillation

The recommended dose is 120–480 mg, divided into 3–4 doses. The maximum daily dose is 480 mg.

Arterial hypertension

The recommended daily dose is 120–360 mg, divided into 3 doses.

A sustained antihypertensive effect develops within one week of starting therapy.

For angina and arrhythmias, the usual dose is 80 mg 3–4 times daily (240–320 mg daily).

Maximum effect is generally achieved within 48 hours after starting treatment.

Renal impairment

Available data are described in the section "Special precautions". Verapamil hydrochloride should be used with caution and under close medical supervision in patients with renal insufficiency.

Hepatic impairment

In patients with impaired liver function, the effect of verapamil hydrochloride is enhanced and prolonged due to slowed drug metabolism. Therefore, dosage must be established with particular caution, starting with low doses (e.g., initially 40 mg 2–3 times daily, i.e., 80–120 mg daily, in patients with hepatic dysfunction), see "Special precautions".

If necessary, the initial dose may be gradually increased depending on the patient's condition and clinical response observed during treatment.

*If administration of verapamil hydrochloride at a dose of 40 mg is required, a formulation allowing such dosing should be used.

Do not take the medication while lying down.

Verapamil hydrochloride must not be administered to patients who have experienced myocardial infarction within the previous 7 days.

After prolonged therapy, the drug should be discontinued gradually by tapering the dose.

The duration of treatment is determined individually by the physician and depends on the patient's condition and disease course.

Children

This medicinal product in the given pharmaceutical form must not be administered to children.

Overdose

The clinical course of verapamil intoxication depends on the amount ingested, the time at which detoxification measures are initiated, and myocardial contractility (age-related).

Symptoms: arterial hypotension (sometimes to unmeasurable levels), shock symptoms, loss of consciousness, first- and second-degree AV block (often as Wenckebach phenomenon with or without gallop rhythm), complete AV block with total AV dissociation, gallop rhythm, asystole, bradycardia progressing to high-grade AV block or sinus arrest, hyperglycemia, stupor, and metabolic acidosis. Fatal outcomes due to overdose have been reported.

Treatment: primarily supportive and individualized. Key measures used to manage symptoms of intentional overdose following oral administration of verapamil hydrochloride include counteracting cardiodepressive effects, hypotension, or bradycardia via β-adrenergic stimulation. Calcium is a specific antidote; for example, 10–20 mL of 10% calcium gluconate solution should be administered intravenously (2.25–4.5 mmol), with repeat doses or continuous intravenous infusion (e.g., 5 mmol/hour) if necessary.

Therapeutic measures depend on the time elapsed since verapamil ingestion, and the type and severity of intoxication symptoms. In cases of overdose with large amounts of sustained-release formulations, it should be noted that release of the active substance and intestinal absorption may take longer than 48 hours.

It should be considered that undissolved tablet fragments may be present throughout the gastrointestinal tract, acting as active drug depots (depending on the time elapsed after ingestion).

In suspected intoxication with modified-release formulations, measures such as induced vomiting, endoscopic removal of gastric and small intestinal contents, intestinal lavage, administration of laxatives, and cleansing enemas are indicated. Standard intensive resuscitation measures such as cardiopulmonary resuscitation, defibrillation, and/or pacemaker therapy should be applied.

In cases of severe arterial hypotension or high-grade AV block, agents that increase arterial pressure (e.g., dopamine, dobutamine, noradrenaline) should be administered.

In cases of asystole, second- or third-degree AV block, or sinus bradycardia, β-adrenergic stimulation (e.g., isoprenaline, orciprenaline) should be administered concurrently with standard resuscitation measures, along with other interventions aimed at increasing blood pressure, cardiac stimulation, or restoring cardiac and respiratory function.

If signs of prolonged myocardial failure are present, dopamine or dobutamine should be administered, and repeated calcium injections may be necessary.

Verapamil hydrochloride is not removed by hemodialysis.

Adverse Reactions

The adverse reactions listed below have been reported during clinical trials, post-marketing use of verapamil, or in phase IV clinical studies.

Adverse reactions are classified by organ systems and frequency of occurrence: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10,000 to < 1/1000); very rare (< 1/10,000); not known (frequency cannot be estimated from available data).

The most commonly observed adverse reactions were: headache, dizziness; gastrointestinal disorders: nausea, constipation, and abdominal pain; as well as bradycardia, tachycardia, palpitations, decreased blood pressure, flushing, peripheral edema, and fatigue.

Ear and labyrinth disorders: rare – tinnitus; not known – vertigo.

Respiratory, thoracic and mediastinal disorders: not known – bronchospasm, dyspnea, acute respiratory distress syndrome.

Gastrointestinal disorders: common – nausea, constipation; uncommon – abdominal pain; rare – vomiting; not known – abdominal discomfort, gastrointestinal disorders such as flatulence, intestinal atony, intestinal obstruction, dry mouth, gingival hyperplasia (gingivitis and bleeding). Gingival hyperplasia may very rarely occur during long-term use of the drug and resolves completely after discontinuation.

Renal and urinary disorders: not known – renal failure.

Metabolism and nutrition disorders: not known – hyperkalemia.

Nervous system disorders: common – dizziness, headache; rare – paresthesia, tremor, somnolence; not known – extrapyramidal disorder, epileptic seizures, cerebral circulation disorders, confusion, loss of consciousness, ataxia, fatigue, insomnia, nervousness, muscle cramps, psychosis, neuropathy.

Cardiovascular system disorders: common – bradycardia, flushing, hot flushes, arterial hypotension, dystonia; uncommon – palpitations, tachycardia; not known – first-, second-, or third-degree AV block, risk of exacerbation/development of heart failure, sinus node arrest, sinus bradycardia, asystole, bradyarrhythmia with atrial fibrillation; angina pectoris, orthostatic reactions; chest pain, myocardial infarction, peripheral edema of ankles, syncope.

Immune system disorders: not known – hypersensitivity.

Skin and subcutaneous tissue disorders: rare – hyperhidrosis; not known – angioneurotic edema, Stevens-Johnson syndrome, Quincke's edema, erythema multiforme, skin rash (including maculopapular rash), alopecia, urticaria, pruritus, itching, pigmentation disorders, erythromelalgia, photodermatitis, bruising, purpura.

Musculoskeletal system: not known – muscle weakness, myalgia, arthralgia.

Reproductive system and breast disorders: not known – erectile dysfunction, including impotence, increased urinary frequency, menstrual cycle disorders, galactorrhea. In elderly men, gynecomastia developed during long-term therapy, which completely resolved after discontinuation of the drug.

Hepatobiliary disorders: not known – increased levels of transaminases, alkaline phosphatase, and bilirubin; possible liver injury with clinical manifestations (malaise, fever and/or right upper quadrant pain). Therefore, periodic monitoring of liver function is recommended in patients. In some cases, these changes resolve spontaneously even with continued therapy.

Other: blurred vision, increased plasma prolactin levels, decreased glucose tolerance, allergic hepatitis.

Cases of paralysis (tetraparesis) associated with concomitant use of verapamil and colchicine have been reported. This may be due to colchicine penetration through the blood-brain barrier as a result of verapamil-induced inhibition of CYP3A4 and P-gp. Therefore, concomitant use of colchicine and verapamil is not recommended.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after drug authorization is an important procedure. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions via the national pharmacovigilance system.

Shelf life. 5 years.

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

Keep out of reach of children.

Packaging. 10 tablets in a blister pack, 5 blisters per carton.

Prescription status. Prescription only.

Manufacturer. Public joint-stock company "Scientific and Production Center "Borshchahivskiy Chemical and Pharmaceutical Plant".

Manufacturer's address and location of operations.

17 Myru Street, Kyiv, 03134, Ukraine.