Verapamil-darnitsa

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT VERAPAMIL-DARNITSA (VERAPAMIL-DARNITSA)

Composition:

active substance: verapamil;

1 tablet contains verapamil hydrochloride 80 mg;

excipients: lactose monohydrate, microcrystalline cellulose, maize starch, hypromellose, sodium croscarmellose, silicon dioxide anhydrous colloidal, talc, magnesium stearate, seppifilm 752 white, macrogol 4000.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: film-coated, round-shaped, white tablets with a biconvex surface.

Pharmacotherapeutic group. Selective calcium channel blockers with direct effects on the heart. Phenylalkylamine derivatives. Verapamil. ATC code C08DA01.

Pharmacological Properties.

Pharmacodynamics.

Verapamil blocks the transmembrane influx of calcium ions into cardiac and vascular smooth muscle cells. It directly reduces myocardial oxygen demand by affecting energy-consuming metabolic processes in myocardial cells and by reducing afterload.

By blocking calcium channels in the smooth muscle of coronary arteries, verapamil enhances blood flow to the myocardium, even in post-stenotic areas, and relieves coronary artery spasm.

The antihypertensive efficacy of Verapamil-Darnitsya is due to reduced peripheral vascular resistance without increasing heart rate as a reflex response. No undesirable changes in physiological blood pressure parameters are observed.

Verapamil-Darnitsya has pronounced antiarrhythmic effects, particularly in supraventricular arrhythmias. It slows impulse conduction through the atrioventricular node, thereby restoring sinus rhythm and/or normalizing ventricular rate, depending on the type of arrhythmia.

Pharmacokinetics.

Verapamil is rapidly and almost completely absorbed in the small intestine. The extent of absorption is 90–92%. Maximum plasma concentration is reached within 1–2 hours after dose administration. The elimination half-life ranges from 3 to 7 hours. Plasma protein binding is approximately 90%. Verapamil is almost completely metabolized, producing various metabolites. Among these, only norverapamil is pharmacologically active. Verapamil and norverapamil are not effectively removed by hemodialysis.

Verapamil and its metabolites are primarily excreted by the kidneys; only 3–4% are excreted unchanged. About 50% of the administered dose is eliminated within 24 hours and 70% within 5 days. Up to 16% of the drug is excreted in feces. Recent data indicate no significant difference in verapamil pharmacokinetics between individuals with healthy kidneys and patients with end-stage renal disease. The elimination half-life is prolonged in patients with liver cirrhosis due to low clearance and increased volume of distribution.

The mean absolute bioavailability in healthy subjects after a single dose is 22%, which is attributed to extensive first-pass hepatic metabolism. Bioavailability increases 1.5–2 fold with repeated dosing.

Clinical characteristics.

Indications.

• Ischemic heart disease, including: stable exertional angina; unstable angina (progressive angina, rest angina); vasospastic angina (variant angina, Prinzmetal's angina); postinfarction angina in patients without heart failure when β-adrenoblockers are not indicated.

• Arrhythmias: paroxysmal supraventricular tachycardia; atrial flutter/fibrillation with rapid atrioventricular conduction [except Wolff-Parkinson-White (WPW) syndrome].

• Arterial hypertension.

Contraindications.

• Cardiogenic shock.

• Severe conduction disturbances: atrioventricular (AV) block of II and III degree (except patients with implanted pacemaker).

• Sinus node dysfunction syndrome (except patients with implanted pacemaker).

• Hypersensitivity to verapamil or to any component of the medicinal product.

• Heart failure with reduced ejection fraction less than 35% and/or pulmonary artery pressure above 20 mm Hg (unless secondary supraventricular tachycardia is unresponsive to verapamil therapy), severe bradycardia (less than 50 beats per minute).

• Acute myocardial infarction complicated by bradycardia, severe hypotension or left ventricular failure.

• Atrial fibrillation/flutter in the presence of accessory conduction pathways [WPW syndrome and LGL syndrome (Lown-Ganong-Levine syndrome)]. In such patients, administration of verapamil hydrochloride may lead to the risk of ventricular tachyarrhythmias, including ventricular fibrillation.

• Concomitant use with ivabradine (see section "Interaction with other medicinal products and other types of interactions").

• Intravenous β-adrenoblockers should not be administered concurrently during verapamil therapy (except in intensive care settings).

• Grapefruit juice consumption is contraindicated.

Interaction with other medicinal products and other types of interactions.

In vitro metabolism studies of verapamil hydrochloride have shown that it is metabolized by cytochrome P450 CYP3A4, CYP1A2, CYP2C8, CYP2C9, and CYP2C18. Verapamil is an inhibitor of CYP3A4 enzymes and P-glycoproteins (P-gp). Clinically significant interactions have been reported with CYP3A4 inhibitors, which were associated with increased plasma levels of verapamil, whereas CYP3A4 inducers caused decreased plasma levels of verapamil hydrochloride. Therefore, monitoring for interactions with other medicinal products is necessary.

Concomitant administration of verapamil and medicinal products that are primarily metabolized by CYP3A4 or are substrates of P-gp may result in increased concentrations of these drugs, potentially enhancing or prolonging both therapeutic and adverse effects of the concomitant medicinal product.

Potential interactions related to the CYP450 enzyme system.

Prazosin: increased Cmax of prazosin (~40%) without affecting elimination half-life. Additive hypotensive effect.

Terazosin: increased AUC (~24%) and Cmax (~25%) of terazosin. Additive hypotensive effect.

Quinidine: decreased oral clearance of quinidine (~35%). Risk of arterial hypotension and, in patients with hypertrophic obstructive cardiomyopathy, pulmonary edema.

Combination of verapamil with antiarrhythmic agents may lead to additive cardiovascular effects (e.g., AV block, bradycardia, hypotension, heart failure).

Flecainide: minimal effect on plasma clearance of flecainide (< ~10%); no effect on plasma clearance of verapamil (see section "Special precautions for use").

Theophylline: decreased oral and systemic clearance by approximately 20%, by 11% in smokers. Elevated serum theophylline levels may lead to increased adverse effects.

Carbamazepine: increased AUC of carbamazepine (~46%) in patients with refractory partial epilepsy; increased carbamazepine levels may cause 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 approximately 28%, AUC by 26%.

Colchicine: increased AUC (approximately 2-fold) and Cmax (approximately 1.3-fold) of colchicine. Dose reduction of colchicine is recommended (see colchicine prescribing information).

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 lead to enhanced effects of colchicine; therefore, combination use is not recommended.

Clarithromycin, erythromycin, telithromycin: possible increase in verapamil levels.

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

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

Phenobarbital: five-fold increase in oral clearance of verapamil.

Buspirone: 3.4-fold increase in AUC and Cmax of buspirone.

Midazolam: three-fold increase in AUC and two-fold increase in Cmax of midazolam.

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 therapy.

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

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

Digoxin: in healthy volunteers, increased Cmax of digoxin (~44%), C12h (~53%), Css (~44%), AUC (~50%) were observed; therefore, caution regarding digitalis toxicity is advised. Digoxin dose reduction is recommended (see section "Special precautions for use").

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

Cimetidine: increased AUC of R-verapamil (~25%) and S-verapamil (~40%) with corresponding decrease in clearance of R- and S-verapamil.

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

Everolimus: increased AUC of everolimus (approximately 3.5-fold) and Cmax (approximately 2.3-fold). Increased Ctrough of verapamil (approximately 2.3-fold). Dose adjustment and therapeutic drug monitoring of everolimus may be required.

Sirolimus: increased AUC of sirolimus (approximately 2.2-fold), increased AUC (approximately 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 medicinal product.

Lipid-lowering agents (HMG-CoA reductase inhibitors (statins): treatment with HMG-CoA reductase inhibitors (simvastatin, atorvastatin, lovastatin) in patients taking verapamil should be initiated at the lowest possible doses and gradually increased. If a patient already receiving verapamil requires initiation of an HMG-CoA reductase inhibitor, statin dose reduction should be considered, and dosing should be adjusted according to plasma cholesterol levels.

Verapamil may increase plasma concentrations of atorvastatin, lovastatin, and simvastatin.

Atorvastatin: possible increase in atorvastatin levels. Atorvastatin increases AUC of verapamil by approximately 43%. Although direct clinical in vivo data are lacking, there is strong potential for verapamil to significantly affect the pharmacokinetics of atorvastatin, as well as simvastatin or lovastatin. Caution is advised when co-administering atorvastatin and verapamil.

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

Simvastatin: approximately 2.6-fold increase in AUC and 4.6-fold increase in Cmax of simvastatin.

Fluvastatin, pravastatin, and rosuvastatin: not metabolized by cytochrome CYP3A4 and have lower potential for interaction with verapamil.

Almotriptan: 20% increase in AUC, 24% increase in Cmax.

Sulfinpyrazone: three-fold increase in oral clearance of verapamil, 60% reduction in bioavailability. May result in reduced antihypertensive effect.

Dabigatran: immediate-release verapamil tablets increase 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 or moderate renal impairment. Dose reduction of dabigatran may be required when co-administered with oral verapamil (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 available data, risk of bleeding is increased, especially in patients with additional risk factors. Dose reduction of DOACs may be required when used with oral verapamil (see DOAC prescribing information for dosing recommendations).

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

Grapefruit juice: increased AUC of R-verapamil (~49%) and S-verapamil (~37%), increased Cmax of R-verapamil (~75%) and S-verapamil (~51%) without changes in elimination half-life or renal clearance. Grapefruit juice consumption should be avoided with verapamil.

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

Other interactions.

Antiviral (HIV) agents: due to the ability of some antiviral agents, such as ritonavir, to inhibit metabolism, plasma concentrations of verapamil may increase. Should be prescribed with caution. Dose reduction of verapamil may be necessary.

Lithium: increased neurotoxicity of lithium has been reported with concomitant administration of verapamil hydrochloride and lithium, with or without increased plasma lithium levels. However, in patients receiving a constant oral dose of lithium, addition of verapamil hydrochloride led to decreased plasma lithium levels. Patients receiving both medicinal products 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 neuromuscular blocking agent may be necessary when used concomitantly.

Acetylsalicylic acid: increased risk of bleeding.

Ethanol (alcohol): increased plasma ethanol levels and delayed elimination. Therefore, alcohol effects may be enhanced.

Antihypertensive agents, diuretics, vasodilators: enhanced hypotensive effect due to possible additive action.

Special precautions for use.

Acute myocardial infarction.

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

Heart block/first-degree AV block/bradycardia/asystole.

Verapamil hydrochloride affects the atrioventricular and sinoatrial nodes and prolongs atrioventricular conduction time. Use with caution, as the development of second- or third-degree AV block (which is a contraindication) or single, dual, or triple bundle branch block of the His bundle requires discontinuation of subsequent doses of verapamil hydrochloride and initiation of appropriate therapy if necessary.

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

Asystole in patients without sick sinus syndrome is usually transient (a few seconds or less), with spontaneous return to atrioventricular nodal or normal sinus rhythm. If this phenomenon is not fleeting, appropriate therapy should be initiated immediately (see section "Adverse reactions").

The effects of verapamil and β-adrenoblockers or other medicinal products on cardiac conduction and contractility may be potentiated; therefore, caution is required when used concomitantly, especially with any intravenous medicinal product.

Antiarrhythmic agents, β-adrenoblockers.

Mutual potentiation of cardiovascular effects (increased degree of high-grade AV block, significant reduction in heart rate, onset of heart failure, marked decrease in blood pressure). Asymptomatic bradycardia (36 beats/min) with an atrial wandering pacemaker has been observed in patients receiving concomitant therapy with timolol eye drops (a β-adrenoblocker) during treatment with verapamil hydrochloride.

Digoxin.

When verapamil is used 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 small and usually not significant. However, existing heart failure may be exacerbated or progress. Therefore, heart failure must be compensated prior to initiating verapamil therapy in patients with ejection fraction greater than 35% (e.g., with digitalis preparations) and adequately controlled throughout the entire 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 (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 through the abnormal pathway may occur, potentially increasing ventricular tachycardia.

Renal impairment.

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

Hepatic impairment.

Since verapamil is extensively metabolized in the liver, dose titration of verapamil should be carefully performed in patients with hepatic disease.

Verapamil should be used with caution in patients with significant hepatic dysfunction (see section "Dosage and administration").

Important information about excipients.

This medicinal product contains lactose; therefore, patients with rare hereditary forms of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome should not take this medicinal product.

This medicinal product contains sodium; therefore, patients on a sodium-controlled diet should exercise caution when using this product.

Use during pregnancy or breastfeeding.

Pregnancy.

Clear and well-established data on the use of verapamil in pregnant women are lacking. Animal studies with verapamil have not revealed reproductive toxicity. Since data from reproductive studies in animals cannot always be extrapolated to humans, the medicinal product should be used during pregnancy only if clearly needed.

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

During treatment, the property of verapamil to cause uterine muscle relaxation should be taken into account.

Breastfeeding.

Verapamil and its metabolites pass into breast milk. Limited human data indicate that the amount of verapamil transferred to the newborn is low (0.1–1% of the oral dose taken by the mother); therefore, the use of verapamil may be compatible with breastfeeding, but the risk to the newborn cannot be excluded. Due to the risk of serious adverse reactions in newborns, verapamil may be used during breastfeeding only if clearly needed for the mother.

Ability to influence reaction speed when driving or operating machinery.

Due to the antihypertensive effect of verapamil hydrochloride, depending on individual response, the ability to drive vehicles, operate machinery, or work under hazardous conditions may be impaired due to drowsiness, especially at the beginning of treatment, when the dose is increased, when changing antihypertensive medication, or when the medicinal product is taken concomitantly with alcohol. Verapamil may increase plasma alcohol levels and delay its elimination, thereby potentiating the effects of alcohol.

Method of Administration and Dosage

Dosage should be individually adjusted for each patient. The medicinal product should be taken without chewing or sucking, with sufficient liquid (e.g., one glass of water; grapefruit juice must not be used under any circumstances), preferably 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 daily 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.

Preschool children aged up to 6 years, only for cardiac rhythm disorders.

Recommended dosage is 80–120 mg daily, divided into 2–3 doses.

Children aged 6–14 years, only for cardiac rhythm disorders.

Recommended dosage is 80–360 mg daily, divided into 2–4 doses.

Renal impairment.

Available data are described in the section "Special precautions for use". 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 should be carefully adjusted and treatment initiated with low doses (for patients with impaired liver function, initially 40 mg 2–3 times daily, i.e., 80–120 mg daily) (see section "Special precautions for use").

If a 40 mg dose is required, the medicinal product should be administered in the appropriate dosage form.

The medicinal product should not be taken while lying down.

Verapamil hydrochloride must not be prescribed to patients who have had myocardial infarction within the preceding 7 days.

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

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

Children.

The medicinal product in this pharmaceutical form may be used in children only for cardiac rhythm disorders (see section "Method of Administration and Dosage").

Overdose.

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

Symptoms: arterial hypotension (sometimes to undetectable 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 complete AV dissociation, gallop rhythm, asystole, bradycardia progressing to high-grade AV block or sinus node arrest, hyperglycemia, stupor, and metabolic acidosis. Fatal outcomes due to overdose have been reported.

Treatment of verapamil hydrochloride overdose: primarily supportive and individualized. Main measures used to counteract symptoms of intentional overdose after oral administration of verapamil hydrochloride include reversal of cardiodepressive effects, hypotension, or bradycardia via β-adrenergic stimulation. The specific antidote is calcium, e.g., 10–20 mL of 10% calcium gluconate solution administered intravenously (2.25–4.5 mmol); repeated administration or continuous intravenous infusion (e.g., 5 mmol/hour) may be necessary.

Therapeutic measures depend on the time elapsed since verapamil ingestion, type, and severity of intoxication symptoms. In cases of overdose with sustained-release formulations, release of the active drug and intestinal absorption may take more than 48 hours.

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

General measures to be taken: gastric lavage with standard protective precautions, even more than 12 hours after ingestion, if no gastrointestinal motility (peristaltic sounds) is detected.

In suspected intoxication with modified-release formulations, measures such as induced emesis, 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 used in addition to standard measures, along with other interventions to increase blood pressure, cardiac stimulation, or restoration of cardiac and respiratory function.

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

Verapamil hydrochloride is not removed by hemodialysis.

Adverse Reactions

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

For each organ system, adverse reactions are classified according to the frequency of reporting: 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); 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, hypotension, flushing, peripheral edema, and fatigue.

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

Respiratory, thoracic and mediastinal disorders: not known – bronchospasm, dyspnea.

Gastrointestinal disorders: common – nausea, constipation; uncommon – abdominal pain; rare – vomiting; not known – abdominal discomfort, intestinal obstruction, gingival hyperplasia (gingivitis and bleeding). Gingival hyperplasia may very rarely occur during prolonged 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 disorders, paralysis (tetraparesis)*, epileptic seizures.

Cardiac disorders: common – bradycardia, flushing, hot flushes, hypotension, dystonia; uncommon – palpitations, tachycardia; not known – first-, second- or third-degree AV block, heart failure, sinoatrial arrest, sinus bradycardia, asystole, bradyarrhythmia in atrial fibrillation.

Immune system disorders: not known – hypersensitivity.

Skin and subcutaneous tissue disorders: rare – hyperhidrosis; not known – angioneurotic edema, Stevens-Johnson syndrome, erythema multiforme, maculopapular rash, alopecia, urticaria, pruritus sensation, pruritus, purpura, erythromelalgia.

Musculoskeletal and connective tissue disorders: not known – myalgia, arthralgia, muscle weakness.

Reproductive system and breast disorders: not known – erectile dysfunction, gynecomastia, galactorrhea. Gynecomastia has been observed in very rare cases in elderly men during long-term verapamil therapy and was fully reversible upon discontinuation of the drug in all cases.

General disorders: common – peripheral edema; uncommon – fatigue.

Investigations: not known – increased levels of liver enzymes and increased serum prolactin levels.

*Paralysis (tetraparesis) has been reported once during post-marketing surveillance in association with concomitant use of verapamil and colchicine. This may be due to colchicine crossing the blood-brain barrier as a result of verapamil’s inhibition of CYP3A4 and P-gp (see section “Interaction with other medicinal products and other forms of interaction”).

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after drug authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions via the national reporting system.

Shelf life. 3 years.

Storage conditions.

Keep 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 blister packs in a carton.

Prescription status. Prescription only.

Manufacturer. JSC "Pharmaceutical Company "Darnytsia".

Manufacturer's address and place of business.

13, Boryspilska Street, Kyiv, 02093, Ukraine.