Verapamil-darnitsa

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

Composition:

Active substance: verapamil;

1 tablet contains verapamil hydrochloride 40 mg;

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

Pharmaceutical form. Film-coated tablets.

Main physical and chemical properties: white, round, biconvex film-coated tablets.

Pharmacotherapeutic group. Selective calcium antagonists with predominant cardiac effect. Phenylalkylamine derivatives. ATC code C08D A01.

Pharmacological Properties

Pharmacodynamics

Verapamil blocks the transmembrane influx of calcium ions into myocardial cells and vascular smooth muscle cells. It directly reduces myocardial oxygen demand by affecting energy-consuming metabolic processes in myocardial cells and indirectly reduces 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 effect of verapamil is due to a reduction in peripheral vascular resistance without increasing heart rate (HR) as a reflex response. No adverse changes in physiological blood pressure values are observed. Verapamil exerts a pronounced antiarrhythmic effect, particularly in supraventricular arrhythmias. It delays impulse conduction in the atrioventricular node, thereby restoring sinus rhythm and/or normalizing ventricular rate, depending on the type of arrhythmia. Normal heart rate remains unchanged or slightly decreases.

Pharmacokinetics

Verapamil is rapidly and almost completely absorbed in the small intestine. The extent of absorption exceeds 90%. The mean absolute bioavailability in healthy volunteers after a single dose is 22%, which is attributed to extensive first-pass hepatic metabolism. Bioavailability doubles with repeated dosing.

Maximum plasma concentration is reached within 1–2 hours after administration. The elimination half-life is 3–7 hours after a single dose and 4.5–12 hours during chronic administration. Plasma protein binding is approximately 90%. Verapamil is almost completely metabolized, producing various metabolites. Among these, only norverapamil is pharmacologically active.

Verapamil and its metabolites are primarily excreted by the kidneys, with only 3–4% excreted unchanged. Approximately 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 increases in patients with liver cirrhosis due to low clearance and a large volume of distribution.

Verapamil and norverapamil are not removed by hemodialysis.

Clinical characteristics.

Indications.

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

Contraindications.

• Cardiogenic shock.
• Severe conduction disorders: AV block of degree II and III (except in patients with implanted artificial pacemaker).
• Sick sinus syndrome (except in patients with implanted artificial pacemaker).
• Known hypersensitivity to verapamil or to any component of the medicinal product.
• 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 (WPW syndrome and LGL syndrome). In such patients, administration of verapamil hydrochloride carries a risk of developing ventricular tachyarrhythmias, including ventricular fibrillation.
• Do not administer intravenous β-adrenoblockers concomitantly during verapamil therapy (except in intensive care settings).

Interaction with other medicinal products and other forms of interactions.

In vitro studies of verapamil hydrochloride metabolism 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.

Potential interactions related to the CYP450 enzyme system

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

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

Quinidine: reduction in quinidine clearance (~35%) with oral administration. Risk of arterial hypotension; in patients with hypertrophic obstructive cardiomyopathy, pulmonary edema may occur.

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

Theophylline: reduction in oral and systemic clearance by approximately 20%, and by 11% in smokers.

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

Phenytoin: decreased plasma concentration of verapamil.

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

Gliburide: increase in Cmax of gliburide by approximately 28% and AUC by 26%.

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

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

Rifampicin: possible reduction in antihypertensive effect. Reduction in verapamil AUC (~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 tumor stage, no significant changes in doxorubicin pharmacokinetics are observed with concomitant intravenous verapamil administration.

Phenobarbital: increases oral clearance of verapamil fivefold.

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

Midazolam: 3-fold increase in AUC and 2-fold increase in Cmax of midazolam.

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

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

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

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

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

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

Everolimus: increase in AUC of everolimus (approximately 3.5-fold) and Cmax (approximately 2.3-fold). Increase in Ctrough of verapamil (approximately 2.3-fold). Precise monitoring and dose adjustment of everolimus may be required.

Sirolimus: increase in AUC of sirolimus (approximately 2.2-fold) and AUC of S-verapamil (approximately 1.5-fold). Monitoring and dose adjustment of sirolimus may be necessary.

Tacrolimus: possible increase in plasma levels of this medicinal product.

Hypolipidemic 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, a reduction in statin dose should be considered, and dosing should be adjusted according to plasma cholesterol levels.

Atorvastatin: possible increase in atorvastatin levels. Atorvastatin increases AUC of verapamil by approximately 43%.

Lo vastatin: possible increase in lovastatin levels. Increase in 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 therefore less likely to interact with verapamil.

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

Sulfinpyrazone: 3-fold increase in oral clearance of verapamil, 60% reduction in bioavailability. A decrease in antihypertensive effect may be observed.

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

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

Other interactions

Antiviral agents (HIV): due to the ability of some antiviral agents, such as ritonavir, to inhibit metabolism, plasma concentrations of verapamil may increase. Use 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 the neuromuscular blocking agent may be necessary when used concomitantly.

Acetylsalicylic acid: increased risk of bleeding.

Ethanol (alcohol): increased plasma levels of ethanol.

Antihypertensive agents, diuretics, vasodilators: enhanced hypotensive effect.

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.

Cardiac block/first-degree atrioventricular 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 atrioventricular block (which are contraindications), or bundle branch block (single, double, 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 very rarely may provoke the occurrence of second- or third-degree atrioventricular block, bradycardia, and extremely rarely—asystole. Such 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 (lasting several seconds or less), with spontaneous return to atrioventricular nodal or normal sinus rhythm. If this phenomenon is not rapidly self-limiting, appropriate therapy should be initiated immediately (see section "Adverse reactions").

Antiarrhythmic agents, β-adrenoblockers

Mutual enhancement of cardiovascular effects (increased degree of high-grade atrioventricular block, significant reduction in heart rate, onset of heart failure, marked decrease in arterial 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 dose of digoxin should be reduced (see section "Interaction with other medicinal products and other forms of interaction").

Heart failure

Heart failure must be compensated prior to initiating verapamil therapy in patients with an ejection fraction greater than 35%, 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 conditions involving impaired neuromuscular transmission (myasthenia gravis, Lambert-Eaton syndrome, progressive Duchenne muscular dystrophy).

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 removed by hemodialysis.

Hepatic impairment

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

Verapamil-Darnytsia contains 31.4 mg of monohydrate lactose; therefore, if you have been diagnosed with an intolerance to certain sugars, consult your physician before taking this medicinal product.

Use during pregnancy or breastfeeding

There are no clear and well-established data on the use of this medicinal product in pregnant women. Animal studies have not revealed any direct or indirect harmful effects with regard to reproductive toxicity. However, since data obtained 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 can be detected in umbilical cord blood.

Verapamil and its metabolites are excreted into breast milk. Limited human data on oral administration indicate that the amount of verapamil transferred to the newborn is low (0.1–1% of the dose taken by the mother). Therefore, verapamil use 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 should be used during breastfeeding only if clearly needed for the mother.

Ability to influence reaction rate when driving or operating machinery

Due to the antihypertensive effect of verapamil hydrochloride, 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, and concomitant use of the medicinal product with alcohol. Verapamil may increase blood 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 an adequate amount of liquid (e.g., one glass of water; grapefruit juice must not be used under any circumstances), preferably during or immediately after meals.

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.

Children of preschool age older than 6 years, only for cardiac rhythm disorders:
The recommended dosage range is 80–120 mg per day, divided into 2–3 doses.

Children aged 6–14 years, only for cardiac rhythm disorders:
The recommended dosage range is 80–360 mg per day, divided into 2–4 doses.

Renal impairment:
Available data are described in the section "Special Instructions." 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, starting with low doses (e.g., initially 40 mg 2–3 times daily, i.e., 80–120 mg daily, for patients with impaired liver function).

Do not take the medicinal product while lying down.

Verapamil hydrochloride must not be administered to patients who have experienced myocardial infarction within the preceding 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

Verapamil-Darnytsia in this pharmaceutical form is indicated for use in children only for cardiac rhythm disorders.

Overdose

Symptoms:
Arterial hypotension, bradycardia progressing to high-degree atrioventricular block and sinus node arrest, hyperglycemia, stupor, and metabolic acidosis. Fatal outcomes have been reported following overdose.

Treatment of verapamil hydrochloride overdose
should primarily be supportive and individualized. β-adrenergic stimulation and/or intravenous administration of calcium preparations (calcium chloride) are effective in counteracting symptoms of intentional overdose following oral administration of verapamil hydrochloride.

In cases of significant arterial hypotension or high-degree atrioventricular block, vasopressors (vasoconstrictors) or cardiac pacemakers, respectively, should be used. In asystole, alongside standard resuscitation measures, β-adrenergic stimulation (e.g., isoprenaline hydrochloride), other agents aimed at increasing arterial pressure, or cardiac and respiratory resuscitation should be implemented.

Verapamil hydrochloride is not removed by hemodialysis.

Adverse Reactions

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

For each organ system, adverse reactions are classified according to frequency of reporting: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), unknown (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; unknown – vertigo.

Respiratory, thoracic and mediastinal disorders: unknown – bronchospasm, dyspnea.

Gastrointestinal disorders: common – nausea, constipation; uncommon – abdominal pain; rare – vomiting; unknown – abdominal discomfort, intestinal obstruction, gingival hyperplasia (gingivitis and bleeding).

Renal and urinary disorders: unknown – renal failure.

Metabolism and nutritional disorders: unknown – hyperkalemia.

Nervous system disorders: common – dizziness, headache; rare – paresthesia, tremor; unknown – extrapyramidal disorders, paralysis (tetraparesis)*, epileptic seizures.

Psychiatric disorders: rare – somnolence.

Cardiovascular disorders: common – bradycardia, flushing, hypotension; uncommon – palpitations, tachycardia; unknown – first-, second- or third-degree atrioventricular block, heart failure, sinus arrest, sinus bradycardia, asystole.

Immune system disorders: unknown – hypersensitivity reactions including urticaria, sensation of itching, pruritus, purpura.

Skin and subcutaneous tissue disorders: rare – hyperhidrosis; unknown – angioneurotic edema, Stevens-Johnson syndrome, erythema multiforme, maculopapular rash, alopecia, urticaria, pruritus, purpura, erythromelalgia.

Musculoskeletal and connective tissue disorders: unknown – muscle pain, joint pain, muscle weakness.

Reproductive system and breast disorders: unknown – erectile dysfunction, gynecomastia, galactorrhea.

General disorders and administration site conditions: common – peripheral edema; rare – fatigue.

Investigations (laboratory findings): unknown – 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 penetration through the blood-brain barrier as a result of CYP3A4 and P-gp inhibition by verapamil; see section "Interaction with other medicinal products and other forms of interaction".

Shelf life. 3 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; 2 blisters per carton.

Prescription status. Prescription only.

Manufacturer. JSC "Pharmaceutical Company "Darnitsya".

Manufacturer's address and place of business.

13, Borispilska Street, Kyiv, 02093, Ukraine.