Verapamil tablets 80 mg

Instructions for use of Verapamil tablets 80 mg

Proprietary name: Verapamil

International nonproprietary or grouping name: verapamil

Dosage form: film-coated tablets

Composition per one tablet:

Description:

Round, biconvex, film-coated tablets of yellow color; the core is white in cross-section.

Pharmacotherapeutic group: slow calcium channel blocker.

ATC code: C08DA01

Pharmacological properties

Pharmacodynamics:

Verapamil is a slow calcium channel blocker (CCB), a phenylalkylamine derivative. It blocks the transmembrane influx of calcium ions (and possibly sodium ions) through "slow" channels into the cells of the cardiac conduction system and the smooth muscle cells of the myocardium and blood vessels.

It reduces myocardial oxygen demand, which is associated both with a direct effect on the myocardium at the level of cellular metabolic processes and with an indirect effect on the heart muscle due to a reduction in afterload. Causes dilation of coronary vessels and increases coronary blood flow. Reduces the tone of peripheral arterial smooth muscle and total peripheral vascular resistance (TPVR) without a compensatory increase in heart rate (HR).

Verapamil significantly slows atrioventricular conduction and suppresses sinoatrial node automaticity. It does not affect or slightly reduces HR during normal sinus rhythm; however, in patients with sick sinus syndrome, it may lead to sinoatrial block and sinus arrest.

Verapamil reduces myocardial contractility. In most patients, including those with organic heart disease, the negative inotropic effect of verapamil is offset by the reduction in afterload. The cardiac index usually does not decrease, but in patients with moderate and severe heart failure (pulmonary capillary wedge pressure greater than 20 mm Hg, left ventricular ejection fraction less than 35%), acute decompensation of chronic heart failure may be observed with verapamil use.

Verapamil does not change the total calcium content in the blood serum; does not affect the blood concentration of other electrolytes, glucose, creatinine; in normolipidemic patients, it does not affect plasma lipoprotein fractions. It has a local anesthetic effect (1.6 times less than procaine in an equimolar ratio).

Verapamil has antihypertensive, antianginal, and antiarrhythmic effects.

The antihypertensive activity of verapamil is due to a reduction in total peripheral vascular resistance without a compensatory increase in HR. Verapamil does not lead to the development of orthostatic hypotension.

The antianginal effect of verapamil is due to the dilation of large coronary arteries and arterioles in both intact and ischemic areas of the myocardium, leading to improved myocardial perfusion. Verapamil relieves coronary artery spasm (both spontaneous and ergonovine-induced), which determines its efficacy in the treatment of vasospastic angina (Prinzmetal's or variant angina). In patients with "classic" angina, the antianginal effect of verapamil is likely due to a reduction in myocardial oxygen demand, a decrease in HR, and a reduction in TPVR (decreased afterload).

The antiarrhythmic effect of verapamil is likely associated with its action on the "slow" calcium channels in the cells of the cardiac conduction system. The electrical activity of the sinoatrial and atrioventricular nodes largely depends on the influx of calcium into the cells through "slow" channels. By blocking calcium influx, verapamil slows atrioventricular conduction and increases the effective refractory period (ERP) of the atrioventricular node proportionally to the HR.

Verapamil does not affect the normal action potential of the atria or intraventricular conduction time, but it reduces the amplitude, depolarization rate, and conduction in altered atrial fibers. This leads to a reduction in ventricular rate in patients with atrial fibrillation and/or flutter. By terminating re-entry in the atrioventricular node, verapamil can restore normal sinus rhythm in patients with paroxysmal supraventricular tachycardia, including Wolff-Parkinson-White syndrome (WPW).

Verapamil shortens the ERP and facilitates antegrade conduction via accessory pathways. Cases of increased ventricular rate and development of ventricular fibrillation after intravenous administration of verapamil to patients with atrial fibrillation and accessory pathways have been described.

Pharmacokinetics:

Verapamil hydrochloride is a racemic mixture consisting of equal amounts of R-enantiomer and S-enantiomer.

Norverapamil is one of 12 metabolites found in urine. The pharmacological activity of norverapamil is 10-20% of the pharmacological activity of verapamil, and the proportion of norverapamil is 6% of the excreted drug. The steady-state concentrations of norverapamil and verapamil in plasma are similar. Steady-state concentration during long-term once-daily administration is achieved after 3-4 days.

Absorption

More than 90% of verapamil is rapidly absorbed in the small intestine after oral administration. The mean systemic bioavailability after a single oral dose of verapamil is from 20 to 35%, due to a significant first-pass effect through the liver. The bioavailability of verapamil upon repeated administration approximately doubles. The time to reach maximum plasma concentration (Tmax) of verapamil is 1-2 hours. The maximum plasma concentration of norverapamil is reached approximately 1 hour after drug intake. Food intake does not affect the bioavailability of verapamil.

Distribution

Verapamil is well distributed in body tissues; the volume of distribution (Vd) in healthy volunteers is 1.8-6.8 L/kg. Plasma protein binding is about 90%. Verapamil crosses the blood-brain and placental barriers and is excreted in breast milk.

Metabolism

Verapamil undergoes extensive metabolism. In vitro metabolic studies have shown that verapamil is metabolized by the cytochrome P450 isoenzymes CYP3A4, CYP1A2, CYP2C8, CYP2C9, and CYP2C18. In healthy volunteers after oral administration, verapamil undergoes extensive metabolism in the liver. Twelve metabolites were detected, most in trace amounts. The main metabolites were identified as N- and O-dealkylated derivatives of verapamil. Among the metabolites, only norverapamil has pharmacological activity (about 20% compared to the parent compound), as identified in a study on dogs.

Elimination

The half-life (T1/2) after a single oral dose of verapamil is 3-7 hours. With repeated oral administration of less than 10 doses at 6-hour intervals, the T1/2 of verapamil increased to 4.5-12 hours.

Within 24 hours, about 50% of the verapamil dose is excreted by the kidneys; within five days - 70%. Up to 16% of the verapamil dose is excreted via the intestines. Approximately 3-4% of verapamil is excreted unchanged by the kidneys. The total clearance of verapamil roughly corresponds to hepatic blood flow, i.e., about 1 L/h/kg (range: 0.7-1.3 L/h/kg).

Special patient groups

Elderly patients

Age may affect the pharmacokinetic parameters of verapamil in patients with arterial hypertension. T1/2 may be prolonged in elderly patients. No correlation was found between the antihypertensive effect of verapamil and age.

Renal impairment

Renal impairment does not affect the pharmacokinetic parameters of verapamil, as identified in comparative studies involving patients with end-stage renal failure and patients with normal renal function. Verapamil and norverapamil are practically not removed by hemodialysis.

Hepatic impairment

In patients with impaired liver function, T1/2 is prolonged to 14-16 hours due to lower oral clearance of verapamil and a larger Vd.

Indications for use:

• Arterial hypertension;
• Ischemic heart disease, including chronic stable angina (classic exertional angina), unstable angina, angina due to vasospasm (Prinzmetal's angina);
• Paroxysmal supraventricular tachycardia;
• Atrial fibrillation/flutter accompanied by tachyarrhythmia (except for Wolff-Parkinson-White and Lown-Ganong-Levine syndromes).

Contraindications:

• Hypersensitivity to the active substance or to any of the excipients;
• Cardiogenic shock;
• Atrioventricular block II or III degree, except for patients with a functioning pacemaker;
• Sick sinus syndrome, except for patients with a functioning pacemaker;
• Heart failure with reduced left ventricular ejection fraction less than 35% and/or pulmonary capillary wedge pressure greater than 20 mm Hg (except for heart failure caused by supraventricular tachycardia amenable to treatment with verapamil);
• Atrial fibrillation/flutter in the presence of accessory pathways (Wolff-Parkinson-White, Lown-Ganong-Levine syndromes). These patients are at risk of developing ventricular tachyarrhythmia, including ventricular fibrillation, in case of verapamil use;
• Concurrent use with ivabradine;
• Pregnancy and breastfeeding period (efficacy and safety not established);
• Age under 18 years (efficacy and safety not established);
• Rare hereditary galactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome.

With caution:

• Arterial hypotension;
• Acute myocardial infarction;
• Left ventricular dysfunction;
• Atrioventricular block I degree;
• Bradycardia;
• Hypertrophic obstructive cardiomyopathy;
• Heart failure;
• Renal impairment and/or severe hepatic impairment;
• Diseases affecting neuromuscular transmission (myasthenia gravis, Lambert-Eaton syndrome, Duchenne muscular dystrophy);
• Concurrent administration with cardiac glycosides, quinidine, flecainide, HMG-CoA reductase inhibitors (simvastatin, lovastatin, atorvastatin); ritonavir and other antiviral drugs for HIV treatment; oral beta-blockers; agents binding to plasma proteins, colchicine, dabigatran, other direct oral anticoagulants;
• Elderly age.

Use during pregnancy and breastfeeding

Pregnancy

Verapamil is contraindicated during pregnancy. There are insufficient data on the use of verapamil in pregnant women. Animal studies do not reveal direct or indirect toxic effects on the reproductive system. Since the results of animal studies do not always predict the response in humans, verapamil can be used during pregnancy only if the benefit to the mother outweighs the potential risk to the fetus/child.

Verapamil crosses the placental barrier and is detected in umbilical vein blood at delivery.

Breastfeeding period

Verapamil and its metabolites are excreted in breast milk. Available limited data regarding oral verapamil intake indicate that the dose of verapamil received by breastfed infants is quite small (0.1-1% of the mother's verapamil dose). However, the presence of risk for newborns and infants cannot be excluded. Given the possibility of serious side effects in breastfed infants, the use of verapamil during breastfeeding is contraindicated.

Dosage and administration

Orally. The tablets should be swallowed whole with water, preferably during or immediately after a meal. The tablets should not be dissolved or chewed.

The dose of verapamil should be individually tailored based on the clinical picture and severity of the disease.

The initial dose for all recommended indications is 40-80 mg 3 times daily.

The average daily dose of verapamil for all recommended indications ranges from 240 to 360 mg (divided into 2 or 3 doses). During long-term treatment, the daily dose should not exceed 480 mg; however, a higher daily dose may be used for short-term therapy. The maximum daily dose of verapamil should be used only in a hospital setting.

The duration of therapy is determined by the physician. There are no restrictions regarding the duration of verapamil use. Verapamil should not be abruptly discontinued after long-term therapy; it is recommended to gradually reduce the dose until complete withdrawal of the drug.

Verapamil 40 mg dose should be used in patients expected to have a satisfactory response to low doses (patients with impaired liver function or elderly patients).

If a daily dose of verapamil exceeding 240 mg is necessary, it is recommended to prescribe verapamil preparations in the form of extended-release tablets.

Special patient groups

Renal impairment

Verapamil should be used with caution and under careful monitoring in patients with renal impairment.

Hepatic impairment

In patients with impaired liver function, the metabolism of verapamil is slowed to a greater or lesser extent depending on the severity of the impairment, leading to an enhanced and prolonged effect of verapamil. Therefore, the dose of verapamil in patients with hepatic impairment should be selected with particular caution, and treatment should be started with lower doses. The recommended initial dose of verapamil in such patients is 40 mg 3 times daily.

Pharmaceutical form:

Film-coated tablets, 40 mg and 80 mg.

10 tablets in a blister pack made of polyvinyl chloride film and printed lacquered aluminum foil.

2, 4, or 5 blister packs together with the instructions for use are placed in a cardboard carton.

Storage conditions

In a dry place, protected from light, at a temperature not exceeding 25 °C.

Keep out of reach of children.

Shelf life

3 years. Do not use after the expiration date printed on the packaging.

Prescription status

Dispensed by prescription.

Name and address of the legal entity in whose name the registration certificate is issued / organization accepting claims:

JSC "AVVA RUS", Russia, 121614, Moscow, Krylatskie Kholmy st., 30, building 9.

Tel./Fax: +7 (495) 956-75-54.

avva.com.ru

ecoantibiotic.ru

Address of the production site:

JSC "AVVA RUS", Russia, 610044, Kirov region, Kirov, Luganskaya st., 53a.

Tel.: +7 (8332) 25-12-29; +7 (495) 956-75-54.