Verapamil 240 mg 20 pcs. extended-release film-coated tablets

pharmachologic effect

Verapamil blocks the transmembrane entry of calcium ions (and possibly sodium ions) into the cells of the myocardial conduction system and the smooth muscle cells of the myocardium and blood vessels. The antiarrhythmic effect of verapamil is probably due to its effect on the “slow” channels in the cells of the cardiac conduction system.

The electrical activity of the sinoatrial and atrioventricular nodes largely depends on the entry of calcium into the cells through “slow” channels. By inhibiting this calcium entry, verapamil slows atrioventricular conduction and increases the effective refractory period in the AV node in proportion to heart rate. This effect leads to a decrease in the ventricular rate in patients with atrial fibrillation and/or atrial flutter. By stopping the reentry of excitation in the atrioventricular node, verapamil can restore correct sinus rhythm in patients with paroxysmal supraventricular tachycardia, including Wolff-Parkinson-White syndrome. Verapamil has no effect on conduction along additional pathways, does not affect the unchanged atrial action potential and intraventricular conduction time, but reduces the amplitude, depolarization rate and conduction in altered atrial fibers. Verapamil does not cause spasm of peripheral arteries and does not change the total calcium content in the blood plasma. The maximum therapeutic effect is observed 3 to 5 minutes after a bolus intravenous administration of verapamil.

Pharmacokinetics

Metabolized during first pass through the liver. Binds to plasma proteins by 90%. Penetrates through the blood-brain and placental barrier and into breast milk (in small quantities).

Rapidly metabolized in the liver by N-dealkylation and O-demethylation to form several metabolites. The accumulation of the drug and its metabolites in the body explains the increased effect during a course of treatment.

The most significant metabolite is the pharmacologically active norverapamil (20% of the antihypertensive activity of verapamil). The metabolism of the drug involves isoenzymes CYP3A4, CYP3A5 and CYP3A7. The half-life is two-phase: about 4 minutes - early and 2-5 hours - late. Excreted by the kidneys 70% (unchanged 3-5%), with bile 25%. Not excreted during hemodialysis.

Under conditions of intravenous administration, the antiarrhythmic effect develops within 1-5 minutes (usually less than 2 minutes), hemodynamic effects - within 3-5 minutes. The antiarrhythmic effect lasts about 2 hours, the hemodynamic effect lasts 10-20 minutes. Excreted mainly by the kidneys and feces (about 16%). Penetrates into breast milk and passes through the placenta. Rapid intravenous administration causes maternal hypotension leading to fetal distress. With prolonged use, clearance decreases and bioavailability increases. Against the background of severe liver dysfunction (liver failure), plasma clearance decreases by 70% and the half-life increases to 14-16 hours.

Verapamil

Metabolic studies in vitro

indicate that verapamil is metabolized by the isoenzymes CYP3A4, CYP1A2, CYP2C8, CYP2C9 and CYP2C18 of cytochrome P450.

Verapamil is an inhibitor of the CYP3A4 isoenzyme and P-glycoprotein. Clinically significant interactions were observed with simultaneous use with inhibitors of the CYP3A4 isoenzyme, and an increase in the concentration of verapamil in the blood plasma was observed, while inducers of CYP3A4 decreased the concentration of verapamil in the blood plasma. When using such drugs simultaneously, the possibility of this interaction should be taken into account.

The combined use of verapamil and a drug that is metabolized by the CYP3A4 isoenzyme or is a P-gp substrate may be accompanied by an increase in drug concentrations. This may result in increased or prolonged duration of both therapeutic and side effects of the drug used in conjunction with verapamil.

The table below presents data on possible drug interactions caused by pharmacokinetic parameters (where Cmax is the maximum concentration in the blood plasma, Css is the average equilibrium concentration in the blood plasma, AUC is the area under the pharmacokinetic concentration-time curve).

Possible interactions with verapamil:

Other possible types of interaction

Dabigatran

When dabigatran etexilate was co-administered with verapamil administered orally, the Cmax and AUC values ​​of dabigatran increased, depending on the time of use and the dosage form of verapamil. The greatest increase in dabigatran values ​​was observed when the first dose of immediate-release verapamil was taken 1 hour before dabigatran etexilate (Cmax increased by 180% and AUC increased by 150%).

When using the sustained release formulation of verapamil, this effect was progressively reduced (Cmax increased by 90% and AUC by 70%), as well as when using multiple doses of verapamil (Cmax increased by 60% and AUC by 50%), which may be explained by the induction of P-glycoprotein in the gastrointestinal tract with long-term use of verapamil. When verapamil was administered 2 hours after taking dabigatran etexilate, no clinically significant interaction was observed (Cmax increased by 10% and AUC by 20%) since dabigatran was completely absorbed after 2 hours. In a study in patients with atrial fibrillation, dabigatran concentrations increased by no more than 21%, and no increase in the risk of bleeding was observed. There are no data on the interaction of dabigatran etexilate with verapamil administered parenterally; no clinically significant interaction is expected

With regard to the prolongation of blood coagulation, the use of verapamil, as a rule, did not affect the plasma concentration-effect relationship of dabigatran. No unexpected safety data were obtained when dabigatran etexilate was co-administered with verapamil.

Drugs that bind to plasma proteins

Verapamil, as a drug that is highly bound to plasma proteins, should be used with caution when taken simultaneously with other drugs that have a similar ability. It is possible to increase the concentrations in the blood plasma of drugs characterized by a high degree of protein binding (including coumarin and indanedione derivatives, non-steroidal anti-inflammatory drugs, quinine, salicylates, sulfinpyrazone).

Means for inhalation general anesthesia

With the simultaneous use of drugs for inhalation anesthesia and BMCA, which include verapamil, the risk of developing bradycardia, atrioventricular block, and heart failure increases, so the dose of each drug should be carefully titrated to achieve the desired effect in order to avoid excessive depression of the cardiovascular system.

Flecainide

When verapamil and flecainide are used together, an additive effect is possible with a decrease in myocardial contractility, a slowdown in atrioventricular conduction and myocardial repolarization.

Disopyramide

Pending evidence of a possible interaction between verapamil and disopyramide, disopyramide should not be administered 48 hours before or 24 hours after verapamil.

Ivabradin

Due to its moderate inhibitory effect on CYP3A4, verapamil (at a dose of 120 mg 2 times a day) when used simultaneously led to an increase in the AUC of ivabradine by 2-3 times.

Both verapamil and ivabradine are heart rate depressants and, therefore, co-administration may worsen the patient's heart rate. The simultaneous use of verapamil with ivabradine is contraindicated due to the development of an additional negative chronotropic effect.

Procainamide, quinidine and other drugs known to prolong the QT interval

Increased risk of developing QT prolongation.

Valproic acid

Verapamil increases the concentration of valproic acid in the blood due to suppression of metabolism involving cytochrome P450.

Nicotine

Nicotine accelerates metabolism in the liver, leads to a decrease in the concentration of verapamil in the blood, and reduces the severity of antianginal, antihypertensive and antiarrhythmic effects.

Ranitidine

The concentration of verapamil in the blood plasma increases.

Calcium preparations

Reduced effectiveness of verapamil.

Nonsteroidal anti-inflammatory drugs (NSAIDs)

NSAIDs reduce the antihypertensive effect of verapamil due to suppression of prostaglandin synthesis, sodium and fluid retention in the body.

Sympathomimetics

Sympathomimetics reduce the antihypertensive effect of verapamil.

Estrogens

Estrogens reduce the antihypertensive effect of verapamil due to fluid retention in the body.

Medicines for the treatment of HIV infection

Some drugs used to treat HIV infection, such as ritonavir, may inhibit the metabolism of verapamil, resulting in increased plasma concentrations of verapamil. Caution should be exercised or the dose of verapamil should be reduced.

Lithium

Increased lithium neurotoxicity was observed during concomitant administration of verapamil and lithium, with no change or increase in serum lithium concentrations. However, additional administration of verapamil also led to a decrease in serum lithium concentrations in patients regularly taking lithium by mouth. Patients taking both drugs should be closely monitored.

Muscle relaxants

Clinical data and preclinical studies suggest that verapamil may enhance the activity of muscle relaxants (such as curare and depolarizing agents). Therefore, it may be necessary to reduce the dose of verapamil and/or the dose of drugs that block neuromuscular conduction when used simultaneously.

Acetylsalicylic acid (as an antiplatelet agent)

Increased risk of bleeding.

Ethanol (alcohol)

Increased concentration of ethanol in blood plasma.

HMG-CoA reductase inhibitors (statins)

For patients receiving verapamil, treatment with HMG-CoA reductase inhibitors (i.e. simvastatin, atorvastatin or lovastatin) should be started at the lowest possible doses and gradually increased during therapy. If it is necessary to prescribe verapamil to patients already receiving HMG-CoA reductase inhibitors (i.e. simvastatin, atorvastatin or lovastatin), then it is necessary to review and reduce their doses according to the concentration of cholesterol in the blood serum.

Fluvastatin, pravastatin and rosuvastatin are not metabolized by CYP3A4 isoenzymes, so their interaction with verapamil is least likely.

Antihypertensives, diuretics, vasodilators

Strengthening the antihypertensive effect.

Indications for use

For the treatment of supraventricular tachyarrhythmias, including:

- restoration of sinus rhythm in paroxysmal supraventricular tachycardia, including conditions associated with the presence of additional pathways in Wolff-Parkinson-White (WPW) and Lown-Ganong-Levine (LGL) syndrome;

- control of the frequency of ventricular contractions during atrial flutter and atrial fibrillation (tachyarrhythmic variant), except for cases when atrial flutter or fibrillation is associated with the presence of additional pathways (WPW and LGL syndromes).

Contraindications

Hypersensitivity, severe left ventricular (LV) dysfunction, second and third degree atrioventricular block (except in patients with an artificial pacemaker), sick sinus syndrome (bradycardia-tachycardia syndrome) except in patients with an artificial pacemaker, atrial flutter and fibrillation and WPW -syndrome or Lown-Ganong-Levine syndrome (except for patients with a pacemaker), chronic heart failure (except for those caused by supraventricular tachycardia, subject to treatment with verapamil), severe arterial hypotension (systolic blood pressure less than 90 mm Hg) or cardiogenic shock, ventricular tachycardia with wide QRS complexes (>0.12 sec.), simultaneous use with colchicine, with intravenous beta-blockers, use of disopyramide 48 hours before and 24 hours after the administration of verapamil, pregnancy, lactation.

Verapamil 240 mg 20 pcs. extended-release film-coated tablets

pharmachologic effect

Selective class I calcium channel blocker, diphenylalkylamine derivative.
It has antianginal, antiarrhythmic and antihypertensive effects. The antianginal effect is associated both with a direct effect on the myocardium and with an effect on peripheral hemodynamics (reduces the tone of peripheral arteries, peripheral arterial resistance). Blockade of calcium entry into the cell leads to a decrease in the transformation of energy contained in macroergic bonds of ATP into mechanical work and a decrease in myocardial contractility. Reduces myocardial oxygen demand, has a vasodilating, negative ino- and chronotropic effect. Increases the period of diastolic relaxation of the left ventricle, reduces the tone of the myocardial wall.

A decrease in peripheral vascular resistance may also be due to the antihypertensive effect of verapamil.

Verapamil significantly reduces AV conduction, prolongs the refractory period and suppresses the automaticity of the sinus node. Has an antiarrhythmic effect in supraventricular arrhythmias.

Composition and release form Verapamil 240 mg 20 pcs. extended-release film-coated tablets

Tablets - 1 tablet: verapamil hydrochloride 240 mg.

20 pcs per package, cardboard packs.

Description of the dosage form

Film-coated tablets.

Directions for use and doses

Individual. Orally for adults - at an initial dose of 40-80 mg 3 times a day. For long-acting dosage forms, the single dose should be increased and the frequency of administration reduced. Children aged 6-14 years - 80-360 mg/day, up to 6 years - 40-60 mg/day; frequency of administration - 3-4 times/day.

If necessary, verapamil can be administered intravenously (slowly, under the control of blood pressure, heart rate and ECG). A single dose for adults is 5-10 mg; if there is no effect after 20 minutes, repeated administration at the same dose is possible. A single dose for children aged 6-14 years is 2.5-3.5 mg, 1-5 years - 2-3 mg, up to 1 year - 0.75-2 mg. For patients with severe liver dysfunction, the daily dose of verapamil should not exceed 120 mg.

The maximum daily dose for adults when taken orally is 480 mg.

Pharmacokinetics

When taken orally, more than 90% of the dose is absorbed. Protein binding - 90%. It is metabolized during the “first pass” through the liver. The main metabolite is norverapamil, which has less pronounced hypotensive activity than unchanged verapamil.

T1/2 when taking a single dose is 2.8-7.4 hours, when taking repeated doses - 4.5-12 hours (due to the saturation of liver enzyme systems and an increase in the concentration of verapamil in the blood plasma). After IV administration, the initial T1/2 is about 4 minutes, the final T1/2 is 2-5 hours.

It is excreted mainly by the kidneys and 9-16% through the intestines.

Indications for use Verapamil 240 mg 20 pcs. extended-release film-coated tablets

Treatment and prevention of coronary artery disease: chronic stable angina (angina pectoris), unstable angina, vasospastic angina (Prinzmetal angina/variant angina).

Treatment and prevention of heart rhythm disturbances: paroxysmal supraventricular tachycardia, chronic form of atrial flutter and fibrillation (tachyarrhythmic variant), supraventricular extrasystole.

Arterial hypertension. Hypertensive crisis.

Hypertrophic cardiomyopathy.

Contraindications

Cardiogenic shock, heart failure, severe impairment of contractile function of the left ventricle, severe arterial hypotension (systolic blood pressure less than 90 mm Hg), bradycardia; SSSU, sinoatrial block, AV block of II and III degrees (except for patients with a pacemaker); atrial flutter and fibrillation in combination with WPW syndrome or Lown-Ganong-Levine syndrome (except for patients with a pacemaker); simultaneous use with colchicine, dantrolene, aliskiren, sertindole; pregnancy, lactation (breastfeeding); hypersensitivity to verapamil.

Application Verapamil 240 mg 20 pcs. extended-release film-coated tablets during pregnancy and lactation

Verapamil is contraindicated during pregnancy and lactation.

Use in children

Use with caution in children and adolescents under 18 years of age (the effectiveness and safety of use have not been studied).

special instructions

Caution should be used in case of AV blockade of the first degree, bradycardia, severe stenosis of the aortic mouth, chronic heart failure, with mild or moderate arterial hypotension, in the acute phase of myocardial infarction, obstructive hypertrophic cardiomyopathy, with hepatic and/or renal failure, in elderly patients age, in children and adolescents under the age of 18 years (the effectiveness and safety of use have not been studied).

If necessary, combination therapy of angina pectoris and arterial hypertension with verapamil and beta-blockers is possible. However, intravenous administration of beta-blockers should be avoided while using verapamil.

Impact on the ability to drive vehicles and operate machinery

After taking verapamil, individual reactions are possible (drowsiness, dizziness), affecting the patient’s ability to perform work that requires high concentration and speed of psychomotor reactions.

Side effects Verapamil 240 mg 20 pcs. extended-release film-coated tablets

From the cardiovascular system: bradycardia (less than 50 beats/min), marked decrease in blood pressure, development or worsening of heart failure, tachycardia; rarely - angina pectoris, up to the development of myocardial infarction (especially in patients with severe obstructive lesions of the coronary arteries), arrhythmia (including ventricular fibrillation and flutter); with rapid intravenous administration - third degree AV block, asystole, collapse.

From the central nervous system and peripheral nervous system: dizziness, headache, fainting, anxiety, lethargy, fatigue, asthenia, drowsiness, depression, extrapyramidal disorders (ataxia, mask-like face, shuffling gait, stiffness of the arms or legs, trembling of the hands and fingers, difficulty swallowing).

From the digestive system: nausea, constipation (rarely - diarrhea), gum hyperplasia (bleeding, pain, swelling), increased appetite, increased activity of liver transaminases and alkaline phosphatase.

Allergic reactions: skin itching, skin rash, facial skin flushing, erythema multiforme exudative (including Stevens-Johnson syndrome).

Other: weight gain, very rarely - agranulocytosis, gynecomastia, hyperprolactinemia, galactorrhea, arthritis, transient loss of vision against the background of maximum plasma concentration (with intravenous administration), pulmonary edema, asymptomatic thrombocytopenia, peripheral edema.

Drug interactions

When used simultaneously with antihypertensive drugs (vasodilators, thiazide diuretics, ACE inhibitors), the antihypertensive effect is mutually enhanced.

When used simultaneously with beta-blockers, antiarrhythmic drugs, and inhalation anesthesia agents, the risk of developing bradycardia, AV blockade, severe arterial hypotension, and heart failure increases due to the mutual increase in the inhibitory effect on the automatism of the sinoatrial node and AV conduction, contractility and conductivity. myocardium.

When verapamil is administered parenterally to patients who have recently received beta-blockers, there is a risk of developing arterial hypotension and asystole.

When used simultaneously with nitrates, the antianginal effect of verapamil is enhanced.

When used simultaneously with aliskiren, its plasma concentration increases and the risk of side effects increases.

When used simultaneously with amiodarone, the negative inotropic effect, bradycardia, conduction disturbances, and AV block are enhanced.

Since verapamil inhibits the CYP3A4 isoenzyme, which is involved in the metabolism of atorvastatin, lovastatin and simvastatin, drug interactions due to increased plasma concentrations of statins are theoretically possible. Cases of rhabdomyolysis have been described.

When used simultaneously with acetylsalicylic acid, cases of increased bleeding time due to additive antiplatelet effect have been described.

When used simultaneously with buspirone, the concentration of buspirone in the blood plasma increases, and its therapeutic and side effects increase.

With the simultaneous administration of verapamil and dantrolene (iv) in experimental studies in animals, ventricular fibrillation was observed with a fatal outcome. This combination is potentially dangerous.

When used simultaneously with digoxin, cases of increased concentrations of digitoxin in the blood plasma have been described.

When used simultaneously with digoxin, the concentration of digoxin in the blood plasma increases.

When used concomitantly with disopyramide, severe hypotension and collapse are possible, especially in patients with cardiomyopathy or decompensated heart failure. The risk of developing severe manifestations of drug interactions is apparently associated with increased negative inotropic effects.

When used simultaneously with diclofenac, the concentration of verapamil in the blood plasma decreases; with doxorubicin - the concentration of doxorubicin in the blood plasma increases and its effectiveness increases.

When used simultaneously with imipramine, the concentration of imipramine in the blood plasma increases and there is a risk of developing undesirable changes on the ECG. Verapamil increases the bioavailability of imipramine by reducing its clearance. Changes in the ECG are due to an increase in the concentration of imipramine in the blood plasma and the additive inhibitory effect of verapamil and imipramine on AV conduction.

When used simultaneously with carbamazepine, the effect of carbamazepine is enhanced and the risk of side effects from the central nervous system increases due to inhibition of the metabolism of carbamazepine in the liver under the influence of verapamil.

When used simultaneously with clonidine, cases of cardiac arrest in patients with arterial hypertension have been described.

Increases plasma concentrations of colchicine (substrate of the isoenzyme CYP3A and P-glycoprotein).

When used simultaneously with lithium carbonate, the manifestations of drug interactions are ambiguous and unpredictable. Cases of increased effects of lithium and the development of neurotoxicity, a decrease in the concentration of lithium in the blood plasma, and severe bradycardia have been described.

The vasodilating effects of alpha-blockers and calcium channel blockers may be additive or synergistic. With the simultaneous use of terazosin or prazosin and verapamil, the development of severe arterial hypotension is partly due to pharmacokinetic interaction: an increase in C max and AUC of terazosin and prazosin.

With simultaneous use, rifampicin induces the activity of liver enzymes, accelerating the metabolism of verapamil, which leads to a decrease in its clinical effectiveness.

When used simultaneously with sertindole, the risk of developing ventricular cardiac arrhythmias, especially ventricular arrhythmias, increases.

With simultaneous use, the concentration of theophylline in the blood plasma increases.

When used simultaneously with tubocurarine chloride and vecuronium chloride, the muscle relaxant effect may be enhanced.

When used simultaneously with phenytoin and phenobarbital, a significant decrease in the concentration of verapamil in the blood plasma is possible.

When used simultaneously with fluoxetine, the side effects of verapamil increase due to a slowdown in its metabolism under the influence of fluoxetine.

With simultaneous use, the clearance of quinidine decreases, its concentration in the blood plasma increases and the risk of side effects increases. Cases of arterial hypotension have been observed.

With simultaneous use, verapamil inhibits the metabolism of cyclosporine in the liver, which leads to a decrease in its excretion and an increase in plasma concentrations. This is accompanied by an increased immunosuppressive effect, and a decrease in the manifestations of nephrotoxicity is noted.

When used simultaneously with cimetidine, the effects of verapamil are enhanced.

When used simultaneously with enflurane, prolongation of anesthesia is possible.

When used simultaneously with etomidate, the duration of anesthesia increases.

special instructions

Arterial hypotension, decreased neuromuscular transmission (for example, Duchenne muscular dystrophy), atrioventricular (AV) block I stage, bradycardia, idiopathic hypertrophic subaortic stenosis (IGSS), hypertrophic obstructive cardiomyopathy, simultaneous use with cardiac glycosides, quinidine, flecainide, ritonavir , lovastatin, simvastatin, atorvastatin; elderly age, age under 18 years (efficacy and safety of use have not been studied), chronic heart failure, liver and/or kidney failure

Directions for use and doses

Administer intravenously only, slowly, over at least 2 minutes, with continuous monitoring of the electrocardiogram, heart rate and blood pressure.

In elderly patients, administration is carried out over at least 3 minutes to reduce the risk of unwanted effects.

To relieve paroxysmal cardiac arrhythmias or hypertensive crisis, 2-4 ml of a solution of 2.5 mg/ml (5-10 mg) is administered intravenously, in a stream (under ECG and blood pressure control). If there is no effect, repeated administration after 30 minutes at the same dose is possible. A verapamil solution is prepared by diluting 2 ml of a 2.5 mg/ml solution of the drug in 100-150 ml of 0.9% sodium chloride solution.

Side effect

Often -1-10%; sometimes - 0.1-1%; rarely - 0.01-0.1%; very rarely - less than 0.001%, including isolated cases.

From the cardiovascular system: severe bradycardia (less than 50 beats/min), marked decrease in blood pressure, development or worsening of heart failure, tachycardia; rarely possible development of angina, up to myocardial infarction (especially in patients with severe obstructive lesions of the coronary arteries), arrhythmia (including ventricular fibrillation and flutter); with rapid administration - third degree atrioventricular block, asystole, collapse.

From the central nervous system: dizziness, headache, fainting, anxiety, lethargy, fatigue, asthenia, drowsiness, depression, extrapyramidal disorders (ataxia, mask-like face, shuffling gait, stiffness of arms or legs, trembling of hands and fingers, difficulty swallowing ), a single case of the development of paralysis (tetraparesis) under the condition of combined use of verapamil and colchicine.

From the digestive system: nausea, constipation (rarely - diarrhea), gum hyperplasia (bleeding, soreness, swelling), increased appetite, increased activity of liver transaminases and alkaline phosphatase.

Allergic reactions: skin itching, rash, facial skin flushing, exudative erythema multiforme (including Stevens-Johnson syndrome).

Other: weight gain, very rarely - agranulocytosis, gynecomastia. hyperprolactinemia, galactorrhea, arthritis, transient loss of vision against the background of maximum concentration, pulmonary edema, asymptomatic thrombocytopenia, peripheral edema (swelling of the ankles, feet and legs).

Overdose

Symptoms: marked decrease in blood pressure, sinus bradycardia, turning into atrioventricular block, sometimes asystole, hyperglycemia, stupor, sinoatrial block, metabolic acidosis. There have been reports of deaths due to overdose.

Treatment: supportive symptomatic therapy should be carried out. To increase blood pressure, vasopressor drugs are prescribed, for atrioventricular block - an artificial pacemaker, for asystole - intravenous administration of vasopressor drugs or resuscitation measures. Hemodialysis is not effective.

Buy Verapamil tablets p.o 40 mg No. 50 in pharmacies

Verapamil Buy Verapamil in pharmacies DOSAGE FORMS tablets 40mg film-coated tablets 40mg film-coated tablets 40mg

MANUFACTURERS

ABVA RUS (Russia) Akrikhin KhFK (Russia) Alkaloid JSC (Macedonia) Valenta Pharmaceuticals (Russia) Irbit Chemical and Pharmaceutical Plant (Russia) Mir Pharmaceutical (Netherlands) Norton Healthcare Ltd (Great Britain) Obolenskoye Pharmaceutical Enterprise (Russia) Ozon LLC (Russia) Northern Star (Russia) Serena Pharma/Shreya Life Sciences (India) Sti-Med-Sorb (Russia) Tyumen Chemical and Pharmaceutical Plant (Russia) Shchelkovo Vitamin Plant (Russia)

GROUP Calcium channel blockers of the phenylalkylamine group

COMPOSITION Active ingredient: Verapamil.

INTERNATIONAL NON-PROPENTED NAME Verapamil

SYNONYMS Veracard, Verapamil hydrochloride, Verapamil Sopharma, Verapamil hydrochloride, Vero-Verapamil, Verogalid EP 240, Veromil, Isoptin, Isoptin SR 240, Finoptin

PHARMACOLOGICAL ACTION Antianginal, hypotensive, antiarrhythmic. Increases myocardial perfusion, reduces the imbalance between the need and supply of oxygen to the heart, promotes regression of left ventricular hypertrophy, and lowers blood pressure. Prevents the development and eliminates spasm of the coronary arteries during variant angina, improves the outflow of blood from the ventricles. Reduces the frequency and severity of headaches of vascular origin. When taken orally, the onset of action is noted after 1-2 hours. Under conditions of intravenous administration, the antiarrhythmic effect develops within 1-5 minutes. It is excreted mainly by the kidneys and feces. Penetrates into breast milk, passes through the placenta and is detected in the blood of the umbilical vein during childbirth.

INDICATIONS FOR USE Paroxysmal supraventricular tachycardia (except WPW syndrome), sinus tachycardia, atrial extrasystole, atrial fibrillation and flutter, angina pectoris (including Prinzmetal, tension, post-infarction), arterial hypertension, hypertensive crisis, idiopathic hypertrophic subaortic stenosis, hypertrophic cardiomyopathy.

CONTRAINDICATIONS Hypersensitivity, severe hypotension, cardiogenic shock, AV block II and III degrees, myocardial infarction (acute or recent and complicated by bradycardia, hypotension, left ventricular failure), chronic heart failure stage III, WPW syndrome and sick sinus syndrome (if no pacemaker implanted), sinoatrial block, Morgagni-Adams-Stokes syndrome, digitalis intoxication, severe aortic stenosis, pregnancy, breastfeeding. Restrictions on use: AV blockade of the first degree, chronic heart failure of stages I and II, severe bradycardia (less than 50 beats/min), mild or moderate hypotension, severe myopathy (Duchenne syndrome), impaired liver or kidney function, ventricular tachycardia with wide QRS complex (for intravenous administration).

SIDE EFFECTS From the cardiovascular system and blood (hematopoiesis, hemostasis): hypotension, bradycardia (sinus), AV block, heart failure. From the nervous system and sensory organs: headache, dizziness, nervousness, lethargy, drowsiness, weakness, fatigue, paresthesia. From the gastrointestinal tract: nausea, dyspeptic symptoms, constipation; rarely - gingival hyperplasia, increased activity of liver transaminases, alkaline phosphatase. Allergic reactions: skin rash, urticaria, itching; rarely - angioedema, Stevens-Johnson syndrome. Other: facial skin flushing, bronchospasm (with intravenous administration), peripheral edema, very rarely - gynecomastia, increased prolactin secretion (isolated cases).

INTERACTION Increases plasma levels of digoxin, cyclosporine, theophylline, carbamazepine, decreases lithium. Weakens the antibacterial activity of rifampicin, the depressing effect of phenobarbital, the clearance of metoprolol and propranolol, and enhances the effect of muscle relaxants. Rifampicin, sulfinpyrazone, phenobarbital, calcium salts, vitamin D - weaken the effect. The hypotensive effect is enhanced by antihypertensive drugs (diuretics, vasodilators), tricyclic and tetracyclic antidepressants and antipsychotics: antianginal - nitrates. Beta-blockers, class IA antiarrhythmics, cardiac glycosides, inhalational anesthetics, radiopaque agents potentiate a (mutually) inhibitory effect on the automatism of the sinoatrial node, AV conductivity and myocardial contractility. When used simultaneously with acetylsalicylic acid, existing bleeding may increase. Cimetidine increases the plasma levels of verapamil. The injection form is incompatible with albumin, injectable forms of amphotericin B, hydralazine, sulfamethoxazole, trimethoprim and may precipitate in solutions with a pH above 6.0.

METHOD OF APPLICATION AND DOSAGE Orally, during or immediately after meals, with a sufficient amount of liquid. The dosage and method of administration are selected individually depending on the disease and condition of the patient.

OVERDOSE Symptoms: arterial hypotension, bradycardia, AV block, cardiogenic shock, coma, asystole. Treatment: calcium gluconate (10-20 ml of 10% IV solution) is used as a specific antidote; for bradycardia and AV block, atropine, isoprenaline or orciprenaline are administered; for hypotension - plasma-substituting solutions, dopamine, norepinephrine; if signs of heart failure appear, dobutamine.

SPECIAL INSTRUCTIONS Rapid intravenous administration causes maternal hypotension leading to fetal distress. With long-term use, Cl decreases and bioavailability increases. Prescribe with caution to patients with hypertrophic cardiomyopathy complicated by left ventricular obstruction, high wedge pressure in the pulmonary capillaries, paroxysmal nocturnal dyspnea or orthopnea, dysfunction of the sinoatrial node. When prescribed to patients with severe impairment of liver function and neuromuscular transmission (Duchenne myopathy), constant medical supervision and possibly a dose reduction are required. Use with caution while working for drivers of vehicles and people whose profession is associated with increased concentration (reaction speed decreases), it is recommended to avoid drinking alcohol.

STORAGE CONDITIONS: In a dry place, protected from light, at room temperature.

Interaction with other drugs

Alpha blockers

— Prazosin: an increase in Cmax of prazosin (~40%) does not affect the half-life of prazosin.

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

Antiarrhythmic drugs

— Flecainide: minimal effect on the clearance of flecainide in blood plasma (<~10%); does not affect the clearance of verapamil in blood plasma.

- Quinidine: decreased oral clearance of quinidine (~35%).

Drugs for the treatment of bronchial asthma

- Theophylline: decreased oral and systemic clearance of theophylline (~20%). In smoking patients there is a decrease of ~11%.

Anticonvulsants

— Carbamazepine: increased AUC of carbamazepine (~46%) in patients with resistant partial epilepsy.

Antidepressants

— Imipramine: increase in AUC of imipramine (~15%). Does not affect the level of the active metabolite, desipramine.

Hypoglycemic agents

— Glyburide: glyburide Cmax increases (~28%), AUC (~26%).

Antimicrobials

- Erythromycin: possible increase in the concentration of verapamil in the blood plasma.

— Rifampicin: decrease in verapamil AUC (~97%), Cmax (~94%), bioavailability ~92%.

- Telithromycin: possible increase in the concentration of verapamil in the blood plasma.

Antitumor agents

- Doxorubicin: an increase in AUC of doxorubicin (89%) and Cmax (61%) when taking verapamil orally in patients with small cell lung cancer. The administration of verapamil intravenously in patients with progressive neoplasms does not affect the pharmacokinetic parameters of doxorubin.

Barbiturates

— Phenobarbital: increase in oral clearance of verapamil ~5 times.

Benzodiazepines and other tranquilizers

— Buspirone: increase in buspirone AUC, Cmax ~ 3.4 times

— Midazolam: increase in midazolam AUC (~ 3 times) and Cmax (~ 2 times).

Beta blockers

— Metoprolol: increase in metoprolol AUC (~32.5%) and Cmax (~41%) in patients with angina pectoris.

— Propranolol: increase in AUC of propranolol (~65%) and Cmax (~94%) in patients with angina pectoris.

Cardiac glycosides

— Digitoxin: decrease in total clearance (~27%) and extrarenal clearance (~29%) of digitoxin.

— Digoxin: in healthy volunteers, Cmax of digoxin increases by ~45-53%, Css of digoxin by ~42% and AUC of digoxin by ~52%.

Immunological agents

- Cyclosporine: increase in AUC, Css, Cmax of cyclosporine by ~45%.

- Everolimus: plasma levels of everolimus may increase.

- Sirolimus: the level of sirolimus in the blood plasma may increase.

- Tacrolimus: the level of tacrolimus in the blood plasma may increase.

Lipid-lowering drugs (HMG-CoA reductase inhibitors)

- Atorvastatin: the level of atorvastatin in the blood plasma may increase.

- Lovastatin: an increase in the level of lovastatin in the blood plasma is possible.

— Simvastatin: increase in AUC (~2.6 times) and Cmax (~4.6 times) of simvastatin.

Serotonin receptor agonists

— Almotriptan: increase in AUC (~20%) and Cmax (~24%) of almotriptan.

Uricosuric drugs

— Sulfinpyrazone: increased clearance of verapamil (~ 3 times) and decreased bioavailability (~ 60%).

Other

— Grapefruit juice: increase in AUC R- (~49%) and S-(~37%) verapamil and Cmax R- (~75%) and S-(~51%) verapamil. The half-life and renal clearance were unchanged.

— St. John's wort: the AUC of R- (~78%) and S-(~80%) verapamil decreases with a corresponding decrease in Cmax.

Other types of interaction

- Cimetidine: reduces the clearance of verapamil when administered intravenously.

Verapamil, as a drug that is highly bound to plasma proteins, should be used with caution when used simultaneously with other drugs that have a similar ability. When using drugs for inhalational general anesthesia and blockers of “slow” calcium channels, which include verapamil, together, the dose of the drug for inhalational general anesthesia should be carefully titrated until the desired effect is achieved in order to avoid excessive depression of the cardiovascular system. Verapamil may enhance the effect of drugs that block neuromuscular conduction (such as curare-like and depolarizing muscle relaxants). Therefore, the dose of verapamil and/or the dose of drugs that block neuromuscular conduction should be reduced when used simultaneously. Potentially increased neurotoxicity of lithium. Verapamil may also reduce serum lithium levels in patients receiving lithium for a long time. If these drugs are used concomitantly, patients should be closely monitored.

— Prazosin, terazosin: additive antihypertensive effect.

- Ritonavir and others: may inhibit the metabolism of verapamil, leading to

antiviral (HIV) to increase its concentration in the blood plasma, therefore

verapamil dosage should be reduced.

- Carbamazepine: an increase in the level of carbamazepine in the blood plasma and the appearance of adverse reactions such as diplopia, headache, ataxia or dizziness.

- Rifampicin: may reduce the antihypertensive effect of verapamil.

- Colchicine: is a substrate for the isoenzymes CYP3A and P-glycoprotein, which in turn inhibit the metabolism of verapamil. Therefore, when used simultaneously with verapamil, the concentration of colchicine in the blood may increase significantly.

- Sulfinpyrazone: may reduce the antihypertensive effect of verapamil.

— Acetylsalicylic acid: increased bleeding. (aspirin)

— Antihypertensive drugs: enhanced antihypertensive effect. diuretics, vasodilators

Lipid-lowering drugs. HMG-CoA reductase inhibitors (statins)

- Simvastatin/lovastatin/atorvastatin: Concomitant use with verapamil may cause atorvastatin to increase serum concentrations of simvastatin or lovastatin. In patients receiving verapamil, treatment with HMG-CoA reductase inhibitors (i.e. simvastatin, atorvastatin, lovastatin) should be started with the lowest possible doses and then increased. If it is necessary to prescribe verapamil to patients already receiving HMG-CoA reductase inhibitors, it is necessary to review and reduce their doses according to the concentration of cholesterol in the blood serum. Similar tactics should be followed when concomitantly prescribing verapamil with atorvastatin, although there is no clinical data confirming their interaction.

- Fluvastatin, pravastatin: not metabolized by CYP3A4 isoenzymes,

and rosuvastatin, therefore their interaction with verapamil is least likely. Although intravenous verapamil has been used in conjunction with digitalis drugs without serious side effects, given that these drugs slow AV conduction, monitoring of patients is necessary for timely detection of AV block or severe bradycardia.

- Quinidine: the development of arterial hypotension is possible with the combined use of quinidine and verapamil intravenously, so this combination of drugs must be used with caution.

Beta blockers: Concomitant intravenous administration of verapamil and beta blockers has resulted in serious side effects (severe bradycardia), especially in patients with cardiomyopathy, heart failure or recent myocardial infarction. Beta blockers should be prescribed several hours before or several hours after verapamil. Disopyramide should not be given 48 hours before or 24 hours after verapamil. When verapamil and flecainide are used together, an additive effect is possible with a decrease in myocardial contractility, prolongation of AV conduction and myocardial repolarization.

VERAPAMIL

Interaction

When used concomitantly with carbamazepine in patients with persistent partial epilepsy due to inhibition of carbamazepine metabolism in the liver, verapamil increases its effect (risk of side effects from the central nervous system, such as diplopia, headache, ataxia and dizziness).
With simultaneous use, verapamil inhibits the metabolism of cyclosporine in the liver, which leads to a decrease in its excretion and an increase in plasma concentrations. This is accompanied by an increased immunosuppressive effect.

With simultaneous use, verapamil increases the concentration of theophylline (due to decreased clearance).

With simultaneous use of verapamil with quinidine, the concentration of quinidine in the blood plasma increases (risk of a pronounced decrease in blood pressure, especially in patients with IHSS).

With simultaneous use, verapamil increases the concentration of ethanol in the blood plasma and prolongs its effect.

Since verapamil inhibits the CYP3A4 isoenzyme, which is involved in the metabolism of atorvastatin, lovastatin and simvastatin, drug interactions due to increased plasma concentrations of statins (rhabdomyolysis) are possible.

With simultaneous use, verapamil increases the plasma concentration of almotriptan and glibenclamide.

With simultaneous use, verapamil increases the plasma concentrations of sirolimus and tacrolimus.

With simultaneous use, verapamil increases the concentration of cardiac glycosides (requires careful monitoring and reduction in the dose of glycosides).

With simultaneous use, verapamil increases the concentration of metoprolol and propranolol in patients with angina pectoris.

With simultaneous use, verapamil increases the plasma concentration of colchicine (a substrate for the CYP3A isoenzyme and P-glycoprotein).

With simultaneous use of verapamil with doxorubicin, the concentration of doxorubicin in the blood plasma increases and its effectiveness increases.

With simultaneous use of verapamil with imipramine, the concentration of imipramine in the blood plasma increases (the risk of developing undesirable changes due to the additive inhibitory effect of verapamil and imipramine on AV conduction). Does not affect the concentration of the active metabolite, desipramine.

Verapamil increases the concentration of prazosin and terazosin when used simultaneously (risk of developing severe arterial hypotension).

When verapamil is used simultaneously with buspirone or midazolam, their concentration in the blood plasma increases (risk of increased side effects).

CYP3A4 inhibitors (including erythromycin, human immunodeficiency virus protease inhibitors), telithromycin increase plasma concentrations of verapamil.

Grapefruit juice increases plasma concentrations of the R- and S-isomers of verapamil. Cimetidine either does not change or reduces the clearance of verapamil (the effects of verapamil may be enhanced).

Rifampin can significantly reduce the bioavailability (up to 92%) as well as the plasma concentration of verapamil, which leads to a decrease in its clinical effectiveness.

Phenobarbital increases the clearance of verapamil by 5 times.

Sulfinpyrazone increases the clearance of verapamil by approximately 3 times and reduces bioavailability by up to 60%.

St. John's wort preparations reduce the concentration of the R- and S-isomer of verapamil in the blood plasma.

With the simultaneous use of verapamil with inhalational anesthetics, the risk of developing bradycardia, AV block, and heart failure increases. The combination of verapamil with beta-blockers can lead to an increased negative inotropic effect, an increased risk of developing AV conduction disorders, bradycardia (the use of verapamil and beta-blockers must be carried out at intervals of several hours).

Prazosin and other alpha-blockers, as well as other antihypertensive drugs (angiotensin-converting enzyme inhibitors, vasodilators, diuretics, beta-blockers) enhance the hypotensive effect of verapamil.

With the simultaneous use of verapamil with disopyramide and flecainide, severe arterial hypotension and collapse, including death, are possible. The risk of developing severe manifestations of drug interactions is associated with increased negative inotropic effects. Disopyramide and flecainide should not be administered within 48 hours before or 24 hours after verapamil.

Verapamil increases the risk of neurotoxic effects of lithium preparations.

Verapamil enhances the effect of peripheral muscle relaxants (may require a change in dosage regimen).

With the simultaneous use of verapamil with acetylsalicylic acid, cases of increased bleeding time have been described.