Tablets from high blood pressure verapamil. Usage Guide

A drug: VERAPAMIL (VERAPAMIL)

Active ingredient: verapamil
ATX code: C08DA01
KFG: Calcium channel blocker
Reg. number: P N011991/02
Date of registration: 07/18/11
The owner of the reg. credit: ALKALOID (Macedonia)

PHARMACEUTICAL FORM, COMPOSITION AND PACKAGING

Solution for intravenous administration transparent, colorless.

Excipients: sodium chloride - 17 mg, citric acid monohydrate - 42 mg, sodium hydroxide - 16.8 mg, concentrated hydrochloric acid - 5.4 μl, water for injection - up to 2 ml.

2 ml - colorless glass ampoules (5) - blister packs (2) - cardboard packs.
2 ml - colorless glass ampoules (5) - blister packs (10) - cardboard packs.

PHARMACHOLOGIC EFFECT

Verapamil belongs to the group of "slow" calcium channel blockers. It has antiarrhythmic, antianginal and antihypertensive activity.

Reduces myocardial oxygen demand by reducing myocardial contractility and reducing heart rate. Causes expansion of the coronary vessels of the heart and increases coronary blood flow; reduces the tone of the smooth muscles of the peripheral arteries and the total peripheral vascular resistance.

Verapamil significantly slows down atrioventricular conduction, inhibits the automatism of the sinus node, which allows the drug to be used to treat supraventricular arrhythmias.

It has an effect in angina pectoris, as well as in the treatment of angina pectoris with supraventricular arrhythmias. Suppresses metabolism with the participation of cytochrome P450.

PHARMACOKINETICS

It 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 course treatment. The most significant metabolite is the pharmacologically active norverapamil (20% of the hypotensive activity of verapamil). The enzyme system CYP3 A4, CYP3 A5 and CYP3 A7 is involved in the metabolism of the drug. T 1/2 two-phase: about 4 minutes - early and 2-5 hours - final. Excreted by the kidneys 70% (unchanged 3-5%), with bile 25%. Not excreted by hemodialysis.

INDICATIONS

Relief of attacks of supraventricular paroxysmal tachycardia; paroxysms of atrial fibrillation and flutter, atrial extrasystole.

DOSING MODE

Administer intravenously, slowly over at least 2 minutes, with continuous monitoring of the electrocardiogram, heart rate and blood pressure. At elderly patients the introduction is carried out for at least 3 minutes to reduce the risk of unwanted effects.

To stop paroxysmal heart rhythm disturbances, 2-4 ml of a 0.25% solution (5-10 mg) are administered intravenously, in a stream (under the control of ECG and blood pressure). If there is no effect, it is possible to re-administer after 30 minutes at the same dose. A solution of verapamil is prepared by diluting 2 ml of a 0.25% solution of the drug in 100-150 ml of a 0.9% sodium chloride solution.

SIDE EFFECT

From the side of the cardiovascular system: severe bradycardia (at least 50 beats / min), a pronounced decrease in blood pressure, the development or aggravation of heart failure, tachycardia; it is possible to develop angina pectoris, up to myocardial infarction (especially in patients with severe obstructive lesions of the coronary arteries), arrhythmias (including ventricular fibrillation and flutter); with rapid administration - atrioventricular blockade of the III degree, asystole, collapse.

From the side of the central nervous system: dizziness, headache, fainting, anxiety, lethargy, fatigue, asthenia, drowsiness, depression, extrapyramidal disorders.

From the digestive system: nausea, increased activity of "liver" transaminases and alkaline phosphatase.

Allergic reactions: skin itching, rash, flushing of the skin of the face, multimorphic exudative erythema (including Stevens-Johnson syndrome).

Others: transient loss of vision against the background of maximum concentration, pulmonary edema, asymptomatic thrombocytopenia, peripheral edema (swelling of the ankles, feet and legs).

CONTRAINDICATIONS

Chronic heart failure IIB-III degree;

arterial hypotension;

Acute myocardial infarction;

Sinoatrial blockade;

Sick sinus syndrome;

Stenosis of the mouth of the aorta;

Morgagni-Adams-Stokes syndrome;

Digitalis intoxication;

Atrioventricular block II and III degree;

Ventricular tachycardia;

Cardiogenic shock;

Wolff-Parkinson-White syndrome or Lown-Ganong-Levin syndrome in combination with atrial flutter or fibrillation (except for patients with a pacemaker);

Porfiria;

Pregnancy;

lactation period;

Parenteral administration within the previous 2 hours of any beta-blocker,

Age up to 18 years (efficacy and safety not established);

Hypersensitivity to the components of the drug,

Carefully: atrioventricular block I degree, bradycardia, concomitant use of beta-blockers, myocardial infarction with left ventricular failure, old age, chronic heart failure I and IIA degree, severe violations of the liver and kidneys.

PREGNANCY AND LACTATION

Contraindicated during pregnancy and lactation.

SPECIAL INSTRUCTIONS

During treatment, it is necessary to control the function of the cardiovascular and respiratory systems, the content of glucose and electrolytes in the blood, the volume of circulating blood and the amount of urine excreted. May prolong the PQ interval at plasma concentrations above 30 ng/mL. It is not recommended to stop treatment suddenly.

Influence on the ability to drive vehicles and control mechanisms

Use with caution during work for drivers of vehicles and people whose profession is associated with increased concentration of attention (reaction speed decreases).

OVERDOSE

Symptoms: sinus bradycardia, turning into atrioventricular block, sometimes asystole, marked decrease in blood pressure, heart failure, shock, sinoatrial block.

Giving help: with bradycardia and conduction disorders - in / in the introduction of isoprenaline, atropine, 10-20 ml of a 10% solution of calcium gluconate, an artificial pacemaker; intravenous infusion of plasma-substituting solutions. To increase blood pressure in patients with hypertrophic obstructive cardiomyopathy, alpha-adrenergic stimulants (phenylephrine) are prescribed; isoprenaline and norepinephrine should not be used. Hemodialysis is not effective.

DRUG INTERACTIONS

Increases the blood concentration of digoxin, theophylline, prazosin, cyclosporine, carbamazepine, muscle relaxants, quinidine, valproic acid due to the suppression of metabolism involving cytochrome P450.

Cimetidine increases the bioavailability of verapamil by almost 40% (by reducing metabolism in the liver), and therefore, it may be necessary to reduce the dose of the latter.

Calcium preparations reduce the effectiveness of verapamil. Rifampicin, barbiturates, nicotine, accelerating metabolism in the liver, lead to a decrease in the concentration of verapamil in the blood, reduce the severity of antianginal, hypotensive and antiarrhythmic effects.

With simultaneous use with inhalation anesthetics, the risk of developing bradycardia, atrioventricular blockade, and heart failure increases. Procainamide, quinidine, and other drugs that prolong the QT interval increase the risk of a significant prolongation of the latter.

The combination with beta-blockers can lead to an increase in the negative inotropic effect, an increase in the risk of developing atrioventricular conduction disorders, bradycardia (verapamil and beta-blockers must be administered at intervals of several hours).

Prazosin and other alpha-blockers enhance the hypotensive effect. Non-steroidal anti-inflammatory drugs reduce the hypotensive effect due to the suppression of the synthesis of prostaglandins, retention of sodium ions and fluid in the body.

Increases the concentration of cardiac glycosides (requires careful monitoring and dose reduction of cardiac glycosides).

Sympathomimetics reduce the hypotensive effect of verapamil.

Disopyramide and flecainide should not be administered within 48 hours before and 24 hours after the use of verapamil (summation of negative inotropic effect, up to death).

Estrogens reduce the hypotensive effect due to fluid retention in the body. It is possible to increase plasma concentrations of drugs characterized by a high degree of protein binding (including coumarin and indandione derivatives, non-steroidal anti-inflammatory drugs, quinine, salicylates, sulfinpyrazone).

Drugs that reduce blood pressure increase the hypotensive effect of verapamil.

Increases the risk of a neurotoxic effect of lithium preparations. Enhances the activity of peripheral muscle relaxants (may require a change in dosing regimen).

TERMS AND CONDITIONS OF DISCOUNT FROM PHARMACIES

On prescription.

TERMS AND CONDITIONS OF STORAGE

In a place protected from light, at a temperature of 15-25 ° C. Keep out of the reach of children. Shelf life - 3 years.

Verapamil is a drug with antiarrhythmic, antianginal and antihypertensive effects.

Release form and composition

Verapamil is available in the following dosage forms:

• Film-coated tablets (10 pieces in blisters, 1 or 5 blisters in a carton box);
• Solution for intravenous administration: colorless, transparent (in colorless glass ampoules of 2 ml, 5 ampoules in blister packs, 2 or 10 packs in a carton box).

The composition of 1 tablet includes:

• Active ingredient: verapamil hydrochloride - 40 or 80 mg;
• Auxiliary components: dibasic calcium phosphate, starch, butylhydroxyanisole, purified talc, magnesium stearate, gelatin, methyl paraben, hydroxypropyl methylcellulose, titanium dioxide, indigo carmine.

The composition of 1 ampoule of the injection solution includes:

• Active ingredient: verapamil hydrochloride - 5 mg;
• Auxiliary components: sodium chloride - 17 mg, sodium hydroxide - 16.8 mg, citric acid monohydrate - 42 mg, concentrated hydrochloric acid - 0.0054 ml, water for injection - up to 2 ml.

Pharmacological properties

Pharmacodynamics

Verapamil is a drug with antiarrhythmic, antihypertensive and antianginal effects. It is a blocker of slow calcium channels. It prevents the transmembrane entry of calcium ions (and, possibly, sodium ions) into the smooth muscle cells of the myocardium and blood vessels, as well as into the cells of the myocardial conduction system. The antiarrhythmic effect of verapamil is probably due to the blockade of the slow channels of the cardiac conduction system. The electrical activity of the sinoatrial and atrioventricular nodes is affected by the entry of calcium into the cells through slow channels. Verapamil inhibits calcium entry, slows down atrioventricular conduction, which leads to an increase in the effective refractory period in the AV node, depending on the heart rate. In patients with atrial flutter and/or atrial fibrillation, this effect causes a decrease in the ventricular rate. Verapamil prevents the re-entry of excitation in the AV node and helps restore the correct sinus rhythm in patients suffering from paroxysmal supraventricular tachycardia, including Wolff-Parkinson-White syndrome.

Reception of Verapamil does not affect the conduction of the impulse along the accessory pathways, and also does not lead to a change in the normal atrial action potential or intraventricular conduction time. In this case, the drug helps to reduce the amplitude, speed of depolarization and impulse conduction in the altered atrial fibers. Verapamil does not cause spasms of peripheral arteries, does not change the total concentration of calcium in the blood serum. The active substance helps to reduce afterload and myocardial contractility. The negative inotropic effect of verapamil in most patients (including those with organic heart disease) is offset by a decrease in afterload. Usually, the heart index does not decrease, however, in severe or moderate chronic heart failure (wedge pressure in the pulmonary artery over 20 mm Hg and with a left ventricular ejection fraction of up to 35%), there is a possibility of acute decompensation of chronic heart failure. As a result of bolus intravenous administration, the maximum therapeutic effect of verapamil occurs after 3-5 minutes. With intravenous administration of Verapamil at a standard therapeutic dose (5-10 mg), a transient, most often asymptomatic, decrease in normal blood pressure, systemic vascular resistance, and contractility is observed. A slight increase in the filling pressure of the left ventricle was recorded.

Pharmacokinetics

When taken orally:

• absorption: about 90-92% of the drug is absorbed in the gastrointestinal tract. The bioavailability of verapamil is low (approximately 20%), which is explained by the effect of the first passage through the liver. The content in the blood plasma increases gradually. The maximum plasma concentration is 81.34 ng / ml. The average time to reach the maximum concentration is 4.75 hours. 1 day after taking the drug, sufficiently high therapeutic concentrations (51.6 ng / ml) are found in the blood plasma. Communication with plasma proteins - about 90%;
• distribution: when taking a single dose, the half-life is from 2.8 to 7.4 hours, and when the drug is taken again, from 4.5 to 12 hours. In elderly patients, the half-life increases. Verapamil crosses the blood-brain and placental barriers, is excreted into breast milk;
• metabolism: metabolized in the liver (first pass effect). 12 verapamil metabolites have been identified, the main of which is the pharmacologically active norverapamil. Other metabolites are mostly inactive;
• excretion: approximately 70% of the dose of Verapamil is excreted in the urine, and approximately 16% or more is excreted in the feces for 5 days after oral administration of the drug. In unchanged form, 3-4% is excreted from the body.

When administered intravenously:

• distribution: verapamil is well distributed in body tissues. In healthy volunteers, the volume of distribution ranges from 1.6 to 1.8 l/kg. About 90% binds to plasma proteins;
• Metabolism: In vitro metabolic studies have shown that verapamil is metabolized by CYP1A2, CYP3A4, CYP2C8, CYP2C18 and CYP2C9 isoenzymes of the cytochrome P 450 family. When administered orally to healthy volunteers, verapamil was extensively metabolized in the liver to form 12 metabolites, most of which were present in trace amounts. The main metabolites include the O- and N-dealkylated forms of verapamil derivatives. Studies in dogs have shown that only norverapamil is the pharmacologically active metabolite (about 20% of the parent compound). Verapamil crosses the blood-brain and placental barriers, is excreted in small amounts into breast milk;
• excretion: the curve of change in the content of verapamil in the blood has a biexponential character with a fast early phase of distribution (half-life - about 4 minutes), as well as a slower terminal phase of elimination (half-life - from 2 to 5 hours). Within 24 hours, approximately 50% of the dose of the drug is excreted by the kidneys, within 5 days - 70%. About 16% of the dose of verapamil is excreted through the intestines. In unchanged form, 3-4% of verapamil is excreted from the body. The total clearance of verapamil approximately corresponds to the hepatic blood flow - about 1 l / h / kg (range from 0.7 to 1.3 l / h / kg).

In case of impaired renal function, the pharmacokinetic parameters of verapamil do not change, which was recorded during studies in two groups of patients: without impaired renal function and with renal failure in the terminal stage. Norverapamil and verapamil are not excreted by hemodialysis.

The age indicator may change the pharmacokinetic parameters of verapamil in the case of its use in patients with arterial hypertension. In elderly patients, the elimination half-life may be increased. The relationship between age and the antihypertensive effect of the drug has not been identified.

Indications for use

Pills

• Heart rhythm disorders, including paroxysmal supraventricular tachycardia, atrial fibrillation and flutter (tachyarrhythmic variant), supraventricular extrasystole - for treatment and prevention;
• Unstable angina (rest angina), chronic stable angina (angina pectoris), vasospastic angina (variant angina, Prinzmetal's angina) - for treatment and prevention;
• Arterial hypertension - for treatment.

injection solution

Verapamil in the form of an injection solution is used to stop attacks of supraventricular paroxysmal tachycardia, atrial premature beats, paroxysms of flutter and atrial fibrillation.

Contraindications

Absolute:

• Chronic heart failure IIB-III stage;
• Morgagni-Adams-Stokes syndrome;
• Sinoatrial blockade;
• Sick sinus syndrome;
• Cardiogenic shock (other than that caused by arrhythmia) (for tablets);
• Severe bradycardia (for tablets);
• Wolff-Parkinson-White syndrome (for tablets);
• Acute heart failure (for tablets);
• Atrioventricular block II and III degree (except for patients with an artificial pacemaker) (for tablets);
• Arterial hypotension (for injection solution);
• Acute myocardial infarction (for injection solution);
• Stenosis of the aortic orifice (for injection solution);
• Digitalis intoxication (for injection solution);
• Ventricular tachycardia (for injection solution);
• Lown-Ganong-Levin syndrome or Wolff-Parkinson-White syndrome in combination with flutter or atrial fibrillation (excluding patients with a pacemaker) (for injection solution);
• Porphyria (for injection solution);
• Simultaneous therapy with intravenous administration of beta-blockers;
• Age up to 18 years;
• Pregnancy and lactation (for injection solution);
• Hypersensitivity to the components of the drug.

Relative (Verapamil should be used with caution in the presence of the following conditions/diseases):

• Atrioventricular block I degree;
• bradycardia;
• Severe functional disorders of the kidneys and liver;
• Arterial hypotension with systolic pressure below 100 mm Hg. (for tablets);
• Chronic heart failure I and II degree (for tablets) and I and IIA degree (for injection solution);
• Simultaneous reception with beta-blockers (for injection solution);
• Myocardial infarction with left ventricular failure (for injection solution);
• Old age (for injection solution).

Instructions for use Verapamil: method and dosage

Pills

Verapamil is taken orally with a small amount of water, preferably during or after a meal.

The doctor sets the dosage regimen and duration of therapy individually, depending on the patient's condition, the severity and characteristics of the course of the disease, as well as the effectiveness of the drug.

The initial adult single dose in the treatment of arterial hypertension and for the prevention of angina attacks, arrhythmias is 40-80 mg, the frequency of administration is 3-4 times a day. A single dose, if necessary, is increased to 120-160 mg (maximum - 480 mg per day).

With severe functional disorders of the liver, it is advisable to start therapy with the smallest doses (maximum - 120 mg per day).

injection solution

Verapamil should be administered intravenously, slowly, over at least 2 minutes, continuously monitoring the electrocardiogram, heart rate and blood pressure. In elderly patients, in order to reduce the risk of developing undesirable effects, the administration of the solution should be carried out for at least 3 minutes.

When arresting paroxysmal cardiac arrhythmias, Verapamil is administered intravenously in a stream of 2-4 ml of a 0.25% solution (5-10 mg), monitoring the electrocardiogram and blood pressure. In cases of no effect, it is possible to re-administer the same dose of the drug after 30 minutes. To dilute 2 ml of a 0.25% solution of Verapamil, use 100-150 ml of a 0.9% solution of sodium chloride.

Side effects

Pills

• Central nervous system: headache, dizziness; in rare cases - lethargy, increased nervous excitability, increased fatigue;
• Digestive system: vomiting, nausea, constipation; in some cases - a transient increase in the activity of hepatic transaminases in the blood plasma;
• Cardiovascular system: redness of the face, AV blockade, severe bradycardia, arterial hypotension, the appearance of symptoms of heart failure (when using high doses of the drug, especially in predisposed patients);
• Allergic reactions: itching, skin rash;
• Other: peripheral edema.

injection solution

• Digestive system: nausea, increased activity of hepatic transaminases and alkaline phosphatase;
• Central nervous system: increased fatigue, anxiety, headache, dizziness, fainting, extrapyramidal disorders, lethargy, asthenia, depression, drowsiness;
• Cardiovascular system: severe bradycardia (not less than 50 beats per minute), a pronounced decrease in blood pressure, aggravation or development of heart failure, tachycardia; possibly - the development of angina pectoris, up to myocardial infarction (especially in patients with severe obstructive lesions of the coronary arteries), arrhythmias (including flutter and ventricular fibrillation); with the rapid introduction of the solution - asystole, atrioventricular blockade of the III degree, collapse;
• Allergic reactions: flushing of the skin of the face, rash, pruritus, erythema multiforme exudative (including Stevens-Johnson syndrome);
• Others: pulmonary edema, transient loss of vision against the background of maximum concentration, asymptomatic thrombocytopenia, peripheral edema (including swelling of the ankles, legs and feet).

Overdose

Symptoms: marked decrease in blood pressure (sometimes to a level that cannot be measured), loss of consciousness, shock, escape rhythm, atrioventricular block I or II degree (wenckebach periods are often observed with or without escape rhythm), complete atrioventricular block, accompanied by complete atrioventricular dissociation, cardiac arrest, sinus arrest, sinus bradycardia, heart failure, sinoatrial block, asystole.

In case of early detection (it should be borne in mind that when taken orally, the release and absorption of verapamil in the intestine occurs within 2 days), gastric lavage is prescribed if no more than 12 hours have passed since the application. With reduced motility of the gastrointestinal tract (in the absence of intestinal noises), this measure can be carried out in later periods.

Treatment is symptomatic and depends on the clinical picture of the overdose.

Calcium is a specific antidote. For the treatment of overdose, a solution of calcium gluconate 10% (10–30 ml) is administered intravenously or slowly as a drip infusion. If necessary, the procedure can be repeated.

With sinus bradycardia, atrioventricular block II and III degree, cardiac arrest, isoprenaline, atropine, orciprenaline, or cardiac stimulation are indicated.

With arterial hypotension, norepinephrine (norepinephrine), dobutamine, dopamine are prescribed. Hemodialysis is ineffective.

special instructions

During therapy, it is necessary to control the function of the respiratory and cardiovascular systems, the level of electrolytes and glucose in the blood, the amount of urine excreted and the volume of circulating blood.

With intravenous administration of Verapamil, a prolongation of the PQ interval is possible at plasma concentrations above 30 mg / ml.

Verapamil should be used with caution by drivers of vehicles and people whose profession is associated with increased concentration of attention (due to a decrease in the reaction rate).

Use during pregnancy and lactation

According to the instructions, Verapamil is contraindicated during pregnancy and lactation.

There are no data on the use of the drug in pregnant women.

In animal studies, direct or indirect toxic effects on the reproductive system have not been identified. Since the results of animal studies do not reliably predict the response to drug therapy in humans, Verapamil can be used during pregnancy only in cases where the potential benefit to the mother is higher than the expected risk to the child.

The drug is characterized by penetration through the placental barrier, it is also found in the blood of the umbilical vein during childbirth.

Verapamil and metabolites are excreted into breast milk. According to the limited data available, the dose of Verapamil that an infant receives with milk is quite low (from 0.1 to 1% of the amount of Verapamil taken by the mother). Since the possibility of complications for infants cannot be excluded, the drug can be used during breastfeeding only in cases where the potential benefit to the mother is higher than the expected risk to the child.

Application in childhood

It is forbidden to use Verapamil for the treatment of patients under the age of 18 years.

For impaired renal function

In severe renal insufficiency, the drug should be used with caution, prescribing a lower initial dose.

For impaired liver function

In case of impaired liver function and severe liver failure, the drug should be used with caution, prescribing a lower initial dose.

Use in the elderly

drug interaction

With the simultaneous use of Verapamil with certain drugs, the following effects may occur:

• Antiarrhythmic drugs, beta-blockers and inhalation anesthetics: increased cardiotoxic effect (the risk of developing atrioventricular blockade, a sharp decrease in heart rate, the development of heart failure, a sharp decrease in blood pressure increases);
• Antihypertensive agents and diuretics: increased hypotensive effect of Verapamil;
• Digoxin: an increase in the level of concentration of digoxin in the blood plasma (to determine the optimal dosage of the drug and prevent intoxication, its level in the blood plasma should be monitored);
• Cimetidine and ranitidine: an increase in the level of concentration of Verapamil in the blood plasma;
• Theophylline, prazosin, cyclosporine: an increase in their concentration in blood plasma;
• Muscle relaxants: increased muscle relaxant action;
• Rifampicin, phenobarbital: a decrease in the concentration of Verapamil in the blood plasma and a weakening of its action;
• Acetylsalicylic acid: increased likelihood of bleeding;
• Quinidine: an increase in the level of concentration of quinidine in the blood plasma, an increased risk of lowering blood pressure, with hypertrophic cardiomyopathy - the development of severe arterial hypotension;
• Carbamazepine, lithium: increased risk of neurotoxic effects.

Analogues

Analogues of Verapamil are: Isoptin, Isoptin CP 240, Caveril, Finoptin, Lecoptin, Gallopamil, Verapamil Sopharma, Verapamil-Eskom, Nifedipine, Nifedipine Retard, Amlodipine, Nicardipine, Riodipine, Nimodipine.

Terms and conditions of storage

Store in a dark, dry place out of the reach of children at temperatures up to 25 °C.

Shelf life - 3 years.