Anti-high blood pressure tablets verapamil. Instructions for use

A drug: VERAPAMIL

Active substance: verapamil
ATX code: C08DA01
KFG: Calcium channel blocker
Reg. number: P N011991/02
Registration date: 07/18/11
Owner reg. ID: ALKALOID (Macedonia)

DOSAGE 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, liquid water - up to 2 ml.

2 ml - colorless glass ampoules (5) - contour cell packaging (2) - cardboard packs.
2 ml - colorless glass ampoules (5) - contour cell packaging (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 smooth muscles of peripheral arteries and total peripheral vascular resistance.

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

It has an effect in angina pectoris, as well as in the treatment of angina pectoris with supraventricular rhythm disturbances. Suppresses metabilism involving cytochrome P450.

PHARMACOKINETICS

Binds to plasma proteins by 90%. Penetrates through the blood-brain and placental barrier and into breast milk (in small quantities). It is rapidly metabolized in the liver by N-dealkylation and O-demethylation to form several metabolites. The accumulation of the drug and its metabilites in the body explains the increased effect during the course of treatment. The most significant metabolite is the pharmacologically active norverapamil (20% of the antihypertensive activity of verapamil). The enzyme system CYP3 A4, CYP3 A5 and CYP3 A7 is involved in the metabolism of the drug. T 1/2 is two-phase: about 4 minutes - early and 2-5 hours - final. Excreted by the kidneys 70% (unchanged 3-5%), with bile 25%. Not excreted during hemodialysis.

INDICATIONS

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

DOSING REGIME

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

To relieve paroxysmal cardiac arrhythmias, 2-4 ml of a 0.25% solution (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 0.25% solution of the drug in 100-150 ml of a 0.9% sodium chloride solution.

SIDE EFFECT

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

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

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

Allergic reactions: skin itching, rash, hyperemia of the facial skin, 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 block;

Sick sinus syndrome;

Aortic stenosis;

Morgagni-Adams-Stokes syndrome;

Digitalis intoxication;

Atrioventricular block II and III degrees;

Ventricular tachycardia;

Cardiogenic shock;

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

Porphyria;

Pregnancy;

Lactation period;

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

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

Hypersensitivity to the components of the drug,

Carefully: atrioventricular block of the first degree, bradycardia, simultaneous use of beta-blockers, myocardial infarction with left ventricular failure, old age, chronic heart failure of degrees I and IIA, severe impairment of liver and kidney function.

PREGNANCY AND LACTATION

Contraindicated during pregnancy and lactation.

SPECIAL INSTRUCTIONS

During treatment, it is necessary to monitor 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.

Impact on the ability to drive vehicles and operate machinery

Use with caution while working for vehicle drivers and people whose profession is associated with increased concentration (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: for bradycardia and conduction disturbances - intravenous administration of isoprenaline, atropine, 10-20 ml of 10% calcium gluconate solution, artificial pacemaker; intravenous infusion of plasma replacement solutions. To increase blood pressure in patients with hypertrophic obstructive cardiomyopathy, alpha-adrenergic agonists (phenylephrine) are prescribed; Isoprenaline and norepinephric 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 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 supplements 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, reducing the severity of antianginal, hypotensive and antiarrhythmic effects.

When used simultaneously with inhalational anesthetics, the risk of developing bradycardia, atrioventricular block, and heart failure increases. Procainamide, quinidine, and other drugs that prolong the QT interval increase the risk of significant prolongation of the QT interval.

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

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

Increases the concentration of cardiac glycosides (requires careful monitoring and reduction in the dose 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 effects, including death).

Estrogens reduce the hypotensive effect due to fluid retention in the body. 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).

Medicines that lower blood pressure enhance the hypotensive effect of verapamil.

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

CONDITIONS OF VACATION FROM PHARMACIES

On prescription.

CONDITIONS AND DURATION 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 cardboard 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 cardboard box).

1 tablet contains:

• Active ingredient: verapamil hydrochloride – 40 or 80 mg;
• Auxiliary components: dibasic calcium phosphate, starch, butylated hydroxyanisole, purified talc, magnesium stearate, gelatin, methylparaben, hydroxypropyl methylcellulose, titanium dioxide, indigo carmine.

The composition of 1 ampoule of 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 slow calcium channel blocker. 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 blockade of the slow channels of the cardiac conduction system. The electrical activity of the sinoatrial and atrioventricular nodes is influenced by the entry of calcium into the cells through slow channels. Verapamil inhibits the entry of calcium, 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 reentry of excitation in the AV node and helps restore proper sinus rhythm in patients suffering from paroxysmal supraventricular tachycardia, including Wolff-Parkinson-White syndrome.

Taking Verapamil does not affect the conduction of impulses along additional 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, depolarization rate and impulse conduction in the altered atrial fibers. Verapamil does not cause spasms of peripheral arteries and does not change the total concentration of calcium in the blood serum. The active substance helps reduce afterload and myocardial contractility. The negative inotropic effect of verapamil in most patients (including those with organic heart lesions) is offset by a decrease in afterload. Usually, the cardiac index does not decrease, but in severe or moderate chronic heart failure (with 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 in 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 left ventricular filling pressure 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 first pass effect through the liver. The content in blood plasma increases gradually. The maximum concentration in blood plasma is 81.34 ng/ml. The average time to reach maximum concentration is 4.75 hours. 1 day after taking the drug, fairly high therapeutic concentrations are found in the blood plasma (51.6 ng/ml). 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 taking the drug repeatedly - from 4.5 to 12 hours. In elderly patients, the half-life increases. Verapamil crosses the blood-brain and placental barriers and is excreted into breast milk;
• metabolism: metabolized in the liver (first pass effect). 12 metabolites of verapamil have been recorded, the main of which is the pharmacologically active norverapamil. Other metabolites are largely inactive;
• excretion: approximately 70% of the taken dose of Verapamil is excreted in the urine, and approximately 16% or more is excreted in the feces within 5 days after oral administration of the drug. 3–4% is excreted unchanged from the body.

For intravenous administration:

• 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 isoenzymes CYP1A2, CYP3A4, CYP2C8, CYP2C18 and CYP2C9 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 forms of O- and N-dealkylated derivatives of verapamil. Studies on dogs revealed that only norverapamil is a pharmacologically active metabolite (about 20% compared to the parent compound). Verapamil crosses the blood-brain and placental barriers and is excreted in small quantities into breast milk;
• elimination: the curve of changes in the content of verapamil in the blood has a bi-exponential character with a fast early distribution phase (half-life - about 4 minutes), as well as a slower terminal elimination phase (half-life - from 2 to 5 hours). Within 24 hours, approximately 50% of the drug dose is excreted by the kidneys, and within 5 days – 70%. About 16% of the verapamil dose is excreted through the intestines. 3–4% of verapamil is excreted unchanged from the body. The total clearance of verapamil approximately corresponds to the hepatic blood flow - about 1 l/h/kg (range 0.7 to 1.3 l/h/kg).

When renal function is impaired, the pharmacokinetic parameters of verapamil do not change, which was recorded in studies in two groups of patients: without impaired renal function and with end-stage renal failure. Norverapamil and verapamil are not eliminated by hemodialysis.

Age may change the pharmacokinetic parameters of verapamil when used in patients with arterial hypertension. In elderly patients, the half-life may be prolonged. The relationship between age and the antihypertensive effect of the drug has not been identified.

Indications for use

Pills

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

Injection solution

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

Contraindications

Absolute:

• Chronic heart failure stage IIB-III;
• Morgagni-Adams-Stokes syndrome;
• Sinoatrial block;
• Sick sinus syndrome;
• Cardiogenic shock (except 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 degrees (except for patients with an artificial pacemaker) (for tablets);
• Arterial hypotension (for injection solution);
• Acute myocardial infarction (for injection solution);
• Aortic stenosis (for injection solution);
• Digitalis intoxication (for injection solution);
• Ventricular tachycardia (for injection solution);
• Lown-Ganong-Levine syndrome or Wolff-Parkinson-White syndrome in combination with atrial flutter or fibrillation (excluding patients with a pacemaker) (for injection solution);
• Porphyria (for injection solution);
• Simultaneous therapy with intravenous 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):

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

Instructions for use of Verapamil: method and dosage

Pills

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

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 for the treatment of arterial hypertension and for the prevention of attacks of angina pectoris and arrhythmia 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).

In case of severe functional disorders of the liver, it is advisable to start therapy with the lowest 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 solution should be administered over at least 3 minutes.

When stopping paroxysmal heart rhythm disturbances, 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 0.25% Verapamil solution, use 100-150 ml of 0.9% sodium chloride solution.

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 liver transaminases in the blood plasma;
• Cardiovascular system: facial flushing, AV block, 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 liver transaminases and alkaline phosphatase;
• Central nervous system: increased fatigue, anxiety, headache, dizziness, fainting, extrapyramidal disorders, lethargy, asthenia, depression, drowsiness;
• Cardiovascular system: severe bradycardia (at least 50 beats per minute), marked decrease in blood pressure, worsening or development of heart failure, tachycardia; possible – 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 rapid administration of the solution – asystole, third degree atrioventricular block, collapse;
• Allergic reactions: facial skin flushing, rash, itching, exudative erythema multiforme (including Stevens-Johnson syndrome);
• Other: 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, first or second degree atrioventricular block (Wenckebach periods with or without escape rhythm are often observed), complete atrioventricular block accompanied by complete atrioventricular block dissociation, cardiac arrest, sinus node arrest, sinus bradycardia, heart failure, sinoatrial block, asystole.

In case of early detection (it should be taken into account 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 administration. With reduced motility of the gastrointestinal tract (in the absence of bowel sounds), this measure can be carried out in later periods.

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

The specific antidote is calcium. To treat an overdose, a 10% calcium gluconate solution (10–30 ml) is administered intravenously or slowly as a drip infusion. If necessary, the procedure can be repeated.

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

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

special instructions

During therapy, it is necessary to monitor 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, an extension of the PQ interval is possible at plasma concentrations above 30 mg/ml.

Verapamil should be used with caution by vehicle drivers and people whose profession involves increased concentration (due to a decrease in reaction speed).

Use during pregnancy and lactation

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

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

In animal studies, no direct or indirect toxic effects on the reproductive system were detected. 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 greater than the estimated risk to the child.

The drug is characterized by penetration through the placental barrier, and 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 available data, the dose of Verapamil that an infant receives via milk is quite low (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 may be used during breastfeeding only in cases where the potential benefit to the mother is higher than the expected risk to the child.

Use in childhood

Verapamil should not be used to treat patients under 18 years of age.

For impaired renal function

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

For liver dysfunction

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

Use in old age

Drug interactions

When Verapamil is used simultaneously with certain medications, the following effects may occur:

• Antiarrhythmic drugs, beta-blockers and inhalational anesthetics: increased cardiotoxic effect (increases the risk of developing atrioventricular block, a sharp decrease in heart rate, the development of heart failure, a sharp decrease in blood pressure);
• Antihypertensive drugs and diuretics: increased hypotensive effect of Verapamil;
• Digoxin: increase in the 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: increase in the concentration of Verapamil in the blood plasma;
• Theophylline, prazosin, cyclosporine: increase in their concentration in blood plasma;
• Muscle relaxants: increased muscle relaxant effect;
• Rifampicin, phenobarbital: decreasing the concentration of Verapamil in the blood plasma and weakening its effect;
• Acetylsalicylic acid: increased likelihood of bleeding;
• Quinidine: an increase in the level of quinidine concentration in the blood plasma, an increased risk of lowering blood pressure, and in hypertrophic cardiomyopathy - the development of severe arterial hypotension;
• Carbamazepine, lithium: increased risk of developing neurotoxic effects.

Analogs

Analogues of Verapamil are: Isoptin, Isoptin SR 240, Kaveril, Finoptin, Lekoptin, Gallopamil, Verapamil Sopharma, Verapamil-Eskom, Nifedipine, Nifedipine Retard, Amlodipine, Nicardipine, Riodipine, Nimodipine.

Terms and conditions of storage

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

Shelf life – 3 years.