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Composition:


active ingredient: verapamil hydrochloride;


1 tablet contains verapamil hydrochloride 240 mg;


excipients: microcrystalline cellulose, sodium alginate, povidone, magnesium stearate, purified water, hypromellose, macrogol 400, macrogol 6000, talc, titanium dioxide (e 171), Quinoline yellow (E 104) + indigotine (e 132) (aluminum varnish E104 + E 132), montane glycol wax.


Dosage form. Long-acting tablets.


Basic physical and chemical properties: Film-coated tablets, light green in color, oblong in shape, have transverse dashes on both sides; on one side – embossed with two company logos.


Pharmacotherapeutic group. Selective calcium channel blockers with direct effects on the heart, phenylalkylamine derivatives. ATX code C08D A01.


Pharmacological properties.


Pharmacodynamics.


Verapamil blocks the transmembrane flow of calcium ions into cardiomyocytes and vascular smooth muscle cells. It directly reduces the need for oxygen in the myocardium by affecting the energy-consuming processes of metabolism in myocardial cells and indirectly affects the reduction of afterload. By blocking the calcium channels of the smooth muscle cells of the coronary arteries, blood flow to the myocardium increases, even in post-stenotic areas, and spasm of the coronary arteries is eliminated. The antihypertensive efficacy of verapamil is due to a decrease in peripheral vascular resistance without an increase in heart rate as a reflex response. Undesirable changes in the physiological values of blood pressure are not observed. Verapamil has a pronounced antiarrhythmic effect, especially in supraventricular arrhythmia. It delays the conduction of the pulse in the atrioventricular node, as a result of which, depending on the type of arrhythmia, the sinus rhythm is restored and/or the frequency of ventricular contractions is normalized. The normal level of heart rate does not change or decreases slightly.


Pharmacokinetics.


Verapamil Hydrochloride is a racemic mixture consisting of equal parts of the R-enantiomer and S-enantiomer. Verapamil is actively metabolized. Norverapamil is one of the 12 metabolites detected in the urine, has 10-20% of the pharmacological activity of verapamil and makes up 6% of the excreted drug. The equilibrium concentrations of norverapamil and verapamil in blood plasma are the same. The equilibrium concentration is reached 3-4 days after repeated administration of the drug 1 time a day.


Absorption


More than 90% of verapamil after oral administration is rapidly and almost completely absorbed in the small intestine. The average bioavailability after a single dose of long-acting verapamil is approximately 33 %, which is explained by extensive metabolism during the first passage through the liver. Bioavailability increases by 2 times after repeated administration.


After taking long – acting verapamil, the maximum concentration of verapamil in blood plasma is reached in 4-5 hours, norverapamil-in 5 hours. Food intake does not affect the bioavailability of verapamil.


Distribution


Verapamil is widely distributed in the body's tissues, with a volume of distribution ranging from 1.8 to 6.8 l/kg in healthy volunteers. The Binding of verapamil to plasma proteins is approximately 90 %.


Metabolism


Verapamil is actively metabolized. After oral administration by healthy male volunteers, verapamil hydrochloride underwent intensive metabolism in the liver with the formation of 12 metabolites, most of which were determined in trace amounts. The main metabolites were identified as various N - and O-dealkylated products of verapamil. Among these metabolites, only norverapamil has a pharmacological effect (approximately 20% of the initial compound), which was established in studies in dogs.


Output


After oral administration, the elimination half-life is 3-7 hours. About 50% of the administered dose is excreted by the kidneys within 24 hours, 70% – within 5 days. Up to 16% of the dose is excreted in the faeces. About 3-4% of the drug excreted by the kidneys is excreted unchanged. The total clearance of verapamil is almost as high as the hepatic blood flow and is approximately 1 L/H/kg (range 0.7 – 1.3 L/H/kg).


Special patient groups


Children. Data on the pharmacokinetics of verapamil in children are limited. After oral administration of the drug, steady-state plasma concentrations are slightly lower in children compared to adults.


Elderly patients. Age may affect the pharmacokinetics of verapamil in patients with arterial hypertension. The elimination half-life may be extended in elderly patients. It was found that the antihypertensive effect of verapamil does not depend on age.


Patients with renal insufficiency. Impaired renal function does not affect the pharmacokinetics of verapamil, which has been demonstrated in comparative studies in patients with end-stage renal failure and individuals with normal renal function. Verapamil and norverapamil are not removed by hemodialysis.


Patients with hepatic insufficiency. The elimination half-life increases in patients with impaired liver function due to low clearance and large volume of distribution.


Clinical characteristics.


Indications.


Coronary heart disease, including: stable tension angina; unstable angina (progressive angina, resting angina); vasospastic angina (variant angina, Prinzmetal angina); post-infarction angina in patients without heart failure, if b-blockers are not indicated. Arrhythmias: paroxysmal supraventricular tachycardia; atrial flutter/flicker with rapid atrioventricular conduction (except for Wolf – Parkinson – White syndrome (WPW). Arterial hypertension.

Contraindications.


Hypersensitivity to verapamil or to any other component of the drug. Cardiogenic shock. Grade II or III atrioventricular block (except in patients with a functioning artificial pacemaker). Sinus node weakness syndrome (except for patients with a functioning artificial pacemaker). Heart failure with a decrease in the ejection fraction of less than 35% and/or pulmonary artery jamming pressure above 20 mm Hg. St. (except in cases where these conditions are secondary to supraventricular tachycardia, which can be treated with verapamil). Atrial fibrillation / flutter in the presence of additional pathways (for example, WPW syndrome and LGL syndrome). In such patients, when using verapamil hydrochloride, there is a risk of developing ventricular tachyarrhythmia, including ventricular fibrillation. Use in combination with ivabradine (see "interactions with other drugs and other types of interactions"). During treatment with isoptin ® SR, do not use concomitant intravenous beta-blockers (except in intensive care).

Interactions with other drugs and other types of interactions.


In vitro studies of verapamil hydrochloride metabolism have shown that it is metabolized by cytochrome P450 CYP3A4, CYP1A2, CYP2C8, CYP2C9, and CYP2C18. verapamil is an inhibitor of CYP3A4 and P-glycoprotein (P-gp) enzymes. Clinically important interactions with CYP3A4 inhibitors have been reported, which were accompanied by an increase in plasma verapamil levels, while CYP3A4 inducers caused a decrease in plasma verapamil hydrochloride levels, so it is necessary to monitor interactions with other drugs. Concomitant use of verapamil and drugs that are mainly metabolized by CYP3A4 or are a substrate of P-gp may be associated with increased drug concentrations, which may increase or prolong both the therapeutic and adverse effects of the concomitant drug.


Potential interactions related to pharmacokinetics


Prazosin: increased Cmax of prazosin (~40%) without affecting the elimination half-life. Additive hypotensive effect.


Terazosin: increased AUC (~24 %) and CMax (~25 %) of terazosin. Additive hypotensive effect. Quinidine: reduced clearance of quinidine (~35 %) when taken orally. Hypotension may develop, and pulmonary edema may occur in patients with hypertrophic obstructive cardiomyopathy.


Flecainide: minimal effect on plasma clearance of flecainide (


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


Carbamazepine: increased carbamazepine AUC (~46%) in patients with refractory partial epilepsy; increased carbamazepine levels, which may cause carbamazepine side effects such as diplopia, headache, ataxia, or dizziness.


Phenytoin: decrease in the concentration of verapamil in blood plasma.


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


Glyburide: increased Cmax of glyburide by approximately 28%, AUC – by 26%.


Metformin: concomitant use of verapamil with metformin may reduce the effectiveness of metformin.


Colchicine: an increase in the AUC (approximately 2 times) and CMax (approximately 1.3 times) of colchicine. It is recommended to reduce the dose of colchicine (see the instructions for medical use of colchicine).


Clarithromycin, erythromycin, telithromycin: verapamil levels may increase.


Rifampicin: it is possible to reduce the hypotensive effect. Reduced AUC (~97 %), Cmax (~94%), and bioavailability after oral administration (~92 %) of verapamil.


Doxorubicin: concomitant administration of doxorubicin and verapamil (orally) increases the AUC (~104 %) and CMax (~61 %) of doxorubicin in patients with small cell lung cancer.


Phenobarbital increases the oral clearance of verapamil by 5 times.


Buspirone: increase the AUC and CMax of buspirone by 3.4 times.


Midazolam: increase the AUC of midazolam by 3 times and CMax by 2 times.

Application features.


Acute myocardial infarction


The drug should be used with caution in patients with acute myocardial infarction complicated by bradycardia, severe hypotension or left ventricular dysfunction.


Cardiac Block/ Grade I atrioventricular block/ bradycardia/ asystole


Verapamil hydrochloride affects the atrioventricular and sinoatrial nodes and prolongs the time of atrioventricular conduction. Use with caution, due to the fact that the development of atrioventricular block II or III degree (which is a contraindication) or single-beam, double-beam or three-beam block of the GIS leg requires discontinuation of subsequent doses of verapamil hydrochloride and the appointment of appropriate therapy if necessary.


Verapamil hydrochloride affects the atrioventricular and sinoatrial nodes and very rarely can provoke the occurrence of atrioventricular block II or III degree, bradycardia and extremely rarely – asystole. Such symptoms are more likely to occur in patients with sinus node weakness syndrome (sinoatrial nodular disease), which is more common in elderly patients.


Asystole in patients who do not have sinus node weakness syndrome is usually short-lived (a few seconds or less), with a spontaneous return to atrioventricular nodular or normal sinus rhythm. If this phenomenon is not fleeting, appropriate therapy should be initiated immediately (see the section "adverse reactions").


Antiarrhythmic drugs, b-blockers


Mutual increase in cardiovascular effects (increased degree of atrioventricular block, significant decrease in heart rate, occurrence of heart failure, significant decrease in blood pressure). Asymptomatic bradycardia (36 beats/min) with a wandering atrial pacemaker was observed in patients who received concomitant therapy with eye drops with timolol (b-blocker) during treatment with verapamil hydrochloride.


Digoxin


When verapamil is co-administered with digoxin, the dose of digoxin should be reduced (see the section "interactions with other drugs and other types of interactions").


Heart failure


Before starting treatment with verapamil, it is necessary to compensate for heart failure in patients with an ejection fraction greater than 35% and adequately monitor the entire treatment period.


HMG-CoA reductase inhibitors (statins)


See the section "interactions with other drugs and other types of interactions".


Neuromuscular conduction disorders


Verapamil hydrochloride should be used with caution in the presence of diseases with neuromuscular conduction disorders (myasthenia gravis, Lambert-Eaton syndrome, progressive Duchenne Muscular Dystrophy).


Kidney failure


Although data from confirmed comparative studies have shown that renal failure does not affect the pharmacokinetics of verapamil in patients with end-stage renal failure, there have been several reports suggesting that patients with renal insufficiency should use verapamil with caution and under close supervision. Verapamil is not eliminated by hemodialysis.


Liver failure


Patients with significant hepatic impairment should use verapamil with caution (see the section "dosage and administration").


Use during pregnancy or lactation.


There are no clear and well-studied data on the use of the drug in pregnant women. Animal studies have not found any direct or indirect harmful effects on reproductive toxicity. Since data obtained from animal reproductive studies cannot always be extrapolated to humans, the drug should only be used during pregnancy if absolutely necessary.


Verapamil passes through the placenta and is detected in cord blood.


Verapamil and its metabolites pass into breast milk. Limited data on oral administration in humans indicate that the dose of verapamil that enters the newborn's body is low (0.1–1% of the dose taken by the mother), so the use of verapamil can be combined with breast-feeding, but the risk for newborns cannot be excluded. Given the risk of serious adverse reactions in breast-fed newborns, verapamil during breast-feeding can only be used if absolutely necessary for the mother.


Ability to influence the reaction rate when driving vehicles or other mechanisms.


Due to the antihypertensive effect of verapamil hydrochloride, depending on the individual reaction, the ability to drive vehicles, work with mechanisms or work in dangerous conditions may be impaired, especially in the initial phase of treatment, when increasing the dose, when changing the antihypertensive drug, as well as when taking the drug simultaneously with alcohol. Verapamil can increase the level of alcohol in the blood plasma and slow its elimination, so the effect of alcohol can increase.


Dosage and administration.


Doses are selected individually for each adult patient. Long-term clinical experience shows that the average daily dose for all indications ranged from 240 to 360 mg per day. With prolonged use of the drug, the average daily dose should not exceed 480 mg, only a short-term increase in the dose is possible. The drug should be taken without dissolving or chewing, with a sufficient amount of liquid (for example, 1 glass of water, in no case grapefruit juice), preferably during or immediately after a meal.The tablet is divided, and you can use a half dose without changing the pharmacokinetic properties.


Coronary heart disease


The recommended dose is in the range of 240-480 mg per day, divided into 2 doses: 0.5–1 tablet of isoptin® SR twice a day. Isoptin® SR should be used when lower doses do not give the desired result.


Arterial hypertension


The recommended dose is in the range of 240-480 mg per day, divided into 2 doses. For example: 1 tablet of isoptin® SR once a day in the morning (equivalent to 240 mg of verapamil hydrochloride per day). If the response is unsatisfactory, add another 0.5–1 tablet of isoptin® SR in the evening (equivalent to 360-480 mg of verapamil hydrochloride per day).


Paroxysmal supraventricular tachycardia, atrial flutter/flicker


The recommended dose is in the range of 240-480 mg per day, divided into 2 doses: 0.5–1 tablet of isoptin® SR twice a day. Isoptin® SR should be used when lower doses do not lead to a satisfactory response.


Impaired renal function

Overdose.


Clinical manifestations: hypotension, bradycardia to high-grade atrioventricular block and sinus node arrest, hyperglycemia, stupor, metabolic acidosis and acute respiratory distress syndrome. Overdose deaths have been reported.


Treatment of verapamil hydrochloride overdose should be mostly supportive and personalized. Beta-adrenergic stimulation and / or intravenous administration of calcium supplements (calcium chloride) are effectively used to eliminate the symptoms of deliberate overdose with oral administration of verapamil hydrochloride.


In case of significant arterial hypotension or high-grade atrioventricular block, it is necessary to use drugs that increase blood pressure (vasoconstrictors), or pacemakers, respectively. For asystole, beta-adrenergic stimulation (for example, isoproterenol hydrochloride), other vasopressors, or cardiopulmonary resuscitation should be used simultaneously with the usual measures.


Due to the possible delayed absorption of long-acting tablets, patients are recommended to be hospitalized and stay under the supervision of a doctor for 48 hours. Verapamil Hydrochloride is not eliminated by hemodialysis.


Adverse reactions.


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


For each organ system, adverse reactions are classified according to the frequency of occurrence: very often (≥1/10), often (≥1/100 to


The most common adverse reactions were headache, dizziness; gastrointestinal disorders: nausea, constipation, and abdominal pain; also bradycardia, tachycardia, palpitations, decreased blood pressure, redness/hot flashes, peripheral edema, and fatigue.


Immune system disorders: unknown-hypersensitivity.


Neurological disorders: often-dizziness, headache; rarely – paresthesia, tremor; unknown-extrapyramidal disorders, paralysis (tetraparesis)*, seizures.


Metabolic disorders, metabolism: unknown-hyperkalemia.


Mental disorders: rarely-drowsiness.


From the side of the organs of hearing and vestibular apparatus: rarely – ringing in the ears; unknown – vertigo.


From the cardiovascular system: often-bradycardia,redness / hot flashes, decreased blood pressure; infrequently – palpitations, tachycardia; unknown – atrioventricular block of I, II or III degrees, heart failure, sinus node arrest, sinus bradycardia, asystole.


From the respiratory system, chest and mediastinal organs: unknown – bronchospasm, dyspnoea.


Gastrointestinal disorders: often-nausea, constipation; infrequently – abdominal pain; rarely – vomiting, unknown – abdominal discomfort, intestinal obstruction, gum hyperplasia.


From the skin and subcutaneous tissue: rarely – hyperhidrosis; unknown – angioedema, Stevens – Johnson syndrome, erythema multiforme, maculopapular rash, alopecia, urticaria, pruritus, pruritus, Purpura.


Musculoskeletal and connective tissue disorders: unknown-myalgia, arthralgia, muscle weakness.


From the side of the kidneys and urinary system: unknown – renal failure.


From the reproductive system and mammary glands: unknown – erectile dysfunction, gynecomastia, galactorrhea.


General disorders: often-peripheral edema, infrequently – fatigue.


Laboratory parameters: unknown-increased levels of liver enzymes and serum prolactin levels.

Tags: Izoptin [Verapamil]