Isoptin^® (Tablets, Solution) Instructions for Use

ATC Code

C08DA01 (Verapamil)

Active Substance

Verapamil (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Calcium channel blocker

Pharmacotherapeutic Group

BMCC (Bone Mineral Crystal Complex)

Pharmacological Action

Selective class I calcium channel blocker, a derivative of diphenylalkylamine. It has antianginal, antiarrhythmic, and antihypertensive action.

The antianginal effect is associated both with a direct action on the myocardium and with an influence on peripheral hemodynamics (lowers the tone of peripheral arteries, total peripheral vascular resistance). Blockade of calcium entry into the cell leads to a decrease in the transformation of the energy contained in the macroergic bonds of ATP into mechanical work, and a decrease in myocardial contractility. It reduces the myocardial oxygen demand, has a vasodilating, negative inotropic and chronotropic effect. It increases the period of diastolic relaxation of the left ventricle and reduces the tone of the myocardial wall.

The antihypertensive effect of verapamil may also be due to a decrease in total peripheral vascular resistance.

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

Pharmacokinetics

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

T_1/2 after a single dose is 2.8-7.4 hours, after repeated doses – 4.5-12 hours (due to saturation of liver enzyme systems and an increase in the concentration of verapamil in plasma). After IV administration, the initial T_1/2 is about 4 minutes, the terminal T_1/2 is 2-5 hours.

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

Indications

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

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

Arterial hypertension. Hypertensive crisis.

Hypertrophic cardiomyopathy.

ICD codes

Dosage Regimen

Tablets, Solution

Individual. Orally for adults – in an initial dose of 40-80 mg 3 times/day. For prolonged-release dosage forms, the single dose should be increased and the frequency of administration decreased. For 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 IV bolus (slowly, under 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 in 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.

Maximum daily dose for adults when taken orally is 480 mg.

Adverse Reactions

From the cardiovascular system bradycardia (less than 50 beats/min), pronounced 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 coronary artery disease), arrhythmia (including ventricular fibrillation and flutter); with rapid IV administration – third-degree AV block, asystole, collapse.

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

From the digestive system nausea, constipation (rarely – diarrhea), gingival hyperplasia (bleeding, soreness, swelling), increased appetite, increased activity of hepatic transaminases and alkaline phosphatase.

Allergic reactions skin itching, skin rash, facial skin hyperemia, multiform exudative erythema (including Stevens-Johnson syndrome).

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

Contraindications

Cardiogenic shock, heart failure, severe impairment of left ventricular contractile function, severe arterial hypotension (systolic blood pressure less than 90 mm Hg), bradycardia; sick sinus syndrome, sinoatrial block, second and third-degree AV block (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 period (breastfeeding); hypersensitivity to verapamil.

Use in Pregnancy and Lactation

Verapamil is contraindicated during pregnancy and lactation.

Use in Hepatic Impairment

Should be used with caution in hepatic insufficiency.

Use in Renal Impairment

Should be used with caution in renal insufficiency.

Pediatric Use

Should be used with caution in children and adolescents under 18 years of age (efficacy and safety of use have not been studied).

Geriatric Use

Should be used with caution in elderly patients.

Special Precautions

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

If necessary, combined therapy of angina and arterial hypertension with verapamil and beta-adrenergic blockers is possible. However, IV administration of beta-adrenergic blockers against the background of verapamil use should be avoided.

Effect on the ability to drive vehicles and machinery

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

Drug Interactions

With simultaneous use with antihypertensive drugs (vasodilators, thiazide diuretics, ACE inhibitors), mutual enhancement of the antihypertensive effect occurs.

With simultaneous use with beta-adrenergic blockers, antiarrhythmic drugs, agents for inhalation anesthesia, the risk of developing bradycardia, AV block, severe arterial hypotension, and heart failure increases, due to mutual enhancement of the inhibitory effect on sinoatrial node automaticity and AV conduction, myocardial contractility and conduction.

With parenteral administration of verapamil to patients who have recently received beta-adrenergic blockers, there is a risk of developing arterial hypotension and asystole.

With simultaneous use with nitrates, the antianginal effect of verapamil is enhanced.

With simultaneous use with aliskiren, its plasma concentration increases and the risk of side effects increases.

With simultaneous use with amiodarone, negative inotropic effect, bradycardia, conduction disturbance, AV block are enhanced.

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

With simultaneous use with acetylsalicylic acid, cases of increased bleeding time due to an additive antiplatelet effect have been described.

With simultaneous use with buspirone, the plasma concentration of buspirone increases, and its therapeutic and side effects are enhanced.

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

With simultaneous use with digitoxin, cases of increased plasma concentration of digitoxin have been described.

With simultaneous use with digoxin, the plasma concentration of digoxin increases.

With simultaneous use with disopyramide, severe arterial hypotension and collapse are possible, especially in patients with cardiomyopathy or decompensated heart failure. The risk of severe manifestations of drug interaction is apparently associated with an enhancement of the negative inotropic effect.

With simultaneous use with diclofenac, the plasma concentration of verapamil decreases; with doxorubicin – the plasma concentration of doxorubicin increases and its effectiveness increases.

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

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

With simultaneous use with clonidine, cases of cardiac arrest in patients with arterial hypertension have been described.

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

With simultaneous use with lithium carbonate, the manifestations of drug interaction are ambiguous and unpredictable. Cases of enhanced effects of lithium and development of neurotoxicity, decreased plasma concentration of lithium, and severe bradycardia have been described.

The vasodilating effect of alpha-adrenergic blockers and calcium channel blockers may be additive or synergistic. With simultaneous use of terazosin or prazosin and verapamil, the development of pronounced 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 efficacy.

With simultaneous use with sertindole, the risk of developing ventricular cardiac arrhythmias, especially torsades de pointes ventricular arrhythmia, increases.

With simultaneous use, the plasma concentration of theophylline increases.

With simultaneous use with tubocurarine chloride, vecuronium chloride, enhancement of the muscle relaxant effect is possible.

With simultaneous use with phenytoin, phenobarbital, a significant decrease in the plasma concentration of verapamil is possible.

With simultaneous use with fluoxetine, the side effects of verapamil are enhanced due to slowing of its metabolism under the influence of fluoxetine.

With simultaneous use, the clearance of quinidine decreases, its plasma concentration 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 concentration. This is accompanied by an enhancement of the immunosuppressive effect; a decrease in the manifestations of nephrotoxicity has been noted.

With simultaneous use with cimetidine, the effects of verapamil are enhanced.

With simultaneous use with enflurane, prolongation of anesthesia is possible.

With simultaneous use with etomidate, the duration of anesthesia increases.

Storage Conditions

Store at 15°C (59°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.