Verapamil-darnitsa

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT VERAPAMIL-DARNITSA (VERAPAMIL-DARNITSA)

Composition:

active substance: verapamil;

1 ml of solution contains verapamil hydrochloride 2.5 mg;

excipients: sodium chloride, citric acid monohydrate, sodium hydroxide, hydrochloric acid diluted (1 M), water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear, colorless liquid.

Pharmacotherapeutic group.

Selective calcium antagonists with predominant action on the heart. ATC code C08DA01.

Pharmacological Properties.

Pharmacodynamics.

Verapamil, the active substance of the medicinal product, blocks transmembrane calcium ion influx into cardiac cells and vascular smooth muscle cells. It directly reduces myocardial oxygen demand by affecting energy-consuming metabolic processes in myocardial cells and by reducing afterload.

By blocking calcium channels in the smooth musculature of coronary arteries, blood flow to the myocardium is enhanced, even in post-stenotic areas, and coronary artery spasm is relieved. These properties determine the anti-ischemic and antianginal efficacy of the medicinal product in all forms of ischemic heart disease.

The antihypertensive efficacy of the medicinal product is due to reduced peripheral vascular resistance without increasing heart rate as a reflex response. No undesirable changes in physiological blood pressure values are observed.

The medicinal product exerts a pronounced antiarrhythmic effect, particularly in supraventricular arrhythmias. It delays impulse conduction in the atrioventricular node, thereby restoring sinus rhythm and/or normalizing ventricular rate, depending on the type of arrhythmia.

Pharmacokinetics.

Approximately 90% of verapamil binds to plasma proteins. Due to extensive metabolism, verapamil forms a large number of metabolites. Among these metabolites, only norverapamil is pharmacologically active (approximately 20% of the antihypertensive activity of verapamil). After intravenous administration, the elimination half-life of verapamil is biphasic: an initial phase of about 4 minutes and a terminal phase of 2–5 hours. Antiarrhythmic effects develop within 1–5 minutes (usually less than 2 minutes) after intravenous administration, while hemodynamic effects occur within 3–5 minutes. After intravenous administration, the antiarrhythmic effect lasts approximately 2 hours, and the hemodynamic effect lasts 10–20 minutes. In patients with impaired liver function, verapamil elimination is prolonged. Approximately 70% of verapamil hydrochloride is excreted by the kidneys as metabolites, with only 3–4% of the drug excreted unchanged. Therefore, renal impairment does not significantly affect verapamil pharmacokinetics. Approximately 16% of verapamil is excreted in feces.

Clinical characteristics.

Indications.

Paroxysmal supraventricular tachycardia; atrial flutter/fibrillation (except Wolff-Parkinson-White (WPW) syndrome).

Unstable angina in patients contraindicated for nitrates and/or β-adrenoblockers, including vasospastic angina, variant angina, Prinzmetal's angina.

Arterial hypertension; hypertensive crisis.

In pediatric practice – for paroxysmal supraventricular tachycardia.

Contraindications.

• Cardiogenic shock.
• Acute phase of myocardial infarction with complications (bradycardia, arterial hypotension, heart failure).
• Severe conduction disturbances: sinoatrial or atrioventricular block of grade II and III, except in patients with implanted artificial pacemaker.
• Bradycardia with heart rate less than 50 beats/min, arterial hypotension with blood pressure below 90 mm Hg.
• Sick sinus syndrome, except in patients with implanted artificial pacemaker.
• Decompensated heart failure.
• Atrial flutter/fibrillation associated with Wolff-Parkinson-White syndrome (risk of ventricular tachycardia).
• Hypersensitivity to verapamil or to any other component of the medicinal product.

Intravenous administration is contraindicated in patients receiving β-adrenoblockers (except during resuscitation procedures).

In cases of acute coronary insufficiency, intravenous administration of the drug must be carefully justified (myocardial infarction must be excluded), and close monitoring of the patient is required.

Interaction with other medicinal products and other types of interactions.

Verapamil hydrochloride is metabolized by cytochrome P450 CYP3A4, CYP1A2, CYP2C8, CYP2C9, and CYP2C18. Verapamil is an inhibitor of CYP3A4 enzymes and P-glycoproteins (P-gp). Clinically significant interactions have been reported with CYP3A4 inhibitors, which were associated with increased plasma levels of verapamil, whereas CYP3A4 inducers caused decreased plasma levels of verapamil hydrochloride; therefore, monitoring for interactions with other medicinal products is necessary.

Antiarrhythmic agents, β-adrenoblockers: mutual enhancement of cardiovascular effects (high-grade AV block, significant decrease in heart rate, development of heart failure, significant reduction in blood pressure).

Quinidine: reduction of oral clearance of quinidine (~35%). Arterial hypotension may develop; in patients with hypertrophic obstructive cardiomyopathy – pulmonary edema.

Flecainide: minimal effect on plasma clearance of flecainide (< ~10%); no effect on plasma clearance of verapamil.

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

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

Antihypertensive agents, diuretics, vasodilators: enhanced hypotensive effect.

Prazosin, terazosin: additional hypotensive effect (prazosin: increase in Cmax of prazosin (~40%) without affecting elimination half-life; terazosin: increase in AUC of terazosin (~24%) and Cmax (~25%)).

Antiviral (HIV) agents: plasma concentrations of verapamil may increase. Should be prescribed with caution or dose reduction of verapamil may be required.

Carbamazepine: increased levels of carbamazepine, increased neurotoxic side effects of carbamazepine – diplopia, headache, ataxia, dizziness. Increased AUC of carbamazepine (~46%) in patients with refractory partial epilepsy.

Lithium: increased neurotoxicity of lithium.

Antimicrobial agents: clarithromycin, erythromycin, telithromycin: possible increase in verapamil levels.

Rifampicin: possible reduction in hypotensive effect. Decreased AUC of verapamil (~97%), Cmax (~94%), oral bioavailability (~92%).

Colchicine: combined administration with verapamil is not recommended due to increased colchicine exposure.

Inhalational anesthetics: should be administered with caution to prevent excessive cardiovascular depression.

Sulfinpyrazone: threefold increase in oral clearance of verapamil, 60% increase in bioavailability. Reduced hypotensive effect may be observed.

Neuromuscular blockers: possible potentiation of effect due to verapamil hydrochloride.

Acetylsalicylic acid: increased risk of bleeding.

Ethanol: increased plasma levels of ethanol.

HMG-CoA reductase inhibitors: treatment with HMG-CoA reductase inhibitors (simvastatin, atorvastatin, lovastatin) in patients receiving verapamil should be initiated at the lowest possible doses, gradually increasing them. If a patient already receiving verapamil requires initiation of an HMG-CoA reductase inhibitor, dose reduction of statins should be considered and dosing adjusted according to plasma cholesterol concentration.

Atorvastatin: possible increase in atorvastatin levels. Atorvastatin increases AUC of verapamil by approximately 42.8%.

Lovastatin: possible increase in lovastatin levels.

Simvastatin: increase in AUC of simvastatin by approximately 2.6 times, Cmax of simvastatin by 4.6 times.

Fluvastatin, pravastatin, and rosuvastatin are not metabolized by cytochrome CYP3A4 and do not interact with verapamil.

Digoxin: in healthy individuals, Cmax of digoxin increases by 45–53%, Css by 42%, AUC by 52%.

Digitoxin: reduced clearance of digitoxin (~27%) and extrarenal clearance (~29%).

Cimetidine: increased AUC of R- (~25%) and S-verapamil (~40%) with corresponding reduction in clearance of R- and S-verapamil.

Antidiabetic agents (glyburide): increased Cmax of glyburide by approximately 28%, AUC by 26%.

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

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

Doxorubicin: when doxorubicin and verapamil (oral) are administered concurrently, AUC (~89%) and Cmax of doxorubicin in plasma (~61%) increase in patients with small cell lung cancer. In patients with progressive tumor, no significant changes in doxorubicin pharmacokinetics are observed with concomitant intravenous administration of verapamil.

Phenobarbital: increases oral clearance of verapamil fivefold.

Buspirone: increased AUC and Cmax by 3–4 times.

Midazolam: increased AUC by 3 times and Cmax by 2 times.

Almotriptan: increased AUC by 20%, Cmax by 24%.

Cyclosporine: increased AUC, Cmax, Css – by approximately 45%.

Everolimus, sirolimus, tacrolimus: possible increase in levels of these medicinal products.

Grapefruit juice: increased AUC of R- (~49%) and S-verapamil (~37%), increased Cmax of R- (~75%) and S-verapamil (~51%) without changes in elimination half-life or renal clearance.

Hypericum perforatum (St. John's wort): reduced AUC of R- (~78%) and S-verapamil (~80%) with corresponding reduction in Cmax.

Special precautions for use.

When prescribing verapamil and determining its dosage, special attention should be paid to patients with the following conditions:

Arterial hypotension.

Intravenous administration of verapamil hydrochloride often leads to a reduction in arterial pressure below baseline values. This is usually transient and asymptomatic, but may manifest as dizziness.

Severe bradycardia, asystole.

Verapamil hydrochloride acts on the atrioventricular and sinoatrial nodes, which rarely may lead to second- or third-degree atrioventricular block, bradycardia, and in extreme cases, asystole. This may occur in patients with sick sinus syndrome, which is more common in elderly patients.

Asystole in patients without sick sinus syndrome is usually short-lived (a few seconds or less), with spontaneous return to atrioventricular rhythm or normal sinus rhythm. If this does not occur promptly, emergency treatment must be initiated immediately.

Heart block.

Verapamil hydrochloride prolongs conduction through the atrioventricular node. Development of second- or third-degree atrioventricular block or 1-, 2-, or 3-bundle branch block requires dose reduction or discontinuation of verapamil therapy, and appropriate treatment if necessary.

Heart failure.

In cases of mild heart failure, control of heart failure with cardiac glycosides and diuretics is required before administration of verapamil hydrochloride. In patients with moderate to severe heart failure, acute worsening of heart failure may occur.

Cardiac glycosides.

Since both cardiac glycosides and verapamil hydrochloride prolong AV conduction, patients should be monitored for AV block and bradycardia.

Disopyramide.

Disopyramide is not recommended within 48 hours before and 24 hours after administration of verapamil hydrochloride.

During treatment with the medicinal product, consumption of grapefruit-containing foods and beverages should be avoided. Grapefruit may increase verapamil hydrochloride plasma levels.

Verapamil-Darnytsia injection solution should be used at the beginning of therapy only in a hospital setting where resuscitation measures are available. Patients receiving intravenous verapamil should be monitored by electrocardiographic and hemodynamic monitoring.

Use during pregnancy or breastfeeding.

The medicinal product should not be used during the first and second trimesters of pregnancy. Use during the third trimester of pregnancy is permitted only if absolutely necessary, when the benefit outweighs the risk to the mother and fetus. Verapamil crosses the placenta and is found in umbilical cord blood.

The active substance passes into breast milk. Limited human data on oral administration indicate that the dose of verapamil transferred to the newborn is low (0.1–1% of the dose taken by the mother); therefore, verapamil use may be compatible with breastfeeding. However, due to the risk of serious adverse reactions in breastfed newborns, verapamil should be used during breastfeeding only if absolutely necessary for the mother.

Ability to influence reaction speed when driving or operating machinery.

Due to the possibility of individual reactions to the medicinal product, reaction ability may be altered to such an extent that driving vehicles or performing other tasks requiring increased attention, and rapid mental and motor responses, may be impaired.

Administration and Dosage

Intravenous administration should be performed slowly (over no less than 2 minutes) under medical supervision with ECG and arterial pressure monitoring. Patients who have received intravenous verapamil as initial treatment for unstable angina should be switched to oral verapamil as soon as possible.

Recommended doses for adults and adolescents weighing more than 50 kg:

The initial dose is 5 mg of verapamil hydrochloride (corresponding to 2 mL of Verapamil-Darnitsya, injection solution). If necessary, an additional 5 mg may be administered after 5–10 minutes. If needed, further intravenous infusion of 5–10 mg of Verapamil-Darnitsya, diluted in 0.9% sodium chloride solution, may be administered over 1 hour. Alternatively, 5% glucose solution with pH < 6.5 may be used as diluent. The average daily dose of verapamil hydrochloride administered intravenously should not exceed 100 mg.

In patients with impaired liver function, verapamil bioavailability is significantly increased. In such cases, dosage should be carefully determined.

Recommended doses for children.

In tachycardia associated with heart failure, digitalization should be performed prior to intravenous administration.

The administration of the drug should be discontinued immediately after the effect occurs.

Children.

Controlled studies of verapamil hydrochloride in children have not been conducted.

Verapamil hydrochloride, injection solution, should be administered to children with caution.

Overdose.

Symptoms of poisoning due to verapamil overdose depend on the amount of drug ingested, the time when detoxification measures were initiated, and the patient's age.

Predominant symptoms: significant reduction in arterial pressure, cardiac arrhythmias (bradycardia, junctional rhythms with AV dissociation and high-degree AV block), which may lead to shock and cardiac arrest, dizziness progressing to coma, stupor, hyperglycemia, hypokalemia, metabolic acidosis, hypoxia, cardiogenic shock with pulmonary edema, renal dysfunction, and seizures.

Therapeutic measures are aimed at removing the substance from the body and restoring cardiovascular stability.

General measures: gastric lavage is recommended even if more than 12 hours have passed since drug ingestion and gastrointestinal motility is not detectable (absence of bowel sounds). General resuscitation measures include indirect cardiac massage, artificial ventilation, defibrillation, and cardiac pacing. Hemodialysis is not indicated. Hemofiltration and possibly plasmapheresis may be beneficial (calcium antagonists are highly protein-bound in plasma).

Specific measures: counteracting cardiodepressive effects, arterial hypotension, and bradycardia. The specific antidote is calcium: administer 10–20 mL of 10% calcium gluconate solution intravenously (2.25–4.5 mmol). The dose may be repeated or additional continuous infusion administered if necessary (e.g., 5 mmol/hour).

Additional measures: for second- and third-degree AV block, sinus bradycardia, or cardiac arrest, administer atropine, isoprenaline, orciprenaline, or apply cardiac pacing. In cases of arterial hypotension due to cardiogenic shock and arterial vasodilation, use dopamine (up to 25 mcg/kg/min), dobutamine (up to 15 mcg/kg/min), or noradrenaline. Serum calcium levels should be at the upper limit of normal or slightly above normal. Due to vasodilation, fluid replacement (Ringer's solution or 0.9% sodium chloride solution) should be administered early.

Verapamil is not removed by hemodialysis.

Adverse Reactions

From the auditory and vestibular system: vertigo, tinnitus.

From the respiratory system, thoracic organs, and mediastinum: bronchospasm.

From the gastrointestinal tract: nausea, vomiting, sensation of fullness (in the stomach), constipation, abdominal pain, discomfort in the abdomen, intestinal obstruction, gingival hyperplasia (gingivitis and bleeding).

From the liver and biliary tract: allergic hepatitis with reversible elevation of liver enzymes may occur.

From metabolism and nutritional status: decreased glucose tolerance.

From the nervous system: dizziness, headache, fainting, anxiety, sedation, increased fatigue, asthenia, somnolence, depression, extrapyramidal disorders (ataxia, mask-like face, shuffling gait, rigidity of arms or legs, tremor of hands and fingers, difficulty swallowing), convulsions, Parkinsonism, choreoathetosis, dystonic syndrome, paresthesia, tremor.

From the cardiovascular system: AV block of degree I, II, or III, bradycardia (less than 50 beats/min), asystole, collapse, marked decrease in arterial pressure, development or worsening of heart failure, tachycardia; angina pectoris, up to myocardial infarction (especially in patients with coronary artery stenosis), arrhythmia (including ventricular fibrillation and flutter), flushing sensation, peripheral edema.

From the immune system: hypersensitivity.

From the skin and subcutaneous tissue: angioneurotic edema, Stevens-Johnson syndrome, erythema multiforme, maculopapular rash, alopecia, erythromelalgia, urticaria, pruritus, hemorrhages into the skin or mucous membranes (purpura), photosensitivity dermatitis, hyperhidrosis.

From the musculoskeletal system and connective tissue: myalgia, arthralgia, muscle weakness, exacerbation of myasthenia gravis, Lambert-Eaton syndrome, progressive Duchenne muscular dystrophy.

From the reproductive system and mammary glands: erectile dysfunction, gynecomastia, increased prolactin levels, galactorrhea.

General disorders: increased fatigue.

Laboratory findings: elevated levels of liver enzymes and alkaline phosphatase, increased serum prolactin.

Other: weight gain, agranulocytosis, transient loss of vision associated with peak plasma concentration of the drug, pulmonary edema, asymptomatic thrombocytopenia.

Cases of paralysis (tetraparesis) have been reported in association with concomitant use of verapamil and colchicine. This may be due to colchicine crossing the blood-brain barrier as a result of CYP3A4 and P-gp inhibition by verapamil. Concomitant use of colchicine and verapamil is not recommended.

In patients with a cardiac pacemaker, an increased pacing-sensing threshold may occur during treatment with verapamil hydrochloride.

Shelf life. 3 years.

Storage conditions.

Store in the original packaging, out of reach of children, at a temperature not exceeding 25°C. Do not freeze.

Incompatibility.

Mixing verapamil hydrochloride solution with albumin, amphotericin B, hydralazine hydrochloride, trimethoprim, or sulfamethoxazole should be avoided. To maintain stability, this medicinal product should not be diluted with solutions containing sodium lactate. Verapamil hydrochloride will precipitate in any solution with a pH above 6.0.

Packaging.

2 ml in a vial; 5 vials in a blister pack; 2 blister packs in a carton; 10 vials in a blister pack; 1 blister pack in a carton.

Prescription category. Prescription only.

Manufacturer.

JSC "Pharmaceutical Company "Darnitsya".

Manufacturer's address and place of business.

13, Borispilska Street, Kyiv, 02093, Ukraine.