Instructions Verapamil-Darnitsa film-coated tablets 80 mg No. 50
Composition
active ingredient: verapamil;
1 tablet contains: verapamil hydrochloride 80 mg;
Excipients: lactose monohydrate, microcrystalline cellulose, corn starch, hypromellose, croscarmellose sodium, colloidal anhydrous silica, talc, magnesium stearate, sepifilm 752 white, macrogol 4000.
Dosage form
Film-coated tablets.
Main physicochemical properties: film-coated tablets, round, white in color, with a biconvex surface.
Pharmacotherapeutic group
Selective calcium antagonists with predominant cardiac action. Phenylalkylamine derivatives. ATC code C08D A01.
Pharmacological properties
Pharmacodynamics.
Verapamil blocks the transmembrane influx of calcium ions into cardiac cells and vascular smooth muscle. 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 muscle of the coronary arteries, blood flow to the myocardium increases, even in post-stenotic areas, and coronary artery spasm is relieved.
The antihypertensive efficacy of Verapamil-Darnitsa is due to a decrease in peripheral vascular resistance without an increase in heart rate as a reflex response. No undesirable changes in physiological blood pressure parameters are observed.
Verapamil-Darnitsa has a pronounced antiarrhythmic effect, especially in supraventricular arrhythmias. It delays impulse conduction in the atrioventricular node, as a result of which, depending on the type of arrhythmia, sinus rhythm is restored and/or the ventricular rate is normalized.
Pharmacokinetics.
Verapamil is rapidly and almost completely absorbed from the small intestine. The extent of absorption is 90-92%. Peak plasma concentrations are reached 1-2 hours after dosing. The elimination half-life is 3 to 7 hours. Plasma protein binding is 90%. Verapamil is almost completely metabolized to various metabolites. Of these metabolites, only norverapamil is pharmacologically active.
Verapamil and its metabolites are excreted primarily by the kidneys; only 3-4% is excreted unchanged. 50% of the administered dose is excreted within 24 hours, 70% within 5 days. Up to 16% of the drug is excreted in the feces. Recent data indicate that there is no difference in the pharmacokinetics of verapamil in people with healthy kidneys and in patients with end-stage renal failure. The half-life is increased in patients with cirrhosis of the liver due to low clearance and a large volume of distribution.
The mean absolute bioavailability in healthy subjects after a single dose is 22%, which is due to extensive first-pass hepatic metabolism. Bioavailability increases 1.5-2-fold after multiple doses.
Indication
Coronary heart disease, including: stable angina pectoris; unstable angina (progressive angina, angina at rest), vasospastic angina (variant angina, Prinzmetal's angina), post-infarction angina in patients without heart failure, if beta-blockers are not indicated.
Arrhythmias: paroxysmal supraventricular tachycardia; atrial flutter/fibrillation with rapid atrioventricular conduction (except Wolff-Parkinson-White (WPW) syndrome).
Arterial hypertension.
Contraindication
Cardiogenic shock.
Severe conduction disorders: AV block II and III degree (except in patients with an implanted artificial pacemaker).
Sick sinus syndrome (except in patients with implanted artificial pacemakers).
Known hypersensitivity to verapamil or to any component of the drug.
Heart failure with reduced ejection fraction less than 35% and/or pulmonary artery pressure greater than 20 mm Hg (unless secondary supraventricular tachycardia is not responsive to verapamil therapy).
Atrial fibrillation/flutter with additional conduction pathways (WPW syndrome and LGL syndrome). These patients are at risk of developing ventricular tachyarrhythmias, including ventricular fibrillation, when using verapamil hydrochloride.
During treatment with verapamil, do not use intravenous β-blockers simultaneously (except in intensive care).
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 and P-glycoprotein (P-gp). Clinically significant interactions have been reported with CYP3A4 inhibitors resulting in increased plasma levels of verapamil, while CYP3A4 inducers have resulted in decreased plasma levels of verapamil hydrochloride, so monitoring for interactions with other drugs is necessary.
Potential interactions related to the CYP-450 enzyme system
Prazosin: increase in Cmax of prazosin (40%) without effect on half-life. Additive hypotensive effect.
Quinidine: Decreased oral clearance of quinidine (35%). Hypotension may occur, and pulmonary edema may occur in patients with hypertrophic obstructive cardiomyopathy.
Flecainidine:
minimal effect on flecainidine plasma clearance (<10%); no effect on verapamil plasma clearance (see section "Special warnings and precautions for use").
Theophylline: decrease in oral and systemic clearance by approximately 20%, in smokers - by 11%.
Carbamazepine: increased AUC of carbamazepine (46%) in patients with refractory partial epilepsy; increased levels of carbamazepine, which may cause side effects of carbamazepine such as diplopia, headache, ataxia or dizziness.
Phenytoin: decreased plasma concentrations of verapamil.
Imipramine: increase in AUC (15%) of imipramine without effect on the active metabolite desipramine.
Glyburide: increase in Cmax of glyburide by approximately 28%, AUC by 26%.
Colchicine: increase in AUC (approximately 2-fold) and Cmax (approximately 1.3-fold) of colchicine. It is recommended to reduce the dose of colchicine (see instructions for medical use of colchicine).
Clarithromycin, erythromycin, telithromycin: possible increase in verapamil levels.
Rifampicin: possible reduction of the hypotensive effect. Decrease in verapamil AUC (97%), Cmax (94%), bioavailability after oral administration (92%).
Doxorubicin: Concomitant administration of doxorubicin and verapamil (oral) increased the AUC (104%) and Cmax (61%) of doxorubicin in plasma in patients with small cell lung cancer.
Phenobarbital increases the oral clearance of verapamil 5-fold.
Buspirone: 3.4-fold increase in AUC and Cmax of buspirone.
Midazolam: 3-fold increase in midazolam AUC and 2-fold increase in Cmax.
Metoprolol:
increase in metoprolol AUC (32.5%) and Cmax (41%) in patients with angina pectoris (see section "Special warnings and precautions for use").
Propranolol:
increase in propranolol AUC (65%) and Cmax (94%) in patients with angina pectoris (see section "Special warnings and precautions for use").
Digoxin: in healthy volunteers
increase in Cmax of digoxin (44%), C12h (53%), Css (44%), AUC (50%). It is recommended to reduce the dose of digoxin (see section "Special instructions").
Digitoxin: decreased digitoxin clearance (27%) and extrarenal clearance (29%).
Cimetidine: increases the AUC of R-verapamil (25%) and S-verapamil (40%) with a corresponding decrease in the clearance of R- and S-verapamil.
Cyclosporine: increase in AUC, Cmax, Css of cyclosporine by approximately 45%.
Everolimus: Increase in everolimus AUC (approximately 3.5-fold) and Cmax (approximately 2.3-fold). Increase in verapamil Ctrough (approximately 2.3-fold). Accurate determination of everolimus concentration and dose may be necessary.
Sirolimus: increase in AUC (approximately 2.2-fold) of sirolimus, increase in AUC (approximately 1.5-fold) of S-verapamil. Concentration determination and dose adjustment of sirolimus may be required.
Tacrolimus: possible increase in plasma levels of this drug.
Lipid-lowering agents (HMG-CoA reductase inhibitors (statins)): Treatment with HMG-CoA reductase inhibitors (simvastatin, atorvastatin, lovastatin) for patients taking verapamil should be started at the lowest possible dose and gradually increased. If a patient already taking verapamil requires the appointment of an HMG-CoA reductase inhibitor, the necessary reduction in the statin dose should be taken into account and the dosage should be selected according to the concentration of cholesterol in the blood plasma.
Atorvastatin: Possible increase in atorvastatin levels. Atorvastatin increases the AUC of verapamil by approximately 43%.
Lovastatin: possible increase in lovastatin levels. Increase in AUC (63%) and Cmax (32%) of verapamil.
Simvastatin: increase in AUC of simvastatin approximately 2.6 times, Cmax of simvastatin - 4.6 times.
Fluvastatin, pravastatin, and rosuvastatin are not metabolized by cytochrome CYP3A4 and are less likely to interact with verapamil.
Almotriptan: increase in AUC by 20%, Cmax by 24%.
Sulfinpyrazone: increase in oral clearance of verapamil by 3 times, decrease in bioavailability by 60%. Decrease in hypotensive effect may be observed.
Grapefruit juice: increases AUC of R-verapamil (49%) and S-verapamil (37%), increases Cmax of R-verapamil (75%) and S-verapamil (51%) without changing half-life and renal clearance. Grapefruit juice should be avoided with verapamil.
St. John's wort: decreases AUC of R-verapamil (78%) and S-verapamil (80%) with a corresponding decrease in Cmax.
Other interactions
Antivirals (HIV): Due to the ability of some antivirals, such as ritonavir, to inhibit metabolism, plasma concentrations of verapamil may increase. Prescribe with caution or a reduction in the dose of verapamil may be necessary.
Lithium: Increased lithium neurotoxicity has been reported with concomitant use of verapamil hydrochloride and lithium, with or without increases in plasma lithium levels. However, in patients receiving the same oral lithium dose, the addition of verapamil hydrochloride has been shown to decrease plasma lithium levels. Patients receiving both drugs should be closely monitored.
Neuromuscular Blockers: Clinical data and animal studies indicate that verapamil hydrochloride may potentiate the activity of neuromuscular blocking agents (curare-like and depolarizing). It may be necessary to reduce the dose of verapamil hydrochloride and/or the dose of the neuromuscular blocker when they are used concomitantly.
Ethanol (alcohol): increased levels of ethanol in blood plasma.
Antihypertensives, diuretics, vasodilators: increased hypotensive effect.
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.
Heart block/first degree atrioventricular block/bradycardia/asystole
Verapamil hydrochloride acts on the atrioventricular and sinoatrial nodes and prolongs atrioventricular conduction time. Use with caution because the development of second- or third-degree atrioventricular block (which is a contraindication) or single-, double- or triple-bundle bundle branch block requires discontinuation of subsequent doses of verapamil hydrochloride and the administration of appropriate therapy if necessary.
Verapamil hydrochloride acts on the atrioventricular and sinoatrial nodes and may very rarely cause second or third degree atrioventricular block, bradycardia and, extremely rarely, asystole. These symptoms are more likely to occur in patients with sick sinus syndrome (sinoatrial node disease), which is more common in the elderly.
Asystole in patients without sick sinus syndrome is usually short-lived (a few seconds or less), with spontaneous return to atrioventricular nodal or normal sinus rhythm. If this phenomenon is not transient, appropriate therapy should be initiated immediately (see section 4.8).
Antiarrhythmics, b-blockers
Mutual enhancement of cardiovascular effects (increased degree of high-degree atrioventricular block, significant decrease in heart rate, occurrence of heart failure, significant decrease in blood pressure). Asymptomatic bradycardia (36 beats/minute) with a wandering atrial pacemaker was observed in patients receiving concomitant therapy with timolol eye drops (a beta-blocker) while being treated with verapamil hydrochloride.
Digoxin
When verapamil is used concomitantly with digoxin, the dose of digoxin should be reduced (see section "Interaction with other medicinal products and other types of interactions").
Heart failure
Before starting verapamil treatment, heart failure in patients with an ejection fraction of more than 35% must be compensated and adequately monitored throughout the treatment period.
HMG-CoA reductase inhibitors (statins)
See section “Interaction with other medicinal products and other types of interactions”.
Neuromuscular conduction disorders
Verapamil hydrochloride should be used with caution in the presence of diseases with neuromuscular conduction disorders ((Myastenia gravis, Lambert-Eaton syndrome, progressive Duchenne muscular dystrophy).
Kidney failure
Although data from validated comparative studies have shown that renal insufficiency does not affect the pharmacokinetics of verapamil in patients with end-stage renal disease, there have been several reports suggesting that verapamil should be used with caution and under close supervision in patients with renal insufficiency. Verapamil is not removed by hemodialysis.
Liver failure
Verapamil should be used with caution in patients with significant hepatic impairment (see section 4.2).
Use during pregnancy or breastfeeding
There are no adequate and well-controlled studies of verapamil in pregnant women. Animal studies of verapamil do not indicate direct or indirect harmful effects with respect to reproductive toxicity. Since animal reproduction studies cannot always be extrapolated to humans, the drug should be used during pregnancy only if clearly needed.
Verapamil crosses the placenta and is detected in cord blood.
Verapamil and its metabolites are excreted in breast milk. Limited human oral data suggest that the dose of verapamil that reaches the newborn is low (0.1-1% of the maternal dose), so the use of verapamil may be compatible with breastfeeding, but a risk to the newborn cannot be excluded. Given the risk of serious adverse reactions in breastfed infants, verapamil should be used during breastfeeding only if clearly needed by the mother.
Ability to influence reaction speed when driving vehicles or other mechanisms
Due to the antihypertensive effect of verapamil hydrochloride, depending on the individual response, the ability to drive vehicles, operate machinery or work in hazardous conditions may be impaired. This is especially true in the initial phase of treatment, when the dose is increased, when the antihypertensive drug is changed, and when the drug is taken simultaneously with alcohol. Verapamil may increase the level of alcohol in the blood plasma and slow down its excretion, so the effect of alcohol may be enhanced.
Method of administration and doses
The dose should be selected individually for each patient. The drug should be taken without dissolving or chewing with sufficient liquid (for example, 1 glass of water, never grapefruit juice), preferably during or immediately after a meal.
Adults and adolescents weighing more than 50 kg.
Coronary heart disease, paroxysmal supraventricular tachycardia, atrial flutter/fibrillation.
The recommended daily dose is 120-480 mg, divided into 3-4 doses. The maximum daily dose is 480 mg.
Arterial hypertension.
The recommended daily dose is 120-360 mg, divided into 3 doses.
Children of older preschool age up to 6 years old, only with heart rhythm disturbances:
The recommended dosage is within 80-120 mg per day, divided into 2-3 doses.
Children aged 6-14 years, only for heart rhythm disorders: recommended dosage is within 80-360 mg per day, divided into 2-4 doses.
Kidney dysfunction.
Available data are described in the section "Special warnings and precautions for use". Verapamil hydrochloride should be used with caution and under close supervision in patients with renal insufficiency.
Liver dysfunction.
In patients with impaired liver function, depending on the severity, the effect of verapamil hydrochloride is enhanced and prolonged due to a slowdown in the breakdown of the drug. Therefore, in such cases, the dosage should be set with special caution and start with small doses (for patients with limited liver function, initially 40 mg 2-3 times a day, respectively 80-120 mg per day), see the section "Special instructions for use".
If a dose of 40 mg is necessary, the drug should be used in the appropriate dosage.
Do not take the drug while lying down.
Verapamil hydrochloride should not be administered to patients with myocardial infarction within 7 days of the event.
After prolonged therapy, the drug should be discontinued by gradually reducing the dose.
The duration of treatment is determined by the doctor individually and depends on the patient's condition and the course of the disease.
Children
The drug in this dosage form can be used in children only for heart rhythm disorders (see the section "Method of administration and dosage").
Overdose
Symptoms: hypotension, bradycardia up to high-degree atrioventricular block and sinus node arrest, hyperglycemia, stupor and metabolic acidosis. Fatal cases of overdose have been observed.
Treatment of verapamil hydrochloride overdose should be primarily supportive and individualized. Beta-adrenergic stimulation and/or intravenous calcium (calcium chloride) have been used effectively to reverse the symptoms of intentional oral verapamil hydrochloride overdose.
In case of significant arterial hypotension or high-degree atrioventricular block, it is necessary to use agents that increase blood pressure (vasoconstrictors) or pacemakers, respectively. In case of asystole, beta-adrenergic stimulation (e.g. isoproterenol hydrochloride), other agents aimed at increasing blood pressure, or to restore cardiac activity and respiration should be used simultaneously with the use of conventional measures.
Verapamil hydrochloride is not removed by hemodialysis.
Adverse reactions
The following adverse reactions have been reported during clinical trials, during post-marketing use of verapamil, or in phase IV clinical trials.
For each system organ class, adverse reactions are classified according to the frequency of reporting: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (frequency cannot be estimated from the available data).
The most frequently observed adverse reactions were: headache, dizziness; gastrointestinal disorders: nausea, constipation and abdominal pain; also bradycardia, tachycardia, palpitations, decreased blood pressure, flushing, peripheral edema and fatigue.
Immune system disorders: unknown - hypersensitivity.
Neurological disorders: often - dizziness, headache; rarely - paresthesia, tremor; unknown - extrapyramidal disorders, paralysis (tetraparesis)*, epileptic seizures.
Metabolic disorders: not known – hyperkalemia.
Mental disorders: rarely - drowsiness.
From the side of the organs of hearing and vestibular apparatus: rarely - tinnitus; unknown - vertigo.
From the cardiovascular system: often - bradycardia, hyperemia, hot flashes, decreased blood pressure; infrequently - palpitations, tachycardia; unknown - atrioventricular block I, II or III degree, heart failure, sinus node arrest, sinus bradycardia, asystole.
Respiratory, thoracic and mediastinal disorders: not known – bronchospasm, dyspnoea.
Gastrointestinal disorders: often - nausea, constipation; infrequently - abdominal pain; rarely - vomiting; unknown - abdominal discomfort, intestinal obstruction, gingival hyperplasia (gingivitis and bleeding).
Skin and subcutaneous tissue disorders: rarely - hyperhidrosis; not known - angioedema, Stevens-Johnson syndrome, erythema multiforme, maculopapular rash, alopecia, urticaria, pruritus, pruritus, purpura.
Renal and urinary disorders: 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.
*A single case of paralysis (tetraparesis) associated with the combined use of verapamil and colchicine has been reported in post-marketing experience. This may be due to the penetration of colchicine across the blood-brain barrier.
due to inhibition of CYP3A4 and P-gp by verapamil, see section “Interaction with other medicinal products and other forms of interaction”.
Expiration date
2 years.
Storage conditions
Store in the original packaging at a temperature not exceeding 25 ºС.
Keep out of reach of children.
Packaging
10 tablets in a contour blister pack; 5 contour blister packs in a pack.
Vacation category
According to the recipe.
Producer
PrJSC "Pharmaceutical Company "Darnitsa".
Location of the manufacturer and its business address
Ukraine, 02093, Kyiv, Boryspilska St., 13.
