Verapamil-Darnitsa

General characteristics. Structure:

Active ingredient: verapamil;

1 tablet contains verapamil of a hydrochloride 80 mg;

excipients: lactose monohydrate, cellulose microcrystallic, corn starch, gipromelloza, croscarmellose sodium, silicon dioxide colloid anhydrous, talc, magnesium stearate, сепифилм 752 white, macrogoal 4000.

Pharmacological properties:

Pharmacodynamics. Verapamil blocks a transmembrane flow of calcium ions in cells of heart and unstriated muscles of vessels. It directly reduces the need of a myocardium for oxygen due to influence on energetically expensive processes of metabolism in cells of a myocardium and due to reduction of an afterload.

Thanks to blocking of calcium channels of smooth muscles of coronary arteries inflow of blood to a myocardium amplifies, even in post-stenotic sites, and the spasm of coronary arteries is removed. These properties define anti-ischemic and anti-anginal efficiency of the drug Verapamil-Darnitsa at all forms of coronary heart disease.

Anti-hypertensive efficiency of the drug Verapamil-Darnitsa is caused by reduction of resistance of peripheral vessels without increase in heart rate as the reflex answer. Undesirable changes of physiological sizes of pressure of blood are not observed.

The drug Verapamil-Darnitsa has the expressed antiarrhytmic action, especially at supraventricular arrhythmia. It detains carrying out an impulse in an atrioventricular node owing to what, depending on arrhythmia type, the sinoatrial rate is recovered and/or the frequency of reductions of ventricles is normalized.

Pharmacokinetics. Verapamil quickly and almost is completely soaked up in a small intestine. Extent of absorption makes 90-92%. The maximum concentration in plasma is reached in 1-2 h after reception of a dose. The elimination half-life makes from 3 to 7 h. Linkng with proteins of plasma makes 90%. Verapamil is almost completely metabolized owing to what different metabolites are formed. Among these metabolites only norverapamit pharmacological active.

Verapamil and its metabolites are removed generally by kidneys; only 3-4% are removed in not changed look. 50% of the entered dose are removed for 24 h, 70% are removed for 5 days. To 16% of drug it is removed with excrements. Recently obtained data demonstrate that there is no distinction in verapamil pharmacokinetics at people with healthy kidneys and at patients with an end-stage of a renal failure. The elimination half-life increases at patients with cirrhosis thanks to low clearance and large volume of distribution.

Average absolute bioavailability at healthy subjects after a single dose of drug makes 22% that is explained by extensive hepatic metabolism of the first passing. Bioavailability increases by 1,5-2 times after reusable reception.

Pharmaceutical characteristics.

Main physical and chemical properties: tablets, coated, a round form, white color, with a biconvex surface.

Indications to use:

• Coronary heart disease, including: stable angina of exertion; unstable stenocardia (the progressing stenocardia, rest stenocardia), vasospastic stenocardia (alternative stenocardia, Printsmetal's stenocardia), postinfarction stenocardia at patients without heart failure if b-adrenoblockers are not shown.
• Arrhythmias: Bouveret's supraventricular disease; trembling/atrial fibrillation with bystry atrioventricular carrying out (except for a WPW-syndrome (WPW).
• Arterial hypertension.

Route of administration and doses:

Doses are selected individually for each patient. Drug should be accepted not rassasyvy and without chewing with enough liquid (for example, 1 glass of water, by no means grapefruit juice), it is the best of all in time or right after food.

Adults and teenagers with body weight more than 50 kg:

Coronary heart disease, Bouveret's supraventricular disease, trembling/atrial fibrillation.

The recommended daily dose makes 120-480 mg divided into 3-4 receptions. The maximum daily dose – 480 mg.

Arterial hypertension.

The recommended daily dose makes 120-360 mg divided into 3 receptions.

Children of the advanced preschool age up to 6 years, only at disturbances of a cordial rhythm: the recommended dosage within 80-120 mg a day divided into 2-3 single doses.

Children of 6-14 years, only at disturbances of a cordial rhythm: the recommended dosage within 80-360 mg a day divided into 2-4 single doses.

Abnormal liver functions.

At patients with the broken function of a liver depending on severity, effect of verapamil of a hydrochloride amplifies and lasts because of medicine disintegration delay. Therefore in such cases the dosage should be established with special care and to begin with small doses (for example, for patients with the broken function of a liver at first 2-3 times in day of 40 mg, respectively 80-120 mg a day).

In need of use of a dose of 40 mg use drug in the corresponding dosage.

Not to accept drug lying.

Hydrochloride it is impossible to appoint verapamil the patient with a myocardial infarction within 7 days after the event.

After long therapy drug should be cancelled, gradually reducing a dose.

Duration of treatment is defined by the doctor individually and depends on a condition of the patient and the course of a disease.

Features of use:

Elimination of cardiodepressive influences, arterial hypotension and bradycardia. A specific antidote is calcium: intravenously enter 10-20 ml of 10% of solution of a gluconate of calcium (2,25-4,5 mmol). If necessary it is possible to repeat introduction or to carry out additional drop infusion (for example, 5 mmol/h).

Additional measures: at AV-blockade of II and III degrees, a sinus bradycardia, a cardiac standstill apply atropine, изопреналин, орципреналин or cardiostimulation.

In case of arterial hypotension owing to cardiogenic shock and an arterial vazodilatation apply a dopamine (to 25 mkg/kg for min.), Dobutaminum (to 15 mkg/kg for min.) or noradrenaline.

Concentration of calcium in serum have to correspond to the upper bound of norm or to be a little higher than norm. Due to the vazodilatation at early stages administration of replaceable liquid (Ringer's solution or normal saline solution) is carried out.

Use during pregnancy or feeding by a breast.

Drug should not be accepted in I and II trimesters of pregnancy. Reception in the III trimester of pregnancy only in urgent cases when the result exceeds risk for mother and the child. Verapamil gets through a placenta and it is found in umbilical blood.
Biologically active agent gets into breast milk. Limited data of oral administration, with participation of the person, demonstrate that the verapamil dose getting to the newborn's organism is low (0,1-1% of the dose accepted by mother) therefore use of verapamil can be compatible to feeding by a breast. Considering risk of emergence of serious side reactions in newborns who are nursed, verapamil during breastfeeding it is necessary to apply only in urgent cases to mother.

Children.

Drug in this dosage form is used at children at disturbances of a cordial rhythm.

At purpose of verapamil and definition of its dose special attention needs to be paid to patients:
• with AV blockade І degrees;
• with arterial hypotension (systolic arterial pressure <90 mm of mercury.);
• with bradycardia (heart rate is less than 50 beats per minute);
• with a fibrillation/atrial flutter and the accompanying Volfa-Parkinsona-Whyte's syndrome (risk of developing of ventricular tachycardia);
• with a liver failure;
• with disturbances of neuromuscular conductivity (Myasthenia gravis, Lambert-Eaton's syndrome, the progressing muscular dystrophy of Dyushen).

During use of drug it is necessary to avoid dishes and drinks with grapefruit. Grapefruit can increase hydrochloride verapamil level in plasma.

Ability to influence speed of response at control of motor transport or work with other mechanisms.

Depending on individual reaction ability to control of vehicles or work with mechanisms can be broken. Especially it concerns an initial phase of treatment, at dosing change.

Side effects:

It was reported about the following side reactions.

From cardiovascular system: AV blockade of I, II or III degrees, a sinus bradycardia, a stop of a sinus node, peripheral hypostases, heartbeat, increase in heart rate (tachycardia), arterial hypotension, rushes of blood, can develop or escalate heart failure.

Gastrointestinal frustration: it was reported about developing of nausea, vomiting, locks, pain, discomfort in a stomach, intestinal impassability, a hyperplasia of gums (an ulitis and bleeding).
Neurologic frustration: there can be a headache, extrapyramidal frustration, dizziness, paresthesia, a tremor.

From an acoustic organ and vestibular mechanism: it was reported about dizziness, a ring in ears.
Changes from skin and hypodermic cellulose: it was reported about a Quincke's disease, Stephens-Johnson's syndrome, a multiformny erythema, makulopapulezny rash, an alopecia, a small tortoiseshell, an itch, hemorrhages in skin or mucous membranes (purpura) were observed.
From reproductive system and mammary glands: erectile dysfunction, gynecomastia, galactorrhoea.

From a musculoskeletal system and connecting fabric: arthralgias, muscular weakness were observed a myalgia.

From immune system: it was reported about hypersensitivity.

Laboratory researches: it was reported about increase in activity of liver enzymes and level of prolactin in blood serum.

It was reported about paralysis (tetraparesis) associated with the combined use of verapamil and colchicine. It can be caused by penetration of colchicine through a blood-brain barrier owing to oppression by CYP3A4 and P-gp verapamil. The combined use of colchicine and verapamil is not recommended.

Interaction with other medicines:

Verapamil the hydrochloride is metabolized by P450 CYP3A4 cytochrome, CYP1A2, CYP2C8, CYP2C9 and CYP2S18. Verapamil is inhibitor of CYP3A4 enzymes and R-glycoproteins (R-gp). It was reported about clinically important interactions with CYP3A4 inhibitors which were followed by increase in level of verapamil in a blood plasma while the inductors CYP3A4 caused decrease in plasma levels of verapamil of a hydrochloride therefore monitoring regarding interaction with other medicines is necessary.

Antiarrhytmic means, beta adrenoblockers: mutual strengthening of cardiovascular action (AV blockade of high degree, considerable decrease in heart rate, emergence of heart failure, considerable lowering of blood pressure).
Quinidine: reduction of oral clearance of quinidine (~ 35%). Arterial hypotension can develop, and patients with a hypertrophic subaortic stenosis have a fluid lungs.
Flekainidin: the minimum action on clearance of a flekainidin in a blood plasma (<~ 10%); does not influence clearance of verapamil in a blood plasma.

Metoprolol: increase in AUC of a metoprolol (~ 32,5%) and Smakh (~ 41%) at patients with stenocardia.
Propranolol: increase in AUC propranolol (~ 65%) and Smakh (~ 94%) at patients with stenocardia.
Antihypertensives, diuretics, vazodilatator: strengthening of hypotensive effect.
Prazozinum, теразозин: additional hypotensive effect (Prazozinum: increase Smakh of Prazozinum (~ 40%) without influence on an elimination half-life; теразозин: increase in AUC of a terazozin (~ 24%) and Smakh (~ 25%)).

Antiviral (HIV) means: plasma concentration of verapamil can grow. Appoint with care, or the verapamil dose decline can be required.

Carbamazepine: increase in level of carbamazepine, increase in neurotoxic side effects of carbamazepine - a diplopia, a headache, an ataxy, dizziness. Increase in AUC carbamazepine (~ 46%) at patients with refractory partial epilepsy.

Lithium: increase in a neurotoxicity of lithium.

Antimicrobic means: кларитромицин, erythromycin, телитромицин: increase in levels of verapamil is possible. Rifampicin: decrease in hypotensive effect is possible. Decrease in AUC verapamil (~ 97%), Smakh (~ 94%), bioavailability after oral administration (~ 92%).
Colchicine: the combined appointment with verapamil is not recommended because of the increased colchicine exposure.

Sulfinpyrazonum: increase in oral clearance of verapamil by 3 time, bioavailability for 60%. Decrease in hypotensive effect can be observed.

Neuromuscular blockers: strengthening of action because of hydrochloride verapamil is possible.
Acetylsalicylic acid: increase in a possibility of bleeding.

Ethanol: increase in level of ethanol in a blood plasma.

HMG-CoA reductase inhibitors: treatment by HMG-CoA reductase inhibitors (симвастатин, аторвастатин, ловастатин) at the patients accepting verapamil has to begin with perhaps low doses and increase gradually. If the patient who is already accepting verapamil needs purpose of inhibitor of HMG-CoA reductase, it is necessary to consider need a dose decline of statines and to pick up dosing according to concentration of cholesterol in a blood plasma.
Atorvastatin: increase in level of an atorvastatin is possible. Atorvastatin increases AUC verapamil approximately by 42,8%.

Lovastatin: increase in level of a lovastatin is possible.

Simvastatin: increase in AUC of a simvastatin approximately by 2,6 times, Smakh of a simvastatin by 4,6 times.
Fluvastatin, правастатин and розувастатин are not metabolized by CYP3A4 cytochrome and do not interact with verapamil.

Digoxin: at healthy subjects Smakh of digoxin increases by 45-53%, Css - for 42%, AUC - for     52%.

Digitoxin: reduction of clearance of digitoxin (~ 27%) and extrarenal clearance (~ 29%).
Cimetidinum: AUC R-(~ 25%) and S-(~ 40%) verapamil with the corresponding decrease in clearance R-and S-verapamil increases.

Anti-diabetic drugs (Glyburidum): Smakh of Glyburidum approximately increases by 28%, AUC for 26%.

Theophylline: decrease in oral and system clearance approximately for 20%, smokers have a decrease by 11%.

Imipraminum: increase in AUC (~ 15%), without influence on an active metabolite desipramine.
Doxorubicine: at simultaneous use of doxorubicine and verapamil AUC (~ 89%) and Smakh of doxorubicine in a blood plasma (~ 61%) at patients with small-celled lung cancer (orally) raises. At patients in a stage of the progressing tumor of considerable changes of pharmacokinetics of doxorubicine at simultaneous intravenous use of verapamil it is not observed.
Phenobarbital: increases oral clearance of verapamil by 5 times.

Buspiron: increase in AUC and Smakh by 3-4 times.

Midazolam: increase in AUC by 3 times and Smakh twice.

Almotriptan: increase in AUC by 20%, Smakh - for 24%.

Immunological drugs:

Cyclosporine: increase in AUC, Smakh, CSS approximately for 45%.

Everolimus, сиролимус, такролимус: increase in levels of these drugs is possible.
Grapefruit juice: AUC R-increases (~ 49%) and S-(~ 37%) verapamil, increases Smakh of R-(~ 75%) and S-(~ 51%) verapamil without change of an elimination half-life and renal clearance.
The St. John's Wort which is made a hole: AUC R-(~ 78%) and S-(~ 80%) verapamil with the corresponding decrease Smakh decreases.

Contraindications:

• Cardiogenic shock.
• An acute phase of a myocardial infarction with complications (bradycardia, arterial hypotension, insufficiency of a left ventricle).
• Heavy disturbances of conductivity: AV-blockade of II and III degrees (except patients to whom the artificial pacemaker is implanted).
• A sick sinus syndrome (except patients to whom the artificial pacemaker is implanted).
• Sinuatrial blockade.
• The known hypersensitivity to verapamil or to any component of drug.
• Dekompensirovanny heart failure.
• A blinking/atrial flutter and simultaneous existence of a syndrome of WPW (the increased risk of provoking of ventricular tachycardia).
• During treatment by verapamil not to apply at the same time intravenously β-adrenoblockers ((((((((((except for an intensive care).

Overdose:

Poisoning symptoms at overdose of verapamil depend on amount of the accepted drug, time when detoksikatsionny actions, and age of the patient were hosted.
Such symptoms prevail:

considerable lowering of arterial pressure, disturbance of a cordial rhythm (for example, boundary rhythms with AV dissociation and AV blockade of high degree) which can lead to shock and a cardiac standstill.

Disturbance of consciousness up to coma, a hyperglycemia, a hypopotassemia, a metabolic acidosis, a hypoxia, cardiogenic shock with a fluid lungs, renal failures and spasms.
The therapeutic measures directed to removal of substance from an organism and recovery
 stability of cardiovascular system.

General actions: the gastric lavage is recommended even if more than 12 passed
hours from the moment of administration of drug and motility of digestive tract are not defined
(lack of intestinal noise). The general resuscitation actions include an indirect cardiac massage, an artificial respiration, a defibrillation, cardiostimulation.

The hemodialysis is not shown. Haemo filtering and, perhaps, a plasma exchange can be useful
(antagonists of calcium well contact proteins of plasma).

Storage conditions:

Period of validity 2 years. To store in the place, unavailable to children, in original packaging at a temperature not over 25 ºС.

Issue conditions:

According to the recipe

Packaging:

On 10 tablets in a blister strip packaging, on 5 blister strip packagings in a pack.