Verapamil - instructions for use, dose, side effects, contraindications

Active substance:
Verapamil hydrochloride	- 2.5 mg
Excipients:
Sodium chloride	- 8.5 mg
Citric acid monohydrate	-18.49 mg
1 M sodium hydroxide solution	- 0.175 ml
A 0.1 M solution of hydrochloric acid	- 0.120 ml
Water for injections	- up to 1 ml

Description:Transparent colorless liquid.

Pharmacotherapeutic group:The blocker of "slow" calcium channels

ATX: & nbsp

C.08.D.A.01 Verapamil

C.08.D.A Phenylalkylamine derivatives

Pharmacodynamics:

Verapamil blocks transmembrannoe intake of calcium ions (and, possibly, sodium ions) in the cells of the conductive system of the myocardium and smooth muscle cells of the myocardium and vessels. Antiarrhythmic action of verapamil is probably associated with its effect on the "slow" channels in the cells of the conduction system of the heart.

The electrical activity of the sinoatrial and atrioventricular node largely depends on the entry of calcium into the cells through the "slow" channels. Inhibiting this intake of calcium, verapamil slows atrioventricular conduction and increases the effective refractory period in AV-The site is proportional to the heart rate.This effect leads to a decrease in the frequency of ventricular contractions in patients with atrial fibrillation and / or atrial flutter. By stopping the re-entry of excitation in the atrioventricular node, verapamil can restore the correct sinus rhythm in patients with paroxysmal supraventricular tachycardia, including Wolff-Parkinson-White syndrome. Verapamil does not affect the conduct on additional conductive paths, does not affect the unchanged action potential atrial and intraventricular timing, but reduces the amplitude, rate of depolarization, and conduction in altered atrial fibers. Verapamil does not cause spasm of the peripheral arteries and does not change the total content of calcium in the blood plasma.

The maximum therapeutic effect is noted 3-5 minutes after the bolus intravenous injection of verapamil.

Pharmacokinetics:

It is metabolized by "primary passage" through the liver. It binds to plasma proteins for 90%. Penetrates through the blood-brain and placental barrier and into breast milk (in small amounts).

Rapidly metabolized in the liver by N-dealkylation and O-demethylation with the formation of several metabolites. Accumulation of the drug and its metabolites in the body explains the increased effect of course treatment.

The most significant metabolite is the pharmacologically active norverapamil (20% from hypotensive activity of verapamil). In the metabolism of the drug involved isoenzyme system CYP3A4, CYP3A5 and CYP3A7. The half-life period is biphasic: about 4 minutes - early and 2-5 hours - final. It is excreted by the kidneys 70% (unchanged 3-5%), from bile 25%. It is not excreted by hemodialysis.

In conditions of intravenous administration, the antiarrhythmic effect develops within 1-5 min (usually less than 2 min), hemodynamic effects - within 3-5 min. Antiarrhythmic action lasts about 2 hours, hemodynamic action - 10-20 minutes. It is excreted mainly by the kidneys and with feces (about 16%). Penetrates into breast milk, passes through the placenta. Rapid intravenous administration causes hypotension in the mother, resulting in distress of the fetus. With prolonged use, clearance decreases and bioavailability increases. Against the backdrop of severe liver dysfunction (with liver failure), plasma clearance is reduced by 70% and the elimination half-life increases to 14-16 hours.

Indications:

For the treatment of supraventricular tachyarrhythmias, including:

- recovery of sinus rhythm in paroxysmal supraventricular tachycardia, including conditions associated with the presence of additional pathways in the Wolf-Parkinson-White syndrome (WPW) and Launa-Ganong-Levin (LGL);

- control of the frequency of ventricular contractions during flutter and atrial fibrillation (tachyarrhythmic variant), except for cases when flutter or atrial fibrillation is associated with the presence of additional pathways (syndromes WPW and LGL).

Contraindications:

Hypersensitivity, severe left ventricular dysfunction (LV), atrioventricular blockade of stage II and III (except for patients with an artificial pacemaker), sinus node weakness syndrome (bradycardia-tachycardia syndrome), except for patients with an artificial pacemaker, atrial flutter and fibrillation and WPW(except for patients with a pacemaker), chronic heart failure (with the exception of a supraventricular tachycardia to be treated with verapamil), severe arterial hypotension (systolic blood pressure less than 90 mm Hg), or cardiogenic shock, ventricular tachycardia with wide complexes QRS (> 0.12 sec), simultaneous use with colchicine, with beta-blockers intravenously, the use of disopyramide 48 hours before and 24 hours after the administration of verapamil, pregnancy, lactation.

Carefully:

Arterial hypotension, reduction of neuromuscular transmission (eg, muscular dystrophy of Duchesne), atrioventricular (AV) blockade I st, bradycardia, idiopathic hypertrophic subaortal stenosis (IGSS), hypertrophic obstructive cardiomyopathy, simultaneous use with cardiac glycosides, quinidine, flecainide, ritonavir, lovastatin, simvastatin, atorvastatin; advanced age, age under 18 years (efficacy and safety of use not studied), chronic heart failure, hepatic and / or renal insufficiency.

Dosing and Administration:

Enter only intravenously, slowly, for at least 2 minutes, with continuous monitoring of the electrocardiogram, heart rate and blood pressure.

In elderly patients The administration is carried out for at least 3 minutes to reduce the risk of unwanted effects.

To relieve paroxysmal arrhythmias or hypertensive crisis injected intravenously, struyno (under the control of ECG and AD) for 2-4 ml of a solution of 2.5 mg / ml (5-10 mg). If there is no effect, re-administration after 30 minutes at the same dose is possible.

A solution of verapamil is prepared by diluting 2 ml of a 2.5 mg / ml solution in 100-150 ml of a 0.9% solution of sodium chloride.

Side effects:

Often - 1-10%; sometimes 0.1-1%; rarely - 0,01-0,1%; very rarely - less than 0.001%, including individual cases.

From the cardiovascular system:

severe bradycardia (less than 50 beats per minute), marked decrease in blood pressure, development or worsening of heart failure, tachycardia; it is rarely possible to develop angina pectoris, up to myocardial infarction (especially in patients with severe obstructive coronary artery disease), arrhythmia (including fibrillation and flutter of the ventricles); with rapid introduction - atrioventricular blockade III degree, asystole, collapse.

From the central nervous system:

dizziness, headache, fainting, anxiety, inhibition, fatigue, asthenia, drowsiness, depression, ecstasyramide disorders (ataxia, masky face, shuffling gait, stiffness of hands or feet, trembling of hands and fingers,difficulty swallowing), a single case of development of paralysis (tetraparesis) under the condition of joint use of verapamil and colchicine.

From the digestive system:

nausea, constipation (rarely diarrhea), gingival hyperplasia (bleeding, soreness, swelling), increased appetite, increased activity of "liver" transaminases and alkaline phosphatase.

Allergic reactions:

skin itch, rash, hyperemia of the facial skin, multiforme exudative erythema (including Stevens-Johnson syndrome).

Other:

increase in body weight; very rarely - agranulocytosis, gynecomastia, hyperprolactinemia, galactorrhea, arthritis, transient loss of vision against a background of maximum concentration, pulmonary edema, thrombocytopenia asymptomatic, peripheral edema (swelling of the ankles, feet and shins).

Overdose:

Symptoms: a pronounced decrease in blood pressure, sinus bradycardia, a transition to atrioventricular blockade, sometimes asystole, hyperglycemia, stupor, sinoatrial block, metabolic acidosis. There are reports of deaths due to an overdose.

Treatment: should support symptomatic therapy.To increase blood pressure prescribe vasopressor drugs, with atrioventricular blockade - an artificial pacemaker, with asystole - intravenous injection of vasopressor drugs or resuscitation. Hemodialysis is ineffective.

Interaction:

A drug	Possible drug interactions
Alpha-blockers
Prazozin	Increase in C_m_Oh prazosin (~ 40%), does not affect the half-life of prazosin.
Terazozin	Increase AUC terazosin (~ 24%) and C_m_Oh (~25%).
Antiarrhythmics
Flecainide	The minimal effect on the clearance of flecainide in the blood plasma (<~ 10%); does not affect the clearance of verapamil in the blood plasma.
Quinidine	Reduction of oral clearance of quinidine (~ 35%).
Means for the treatment of bronchial asthma
Theophylline	Reduction of oral and systemic clearance of theophylline (~ 20%). Smoking patients have a decrease of ~ 11%.
Anticonvulsants
Carbamazepine	Increase AUC carbamazepine (~ 46%) in patients with stable partial epilepsy.
Antidepressants
Imipramine	Increase AUC imipramine (~ 15%). Does not affect the level of the active metabolite, desipramine.
Hypoglycemic agents
Glyburide	C increases_m_Oh glyburide (~ 28%), AUC (~26%).
Antimicrobial medications
Erythromycin	It is possible to increase the concentration of verapamil in the blood plasma.
Rifampicin	Decrease AUC verapamil (~ 97%), C_m_Oh (~ 94%), bioavailability of ~ 92%.
Telithromycin	It is possible to increase the concentration of verapamil in the blood plasma.
Antineoplastic agents
Doxorubicin	Increase AUC doxorubicin (89%) and C_m_Oh (61%) with verapamil ingestion in patients with small cell lung cancer. The administration of verapamil intravenously in patients with progressive neoplasms does not affect the pharmacokinetic parameters of doxyrubin.
Barbiturates
Phenobarbital	Increased oral clearance of verapamil - 5 times.
Benzodiazepines and other tranquilizers
Buspirone	Increase AUC buspirone, C_m_Oh - in 3,4 times
Midazolam	Increase AUC Midazolam (~ 3 times) and C_m_Oh (~ 2 times).
Beta-blockers
Metoprolol	Increase AUC metoprolol (~ 32.5%) and C_m_Oh (~ 41%) in patients with angina pectoris.
Propranolol	Increase AUC propranolol (~ 65%) and C_m_Oh (~ 94%) in patients with angina pectoris
Cardiac glycosides
Digitoxin	Decrease in total clearance (~ 27%) and extrarenal clearance (~ 29%) of digitoxin.
Digoxin	In healthy volunteers, C increases_m_Oh digoxin on ~ 45-53%, Css of digoxin by ~ 42% and AUC of digoxin by ~ 52%.
Immunological means
Cyclosporin	Increase AUC, Css, FROM_m_Oh cyclosporine by ~ 45%.
Everolimus	It is possible to increase the level of everolimus in the blood plasma.
Sirolimus	There may be an increase in the level of sirolimus in the blood plasma.
Tacrolimus	It is possible to raise the level of tacrolimus in the blood plasma.
Hypolipidemic agents (inhibitors of HMG-CoA reductase)
Atorvastatin	Possible increase in the level of atorvastatin in blood plasma.
Lovastatin	It is possible to increase the level of lovastatin in the blood plasma.
Simvastatin	Increase AUC (~ 2.6 times) and C_m_Oh (~ 4.6 times) of simvastatin.
The receptor agonists ceRotonin
Almotriptan	Increase AUC (~ 20%) and C_m_Oh (~ 24%) of almotriptan.
Urikozuric means
Sulfinpyrazone	Increased clearance of verapamil (~ 3 times) and a decrease in its bioavailability (~ 60%).
Other
Grapefruit juice	Increase AUC R- (~ 49%) and S-(~37%) verapamil and C_m_Oh R- (~ 75%) and S-(-51%) of verapamil. Half-life and renal clearance did not change.
St. John's wort perforated	Decreased AUC R- (~ 78%) and S- (~80%) verapamil with a corresponding decrease in C_m_Oh.
Other types of interaction
Cimetidine	Reduces the clearance of verapamil with intravenous administration.
	Verapamil as a means, highly binding to blood plasma proteins, should be used with caution when used simultaneously with other drugs with this ability. With the joint application of funds for inhalation of general anesthesia and blockers of "slow" calcium channels, which includes verapamil, the dose of the inhalation general anesthetic should be carefully titrated until the desired effect is achieved in order to avoid excessive inhibition of the cardiovascular system. Verapamil may enhance the effect of drugs that block neuromuscular conduction (such as curare-like and depolarizing muscle relaxants). Therefore, the dose of verapamil and / or doses of drugs blocking neuromuscular conduction should be reduced when they are used simultaneously. It is possible to increase the neurotoxicity of lithium. Verapamil can also reduce lithium levels in serum from patients who receive lithium for a long time. With the simultaneous use of these drugs, careful monitoring of patients is necessary.
Prazosin, terazosin	Additive antihypertensive action.
Ritonavir and other antiviral (HIV) agents	They can inhibit the metabolism of verapamil, which leads to an increase in its concentration in the blood plasma, so the dose of verapamil should be reduced.
Carbamazepine	An increase in the level of carbamazepine in the blood plasma and the occurrence of adverse reactions, such as diplopia, headache, ataxia or dizziness.
Rifampicin	May reduce the antihypertensive effect of verapamil.
Colchicine	Is a substrate for isoenzymes CYP3A and P-glycoprotein, which in turn suppress the metabolism of verapamil. Therefore, with simultaneous use with verapamil, the concentration of colchicine in the blood can significantly increase.
Sulfinpyrazone	May reduce the antihypertensive effect of verapamil.
Acetylsalicylic acid (aspirin)	Increased bleeding.
Hypotensive drugs, diuretics, vasodilators	Increased antihypertensive action.
Lipid-lowering cp- HMG-CoA reductase inhibitors (statins)
Simvastatin / lovastatin / atorvastatin	Simultaneous use with verapamil may lead to an increase in serum concentrations of simvastatin or lovastatin. Patients receiving verapamil, treatment with HMG-CoA reductase inhibitors (ie simvastatin, atorvastatin, lovastatin) should be started with as low a dose as possible, which is further increased. If it is necessary to appoint verapamil to patients already receiving inhibitors of HMG-CoA reductase, it is necessary to review and reduce their doses according to the concentration of cholesterol in serum. Similar tactics should be followed and with the simultaneous appointment of verapamil with atorvastatin, although there is no clinical data confirming their interaction.
Fluvastatin, pravastatin and rosuvastatin	Do not metabolize under the action of isoenzymes CYP3A4, so their interaction with verapamil is least likely. Although intravenous verapamil and was used in conjunction with digitalis preparations without serious side effects, but, given that these drugs slow down AV conductivity, it is necessary to monitor patients for timely detection AV blockade or severe bradycardia.
Quinidine	Perhaps the development of arterial hypotension with the combined use of quinidine and verapamil intravenously, so this combination of drugs should be used with caution.
Beta-blockers	Simultaneous intravenous administration of verapamil and beta-blockers led to serious side effects (severe bradycardia), especially in patients with cardiomyopathy, heart failure, or recent myocardial infarction. Beta-blockers should be administered several hours before or several hours after the use of verapamil. Do not administer disopyramide 48 hours before or 24 hours after using verapamil. With the combined use of verapamil and flecainide, additive action is possible with a decrease in myocardial contractility, lengthening of AV conduction and repolarization of the myocardium.

Pharmaceutical interaction

To avoid disturbance of stability, it is not recommended to dilute Verapamil with sodium lactate solutions in plastic bags of PVC. It should avoid mixing solutions of the drug Verapamil and albumin, amphotericin B, hydralazine or trimethoprim and sulfamethoxazole.

Special instructions:Chronic heart failure (other than severe or caused by arrhythmia) should be compensated with cardiac glycosides and diuretics before the drug therapy begins.

In patients with moderate and severe (III and IV functional class by classification NYHA) chronic heart failure (pulmonary artery wedge pressure more than 20 mm Hg, left ventricular ejection fraction less than 30%) with the prescription of the drug may develop acute decompensation of chronic heart failure.

Effect on the ability to drive transp. cf. and fur:After using verapamil, individual reactions (drowsiness, dizziness) are possible. It can affect the ability to concentrate (driving and working with mechanisms), especially at the beginning of treatment and / or with the simultaneous intake of alcohol. With caution apply during work drivers of vehicles and people whose profession is associated with increased concentration of attention.

Form release / dosage:

Solution for intravenous administration, 2.5 mg / ml.

Packaging:

2 ml per ampoule of neutral glass.

5 ampoules are placed in a contour mesh package made of a polyvinyl chloride film. 2 contour squares are placed in a pack of cardboard.

10 ampoules are placed in a box of cardboard with corrugated paper partitions.

In each pack, a box of cardboard insert instructions for use, a knife ampoule or scarifier. When packing ampoules with a ring of fracture, break points and incisions, the ampoule opener or scarifier is not inserted.

Storage conditions:

In the dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LS-001594

Date of registration:24.06.2011

Expiration Date:Unlimited

The owner of the registration certificate:BIOSINTEZ, PAO BIOSINTEZ, PAO Russia

Manufacturer: & nbsp

BIOSINTEZ, PAO Russia

Information update date: & nbsp28.01.2017

Illustrated instructions

Instructions

Verapamil (Verapamil)