Pharmacological properties

Pharmacodynamics. verapamil belongs to derivatives of a fenilalkilamin. selection blocker of calcium channels. medicament shows antihypertensive, anti-anginal, anti-ischemic and antiarrhytmic properties. the mechanism of pharmacological effect of medicament consists in blockade of sa2+-channels and oppression of transmembrane transfer of ions sa2 + mainly in cells of unstriated muscles of vessels and a myocardium. in myocardium ischemia verapamil eliminates a disproportion between requirement and supply of heart with oxygen, reduces contractility of a myocardium, has vazodilatiruyushchy effect. decrease in a tone of peripheral arteries promotes decrease opss and hell. verapamil oppresses sinuatrial and the av-conductivity, possesses antiarrhytmic action. normal level chss does not change or slightly decreases.

Pharmacokinetics. After administration of medicament inside verapamil is gradually released from capsular weight at the expense of what constant concentration in blood is maintained it. Time of achievement of the C _max in blood plasma — 5–7 h. Release of medicament happens almost linearly during 8–12 h. It is metabolized at the first passing through a liver with formation of several metabolites. The basic from them is norverapamit, the verapamil having less significant hypotensive activity, than not changed. Linking with proteins of blood plasma — 90%.

Owing to effect of the first passing through a liver the bioavailability of medicament at single dose is 30%, and T _½ — about 7 h. At multiple dose of T _½ 12 h average that is connected with saturation of fermental systems of a liver and increase in concentration of verapamil in blood plasma. It is excreted generally with urine (70%) in the form of metabolites, partially — with a stake.

Indication

Ag; ischemic heart disease: a stable angina of exertion, alternative stenocardia (stenocardia printsmetat); arrhythmia: Bouveret's supraventricular disease; trembling/fibrillation of auricles with fast av-carrying out (except for wpw with-ma).

a medicament Dose the doctor selects

individually. the average daily dose at all indications makes 180–360 mg. in an initiation of treatment appoint on 1 capsule (180 mg) of 1 times a day, in the morning. if necessary the dose is raised to 360 mg/days (on 1 capsule in the morning and in the evening, with an interval about 12 h between receptions). exceeding a dose is possible only for very short time and under careful observation of the doctor.

, depending on severity, effect of verapamil of a hydrochloride amplifies and extended with

At patients with an abnormal liver function in connection with medicine disintegration delay. Therefore in such cases the dosing needs to be established with extra care and to begin with low doses (for example 2–3 times a day on 40 mg, according to 80–120 mg/days). Verapamil medicaments with a possibility of such dosing are used.

Verapamil can be accepted to, in time or after a meal, without chewing and not rassasyvy, washing down with a small amount of water.

not to take the medicament in a prone position.

Verapamil cannot appoint a hydrochloride the patient with a myocardial infarction for 7 days after its development.

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

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

Contraindication

Hypersensitivity to verapamil or other components of drug; kardiogenny shock; a sharp phase of a myocardial infarction with complications (bradycardia 50 ud. / min., arterial hypotension (systolic hell is lower than 90 mm Hg.), insufficiency of a left ventricle); heavy disturbances of conductivity: sinuatrial and av-blockade of ii-iii of degree (except for patients with an artificial pacemaker); a syndrome of weakness of a sinus node (except for patients with an artificial pacemaker); stagnant heart failure; a blinking/atrial flutter (against the background of wpw with-ma and a syndrome of Loen — a genome — Levine (lgl). simultaneous in/in introduction of blockers of β-adrenoceptors (except for intensive care).

Period of pregnancy and feeding by a breast.

Side effects

from a cardiovascular system: stenocardia, arterial hypotension, sinuatrial and av-blockade (av-blockade of i, ii or iii of degree), bradycardia, bradyarrhythmia with fibrillation of auricles, a stop of sinus node, an asystolia. risk of aggravation/development of heart failure, orthostatic reactions. in the rare occurences — tachycardia. also the myocardial infarction, heart consciousness, peripheral hypostases of ankles, a syncope, inflows were noted pain behind a breast.

from a GIT: gastrointestinal disorders, such as nausea, (sometimes — vomiting), a meteorism, an intestines atony, a constipation. It was reported about dryness in a mouth, a hyperplasia of gums (ulitis and bleeding), discomfort in a stomach, intestinal impassability, pain.

from central nervous system: disturbance of cerebral circulation, confusion of consciousness, balance disturbance, fatigue, insomnia, nervousness, muscular spasms, psychosis, neuropathy, extrapyramidal syndrome, drowsiness, headache, touch disorders, such as sonitus, paresthesia, tremor, dizziness.

from an organ of hearing and a vestibular mechanism: dizziness, a ring in ears.

from an urinogenital system: erectile dysfunction, including impotence, frequent urinations, disturbance of a menstrual cycle. In isolated cases at elderly people at long therapy the gynecomastia which completely stopped after medicament withdrawal, in the rare occurences — a galactorrhoea developed.

from a basic and muscular system: muscle weakness, myalgia, arthralgia.

Skin and hypodermic fabrics: an enanthesis (including a small tortoiseshell), an itching, an allopecia, a hyperkeratosis, pigmentation disturbance, an eritromelalgiya, a multiformny erythema, makulopapulezny rash, in the rare occurences — Stephens's syndrome — Johnson, a hemorrhage, a Quincke's edema, photodermatites. In isolated cases — a purpura.

from a gepatobiliarny system: increase in level of transaminases, alkaline phosphatase and bilirubin can be noted. Injuries of a liver with clinical manifestations (feeling sick, fervescence and/or pain in right hypochondrium) therefore it is reasonable to control function of a liver periodically are possible. In certain cases these changes independently disappear at long therapy.

from the immune system: in isolated cases it was reported about hypersensitivity. In the rare occurences it was reported about allergic hepatitis, a bronchospasm.

Other manifestations: illegibility of sight, increase in level of prolactin in blood plasma. Decrease in tolerance to glucose was sometimes noted. It was reported about paralysis (tetraparesis) associated with the combined use of verapamil and colchicine therefore the combined use of colchicine and verapamil is not recommended.

Special instructions

during use of verapamil and definition of its dose needs to pay special attention to patients with av-blockade of i of degree; with arterial hypotension (systolic hell of 90 mm Hg.); with bradycardia (chss 50 ud. / mines).

With care is appointed:

• to patients with heart failure — can cause asymptomatic AV blockade of the II degree or passing bradycardia. At development of AV blockade it is necessary to lower a dose or to stop administration of drug;
• to patients with the hypertrophic cardiomyopathy including complicated by obstruction of a left ventricle, high pressure of jamming in pulmonary capillaries, dysfunction sinus peredserdnogo a node;
• to patients with fibrilyatsiyey / an atrial flutter and the accompanying WPW with-mom (risk of developing of ventricular tachycardia);
• in diseases with disturbances of neuromuscular transmission (a myasthenia (Myastenia gravis), Lambert's syndrome — Eaton);
• to patients with muscular dystrophy of Dyushen — verapamil reduces neuromuscular conductivity and extends the restoration period after the neuromuscular blockade caused vekuroniy. The medicament dose decline is necessary;
to patients with an abnormal liver function — depending on severity the effect of verapamil of a hydrochloride amplifies and extended with
• in connection with medicine disintegration delay therefore dosing needs to be observed with extra care;
• to patients with a renal failure (under careful observation);
• to elderly people with hypersensitivity to effect of drug, even under conditions of usual dosing;
• at surgeries in connection with potentiation of the oppressing influence of the general anesthetics on a myocardium and muscle relaxants on skeletal muscles.

needs to control R-Q interval duration on the ECG and also other signs of possible overdose of verapamil (regular control of ChSS, etc.).

during use of medicament needs to avoid the use of dishes and drinks with grapefruit as it can increase hydrochloride verapamil level in blood plasma.

Use during pregnancy and feeding by a breast.

should not take the Drug in I and II trimester of pregnancy. Use of medicament in the III trimester of pregnancy is possible only in urgent cases when the positive effect for mother exceeds potential risk for the fruit/child. Verapamil gets through a placenta into umbilical blood.

Biologically active agent gets into breast milk. Limited data on oral administration 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 combined with feeding by a breast. In view of risk of emergence of serious side reactions in newborns who are nursed, verapamil during this period is applied only in urgent cases to mother.

Children. To children medicament in this dosage form is not appointed.

Ability to influence speed of response at control of vehicles or work with other mechanisms. Depending on individual reaction the ability to control of vehicles or work with mechanisms can be broken. Especially it concerns an initial phase of treatment, at increase in a dose, change of hypotensive drug.

Interaction

Single use:

with blockers of β-adrenoceptors is increased by the mutual oppressing action by automatism of a SA node, AV-conductivity and contractility of a myocardium thereof risk of developing the profound arterial hypotension, AV- and SA blockade, bradycardia, heart failure increases, especially at use of high doses of blockers of β-adrenoceptors or at them in in introduction — appointment only according to accurate indications and under stringent control of the doctor;

with antihypertensive medicaments (for example vazodilatator, APF inhibitors, diuretics, blockers of α-adrenoceptors, Prazozinum and terazozin) — their potentsiirovany actions;

with tricyclic antidepressants, neuroleptics — exponentiate hypotensive effect of verapamil;

with cardiac glycosides (for example digoxin) — in an initiation of treatment (1st week) the digoxin level in blood serum increases by 50–70% therefore it is necessary to modify a digoxin dose, and periodically to control its level in blood serum;

with digitoxin — decrease in clearance of digitoxin (~ 27%) and extrarenal clearance (~ 29%);

does not recommend a verapamil combination with:

antiarrhytmic medicaments I-III of a class (including Amiodaronum);

not earlier, than in 24 h after the termination of its reception;

acetylsalicylic acid — the raised possibility of bleeding;

flekainidy — the mutual oppressing action on a myocardium essentially changes, slows down AV conductivity and repolarization duration increases;

quinidine — the profound arterial hypotension at patients with a hypertrophic cardiomyopathy can develop;

oral contraceptive drugs, hydantoin, salicylates, streptocides and derivatives of sulphonylurea — owing to high extent of binding, as well as verapamil, with proteins;

salts of calcium and vitamin D — the pharmacological effect of verapamil decreases;

propranolol, metoprololy — their clearance can decrease;

rifampicin, phenobarbital — can reduce efficiency of verapamil;

buspirony — increase in AUC and C _max by 3–4 times;

Sulfinpyrazonum — decrease in hypotensive effect can be noted;

midazolam — increase in AUC by 3 times and the C _max — twice;

lithium salts — their concentration in blood serum can change therefore patients have to be under careful observation;

cyclosporine, everolimusy, sirolimusy, takrolimusy, inhibitors of serotoninovy receptors (such, as almotriptan), carbamazepine, theophylline; with substrates of P450 cytochrome of isoenzyme 3A4, for example, CSE inhibitors (lovastatin or atorvastatin) — increase in their level in blood serum;

Imipraminum — increase in AUC (~ 15%) without influence on an active metabolite desipramine;

antagonists of H ₂ - receptors (Cimetidinum),

antiretrovirusny medicaments (ritonavir, indinavir) — increase in concentration of verapamil in blood plasma is possible. Appoint with care, the verapamil dose decline can be necessary with:

inhalation anesthetics or blockers of neuromuscular transfer — doses of medicaments needs to be modified in order to avoid the oppressing action on action of the heart;

macroleads (for example erythromycin, klaritromitsin) — mutual increase in level in blood plasma;

GMG-KoA-reduktazy inhibitors (simvastatiny, atorvastatiny, lovastatiny) in high doses — the risk of a myopathy, a rhabdomyolysis increases. Dosing has to be respectively coordinated. If the patient who already accepts verapamil needs prescribing of inhibitor of GMG-KoA-reduktazy, it is necessary to remember need of a dose decline of statines and to pick up dosing according to concentration of XC in blood plasma;

anti-diabetic medicaments (Glyburidum) — the C _max Glyburidum increases by 28%;

doxorubicine — also the maximum level of doxorubicine in blood plasma at patients with small cell lung cancer increases biodostupnist;

X-ray contrast means — oppressed influence of verapamil on automatism of a SA node, AV-conductivity and contractility of a myocardium can exponentiate;

ethanol — disintegration is delayed and its level in blood plasma increases, thereby strengthening effect of alcohol;

grapefruit juice — raises biodostupnist verapamil;

St. John's wort which is made a hole — AUC R-(~ 78%) and S-verapamil (~ 80%) with the corresponding decrease in the C _{max decreases} .

Fluvastatin, pravastatin and rosuvastatin practically do not interact with verapamil.

to increase in effect of colchicine. The combined use is not recommended.

Overdose

Main symptoms of overdose of verapamil: decrease hell (in certain cases to the level which cannot be determined); shock symptoms, loss of consciousness; av-blockade of i and ii of degree, it is frequent in the form of the periods of a venkebakh; full av-blockade, av-dissociation, sinus bradycardia, blockade of a sinus node, cardiac arrest or an asystolia, dizziness up to coma, a stupor, a hyperglycemia, a hypopotassemia, a metabolic acidosis, a hypoxia, kardiogenny shock with a fluid lungs, a renal failure and spasms.

Treatment: the therapeutic measures directed to removal of substance from an organism and restoration of stability of a cardiovascular system.

General measures: it is recommended to wash out a stomach even if there passed more than 12 h from the moment of administration of medicament and the motility of a GIT is not defined (lack of intestinal noise). The general resuscitation measures include indirect cardiac massage, artificial respiration, a defibrillation, cardiostimulation.

. Haemo filtration and, perhaps, a plasma exchange can be effective (antagonists of calcium well contact proteins of plasma).

Special measures: elimination of cardiodepressive influences, arterial hypotension and bradycardia. Specific antidote is calcium: in/in 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 the additional slowed-down drop infusion (5 mmol/h).

Additional measures: at AV blockade of II and III degree, sinus bradycardia, cardiac arrest apply atropine, Isoproterenolum, ortsiprenalin or cardiostimulation.

in case of arterial hypotension owing to cardiogenic shock and an arterial vazodilatation apply a dopamine (to 25 mkg/kg/min.), Dobutaminum (up to 15 mkg/kg/min.) or noradrenaline. Concentration of calcium in blood serum has to answer the upper bound of norm or to be a little higher. Due to the vazodilatation at early stages the replaceable input of the fluid is carried out (Ringera solution or 0.9% chloride sodium solution).

Storage conditions

In original packing at a temperature not above 25 °C.