Изоптин® WEDNESDAY 240

General characteristics. Structure:

Contains in one tablet:

Active agent: verapamil hydrochloride of 240 mg.

Excipients: cellulose of microcrystallic 78,8 mg, sodium алгинат 320,0 mg, povidon-K30 48,0 mg, magnesium stearate of 3,2 mg, the water purified 30,0 mg.

Film covering: gipromelloza-2910 4,90 mg, macrogoal-400 of 1,26 mg, macrogoal-6000 of 0,84 mg, talc of 8,40 mg, titanium dioxide of 6,16 mg, varnish aluminum: (dye quinolinic yellow (E 104) + indigo dye carmine (E 132) of 0,14 mg, wax of mountain glikoliyevy 0,30 mg.

Description

Light green tablets of oblong shape, film coated. Tablets on both sides have cross risks. On one party two signs "D" are engraved.

Pharmacological properties:

Pharmacodynamics. Verapamil blocks transmembrane current of calcium ions to sokratitelny fibers of smooth muscle cells of a myocardium and coronary vessels. Reduces the need of a myocardium for oxygen that is connected as with direct action on a myocardium at the level of cellular metabolic processes, and with the mediated action on a cardiac muscle due to decrease in an afterload.

Blocking receipt of calcium ions to sokratitelny fibers of smooth muscle cells of coronary arteries, increases perfusion of a myocardium, even in post-stenosed sites, and removes a spasm of coronary arteries.

Anti-hypertensive activity of verapamil is caused by decrease in the general resistance of peripheral vessels without compensatory increase in the heart rate (HR). Verapamil does not influence the normal arterial pressure (AP).

Verapamil possesses the expressed antiarrhytmic action, in particular at supraventricular arrhythmia. Carrying out an impulse in an atrioventricular (AV) node therefore the sinoatrial rate is recovered detains and/or the frequency of reductions of ventricles is normalized depending on arrhythmia type. Verapamil does not influence or slightly urezhat ChSS.

Pharmacokinetics. Verapamil, active agent of the drug Izoptin® WEDNESDAY 240, quickly and almost is completely soaked up in a small bowel. Extent of absorption makes more than 90%. Average system bioavailability at healthy volunteers after a single dose of verapamil inside makes 22% that is caused by effect of "primary passing" through a liver. Bioavailability of verapamil at repeated use increases approximately twice. Time of achievement of the maximum concentration in a blood plasma makes 1-2 hours. The elimination half-life (T1/2) is equal on average 3-7 hours. Communication with proteins of a blood plasma about 90%.

Verapamil is exposed to intensive metabolism with formation of a large number of metabolites. Among metabolites only norverapamit has pharmacological activity (about 20% in comparison with initial connection).

Verapamil and its metabolites are removed generally through kidneys, and only 3-4% in not changed look. Within 24 hours of 50% of the entered dose of verapamil it is removed by kidneys, within five days — 70%. To 16% it is removed through intestines.

Verapamil gets through a placental barrier and is emitted with breast milk.

Renal failure

Recently received results of comparative researches demonstrate that there are no distinctions of pharmacokinetic indicators of verapamil at healthy volunteers with normal function of kidneys and at patients with an end-stage of a renal failure. Verapamil is not removed at a hemodialysis.

Abnormal liver function

At patients with an abnormal liver function the elimination half-life of verapamil is extended because of lower peroral clearance of verapamil and bigger volume of distribution.

Indications to use:

Arterial hypertension.
Coronary heart disease, including chronic stable stenocardia (a classical angina of exertion); unstable stenocardia; the stenocardia caused by a spasm of coronary vessels (Printsmetal's stenocardia).
Bouveret's supraventricular disease.
Blinking/atrial flutter, followed by a tachyarrhythmia (except for a WPW-syndrome and Launa-Ganonga-Levina).

Route of administration and doses:

Inside.

Изоптин® WEDNESDAY 240 it is necessary to swallow entirely, washing down with water, it is desirable during meal or right after food, they cannot be rassasyvat or chewed. Tablets can be divided on put risk.

The dose of the drug Izoptin® WEDNESDAY 240 should be selected individually depending on a clinical picture and disease severity.

The dose for all recommended indications to use varies from 120 (1/2 tablets) up to 480 mg (2 tablets) once a day or in 2 receptions at an interval of 12 hours.

At prolonged treatment it is not necessary to exceed a daily dose of 480 mg. In the maximum daily dose drug is recommended to be accepted only in a hospital.

Duration of therapy is defined by the doctor.

Drug cannot be cancelled sharply, it is recommended to reduce gradually a dose by means of use of the drug Izoptin® in doses of 40 mg and 80 mg to full drug withdrawal.

At patients with the broken function of a liver and to elderly patients the dose should be selected with extra care and treatment should be begun with lower doses (by means of use of the drug Izoptin® in doses of 40 mg and 80 mg).

Features of use:

Clinical trials showed that the pharmacokinetics of verapamil does not change at patients in an end-stage of a renal failure. However several registered cases demonstrate that at use of verapamil it is necessary to be careful and control of a condition of patients with a renal failure is necessary.

Influence on ability to control of motor transport and work with mechanisms

It is necessary to be careful at control of motor transport and work with the mechanisms demanding the increased concentration of attention.

Side effects:

From immune system: hypersensitivity reactions.

From the central nervous system: a headache, dizziness, paresthesias, a tremor, increased fatigue, extrapyramidal disturbances (the ataxy, a "masklike" face "shuffling" gait, rigidity of hands or legs, trembling of brushes and fingers of hands, swallowing difficulty).

From an acoustic organ: a ring in ears.

From cardiovascular system: AV blockade of I, II, III degrees, a stop of a sinus node, peripheral hypostases, tachycardia, a sinus bradycardia, heart failure, the expressed lowering of arterial pressure, "inflows" of blood to face skin, a heart consciousness.

From the alimentary system: nausea, vomiting, a lock, intestinal impassability, a hyperplasia of gums, pain or discomfort in a stomach.

From integuments: Quincke's disease, Stephens-Johnson's syndrome, makulopapulezny rash, small tortoiseshell, purpura, skin itch, mnogoformny erythema, alopecia.

From a musculoskeletal system: muscular weakness, mialgiya, arthralgia.

From reproductive system and chest glands: erectile dysfunction, galactorrhoea, gynecomastia.

From laboratory indicators: increase in activity of "hepatic" enzymes, giperprolaktinemiya.

Interaction with other medicines:

The researches in vitro demonstrate that verapamil is metabolized by means of isoenzymes of CYP3A4, CYP1A2, CYP2C8, CYP2C9 and CYP2C18 of P450 cytochrome and is inhibitor of an isoenzyme CYP3A4 and R-glycoprotein. Clinically significant interaction was noted at simultaneous use of inhibitors of an isoenzyme of CYP3A4 which caused increase in concentration of verapamil in a blood plasma while inductors of an isoenzyme CYP3A4 reduced its concentration in a blood plasma. Respectively, at simultaneous use of similar means, it is necessary to consider a possibility of this interaction.

The list of possible pharmacokinetic interaction of medicines where Cmax — the maximum concentration in a blood plasma, is presented to Css in the table — average equilibrium concentration in a blood plasma, AUC — the area under a pharmacokinetic curve "concentration time".

Drug                                                              Possible interaction 
Alpha adrenoblockers
Prazozinum                                         Increase in Cmax of Prazozinum (~ 40%), does not influence Prazozinum T1/2.
Terazozin                                        Increase in AUC of a terazozin (~ 24%) and Cmax (~ 25%).
Antiarrhytmic means
Flekainid                                      the Minimum action on clearance of a flekainid in a blood plasma (<~ 10%); does not influence clearance of verapamil in a blood plasma.
Quinidine                                           Reduction of peroral clearance of quinidine (~ 35%).
Bronkhodilatiruyushchy means
Theophylline                                       Reduction of peroral and system clearance of quinidine (~ 20%). The smoking patients have a reduction approximately for 11%.
Anticonvulsants
Carbamazepine                                Increase in AUC carbamazepine (~ 46%) at patients with steady partial epilepsy.
Antidepressants
Imipraminum                                     Increase in AUC of Imipraminum (~ 15%).

                                                       Does not influence concentration of an active metabolite of desipramine.
Hypoglycemic means for intake
Glibenclamidum                                 Increase in Cmax of Glibenclamidum (~ 28%) and AUC (~ 26%).
Antimicrobic means
Klaritromitsin                                Vozmozhno increase in concentration of verapamil in a blood plasma.
Erythromycin                                   increase in concentration of verapamil in a blood plasma is possible.
Rifampicin                                     AUC verapamil Reduction (~ 97%), Cmax (~ 94%), bioavailability (~ 92%).
Telitromitsin                                 Vozmozhno increase in concentration of verapamil in a blood plasma.
Antineoplastic means
Doxorubicine                                Increase in AUC (89%) of doxorubicine and Cmax (~ 61%) at patients with small-celled cancer of a lung.
Barbiturates
Phenobarbital                                  Increase in peroral clearance of verapamil ~ by 5 times.
Benzodiazepines and other tranquilizers
Buspiron                                         Increase in AUC of a buspiron and Cmax ~ by 3,4 times.
Midazolam                                       Increase in AUC midazolam (~ by 3 times) and Cmax (~ twice).
Beta adrenoblockers
Metoprolol                                    Increase in AUC of a metoprolol (~ 32,5%) and Cmax (~ 41%) at patients with stenocardia.
Propranolol                                  Increase in AUC propranolol (~ 65%) and Cmax (~ 94%) at patients with stenocardia.
Cardiac glycosides
Digitoxin                                       Reduction of the general clearance (~ 27%) and extrarenal clearance (~ 29%) digitoxin.
Digoxin                                         At healthy volunteers digoxin Cmax on ~ 45-53%, digoxin Css on ~ 42% and AUC on ~ 52% increase.
Blockers of H2-histamine receptors
Cimetidinum                                     Increase in AUC R-(~ 25%) and S-(~ 40%) verapamil with the corresponding reduction of clearance of R-and S-verapamil.
Immunodepressive means
Cyclosporine                                         Increase in AUC, Css, cyclosporine Cmax on ~ 45%
Sirolimus                                       Vozmozhno increase in concentration of a sirolimus in a blood plasma
Takrolimus                                      Vozmozhno increase in concentration of a takrolimus in a blood plasma
Everolimus                                      Vozmozhno increase in concentration of an everolimus in a blood plasma
Hypolipidemic means — GMG-KOA-reduktazy inhibitors
Atorvastatin                                 Vozmozhno increase in concentration of an atorvastatin in a blood plasma

                                                     Increase in AUC is possible (~ 42,8%)
Lovastatin                                      Vozmozhno increase in concentration of a lovastatin in a blood plasma
Simvastatin                                   Increase in AUC (~ by 2,6 times) and Cmax (~ by 4,6 times) a simvastatina
Antagonists of receptors of serotonin
Almotriptan                                      Increase in AUC (~ 20%) and Cmax (~ 24%) almotriptana
Uricosuric means
Sulfinpyrazonum                            Increase in peroral clearance of verapamil (~ by 3 times), decrease in bioavailability (~ 60%)
Others
Grapefruit juice                        Increase in AUC R-(~ 49%) and S-(~ 37%) verapamil and Cmax R-(~ 75%) and S-(~ 51%) verapamil. The elimination half-life and renal clearance did not change.
The St. John's Wort which is made a hole           Decreases AUC R-(~ 78%) and S-(~ 80%) verapamil with the corresponding decrease in Cmax.
Antiarrhytmic means, beta adrenoblockers      Mutual strengthening of cardiovascular effects (the blockade which was more expressed to AV, more considerable urezheniye of ChSS, development of symptoms of heart failure and strengthening of arterial hypotension).

Antihypertensives, diuretics, vazodilatator       Strengthening of hypotensive effect.

Prazozinum, теразозин

The additive hypotensive action.

Antiviral means for treatment of HIV infection

Ritonavir and other antiviral means for treatment of HIV infection can inhibit verapamil metabolism that leads to increase in its concentration in a blood plasma. At simultaneous use of a dose of the drug Izoptin® WEDNESDAY have to be reduced.

Quinidine

At simultaneous use with verapamil strengthening of hypotensive action is possible.

At patients with a hypertrophic subaortic stenosis the fluid lungs can develop.

Carbamazepine

Increase in concentration of carbamazepine in a blood plasma. Side reactions inherent to carbamazepine, such as diplopia, headache, ataxy or dizziness can be observed.

Lithium

Increase in a neurotoxicity of lithium.

Rifampicin

Can reduce hypotensive effect of verapamil.

Sulfinpyrazonum

Can reduce hypotensive effect of verapamil.

Muscle relaxants

The effect of muscle relaxants can amplify.

Acetylsalicylic acid

Increase in bleeding.

Ethanol (alcohol)

Increase in concentration of ethanol in a blood plasma.

Hypolipidemic means — inhibitors of GMG-KOA-reduktazy (statines)

To the patients accepting Izoptin® of WEDNESDAY 240, treatment by GMG-KOA-reduktazy inhibitors (for example: simvastatiny, lovastatiny, atorvastatiny) it is necessary to begin with perhaps lower doses which at therapy continuation gradually raise further. If it is necessary to use the drug Izoptin® WEDNESDAY 240 at the patients who are already receiving GMG-KOA-reduktazy inhibitors it is recommended to consider the possibility of a dose decline of statines and repeated titration of a dose taking into account concentration of cholesterol in blood serum.

Fluvastatin, правастатин and розувастатин are not metabolized under the influence of CYP3A4 isoenzyme therefore their interaction with verapamil is least probable.

Colchicine

Colchicine is substrate for an isoenzyme of CYP3A and a P-glycoprotein which in turn, suppress verapamil metabolism. Therefore at simultaneous use with verapamil concentration of colchicine in blood can increase considerably.

In the post-marketing period of use 1 message on paralysis (tetraparesis) connected with simultaneous use of verapamil and colchicine is received. Perhaps, this state was caused by the colchicine which passed through a blood-brain barrier owing to inhibition of an isoenzyme of CYP3A4 and a P-glycoprotein verapamil.

Contraindications:

Hypersensitivity to active agent or auxiliary components of drug.
Cardiogenic shock.
The acute myocardial infarction complicated by bradycardia, arterial hypotension and a left ventricular failure.
AV blockade of II or III degrees except for patients with an artificial pacemaker.
Sick sinus syndrome (syndrome of "bradycardia tachycardia") except for patients with an artificial pacemaker.
Chronic heart failure.
Blinking/atrial flutter in the presence of additional ways of carrying out (a WPW-syndrome and Launa-Ganonga-Levina).
Concomitant use with colchicine.
Pregnancy.
Age up to 18 years (efficiency and safety are not established).
With care

AV the blockade of the I degree, bradycardia, arterial hypotension expressed an abnormal liver function and kidneys, the diseases concerning neuro and muscular transfer (gravis myasthenia, a syndrome of Lambera-Eton, muscular dystrophy of Dyushen), the breastfeeding period.

Use at pregnancy and during breastfeeding

Data on a clinical use of the drug Izoptin® WEDNESDAY 240 during pregnancy are not enough therefore drug should not be used during pregnancy.

It is established that verapamil gets through a gematoplatsentarny barrier.

The verapamil dose which is received by children with mother's milk makes 0,1-1% of a verapamil dose which was accepted by mother. Considering possibility of side effects at the child receiving verapamil with mother's milk, the drug Izoptin® WEDNESDAY 240 during breastfeeding should be accepted only if the advantage for mother exceeds possible risk for the child.

Overdose:

Symptoms: the expressed decrease in the ABP, the sinus bradycardia passing blockade of high degree into AV a stop of a sinus node, a hyperglycemia, a stupor and a metabolic acidosis. It was reported about lethal cases as a result of overdose.

Treatment: it is necessary to carry out a symptomatic and maintenance therapy, including a gastric lavage and intestines, reception of absorbent carbon, parenteral administration of drugs of calcium and beta-adrenergic agonists. Verapamil is not removed by means of a hemodialysis.

Storage conditions:

To store at a temperature from 15 to 25 °C. To store in the place, unavailable to children. Period of validity 3 years. Not to apply after the period of validity specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Tablets of the prolonged action film coated, 240 mg. On 10, 15 or 20 tablets in the blister from foil PVH/PVDH/AL. On 1, 2, 3, 5 or 10 blisters together with the application instruction in a cardboard pack.