Universal reference book for medicines
Product name: ISOPTIN ® (ISOPTIN ® )

Active substance: verapamil

Type: Calcium channel blocker

Manufacturer: ABBOTT (Germany)
Composition, form of production and packaging
The tablets covered with a film cover of
white color, round, biconcave, with an engraving "40" on one side and a triangle - on another.

1 tab.

verapamil hydrochloride 40 mg

Excipients: calcium hydrophosphate dihydrate - 70 mg, microcrystalline cellulose - 23 mg, silicon dioxide colloid - 0.7 mg, croscarmellose sodium - 1.8 mg, magnesium stearate - 1.5 mg.

Composition of the film coat: hypromellose 3 mPa - 1.7 mg, sodium lauryl sulfate - 0.1 mg, macrogol 6000 - 2 mg, talc - 4 mg, titanium dioxide - 1 mg.

10 pieces.
- blisters (2) - packs of cardboard.
10 pieces.
- blisters (10) - packs of cardboard.
20 pcs.
- blisters (1) - packs of cardboard.
20 pcs.
- blisters (5) - packs of cardboard.
The tablets covered with a film shell of white color, round, biconcave, with engraving "ISOPTIN 80" on one side and "KNOLL" above the risk for division - on the other.

1 tab.

verapamil hydrochloride 80 mg

Excipients: calcium hydrophosphate dihydrate - 140 mg, microcrystalline cellulose - 46 mg, silicon dioxide colloid - 1.4 mg, croscarmellose sodium - 3.6 mg, magnesium stearate - 3 mg.

The composition of the film coat: hypromellose 3 mPa - 2 mg, sodium lauryl sulfate - 0.1 mg, macrogol 6000 - 2.3 mg, talc - 4.5 mg, titanium dioxide - 1.1 mg.

10 pieces.
- blisters (2) - packs of cardboard.
10 pieces.
- blisters (10) - packs of cardboard.
20 pcs.
- blisters (1) - packs of cardboard.
20 pcs.
- blisters (5) - packs of cardboard.
25 pcs.
- blisters (4) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.

Description of the drug approved by the manufacturer for the printed edition of 2011.

PHARMACHOLOGIC EFFECT

Verapamil blocks the transmembrane current of calcium ions to the contractile fibers of the smooth muscle cells of the myocardium and coronary vessels.
Reduces the need for myocardium in oxygen, which is associated with both direct action on the myocardium at the level of cellular metabolic processes, and with an indirect effect on the cardiac muscle due to decreased afterload.
Blocking the flow of calcium ions to the contractile fibers of the smooth muscle cells of the coronary arteries, increases myocardial perfusion, even in post-stenotic areas, and relieves coronary spasm.
Antihypertensive activity of verapamil is caused by a decrease in the overall resistance of peripheral vessels without a compensatory increase in heart rate. Verapamil does not affect normal blood pressure.
Verapamil has a pronounced antiarrhythmic effect, especially with supraventricular arrhythmia, delays the holding of a pulse in the AV node, resulting in the restoration of the sinus rhythm and / or the frequency of ventricular contractions is normalized depending on the type of arrhythmia.
Verapamil does not affect or slightly reduces the heart rate.
PHARMACOKINETICS

Verapamil, the active substance of Isoptin, is rapidly and almost completely absorbed into the small intestine.
The degree of absorption is more than 90%. The average systemic bioavailability in healthy volunteers after a single dose of verapamil inside is 22%, which is due to the effect of a "first pass" through the liver. The bioavailability of verapamil is increased by approximately 2 times with repeated application. The time to reach C max in blood plasma is 1-2 hours. T 1/2 is an average of 3-7 hours. Binding to plasma proteins is about 90%.
Verapamil undergoes intensive metabolism with the formation of a large number of metabolites.
Among metabolites, only noravapamil has pharmacological activity (about 20% compared to the parent compound).
Verapamil and its metabolites are excreted mainly through the kidneys, with only 3-4% unchanged.
Within 24 hours, 50% of the injected dose of verapamil is excreted by the kidneys, within five days - 70%. Up to 16% is excreted through the intestine.
Verapamil penetrates the placental barrier and is excreted in breast milk.

Impaired renal function

Recently obtained results of comparative studies indicate that there are no differences in the pharmacokinetic parameters of verapamil in healthy volunteers with normal renal function and in patients in the terminal stage of renal failure.
Verapamil is not excreted in hemodialysis.
Impaired liver function

In patients with impaired liver function, T 1/2 verapamil is elongated due to lower oral clearance of the drug and a larger V d .

INDICATIONS

- arterial hypertension;

- Ischemic heart disease, including chronic stable angina (classical angina of tension), unstable angina, angina due to vasospasm (Prinzmetal angina);

paroxysmal supraventricular tachycardia;

- Atrial fibrillation / flutter, accompanied by tachyarrhythmia (with the exception of Wolff-Parkinson-White syndrome and Laun-Ganong-Levin syndrome).

DOSING MODE

Inside.

Tablets should be swallowed whole, washed down with water, taken preferably during meals or immediately after meals, they can not be dissolved or chewed.

The dose of Isoptin should be administered individually, depending on the clinical picture and the severity of the disease.

The average dose for all recommended indications for use varies from 240 to 480 mg per day.

The initial dose is 40-80 mg 3-4 times / day.

With prolonged treatment, the daily dose of 480 mg should not be exceeded.
In the maximum daily dose the drug must be taken only in a hospital.
The duration of therapy is determined by the doctor.

Impaired liver function

Treatment should begin with taking 1 tablet (40 mg) 2-3 times / day.
In the future, the dose is selected individually.
SIDE EFFECT

On the part of the immune system: reactions of increased sensitivity.

From the side of the central nervous system: headache, dizziness, paresthesia, tremor, fatigue, extrapyramidal disorders (ataxia, "masky" face, shuffling gait, stiffness of hands or feet, trembling of hands and fingers, difficulty swallowing).

From the side of the organ of hearing: ringing in the ears.

From the cardiovascular system: AV blockade I, II, III degree, stopping the sinus node, peripheral edema, tachycardia, sinus bradycardia, heart failure, marked decrease in blood pressure, flushing of the blood to the skin of the face, palpitation.

On the part of the digestive system: nausea, vomiting, constipation, intestinal obstruction, gingival hyperplasia, pain or discomfort in the abdomen.

On the part of the skin: angioedema, Stevens-Johnson syndrome, maculopapular rash, hives, purpura, pruritus, erythema multiforme, alopecia.

From the musculoskeletal system: muscle weakness, myalgia, arthralgia.

On the part of the reproductive system and mammary glands: erectile dysfunction, galactorrhea, gynecomastia.

On the part of laboratory indicators: increased activity of liver enzymes, hyperprolactinemia.

CONTRAINDICATIONS

- cardiogenic shock;

- Acute myocardial infarction complicated by bradycardia, severe arterial hypotension and left ventricular failure;

- AV blockade II or III degree except for patients with an artificial pacemaker;

- syndrome of weakness of the sinus node (syndrome of "bradycardia-tachycardia") except for patients with an artificial pacemaker;

- Chronic heart failure;

- Atrial fibrillation / flutter in the presence of additional routes (Wolff-Parkinson-White-Laun-Ganong-Levin syndrome);

- simultaneous reception with colchicine;

- age under 18 years (effectiveness and safety not established);

- Hypersensitivity to the active substance or auxiliary components of the drug.

With caution: AV-blockade of the first degree, bradycardia, arterial hypotension, expressed violations of the liver and kidneys, diseases related to neuromuscular transmission (myasthenia gravis, Lambert-Eaton syndrome, Duchenne muscular dystrophy).

PREGNANCY AND LACTATION

Data on the clinical use of the drug Isoptin in pregnancy is not enough, so the drug should not be used during pregnancy.
It was found that verapamil penetrates the hematoplacental barrier. The dose of verapamil, which is given to children with mother's milk, is 0.1-1% of the dose of verapamil taken by the mother. Given the potential for side effects in a child receiving verapamil with mother's milk, Isoptin should be taken during breastfeeding only if the benefit to the mother exceeds the possible risk to the child.
APPLICATION FOR FUNCTIONS OF THE LIVER

Carefully.

APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS

Carefully.

Treatment should begin with taking 1 tablet (40 mg) 2-3 times / day.
In the future, the dose is selected individually.
APPLICATION FOR CHILDREN

Contraindicated:

- age under 18 years (efficiency and safety not established).

SPECIAL INSTRUCTIONS

The drug can not be abruptly abolished, it is recommended to gradually reduce the dose until the drug is completely discontinued.

Clinical studies have shown that the pharmacokinetics of verapamil does not change in patients in the terminal stage of renal failure.
However, several reported cases indicate that when verapamil is used, care should be taken and the condition of patients with renal insufficiency must be monitored.
Impact on the ability to drive vehicles and manage mechanisms

Care must be taken when driving vehicles and working with mechanisms that require increased concentration.

OVERDOSE

Symptoms: marked decrease in blood pressure, sinus bradycardia passing into AV blockade of high degree, stopping sinus node, hyperglycemia, stupor and metabolic acidosis.
Reported lethal cases as a result of an overdose.
Treatment: symptomatic and supportive therapy should be provided, including gastric and intestinal washing, activated charcoal intake, parenteral administration of calcium preparations and beta-adrenomimetics.
Verapamil is not excreted by hemodialysis.
DRUG INTERACTION

In vitro studies suggest that verapamil is metabolized with the isoenzymes CYP3A4, CYP1A2, CYP2C8, CYP2C9 and CYP2C18 cytochrome P450 and is an inhibitor of the isoenzyme CYP3A4 and P-glycoprotein.
Clinically significant interaction was noted with the simultaneous use of inhibitors of the isoenzyme CYP3A4, which caused an increase in the concentration of verapamil in the blood plasma, while inducers of the isoenzyme CYP3A4 reduced its concentration in the blood plasma. Accordingly, with the simultaneous use of such tools, the possibility of this interaction should be taken into account.
The table lists the possible pharmacokinetic interaction of drugs, where C max is the maximum concentration in the blood plasma, C ss is the average equilibrium concentration in the blood plasma, and AUC is the area under the pharmacokinetic curve "concentration-time".

Preparation Possible change in the pharmacokinetic parameters of verapamil or another drug when administered concomitantly

Alpha-blockers

Prazosin An increase in C max prazosin (by 40%) does not affect T 1/2 of prazosin

Terazosin Increase in AUC terazosin (by 24%) and C max (by 25%)

Antiarrhythmics

Flecainide Minimal effect on clearance of flecainide in plasma (<10%);
does not affect the clearance of verapamil in plasma
Quinidine A decrease in clearance of quinidine (by 35%)

Bronchodilators

Theophylline Reduced systemic clearance of theophylline (by 20%).
For smokers, the clearance is reduced by 11%
Anticonvulsants

Carbamazepine AUC increase in carbamazepine (by 46%) in patients with persistent partial epilepsy

Antidepressants

Imipramine Increase in AUC of imipramine (by 15%).
Does not affect the concentration of desipramine (active metabolite imipramine)
Hypoglycemic agents

Glibenclamide Increases C max glibenclamide (by 28%), AUC (by 26%)

Antibiotics

Clarithromycin May increase the concentration of verapamil

Erythromycin A possible increase in the concentration of verapamil

Rifampicin Decreased AUC verapamil (97%), C max (94%), oral bioavailability (by 92%)

Telithromycin May increase the concentration of verapamil

Antineoplastic agents

Doxorubicin AUC (89%) increased doxorubicin and C max (by 61%) in patients with small cell lung cancer.

Barbiturates

Phenobarbital Verapamil clearance increases 5-fold

Tranquilizers

Buspirone AUC increases buspirone, C max increases by 3.4 times

Midazolam AUC increased midazolam (3 times) and C max (2 times)

Beta-blockers

Metoprolol AUC increases in metoprolol (by 32.5%) and C max (by 41%) in patients with angina pectoris

Propranolol Propranolol AUC (65%) and C max (94%) increase in patients with angina pectoris

Cardiac glycosides

Digitoxin The total clearance (by 27%) and extrarenal clearance (by 29%) of digitoxin decreases

Digoxin In healthy volunteers, C max digoxin is increased by 45-53%, C ss by 42% and AUC by 52%

Blockers of histamine H 2 -receptors

Cimetidine AUC R-enantiomer (by 25%) and S-enantiomer (40%) verapamil is increased with a corresponding decrease in the clearance of R- and S-verapamil

Immunosuppressive means

Cyclosporin AUC increases in cyclosporine, C ss , C max by 45%

Sirolimus May increase the concentration of sirolimus

Tacrolimus Possible increase in tacrolimus concentration

Hypolipidemic agents - inhibitors of HMG-CoA reductase

Atorvastatin May increase the concentration of atorvastatin.
Perhaps an increase in AUC (by 42.8%).
Lovastatin may increase the concentration of lovastatin

Simvastatin AUC (2.6 times) and C max (4.6 times) of simvastatin increased

Serotonin Receptor Antagonists

Almotriptan AUC (20%) and Cmax (24%) of almotriptan are increasing

Urikozuric means

Sulfinpyrazone Increased clearance of verapamil (3-fold), decreased bioavailability (by 60%)

Other

St. John's wort Perforated Reduces the AUC R-enantiomer (by 78%) and the S-enantiomer (by 80%) verapamil with a corresponding decrease in C max

Grapefruit juice An increase in the AUC R-enantiomer (by 49%) and the S-enantiomer (by 37%) of verapamil and the C max R enantiomer (by 75%) and the S-enantiomer (by 51%) of verapamil.
T 1/2 and renal clearance did not change.
Antiarrhythmics, beta-blockers

Mutual enhancement of cardiovascular effects (more pronounced AV-blockade, more significant decrease in heart rate, development of symptoms of heart failure and increased arterial hypotension).

Hypotensive drugs, diuretics, vasodilators

Strengthening of the hypotensive effect.

Prazosin, terazosin

Additive hypotensive effect.

Antiviral drugs for HIV treatment

Ritonavir and other antiviral agents for the treatment of HIV infection can inhibit the metabolism of verapamil, which leads to an increase in its concentration in the blood plasma.
With simultaneous application of a dose of Isoptin should be reduced.
Quinidine

With simultaneous use with verapamil, hypotensive action can be intensified.

In patients with hypertrophic obstructive cardiomyopathy, pulmonary edema may develop.

Carbamazepine

Increase in the concentration of carbamazepine in blood plasma.
Carbamazepine-specific adverse reactions such as diplopia, headache, ataxia, or dizziness may be observed.
Lithium

Increased neurotoxicity of lithium.

Rifampicin

May reduce the hypotensive effect of verapamil.

Sulfinpyrazone

May reduce the hypotensive effect of verapamil.

Muscle relaxants

The effect of muscle relaxants can increase.

Acetylsalicylic acid

Increased bleeding.

Ethanol (alcohol)

Increase in the concentration of ethanol in blood plasma.

Hypolipidemic agents - inhibitors of HMG-CoA reductase (statins)

For patients taking isoptin, treatment with HMG-CoA reductase inhibitors (eg simvastatin, lovastatin, atorvastatin) should begin with the lowest possible doses, which then gradually increase with continued therapy.
If it is necessary to use Isoptin in patients already receiving HMG-CoA reductase inhibitors, it is recommended to consider the possibility of reducing the dose of statins and re-titrating the dose taking into account the concentration of cholesterol in the serum.
Fluvastatin, pravastatin and rosuvastatin are not metabolized by the isoenzyme CYP3A4, so their interaction with verapamil is least likely.

Colchicine

Colchicine is a substrate for the isoenzyme CYP3A and P-glycoprotein, which in turn inhibit the metabolism of verapamil.
Therefore, with simultaneous use with verapamil, the concentration of colchicine in the blood can significantly increase.
In the postmarketing period of application, 1 report on paralysis (tetraparesis) was obtained, associated with the simultaneous use of verapamil and colchicine.
Perhaps this condition was caused by colchicine, passed through the blood-brain barrier due to inhibition of the isoenzyme CYP3A4 and P-glycoprotein verapamil.
TERMS OF RELEASE FROM PHARMACY

The drug is released by prescription.

TERMS AND CONDITIONS OF STORAGE

Store at temperatures between 15 ° and 25 ° C.
Keep out of the reach of children. Shelf life - 5 years.
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