Isoptin CP 240, 30 pcs., 240 mg, extended-release film-coated tablets

Isoptin CP 240, 30 pcs., 240 mg, extended-release film-coated tablets

In vitro studies indicate that verapamil hydrochloride is metabolized by the cytochrome P450 isoenzymes CYP3A4, CYP1A2, CYP2C8, CYP2C9 and CYP2C18. A clinically significant interaction was observed with concomitant use of CYP3A4 inhibitors, which caused an increase in plasma levels of verapamil, while CYP3A4 inducers decreased its plasma concentration. Accordingly, when using such agents simultaneously, the possibility of interaction should be taken into account.

The table provides a list of possible interactions between drugs and verapamil due to changes in their pharmacokinetic parameters.

Possible drug interactions when taking verapamil

Drug Possible effect on verapamil or verapamil on another drug with simultaneous use of Alpha-blockers Prazosin Increase in Cmax of prazosin (~40%); does not affect the half-life of prazosin Terazosin Increased terazosin AUC (~24%) and C max (~25%) Antiarrhythmics Flecainide Minimal effect on plasma flecainide Cl (< or ~10%); does not affect verapamil plasma Cl Quinidine Reduce oral Cl quinidine (~35%) Drugs for the treatment of asthma Theophylline Reduce oral and systemic Cl quinidine (~20%). In smokers, a decrease of ~11% Anticonvulsants Carbamazepine Increased AUC of carbamazepine (~46%) in patients with persistent partial epilepsy Antidepressants Imipramine Increased AUC of imipramine (~15%); does not affect the level of the active metabolite of desipramine Antidiabetic agents Glyburide Glyburide Cmax increases (~28%), AUC (~26%) Antimicrobial agents Erythromycin Verapamil levels may increase Rifampicin Verapamil AUC decreases (~97%), Cmax (~94%) , oral bioavailability (~92%) Telithromycin Possible increase in the level of verapamil Antineoplastic drugs Doxorubicin T1/2 of doxorubicin decreases (~27%) and Cmax (~38%)* Barbiturates Phenobarbital Oral Cl of verapamil increases ~5 times Benzodiazepines and other tranquilizers Buspirone The AUC of buspirone increases, C max ~ 3.4 times Midazolam The AUC of midazolam increases (~ 3 times) and C max (~ 2 times) Beta-blockers Metoprolol The AUC of metoprolol increases (~ 32.5%) and C max ( ~41%) in patients with angina Propranolol AUC of propranolol increases (~65%) and Cmax (~94%) in patients with angina Cardiac glycosides Digitoxin Total Cl (~27%) and extrarenal Cl (~29%) of digitoxin decrease Digoxin In healthy people volunteers increases C max (~45–53%), C SS (~42%) and AUC (~52%) H2 receptor antagonists Cimetidine AUC R- (~25%) and S- (~40%) verapamil increases with a corresponding decrease in Cl R- and S-verapamil Immunological agents Cyclosporine AUC, C SS , Cmax increases (~45%) of cyclosporine Sirolimus Possible increase in sirolimus levels Tacrolimus Possible increase in tacrolimus levels Lipid-lowering agents Atorvastatin Possible increase in atorvastatin levels Lovastatin Possible increase level of lovastatin Simvastatin Increases AUC (~ 2.6 times) and Cmax (~ 4.6 times) of simvastatin Serotonin receptor antagonists Almotriptan Increases AUC (~ 20%) and Cmax (~ 24%) of almotriptan Uricosuric drugs Sulfinpyrazone Increased oral Cl of verapamil (~3 times), decreased bioavailability (~60%) Others Grapefruit juice Increased AUC R- (~49%) and S- (~37%) of verapamil and C max R- (~75%) and S- (~51%) verapamil. Half-life and renal clearance did not change St. John's wort The AUC of verapamil R- (~ 78%) and S- (~ 80%) decreases with a corresponding decrease in Cmax

* in patients with progressive neoplasms, verapamil does not affect the level or clearance of doxorubicin; in patients with small cell lung cancer, verapamil reduced T1/2 and Cmax of doxorubicin.

Antiarrhythmic drugs, beta blockers. Mutual enhancement of effects on the cardiovascular system is possible (more pronounced AV block, more significant decrease in heart rate, development of heart failure and increased hypotension).

Antihypertensives, diuretics, vasodilators. Strengthening the hypotensive effect.

Prazosin, terazosin. Additive hypotensive effect.

Antiviral and drugs for the treatment of HIV infection. Ritonavir and antiviral drugs may inhibit the metabolism of verapamil, resulting in increased plasma concentrations. In this regard, the dose of verapamil should be reduced.

Quinidine. Hypotension.

Patients with hypertrophic obstructive cardiomyopathy may develop pulmonary edema.

Carbamazepine. Increased plasma levels of carbamazepine and increased neurotoxicity. Adverse reactions characteristic of carbamazepine, such as diplopia, headache, ataxia or dizziness, may occur.

Lithium. Increased lithium neurotoxicity.

Rifampicin. May reduce the hypotensive effect of verapamil.

Sulfinpyrazone. May reduce the hypotensive effect of verapamil.

Muscle relaxants. The effect of muscle relaxants may be enhanced.

Aspirin (acetylsalicylic acid). Increased bleeding.

Ethanol (alcohol). Increased plasma ethanol levels.

HMG-CoA reductase inhibitors (statins). Simvastatin/lovastatin. Concomitant use with verapamil may result in increased serum levels of simvastatin or lovastatin.

In patients receiving verapamil, treatment with HMG-CoA reductase inhibitors (i.e. simvastatin/lovastatin) should be started at the lowest possible doses and increased thereafter. If it is necessary to prescribe verapamil to patients already receiving HMG-CoA reductase inhibitors, it is necessary to review and reduce their doses in accordance with the concentration of cholesterol in the blood serum. Similar tactics should be followed when concomitantly prescribing verapamil with atorvastatin (although there is no clinical data confirming the interaction of verapamil and atorvastatin), since pharmacokinetic studies are clearly known to confirm that verapamil had a similar effect on the level of atorvastatin.

Fluvastatin, pravastatin and rosuvastatin are not metabolized by CYP3A4 isoenzymes, so their interaction with verapamil is least likely.

Isoptin® SR 240 (Isoptin® SR 240)

Metabolic studies in vitro

indicate that verapamil is metabolized by the isoenzymes CYP3A4, CYP1A2, CYP2C8, CYP2C9 and CYP2C18 of cytochrome P450. Verapamil is an inhibitor of the CYP3A4 isoenzyme and P-glycoprotein. Clinically significant interactions were observed when used concomitantly with inhibitors of the CYP3A4 isoenzyme, and an increase in the concentration of verapamil in the blood plasma was observed, while inducers of the CYP3A4 isoenzyme decreased the concentration of verapamil in the blood plasma, therefore monitoring patients for drug interactions is necessary. The combined use of verapamil and a drug that is metabolized by the CYP3A4 isoenzyme or is a P-gp substrate may be accompanied by an increase in drug concentrations. This may result in increased or prolonged duration of both therapeutic and side effects of the drug used in conjunction with verapamil.

The table below presents data on possible drug interactions caused by pharmacokinetic parameters (where Cmax is the maximum concentration in the blood plasma, Css is the average equilibrium concentration in the blood plasma, AUC is the area under the pharmacokinetic concentration-time curve).

Other possible types of interaction

Dabigatran

When dabigatran etexilate was co-administered with verapamil administered orally, the Cmax and AUC values ​​of dabigatran increased depending on the time of use and the dosage form of verapamil.

The greatest increase in dabigatran values ​​was observed when the first dose of immediate-release verapamil was taken 1 hour before dabigatran etexilate (Cmax increased by 180% and AUC increased by 150%). When using the sustained release formulation of verapamil, this effect was progressively reduced (Cmax increased by 90% and AUC by 70%), as well as when using multiple doses of verapamil (Cmax increased by 60% and AUC by 50%), which may be explained by the induction of P-glycoprotein in the gastrointestinal tract with long-term use of verapamil.

When verapamil was administered 2 hours after taking dabigatran etexilate, no clinically significant interaction was observed (Cmax increased by 10% and AUC by 20%), since dabigatran was completely absorbed after 2 hours. In a study in patients with atrial fibrillation, dabigatran concentrations increased by no more than 21%, and no increase in the risk of bleeding was observed. There are no data on the interaction of dabigatran etexilate with verapamil administered parenterally; no clinically significant interaction is expected.

With regard to the prolongation of blood coagulation, the use of verapamil, as a rule, did not affect the plasma concentration-effect relationship of dabigatran. No unexpected safety data were obtained when dabigatran etexilate was co-administered with verapamil.

Drugs that bind to plasma proteins

Verapamil, as a drug that is highly bound to plasma proteins, should be used with caution when taken simultaneously with other drugs that have a similar ability. It is possible to increase the concentrations in the blood plasma of drugs characterized by a high degree of protein binding (including coumarin and indanedione derivatives, non-steroidal anti-inflammatory drugs, quinine, salicylates, sulfinpyrazone).

Means for inhalation general anesthesia

With the simultaneous use of drugs for inhalation anesthesia and BMCA, which include verapamil, the risk of developing bradycardia, atrioventricular block, and heart failure increases, so the dose of each drug should be carefully titrated to achieve the desired effect in order to avoid excessive depression of the cardiovascular system.

Flecainide

A study involving healthy volunteers showed that the combined use of verapamil and flecainide may have an additive effect with a decrease in myocardial contractility, a slowdown in atrioventricular conduction and myocardial repolarization.

Disopyramide

Pending data on a possible interaction between verapamil and disopyramide, disopyramide should not be administered 48 hours before or 24 hours after use.

Ivabradin

Due to its moderate inhibitory effect on CYP3A4, verapamil (at a dose of 120 mg 2 times a day) when used simultaneously led to an increase in the AUC of ivabradine by 2-3 times.

Both verapamil and ivabradine are heart rate depressants and, therefore, co-administration may worsen the patient's heart rate. The simultaneous use of verapamil with ivabradine is contraindicated due to the development of an additional negative chronotropic effect.

Procainachide, quinidine and other drugs known to prolong the QT interval

Increased risk of developing QT prolongation.

Valproic acid

Verapamil increases the concentration of valproic acid in the blood due to suppression of metabolism involving cytochrome P450.

Nicotine

Nicotine accelerates metabolism in the liver, leads to a decrease in the concentration of verapamil in the blood, and reduces the severity of antianginal, antihypertensive and antiarrhythmic effects.

Ranitidine

The concentration of verapamil in the blood plasma increases.

Calcium preparations

Reduced effectiveness of verapamil.

Nonsteroidal anti-inflammatory drugs (NSAIDs)

NSAIDs reduce the antihypertensive effect of verapamil due to suppression of prostaglandin synthesis, sodium and fluid retention in the body.

Sympathomimetics

Sympathomimetics reduce the antihypertensive effect of verapamil.

Estrogens

Estrogens reduce the antihypertensive effect of verapamil due to fluid retention in the body.

Medicines for the treatment of HIV infection

Some drugs used to treat HIV infection, such as ritonavir, may inhibit the metabolism of verapamil, resulting in increased plasma concentrations of verapamil. Caution should be exercised or the dose of verapamil should be reduced.

Lithium

Increased lithium neurotoxicity has been observed during concomitant administration of verapamil and lithium, with no change or increase in serum lithium concentrations. However, additional administration of verapamil also led to a decrease in serum lithium concentrations in patients regularly taking lithium by mouth. Patients taking both drugs should be closely monitored.

Muscle relaxants

Clinical data and preclinical studies suggest that verapamil may enhance the activity of muscle relaxants (such as curare and depolarizing agents). Therefore, it may be necessary to reduce the dose of verapamil and/or the dose of drugs that block neuromuscular conduction when used simultaneously.

Acetylsalicylic acid (as an antiplatelet agent)

Increased risk of bleeding.

Ethanol (alcohol)

Increased concentration of ethanol in blood plasma.

HMG-CoA reductase inhibitors (statins)

In patients receiving verapamil, treatment with HMG-CoA reductase inhibitors (i.e. simvastatin, atorvastatin or lovastatin) should be started at the lowest possible doses and gradually increased during therapy. If it is necessary to prescribe verapamil to patients already receiving HMG-CoA reductase inhibitors (i.e., simvastatin, atorvastatin or lovastatin), then it is necessary to review and reduce their doses according to the concentration of cholesterol in the serum. Fluvastatin, pravastatin and rosuvastatin are not metabolized by the CYP3A4 isoenzyme, so their interaction with verapamil is least likely.

Antihypertensives, diuretics, vasodilators

Strengthening the antihypertensive effect.

Isoptin -SR-240 retard tablets 240 mg 30 pcs. in Orekhovo-Zuevo

Light green capsule-shaped tablets, film-coated. The tablets have transverse marks on both sides. There are two "7" signs on one side.

Verapamil, the active substance of the drug Isoptin CP 240, is quickly and almost completely absorbed in the small intestine. The degree of absorption is 90–92%. T1/2 - from 3 to 7 hours after a single dose of the drug orally. With repeated doses, T1/2 of verapamil can almost double compared to a single dose.

Verapamil is almost completely metabolized. The main metabolite is norverapamil, which has pharmacological activity; other metabolites are largely inactive.

Verapamil and its metabolites are excreted mainly through the kidneys; only 3–4% is unchanged. Within 24 hours, 50% of the administered dose of the drug is excreted in the urine, within 48 hours - 55–60% and within 5 days - 70%. Up to 16% is excreted in feces. Recent results indicate that there are no differences in the pharmacokinetics of verapamil between subjects with normal renal function and those with end-stage renal disease.

In case of coronary artery disease and arterial hypertension, no correlation was found between the therapeutic effect and the concentration of the drug in the blood plasma; there is only a definite relationship between plasma drug levels and the effect on the PR interval. After taking extended-release dosage forms, the plasma concentration curve of verapamil stretches and becomes flatter than with the administration of normal-release dosage forms.

About 90% of the drug binds to blood plasma proteins.

Bioavailability

Following oral administration, verapamil undergoes significant first-pass metabolism, which occurs almost exclusively in the liver.

The average absolute bioavailability in healthy volunteers after a single dose of the drug is 22%. Recent studies in patients with atrial fibrillation or angina showed mean bioavailability levels of 35 and 24% after a single oral and IV dose, respectively.

With repeated doses of the drug, bioavailability increases almost 2 times compared to a single dose. This effect is likely due to partial saturation of liver enzyme systems and/or a transient increase in hepatic blood flow after a single dose of verapamil. In patients with liver failure, compared with those with normal liver function, the bioavailability of verapamil was much higher and a delay in drug elimination was observed.

Penetration through the placenta

Verapamil penetrates the placental barrier; the concentration found in umbilical vein plasma was 20–92% of that in maternal plasma.

Excretion in breast milk

Verapamil is excreted in breast milk, but at therapeutic doses its concentration is so low that clinical effect in newborns is unlikely.

Verapamil inhibits the transmembrane current of calcium ions into smooth muscle cells. The antianginal effect is associated with a direct effect on the myocardium and an effect on peripheral hemodynamics (reduces the tone of peripheral arteries, peripheral arterial resistance). Blockade of the entry of calcium ions into the cell leads to a decrease in the transformation of energy contained in high-energy bonds of ATP into mechanical work and a decrease in myocardial contractility.

The antihypertensive effectiveness of Isoptin SR 240 is due to a decrease in peripheral vascular resistance without an increase in heart rate as a reflex response. Blood pressure begins to decrease immediately on the first day of treatment; this effect persists with long-term therapy. The drug Isoptin CP 240 is used for the treatment of all types of arterial hypertension: for monotherapy of mild or moderate arterial hypertension in combination with other antihypertensive drugs, especially diuretics and, according to recent observations, ACE inhibitors for more severe arterial hypertension. It has a vasodilating, hypotensive, negative ino- and chronotropic effect. The drug Isoptin CP 240 has a pronounced antiarrhythmic effect, especially in cases of supraventricular arrhythmia. It delays the conduction of impulses in the AV node. As a result, sinus rhythm is restored and/or the ventricular rate is normalized, depending on the type of arrhythmia. Normal heart rate does not change or decreases slightly.