Isoptin sr 240 extended-release film-coated tablets 240 mg No. 30

Registration number

P N015230/01

Trade name of the drug

Isoptin CP 240

International nonproprietary name

Verapamil.

Dosage form

extended-release, film-coated tablets.

Compound

1 tablet contains: active substance: verapamil hydrochloride 240 mg.

excipients: microcrystalline cellulose - 78.8 mg, sodium alginate - 320.0 mg, povidone-KZO - 48.0 mg, magnesium stearate - 3.2 mg, water - 30.0 mg.

film coating: hypromellose-2910 - 4.90 mg, macrogol-400 - 1.26 mg, macrogol-6000 - 0.84 mg, talc - 8.40 mg, titanium dioxide - 6.16 mg, aluminum varnish: quinoline dye yellow (E 104) + indigo carmine dye (E 132) - 0.14 mg, mountain glycolic wax - 0.30 mg.

Description

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

Pharmacotherapeutic group

Calcium channel blocker.

ATX code: C0DA01

Pharmacological properties

Pharmacodynamics

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.

Pharmacokinetics

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.

Contraindications

• Absolute:
• cardiogenic shock;
• complicated acute myocardial infarction (bradycardia, severe arterial hypotension, left ventricular failure);
• AV block II–III degree;
• sick sinus syndrome (bradycardia-tachycardia syndrome);
• sinoatrial block.
• Relative:
• AV block of the first degree;
• bradycardia (<50 beats per minute);
• arterial hypotension (sBP <90 mm Hg);
• atrial fibrillation/flutter with WPW syndrome (risk of ventricular tachycardia);
• heart failure (if necessary, cardiac glycosides are prescribed before starting treatment with Isoptin CP 240);
• children's age (currently there is no convincing data on the safety of the drug in children under 18 years of age).

Side effects

Sometimes, when taking verapamil in high doses or in the presence of any cardiovascular disorders, the following may be observed: arrhythmia due to bradycardia (sinus bradycardia, sinoatrial block, AV block I, II or III degree or bradyarrhythmia with atrial fibrillation), arterial hypotension, palpitations , tachycardia, development or worsening of symptoms of heart failure.

Constipation has been reported to occur quite frequently when taking the drug orally; in rare cases, nausea, vomiting, intestinal obstruction, abdominal pain or discomfort, dizziness or drowsiness, increased fatigue, increased nervousness/tremor, swelling of the lower leg, erythromelalgia or paresthesia may develop.

In rare cases, dizziness, headache and hot flashes may occur. In very rare cases, myalgia and arthralgia may occur.

Allergic reactions (exanthema, urticaria, urticaria, angioedema, Stevens-Johnson syndrome) have been rarely reported. A reversible increase in the levels of liver transaminases and/or alkaline phosphatase and an increase in prolactin levels have also been described.

In rare cases, gynecomastia developed in elderly patients during long-term therapy, which in all cases was completely reversible after discontinuation of the drug. Cases of galactorrhea and impotence have been reported.

In extremely rare cases, during long-term treatment, gum hyperplasia may develop, which is completely reversible after discontinuation of the drug.

Interaction

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 when used simultaneously

Alpha blockers

Prazosin Increased Cmax of prazosin (~40%); does not affect the half-life of prazosin

Terazosin Increased terazosin AUC (~24%) and Cmax (~25%)

Antiarrhythmic drugs

Flecainide Minimal effect on plasma flecainide Cl (< or ~10%); does not affect plasma verapamil Cl

Quinidine Decreased oral quinidine Cl (~35%)

Asthma Treatments

Theophylline Decreases oral and systemic quinidine Cl (~20%). For smokers, a decrease of ~11%

Anticonvulsants

Carbamazepine Increased AUC of carbamazepine (~46%) in patients with resistant partial epilepsy

Antidepressants

Imipramine Increased AUC of imipramine (~15%); does not affect the level of the active metabolite of desipramine

Antidiabetic agents

Glyburide Increased glyburide Cmax (~28%), AUC (~26%)

Antimicrobials

Erythromycin Possible increase in verapamil levels

Rifampicin Decreases verapamil AUC (~97%), Cmax (~94%), oral bioavailability (~92%)

Telithromycin Possible increase in verapamil levels

Antitumor drugs

Doxorubicin T1/2 of doxorubicin decreases (~27%) and Cmax (~38%)*

Barbiturates

Phenobarbital Increases oral Cl of verapamil ~5 times

Benzodiazepines and other tranquilizers

Buspirone Buspirone AUC, Cmax increases ~3.4 times

Midazolam Increases midazolam AUC (~3 times) and Cmax (~2 times)

Beta blockers

Metoprolol Metoprolol AUC (~32.5%) and Cmax (~41%) increases in patients with angina pectoris

Propranolol Propranolol AUC (~65%) and Cmax (~94%) increases in patients with angina pectoris

Cardiac glycosides

Digitoxin Total Cl (~27%) and extrarenal Cl (~29%) of digitoxin decrease

Digoxin Cmax (~45–53%), CSS (~42%) and AUC (~52%) increase in healthy volunteers

H2 receptor antagonists

Cimetidine Increases the AUC of R- (~25%) and S- (~40%) verapamil with a corresponding decrease in Cl R- and S-verapamil

Immunological agents

Cyclosporine AUC, CSS, Cmax (~45%) of cyclosporine increases

Sirolimus Possible increase in sirolimus levels

Tacrolimus Tacrolimus levels may increase

Lipid lowering agents

Atorvastatin Possible increase in atorvastatin levels

Lovastatin Possible increase in lovastatin levels

Simvastatin AUC (~2.6-fold) and Cmax (~4.6-fold) of simvastatin increases

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%)

Other

Grapefruit juice Increased AUC R- (~49%) and S- (~37%) verapamil and Cmax R- (~75%) and S- (~51%) verapamil. Elimination half-time and renal clearance were unchanged

St. John's wort Decreases the AUC of R- (~ 78%) and S- (~ 80%) verapamil 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)

In vitro metabolic studies indicate that verapamil is metabolized by the cytochrome P450 isoenzymes CYP3A4, CYP1A2, CYP2C8, CYP2C9 and CYP2C18. 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 dosage form 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.

agents that bind to blood 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 bmkk, which include verapamil, the risk of developing bradycardia, atrioventricular block, and heart failure increases, therefore 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 with the combined use of verapamil and flecainide, an additive effect is possible 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 prescribed 48 hours before or 24 hours after use.

ivabradine

Due to the 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. simultaneous use of verapamil with ivabradine is contraindicated due to the development of an additional negative chronotropic effect.

procainachide, quinidine and other drugs that cause QT prolongation

increased risk of developing qt interval 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 level of verapamil concentration in the blood plasma increases.

calcium supplements

decreased effectiveness of verapamil.

non-steroidal 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.

drugs for the treatment of HIV infection

Some drugs for the treatment of HIV infection, such as ritonavir, can inhibit the metabolism of verapamil, which leads to an increase in its concentration in blood plasma. Use caution or reduce the dose of verapamil.

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 resulted in decreased serum lithium concentrations in patients regularly taking oral lithium. 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)

increase in ethanol concentration 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 with 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 their doses must be reconsidered and reduced 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

increased antihypertensive effect.

Directions for use and doses

Orally, swallow whole, with water, preferably during a meal or immediately after a meal.

Doses of verapamil should be used depending on the clinical picture of the disease; Many years of clinical experience have shown that the average dose for all indications is 240–360 mg/day.

For long-term treatment, the daily dose should not exceed 480 mg; a temporary dose increase above this level is possible.

In patients with impaired liver function, the effect of verapamil is enhanced and becomes longer lasting as a result of slow metabolism of the drug, which depends on the severity of liver dysfunction. In such cases, the dose should be set with extreme caution and treatment should begin with lower doses (i.e., patients with liver cirrhosis are initially prescribed 1 film-coated tablet of Isoptin 40 mg 2-3 times a day).

Indications for use:

IHD: chronic stable angina; angina caused by vasospasm (Prinzmetal's angina, variant)

Recommended dose for adults:

240–480 mg/day Isoptin SR 240 — ½–1 tablet, film-coated, prolonged action, 2 times a day with an interval of 12 hours

Indications for use:

Arterial hypertension (mild to moderate)

Recommended dose for adults:

Isoptin SR 240 - 1 tablet, coated, prolonged action, in the morning. In cases where patients are especially indicated for a slow decrease in blood pressure, treatment should begin with ½ tablet, film-coated, prolonged release, in the morning. If necessary, additionally ½–1 tablet, film-coated, prolonged action, in the evening with an interval between doses of about 12 hours. If necessary, the dose should be increased every 2 weeks of treatment

Indications for use:

Paroxysmal supraventricular tachycardia; atrial fibrillation/flutter accompanied by tachyarrhythmia.

Isoptin SR 240 - ½–1 tablet, film-coated, prolonged action, 2 times a day with an interval of 12 hours.

The duration of use is not limited.

Isoptin sr 240 tablets p/o film prolong. 240 mg 30 pcs

Pharmacological group:

Calcium channel blocker.
Pharmacological properties:
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, total peripheral resistance). Blockade of the entry of calcium ions into the cell leads to a decrease in the transformation of energy contained in macroergic bonds of ATP into mechanical work and to a decrease in myocardial contractility.

The antihypertensive effectiveness of the drug Isoptin 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 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, with ACE inhibitors for more severe arterial hypertension. It has a vasodilating, hypotensive, negative ino- and chronotropic effect. The drug Isoptin has a pronounced antiarrhythmic effect, especially in cases of supraventricular arrhythmia. It delays the conduction of impulses in the atrioventricular node. As a result, sinus rhythm is restored and/or the frequency of ventricular contractions is normalized, depending on the type of arrhythmia. The normal heart rate remains unchanged or decreases slightly.

Pharmacokinetics:

Verapamil, the active substance of the drug Isoptin, is quickly and almost completely absorbed in the small intestine. The degree of absorption is 90-92%. The half-life is from three to seven hours after a single oral dose. With repeated dosing, the half-life of verapamil can be almost doubled 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 excreted unchanged. Within 24 hours, 50% of the administered dose of the drug is excreted in the urine, within 48 hours 55-60% and within five 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 heart disease and arterial hypertension, no correlation has been identified between the therapeutic effect and the concentration of the drug in the blood plasma; There is only a definite relationship between the plasma level of the drug 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 is bound to plasma protein.

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 intravenous dose, respectively.

With repeated administration of the drug, bioavailability almost doubles compared to a single dose. This effect is likely due to partial saturation of hepatic 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.

Overdose

Symptoms of poisoning resulting from an overdose of the drug Isoptin depend on the amount of the drug taken, the time of detoxification measures and the contractility of the myocardium (depending on age). Fatal cases resulting from overdose have been reported.

The following symptoms predominate: a drop in blood pressure (in some cases to levels that cannot be measured); shock, loss of consciousness; AV block of the 1st and 2nd degree, often with Wenckebach periods with or without escape rhythm; complete AV block with complete AV dissociation, escape rhythm, cardiac arrest; sinus bradycardia, sinus node arrest.

Treatment. Therapeutic measures should be carried out depending on the duration and method of taking the drug Isoptin and on the nature and severity of the symptoms of poisoning.

In case of overdose with a large number of long-acting film-coated tablets (i.e. Isoptin CP 240), it must be borne in mind that the active substance is released and absorbed in the intestine within 48 hours after taking the drug orally. Depending on the timing of oral administration of the drug, individual conglomerates of swollen tablet residues, acting as active depots, are likely to be located throughout the gastrointestinal tract.

General events.

If there is no motility of the stomach and intestines (signs of peristalsis during auscultation), then it is advisable to perform gastric lavage even 12 hours after taking the drug orally. If there is a suspicion of an overdose of the drug Isoptin CP 240, then appropriate measures aimed at eliminating the drug are indicated, for example, inducing vomiting, washing the stomach and intestines in combination with an endoscopic examination, taking laxatives and emetics.

Common emergency resuscitation measures include chest compressions, artificial respiration, and electrical stimulation of the heart.

Special events.

Elimination of effects associated with depression of cardiac function, arterial hypotension and bradycardia.

Calcium is a specific antidote: 10–30 ml of a 10% calcium gluconate solution is administered as an intravenous injection (2.25–4.5 mmol), if necessary, re-injected or as a slow drip infusion (for example, 5 mmol/h).

The following activities may be required.

In case of 2nd or 3rd degree AV block, sinus bradycardia, cardiac arrest: atropine, isoprenaline, orciprenaline or cardiac stimulation.

In case of arterial hypotension: dopamine, dobutamine, norepinephrine.

In case of persistent signs of myocardial failure: dopamine, dobutamine, additional calcium injections as necessary.

Isoptin sr 240 30 pcs. extended-release film-coated tablets

pharmachologic effect

Antianginal, hypotensive, antiarrhythmic, vasodilating.

Composition and release form Isoptin sr 240 30 pcs. extended-release film-coated tablets

Tablets - 1 tablet:

• active substances: verapamil hydrochloride - 240 mg (the active substance is embedded in a hydrocolloid matrix of alginate, a natural polysaccharide; the release rate is determined by diffusion and surface erosion; upon contact with the liquid contents of the intestine, the surface of the tablet swells to form a gel-like diffusion layer; specially included surface defects cause uniform erosion gel, and therefore provide almost constant diffusion characteristics; the combination of these two mechanisms allows controlled release of the active substance with almost zero-order kinetics around 7 h);
• excipients: MCC; sodium alginate; povidone (constant K = 30); magnesium stearate; purified water; hypromellose; macrogol 400; macrogol 6000; talc; titanium dioxide; quinoline yellow; indigotine; Glycol mountain wax.

There are 10, 15 or 20 pcs in a blister; There are 1, 2, 3, 5 or 10 blisters in a cardboard box.

Description of the dosage form

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

Directions for use and doses

Orally, swallow whole, with water, preferably during a meal or immediately after a meal.

Doses of verapamil should be used depending on the clinical picture of the disease; Many years of clinical experience have shown that the average dose for all indications is 240–360 mg/day.

For long-term treatment, the daily dose should not exceed 480 mg; a temporary dose increase above this level is possible.

In patients with impaired liver function, the effect of verapamil is enhanced and becomes longer lasting as a result of slow metabolism of the drug, which depends on the severity of liver dysfunction. In such cases, the dose should be set with extreme caution and treatment should begin with lower doses (i.e., patients with liver cirrhosis are initially prescribed 1 film-coated tablet of Isoptin 40 mg 2-3 times a day).

The duration of use is not limited.

Pharmacodynamics

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.

Pharmacokinetics

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.

Indications for use Isoptin sr 240 30 pcs. extended-release film-coated tablets

• arterial hypertension;
• chronic stable angina (classical angina pectoris);
• angina caused by vasospasm (Prinzmetal's angina, variant);
• paroxysmal supraventricular tachycardia;
• atrial fibrillation/flutter accompanied by tachyarrhythmia (with the exception of WPW syndrome).

Contraindications

Absolute:

• cardiogenic shock;
• complicated acute myocardial infarction (bradycardia, severe arterial hypotension, left ventricular failure);
• AV block II–III degree;
• sick sinus syndrome (bradycardia-tachycardia syndrome);
• sinoatrial block.

Relative:

• AV block of the first degree;
• bradycardia (
• arterial hypotension (sBP
• atrial fibrillation/flutter with WPW syndrome (risk of ventricular tachycardia);
• heart failure (if necessary, cardiac glycosides are prescribed before starting treatment with Isoptin CP 240);
• children's age (currently there is no convincing data on the safety of the drug in children under 18 years of age).

Application Isoptin sr 240 30 pcs. extended-release film-coated tablets during pregnancy and lactation

During pregnancy (especially in the first trimester) and during breastfeeding, the potential benefits of taking Isoptin CP 240 should be analyzed against the possible risks for the mother and child. During breastfeeding, the drug must be discontinued.

special instructions

Impact on the ability to drive a car and operate machinery

Treatment of arterial hypertension with Isoptin CP 240 requires regular medical supervision. Depending on the individual's response to treatment, the patient's ability to drive or use machinery may be reduced. This is especially important in the initial period of treatment when transferring from one drug to another and taking it in combination with alcohol.

Overdose

Symptoms of poisoning resulting from an overdose of the drug Isoptin depend on the amount of the drug taken, the time of detoxification measures and the contractility of the myocardium (depending on age). Fatal cases resulting from overdose have been reported.

The following symptoms predominate: a drop in blood pressure (in some cases to levels that cannot be measured); shock, loss of consciousness; AV block of the 1st and 2nd degree, often with Wenckebach periods with or without escape rhythm; complete AV block with complete AV dissociation, escape rhythm, cardiac arrest; sinus bradycardia, sinus node arrest.

Treatment. Therapeutic measures should be carried out depending on the duration and method of taking the drug Isoptin and on the nature and severity of the symptoms of poisoning.

In case of overdose with a large number of long-acting film-coated tablets (i.e. Isoptin CP 240), it must be borne in mind that the active substance is released and absorbed in the intestine within 48 hours after taking the drug orally. Depending on the timing of oral administration of the drug, individual conglomerates of swollen tablet residues, acting as active depots, are likely to be located throughout the gastrointestinal tract.

General events.

If there is no motility of the stomach and intestines (signs of peristalsis during auscultation), then it is advisable to perform gastric lavage even 12 hours after taking the drug orally. If there is a suspicion of an overdose of the drug Isoptin CP 240, then appropriate measures aimed at eliminating the drug are indicated, for example, inducing vomiting, washing the stomach and intestines in combination with an endoscopic examination, taking laxatives and emetics.

Common emergency resuscitation measures include chest compressions, artificial respiration, and electrical stimulation of the heart.

Special events.

Elimination of effects associated with depression of cardiac function, arterial hypotension and bradycardia.

Calcium is a specific antidote: 10–30 ml of a 10% calcium gluconate solution is administered as an intravenous injection (2.25–4.5 mmol), if necessary, re-injected or as a slow drip infusion (for example, 5 mmol/h).

The following activities may be required.

In case of 2nd or 3rd degree AV block, sinus bradycardia, cardiac arrest: atropine, isoprenaline, orciprenaline or cardiac stimulation.

In case of arterial hypotension: dopamine, dobutamine, norepinephrine.

In case of persistent signs of myocardial failure: dopamine, dobutamine, additional calcium injections as necessary.

Side effects Isoptin sr 240 30 pcs. extended-release film-coated tablets

Sometimes, when taking verapamil in high doses or in the presence of any cardiovascular disorders, the following may be observed: arrhythmia due to bradycardia (sinus bradycardia, sinoatrial block, AV block I, II or III degree or bradyarrhythmia with atrial fibrillation), arterial hypotension, palpitations , tachycardia, development or worsening of symptoms of heart failure.

Constipation has been reported to occur quite frequently when taking the drug orally; in rare cases, nausea, vomiting, intestinal obstruction, abdominal pain or discomfort, dizziness or drowsiness, increased fatigue, increased nervousness/tremor, swelling of the lower leg, erythromelalgia or paresthesia may develop.

In rare cases, dizziness, headache and hot flashes may occur. In very rare cases, myalgia and arthralgia may occur.

Allergic reactions (exanthema, urticaria, urticaria, angioedema, Stevens-Johnson syndrome) have been rarely reported. A reversible increase in the levels of liver transaminases and/or alkaline phosphatase and an increase in prolactin levels have also been described.

In rare cases, gynecomastia developed in elderly patients during long-term therapy, which in all cases was completely reversible after discontinuation of the drug. Cases of galactorrhea and impotence have been reported.

In extremely rare cases, during long-term treatment, gum hyperplasia may develop, which is completely reversible after discontinuation of the drug.

Drug interactions

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

* 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.

Precautionary measures

Impact on the ability to drive a car and operate machinery

Treatment of arterial hypertension with Isoptin CP 240 requires regular medical supervision. Depending on the individual's response to treatment, the patient's ability to drive or use machinery may be reduced. This is especially important in the initial period of treatment when transferring from one drug to another and taking it in combination with alcohol.

Release form

extended-release film-coated tablets 240 mg

10, 15 or 20 tablets per blister made of PVC/PVDC/AL foil. 1, 2, 3, 5 or 10 blisters along with instructions for use in a cardboard box.