Isoptin SR tabs 240mg #30

Instruction for Isoptin SR

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Isoptin SR is a drug of antiarrhythmic, hypotensive, antianginal and vasodilating action, a calcium channel blocker.

Release form and composition

Isoptin SR is a preparation in the form of tablets of prolonged action, coated / film-coated: oblong, pale green, on both sides with a transverse line, on one side with two engraved “Δ” signs (10, 15 or 20 pcs. in a blister, in a cardboard box 1, 2, 3, 5 or 10 blisters).
1 tablet contains:
    active substance: verapamil hydrochloride * - 240 mg;
    additional components: sodium alginate, magnesium stearate, microcrystalline cellulose, povidone-KZO, purified water;
    shell / film shell: macrogol-400, hypromellose, macrogol-6000, titanium dioxide, talc, mountain glycol wax, quinoline yellow dyes (E 104) and indigo carmine (E 132).
* The release rate of verapamil hydrochloride depends on diffusion and surface erosion. The active substance is placed in the hydrocolloid matrix of the natural polysaccharide alginate. When interacting with the liquid contents of the intestine, the surface of the tablet swells with the formation of a gel-like diffusion layer. Specially present surface defects lead to uniform erosion of the gel and, as a consequence, provide almost constant characteristics of the diffusion process. The combination of these two mechanisms allows for the control of the release of the active substance with kinetics of almost zero order for about 7 hours.

Pharmacodynamics

Verapamil hydrochloride prevents transmembrane entry through slow channels of calcium (and possibly sodium) ions into myocardial smooth muscle cells and vascular walls.
The antianginal effect of the substance is caused by its direct effect on the myocardium and the ability to reduce the tone of the peripheral arteries and the total peripheral vascular resistance. Disruption of the flow of calcium ions into cells causes a decrease in the transformation of ATP energy (produced by adenosine triphosphoric acid) into mechanical work and a weakening of the contractility of the myocardium.
The antihypertensive effect of the drug is due to a decrease in the resistance of peripheral vessels without a reflex increase in the heart rate (HR). A decrease in blood pressure (BP) is noted already on the first day of therapy, this effect persists against the background of a long course. Isoptin SR 240 is used in the treatment of all types of arterial hypertension, including monotherapy of mild or moderate disease, in combination with other antihypertensive drugs, mainly with diuretics and angiotensin-converting enzyme inhibitors (ACE inhibitors) - with a more severe form of arterial hypertension.
Verapamil has hypotensive, vasodilating and negative foreign and chronotropic effects. The drug demonstrates a pronounced antiarrhythmic effect, especially against the background of supraventricular arrhythmia. By delaying the conduction of the impulse in the AV (atrioventricular) node, the drug, depending on the type of arrhythmia, helps to restore sinus rhythm and / or normalize the frequency of ventricular contractions, normal heart rate does not change or slightly decreases.

Pharmacokinetics

After oral administration, Verapamil is rapidly and almost completely (90–92%) absorbed in the small intestine. The half-life (T½) with a single dose can be 3-7 hours, with repeated administration, this indicator may approximately double. The agent is almost completely metabolized. The main metabolite of verapamil, norverapamil, has pharmacological activity, the rest of the metabolites are mostly inactive.
The substance and its metabolites are excreted mainly by the kidneys, unchanged - 3-4%. With urine, after taking the drug, 50% of the administered dose is excreted within 24 hours, about 55-60% within 48 hours, and 70% within 5 days. Up to 16% of the dose is evacuated with feces.
According to the results obtained, there are no significant differences in the pharmacokinetics of the drug with normal renal function and end-stage renal failure.
In ischemic heart disease (IHD) and arterial hypertension, no correlation was found between the plasma concentration of verapamil in the blood and its therapeutic effect. Only a definite relationship was found between the level of the substance in plasma and the effect on the value of the PR interval (the interval on the electrocardiogram from the beginning of the P wave to the beginning of the R wave). After taking prolonged-release drugs, the curve representing the concentration of verapamil in the blood plasma becomes flatter and stretched in comparison with that when using dosage forms of the drug with normal release.
Approximately 90% of the substance binds to blood plasma proteins. The drug has a good distribution in body tissues; in healthy volunteers, the volume of distribution (Vd) is approximately 1.8-6.8 l / kg. After oral administration, verapamil undergoes an intensive first-pass metabolism that occurs almost entirely in the liver.
The average bioavailability of the substance after a single oral administration in healthy volunteers is approximately 22%, in patients with angina pectoris or atrial fibrillation it can reach 35%. When compared with a single dose, in the case of repeated use of verapamil, the bioavailability increases almost 2 times. It is assumed that this is caused by the effect of partial saturation of the liver enzyme systems and / or a transient increase in blood circulation in the liver after a single dose of the drug.
It was noted that in patients with hepatic insufficiency, the bioavailability of the drug when compared with patients with normal liver function was much higher, and there was also a delay in the elimination of Isoptin SR.

Indications for use

    arterial hypertension;
    paroxysmal supraventricular tachycardia;
    IHD, including chronic stable angina pectoris (classic exertional angina); unstable angina; angina pectoris caused by spasm of the coronary vessels (Prinzmetal's angina);
    atrial fibrillation / flutter, occurring with tachyarrhythmia, with the exception of the Wolff-Parkinson-White (WPW syndrome) and Lown-Ganong-Levin syndromes (see section "Contraindications").

Contraindications

    sick sinus syndrome (SSS), except for patients with a pacemaker;
    cardiogenic shock;
    atrial fibrillation / flutter in the presence of additional pathways - WPW and Laun-Ganong-Levin syndromes (due to the aggravation of the threat of ventricular tachyarrhythmias, including ventricular fibrillation while taking verapamil);
    AV block II or III degree (except for patients with a pacemaker);
    heart failure with a reduced left ventricular ejection fraction (below 35%) and / or a pulmonary artery wedge pressure exceeding 20 mm Hg. Art. (except for cases of heart failure due to supraventricular tachycardia, subject to therapy with verapamil);
    age up to 18 years;
    pregnancy and lactation;
    hypersensitivity to any of the constituents of the drug.
Isoptin SR should be taken with extreme caution in the following diseases / conditions:
    acute myocardial infarction, marked decrease in blood pressure, AV-blockade I degree, left ventricular dysfunction, bradycardia, asystole, heart failure, hypertrophic obstructive cardiomyopathy;
    diseases associated with neuromuscular transmission (Duchenne muscular dystrophy, Lambert-Eaton syndrome, myasthenia gravis);
    severe functional disorders of the liver and / or impaired renal function;
    elderly age.

Instructions for the use of Isoptin SR: method and dosage

Isoptin SR is taken orally, swallowing whole, without dissolving or chewing, with water, preferably during or immediately after a meal. If necessary, the tablet can be divided according to the risk applied.
The dose of the drug is selected individually, taking into account the indications and the severity of the disease. According to many years of clinical experience, the average daily dose of verapamil for all indications is 240-360 mg. With prolonged therapy, it is not recommended to take more than 480 mg of Isoptin SR 240 per day, but if necessary, a short-term dose may be taken that exceeds this level.
Recommended dosage regimen depending on indications:
    arterial hypertension in mild or moderate degree: take once a day in the morning, 240 mg (1 tablet); if the patient requires a slow decrease in blood pressure, the course should be started with the use of 120 mg (½ tablet) once a day in the morning; if the therapeutic effect is insufficient, it is possible to prescribe an additional dose in the evening at a dose of 120–240 mg (½ – 1 tablet), in this case the interval between doses should be approximately 12 hours; if necessary, the dose can be increased every 14 days of therapy;
    IHD, including chronic stable angina pectoris, angina pectoris caused by vasospasm (Prinzmetal's angina, variant); atrial fibrillation / flutter, occurring with tachyarrhythmia; paroxysmal supraventricular tachycardia: take twice a day, 120–240 mg (½ – 1 tablet), the break between doses is 12 hours.
The duration of therapy with Isoptin SR is not limited.

Side effects

    immune system: with unknown frequency - hypersensitivity;
    metabolism and nutrition: with an unknown frequency - hyperkalemia;
    mental disorders: rarely - drowsiness;
    nervous system: often - headache, dizziness; rarely - tremor, paresthesia; with an unknown frequency - extrapyramidal disorders, seizures; isolated cases - paralysis (tetraparesis);
    organ of hearing and labyrinthine disorders: rarely - tinnitus; with an unknown frequency - vertigo;
    cardiovascular system: often - bradycardia, marked decrease in blood pressure, flushing of the face; infrequently - tachycardia, palpitations; with an unknown frequency - heart failure, AV-blockade of I – III degree, sinus bradycardia, cessation of sinus node activity, asystole;
    respiratory system: with an unknown frequency - shortness of breath, bronchospasm;
    gastrointestinal tract: often - nausea, constipation; infrequently - abdominal pain; rarely - vomiting; with an unknown frequency - gingival hyperplasia (completely reversible after stopping treatment), abdominal discomfort, intestinal obstruction;
    skin and subcutaneous tissues: rarely - hyperhidrosis; with an unknown frequency - Stevens-Johnson syndrome, angioedema, alopecia, erythema multiforme, maculopapular rash, pruritus, urticaria, purpura;
    musculoskeletal and connective tissue: with an unknown frequency - muscle weakness, arthralgia, myalgia;
    urinary system: with an unknown frequency - renal failure;
    mammary gland and genitals: with an unknown frequency - gynecomastia (reversible after drug withdrawal), galactorrhea, erectile dysfunction;
    general disorders: often - peripheral edema; infrequently - increased fatigue;
    laboratory and instrumental data: with an unknown frequency - an increase in the level of prolactin, an increase in the activity of liver enzymes.

Overdose

Symptoms of intoxication arising from an overdose of verapamil depend on its dose, the time of the detoxification measures and the contractility of the heart muscle (depending on age). There are reports of fatal cases due to overdose.
The most common symptoms of an Isoptin SR overdose are: loss of consciousness, shock, marked decrease in blood pressure, grade I – II AV block (often with Wenckebach periods with or without a slip rhythm), complete AV block with complete AV dissociation, sinus bradycardia , escaping rhythm, sinus node arrest, cardiac arrest.
In case of an overdose of the drug in large quantities, it should be borne in mind that verapamil hydrochloride is released and absorbed in the intestine within 48 hours after oral administration. Depending on the time of administration, some conglomerates of swollen tablet fragments will act as active depots and are presumably located throughout the digestive tract.
If an overdose is suspected, it is required to induce vomiting, wash the stomach and intestines in combination with endoscopic examination, take emetics, laxatives. If necessary, a closed heart massage, artificial respiration and cardiac pacing are performed. Effective measures for this condition include parenteral administration of calcium preparations (solution of 10% calcium gluconate intravenously at a dose of 10-30 ml) and / or beta-adrenergic stimulation.
In case of significant hypotensive reactions, vasopressor and inotropic drugs (norepinephrine, dobutamine, dopamine) are prescribed. In case of development of sinus bradycardia, AV-blockade of II – III degree or in case of cardiac arrest, isoprenaline, atropine, orciprenaline are administered, or cardiac stimulation is performed. If persistent signs of myocardial insufficiency are observed, dobutamine, dopamine and additional calcium are prescribed. Hemodialysis is ineffective.

Special instructions

Verapamil affects SA and AV nodes and slows down AV conduction. With the development of a single-bundle, two-bundle or three-bundle bundle branch block or II-III degree AV block, it is necessary to stop using the drug and, if necessary, conduct appropriate treatment.
The risk of developing II – III degree AV blockade, bradycardia, and asystole on the background of therapy, is aggravated by the presence of SSS, which is most common in elderly patients. In the absence of SSS, the resulting asystole is, as a rule, short-term (within a few seconds) with spontaneous restoration of atrioventricular or normal heart rhythm. If timely restoration of sinus rhythm is not observed, appropriate treatment is required immediately.
In the presence of heart failure and a left ventricular ejection fraction of more than 35%, a stable state should be achieved before taking the drug and further appropriate therapy should be continued.
Influence on the ability to drive vehicles and complex mechanisms
According to the instructions, Isoptin SR, due to its antihypertensive effect and the existing individual sensitivity to it, can lead to a decrease in the speed of psychomotor reactions. Patients who drive a car or work with other complex mechanisms during the treatment period, especially at the beginning of the course, when adjusting the dose and in the case of transferring from therapy with another drug to taking verapamil, should be especially careful.

Application during pregnancy and lactation

There is no sufficient data on the use of Isoptin SR during pregnancy. In studies on animals, no direct or indirect toxic effects on the reproductive system were found. However, it is known that verapamil penetrates the placental barrier and is detected during childbirth in the blood of the umbilical vein (in the amount of 20–92% of the plasma level in the mother's blood).
Pregnant women are allowed to use Isoptin SR (especially in the first trimester) only when the expected benefit for them from the treatment can significantly exceed the potential threat to the fetus.
The active substance of the drug and its metabolites are excreted in breast milk. According to the limited data available, when verapamil is taken in therapeutic doses, its concentration in breast milk is very low. But since it is impossible to completely exclude the likelihood of a negative effect of the drug on the health of infants, it is recommended to cancel its intake during lactation.

Childhood use

Due to the lack of convincing data confirming the safety of taking verapamil in children and adolescents under 18 years of age, the use of Isoptin SR 240 in patients of this age group is contraindicated.

With impaired renal function

In the course of comparative studies, in which patients with end-stage renal failure and persons with normal renal function took part, it was found that impaired renal function does not affect the pharmacokinetic parameters of verapamil. But in connection with some existing reports, in the presence of impaired renal activity, Isoptin SR 240 is recommended to be taken with extreme caution, under close medical supervision.

For violations of liver function

In the presence of liver dysfunctions, a slowdown in the metabolism of verapamil, depending on their severity, was noted, which contributed to an increase in the duration and enhancement of the action of the drug. As a result, patients with hepatic insufficiency should take Isoptin SR 240 with extreme caution and at lower initial doses, in particular in patients with cirrhosis of the liver, the recommended dose is 40 mg 2-3 times a day.

Use in the elderly

Elderly patients should take Isoptin SR  with caution, since they may have an increase in T½. No relationship was found between age and the antihypertensive effect of verapamil.

Drug interactions

The data obtained as a result of in vitro studies indicate that the metabolic transformation of verapamil hydrochloride occurs with the participation of isoenzymes CYP1A2, CYP3A4, CYP2C9, CYP2C8 and CYP2C18 of cytochrome P450. A clinically significant interaction was noted with the combined use of the active substance of the drug with CYP3A4 inhibitors, causing an increase in plasma levels of verapamil, while inducers of this isoenzyme led to a decrease in the concentration of the substance in plasma. When combining such drugs, it is necessary to take into account the likelihood of this interaction.
The possible effect of verapamil on other drugs used simultaneously, leading to a change in the pharmacokinetic parameters of these drugs:
    prazosin: the maximum concentration (Cmax) increases by 40%, T½ does not change; there is an additional antihypertensive effect;
    terazosin: Cmax increases (by 25%) and the area under the concentration-time curve (AUC) (~ 24%);
    quinidine: decreases oral clearance (Cl) by 35%; there may be a significant decrease in blood pressure, with hypertrophic obstructive cardiomyopathy, pulmonary edema is possible;
    theophylline: there is a decrease in systemic and oral Cl (~ 20%), in smokers it decreases by almost 11%;
    carbamazepine: with persistent partial epilepsy, AUC increases (~ 46%); the appearance of diplopia, headache, ataxia or dizziness is possible;
    imipramine: increases the AUC (by 15%);
    glibenclamide: increases Cmax (by 28%), AUC (~ 26%);
    colchicine: AUC increases (~ 2 times), Cmax (~ 1.3 times); dose reduction may be required;
    doxorubicin: increases Cmax (61%) and AUC (104%) in patients with small cell lung cancer;
    buspirone: Cmax and AUC increase (~ 3.4 times);
    midazolam: Cmax increases (~ 2 times), AUC (~ 3 times);
    metoprolol: increases Cmax (~ 41%) and AUC (~ 32.5%) against the background of angina pectoris;
    propranolol: increases Cmax (~ 94%) and AUC (~ 65%) against the background of angina pectoris;
    digitoxin: total (~ 27%) and extrarenal (~ 29%) Cl decreases;
    digoxin: increases in healthy volunteers Cmax (~ 44–53%), AUC (~ 50%) and equilibrium concentration (Css) (~ 44%); dose reduction may be required;
    cyclosporine: Cmax, Css, AUC increases (~ 45%);
    sirolimus, tacrolimus, lovastatin, atorvastatin: the concentration level may increase;
    simvastatin: Cmax increases (~ 4.6 times) and AUC (~ 2.6 times);
    almotriptan: increases Cmax (~ 24%) and AUC (~ 20%).
Possible effect of other drugs used simultaneously on verapamil, leading to a change in its pharmacokinetic parameters:
    erythromycin, clarithromycin, telithromycin: possible increase in concentration;
    flecainide: no effect on Cl in plasma, the effect on Cl of flecainide in plasma is less than 10%;
    rifampicin: decreases Cmax (~ 94%), AUC (~ 97%), bioavailability (~ 92%); possibly weakening of the antihypertensive action;
    phenobarbital: oral Cl increases (~ 5 times);
    cimetidine: AUC S- (~ 40%) and R- (~ 25%) increases and, accordingly, Cl S- and R- decreases;
    sulfinpyrazone: oral Cl increases (~ 3 times) and bioavailability decreases (~ 60%); decreases the antihypertensive effect;
    St. John's wort: decreases AUC S- (~ 80%) and R- (~ 78%) and, accordingly, decreases Cmax;
    grapefruit juice: increases Cmax R- (~ 75%) and S- (~ 51%), AUC R- (~ 49%) and S- (~ 37%); renal clearance and T½ do not change; not recommended to be taken simultaneously.
Other possible interactions of verapamil with drugs / substances when used in combination:
    antiviral agents for the treatment of HIV infection (including ritonavir): the metabolism of verapamil is suppressed and its concentration in the blood plasma increases, a decrease in the dose of verapamil may be required;
    acetylsalicylic acid (as an antiplatelet agent): the risk of bleeding is aggravated;
    ethanol: its plasma level rises and excretion slows down, which enhances its effectiveness;
    vasodilators, diuretics, antihypertensive drugs: the antihypertensive effect increases;
    beta-blockers, antiarrhythmic drugs: the risk of mutual enhancement of effects on the cardiovascular system increases (the severity of AV blockade, a decrease in heart rate, the threat of heart failure, increased hypotension increases);
    muscle relaxants: their effect may increase;
    lithium: its neurotoxicity increases.
If therapy with HMG-CoA reductase inhibitors (lovastatin, atorvastatin, simvastatin) is prescribed against the background of treatment with verapamil, the use of the latter is required to start with the lowest possible dose, which can be further increased. In the case when verapamil is prescribed to patients already taking HMG-CoA reductase inhibitors, their dose must be reduced taking into account the level of cholesterol in the blood serum. Drugs such as pravastatin, rosuvastatin and fluvastatin are not metabolized with the participation of CYP3A4 isoenzymes, therefore their interaction with verapamil is less likely.

Terms and conditions of storage

Store out of the reach of children at a temperature of 15-25 ° С.
The shelf life is 3 years.

Reviews of Isoptin SR

The few reviews about Isoptin SR 240 are mostly positive. Many patients who took the drug confirm its effectiveness in the treatment of coronary artery disease, tachycardia, arterial hypertension. According to reviews, the tool significantly improves the quality of life of patients with cardiac diseases.
However, there are also reviews that indicate the development of a significant number of adverse drug reactions, such as palpitations, a marked decrease in blood pressure, headache, dizziness, hot flashes, sweating. Some patients note the insufficient effect of Isoptin SR 240 in the treatment of arterial hypertension.

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