Universal reference book for medicines
Product name: ISOPTIN ® SR 240 (ISOPTIN ® SR 240)

Active substance: verapamil

Type: Calcium channel blocker

Manufacturer: ABBOTT (Germany)
Composition, form of production and packaging
Tablets of prolonged action, covered with a film shell of
light green color, oblong form, with transverse risks on both sides, on one side two "?" Signs are engraved.

1 tab.

verapamil hydrochloride 240 mg

Excipients: microcrystalline cellulose - 78.8 mg, sodium alginate - 320 mg, povidone K30 - 48 mg, magnesium stearate - 3.2 mg, purified water - 30 mg.

The composition of the film coating: hypromellose 2910 - 4.9 mg, macrogol 400-1.26 mg, macrogol 6000 - 0.84 mg, talc 8.4 mg, titanium dioxide 6.16 mg, aluminum lacquer (dye quinoline yellow (E104) + dye indigo carmine (E132)) - 0.14 mg, glycolic mountain wax 0.3 mg.

10 pieces.
- blisters (3) - packs of cardboard.
15 pcs.
- blisters (2) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.

Description of the drug approved by the manufacturer for the printed edition of 2012.

PHARMACHOLOGIC EFFECT

The calcium channel blocker.
Inhibits the transmembrane current of calcium ions in the smooth muscle cells of the myocardium and vessels. Has antianginal, antiarrhythmic and antihypertensive action.
The antianginal effect is associated with direct action on the myocardium and influence on peripheral hemodynamics (reduces the tone of the peripheral arteries, OPSS).
The blockade of calcium ions entering the cell leads to a decrease in the transformation of the energy contained in the macroergic ATP bonds into mechanical work and to a decrease in myocardial contractility.
Antihypertensive effect of the drug is due to a decrease in the resistance of peripheral vessels without a reflex increase in heart rate.
BP begins to decline directly on the first day of treatment and this effect persists with long-term therapy. Isoptin SR 240 is used to treat all types of arterial hypertension: for monotherapy of mild or moderate hypertension, in combination with other antihypertensive agents, especially diuretics and (in accordance with recent observations) ACE inhibitors. The drug has a vasodilating, negative, foreign and chronotropic action .
The drug has a pronounced antiarrhythmic effect, especially effective in supraventricular arrhythmia.
Delays the holding of a pulse in the AV node, as a result, the sinus rhythm is restored and / or the heart rate is normalized, depending on the type of arrhythmia. Normal heart rate does not change or slightly decreases.
PHARMACOKINETICS

Suction

When ingestion is quickly and almost completely absorbed in the small intestine.
The degree of absorption is 90-92%. The average systemic bioavailability in healthy volunteers after a single dose is 22%. Studies among patients with atrial fibrillation or angina have shown that the average bioavailability levels are 35% and 24% after a single dose of the drug inside and / or in the dose, respectively. With repeated administration of the drug, bioavailability increases almost 2-fold compared to a single dose (this effect is probably due to partial saturation of the hepatic enzyme systems and / or a transient increase in blood circulation in the liver after a single dose of verapamil).
Distribution

With coronary artery disease and hypertension, there was no correlation between the therapeutic effect and the concentration of the drug in the blood plasma;
There is only a definite relationship between the level of the drug in the blood plasma and the effect on the PR interval.
After taking a sustained-release dosage form, the curve of concentration of verapamil in the blood plasma is stretched and becomes more flat than when administered with normal release dosage forms.

Binding to plasma proteins is 90%.

Penetrates through the placental barrier;
the concentrations found in the blood plasma of the umbilical vein were 20-92% of the concentrations in the mother's blood plasma.
It is excreted in breast milk, but with therapeutic doses, its concentrations are so low that the clinical effect in newborns is unlikely.

Metabolism

Verapamil undergoes the "first pass" effect through the liver.
Almost completely metabolized. The main metabolite is norverapamil, which has pharmacological activity; other metabolites are mostly inactive.
Excretion

T 1/2 is from 3 to 7 hours after a single dose of the drug inside.
With repeated admission of T 1/2 verapamil may increase almost 2 times compared with a single dose.
Verapamil and its metabolites are excreted mainly through the kidneys (3-4% unchanged).
Within 24 hours 50% of the administered dose is withdrawn, within 48 hours - 55-60%, within 5 days - 70%. Up to 16% is excreted with feces.
Pharmacokinetics in special clinical cases

In patients with hepatic impairment compared with those with normal liver function, the bioavailability of verapamil was much higher, and an elongation of T 1/2 was observed.

Recent results suggest that there is no difference in the pharmacokinetics of verapamil in individuals with normal renal function and in patients with terminal renal failure.

INDICATIONS

- arterial hypertension;

- chronic stable angina (stress angina);

- angina due to spasm of blood vessels (Prinzmetal angina, variant);

paroxysmal supraventricular tachycardia;

- Atrial fibrillation / flutter, accompanied by tachyarrhythmia (with the exception of WPW syndrome).

DOSING MODE

The average daily dose of the drug is 240-360 mg.
With prolonged treatment, the daily dose of 480 mg should not be exceeded; possibly a temporary increase in the dose above this level.
With IHD (chronic stable angina, angina due to vascular spasm / angina prinzmetal, variant I) Isoptin SR 240 is prescribed in a daily dose of 240-480 mg (1 / 2-1 tablets 2 times / day with an interval of 12 hours).

With arterial hypertension (mild or moderate), Isoptin SR 240 is prescribed 240 mg (1 tab.) 1 time / day in the morning.
If a slow decrease in blood pressure is preferable, then treatment should be started with a dose of 120 mg (1/2 table isotope SR 240) 1 time / day in the morning. If necessary, additionally appoint 1 / 2-1 tab.in the evening with an interval between doses of about 12 hours. If necessary, the dose should be increased every 2 weeks of treatment.
With paroxysmal supraventricular tachycardia, atrial fibrillation / flutter accompanied by tachyarrhythmia, Isoptin CP 240 is prescribed 120-240 mg (1 / 2-1 tab.) 2 times / day with an interval of 12 hours.

If liver function is impaired, the effect of the drug is increased and becomes more prolonged as a result of delayed metabolism of verapamil, which depends on the severity of liver function disorders.
In such cases, the dose should be administered with extreme caution; treatment should start with taking the drug at lower doses (that is, patients with cirrhosis are prescribed Isoptin 40 mg 2-3 times / day).
Tablets should be taken during meals or immediately after meals, swallowing whole and with water.

The duration of use is unlimited.

SIDE EFFECT

From the cardiovascular system: sometimes (when taken in high doses or in the presence of cardiovascular disorders) - arrhythmia in the background of bradycardia (sinus bradycardia, sinoatrial blockade, AV blockade I, II or III degree or bradyarrhythmia with atrial fibrillation), Arterial hypotension, palpitations, tachycardia, development or intensification of heart failure symptoms.

From the side of the central nervous system and peripheral nervous system: rarely - headache, dizziness, drowsiness, increased fatigue, increased nervousness, tremor, paresthesia.

From the digestive system: often - constipation;
rarely - nausea, vomiting, intestinal obstruction, pain or discomfort in the abdomen; a reversible increase in hepatic transaminase and / or AFP levels is described; in extremely rare cases during long-term treatment - gingival hyperplasia, completely reversible after discontinuation of the drug.
From the musculoskeletal system: in very rare cases - myalgia and arthralgia.

Allergic reactions: rarely - exanthema, urticaria, angioedema, Stevens-Johnson syndrome.

On the part of the endocrine system: a reversible increase in the level of prolactin;
rarely (in elderly patients with prolonged therapy) - gynecomastia, completely reversible after drug withdrawal; in some cases - galactorrhea, impotence.
Other: rarely - edema of the shins, erythromelalgia, hot flushes.

CONTRAINDICATIONS

Absolute contraindications

- cardiogenic shock;

- Complicated acute myocardial infarction (bradycardia, severe arterial hypotension, left ventricular failure);

- AV blockade II or III degree;

- SSSU (bradycardia-tachycardia syndrome);

- Sinoatrial blockade.

Relative contraindications

- AV blockade of the 1st degree;

- bradycardia (less than 50 beats per minute);

- arterial hypotension (systolic blood pressure less than 90 mm Hg);

- Atrial fibrillation / flutter with WPW syndrome (risk of ventricular tachycardia);

- Heart failure (if necessary, before the start of treatment with the drug Isoptin CP 240 appoint cardiac glycosides).

PREGNANCY AND LACTATION

The prescription of Isoptin SR 240 during pregnancy (especially in the first trimester) and during lactation is possible only if the expected benefit for the mother exceeds the potential risk to the fetus.

During the lactation period, the drug should be discontinued.

APPLICATION FOR FUNCTIONS OF THE LIVER

Recent results suggest that there is no difference in the pharmacokinetics of verapamil in individuals with normal renal function and in patients with terminal renal failure.

APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS

When the liver function is impaired, the effect of verapamil is strengthened and becomes more prolonged as a result of delayed metabolism of verapamil, which depends on the severity of liver function disorders.
In such cases, the dose should be administered with extreme caution and treatment should begin with taking the drug at lower doses (that is, patients with cirrhosis of the drug are prescribed Isoptin 40 mg 2-3 times / day.
APPLICATION FOR CHILDREN

At present, there are no convincing data on the safety of the drug in children under the age of 18 years.

SPECIAL INSTRUCTIONS

Use in Pediatrics

At present, there are no convincing data on the safety of the drug in children under the age of 18 years.

Impact on the ability to drive vehicles and manage mechanisms

Depending on the individual response to taking the drug, the patient's ability to drive or work with the machines during the period of admission can be reduced.
This is especially important to take into account in the initial period of therapy, when transferring to the intake of Isoptin CP 240 after the use of another drug, as well as with the simultaneous intake of alcohol.
OVERDOSE

Symptoms of poisoning due to an overdose of Isoptin SR 240 depend on the amount of drug taken, the time taken for detoxification and the contractile ability of the myocardium, depending on age.
Fatal cases have been reported as a result of an overdose.
Symptoms: a drop in blood pressure (in some cases to levels that can not be measured), shock, unconsciousness, AV blockade of I or II degree, often in the form of Wenckebach periods with or without a slipping rhythm, complete AV blockade with complete AV dissociation , slipping rhythm, cardiac arrest;
sinus bradycardia, stopping the sinus node.
In case of an overdose of Isoptin CP 240, it should be borne in mind that the active substance is released and absorbed from the intestine within 48 hours after ingestion.
Depending on the time of taking the drug, individual conglomerates of the remains of swollen tablets, acting as active depots, will be located throughout the digestive tract.
Treatment: the measures aimed at removing the drug are indicated (for example, it is necessary to induce vomiting, rinse the stomach and intestines in combination with an endoscopic examination, prescribe laxatives, emetics).
If there is no motility of the stomach and intestines (signs of peristalsis in auscultation), it is advisable to perform gastric lavage even after 12 hours after ingestion. Ordinary emergency resuscitation measures include closed cardiac massage, artificial respiration, and electrical heart stimulation.
It is necessary to exclude the effects associated with oppression of heart function, arterial hypotension and bradycardia.

Calcium is a specific antidote: 10-30 ml of 10% calcium gluconate solution in the form of IV infusions (2.25-4.5 mmol) is injected, if necessary, injected repeatedly or as a slow drop infusion (5 mmol / h).

In the case of AV blockade II or III degree, sinus bradycardia, cardiac arrest, there is an introduction of atropine, isoprenaline, orciprenaline, conduction of heart stimulation.

In the case of arterial hypotension, dopamine, dobutamine, norepinephrine (norepinephrine) is administered.

In the case of persistent signs of myocardial insufficiency, dopamine, dobutamine is administered, if necessary, additional calcium is administered.

DRUG INTERACTION

In vitro studies indicate that verapamil hydrochloride is metabolized with the participation of isoenzymes CYP3A4, CYP1A2, CYP2C8, CYP2C9 and CYP2C18.
A clinically significant interaction was noted with concomitant use of CYP3A4 inhibitors that caused elevations in verapamil levels in plasma, while CYP3A4 inducers decreased its plasma concentration. Accordingly, with the simultaneous use of such tools, the possibility of interaction should be taken into account.
The table presents a list of possible interactions of drugs with the administration of Isoptin CP 240.

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

Gliburid Increases C max glyburide (by 28%), AUC (by 26%)

Antibiotics

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 Decreases T 1/2 of doxorubicin (by 27%) and C max (by 38%) *

Tranquilizers

Phenobarbital Verapamil clearance increases 5-fold

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

Immunomodulators

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

Sirolimus May increase the concentration of sirolimus

Tacrolimus Possible increase in tacrolimus concentration

Lipid-lowering drugs

Atorvastatin May increase the concentration of atorvastatin

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.
* 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 C max of doxorubicin.
With the simultaneous use of Isoptin SR 240 with antiarrhythmics, beta-blockers, the effects on the cardiovascular system may increase (appearance of AV blockade, reduction in heart rate, increased arterial hypotension, and development of heart failure).

Isoptin SR 240 enhances the antihypertensive effect of other antihypertensive drugs (including diuretics, vasodilators).

With the simultaneous use of Isoptin CP 240 with prazosin, terazosin, an additive hypotensive effect is noted.

Ritonavir and antiviral drugs can inhibit the metabolism of verapamil, which leads to an increase in its plasma concentration.
In this regard, the dose of Isoptin CP 240 should be reduced.
With the simultaneous use of the drug Isoptin SR 240 with quinidine - hypotension;
in patients with hypertrophic obstructive cardiomyopathy, the development of pulmonary edema is possible.
With the simultaneous use of the drug Isoptin SR 240 with carbamazepine, carbamazepine levels in the plasma are increased and its neurotoxicity is increased.Possible side effects of carbamazepine, such as diplopia, headache, ataxia or dizziness.

Isoptin SR 240 with simultaneous application increases the neurotoxicity of lithium.

The hypotensive effect of Isoptin CP 240 may decrease with simultaneous use with rifampicin and sulfinpyrazone.

With the simultaneous use with the drug Isoptin SR 240, the effect of muscle relaxants can be enhanced.

With simultaneous use with acetylsalicylic acid, there is an increase in bleeding.

When ethanol is simultaneously used with Isoptin SR 240, the level of ethanol in plasma is increased.

Simultaneous use with the preparation of Isoptin CP 240 can lead to an increase in the concentrations in the blood plasma of simvastatin or lovastatin.

Patients receiving verapamil, treatment with HMG-CoA reductase inhibitors (simvastatin, lovastatin) should be started with as low a dose as possible, which is further increased.
If it is necessary to prescribe verapamil, patients who are already receiving HMG-CoA reductase inhibitors should review and reduce their doses, respectively serum cholesterol concentrations. Similar tactics should be followed even with concomitant administration of verapamil with atorvastatin (although there is no clinical evidence to support the interaction of verapamil and atorvastatin), as pharmacokinetic studies confirm that verapamil has a similar effect on atorvastatin levels.
Fluvastatin, pravastatin and rosuvastatin are not metabolized by CYP3A4 isozymes, so their interaction with verapamil is least likely.

TERMS OF RELEASE FROM PHARMACY

The drug is released by prescription.

TERMS AND CONDITIONS OF STORAGE

The drug should be stored out of the reach of children at a temperature of no higher than 25 ° C.
Shelf life - 3 years.
Tablets should be stored in a blister pack before use.

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