KARDIL

Active material: Diltiazem
When ATH: C08DB01
CCF: Kalьcievыh channel blocker
When CSF: 01.03.03
Manufacturer: ORION CORPORATION (Finland)

Pharmaceutical form, composition and packaging

30 PC. – plastic bottles (1) – packs cardboard.
30 PC. – vials of dark glass (1) – packs cardboard.

30 PC. – plastic bottles (1) – packs cardboard.
100 PC. – plastic bottles (1) – packs cardboard.

DESCRIPTION OF ACTIVE SUBSTANCES

Pharmacological action

Selective calcium channel blocker class III, benzothiazepine derivative. It has antianginalnoe, hypotensive and antiarrhythmic action. Reduces myocardial contractility, slows AV-conduction, reduces heart rate, reducing myocardial oxygen demand, dilates coronary arteries, increases coronary blood flow. It reduces the tone of smooth muscles of peripheral arteries and PR.

Reduces the intracellular concentration of calcium ions in cardiomyocytes and smooth muscle cells of blood vessels, reduce heart rate, may have a slight negative inotropic effect, increase coronary, cerebral and renal blood flow. The concentrations, where there is no negative inotropic effect, It causes relaxation of smooth muscles of coronary and vascular dilation of both large, and small arteries.

Antianginal effect is due to the improvement of myocardial perfusion and reducing its need for oxygen by reducing systemic vascular resistance, systemic blood pressure (afterload), reduce the tone of the myocardium and increase the time left ventricular diastolic relaxation.

Antiarrhythmic effect is due to inhibition of calcium transport in heart tissues, which leads to a lengthening of the effective refractory period and a deceleration of AV-node (in patients with sick sinus syndrome, seniors, in which calcium channel blockade may interfere with pulse generation in the sinus node and cause sinoatrial block). A normal atrial action potential or intraventricular conduction unchanged (a normal sinus rhythm is usually not affected), but with a decrease in the amplitude of atrial depolarization rate and the rate of decrease. Anterograde effective refractory period of additional bypass beams can be shortened. For parenteral administration causes a rapid transition of paroxysmal supraventricular tachycardia (including associated optional bypass of beams) in sinus rhythm, as well as the temporary suspension of ventricular tachycardia or fibrillation in the Atrial Fibrillation.

The antihypertensive effect is due to dilatation of resistance vessels and a decrease in systemic vascular resistance. The degree of reduction in blood pressure correlated with its baseline (with fluctuations in blood pressure in the normal range there is minimal impact on blood pressure). It reduces blood pressure in both the horizontal, and in a vertical position. Rarely cause postural hypotension and reflex tachycardia. It does not change or only slightly reduces the maximum heart rate under load. Long-term treatment does not lead to giperkateholaminemii, increase the activity of the renin-angiotensin-aldosterone system. Decreases renal and peripheral effects of angiotensin II. Promotes relaxation of myocardial diastolic hypertension, CHD, hypertrophic obstructive cardiomyopathy, reduces platelet aggregation. Able to cause regression of left ventricular hypertrophy in patients with hypertension.

Little effect on the smooth muscles of the digestive tract. For a long (8 Months) therapy did not develop tolerance. No effect on blood lipid profile.

The start and duration depends upon the dosage form.

Pharmacokinetics

After oral diltiazem is almost completely absorbed from the gastrointestinal tract. Subjected to intensive metabolism in the “first pass” through the liver. Bioavailability is about 40%. Plasma concentration is variable.

Plasma protein binding is about 80%. Diltiazem is excreted in breast milk. Intensively metabolized in the liver with the participation of the enzyme system of the cytochrome P₄₅₀. One of the metabolites – desacetildiltiazem – has 25-50% activity unchanged substance.

T_1/2 diltiazem is 3-5 no. Write mainly in the form of metabolites in bile and urine, about 2-4% excreted in the urine as unchanged.

Diltiazem poorly displayed during dialysis.

Testimony

Prevention of angina attacks (incl. Prinzmetal angina). Arterial hypertension. Prophylaxis of supraventricular arrhythmias (paroxysmal supraventricular tachycardia, auricular fibrillation, auricular flutter, arrythmia).

For i / v administration: relief of acute attacks of angina, prevention of coronary artery spasm during coronary angiography or bypass surgery, paroxysmal ventricular tachycardia, for the relief of frequent ventricular rate during atrial flutter or blink (except WPW syndrome).

Dosage regimen

When administered an initial dose – by 60 mg 3 times / day, or 90 mg 2 times / day. With the lack of an effective dose is increased to 180 mg 2 times / day. Prolonged use form 1-2 times / day depending on the dose. The maximum dose ingestion – 360 mg / day.

The on / in a single dose – 300 mg / kg. For in / drip 2.8-14 ug / kg / min, the maximum dose – 300 mg / day.

Side effect

From the central and peripheral nervous system: headache, dizziness, fainting, fatigue, asthenia, sleep disorders, drowsiness, anxiety, extrapyramidal (parkinsonizm) infringement (ataxia, mask-like face, shuffling gait, stiffness in the arms or legs, shaking hands and fingers, difficulty weight management), depression; when used in high doses – paresthesia, tremor, blurred vision (transient loss of vision).

Cardio-vascular system: asymptomatic decrease in blood pressure; rarely – angina, arrhythmia (incl. atrial and ventricular fibrillation), bradycardia (less 50 u. / min) or tachycardia, AV blockade II-III century. until asystole, development or exacerbation of congestive heart failure; when used in high doses and / introduction – angina, bradycardia, OF блокада, marked reduction in blood pressure, exacerbation of chronic heart failure.

From the digestive system: dry mouth, increased appetite, nausea, vomiting, constipation or diarrhea, increase in liver transaminases, giperplaziya right (angiostaxis, soreness, puffiness).

From the hematopoietic system: rarely – thrombocytopenia, agranulocytosis.

Allergic reactions: facial flushing, skin rash, arthritis, erythema multiforme exudative (incl. Stevens-Johnson syndrome).

Other: when used in high doses – pulmonary edema (difficulty breathing, cough, stridor); peripheral edema (edema of the lower extremities – ankles, stop, goleneй), elevation of serum creatinine; rarely – galactorrhea, weight gain.

Contraindications

Vыrazhennaya bradycardia, AV-blockade II and III degrees (except in patients with a pacemaker), SSS, cardiogenic shock, atrial fibrillation in WPW syndrome and Lown-Ganoga-Levine, myocardial infarction, congestive lung, hypotension, chronic heart failure II B-III stage, acute heart failure, aortalnыy stenosis hemodynamically znachymыy, of the liver and kidneys, pregnancy, lactation, Hypersensitivity to the benzothiazepine derivative.

Pregnancy and lactation

Contraindicated during pregnancy and lactation (breast-feeding).

IN experimental studies established teratogenic effect of diltiazem.

Cautions

Use caution when AV-blockade of I degree, intraventricular conduction disorders, patients, prone to hypotension, chronic heart failure, myocardial infarction with left ventricular failure, ventricular tachycardia with the expansion of the complex ORS, hepatic insufficiency, renal failure, in elderly patients, children (efficacy and safety have not been studied).

B / used only for emergency treatment, but if necessary, can be introduced within a few days. When administered diltiazem careful monitoring of the cardiovascular system. Against the background of the regular intake of beta-blockers should be strictly clarify indications for / in the diltiazem and apply it only after ECG monitoring in the ICU, bearing in mind the possible need for a pacemaker.

Not recommended simultaneous application of beta-blockers and diltiazem for parenteral administration.

The sudden cancellation of diltiazem can lead to angina attack.

Patients with impaired liver and / or kidney disease, and the elderly require correction mode.

Drug Interactions

While the use of beta-blockers (incl. with propranolol, atenolol, metoprolol, pindolol, sotalol) cardiodepressive possible additive effects, along with the strengthening of the majority of patients antianginalnogo. In patients with previous left ventricular dysfunction or conduction disorders are at increased risk of severe and threatening bradycardia.

Diltiazem inhibits the metabolism of propranolol, metoprolol, but not atenolol.

In an application with amiodarone increases the negative inotropic effect, bradycardia, asequence, AV блокада.

Since diltiazem inhibits the CYP3A4 isoenzyme, which is involved in the metabolism of atorvastatin, lovastatin and simvastatin, theoretically possible manifestations of drug interactions, caused by increasing concentrations of statins in the blood plasma. There are cases of rhabdomyolysis.

While the use of buspirone buspirone increases the concentration in the blood plasma, enhances its therapeutic and side effects.

In an application with vecuronium chloride may increase the duration of neuromuscular blockade.

In an application with digoxin, digitoxin may increase the concentration of digoxin and digitoxin in the blood plasma.

In an application with imipramine imipramine increased concentration in plasma and the risk of adverse changes in the electrocardiogram.

Cases of increase in plasma concentrations of trimipramine and nortriptyline while the use of diltiazem.

Diltiazem increases the bioavailability of imipramine by reducing its clearance. ECG changes are due to an increase in the concentration of imipramine in plasma and additive inhibitory effect of diltiazem and imipramine on AV-conduction. It is believed, that diltiazem is reacted in the same manner with nortriptyline and trimipramine.

While the use of insulin, a case reduce the effectiveness of insulin.

Because of inhibiting the metabolism of anticonvulsants in the liver under the influence of diltiazem and decrease their clearance from the body may increase the concentrations of carbamazepine and phenytoin in blood plasma with a risk of toxic effects.

In an application with lithium carbonate described cases of acute parkinsonian syndrome, psychosis.

In an application with midazolam, triazolam increases the concentration of midazolam and triazolam in plasma and enhances their effects due to the inhibition under the influence of diltiazem of CYP3A4, with the assistance of which the metabolism of these benzodiazepines.

While the use of sodium amidotrizoat may increase antihypertensive action of diltiazem.

While the use of sodium nitroprusside, a considerable increase in efficiency when controlled hypotension.

While the use of nifedipine increased antihypertensive effect.

Rifampicin induces liver enzymes, speeding up the metabolism of diltiazem, which reduces its effectiveness.

While the use of theophylline may be a small reduction in the metabolism of theophylline in the liver, apparently, due to inhibition of CYP1A2 isoenzyme under the influence of diltiazem.

While the use of cisapride, a case of violation of consciousness, apparently, in connection with a pronounced prolongation of the QT interval. It is believed, that diltiazem inhibits the activity of CYP3A4, which leads to increased concentrations of cisapride in plasma and, perhaps, strengthening its cardiotoxicity.

With simultaneous use of diltiazem inhibits the metabolism of cyclosporine in the liver, which leads to a decrease of its excretion and increased concentrations in plasma. This marked reduction in symptoms of nephrotoxicity and increased immunosuppressive action.

In an application with cimetidine diltiazem increases the concentration in the blood plasma due to its inhibition of oxidative metabolism in the liver under the influence of cimetidine. Intensifying effect of diltiazem.

In an application with enflurane marked by violations of AV-conduction infarction.