Diltiazem (Tablets, Capsules) Instructions for Use

ATC Code

C08DB01 (Diltiazem)

Active Substance

Diltiazem (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Calcium channel blocker

Pharmacotherapeutic Group

Calcium channel blockers; selective calcium channel blockers with direct cardiac action; benzodiazepine derivatives

Pharmacological Action

A selective class III calcium channel blocker, a benzothiazepine derivative. It has antianginal, antihypertensive, and antiarrhythmic effects.

It reduces myocardial contractility, slows AV conduction, decreases heart rate, reduces myocardial oxygen demand, dilates coronary arteries, and increases coronary blood flow. It lowers the tone of peripheral arterial smooth muscle and systemic vascular resistance.

It decreases the intracellular calcium ion content in cardiomyocytes and vascular smooth muscle cells, reduces heart rate, may have a slight negative inotropic effect, and increases coronary, cerebral, and renal blood flow.

At concentrations where a negative inotropic effect is absent, it causes relaxation of coronary vascular smooth muscle and dilation of both large and small arteries.

The antianginal effect is due to improved myocardial blood supply and reduced oxygen demand resulting from decreased systemic vascular resistance, systemic blood pressure (afterload), reduced myocardial tone, and increased time for diastolic relaxation of the left ventricle.

The antiarrhythmic action is due to the suppression of calcium ion transport in heart tissues, leading to a prolongation of the effective refractory period and slowed conduction in the AV node (in patients with sick sinus syndrome, elderly individuals, in whom calcium channel blockade may impede impulse generation in the sinus node and cause sinoatrial block).

The normal atrial action potential or intraventricular conduction is not altered (normal sinus rhythm is usually unaffected), but with a reduction in atrial contraction amplitude, the depolarization rate and conduction velocity decrease.

The anterograde effective refractory period in accessory bypass tracts may shorten.

With parenteral administration, it causes rapid conversion of paroxysmal supraventricular tachycardia (including that associated with accessory bypass tracts) to sinus rhythm, as well as temporary cessation of ventricular tachycardia during atrial flutter or fibrillation.

The antihypertensive effect is due to the dilation of resistant vessels and a reduction in systemic vascular resistance.

The degree of blood pressure reduction correlates with its initial level (with blood pressure fluctuations within normal limits, a minimal effect on blood pressure is noted).

It lowers blood pressure in both horizontal and vertical positions.

It rarely causes postural arterial hypotension and reflex tachycardia.

It does not change or slightly reduces the maximum heart rate during exercise.

Long-term therapy does not lead to hypercatecholaminemia or increased activity of the RAAS.

It reduces the renal and peripheral effects of angiotensin II.

It promotes diastolic relaxation of the myocardium in arterial hypertension, coronary artery disease, hypertrophic obstructive cardiomyopathy, and reduces platelet aggregation.

It is capable of causing regression of left ventricular hypertrophy in patients with arterial hypertension.

It has a slight effect on the smooth muscle of the gastrointestinal tract.

Tolerance does not develop during long-term (8 months) therapy.

It does not affect the blood lipid profile.

The onset and duration of action depend on the dosage form used.

Pharmacokinetics

After oral administration, Diltiazem is almost completely absorbed from the gastrointestinal tract.

It undergoes intensive first-pass metabolism in the liver.

Bioavailability is about 40%.

Plasma concentration is variable.

Plasma protein binding is about 80%.

Diltiazem is excreted in breast milk.

It is intensively metabolized in the liver by the cytochrome P₄₅₀ enzyme system.

One of the metabolites, desacetyldiltiazem, has 25-50% of the activity of the unchanged substance.

The T_1/2 of diltiazem is 3-5 hours.

It is excreted mainly as metabolites in bile and urine, with approximately 2-4% excreted unchanged in the urine.

Diltiazem is poorly removed by dialysis.

Indications

Prevention of angina attacks (including Prinzmetal’s angina). Arterial hypertension. Prevention of supraventricular arrhythmias (paroxysmal supraventricular tachycardia, atrial fibrillation, atrial flutter, extrasystole).

For intravenous administration: relief of acute angina attacks, prevention of coronary artery spasm during coronary angiography or coronary artery bypass surgery, paroxysmal ventricular tachycardia, for controlling rapid ventricular rate in atrial fibrillation or flutter (except in WPW syndrome).

ICD codes

Dosage Regimen

Tablets, Capsules

When taken orally, the initial dose is 60 mg 3 times/day or 90 mg 2 times/day. If the effect is insufficient, the dose is increased to 180 mg 2 times/day. Extended-release forms are used 1-2 times/day depending on the dose.

The maximum daily dose when taken orally is 360 mg.

For intravenous administration, a single dose is 300 mcg/kg.

For intravenous drip infusion, the dose is 2.8-14 mcg/kg/min. The maximum daily dose is 300 mg.

Adverse Reactions

From the central and peripheral nervous system headache, dizziness, fainting, increased fatigue, asthenia, sleep disorders, drowsiness, anxiety, extrapyramidal (parkinsonism) disorders (ataxia, mask-like face, shuffling gait, stiffness of arms or legs, trembling of hands and fingers, difficulty swallowing), depression; with high doses – paresthesia, tremor, visual impairment (transient vision loss).

From the cardiovascular system asymptomatic decrease in blood pressure; rarely – angina, arrhythmia (including ventricular flutter and fibrillation), bradycardia (less than 50 beats/min) or tachycardia, second and third degree AV block up to asystole, development or worsening of heart failure; with high doses and intravenous administration – angina, bradycardia, AV block, pronounced decrease in blood pressure, worsening of chronic heart failure.

From the digestive system dry mouth, increased appetite, nausea, vomiting, constipation or diarrhea, increased activity of liver transaminases, gingival hyperplasia (bleeding, tenderness, swelling).

From the hematopoietic system rarely – thrombocytopenia, agranulocytosis.

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

Other with high doses – pulmonary edema (difficulty breathing, cough, stridor); peripheral edema (edema of the lower extremities – ankles, feet, legs), increased serum creatinine content; rarely – galactorrhea, weight gain.

Contraindications

Severe bradycardia, second and third degree AV block (except in patients with a pacemaker), sick sinus syndrome, cardiogenic shock, atrial fibrillation in WPW syndrome and Lown-Ganong-Levine syndrome, myocardial infarction with pulmonary congestion, arterial hypotension, chronic heart failure stage IIB-III, acute heart failure, hemodynamically significant aortic stenosis, impaired liver and kidney function, pregnancy, lactation, hypersensitivity to benzothiazepine derivatives.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and lactation (breastfeeding).

Experimental studies have established the teratogenic effect of diltiazem.

Use in Hepatic Impairment

Contraindicated in impaired liver function. Use with caution in hepatic insufficiency.

Use in Renal Impairment

Contraindicated in impaired kidney function. Use with caution in renal insufficiency.

Pediatric Use

Use with caution in children (efficacy and safety of use have not been studied).

Geriatric Use

Use with caution in elderly patients.

Special Precautions

Use with caution in first-degree AV block, intraventricular conduction disorders, in patients prone to arterial hypotension, chronic heart failure, myocardial infarction with left ventricular failure, ventricular tachycardia with widened QRS complex, hepatic insufficiency, renal insufficiency, in elderly patients, in children (efficacy and safety of use have not been studied).

Intravenous use is only for emergency therapy, but if necessary, administration over several days is possible. When administering diltiazem, careful monitoring of cardiovascular function is necessary. Against the background of regular beta-blocker use, the indications for intravenous diltiazem administration should be strictly clarified and it should be used only after ECG monitoring in the intensive care unit, taking into account the possible need for a pacemaker.

Simultaneous use of beta-blockers and diltiazem for parenteral administration is not recommended.

Sudden withdrawal of diltiazem may lead to the development of an anginal attack.

Patients with impaired liver and/or kidney function and elderly individuals require dose regimen adjustment.

Drug Interactions

With simultaneous use with beta-blockers (including propranolol, atenolol, metoprolol, pindolol, sotalol), an additive cardiodepressant effect is possible along with an enhancement of the antianginal effect in most patients. In patients with pre-existing left ventricular dysfunction or conduction disorders, the risk of developing severe and life-threatening bradycardia is increased.

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

With simultaneous use with amiodarone, negative inotropic effects, bradycardia, conduction disturbances, and AV block are enhanced.

Since Diltiazem inhibits the CYP3A4 isoenzyme, which is involved in the metabolism of atorvastatin, lovastatin, and simvastatin, manifestations of drug interaction due to increased plasma concentrations of statins are theoretically possible. Cases of rhabdomyolysis have been reported.

With simultaneous use with buspirone, the plasma concentration of buspirone increases, and its therapeutic and side effects are enhanced.

With simultaneous use with vecuronium chloride, an increase in the duration of neuromuscular blockade is possible.

With simultaneous use with digoxin, digitoxin, an increase in the plasma concentrations of digoxin and digitoxin is possible.

With simultaneous use with imipramine, the plasma concentration of imipramine increases and there is a risk of undesirable ECG changes.

Cases of increased plasma concentrations of trimipramine and nortriptyline with simultaneous use with diltiazem have been reported.

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

With simultaneous use with insulin, a case of reduced insulin effectiveness has been reported.

Due to inhibition of the metabolism of anticonvulsants in the liver under the influence of diltiazem and a decrease in their clearance from the body, an increase in the plasma concentrations of carbamazepine and phenytoin with a risk of toxic effects is possible.

With simultaneous use with lithium carbonate, cases of acute parkinsonian syndrome and psychosis have been reported.

With simultaneous use with midazolam, triazolam, the plasma concentration of midazolam and triazolam increases and their effects are enhanced due to inhibition by diltiazem of the CYP3A4 isoenzyme, which is involved in the metabolism of these benzodiazepines.

With simultaneous use with sodium amidotrizoate, an enhancement of the antihypertensive effect of diltiazem is possible.

With simultaneous use with sodium nitroprusside, a significant increase in effectiveness during controlled arterial hypotension is possible.

With simultaneous use with nifedipine, the antihypertensive effect is enhanced.

Rifampicin induces liver enzyme activity, accelerating the metabolism of diltiazem, which leads to a decrease in its effectiveness.

With simultaneous use with theophylline, a slight decrease in the metabolism of theophylline in the liver is possible, apparently due to inhibition of the CYP1A2 isoenzyme by diltiazem.

With simultaneous use with cisapride, a case of impaired consciousness has been reported, apparently due to a marked prolongation of the QT interval. It is believed that Diltiazem inhibits the activity of the CYP3A4 isoenzyme, leading to an increase in the plasma concentration of cisapride and possibly enhancing its cardiotoxicity.

With simultaneous use, Diltiazem inhibits the metabolism of cyclosporine in the liver, leading to a decrease in its excretion and an increase in plasma concentration. At the same time, a decrease in nephrotoxicity manifestations and an enhancement of the immunosuppressive effect were noted.

With simultaneous use with cimetidine, the plasma concentration of diltiazem increases due to inhibition of its oxidative metabolism in the liver under the influence of cimetidine. An enhancement of diltiazem effects is possible.

With simultaneous use with enflurane, cases of impaired AV myocardial conduction have been noted.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.