Diltiazem

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DILTIAZEM (DILTIAZEM)

Composition:

Active substance: diltiazem;

1 tablet contains diltiazem hydrochloride (calculated as 100% diltiazem hydrochloride content) – 60 mg;

Excipients: lactose monohydrate; microcrystalline cellulose; potato starch; povidone; colloidal anhydrous silicon dioxide; calcium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: intact, regular, round cylindrical tablets with flat upper and lower surfaces, beveled edges, a dividing line marked on the surface, white or white with a creamy shade.

Pharmacotherapeutic group.

Selective calcium antagonists with predominant cardiac effect. Benzothiazepine derivatives.

ATC code C08DB01.

Pharmacological Properties

Pharmacodynamics

Diltiazem is a calcium ion antagonist of the benzothiazepine derivative group. It reduces calcium ion influx through slow calcium channels in the cell membrane of cardiomyocytes and smooth muscle cells. It exerts antianginal, antihypertensive, and antiarrhythmic effects.

The mechanism of action in angina pectoris is due to dilation of coronary vessels and reduction of myocardial afterload. It is effective in the treatment of stable angina, which objectively manifests as an increased duration of exercise-induced ST-segment depression, and subjectively as a reduction in the frequency of angina attacks and the need for nitroglycerin. The efficacy of diltiazem in treating unstable angina is approximately equivalent to that of nifedipine or verapamil, while the incidence of adverse effects with diltiazem is significantly lower than with these agents.

Diltiazem exerts antihypertensive effects by reducing both systolic and diastolic blood pressure, without affecting normal blood pressure levels. Unlike most peripheral vasodilators, it does not induce reflex tachycardia. Despite its mild negative inotropic effect, diltiazem does not reduce cardiac stroke volume or left ventricular ejection fraction. With long-term regular use, diltiazem may promote regression of left ventricular hypertrophy. The drug can be used as monotherapy or in combination with other antihypertensive agents, particularly diuretics and ACE inhibitors. Diltiazem may be prescribed in cases where β-adrenergic receptor blockers are contraindicated (e.g., in patients with bronchial asthma, diabetes mellitus, or peripheral angiopathies). Diltiazem has no adverse effect on plasma lipid profile.

The drug suppresses calcium influx into cells of the sinus and AV nodes, providing therapeutic efficacy in supraventricular arrhythmias.

Pharmacokinetics

Diltiazem is completely absorbed from the gastrointestinal tract after oral administration. During first-pass metabolism in the liver, the absolute bioavailability of diltiazem is approximately 40% (individual variations range from 24% to 74%). Bioavailability is the same for all dosage forms and is not dose-dependent within clinically used doses. Maximum plasma concentration is reached approximately 3–4 hours after administration of a 60 mg tablet (after a single 60 mg dose, peak concentration ranges from 39 to 120 ng/mL).

Approximately 80% of diltiazem is bound to plasma proteins, with only up to 40% bound to albumin. Diltiazem is effectively distributed into various tissues. The volume of distribution is 5 L/kg, and the central vascular volume is 0.9 L/kg. In blood, the drug rapidly distributes between plasma and blood cells. Steady-state plasma concentrations are achieved within 3 days when administering 60 mg three times daily. At daily doses of 120–300 mg, steady-state plasma concentrations range from 20 to 200 ng/mL (minimum therapeutic concentration is approximately 70–100 ng/mL).

Diltiazem is metabolized by the cytochrome P450 enzyme CYP3A4 and is a substrate for P-glycoprotein. Diltiazem is also an inhibitor of the cytochrome P450 enzyme CYP3A4. Phase I metabolism involves deacetylation, N-demethylation, and O-demethylation. Deacetyldiltiazem is an active metabolite (with 40–50% of the activity of diltiazem); its concentration is approximately 15–35% of that of diltiazem. The pharmacodynamic significance of this metabolite is minimal.

Only 0.1–4% of diltiazem is excreted unchanged in urine; therefore, elimination occurs predominantly in the form of metabolites. Total clearance of diltiazem is 0.7–1.3 L/kg/h. Five non-conjugated metabolites have been identified in urine, two of which also occur in conjugated form. Diltiazem elimination follows monophasic kinetics. According to a three-compartment model, the half-life is approximately 0.1 hour for the fastest distribution phase, 2.1 hours for the intermediate phase, and 9.8 hours for the terminal elimination phase. The elimination half-life ranges from 4 to 7 hours.

With prolonged administration, no changes in the pharmacokinetics of diltiazem have been observed. The drug does not accumulate in the body and does not induce its own metabolism. The pharmacokinetics of diltiazem in patients with angina pectoris and impaired renal function do not differ from those in healthy volunteers.

Clinical characteristics.

Indications.

Angina pectoris. Arterial hypertension. Prinzmetal's angina. For reduction of ventricular rate in atrial fibrillation.

Contraindications.

Hypersensitivity to diltiazem or to any of the excipients, or to benzothiazepine derivatives. Sick sinus syndrome; second- or third-degree atrioventricular block (except in cases with a functioning pacemaker); arterial hypotension (systolic blood pressure < 90 mm Hg); marked bradycardia (< 50 beats/min); Wolff-Parkinson-White syndrome; decompensated heart failure; acute myocardial infarction with complicated course; cardiogenic shock (including due to digitalis intoxication); ventricular extrasystoles; acute heart failure, chronic heart failure stages II-III; atrial flutter or atrial fibrillation in the presence of Lown-Ganong-Levine syndrome (except in patients with implanted cardiac pacemakers); concomitant use of dantrolene administered intravenously (see section "Interaction with other medicinal products and other forms of interaction"); combination with ivabradine (see section "Interaction with other medicinal products and other forms of interaction").

Concomitant use with lomitapide (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

The drug may be combined with nitrates, anticoagulants, diuretics, and hypoglycemic agents.

Potentiation of the effect of other antihypertensive drugs is possible. Concomitant use of the drug with β-blockers, amiodarone, or digoxin may suppress AV conduction and increase the risk of bradycardia. Diltiazem may enhance the myocardial depressant effect of halothane and isoflurane. Intravenous administration of calcium salts reduces the pharmacological response to diltiazem.

Diltiazem is primarily metabolized via the cytochrome CYP3A4 enzyme system. Cimetidine, as an inhibitor of cytochrome CYP3A4, may increase diltiazem plasma concentration. Potentiation of diltiazem's effect is possible when used concomitantly with macrolides, antifungal agents, azole derivatives, fluoxetine, tamoxifen, nifedipine, and HIV protease inhibitors. When used concomitantly with drugs that induce cytochrome CYP3A4, such as carbamazepine, moricizine, phenobarbital, and rifampicin, accelerated metabolism of diltiazem may occur. Diltiazem inhibits the metabolism of drugs metabolized by cytochrome CYP3A4 and P-glycoprotein. Diltiazem is also a substrate for cytochrome CYP3A4 and P-glycoprotein. Plasma concentrations and adverse effects should be monitored when using such drugs: quinidine, cyclosporine, valproic acid, carbamazepine, phenytoin, cyclosporine, sirolimus, tacrolimus, digoxin, digitoxin, methylprednisolone, and theophylline. Concomitant administration of diltiazem with disopyramide, procainamide, or quinidine may significantly enhance the negative inotropic effect. When diltiazem is used concomitantly with HMG-CoA reductase inhibitors metabolized by cytochrome CYP3A4, such as simvastatin, atorvastatin, lovastatin, and cerivastatin, the doses of the latter should be reduced to prevent the development of rhabdomyolysis and liver injury. The drug does not inhibit the clearance of pravastatin and fluvastatin.

Concomitant use of diltiazem with nifedipine, quinidine, propranolol, metoprolol, imipramine, nortriptyline, sildenafil, buspirone, midazolam, triazolam, diazepam, alprazolam, alfentanil, and cisapride may increase plasma concentrations of these agents.

Thiazide diuretics enhance the hypotensive effect of diltiazem. Inhalational anesthetics (hydrocarbon derivatives) may enhance arterial hypotension.

Enhances the cardiodepressant effect of general anesthetics.

Concomitant use of lithium and diltiazem may lead to neurotoxicity; therefore, serum lithium concentration should be carefully monitored.

Medicinal products whose concomitant use is contraindicated

Dantrolene (infusions). In animals receiving intravenous verapamil and dantrolene simultaneously, fatal ventricular fibrillation has been regularly observed. Therefore, the combination of a calcium channel blocker and dantrolene is potentially hazardous (see section "Contraindications").

Ivabradine. Concomitant use of the drug with ivabradine is contraindicated due to the additive effect on reducing heart rate when diltiazem is used (see section "Contraindications").

Lomitapide

Diltiazem (a moderate CYP3A4 inhibitor) may increase lomitapide plasma concentration by inhibiting CYP3A4, leading to an increased risk of elevated liver enzymes (see section "Contraindications").

Acetylsalicylates [acetylsalicylic acid (ASA)/lysine acetylsalicylate (LAS)]. Acetylsalicylates (ASA/LAS) should be used with caution together with diltiazem due to an increased risk of bleeding associated with a potential additive effect on platelet aggregation.

Contrast media. Cardiovascular effects of intravenous bolus injection of ionic contrast media, such as arterial hypotension, may be enhanced in patients receiving diltiazem. Special caution is required if patients are receiving both diltiazem and ionic contrast media.

Special precautions.

The drug should be used with caution in patients with severe hepatic or renal impairment.

Diltiazem clearance may be reduced in elderly patients. Elderly patients at risk of developing symptoms of heart failure may exhibit increased sensitivity to the drug's effects, even during standard treatment.

The drug should be used cautiously in patients with acute porphyria.

Caution is advised when prescribing the drug to patients with first-degree atrioventricular block, impaired ventricular conduction, or those prone to arterial hypotension. Electrocardiographic (ECG) changes may occur in patients (prolongation of the PQ interval).

Diltiazem should be administered with caution to patients with left atrial insufficiency, bradycardia, prolonged PQ interval, or aortic stenosis. Caution is also required when co-administering the drug with β-blockers or other agents that reduce myocardial contractility or AV conduction.

Cases of acute renal failure due to reduced renal perfusion have been reported in patients with cardiovascular diseases, particularly those with impaired left ventricular function, marked bradycardia, or severe hypotension. Careful monitoring of renal function is recommended.

Calcium antagonists may potentiate the effects of anesthetics on cardiac impulse generation and may affect conduction, contractility, and vascular tone. If a patient undergoing therapy requires surgical intervention under general anesthesia, the anesthesiologist must be informed about the ongoing treatment.

Calcium antagonists may contribute to reduced male fertility; this should be considered if a patient taking calcium antagonists is diagnosed with infertility of unknown etiology. This effect is reversible upon discontinuation of therapy.

Diltiazem absorption may be reduced in patients with chronic diarrhea (e.g., in ulcerative colitis or Crohn's disease).

Intravenous administration of β-adrenergic blockers is not recommended during treatment.

Use of calcium channel blockers such as diltiazem may be associated with mood changes, including the development of depression.

Like other calcium channel blockers, diltiazem exerts an inhibitory effect on intestinal peristalsis. Therefore, it should be used cautiously in patients at risk of intestinal obstruction.

Alcoholic beverages should be avoided during treatment.

Since the drug contains lactose as an excipient, it should not be administered to patients with lactase deficiency, galactosemia, or glucose-galactose malabsorption syndrome.

Use during pregnancy or breastfeeding.

The drug is not used during pregnancy or breastfeeding.

If treatment with the drug is necessary, breastfeeding must be discontinued.

Ability to influence reaction rate while driving or operating machinery.

It should be noted that at the beginning of diltiazem therapy, a decrease in blood pressure, dizziness, fatigue, and nausea may occasionally occur. Therefore, patients should avoid driving or operating machinery while taking this medication.

Dosage and Administration

The drug should be taken with food or on an empty stomach. The tablet should be swallowed whole with sufficient amount of water.

Dosage should be individually adjusted.

The usual daily dose for adults is 180–240 mg. The maximum daily dose is 480 mg.

The usual initial dose is 60 mg 3–4 times daily. The dose may be increased according to therapeutic response up to 120 mg 3 times daily.

For elderly patients or patients with impaired liver function, it is recommended to initiate treatment with a lower dose – 30 mg 3–4 times daily.

Children

The drug is contraindicated in children.

Overdose

Clinical manifestations of acute overdose may include severe arterial hypotension, which may lead to collapse and acute kidney injury, sinus bradycardia with or without isorhythmic dissociation, sinus arrest, disturbances of atrioventricular conduction, and cardiac arrest.

Treatment
Diltiazem is poorly dialyzed. Management of overdose includes gastric lavage, administration of activated charcoal, and intravenous calcium.

In cases of bradycardia and atrioventricular block, intravenous atropine and electrical cardiac pacing should be considered; in cases of heart failure – intravenous administration of dopamine and diuretics; in cases of arterial hypotension – intravenous dopamine and fluid infusion.

In patients with the Lown–Ganong–Levine syndrome, conduction disorders leading to accelerated ventricular response or atrial fibrillation, cardioversion and intravenous administration of lidocaine or mepivacaine are recommended.

Adverse Reactions

Cardiovascular system: First-degree AV block, sinus bradycardia, bradycardia, second- to third-degree AV block, sinus node arrest, worsening of angina symptoms, congestive heart failure, arterial hypotension, tachycardia, palpitations, arrhythmia, extrasystoles, loss of consciousness, flushing, peripheral edema, syncope.

Gastrointestinal tract: Nausea, constipation, diarrhea, stomach pain, dryness of mouth and throat, anorexia, dyspepsia, vomiting, weight gain, gingivitis, gingival hyperplasia.

Skin: Exanthema, pruritus, skin rash, Stevens-Johnson syndrome, angioneurotic edema, toxic epidermal necrolysis, exfoliative dermatitis, lupus erythematosus, lupus-like syndrome, petechiae, photosensitivity, urticaria, skin allergic reactions including erythema multiforme, vasculitis, lymphadenopathy, eosinophilia, acute generalized exanthematous pustulosis, desquamative erythema with or without fever.

Hepatobiliary system: Increased levels of aminotransferases, granulomatous hepatitis, increased levels of liver enzymes (aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, alkaline phosphatase), hyperglycemia.

Blood and lymphatic system: Thrombocytopenia, leukopenia, prolonged bleeding time.

Psychiatric disorders: Confusion, amnesia, depression, hallucinations, insomnia, nervousness, personality changes, taste and smell disturbances.

Nervous system: Headache, dizziness, gait disturbance, paresthesia, somnolence, tremor, asthenia, extrapyramidal syndrome.

Eye disorders: Amblyopia, eye irritation.

Ear disorders: Tinnitus.

Musculoskeletal system: Bone and joint pain, myalgia.

Respiratory system: Dyspnea, epistaxis, nasal edema.

Urinary system: Nocturia, polyuria, increased creatine kinase levels.

Reproductive system: Gynecomastia, sexual dysfunction.

General disorders: Weakness and fatigue, increased sweating, malaise.

Reporting of suspected adverse reactions. Reporting suspected adverse reactions after marketing authorization is of great importance. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, as well as patients or their legal representatives, are encouraged to report any suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life.

2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach and sight of children.

Packaging.

Tablets 60 mg: pack of 10 (10×1), pack of 30 (10×3) in blisters.

Prescription status.

By prescription only.

Manufacturer.

JSC "Lubnipharm".

Manufacturer's address and location of operations.

16 Barvinkova St., Lubny, Poltava region, 37500, Ukraine.