INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ALDIZEM (ALDIZEM®)

Composition:

Active substance: diltiazem hydrochloride;

One tablet contains 90 mg of diltiazem hydrochloride;

Excipients: lactose monohydrate; magnesium stearate; hydrogenated castor oil; macrogol 6000.

Pharmaceutical form. Tablets.

Main physicochemical properties: white, round, biconvex tablets with a score line on one side.

Pharmacotherapeutic group. Selective calcium antagonists with predominantly cardiac effects.

ATC code C08DB01.

Pharmacological properties.

Pharmacodynamics.

The mechanism of action of diltiazem involves blockade of calcium ion transport into cardiac and vascular smooth muscle cells. The drug causes dilation of coronary vessels and increases coronary blood flow, reduces elevated arterial pressure and total peripheral vascular resistance. Diltiazem reduces myocardial oxygen demand by decreasing myocardial contractility, reducing heart rate, and decreasing myocardial afterload.

Pharmacokinetics.

Absorption. After oral administration, diltiazem is rapidly and almost completely absorbed from the gastrointestinal tract. Maximum plasma concentration is reached within 3–4 hours after oral administration. Plasma concentration levels may vary considerably among individual patients.

Distribution. Plasma protein binding ranges between 77% and 93%. The volume of distribution in the body is approximately 5.3 L/kg body weight.

Metabolism and elimination. Following absorption from the gastrointestinal tract, diltiazem undergoes extensive first-pass metabolism in the liver. It is metabolized in the liver to form several intermediate metabolites and is primarily excreted from the body via bile (65%), with partial excretion in urine (35%).

The elimination half-life from plasma is 4.5 hours.

Clinical characteristics.

Indications.

Long-term treatment:

of ischemic heart disease, including chronic stable angina, vasospastic angina (Prinzmetal's angina), and post-myocardial infarction angina;
of arterial hypertension.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients;
cardiogenic shock associated with myocardial infarction or heart failure;
acute myocardial infarction with complications;
acute heart failure;
moderate or severe heart failure (NYHA functional class II or III);
sick sinus syndrome, sinoatrial block, second- or third-degree atrioventricular (AV) block in patients without a functioning pacemaker;
atrial flutter or atrial fibrillation in patients with Wolff-Parkinson-White syndrome (risk of ventricular tachycardia);
Lown-Ganong-Levine syndrome;
severe bradycardia (heart rate less than 50 beats/min);
left ventricular failure with pulmonary congestion;
arterial hypotension (systolic blood pressure below 90 mm Hg);
concomitant intravenous administration of beta-blockers;
concomitant use with dantrolene infusion (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");
combination with ivabradine (see section "Interaction with other medicinal products and other forms of interaction");
pregnancy and lactation;
pediatric population.

Interaction with other medicinal products and other forms of interaction.

Medicinal products whose concomitant use is contraindicated for safety reasons

Dantrolene (infusion)

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

Ivabradine

Concomitant use of the medicinal product with ivabradine is contraindicated due to the additional reduction in heart rate caused by diltiazem, which adds to the effect of ivabradine (see section "Contraindications").

Lomitapide

Diltiazem (a moderate CYP3A4 inhibitor) may increase lomitapide plasma concentrations by inhibiting CYP3A4, thereby increasing the risk of elevated liver enzymes (see section "Contraindications").

Medicinal products whose concomitant use requires caution

Lithium

Risk of increased neurotoxic reactions caused by lithium.

Nitrates

Enhanced hypotensive effect and loss of consciousness (additive vasodilatory effects). Nitrates should be prescribed to patients receiving calcium channel blockers only with gradual dose escalation.

Theophylline

Increased circulating levels of theophylline.

Alpha-blockers

Enhanced antihypertensive effect. Concomitant treatment with alpha-blockers may cause or exacerbate symptomatic hypotension. The combination of diltiazem with alpha-blockers should be carefully considered and administered only under strict blood pressure monitoring.

Amiodarone, digoxin

Increased risk of bradycardia. Caution is required when combining these drugs with diltiazem, especially in elderly patients and when high doses are prescribed.

Halothane and isoflurane

Diltiazem may enhance the myocardial depressant effects of halothane and isoflurane.

Calcium salts (infusions)

Intravenous administration of calcium salts reduces the pharmacological response to diltiazem.

HMG-CoA reductase inhibitors

When diltiazem is used concomitantly with HMG-CoA reductase inhibitors metabolized by the CYP3A4 enzyme (e.g., simvastatin, atorvastatin, lovastatin, cerivastatin), the dose of the latter should be reduced to prevent the development of rhabdomyolysis and liver injury.

Beta-blockers

Risk of cardiac rhythm disturbances (marked bradycardia, sinus arrest), sinoatrial and atrioventricular conduction disorders, and heart failure (synergistic effect). This combination may be used only under careful clinical and ECG monitoring, especially at the beginning of treatment.

In patients receiving diltiazem concomitantly with beta-blockers, the risk of developing depression is increased (see section "Adverse reactions").

Other antiarrhythmic drugs

Since diltiazem has antiarrhythmic properties, its concomitant use with other antiarrhythmic agents is not recommended (additive risk of cardiac adverse effects). Such a combination should be used only under careful clinical and ECG monitoring.

Carbamazepine

Increased circulating levels of carbamazepine. Plasma carbamazepine levels should be monitored quantitatively, and the dose adjusted if necessary.

Rifampicin

Risk of decreased diltiazem plasma levels after initiation of rifampicin therapy. Close monitoring is required at the start of rifampicin treatment or upon its discontinuation.

H2-receptor blockers (cimetidine, ranitidine)

Increased plasma concentrations of diltiazem. Close monitoring is required at the initiation or discontinuation of H2-receptor blocker therapy. Adjustment of the daily dose of diltiazem may be necessary.

Cyclosporine

Increased circulating levels of cyclosporine. It is recommended to reduce the cyclosporine dose, monitor renal function, measure cyclosporine plasma levels, and adjust the dose during and after combined therapy.

Phenytoin

Diltiazem may increase phenytoin plasma concentrations when used concomitantly. Monitoring of phenytoin plasma levels is recommended.

Acetylsalicylates (acetylsalicylic acid [ASA] / lysine acetylsalicylate [LAS])

Due to the increased risk of bleeding associated with a potential additive effect on platelet aggregation, concomitant use of acetylsalicylates (ASA/LAS) with diltiazem should be performed with caution.

Contrast media

In patients receiving diltiazem, cardiovascular effects of intravenous bolus of ionic contrast media, such as arterial hypotension, may be enhanced. Particular caution is required in patients receiving diltiazem and ionic contrast media simultaneously.

Antiplatelet agents

A pharmacodynamic study has shown that diltiazem inhibits platelet aggregation. Although the clinical significance of this finding is unknown, potential additive effects should be considered when using the drug with antiplatelet agents.

General information to be considered

Due to the potential for additive effects, caution and careful dose titration are required in patients receiving diltiazem concomitantly with other agents known to affect myocardial contractility and/or conduction.

Diltiazem is metabolized by the CYP3A4 enzyme. A moderate (less than two-fold) increase in diltiazem plasma concentrations has been documented when co-administered with a more potent CYP3A4 inhibitor. Grapefruit juice may increase diltiazem blood levels (by 1.2-fold). Patients consuming grapefruit juice should be monitored for possible increased adverse effects of diltiazem. In case of suspected interaction, grapefruit juice consumption should be avoided.

Diltiazem is also an inhibitor of the CYP3A4 isoenzyme. Concomitant administration with other CYP3A4 substrates may lead to increased plasma concentrations of either drug. Concomitant use of diltiazem with a CYP3A4 inducer may result in decreased diltiazem plasma concentrations.

Diltiazem may potentiate the reduction in myocardial contractility, conduction, and automaticity, and may enhance vasodilation induced by anesthetics.

Benzodiazepines (midazolam, triazolam)

Diltiazem significantly increases plasma concentrations of midazolam and triazolam and prolongs their elimination half-life. Particular caution is required when prescribing short-acting benzodiazepines metabolized by CYP3A4 to patients taking diltiazem.

Corticosteroids (methylprednisolone)

Inhibition of methylprednisolone metabolism (CYP3A4) and inhibition of P-glycoprotein. Monitoring is required at the initiation of methylprednisolone therapy. Dose adjustment of methylprednisolone may be necessary.

Statins

Diltiazem is an inhibitor of the CYP3A4 enzyme. It has been shown to significantly increase the AUC of certain statins. When used concomitantly with diltiazem, the risk of statin-induced myopathy and rhabdomyolysis, particularly with statins metabolized by CYP3A4, may increase. Where possible, statins not metabolized by CYP3A4 should be used with diltiazem; otherwise, careful monitoring for signs and symptoms of potential statin toxicity is required.

Cilostazol

Inhibition of cilostazol metabolism (CYP3A4). Diltiazem has been shown to increase the effect of cilostazol and enhance its pharmacological activity.

Oral hypoglycemic agents

Enhanced effect of oral hypoglycemic agents (chlorpropamide and glipizide).

Alcohol or anesthetic agents

Concomitant use of diltiazem with alcohol or anesthetic agents may enhance the hypotensive effect.

Neuromuscular blocking agents (e.g., curare-type)

Diltiazem may potentiate neuromuscular blockade.

Food intake increases the absorption and bioavailability of diltiazem by 20–30%.

Special precautions for use.

The drug should be used with caution in patients with asymptomatic or mild heart failure (NYHA functional class I or II), first-degree sinoatrial block, first-degree atrioventricular block, prolonged PQ interval, impaired left ventricular function, patients prone to arterial hypotension and bradycardia, and in patients with aortic stenosis.

Close monitoring is required in patients with left ventricular dysfunction, bradycardia (risk of exacerbation), or first-degree AV block or prolonged PR interval detected on electrocardiogram (risk of progression, and in rare cases, complete heart block).

Cases of acute renal failure caused by reduced renal perfusion have been reported in patients with pre-existing cardiovascular disorders, particularly those with impaired left ventricular function, marked bradycardia, or marked hypotension. Careful monitoring of renal function is recommended.

In patients with renal or hepatic insufficiency and in elderly patients, blood pressure and heart rate should be closely monitored. Dose reduction may be necessary.

Aldizem should be used with caution in treating patients with severe hepatic or renal impairment. In such patients, dosage reduction may be required, and monitoring of blood urea nitrogen, creatinine, and liver function is recommended. In patients with hepatic dysfunction or hepatic porphyria, the daily dose should not exceed 90 mg, and regular monitoring of liver function is advised.

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

Due to safety concerns, discontinuation of the drug should not be abrupt, especially in patients with ischemic heart disease, after long-term therapy, or following bypass surgery, as this may provoke recurrence of angina attacks. If discontinuation is necessary, the dose should first be gradually reduced.

During prolonged treatment, liver function parameters should be monitored, particularly in patients with predisposing factors for hepatic impairment.

Concomitant use of diltiazem with agents that suppress cardiac function or conduction (e.g., oral beta-blockers, antiarrhythmics, digitalis preparations, certain inhaled anesthetics) should only be considered if the benefit outweighs the risk, and under close clinical monitoring.

If persistent skin rashes develop that progress to erythema multiforme or exfoliative dermatitis, the drug should be discontinued.

Diltiazem may cause bronchospasm, including exacerbation of bronchial asthma, particularly in patients with pre-existing bronchial hyperreactivity. Such cases have also been reported after dose escalation. Patients should be monitored for signs and symptoms of respiratory dysfunction during diltiazem therapy.

If general anesthesia is required, the anesthesiologist should be informed that the patient is taking diltiazem. Calcium antagonists may potentiate the effects of anesthetics on cardiac impulse generation, conduction, contractility, and vascular tone.

Diltiazem therapy may cause mood changes, including depression. Early recognition of such symptoms is important, especially in patients with predisposing factors. In such cases, discontinuation of the drug should be considered.

Calcium antagonists may impair male fertility. This should be considered if a patient receiving calcium antagonists is diagnosed with infertility of unknown etiology. This effect is reversible upon discontinuation of therapy.

Diltiazem suppresses intestinal motility. Therefore, it should be used with caution in patients at risk of intestinal obstruction.

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

Close monitoring is required in patients with latent or overt diabetes mellitus due to the possible increase in blood glucose levels.

Alcoholic beverages are not recommended during treatment.

The drug contains lactose; therefore, appropriate precautions should be taken in patients with lactose intolerance and/or glucose-galactose malabsorption syndrome.

Use during pregnancy or breastfeeding.

There are insufficient data on the use of this drug during pregnancy. Treatment should only be initiated after pregnancy has been excluded.

Diltiazem passes into breast milk; therefore, the drug is contraindicated during breastfeeding.

Ability to affect reaction speed when driving or operating machinery.

Due to possible individual reactions such as hypotension, dizziness, fatigue, and nausea, the ability to drive or operate machinery may be impaired. This is particularly relevant at the beginning of treatment, when switching medications, and during concomitant alcohol consumption.

Dosage and Administration.

The dosage for oral administration is individually determined for each patient depending on the severity of the disease and the patient's condition.

Tablets should be taken whole, without chewing, with a small amount of water.

For the treatment of angina pectoris, the recommended dose is 180–360 mg per day administered in two divided doses.

For arterial hypertension: 240–360 mg per day in two divided doses. Usually, 90 mg twice daily is prescribed. The maximum daily dose is 360 mg.

During prolonged therapy, after achieving a stable therapeutic effect with high doses, an attempt should be made to reduce the dosage.

Patients with ischemic heart disease, especially after long-term treatment or bypass surgery, must not abruptly discontinue the drug; the dose should be gradually reduced prior to stopping.

Elderly patients. Elderly patients generally can take the standard dose. If necessary, the dose should be adjusted according to tolerability.

Renal impairment. Patients with renal impairment generally can take the standard dose. If necessary, the dose should be adjusted according to tolerability.

Hepatic impairment. Patients with mild to moderate hepatic impairment can take the standard dose. If necessary, the dose should be adjusted according to tolerability.

In severe hepatic impairment, a reduced dose is recommended.

Children.

The efficacy and safety of the drug in children have not been studied.

Overdose.

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

Treatment of overdose is determined by the type and severity of symptoms. There is no specific antidote.

In addition to gastric lavage and administration of absorbents (activated charcoal), the following measures are required:

Low blood pressure: appropriate patient positioning, fluid administration to increase circulating blood volume, and, if indicated, dopamine, dobutamine, and norepinephrine;
Bradycardia, second- or third-degree atrioventricular block: if indicated, atropine, isoprenaline, oxyprenaline, and pacemaker insertion;
Reduced heart rate, acute heart failure: dopamine, dobutamine, diuretics;
Cardiac arrest: indirect cardiac massage, artificial ventilation, ECG monitoring, and further intensive care measures such as defibrillation and pacemaker insertion.

If indicated, toxic symptoms can be counteracted by intravenous administration of 10–20 mL of 10% calcium gluconate solution.

Hemodialysis is ineffective in removing the active substance due to its high plasma protein binding (approximately 80%).

Adverse Reactions

Classification of frequency of adverse reactions: very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare (>1/10,000 to <1/1,000); very rare (<1/10,000), frequency not known (cannot be estimated based on available data).

Cardiac disorders.

Common: AV block (first degree, bundle branch block), palpitations, sinus bradycardia.
Uncommon: bradycardia.
Very rare: heart failure with pulmonary edema.
Rare: second to third degree AV block, sinus node arrest, worsening of angina symptoms, arterial hypotension, tachycardia, arrhythmia, extrasystoles, facial flushing, peripheral edema, syncope.
Frequency not known: sinoatrial block¹, congestive heart failure¹, sinus node arrest¹, cardiac arrest (asystole)¹.

Vascular disorders.

Common: hyperemia.
Uncommon: orthostatic hypotension.
Frequency not known: vasculitis (including leukocytoclastic vasculitis).

Gastrointestinal disorders.

Common: nausea, constipation, dyspepsia, diarrhea, stomach pain, dryness of mouth and throat.
Rare: anorexia, vomiting, weight gain, gingivitis.
Frequency not known: gingival hyperplasia¹.

Skin and subcutaneous tissue disorders.

Common: erythema, pruritus.
Rare: lupus erythematosus, petechiae, urticaria, skin allergic reactions, lymphadenopathy, eosinophilia.
Frequency not known: photosensitivity (including lichenoid keratosis in sun-exposed skin areas)¹, angioneurotic edema¹, rash¹, Stevens-Johnson syndrome and toxic epidermal necrolysis as part of multiform erythema¹, sweating¹, exfoliative dermatitis¹, acute generalized exanthematous pustulosis¹, desquamative erythema with or without fever¹, lupus-like syndrome.

Hepatobiliary disorders.

Uncommon: increased levels of liver enzymes (AST, ALT, LDH, alkaline phosphatase).
Frequency not known: hepatitis¹.

Blood and lymphatic system disorders.

Rare: leukopenia, prolonged bleeding time.
Frequency not known: thrombocytopenia.

Metabolism and nutrition disorders.

Frequency not known: hyperglycemia.

Psychiatric disorders.

Uncommon: insomnia, nervousness.
Rare: confusion, amnesia, hallucinations, personality changes, taste and smell disturbances.
Frequency not known: mood changes (including depression)¹.

Nervous system disorders.

Common: headache, dizziness.
Rare: gait disturbance, paresthesia, somnolence, tremor.
Frequency not known: extrapyramidal syndrome¹.

Eye disorders.

Rare: amblyopia, eye irritation.

Ear and labyrinth disorders.

Rare: tinnitus.

Musculoskeletal and connective tissue disorders.

Rare: bone and joint pain, myalgia.

Respiratory, thoracic and mediastinal disorders.

Rare: dyspnea, epistaxis, nasal congestion.
Frequency not known: bronchospasm (including exacerbation of bronchial asthma).

Renal and urinary disorders.

Rare: nocturia, polyuria.

Investigations.

Common: increased creatine phosphokinase (CPK) levels.

Reproductive system and breast disorders.

Rare: sexual dysfunction in men and women.
Frequency not known: gynecomastia.

General disorders and administration site conditions.

Very common: lower limb edema.
Common: malaise.
Uncommon: weakness, fatigue, asthenia.

¹ Information on adverse reactions observed during post-marketing experience was received via spontaneous reports; therefore, the frequency of these adverse reactions is not known.

Reporting of adverse reactions after drug registration is highly important. It enables continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: http://aisf.dec.gov.ua

Shelf life. 3 years.

Do not use after the expiry date stated on the packaging.

Storage conditions.

Store at a temperature not exceeding 25 °C.

Keep out of reach and sight of children.

Packaging.

10 tablets in a perforated blister pack, 3 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer.

ALKALOID AD Skopje.

Manufacturer's address and place of business.

Boulevard Alexander the Great, 12, Skopje, 1000, Republic of North Macedonia.