Cardicet® retard

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KARDIKET® RETARD

Composition:

Active substance: isosorbide dinitrate;

One prolonged-release tablet contains 20 mg or 40 mg of isosorbide dinitrate;

Excipients: lactose monohydrate; talc; magnesium stearate; polyvinyl acetate; potato starch.

Pharmaceutical form. Prolonged-release tablets.

Main physicochemical properties: white-colored tablet.

Upper side: flat with bevel and a break line, engraved: "IR" on one side of the break line, "20" or "40" on the other.

Reverse side: convex, inscription "SCHWARZ PHARMA".

Pharmacotherapeutic group. Medicinal products affecting the cardiovascular system. Cardiological medicinal products. Vasodilators used in cardiology. Organic nitrates. Isosorbide dinitrate. ATC code C01DA08.

Pharmacological Properties

Pharmacodynamics

Mechanism of action

Like all organic nitrates, isosorbide dinitrate (ISDN) acts as a donor of nitric oxide (NO). Nitric oxide induces relaxation of vascular smooth muscle by stimulating guanylate cyclase and subsequently increasing intracellular levels of cyclic guanosine monophosphate (cGMP). This, in turn, activates cGMP-dependent protein kinase, leading to altered phosphorylation of various proteins in smooth muscle cells. As a result, dephosphorylation of myosin light chains occurs, reducing their contractility.

Pharmacodynamic effect

ISDN causes relaxation of vascular smooth muscle, resulting in vasodilation. The effect of isosorbide dinitrate extends to peripheral veins and arteries, promoting venous pooling of blood and reducing venous return to the heart. Thus, left ventricular end-diastolic pressure and volume (preload) are reduced.

Effects on arteries, and at higher doses on arterioles, lead to a reduction in systemic vascular resistance (afterload). This, in turn, reduces cardiac workload.

The combined effect on both preload and afterload results in a further decrease in myocardial oxygen demand.

Additionally, ISDN redistributes blood flow to subendocardial regions of the heart when coronary circulation is partially impaired by atherosclerotic lesions. This effect may be explained by selective dilation of large coronary vessels. Nitrate-induced dilation of collateral arteries may improve myocardial perfusion. Moreover, nitrates dilate the lumen at sites of eccentric stenosis by counteracting potential constrictive influences on the partially preserved smooth muscle of the coronary vessel at the site of narrowing. Furthermore, nitrates reduce coronary spasm.

In patients with congestive heart failure, nitrates improve hemodynamics at rest and during exertion. This beneficial effect arises from several mechanisms, including reduction of valvular regurgitation (by decreasing ventricular dilation) and decreased myocardial oxygen demand.

Thus, increased oxygen supply coupled with reduced myocardial oxygen demand decreases the extent of myocardial injury. Therefore, isosorbide dinitrate may be beneficial in patients with myocardial infarction.

Effects on other organ systems include relaxation of bronchial smooth muscle, gastrointestinal tract muscles, and smooth muscles of biliary and urinary tracts. There have been reports of relaxation effects on uterine smooth muscle.

Pharmacokinetics

In the gastrointestinal tract, isosorbide dinitrate is slowly released from the prolonged-release tablet over several hours. The drug is rapidly absorbed, beginning from the oral mucosa. The onset of therapeutic effect for 20 mg and 40 mg tablets occurs within 1 minute and 2 minutes, respectively, with peak plasma concentrations (Cmax) reached within 6 minutes and 10 minutes, respectively. In the gastrointestinal tract, absorption is somewhat slower (onset of action within 15–30 minutes), with time to Cmax ranging from 15 minutes to 1–2 hours. Absorption of the active substance is high. Plasma protein binding is 30%.

First-pass metabolism is more pronounced with oral administration.

ISDN is metabolized in the liver to isosorbide-2-mononitrate (T1/2 = 1.5–2 hours) and isosorbide-5-mononitrate (T1/2 = 4–6 hours). Both metabolites are pharmacologically active.

Bioavailability

The relative bioavailability of Kardeket® Retard following oral administration is approximately 80% compared to non-prolonged-release isosorbide dinitrate tablets. After first-pass hepatic metabolism, bioavailability is 15–30%.

Clinical characteristics.

Indications.

Prevention and long-term treatment of angina pectoris.

Contraindications.

The drug is contraindicated:

• in hypersensitivity to isosorbide dinitrate, other nitrate compounds, or to any excipient;

• in acute circulatory failure (shock, vascular collapse);

• in cardiogenic shock (unless appropriate measures maintain adequate end-diastolic pressure);

• in hypertrophic obstructive cardiomyopathy;

• in constrictive pericarditis;

• in cardiac tamponade;

• in severe hypotension (systolic blood pressure below 90 mm Hg);

• in severe anemia;

• in severe hypovolemia.

• Phosphodiesterase inhibitors, such as sildenafil, tadalafil, vardenafil, must not be used during nitrate therapy (see sections "Special precautions" and "Interaction with other medicinal products and other forms of interaction").

• Soluble guanylate cyclase stimulator riociguat must not be used during nitrate therapy (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

The hypotensive effect of the drug may be enhanced when used concomitantly with antihypertensive agents (e.g., β-blockers, diuretics, calcium channel blockers, angiotensin-converting enzyme (ACE) inhibitors, monoamine oxidase (MAO) inhibitors), vasodilators, neuroleptics, tricyclic antidepressants, and also with alcohol consumption.

The interaction occurring with concomitant use of isosorbide mononitrate and ACE inhibitors or arterial vasodilators may be desirable, provided the antihypertensive effect is not excessive and dosage reduction of one or both agents may be required.

The hypotensive effect of the drug is enhanced when taken concomitantly with phosphodiesterase inhibitors (such as sildenafil, tadalafil, vardenafil), which may lead to life-threatening cardiovascular complications (see sections "Contraindications" and "Special precautions"). Concomitant use of isosorbide dinitrate and phosphodiesterase inhibitors (such as sildenafil, tadalafil, vardenafil) is not permitted.

The use of Cardicet® retard together with riociguat, a soluble guanylate cyclase stimulator, is contraindicated (see section "Contraindications"), as concomitant administration of these agents may cause arterial hypotension.

Patients who have recently received therapy with phosphodiesterase inhibitors (e.g., sildenafil, vardenafil, tadalafil) must not be treated with isosorbide dinitrate for acute conditions within 24 hours after discontinuation of sildenafil and vardenafil, and within 48 hours after discontinuation of tadalafil.

There have been reports that concomitant use of the drug with dihydroergotamine may increase dihydroergotamine blood concentration and thereby enhance its effects.

Sapropterin (tetrahydrobiopterin, BH4) – a cofactor of nitric oxide synthase. Medicinal products containing sapropterin should be used with caution concomitantly with any vasodilators whose mechanism of action is also related to nitric oxide metabolism or which are classical nitric oxide donors (including nitroglycerin (GTN), isosorbide dinitrate (ISDN), isosorbide mononitrate (ISMN)).

Special precautions for use.

The medicinal product should be used with special caution and under medical supervision in the following cases:

• in low filling pressure, including acute myocardial infarction with impaired left ventricular function (left ventricular failure). Blood pressure should be maintained at not less than 90 mm Hg;
• in aortic and/or mitral stenosis;
• in orthostatic dysfunction;
• in conditions associated with increased intracranial pressure (further increase is possible. Such symptoms have been observed only after intravenous administration of high doses of nitroglycerin so far);
• in severe liver diseases.

The drug is not intended for the treatment of acute angina attacks.

Development of tolerance (reduced efficacy), as well as cross-tolerance to other drugs of the nitrate group (reduced effect if the patient previously took another nitrate), has been reported. To prevent reduction or loss of efficacy, prolonged administration of high doses (120 mg per day) should be avoided.

Patients on maintenance therapy with the drug must be informed that they must not take medicinal products containing phosphodiesterase inhibitors (e.g., sildenafil, tadalafil, vardenafil) due to the risk of developing uncontrolled arterial hypotension.

The drug should not be used as emergency relief in patients who have recently taken phosphodiesterase inhibitors (e.g., within 24 hours after discontinuation of sildenafil or vardenafil and within 48 hours after discontinuation of tadalafil); see sections "Contraindications" and "Interaction with other medicinal products and other types of interactions".

ISDN therapy must not be discontinued in order to take medicinal products containing phosphodiesterase inhibitors (e.g., sildenafil, tadalafil, vardenafil) due to the increased risk of angina attack (see sections "Contraindications" and "Interaction with other medicinal products and other types of interactions").

Since the drug contains lactose, it should not be prescribed to patients with such rare hereditary conditions as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

Caution should be exercised in patients with hypoxemia and ventilation/perfusion imbalance due to lung diseases or ischemic heart failure.

As a potent vasodilator, isosorbide dinitrate may lead to increased perfusion of poorly ventilated areas, worsening of ventilation/perfusion imbalance, and further reduction in arterial partial oxygen pressure.

Alcohol consumption should be avoided during treatment with isosorbide dinitrate, as it may enhance the hypotensive effect of the drug.

Use during pregnancy or breastfeeding.

Pregnancy

Reproductive toxicity studies in animals using isosorbide dinitrate at doses toxic to adult animals did not reveal evidence of fetal toxicity. However, adequate and well-controlled studies in pregnant women are lacking.

Since animal studies do not always predict effects in humans, the drug should be used during pregnancy only if clearly needed and under constant medical supervision.

Breastfeeding

It is unknown whether isosorbide dinitrate passes into breast milk; therefore, the drug is not recommended for administration to women during breastfeeding.

Fertility

There are no data on the effect of isosorbide dinitrate on human fertility.

Ability to affect reaction speed when driving or operating machinery.

Adverse effects such as headache, fatigue, and dizziness may reduce reaction speed or cause dizziness; therefore, patients should refrain from driving or operating machinery during treatment.

This is of particular importance in cases where the drug is taken concomitantly with alcohol.

Dosage and Administration

Cardiket® retard, 20 mg: 1 tablet twice daily (equivalent to 40 mg of isosorbide dinitrate). The second/subsequent dose should be taken no sooner than 6–8 hours after the first dose.

In cases of increased need for nitrate medications, the daily dose may be increased to 1 tablet three times daily, provided a 12-hour interval is maintained before the next dose within a 24-hour period.

Cardiket® retard, 40 mg: 1 tablet once daily (equivalent to 40 mg of isosorbide dinitrate). In cases of increased need for nitrate medications, the daily dose may be increased to 1 tablet twice daily (equivalent to 80 mg of isosorbide dinitrate), provided a 12-hour interval is maintained before the next dose within a 24-hour period.

Elderly Patients

There is no evidence indicating the need to adjust dosage for elderly patients.

Pediatric Population

The safety and efficacy of isosorbide dinitrate in children have not been established.

Administration Method

Tablets should be swallowed whole, without chewing, with an adequate amount of liquid (e.g., a glass of water).

Treatment should be initiated with the lowest doses, gradually increasing to the maximum effective dose. The duration of treatment is determined by the physician.

Since Cardiket® retard consists of matrix tablets, in some cases the matrix scaffold without active ingredient may be observed in the feces.

Children. Not to be used in children.

Overdose.

Experience from animal studies

Significant lethality (LD50) was observed in mice following a single intravenous administration of the drug at a dose of 33.4 mg/kg.

Symptoms of overdose in humans:

• Reduction in arterial blood pressure ≤ 90 mm Hg;
• Pallor;
• Sweating;
• Weak pulse filling;
• Tachycardia;
• Dizziness (orthostatic reactions upon changing body position);
• Headache;
• Asthenia;
• Weakness;
• Dizziness;
• Nausea;
• Vomiting;
• Diarrhea;
• Cases of methemoglobinemia have been reported in patients receiving other organic nitrates. During biotransformation of isosorbide mononitrate, nitrite ions are released, which may induce methemoglobinemia and cyanosis, followed by tachypnea, anxiety, loss of consciousness, and cardiac arrest. This adverse reaction cannot be excluded in cases of isosorbide dinitrate overdose;
• Excessive doses may increase intracranial pressure, sometimes causing cerebral symptoms.

General measures in case of overdose:

• Discontinue the drug;
• General measures used in nitrate-induced arterial hypotension:
  • Place the patient in a horizontal position with low head elevation and elevated lower limbs;
  • Ensure oxygen supply;
  • Increase plasma volume (intravenous infusion);
  • Initiate specialized anti-shock therapy (the patient should be admitted to an intensive care unit!).

Specific measures in case of overdose:

• In case of severe hypotension, measures to raise blood pressure should be implemented;
• Vasopressor (vasoconstrictor) agents should be used if the patient does not respond adequately to fluid therapy.

Treatment of methemoglobinemia resulting from overdose:

• Reductive therapy with vitamin C, methylene blue, or toluidine blue, at the physician’s discretion;
• Oxygen administration (if needed);
• Initiate mechanical ventilation; consider blood transfusion (if needed);
• Hemodialysis (if needed).

Resuscitation measures:

• In case of signs of respiratory or circulatory arrest, immediate resuscitation measures should be initiated.

Adverse Reactions

The frequency of adverse effects is defined as follows: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10,000, < 1/1000), very rare (< 1/10,000), not known (cannot be estimated from available data).

The following adverse events may occur during treatment with this medicinal product.

Central nervous system: very common – headache ("nitrate headache"); common – dizziness, drowsiness.

Cardiac disorders: common – tachycardia; uncommon – worsening of angina symptoms.

Vascular disorders: common – orthostatic hypotension; uncommon – vascular collapse (sometimes accompanied by bradycardia and loss of consciousness); not known – hypotension.

Gastrointestinal disorders: uncommon – nausea, vomiting; very rare – heartburn.

Skin and subcutaneous tissue disorders: uncommon – allergic skin reactions (e.g. rash), flushing; very rare – angioneurotic edema, Stevens-Johnson syndrome; not known – exfoliative dermatitis.

General disorders: common – asthenia.

Severe hypotensive reactions have been reported during treatment with organic nitrates, accompanied by nausea, vomiting, restlessness, pallor, and increased sweating.

Transient hypoxemia may occur during therapy due to a relative redistribution of blood flow to alveolar areas with hypoventilation. In particular, in patients with ischemic heart disease, this may lead to myocardial hypoxia.

Increasing the dose and/or changing the dosing interval may lead to reduced efficacy or lack of effect.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risks balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions through the national reporting system.

Shelf life

5 years.

Storage conditions

No special storage conditions required.

Keep out of the reach and sight of children.

Packaging

10 tablets in a blister. 5 blisters in a cardboard box.

Prescription status

Prescription only.

Manufacturer

Aescula Pharmaceuticals GmbH, Germany.

Manufacturer's address

Alfred-Nobel-Str. 10, 40789 Monheim am Rhein, Germany.

Marketing Authorization Holder

Zentiva k.s.

Address of Marketing Authorization Holder

Prague-10 Dolní Měcholupy, U kabelovny 130, postal code 102 37, Czech Republic.