Cordipin xl

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Cordipin XL (Cordipin® XL)

Composition:

Active substance: nifedipine;

One modified-release tablet contains 40 mg of nifedipine;

Excipients: microcrystalline cellulose, cellulose, lactose monohydrate, magnesium stearate, colloidal anhydrous silicon dioxide, macrogol 400, talc, macrogol 6000, hypromellose, titanium dioxide (E 171), iron oxide red (E 172).

Pharmaceutical form. Modified-release tablets.

Main physico-chemical properties:

Round, biconvex, red-brown tablets coated with a film coating.

Pharmacotherapeutic group. Selective calcium antagonists with predominant vascular effect. Dihydropyridine derivatives. ATC code C08CA05.

Pharmacological properties.

Pharmacodynamics.

Nifedipine is a calcium antagonist of the 1,4-dihydropyridine type. Calcium antagonists inhibit the transmembrane influx of calcium ions into the cell through slow calcium channels. As a specific and potent calcium antagonist, nifedipine acts particularly on myocardial cells and smooth muscle cells of coronary arteries, and also reduces peripheral vascular resistance. The primary action of nifedipine is relaxation of smooth muscles of coronary arteries and peripheral vessels. Cordipin XL with controlled release of nifedipine is designed to achieve clinical effect with once-daily administration.

In arterial hypertension, the main action of nifedipine is peripheral vasodilation, which leads to a reduction in peripheral vascular resistance. Administration of nifedipine once daily provides 24-hour control of elevated blood pressure. Nifedipine reduces blood pressure in such a way that the percentage of reduction is directly related to the initial blood pressure level. In individuals with normal blood pressure, nifedipine has minimal or no effect on blood pressure.

In angina pectoris, nifedipine reduces both peripheral and coronary vascular resistance, increasing coronary blood flow, cardiac output, and stroke volume, while simultaneously reducing afterload.

Nifedipine also submaximally dilates both healthy and atherosclerotic coronary arteries, thereby protecting the heart from coronary artery spasm and improving perfusion of ischemic myocardium.

Nifedipine reduces the frequency of angina attacks and ischemic changes on ECG regardless of the relative contribution of coronary artery spasm or atherosclerosis.

Children

Limited data are available comparing nifedipine with other antihypertensive agents in various dosage forms and doses for the treatment of acute and long-term arterial hypertension. Nifedipine has demonstrated hypotensive effects; however, recommended doses, safety, and impact on cardiovascular outcomes remain to be established. Dosage forms for pediatric use are not available.

Pharmacokinetics.

Absorption

Nifedipine is almost completely absorbed from the gastrointestinal tract. Nifedipine undergoes extensive first-pass metabolism in the liver, and the systemic bioavailability of orally administered nifedipine is 50–70%. The release of nifedipine from modified-release tablets is slower, and peak plasma concentration is reached 4–6 hours after administration; its effect lasts for 24 hours.

Distribution

Nifedipine is bound to plasma proteins, primarily albumin, by 94–99%. Animal studies have demonstrated that administered nifedipine is distributed throughout all organs and tissues. Concentrations in cardiac muscle were higher than in skeletal muscle. Neither nifedipine nor its metabolites accumulate in tissues.

Metabolism

Nifedipine is almost completely metabolized in the liver via the cytochrome P450 isoenzyme CYP3A4. The metabolites are pharmacologically inactive. In patients with impaired liver function, metabolism is slightly slowed.

Excretion

Approximately 80% of metabolites are excreted in urine, the remainder in feces. Less than 0.1% of unchanged nifedipine is excreted in urine. The elimination half-life after oral administration of modified-release tablets is 8–10 hours; it may be slightly prolonged in patients with renal insufficiency. In such cases, the dose should be reduced if necessary.

Nifedipine passes in small amounts through the blood-brain barrier, possibly the placental barrier, and is also excreted into breast milk.

Nifedipine is practically not removed by hemodialysis. Plasmapheresis may be beneficial for drug elimination.

Clinical characteristics.

Indications.

• Treatment of arterial hypertension.
• Prophylaxis of stable exertional angina – as monotherapy or in combination with beta-blockers (vasospastic and stable exertional angina).

Contraindications.

Cordipin XL is contraindicated in patients with hypersensitivity to nifedipine or to other dihydropyridines due to the risk of cross-reactivity; and in patients with hypersensitivity to any component of the drug.

Cordipin XL is contraindicated in cases of cardiogenic shock, high-grade aortic stenosis, unstable angina, or during and within 4 weeks following myocardial infarction.

Cordipin XL should not be used for the treatment of acute angina attacks.

The safety of Cordipin XL has not been established for the treatment of malignant hypertension.

Cordipin XL should not be used for secondary prevention of myocardial infarction.

Due to its prolonged action, Cordipin XL should not be prescribed to patients with impaired liver function.

The combination of Cordipin XL with rifampicin is contraindicated due to the inability to achieve effective plasma levels of nifedipine as a result of enzyme induction.

Cordipin XL should not be used before the 20th week of pregnancy or during breastfeeding.

Interaction with other medicinal products and other forms of interaction.

Medicinal products affecting nifedipine.

Nifedipine is metabolized by the cytochrome P450 3A4 system located in the intestinal mucosa and liver. Drugs that inhibit or induce this enzyme system may alter the first-pass metabolism (after oral administration) or clearance of nifedipine (see section "Special instructions").

The extent and duration of interaction should be considered when using nifedipine with the following drugs:

Medicinal products that inhibit the cytochrome P450 3A4 system

When nifedipine is used concomitantly with medicinal products such as weak or moderate inhibitors of this enzyme system, blood pressure should be monitored and the dose of nifedipine adjusted if necessary (see section "Dosage and administration").

Macrolide antibiotics (e.g., erythromycin)

No studies on the interaction between nifedipine and macrolide antibiotics have been conducted. Some macrolide antibiotics inhibit cytochrome P450 3A4-mediated metabolism of other drugs. Therefore, an increased plasma concentration of nifedipine cannot be excluded when both drugs are used concomitantly (see section "Special instructions").

Azithromycin, which is structurally similar to macrolide antibiotics, does not inhibit CYP3A4.

HIV protease inhibitors (e.g., ritonavir)

Studies on the interaction between nifedipine and HIV protease inhibitors have not been conducted. It is known that drugs in this class inhibit the cytochrome P450 3A4 system. In addition, in vitro studies show that drugs in this class inhibit cytochrome P450 3A4-mediated metabolism of nifedipine. When used concomitantly with nifedipine, a significant increase in nifedipine plasma concentration cannot be excluded due to reduced first-pass metabolism and decreased elimination rate (see section "Special instructions").

Azole antifungal agents (e.g., ketoconazole)

Formal clinical studies on the interaction between nifedipine and certain azole antifungal agents have not yet been conducted. It is known that drugs in this class inhibit the cytochrome P450 3A4 system. When administered orally concomitantly with nifedipine, a significant increase in systemic bioavailability of nifedipine due to reduced first-pass metabolism cannot be excluded (see section "Special instructions").

Fluoxetine

Clinical studies on the interaction between nifedipine and fluoxetine have not been conducted. It is known that fluoxetine inhibits in vitro the cytochrome P450 3A4-mediated metabolism of nifedipine. An increase in nifedipine plasma concentration cannot be excluded when both drugs are used concomitantly (see section "Special instructions").

NeFazodone

Clinical studies on the interaction between nifedipine and nefazodone have not been conducted. It is known that nefazodone inhibits in vitro the cytochrome P450 3A4-mediated metabolism of other drugs. An increase in nifedipine plasma concentration cannot be excluded when both drugs are used concomitantly (see section "Special instructions").

Quinupristin/dalfopristin

Concomitant use of quinupristin/dalfopristin and nifedipine may lead to increased plasma concentration of nifedipine (see section "Special instructions").

Valproic acid

Studies on the interaction between nifedipine and valproic acid have not been conducted. It is known that valproic acid increases plasma concentration of the structurally similar calcium channel blocker nimodipine due to enzyme inhibition. An increase in nifedipine plasma concentration and enhanced effect cannot be excluded (see section "Special instructions").

Cimetidine

Due to inhibition of cytochrome P450 3A4, cimetidine increases nifedipine plasma concentrations and may enhance its antihypertensive effect (see section "Special instructions").

Tricyclic antidepressants, vasodilators

Combination of nifedipine with tricyclic antidepressants or vasodilators may result in a possible enhancement of the hypotensive effect.

Cisapride

Concomitant use of cisapride and nifedipine may lead to increased plasma concentration of nifedipine.

Medicinal products that induce the cytochrome P450 3A4 system

Rifampicin strongly induces the cytochrome P450 3A4 system. When used concomitantly with rifampicin, the bioavailability of nifedipine is significantly reduced, thus decreasing its efficacy. Therefore, the combination of nifedipine with rifampicin is contraindicated (see section "Contraindications").

Antiepileptic drugs (e.g., phenytoin, carbamazepine, and phenobarbital)

Phenytoin induces the cytochrome P450 3A4 system. When used concomitantly with phenytoin, the bioavailability of nifedipine is reduced and its efficacy diminished. When both drugs are used concomitantly, the clinical response to nifedipine therapy should be monitored, and if necessary, the nifedipine dose should be increased. If the nifedipine dose was increased during concomitant use, consideration should be given to reducing the nifedipine dose upon discontinuation of phenytoin.

Formal clinical studies on the interaction between nifedipine and carbamazepine or phenobarbital have not been conducted. It is known that both drugs reduce plasma concentrations of the structurally similar calcium channel blocker nimodipine due to enzyme induction. Therefore, a reduction in nifedipine plasma concentration and decreased efficacy cannot be excluded.

Effect of nifedipine on other medicinal products

Antihypertensive drugs

Nifedipine may enhance the antihypertensive effect of concomitantly administered antihypertensive drugs, such as:

− diuretics;

− β-adrenoreceptor blockers;

− ACE inhibitors (angiotensin-converting enzyme inhibitors);

− AT1-receptor antagonists;

− other calcium antagonists;

− α-adrenoreceptor blockers;

− PDE-5 inhibitors (phosphodiesterase-5 inhibitors);

− α-methyldopa.

Careful monitoring of patients is required when nifedipine is used concomitantly with β-adrenoreceptor blockers, as isolated cases of worsening heart failure have been reported.

Digoxin

When used concomitantly with digoxin, digoxin clearance may be reduced, leading to increased plasma concentration. Patients should be monitored for signs of digoxin overdose, and the dose should be adjusted if necessary.

Theophylline

Nifedipine may increase theophylline plasma levels.

Vincristine

Nifedipine reduces vincristine elimination, which may enhance its adverse effects. Therefore, a reduction in vincristine dose should be considered.

Cephalosporins

It has been reported that concomitant use of cephalosporins (e.g., cefixime) and nifedipine may increase cephalosporin plasma levels.

Quinidine

Concomitant use of nifedipine may reduce quinidine plasma levels, whereas after discontinuation of nifedipine, a marked increase in quinidine levels may occur in some cases. Therefore, quinidine plasma concentration should be monitored after adding or discontinuing nifedipine, and the dose should be adjusted accordingly if necessary. Blood pressure should be carefully monitored, and the nifedipine dose reduced if needed.

Tacrolimus

Tacrolimus is metabolized by the cytochrome P450 3A4 system. Available data suggest that the dose of tacrolimus may need to be reduced in some cases when co-administered with nifedipine. Monitoring of tacrolimus plasma concentration is recommended, and the dose should be reduced if necessary.

Interaction with food.

Grapefruit juice inhibits the cytochrome P450 3A4 system. Concomitant intake with nifedipine may increase nifedipine plasma concentration and prolong its action due to reduced first-pass effect or decreased clearance, thereby enhancing its hypotensive effect. After regular consumption of grapefruit juice, this effect may persist for at least three days after the last intake. Grapefruit and grapefruit juice should be avoided during nifedipine therapy.

Other interactions.

Nifedipine may cause false-positive results in spectrophotometric determination of vanillylmandelic acid. However, results of high-performance liquid chromatography (HPLC) are not affected.

Special precautions for use.

Cordipin XL tablets should be swallowed whole and must not under any circumstances be broken, crushed, or chewed.

Cordipin XL should be used with caution in patients with arterial hypotension due to the risk of further reduction in blood pressure, particularly in patients with marked arterial hypotension (systolic pressure less than 90 mm Hg).

Careful monitoring of blood pressure is required when the drug is used concomitantly with intravenous administration of magnesium sulfate due to the possibility of significant blood pressure reduction, which may harm both mother and fetus (see "Use during pregnancy or breastfeeding").

Cordipin XL is not recommended during breastfeeding, as nifedipine is excreted in breast milk; the effect of nifedipine on the infant is unknown (see "Use during pregnancy or breastfeeding").

Patients with impaired liver function should be monitored; in severe cases, dose reduction should be considered.

Cordipin XL may be taken concomitantly with beta-blockers and other antihypertensive agents; however, the possibility of postural hypotension due to additive effects should be taken into account. Cordipin XL does not prevent rebound effects after discontinuation of other antihypertensive drugs.

Cordipin XL should be used with caution in patients with low cardiac reserve due to the possibility of worsening heart failure. Worsening of heart failure has been observed with nifedipine use.

Use of Cordipin XL in diabetic patients may require adjustment of treatment. The drug should be prescribed with particular caution to patients undergoing hemodialysis, those with malignant hypertension, or those with hypovolemia, as vasodilation may cause a significant drop in blood pressure.

Nifedipine is metabolized via the cytochrome P450 3A4 system. Therefore, drugs that inhibit or induce this enzyme system may alter the first-pass effect or clearance of nifedipine.

Drugs that are weak or moderate inhibitors of the cytochrome P450 3A4 system and may lead to increased plasma concentrations of nifedipine include:

• macrolide antibiotics (e.g., erythromycin);
• anti-HIV protease inhibitors (e.g., ritonavir);
• azole antifungals (e.g., ketoconazole);
• antidepressants, nefazodone, and fluoxetine;
• quinupristin/dalfopristin;
• valproic acid;
• cimetidine;
• tricyclic antidepressants, vasodilators;
• cisapride.

When Cordipin XL is used concomitantly with these drugs, blood pressure should be monitored, and dose reduction of nifedipine should be considered if necessary.

Nifedipine is contraindicated before the 20th week of pregnancy. Nifedipine should not be used during pregnancy except when the woman's clinical condition requires treatment with nifedipine. Nifedipine should be prescribed to women with severe arterial hypertension who do not respond to standard therapy (see section "Use during pregnancy or breastfeeding").

Careful monitoring of blood pressure is required when nifedipine is used concomitantly with intravenous magnesium sulfate, due to the possibility of excessive reduction in blood pressure, which may be harmful to both mother and fetus.

Special warnings regarding excipients.

Cordipin XL contains lactose and therefore should not be taken by patients with rare hereditary galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

Use during pregnancy or breastfeeding.

Pregnancy

Nifedipine is contraindicated before the 20th week of pregnancy. Cordipin XL should not be used during pregnancy unless the clinical condition of the pregnant woman requires treatment with nifedipine.

Animal studies have shown embryotoxicity, fetotoxicity, and teratogenicity of the drug.

There are no adequate and well-controlled studies on the use of the drug in pregnant women.

A specific prenatal risk has not been identified; however, increased incidences of perinatal asphyxia, cesarean section, preterm delivery, and intrauterine growth retardation have been reported. It is unknown whether these events are related to arterial hypertension and its treatment or to the effect of nifedipine itself.

There is insufficient available information to exclude an adverse effect of the drug on the fetus and newborns; therefore, any use of the drug during pregnancy requires a very careful individual risk/benefit assessment. Therapy with the drug should be considered only if all other treatment regimens are unsuitable or have proven ineffective.

When calcium channel blockers, including nifedipine, are administered intravenously to suppress labor or used concomitantly with beta-2 agonists, acute pulmonary edema has been reported (particularly in cases of multiple pregnancy).

Breastfeeding.

Nifedipine is contraindicated during breastfeeding. Nifedipine passes into breast milk. The concentration of nifedipine in breast milk is comparable to that in blood serum. To minimize the effect on the infant, breastfeeding should be delayed for 3–4 hours after administration of immediate-release nifedipine formulations.

Fertility

Individual in vitro experiments have revealed an association between the use of calcium antagonists, particularly nifedipine, and reversible biochemical changes in the sperm head, which impair the sperm's fertilizing capacity. If in vitro fertilization attempts fail without other explanations, calcium antagonists, particularly nifedipine, may be considered as a possible cause.

Ability to affect reaction speed when driving or operating machinery.

Variable individual responses to the drug may impair the ability to drive or operate machinery, particularly at the beginning of treatment, when switching to another medication, or when consuming alcohol concurrently.

Method of Administration and Dosage

The dosage is determined by a physician individually, depending on the patient's condition, severity of the disease, and sensitivity to the drug. The effectiveness of treatment and dosage adjustment are based on blood pressure levels and/or frequency and severity of angina attacks.

Patients with impaired liver function require careful monitoring, and the dose may be reduced if necessary.

Patients with severe impairment of cerebral blood supply (severe cerebrovascular disease) should be prescribed reduced doses of the drug.

The usual initial and maintenance dose of Cordipine XL in all cases is 1 tablet once daily.

Patients should take the tablets before, during, or after breakfast, swallowing them with a glass of water. Tablets must not be broken, crushed, or chewed. Patients should be instructed to take the medication regularly at the same time each day, in doses not exceeding the recommended amounts. If a dose is missed, it should be taken as soon as possible; however, if the next dose is due within a few hours, the missed dose should be skipped. In such a case, the next dose should be taken at the usual time. Double doses must never be taken.

Children

The safety and efficacy of nifedipine in children have not been sufficiently studied; therefore, this drug is not prescribed for children under 18 years of age.

Overdose

Symptoms

Symptoms observed in severe intoxication following ingestion of high doses of nifedipine include disturbances of consciousness up to coma, arterial hypotension, tachycardia, bradycardia, hyperglycemia, metabolic acidosis, hypoxia, cardiogenic shock with pulmonary edema.

Treatment

In case of overdose, the primary goals of treatment are elimination of nifedipine and restoration of stable cardiovascular function. Elimination should be as complete as possible, including removal from the small intestine to prevent further absorption of the active substance.

The benefit of gastric decontamination is uncertain.

1. Administration of activated charcoal (50 g for adults, 1 g/kg for children) within 1 hour after ingestion of a potentially toxic amount.

There is no evidence that late administration of activated charcoal is beneficial after ingestion of modified-release (prolonged-release) formulations.

2. As an alternative, gastric lavage should be considered in adults within 1 hour after ingestion of potentially life-threatening doses.
3. Administration of activated charcoal every 4 hours and a single dose of an osmotic laxative (e.g., sorbitol, lactulose, or magnesium sulfate).
4. After ingestion of high doses, asymptomatic patients should be observed for at least 4 hours, and for 12 hours after ingestion of modified-release formulations.

Hemodialysis is ineffective in removing nifedipine from the body. Plasmapheresis is recommended due to the high plasma protein binding and relatively low volume of distribution of the drug.

Arterial hypotension leading to cardiogenic shock and arterial vasodilation may be treated with calcium (10–20 mL of 10% calcium gluconate solution administered intravenously over 5–10 minutes). If effects are insufficient, treatment may be continued with ECG monitoring. If blood pressure does not adequately respond to calcium, vasoconstrictive sympathomimetics such as dopamine or norepinephrine should be administered. The dosage of these agents should be titrated according to the patient's response.

Symptomatic bradycardia should be treated with atropine or β-sympathomimetics; in more severe cases, temporary cardiac pacing may be required.

Additional fluid volumes should be administered cautiously to avoid cardiac overload.

Adverse reactions

Adverse reactions that may occur during the use of nifedipine are categorized into the following groups according to their frequency:

• common (> 1/100 to < 1/10);
• uncommon (> 1/1000 to < 1/100);
• rare (> 1/10000 to < 1/1000);
• frequency not known (cannot be estimated from the available data).

Within each frequency group, adverse reactions are listed in order of decreasing severity.

*May be life-threatening

**Sometimes, especially at the beginning of treatment, angina pectoris may occur or an increase in the frequency, duration, and severity of attacks may be observed in patients with existing angina. In isolated cases, myocardial infarction has been reported.

***Cases of use as a tocolytic during pregnancy have been reported (see section "Use during pregnancy or breastfeeding").

In patients with malignant hypertension and hypovolemia undergoing dialysis, a significant decrease in blood pressure may occur due to vasodilation.

Reporting of suspected adverse reactions

Reporting of adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, should report all suspected adverse reactions and lack of efficacy of the medicinal product via the Automated Pharmacovigilance System at the following link: https://aisf.dec.gov.ua.

Shelf life.

3 years.

Storage conditions.

No special storage conditions are required for this medicinal product. Keep out of reach and sight of children.

Packaging.

10 tablets in a blister pack, 2 blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

KRKA, d.d., Novo mesto / KRKA, d.d., Novo mesto.

Address of manufacturer and location of business operation.

Smarjeska cesta 6, 8501 Novo mesto, Slovenia / Smarjeska cesta 6, 8501 Novo mesto, Slovenia.