INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KORINFAR® RETARD (CORINFAR® RETARD)

Composition:

Active substance: nifedipine;

1 tablet contains 20 mg of nifedipine;

Excipients: lactose monohydrate, potato starch, microcrystalline cellulose, povidone, magnesium stearate, hypromellose, macrogol 6000, macrogol 35000, quinoline yellow (E 104), titanium dioxide (E 171), talc.

Pharmaceutical form. Prolonged-release tablets.

Main physicochemical properties: yellow, biconvex, round tablets with a film coating, with beveled, undamaged edges and a uniform appearance.

Pharmacotherapeutic group. Selective calcium antagonists with predominant effect on blood vessels. Dihydropyridine derivatives. Nifedipine. ATC code C08CA05.

Pharmacological properties.

Pharmacodynamics. Nifedipine is a calcium antagonist of the 1,4-dihydropyridine type. Calcium antagonists reduce the influx of calcium ions through slow calcium channels into cells. Nifedipine primarily acts on smooth muscles of coronary arteries and pressurized peripheral arteries. This effect causes vasodilation and normalization of arterial pressure. At therapeutic doses, nifedipine has virtually no direct effect on myocardium.

Nifedipine promotes dilation of coronary arteries and reduction of peripheral vascular resistance, thereby improving blood flow.

At the beginning of therapy with calcium antagonists, reflex tachycardia and an increase in cardiac output may occur. However, this increase is insufficient to compensate for the vasodilation.

With long-term therapy using nifedipine, heart rate and cardiac output return to pre-treatment values.

Significant reduction in arterial pressure with nifedipine is observed in patients suffering from arterial hypertension.

Pharmacokinetics. Nifedipine is rapidly and almost completely absorbed after oral administration on an empty stomach. Nifedipine undergoes a "first-pass" effect in the liver; therefore, systemic bioavailability after oral administration ranges from 50–70%. Maximum plasma concentration of nifedipine is reached approximately within 15 minutes after administration of nifedipine solution and within 30–85 minutes after administration of the prolonged-release tablet formulation. 95–98% of nifedipine is bound to plasma proteins (albumin). The mean value of the volume of distribution (Vss) of nifedipine is 0.77–1.12 L/kg. Nifedipine is almost completely metabolized in the liver (first-pass effect), primarily via oxidative processes. The metabolites formed in this process are pharmacodynamically inactive. Neither unchanged drug nor M-1 metabolite is excreted by the kidneys to any significant extent (< 0.1% of the administered dose). Approximately 50% of the administered dose is excreted in urine as polar metabolites M-2 and M-3 (partially in conjugated form), with almost complete elimination within 24 hours. The remainder is excreted in feces.

The elimination half-life ranges from 1.7 to 3.4 hours.

Accumulation of the drug in the body during long-term treatment with therapeutic doses has not been reported. In cases of impaired liver function, a clear prolongation of the elimination half-life of the active substance and a reduction in total plasma clearance are observed. If necessary, the dose of the drug should be reduced in such cases.

Clinical characteristics.

Indications.

Chronic stable angina;
Vasospastic angina (Prinzmetal's angina, variant angina);
Essential hypertension.

Contraindications.

Hypersensitivity to nifedipine or to any other component of the medicinal product;
Cardiogenic shock;
Unstable angina;
Acute myocardial infarction (within the first 4 weeks);
Treatment of acute angina attack;

− secondary prevention of myocardial infarction;

− safety of the drug has not been established for the treatment of malignant hypertension;

High-grade aortic stenosis;

− ileostomy or colostomy;

Concomitant use of rifampicin (due to the inability to achieve effective plasma levels of nifedipine as a result of enzyme induction);

‒ Pregnancy.

Interaction with other medicinal products and other forms of interaction.

Medicinal products affecting the efficacy of nifedipine

Nifedipine is metabolized via the cytochrome P450 3A4 system located in the intestinal mucosa and liver. Therefore, medicinal products that inhibit or induce this enzyme system may alter the "first-pass" effect (after oral administration) or clearance of nifedipine.

When using nifedipine concomitantly with the following medicinal products, the degree and duration of interaction should be taken into account.

Rifampicin

Rifampicin strongly induces the cytochrome P450 3A4 system. When administered concomitantly with rifampicin, the bioavailability of nifedipine is significantly reduced, thus decreasing its efficacy. Therefore, the concomitant use of nifedipine with rifampicin is contraindicated.

When using the following weak or moderate inhibitors of the cytochrome P450 3A4 system concomitantly with nifedipine, blood pressure should be monitored and, if necessary, the dose of nifedipine should be considered for reduction.

Macrolide antibiotics (e.g., erythromycin)

No clinical studies on the interaction between nifedipine and macrolide antibiotics have been conducted. Certain 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.

Azithromycin, structurally related to macrolide antibiotics, does not inhibit CYP3A4.

Anti-HIV protease inhibitors (e.g., ritonavir)

No clinical study has been conducted to evaluate the potential interaction between nifedipine and anti-HIV protease inhibitors. It is known that drugs in this class inhibit the cytochrome P450 3A4 system. In addition, these drugs inhibit in vitro the cytochrome P450 3A4-mediated metabolism of nifedipine. When used concomitantly with nifedipine, a significant increase in plasma concentration of nifedipine due to reduced metabolism during "first-pass" and reduced elimination cannot be excluded.

Azole antifungal agents (e.g., ketoconazole)

No formal clinical study has been conducted to evaluate the potential interaction between nifedipine and azole antifungal agents. 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 metabolism during "first-pass" cannot be excluded.

Fluoxetine

No clinical study has been conducted to evaluate the potential interaction between nifedipine and fluoxetine. It is known that fluoxetine inhibits in vitro the cytochrome P450 3A4-mediated metabolism of nifedipine. An increase in plasma concentration of nifedipine cannot be excluded when both drugs are used concomitantly.

NeFazodone

No clinical study has been conducted to evaluate the potential interaction between nifedipine and nefazodone. It is known that nefazodone inhibits in vitro the cytochrome P450 3A4-mediated metabolism of other drugs. An increase in plasma concentration of nifedipine cannot be excluded when both drugs are used concomitantly.

Quinupristin/dalfopristin

Due to inhibition of cytochrome P450 3A4, concomitant use of these drugs with nifedipine may lead to increased plasma concentration of nifedipine and enhanced antihypertensive effect.

Valproic acid

No formal clinical study has been conducted to evaluate the potential interaction between nifedipine and valproic acid. It is known that valproic acid increases plasma concentrations of the structurally similar calcium channel blocker nimodipine due to enzyme inhibition. Therefore, an increase in plasma concentration of nifedipine and enhanced efficacy cannot be excluded.

Cimetidine, ranitidine

Due to inhibition of cytochrome P450 3A4, cimetidine/ranitidine increases plasma concentration of nifedipine and may enhance the antihypertensive effect. Cimetidine acts as an inhibitor of the cytochrome isoenzyme CYP3A4. Nifedipine should be administered with caution to patients already taking cimetidine, and its dosage should be increased more gradually.

Tricyclic antidepressants, vasodilators

Combination of nifedipine with tricyclic antidepressants or vasodilators may potentiate the hypotensive effect.

Additional investigations

Cisapride

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

Antiepileptic drugs inducing the cytochrome P450 3A4 system, such as 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 decreased. When both drugs are used concomitantly, the clinical response to nifedipine therapy should be monitored, and if necessary, the dose of nifedipine should be considered for increase. If the dose of nifedipine is increased during concomitant use, upon discontinuation of phenytoin, the dose of nifedipine should be considered for reduction.

No formal clinical studies have been conducted on the potential interaction between nifedipine and carbamazepine or phenobarbital. It is known that both drugs reduce plasma concentrations of the structurally similar calcium channel blocker nimodipine due to enzyme induction. Therefore, a decrease in plasma concentration of nifedipine and reduced efficacy cannot be excluded.

Diltiazem reduces the biotransformation of nifedipine, which may necessitate dose reduction.

Effect of nifedipine on other medicinal products

Antihypertensive drugs

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

Diuretics;
β-blockers;
ACE inhibitors (angiotensin-converting enzyme inhibitors);
AT1-receptor antagonists;
Other calcium channel blockers;
α-adrenergic blockers;
PDE-5 inhibitors (phosphodiesterase-5 inhibitors);
α-methyldopa;
Magnesium sulfate.

When used concomitantly with glyceryl trinitrate and isosorbide with prolonged release, the synergistic effect of nifedipine should be considered.

In patients treated with nifedipine, fentanyl may cause arterial hypotension. Nifedipine should be withheld for at least 36 hours prior to elective surgery using fentanyl-based anesthesia.

Nifedipine may lead to toxic effects of magnesium sulfate, causing neuromuscular blockade. Concomitant use of nifedipine and magnesium sulfate is not recommended, as it is dangerous and may be life-threatening.

In patients taking warfarin-type anticoagulants, prolonged prothrombin time has been observed after adding nifedipine. The clinical significance of this interaction has not been fully evaluated.

Nifedipine may alter bronchial reactivity to methacholine. Nifedipine should be discontinued (if possible) prior to non-specific bronchoprovocation testing with methacholine.

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

Digoxin, theophylline

Concomitant use of nifedipine with theophylline or digoxin may increase plasma concentrations of theophylline or digoxin. Monitoring of plasma concentrations of theophylline or digoxin is recommended, along with observation for symptoms of digoxin overdose, and dose adjustment as necessary based on plasma digoxin levels.

Quinidine

When nifedipine and quinidine are used concomitantly, decreased quinidine levels have been observed in some cases, and a sharp increase in plasma quinidine concentration upon discontinuation of nifedipine. Therefore, monitoring of plasma quinidine concentration is recommended when starting or stopping nifedipine, and dose adjustment of quinidine may be necessary. Occasionally, increased plasma concentration of nifedipine has been reported when both drugs are used concomitantly, although cases with no change in nifedipine pharmacokinetics have also been reported.

Therefore, careful monitoring of blood pressure is required when quinidine is added to nifedipine therapy. If necessary, the dose of nifedipine should be reduced.

Tacrolimus

It is known that tacrolimus is metabolized via the cytochrome P450 3A4 system. Published data indicate that in some cases the dose of tacrolimus may be reduced when used concomitantly with nifedipine. When both drugs are used concomitantly, monitoring of tacrolimus plasma concentration is recommended, and dose reduction of tacrolimus should be considered if necessary.

Concomitant use of vincristine may reduce vincristine elimination, potentially increasing the severity of adverse reactions, requiring dose reduction; concomitant use with cephalosporins (e.g., cefixime) may increase plasma levels of cephalosporins.

Other forms of interaction

Grapefruit juice

Grapefruit juice inhibits the cytochrome P450 3A4 system. Consumption of grapefruit juice during nifedipine therapy leads to increased plasma concentration of the drug and prolonged duration of action due to reduced "first-pass" metabolism or reduced clearance. As a result, the antihypertensive effect of the drug may be enhanced. This effect may persist for at least 3 days after the last intake of grapefruit juice following regular consumption.

Therefore, grapefruit/grapefruit juice should be avoided during nifedipine therapy.

Nifedipine use may lead to falsely elevated results in spectrophotometric determination of vanillylmandelic acid concentration in urine (however, this effect is not observed when using high-performance liquid chromatography).

Special precautions for use

Nifedipine should be administered with caution in patients with severe arterial hypotension (systolic blood pressure below 90 mm Hg) or severe heart failure.

Patients with impaired liver function require close monitoring, and in some cases dose reduction may be necessary.

Nifedipine is metabolized via the cytochrome P450 3A4 system; therefore, drugs that inhibit or induce this enzyme system may alter the "first-pass" metabolism 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, for example:

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

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

Patients receiving nifedipine together with β-adrenergic blockers should be carefully monitored, as this combination may lead to a pronounced decrease in arterial pressure, and in some cases, heart failure has been observed.

Nifedipine should be used with caution in patients with low cardiac reserve. In addition, in some cases, nifedipine administration has led to exacerbation of heart failure.

Nifedipine may slow the elimination of digoxin. Concomitant use of nifedipine with digoxin may increase digoxin plasma concentrations and may lead to adverse reactions associated with elevated levels of cardiac glycosides.

Within 1–4 hours after starting nifedipine, some patients have reported mild ischemic pain. Although there is no confirmed evidence of coronary steal syndrome, treatment with nifedipine should be discontinued in patients who develop such symptoms.

As with other non-deformable materials, caution is required when administering this medicinal product to patients with marked narrowing of the gastrointestinal tract due to the possibility of obstructive symptoms. Very rarely, bezoar formation may occur, which may require surgical intervention.

In isolated cases, obstructive symptoms have been reported in patients without prior gastrointestinal disorders.

The medicinal product should not be used in patients with ileostomy (after proctocolectomy).

Use of the medicinal product may lead to false-positive results in X-ray examinations using barium contrast agents (e.g., filling defects may be interpreted as polyps).

The medicinal product should not be used if there is a suspected association between prior nifedipine use and ischemic pain. In patients with angina, attacks may occur more frequently, and their duration and intensity may increase, especially at the beginning of treatment.

Nifedipine should not be used in patients experiencing an acute attack of stable angina.

Use of nifedipine in patients with diabetes mellitus may require adjustment of antidiabetic therapy.

The drug should be prescribed with particular caution to patients with chronic renal failure undergoing hemodialysis, or in cases of malignant hypertension or hypovolemia, as vasodilation may cause a significant drop in blood pressure.

If a patient has intolerance to certain sugars, consultation with a physician is required before taking this medicinal product. The product contains 31.6 mg of lactose monohydrate per prolonged-release tablet. The drug should not be administered to patients with rare hereditary conditions such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

Grapefruit juice inhibits the metabolism of nifedipine, leading to increased plasma concentrations.

Use during pregnancy or breastfeeding.

Pregnancy. Nifedipine is contraindicated during pregnancy except when absolutely necessary due to the mother’s clinical condition—specifically, in cases of severe hypertension when all other treatment strategies are either contraindicated or have proven ineffective. There are no adequate and well-controlled studies on the use of nifedipine in pregnant women. Available data are insufficient to exclude possible adverse effects on the fetus and newborn.

Animal studies have shown embryotoxic, fetotoxic, and teratogenic effects of the drug.

Specific prenatal risk has not been established from available clinical data. However, reports of increased perinatal asphyxia, cesarean sections, prematurity, and intrauterine growth retardation have been documented. It is unclear whether these reports are related to hypertension, its treatment, or the specific effect of nifedipine.

Acute pulmonary edema (especially in multiple pregnancies) has been reported when calcium channel blockers, including nifedipine, are administered intravenously to suppress labor and/or when used concomitantly with β2-adrenergic agonists.

Careful monitoring of blood pressure is required when nifedipine is used concomitantly with intravenous magnesium sulfate, due to the risk of significant hypotension, which may harm both mother and fetus.

Breastfeeding. Nifedipine is not recommended during breastfeeding. Nifedipine is excreted in breast milk (the concentration in breast milk is nearly comparable to that in maternal plasma). The impact of small amounts of absorbed nifedipine on the infant is unknown; therefore, breastfeeding should be discontinued if nifedipine is required during lactation.

Fertility. In some in vitro experiments, an association has been observed between the use of calcium antagonists, particularly nifedipine, and reversible biochemical changes in spermatozoa that impair their fertilizing capacity. If in vitro fertilization attempts fail without other explanations, calcium antagonists, including nifedipine, may be considered as a possible contributing factor.

Ability to influence reaction speed when driving or operating machinery.

Treatment with this medicinal product requires ongoing medical supervision. Due to individual responses to the drug, the ability to drive or operate machinery may be impaired. These precautions are particularly relevant during the initial treatment period, dose escalation, switching to another drug, or when alcohol is consumed.

Dosage and Administration.

The dosage regimen should be determined individually, taking into account the severity of the disease and the patient's response to treatment.

The recommended dose for all indications is 1 tablet twice daily. If necessary, the dose may be increased to 40 mg of nifedipine (i.e., 2 tablets) twice daily.

Depending on the individual clinical picture, the recommended dose should be gradually increased.

Patients with hepatic impairment require close monitoring, and a reduction in the dose of the drug may be necessary.

Patients with severe cerebrovascular disorders should receive low doses.

"Corinfar® Retard" tablets should be swallowed whole, without chewing, after meals, with sufficient fluid (except grapefruit juice), preferably in the morning and evening at the same time each day. Food intake together with the tablet leads to delayed but not reduced absorption.

The duration of treatment is determined by the physician.

Due to the possible occurrence of rebound syndrome, therapy with "Corinfar® Retard" should be discontinued gradually, especially after high-dose or long-term treatment.

Prolonged-release tablets should not be divided, as the light-protective coating will no longer provide adequate protection in such cases.

Children.

The safety and efficacy of nifedipine in children (under 18 years of age) have not been established. The drug is not indicated for use in children.

Overdose.

Symptoms of acute intoxication: impaired consciousness up to coma, arterial hypotension, tachycardia/bradycardia, arrhythmia, hyperglycemia, metabolic acidosis, hypoxia, cardiogenic shock accompanied by pulmonary edema.

Treatment. The most important therapeutic measures are elimination of the drug from the body and restoration of cardiovascular stability.

After oral administration, gastric lavage is recommended, if necessary, in combination with small intestinal lavage. Activated charcoal may be administered if needed. In cases of intoxication caused by sustained-release formulations, every effort should be made to eliminate the drug as completely as possible from the body, including from the small intestine, to prevent absorption of the active substance. Although there is a theoretical benefit of delayed administration of activated charcoal in cases of overdose with prolonged-release formulations, there is no evidence to support this practice.

For life-threatening overdose in adults, gastric lavage should be considered within 1 hour after ingestion of a potentially toxic dose.

After ingestion of a clinically significant amount of a slowly eliminated drug, administration of a single dose of an osmotic laxative (e.g., sorbitol, lactulose, or magnesium sulfate) within four hours, along with activated charcoal, should be considered.

When using laxatives, it should be noted that calcium antagonists may reduce intestinal muscle tone up to intestinal atony. Because nifedipine is highly protein-bound and has a relatively small volume of distribution, hemodialysis is ineffective; however, plasmapheresis is recommended.

Bradycardia can be treated with β-sympathomimetics. In case of life-threatening bradycardia, artificial cardiac pacing is recommended.

Arterial hypotension resulting from cardiogenic shock and vasodilation can be managed with calcium preparations (10–20 mL of 10% calcium chloride or calcium gluconate solution administered slowly intravenously, repeated if necessary under ECG monitoring). Serum calcium levels may reach the upper limit of normal or be slightly elevated. If calcium administration is insufficiently effective, dopamine, dobutamine, epinephrine, or norepinephrine may be used. Doses of these agents should be adjusted according to the therapeutic response. Additional fluid administration should be approached with extreme caution, as it may increase the risk of cardiac overload.

Patients without pronounced symptoms of intoxication should remain under medical observation for at least 4 hours after ingestion of a short-acting formulation and at least 12 hours after ingestion of a prolonged-release formulation.

Adverse reactions.

Blood and lymphatic system disorders: changes in blood count parameters, anemia, leukopenia, thrombocytopenia and thrombotic microangiopathy, agranulocytosis, thrombocytopenic purpura.

Immune system disorders: allergic reactions, allergic edema (including laryngeal edema*), pruritus, urticaria, rash, anaphylactic/anaphylactoid reaction, angioedema, facial swelling.

Metabolism and nutrition disorders: hyperglycemia (particularly in patients with diabetes mellitus).

Nervous system disorders: headache, dizziness, migraine, tremor, paresthesia, dysesthesia, hypoesthesia, hyperesthesia, somnolence, vertigo.

Psychiatric disorders: anxiety reactions, sleep disorders, mood changes, nervousness.

Eye disorders: mild transient changes in visual perception, visual disturbances, eye pain, excessive lacrimation, amblyopia.

Cardiovascular disorders: flushing, palpitations, tachycardia, angina, edema (including peripheral edema), vasodilation, loss of consciousness, arterial hypotension, collapse, symptomatic hypotension, orthostatic hypotension, myocardial infarction, chest pain, erythromelalgia, particularly at the beginning of treatment. In patients with malignant hypertension and hypovolemia undergoing hemodialysis, significant reduction in blood pressure may occur due to vasodilation.

Respiratory system disorders: nosebleeds, nasal congestion, dyspnea, pulmonary edema (when used in pregnancy as a tocolytic agent), cough, bronchial muscle spasm, up to life-threatening respiratory distress, which resolves after discontinuation of treatment.

Gastrointestinal disorders: constipation, gastrointestinal dysfunction such as dyspepsia, bloating, diarrhea, abdominal pain, flatulence, nausea, vomiting, dry mouth, gingival hyperplasia, gastroesophageal sphincter insufficiency, feeling of stomach fullness, belching, loss of appetite, gastrointestinal pain, bezoar, dysphagia, intestinal ulcer, intestinal obstruction.

Hepatobiliary disorders: transient increase in transaminase activity, jaundice, liver dysfunction (intrahepatic cholestasis, increased levels of γ-glutamyltransferase).

Skin and subcutaneous tissue disorders: erythema, Mitchell's disease, skin hypersensitivity reactions such as pruritus, exanthema, skin and mucous membrane swelling, edema or peripheral edema not caused by heart failure or weight gain, increased sweating, urticaria, photodermatitis, palpable purpura, toxic epidermal necrolysis, exfoliative dermatitis, photosensitivity reaction.

Musculoskeletal and connective tissue disorders: myalgia, arthralgia, muscle cramps, joint swelling.

Renal and urinary disorders: transient decrease in kidney function in cases of renal impairment; increased frequency of urination, increased daily urine output, polyuria, dysuria, nocturia.

Reproductive system and breast disorders: reversible gynecomastia (symptoms resolve after discontinuation of nifedipine), erectile dysfunction.

General disorders: increased fatigue, apathy, asthenia, malaise, fever, nonspecific pain, chills.

*May be life-threatening.

Shelf life. 3 years.

Storage conditions. Store at temperatures not exceeding 25°C in the original packaging to protect from light. Keep out of reach of children.

Packaging.

10 tablets per blister, 3 blisters per carton; 50 or 100 tablets per bottle, 1 bottle per carton.

Prescription status. Prescription only.

Manufacturer. PLIVA Hrvatska d.o.o.

Manufacturer's address and location of operations.

Prilaz baruna Filipovića 25, 10000 Zagreb, Croatia.

Corinfar® retard