Corinfar retard prolonged-release tablets 20 mg 30 pcs.

Pharmacodynamics. Nifedipine is a 1,4-dihydropyridine type calcium antagonist. Calcium antagonists reduce the influx of calcium ions through slow calcium channels into cells. Nifedipine mainly acts on the smooth muscles of the coronary and peripheral arteries, which are under pressure. This effect causes vasodilation and normalization of blood pressure. In therapeutic doses, nifedipine has practically no direct effect on the myocardium.

Nifedipine helps dilate coronary arteries and reduce peripheral vascular resistance, which leads to improved blood circulation.

At the beginning of therapy with calcium antagonists, a reflex increase in heart rate and cardiac output may be observed. However, this increase is not sufficient to compensate for the vasodilation.

In the case of long-term therapy with nifedipine, heart rate and cardiac output return to their previous values. A significant decrease in blood pressure against the background of nifedipine is observed in patients with hypertension.

Pharmacokinetics. Nifedipine is rapidly absorbed almost completely when taken orally on an empty stomach. Nifedipine has a first-pass effect through the liver, therefore, the systemic bioavailability of the drug when taken orally is 50-70%. C _max of nifedipine in plasma and serum is achieved approximately 15 minutes after parenteral administration of nifedipine and 30-85 minutes after taking the drug in the form of prolonged-release tablets.

95-98% of nifedipine is bound to plasma proteins (albumin). The average volume of distribution of nifedipine (Vss) is 0.77-1.12 l/kg.

Nifedipine is almost completely metabolized in the liver (first-pass effect), mainly due to the oxidative process. The metabolites formed as a result of this process do not exhibit pharmacodynamic activity. Neither the unchanged substance nor the metabolite M1 are almost not excreted by the kidneys (0.1% of the dose). About 50% of the dose is excreted in the urine in the form of polar metabolites M2 and M3 (partly in a bound form), almost completely excreted within 24 hours. The rest is excreted in the feces.

T _½ is 1.7-3.4 hours.

Accumulation of the drug in the body during long-term treatment in therapeutic doses has not been described. With a decrease in liver function, a clear prolongation of T _½ of the active substance and a decrease in total plasma clearance are noted. If necessary, in such cases, the dose of the drug is reduced.

• Chronic stable angina; vasospastic angina (Prinzmetal’s angina, variant angina); essential hypertension.

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

The recommended dose for all indications is 1 tablet 2 times a day. If necessary, the dose can be increased to 40 mg of nifedipine 2 times a day.

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

Patients with hepatic insufficiency require constant monitoring and may require a reduction in the dose of the drug.

Patients with severe cerebrovascular disease should take the drug in low doses.

Corinfar retard tablets should be swallowed without chewing, after a meal, with sufficient liquid (except grapefruit juice), preferably in the morning and evening at the same time. Taking food with the tablet slows down, but does not reduce absorption.

Therapy with Corinfar retard should be discontinued gradually, especially when taking the drug in high doses.

Prolonged-release tablets should not be divided, as in this case the protection against light guaranteed by the protective coating is no longer provided.

• Hypersensitivity to nifedipine or excipients; cardiogenic shock; concomitant use of rifampicin (due to the inability to achieve effective levels of nifedipine in the blood plasma due to enzyme induction); unstable angina; acute myocardial infarction (within the first 4 weeks); high-grade aortic stenosis; ileostomy or colostomy.

From the side of the hematopoietic and lymphatic systems: changes in blood counts, anemia, leukopenia, thrombocytopenia and thrombotic microangiopathy, agranulocytosis, thrombocytopenic purpura.

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

Metabolic: hyperglycemia (especially in patients with diabetes).

From the nervous system: headache, dizziness, headache, tremor, paresthesia, dysesthesia, hypoesthesia, drowsiness, vertigo.

On the part of the psyche: anxiety reactions, sleep disturbances, mood changes, nervousness.

On the part of the organ of vision: slight temporary change in visual perception, visual impairment, eye pain, excessive tearing.

Cardiovascular: hot flashes, palpitations, tachycardia, angina pectoris, edema, vasodilation, loss of consciousness, hypotension, symptomatic hypotension, orthostatic hypotension, myocardial infarction, chest pain, erythromelalgia, especially at the beginning of treatment. In patients with malignant hypertension and hypovolemia on hemodialysis, a significant decrease in blood pressure due to vasodilation is possible.

On the part of the respiratory system: nosebleeds, nasal congestion, shortness of breath, cough, spasm of bronchial muscles, up to life-threatening shortness of breath, which passes after discontinuation of treatment.

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

On the part of the digestive system: transient increase in transaminase activity, jaundice, cholestasis.

Skin and subcutaneous tissue disorders: erythema, Mitchell’s disease, hypersensitivity skin reactions such as itching, exanthema, swelling of the skin and mucous membranes, increased sweating, urticaria, photodermatitis, purpura, toxic dermal necrolysis, exfoliative dermatitis, photosensitivity reaction.

Musculoskeletal system: muscle pain, joint pain, muscle cramps, joint swelling.

On the part of the kidneys and urinary tract: temporary decrease in kidney function in renal failure; increased frequency of urination, increased daily urine output, polyuria, dysuria, nocturia.

From the reproductive system and mammary glands: reversible gynecomastia (symptoms disappear after discontinuation of nifedipine), erectile dysfunction.

General disorders: increased fatigue, malaise, fever, nonspecific pain.

In case of severe arterial hypotension (systolic blood pressure below 90 mm Hg), severe heart failure, the drug should be used with caution.

Patients with impaired liver function require careful monitoring, and in severe cases, a dose reduction.

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

Drugs that are weak or moderate inhibitors of the cytochrome P450 3A4 system and may cause an increase in nifedipine plasma concentrations include, for example: 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.

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

As with other non-deformable materials, caution should be exercised when using the product in patients with significant gastrointestinal narrowing due to the possibility of symptoms of obstruction. Very rarely, bezoars may occur, which may require surgical intervention.

In isolated cases, obstructive symptoms have been described in the absence of a history of gastrointestinal disorders.

The drug should not be used in patients with an ileostomy (after proctocolectomy).

The use of the drug may lead to false-positive results in X-ray examinations using barium contrast medium (for example, filling defects are interpreted as a polyp).

The drug should not be used if there is a possible connection between previous use of nifedipine and ischemic pain. In patients with angina pectoris, attacks may occur more frequently, and their duration and intensity may increase, especially at the beginning of treatment.

Medicines with the active ingredient nifedipine should not be used in patients with an acute attack of stable angina.

The use of nifedipine in patients with diabetes mellitus may require treatment adjustment.

The drug should be administered with caution to patients on hemodialysis, in conditions of malignant hypertension or hypovolemia, since dilation of blood vessels can cause a significant decrease in blood pressure.

In some in vitro experiments, a relationship has been found between the use of calcium antagonists, in particular nifedipine, and reversible biochemical changes in spermatozoa, which impair their ability to fertilize. If in vitro fertilization attempts are unsuccessful, in the absence of other explanations, calcium antagonists, in particular nifedipine, may be considered as a possible cause of this phenomenon.

Patients with rare hereditary diseases such as galactose intolerance, lactase deficiency or glucose-galactose malabsorption should not be prescribed the drug.

Grapefruit juice inhibits the metabolism of nifedipine, which leads to an increase in its concentration in the blood plasma.

Use during pregnancy and breastfeeding. The use of nifedipine is contraindicated during pregnancy (up to the 20th week).

The use of nifedipine during pregnancy after the 20th week requires a careful assessment of the risk/benefit ratio, and the question of therapy with the drug should be considered only when all other treatment tactics are either not indicated or have been ineffective. There are no results of adequate and well-controlled studies of the use of the drug in pregnant women.

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

When using the drug simultaneously with intravenous administration of magnesium sulfate, careful monitoring of blood pressure is necessary due to the possibility of its significant decrease, which can harm the mother and fetus.

Nifedipine passes into breast milk, so breastfeeding should be discontinued if the drug must be used during breastfeeding.

Children. The drug is not used in children.

Ability to influence the reaction rate when driving vehicles or other mechanisms. Therapy with this drug requires constant medical supervision. Due to the different individual reaction of the body to the drug, the ability to drive vehicles or other mechanisms, to perform actions that require a body position without support, is impaired. To a greater extent, these warnings relate to the initial period of therapy, the period of increasing the dose of the drug, when switching to another drug.

Drugs affecting the efficacy of nifedipine. Nifedipine is metabolized via the cytochrome P450 3A4 system. Therefore, drugs that inhibit or induce this enzyme system may alter the first-pass (after oral administration) or clearance of nifedipine.

When using nifedipine together with the following drugs, the degree and duration of interaction should be taken into account.

Rifampicin. Rifampicin significantly induces the cytochrome P450 3A4 system. When used simultaneously with rifampicin, the bioavailability of nifedipine is significantly reduced and, therefore, its efficacy is reduced. In view of this, the use of the combination of nifedipine with rifampicin is contraindicated.

When using such weak or moderate inhibitors of the cytochrome P450 3A4 system simultaneously, blood pressure should be monitored and, if necessary, a reduction in the nifedipine dose should be considered.

Macrolide antibiotics (e.g. erythromycin). Interaction studies between nifedipine and macrolide antibiotics have not been conducted. Certain macrolide antibiotics inhibit the cytochrome P450 3A4-mediated metabolism of other drugs. Therefore, an increase in nifedipine plasma concentrations cannot be excluded when both drugs are used simultaneously.

Azithromycin, which is structurally similar to members of the macrolide class of antibiotics, does not inhibit CYP 3A4.

Anti-HIV protease inhibitors (e.g. ritonavir). No clinical studies have been conducted to investigate the interaction of nifedipine with certain anti-HIV protease inhibitors. Drugs of this class are known to inhibit the cytochrome P450 3A4 system. In addition, drugs of this class inhibit the cytochrome P450 3A4-mediated metabolism of nifedipine in vitro. When co-administered with nifedipine, a significant increase in nifedipine plasma concentrations cannot be excluded due to a decrease in first-pass metabolism and a decrease in the rate of elimination.

Azole antifungals (e.g. ketoconazole). No formal clinical studies have been conducted to investigate the potential for interactions between nifedipine and certain azole antifungals. Drugs of this class are known to inhibit the cytochrome P450 3A4 system. When administered orally with nifedipine, a significant increase in the systemic bioavailability of nifedipine due to a decrease in first-pass metabolism cannot be excluded.

Fluoxetine. No clinical study has been conducted to investigate the potential interaction between nifedipine and fluoxetine. Fluoxetine is known to inhibit the cytochrome P450 3A4-mediated metabolism of nifedipine in vitro. With simultaneous use of both drugs, an increase in nifedipine plasma concentrations cannot be excluded.

Nefazodone. No clinical study has been conducted to investigate the potential for interaction between nifedipine and nefazodone. Nefazodone is known to inhibit the cytochrome P450 3A4-mediated metabolism of other drugs in vitro. When both drugs are used simultaneously, an increase in nifedipine plasma concentrations cannot be excluded.

Quinupristin/dalfopristin. Due to inhibition of cytochrome P450 3A4, the use of these drugs together with nifedipine may lead to an increase in nifedipine plasma concentrations and an increase in the antihypertensive effect.

Valproic acid. No formal clinical study has been conducted to investigate the potential for interaction between nifedipine and valproic acid. Valproic acid is known to increase the plasma concentration of the structurally similar calcium channel blocker nimodipine due to enzyme inhibition, however, an increase in nifedipine plasma concentration and efficacy cannot be ruled out.

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

Tricyclic antidepressants, vasodilators. In the case of a combination of nifedipine with tricyclic antidepressants, vasodilators, an increase in the hypotensive effect is possible.

additional research

Cisapride. Concomitant use of cisapride and nifedipine may lead to an increase in the concentration of nifedipine in the blood plasma.

Antiepileptic drugs that induce the cytochrome P450 3A4 system, such as phenytoin, carbamazepine and phenobarbital. Phenytoin induces the cytochrome P450 3A4 system. When used simultaneously with phenytoin, the bioavailability of nifedipine is reduced and the efficacy is reduced. When using both drugs simultaneously, the clinical response to nifedipine therapy should be monitored and, if necessary, an increase in the nifedipine dose should be considered. When increasing the nifedipine dose with the simultaneous use of both drugs, a decrease in the nifedipine dose should be considered when phenytoin is discontinued.

No formal clinical studies have been conducted to investigate the potential interaction of nifedipine with carbamazepine or phenobarbital. Both drugs are known to reduce plasma concentrations of the structurally similar calcium channel blocker nimodipine due to enzyme induction. Therefore, a decrease in nifedipine plasma concentrations and reduced efficacy cannot be excluded.

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

Effect of nifedipine on other drugs

Antihypertensive drugs. Nifedipine may increase the hypotensive effect of concomitantly used antihypertensive drugs, such as diuretics; β-adrenergic blockers; ACE inhibitors; AT1 _{receptor antagonists;} other calcium channel blockers; α-adrenergic blockers; phosphodiesterase-5 inhibitors; α-methyldopa; magnesium sulfate.

When using glyceryl trinitrate and prolonged-release isosorbide, the synergistic effect of nifedipine should be taken into account.

Fentanyl may cause hypotension in patients taking nifedipine. Nifedipine should be withheld for at least 36 hours prior to elective surgery using fentanyl-based anesthesia.

Nifedipine may lead to toxicity of magnesium sulfate, which causes neuromuscular blockade. The simultaneous administration of nifedipine and magnesium sulfate is not recommended, as it is dangerous and can threaten the patient’s life.

In patients taking coumarin-based anticoagulants, prolongation of prothrombin time has been observed after the addition of nifedipine. The significance of this interaction has not been fully investigated.

Nifedipine may alter bronchial reactivity to methacholine. Before a nonspecific bronchoprovocation test with methacholine, nifedipine should be discontinued (if possible).

When nifedipine is used concomitantly with β-adrenergic blockers, careful monitoring of the patient’s condition is necessary, as isolated cases of exacerbation of heart failure are known.

Digoxin, theophylline. When nifedipine is taken simultaneously with theophylline or digoxin, the concentration of theophylline or digoxin in the blood plasma may increase. It is recommended to monitor the concentration of theophylline or digoxin in the blood plasma and, if necessary, adjust the dose.

Quinidine. When nifedipine and quinidine are used simultaneously, in some cases a decrease in quinidine levels was observed, and when nifedipine was discontinued, a sharp increase in quinidine plasma concentrations was observed. In view of this, when nifedipine is used simultaneously or discontinued, it is recommended to monitor quinidine plasma concentrations and, if necessary, adjust the quinidine dose. Sometimes an increase in nifedipine plasma concentrations has been reported with the simultaneous use of both drugs, but there have been cases when changes in the pharmacokinetics of nifedipine were noted.

Therefore, blood pressure should be closely monitored when quinidine is included in the nifedipine regimen. If necessary, the nifedipine dose should be reduced.

Tacrolimus: Tacrolimus is known to be metabolised by the cytochrome P450 3A4 system. Published data suggest that in some cases the dose of tacrolimus may need to be reduced when co-administered with nifedipine. Plasma tacrolimus concentrations should be monitored when both drugs are co-administered and a reduction in the tacrolimus dose should be considered if necessary.

With simultaneous use of vincristine, a decrease in the excretion of vincristine was found, which requires a dose reduction; with cephalosporins – an increase in cephalosporin levels in the blood plasma.

Other types of interactions

Grapefruit juice. Grapefruit juice inhibits the cytochrome P450 3A4 system. The use of grapefruit juice with nifedipine leads to an increase in the concentration of the drug in the blood plasma and an increase in the duration of action of nifedipine due to a decrease in first-pass metabolism or a decrease in clearance. As a result, the antihypertensive effect of the drug may be increased. After regular consumption of grapefruit juice, this effect may persist for at least 3 days after the last intake of the juice.

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

The use of nifedipine may lead to false-positive results in spectrophotometric determination of the concentration of vanillylmandelic acid in urine (however, this effect is not observed when using the high-performance liquid chromatography method).

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

Treatment. The most important therapeutic measures are to remove the drug from the body and restore stable functioning of the cardiovascular system.

After ingestion, it is recommended to completely empty the stomach, if necessary, in combination with small bowel lavage. In case of intoxication caused by prolonged-release preparations, measures should be taken to eliminate the drug from the body as completely as possible, including from the small intestine, to prevent absorption of the active substance.

When using laxatives, it should be borne in mind that calcium antagonists lead to a decrease in intestinal muscle tone up to atony. Since nifedipine is characterized by a high degree of binding to plasma proteins and a relatively small volume of distribution, hemodialysis is ineffective, but plasmapheresis is recommended.

Bradycardia can be treated with β-sympathomimetics. In case of life-threatening slowing of the heart rate, the use of an artificial pacemaker is recommended.

Hypotension resulting from cardiogenic shock and vasodilation can be treated with calcium preparations (10-20 ml of a 10% solution of calcium chloride or gluconate is administered intravenously slowly, repeated if necessary). As a result, plasma calcium levels may reach the upper limit of normal or be slightly elevated. If calcium administration is not effective enough, it is advisable to use dopamine, dobutamine, adrenaline or noradrenaline. The doses of these drugs are selected taking into account the achieved clinical effect. Additional fluid administration should be approached very carefully, since this increases the risk of cardiac overload.

In the original packaging to protect from light at a temperature not exceeding 30 °C.