Nifedipine-Darnitsa film-coated tablets 10 mg No. 50

Translation of the instructions can be

Instruction

For medical use of the medicinal product

Composition:

Active ingredient: nifedipine;

1 tablet contains nifedipine 10 mg;

excipients: corn starch, lactose monohydrate, microcrystalline cellulose, povidone, magnesium stearate, sepifilm 752 white, macrogol 6000, sunset yellow FCF (E 110).

Dosage form.

The pills are coated.

Main physicochemical properties: film-coated tablets, orange in color, round in shape with a biconvex surface.

Pharmacotherapeutic group.

Selective calcium channel blockers with a predominant effect on blood vessels. Dihydropyridine derivatives. Nifedipine. ATC code c08c A05.

Pharmacological properties.

Pharmacodynamics.

Nifedipine - the active substance of the drug - a selective calcium channel blocker, a dihydropyridine derivative. Has antianginal and antihypertensive effects. Inhibits the influx of calcium into cardiomyocytes and vascular smooth muscle cells. Reduces the tone of vascular smooth muscle. Dilates coronary and peripheral arteries, reduces total peripheral vascular resistance, blood pressure and to a small extent - myocardial contractility, reduces afterload and myocardial oxygen demand. Improves coronary blood flow. Does not inhibit myocardial conductivity. With prolonged use, nifedipine can prevent the formation of new atherosclerotic plaques in the coronary vessels. At the beginning of treatment with nifedipine, transient reflex tachycardia and an increase in cardiac output may occur, which do not compensate for the vasodilation caused by the use of the drug. Nifedipine increases the excretion of sodium and fluid from the body. In Raynaud's syndrome, the drug can prevent or reduce spasm of the blood vessels of the extremities.

Pharmacokinetics.

After oral administration, nifedipine is rapidly and almost completely absorbed. Bioavailability due to first pass metabolism in the liver is 50%. Maximum concentration (T max) in blood plasma is reached 1-3 hours after administration.

Nifedipine is metabolized in the intestinal wall and in the liver via the cytochrome P450 3A4 system. Metabolites do not exhibit pharmacological activity. It is excreted from the body in the form of metabolites mainly by the kidneys and about 5-15% - through the intestines with bile. A small amount of unchanged substance (less than 0.1%) was detected in the urine. The half-life (T 1/2) of nifedipine from blood plasma is 2-5 hours.

Clinical characteristics.

Indication.

Arterial hypertension, coronary heart disease: chronic stable angina, vasospastic angina (Prinzmetal's angina).

Contraindication.

Interaction with other drugs and other types of interactions.

Nifedipine is metabolized by the cytochrome P450 3A4 system, which is located in the intestinal mucosa and liver. Therefore, drugs that inhibit or induce this enzyme system (e.g. erythromycin, clarithromycin, ciprofloxacin, norfloxacin, ketoconazole, itraconazole, fluconazole, progestin-containing agents, fluoxetine, indinavir, nelfinavir, ritonavir, amprenavir and saquinavir) may alter the first-pass (after oral administration) or clearance of nifedipine.

Although no in vivo drug interaction studies have been conducted, there is a potential for increased plasma concentrations of nifedipine when co-administered. Therefore, blood pressure should be monitored and a reduction in the nifedipine dose may be necessary.

The antihypertensive effect of nifedipine may be enhanced by the use of other antihypertensive drugs and tricyclic antidepressants.

Drugs that affect the effectiveness of nifedipine

With quinupristin/dalfopristin, cimetidine, cisapride - due to inhibition of cytochrome P450 3A4, the concentration of nifedipine in the blood plasma increases; with simultaneous use of drugs, it is recommended to monitor blood pressure and, if necessary, reduce the dose of nifedipine.

With inhibitors of the cytochrome P450 3A4 system, such as macrolide antibiotics (e.g. ketoconazole), HIV protease inhibitors (e.g. ritonavir), azole antifungals (e.g. ketoconazole), fluoxetine, nefazodone - clinical studies of the interaction of these drugs and nifedipine have not been conducted. It is known that drugs of this class inhibit in vitro cytochrome P450 3A4-mediated metabolism of nifedipine, therefore, with simultaneous use, an increase in the concentration of the latter in the blood plasma and a decrease in the rate of excretion from the body cannot be ruled out; it is recommended to monitor blood pressure and, if necessary, reduce the dose of nifedipine.

Azithromycin, which has structural similarity to macrolide antibiotics, does not inhibit CYP3A4.

With phenytoin - due to induction of cytochrome P450 3A4, the bioavailability and efficacy of nifedipine are reduced; with simultaneous use of drugs, it is recommended to monitor the clinical response to nifedipine therapy and, if necessary, increase its dose; if the dose of nifedipine was increased during simultaneous use, after discontinuation of phenytoin, an appropriate dose reduction should be considered.

With inducers of the cytochrome P450 3A4 system, such as carbamazepine, phenobarbital, valproic acid - clinical studies of the interaction of the above-mentioned drugs and nifedipine have not been conducted. It is known that these drugs, due to the induction of cytochrome P450 3A4, reduce the plasma concentration of the structurally similar calcium channel blocker nimodipine, therefore, when used simultaneously with nifedipine, an increase in its plasma concentration cannot be excluded.

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

With cisapride - simultaneous use of cisapride and nifedipine may lead to an increase in the concentration of nifedipine in the blood plasma. Therefore, constant monitoring of blood pressure is necessary and a reduction in the dose of nifedipine may be required.

With diltiazem - weakens the breakdown and reduces the clearance of nifedipine, while increasing its concentration in the blood plasma. Therefore, it is necessary to use nifedipine with caution simultaneously with diltiazem, and a reduction in the dose of nifedipine may be required.

With antihypertensive agents (diuretics, α- and β-adrenoblockers, ACE inhibitors, calcium receptor antagonists, AT-1 receptor antagonists, phosphodiesterase-5 inhibitors, α-methyldopa, magnesium sulfate) - possible enhancement of the hypotensive effect; with simultaneous use of nifedipine with β-adrenoblockers, careful monitoring of the patient is required, since isolated cases of exacerbation of heart failure are known.

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

Concomitant administration of nifedipine and tricyclic antidepressants may lead to increased plasma concentrations of these drugs and increased antihypertensive effects of nifedipine.

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

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

In patients taking coumarin-based anticoagulants, an increase in 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).

With theophylline - it is necessary to check the appropriateness of using theophylline with nifedipine, since the concentration of theophylline in the blood plasma may increase during the simultaneous administration of nifedipine with theophylline.

With digoxin - a decrease in digoxin clearance and an increase in its concentration in blood plasma are possible; it is recommended to monitor the patient for symptoms of digoxin overdose and, if necessary, adjust the dose according to the concentration of digoxin in blood plasma.

With amiodarone - certain drugs belonging to the group of calcium channel blockers may enhance the negative inotropic effect of antiarrhythmics such as amiodarone. However, there is no information on the interaction specifically with nifedipine.

With quinidine - a decrease in quinidine concentration has been reported, and when nifedipine is canceled - a sharp increase in quinidine concentration in blood plasma; it is recommended to monitor the concentration of quinidine in blood plasma and, if necessary, adjust its dose; there have also been reports of an increase in nifedipine concentration in blood plasma with their simultaneous use, but no changes in the pharmacokinetics of nifedipine were noted. In view of this, blood pressure should be carefully monitored when quinidine is included in the nifedipine therapy regimen. If necessary, the dose of nifedipine should be reduced.

With tacrolimus - increased plasma concentrations of tacrolimus have been reported as a result of its metabolism via the cytochrome P450 3A4 system. Published data indicate that in some cases the dose of tacrolimus may need to be reduced when co-administered with nifedipine. It is recommended to monitor tacrolimus plasma concentrations and adjust the dose if necessary.

Other types of interactions

Grapefruit juice inhibits the cytochrome P450 3A4 system. The use of grapefruit juice during the use of 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 enhanced. After regular consumption of grapefruit juice, this effect may persist for at least 3 days after the last consumption of the juice. In view of this, grapefruit / grapefruit juice should be avoided during therapy with nifedipine.

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

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).

Application features.

The drug can be used in combination with other antihypertensive agents, but the possibility of developing postural hypotension should be borne in mind.

When using the drug and β-blockers simultaneously, it is recommended to monitor the patient's condition, as this can lead to a sharp drop in blood pressure and weakening of cardiac activity.

The drug should not be used in patients with an acute attack of stable angina.

There is limited evidence that patients with essential hypertension or chronic stable angina may experience a dose-dependent increase in the risk of cardiovascular events (e.g. myocardial infarction) and mortality. Therefore, nifedipine is recommended for the treatment of patients with essential hypertension or chronic stable angina when other treatments are not appropriate.

The drug should not be used if there is a possible connection between previous use of nifedipine and ischemic pain. Some patients have complained of minor ischemic pain within 1-4 hours after starting nifedipine. Although there is no evidence of a steal syndrome, nifedipine treatment should be discontinued in patients who develop such symptoms. In patients with angina pectoris, attacks may occur more frequently and their duration and intensity may increase, especially at the beginning of treatment.

Nifedipine may slow the excretion of digoxin. Simultaneous administration of nifedipine with digoxin may lead to an increase in the concentration of digoxin and to the occurrence of adverse reactions due to an increase in the concentration of cardiac glycoside drugs.

The drug should be used with extreme caution in patients with severe arterial hypotension (systolic blood pressure below 90 mm Hg), severe heart failure, severe cerebral circulation disorders, diabetes mellitus, impaired liver function. It is recommended to monitor the patient's condition and, if necessary, adjust the dose of nifedipine.

The drug should be used with caution in patients with chronic renal failure, on hemodialysis, in the presence of malignant arterial hypertension or hypovolemia, since dilation of blood vessels may cause a significant decrease in blood pressure in them.

The drug should be used with caution in patients who are simultaneously taking inhibitors of the cytochrome P450 3A4 system, as they may alter the first-pass or clearance of nifedipine.

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

It is recommended to monitor blood pressure and adjust the dose of nifedipine if necessary.

The drug should be used with caution in patients with severe narrowing of the gastrointestinal tract due to the possibility of obstructive symptoms. Obstructive symptoms have been described in the absence of a history of gastrointestinal disorders. 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.

Not to be used in patients with an ileal reservoir (ileostomy after proctocolectomy).

Excipients

The medicine contains lactose, therefore patients with rare hereditary forms of galactose intolerance, lactase deficiency or glucose-galactose malabsorption syndrome should not take the medicine.

Use during pregnancy or breastfeeding.

Pregnancy.

Animal studies have shown embryotoxicity, fetotoxicity and teratogenicity of the drug, as well as negative effects on reproductive function. Nifedipine should not be used in women planning a pregnancy in the near future.

There are no adequate and well-controlled studies on the safety of the drug in pregnant women. No specific prenatal risk has been identified from the available clinical data. Although an increased incidence of perinatal asphyxia, cesarean section, preterm birth and intrauterine growth retardation have been reported. It is not yet clear whether these events are a consequence of the presence of arterial hypertension, its treatment or a specific effect of the drug. The available information is insufficient to exclude serious adverse effects on the fetus or newborn.

Acute pulmonary edema has been reported (especially in multiple pregnancies) with intravenous administration of calcium channel blockers, including nifedipine, to reduce labor and/or with concomitant use of β2-adrenergic agonists.

When using nifedipine simultaneously with the administration of magnesium sulfate, careful monitoring of blood pressure is necessary due to the possibility of a significant decrease in it, which may harm the mother and fetus.

Breastfeeding.

Breastfeeding should be discontinued during the period of use of the drug.

Nifedipine passes into breast milk, the concentration of nifedipine in breast milk is almost comparable to the concentration in maternal plasma. The effect of small amounts of absorbed nifedipine is unknown.

Fertility.

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

The ability to influence the reaction speed when driving vehicles or other mechanisms.

Therapy with this drug requires constant medical supervision. When using the drug, adverse reactions may occur; due to different individual reactions of the body to the drug, which affect the speed of reaction when driving vehicles or other mechanisms, the performance of actions that require a body position without support is impaired. To a greater extent, these warnings apply, especially at the beginning of treatment, during the period of increasing the dose of the drug, switching to another drug or drinking alcohol.

Method of administration and doses.

The drug is for adults to take orally. The tablets should be taken at the same time, regardless of the meal, without chewing and with sufficient liquid (except grapefruit juice). Taking food with the tablet slows down, but does not reduce absorption.

The recommended interval between taking the drug is 12 hours (but not less than 6 hours).

The dose of the drug and the duration of the course of treatment are determined individually, taking into account the severity of the disease and the patient's response to treatment.

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

Arterial hypertension.

The drug should be used at a dose of 20 mg 2 times a day.

Ischemic heart disease.

The drug should be used at a dose of 20 mg 2 times a day. If necessary, the dose of nifedipine may be increased to 60 mg/day. The dose should be increased gradually.

The maximum daily dose of the drug should not exceed 80 mg.

Patients concomitantly using inhibitors or inducers of cytochrome CYP 3A4. Concomitant use with inhibitors or inducers of cytochrome CYP 3A4 may require dose adjustment or discontinuation of the drug.

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

Due to the possibility of rebound syndrome, the drug should be discontinued gradually, especially when using high doses and during long-term treatment.

The tablets should not be divided, as in this case the protection against light guaranteed by the protective coating is no longer ensured.

Children.

The drug should not be used in children, as the safety and effectiveness of nifedipine in children (under 18 years of age) have not been established.

Overdose.

Treatment. Emergency measures should be directed primarily at removing the drug from the body and restoring stable hemodynamics. After oral administration, it is recommended to completely empty the stomach, if necessary in combination with gastric and small intestinal lavage. It is recommended to consider the need for activated charcoal. In cases of intoxication caused by prolonged-release drugs, efforts should be made to remove the drug from the body as completely as possible, including from the small intestine, to prevent absorption of the active substance. Although it is considered reasonable to assume the benefit of late use of activated charcoal in case of overdose with prolonged-release drugs, it should be noted that there is no evidence to support this.

In the treatment of life-threatening overdose in adults, gastric lavage should be considered as an alternative one hour after ingestion of a potentially toxic dose.

When a clinically significant amount of a slow-release drug is ingested, consideration should be given to administering a single dose of an osmotic laxative (e.g., sorbitol, lactulose, and magnesium sulfate) within four hours, with concomitant administration of activated charcoal.

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

In case of bradycardia, it is recommended to use β-sympathomimetics or atropine. 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 eliminated with calcium preparations (10-20 ml of a 10% solution of calcium chloride or gluconate is administered intravenously slowly, then repeated if necessary under ECG monitoring). As a result, serum 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 sympathomimetics such as dopamine, dobutamine, epinephrine or noradrenaline. The doses of these drugs should be selected taking into account the achieved therapeutic effect. Additional fluid administration should be approached with great caution, since this increases the risk of cardiac overload. 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.

Patients without pronounced symptoms of intoxication should be observed for at least 4 hours after taking an excessive dose of a short-acting drug and for at least 12 hours after taking a prolonged-acting drug.

Adverse reactions.

Most adverse reactions occur due to the vasodilatory effect of nifedipine and usually disappear after discontinuation of drug therapy.

On the part of the organs of vision: slight, temporary change in visual perception, visual impairment, feeling of pain in the eyes, excessive tearing, amblyopia.

On the part of the respiratory system, chest organs and mediastinum: epistaxis, nasal congestion, dyspnea, pulmonary edema (when used by pregnant women as a tocolytic agent), cough, spasticity of the bronchial muscles up to life-threatening shortness of breath, which passes after discontinuation of treatment.

Gastrointestinal: nausea, vomiting, dyspepsia, diarrhea, constipation, flatulence, discomfort/pain in the digestive tract, feeling of fullness in the stomach, gastric disorders, bloating, belching, lack of appetite, abdominal pain, intestinal obstruction, intestinal ulcer, gastroesophageal sphincter insufficiency, bezoar, dry mouth, gingival hyperplasia, dysphagia.

From the liver and biliary tract: impaired liver function, transient increase in liver enzyme activity, jaundice, intrahepatic cholestasis, increased γ-glutamyl transpeptidase levels.

On the part of the kidneys and urinary system: polyuria, dysuria, in patients with renal failure - deterioration of renal function, increased frequency of urination, increased amount of daily urine output, nocturia.

Metabolism: hyperglycemia (especially in patients with diabetes).

From the nervous system: headache, migraine, dizziness/vertigo, tremor, par-/di/hypesthesia, hyperesthesia, sleep disorders, insomnia, drowsiness.

On the part of the psyche: feelings of anxiety, mood swings, nervousness.

Cardiovascular system: tachycardia, palpitations, hypotension (symptomatic and orthostatic), edema, vasodilation, hyperemia, collapse, chest pain (including typical angina attacks), myocardial infarction, erythromegaly, especially at the beginning of treatment, loss of consciousness.

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

Skin and subcutaneous tissue disorders: rash, pruritus, urticaria, facial edema, erythema, Mitchell's disease, hypersensitivity skin reactions such as pruritus, exanthema, edema of the skin and mucous membranes, edema or peripheral edema not caused by heart failure or weight gain, photosensitivity, photodermatitis, purpura, exfoliative dermatitis, toxic epidermal necrolysis (Lyell's syndrome).

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

From the reproductive system and mammary gland function: erectile dysfunction, gynecomastia (in elderly men).

General disorders: general weakness, malaise, increased fatigue, apathy, increased sweating, chills, nonspecific pain, with prolonged use, fever is possible.

Patients with malignant hypertension and hypovolemia undergoing hemodialysis may experience a significant decrease in blood pressure due to vasodilation.

Expiration date.

2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 ° C. Keep out of the reach of children.

Packaging.

10 tablets in a blister; 5 blisters in a pack.

Vacation category.

According to the recipe.

Producer.

Chao "Darnitsa Pharmaceutical Company".

Location of production and its address of place of business.

Ukraine, 02093, Kyiv, Boryspilska St., 13.