Fenigidin-zdorov'ya

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT FENIGIDIN-ZDOROV'YA (PHENIHYDIN-ZDOROVYE)

Composition:

Active substance: nifedipine;

1 tablet contains nifedipine 10 mg;

Excipients: potato starch, lactose monohydrate, refined sugar, calcium stearate, polysorbate-80.

Pharmaceutical form. Tablets.

Main physicochemical properties: yellow or yellowish-green, flat cylindrical tablets with a bevel.

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

Pharmacological properties.

Pharmacodynamics.

Nifedipine – the active substance of the drug – is a selective calcium channel blocker, a derivative of dihydropyridine. It exerts antianginal and antihypertensive effects. It inhibits calcium influx into cardiomyocytes and vascular smooth muscle cells. It reduces the tone of vascular smooth muscle. It dilates coronary and peripheral arteries, reduces total peripheral vascular resistance and arterial pressure, and to a slight extent – myocardial contractility, decreases afterload and myocardial oxygen demand. It improves coronary blood flow. It does not suppress myocardial conduction. With prolonged use, nifedipine may prevent the formation of new atherosclerotic plaques in coronary vessels. At the beginning of nifedipine therapy, transient reflex tachycardia and increased cardiac output may occur, which do not counteract the vasodilation caused by the drug. Nifedipine enhances excretion of sodium and fluid from the body. In Raynaud's syndrome, the drug may prevent or alleviate vasospasm in the extremities.

Pharmacokinetics.

After oral administration, nifedipine is rapidly and almost completely absorbed. Due to presystemic metabolism in the liver, bioavailability is approximately 50%. Maximum plasma concentration (Tmax) is reached within 1–3 hours after administration.

Nifedipine is metabolized in the intestinal wall and liver via the cytochrome P450 3A4 system. The metabolites have no pharmacological activity. The drug is excreted from the body primarily as metabolites via the kidneys, and about 5–15% via the intestine with bile. Trace amounts of unchanged substance (less than 0.1%) have been detected in urine.

The elimination half-life (T1/2) of nifedipine from plasma is 2–5 hours.

Clinical characteristics.

Indications.

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

Contraindications.

Hypersensitivity to nifedipine, other dihydropyridine derivatives, or any component of the drug; cardiogenic shock; severe aortic stenosis; unstable angina; acute myocardial infarction (within the first 4 weeks); ileostomy; colostomy; concomitant use with rifampicin (due to inability to achieve effective plasma concentrations of nifedipine).

Interaction with other medicinal products and other forms of interaction.

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

The following interactions may occur when used concomitantly with other medicinal products:

with quinupristin/dalfopristin, cimetidine, cisapride – due to inhibition of cytochrome P450 3A4, plasma concentrations of nifedipine may increase; when used concomitantly, monitoring of blood pressure is recommended and, if necessary, reduction of nifedipine dose;

with the following inhibitors of the cytochrome P450 3A4 system: macrolide antibiotics, HIV protease inhibitors, azole antifungals, fluoxetine, nefazodone, valproic acid – clinical studies on interactions between these drugs and nifedipine have not been conducted. However, it is known that drugs in this class inhibit cytochrome P450 3A4-mediated metabolism of nifedipine; therefore, increased plasma concentrations of nifedipine cannot be excluded during concomitant use. Monitoring of blood pressure is recommended and, if necessary, reduction of nifedipine dose;

with rifampicin – due to induction of cytochrome P450 3A4, bioavailability and efficacy of nifedipine are significantly reduced; concomitant use is contraindicated;

with phenytoin – due to induction of cytochrome P450 3A4, bioavailability and efficacy of nifedipine are reduced; when used concomitantly, clinical response to nifedipine therapy should be monitored and, if necessary, the dose of nifedipine increased. If the dose of nifedipine has been increased during concomitant use, dose reduction should be considered after discontinuation of phenytoin;

with the following inducers of the cytochrome P450 3A4 system: carbamazepine, phenobarbital – clinical studies on interactions between these drugs and nifedipine have not been conducted. It is known that both drugs reduce plasma concentrations of the structurally similar calcium channel blocker nimodipine via induction of cytochrome P450 3A4; therefore, a decrease in nifedipine plasma concentration cannot be excluded during concomitant use;

with antihypertensive agents (diuretics, α- and β-adrenoblockers, ACE inhibitors, calcium channel antagonists, AT-1 receptor antagonists, PDE-5 inhibitors, methyldopa, magnesium sulfate) – an enhanced hypotensive effect is possible. Careful monitoring of the patient is required when nifedipine is used concomitantly with β-adrenoblockers, as isolated cases of worsening heart failure have been reported;

with digoxin – possible reduction in digoxin clearance and increased plasma digoxin concentrations; monitoring for signs of digoxin overdose is recommended and, if necessary, dose adjustment;

with quinidine – decreased plasma quinidine concentrations have been reported, and a sharp increase in quinidine plasma concentration upon discontinuation of nifedipine; monitoring of plasma quinidine concentration is recommended and, if necessary, dose adjustment. Some authors have also reported increased plasma nifedipine concentrations during concomitant use;

with tacrolimus – increased plasma tacrolimus concentrations have been reported; monitoring of plasma tacrolimus concentration is recommended and, if necessary, dose adjustment.

Grapefruit juice inhibits the cytochrome P450 3A4 system. Consumption of grapefruit juice during nifedipine therapy leads to increased plasma concentrations of the drug and prolonged duration of action due to reduced first-pass metabolism or decreased 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.

The use of the drug 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).

The use of the drug may lead to falsely positive results in X-ray examinations using barium contrast agents (e.g., filling defects may be interpreted as polyps).

Special precautions for use.

The drug may be used in combination with other antihypertensive agents. However, the possibility of postural arterial hypotension should be taken into account.

When this drug is used concomitantly with β-adrenoblockers, patient monitoring is recommended, as this may lead to a more pronounced decrease in arterial pressure and suppression of cardiac function.

The drug should not be administered to patients experiencing an acute attack of stable angina.

The drug should not be used if there is a possible 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.

The drug should be used with caution in patients with marked arterial hypotension (systolic pressure below 90 mm Hg), severe heart failure, serious cerebrovascular disorders, diabetes mellitus, or impaired liver function. Patient status should be monitored, and the dose of nifedipine should be adjusted if necessary.

The drug should be used with particular caution in patients undergoing hemodialysis, or in cases of malignant arterial hypertension or hypovolemia, as vasodilation may cause a significant drop in arterial pressure.

The drug should be used with caution in patients who are concurrently taking inhibitors of the cytochrome P450 3A4 system. Arterial pressure should be monitored, and the dose of nifedipine should be adjusted if necessary.

The drug should be used with caution in patients with pre-existing severe narrowing of the gastrointestinal tract due to the possibility of developing obstructive symptoms. Cases of obstructive symptoms have been reported even in the absence of prior gastrointestinal disorders. Formation of bezoars is possible, which may require surgical intervention.

In vitro experiments have revealed an association 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 such as nifedipine may be considered as a possible contributing factor.

The medicinal product contains lactose and refined sugar; therefore, if a patient has known intolerance to certain sugars, medical advice should be sought before taking this medicinal product.

Use during pregnancy or breastfeeding.

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

There are no adequate and well-controlled studies on the use of the drug in pregnant women. Reports have indicated increased incidence of perinatal asphyxia, cesarean deliveries, preterm births, and intrauterine growth retardation. It has not been definitively established whether these outcomes are due to the presence of arterial hypertension, its treatment, or the specific effect of the drug. Available data are insufficient to exclude serious adverse effects on the fetus or newborn.

The use of nifedipine is contraindicated during pregnancy up to the 20th week. Use of nifedipine after the 20th week of pregnancy requires careful assessment of the risk-benefit ratio. Treatment with this drug should be considered only if there are no alternative therapeutic options. When nifedipine is used concomitantly with intravenous administration of magnesium sulfate, careful monitoring of arterial pressure is required due to the possibility of a significant drop in blood pressure, which may harm both mother and fetus.

Nifedipine passes into breast milk. Breastfeeding should be discontinued during treatment with this drug.

Ability to affect reaction speed when driving or operating machinery. Adverse reactions that may affect reaction speed when driving or operating machinery may occur during treatment with this drug, particularly at the beginning of therapy or when switching to another medication.

Dosage and Administration

The medication should be administered orally to adults. Take tablets at the same time each day, regardless of food intake, without chewing, and with sufficient fluid (except grapefruit juice). The recommended interval between doses is 12 hours (but not less than 6 hours).

The dosage and duration of treatment are determined individually, depending on the severity of the disease and the patient's response to therapy.

Arterial hypertension.

Administer the drug at a dose of 20 mg twice daily.

Ischemic heart disease.

Administer the drug at a dose of 20 mg twice daily. If necessary, the dose of nifedipine may be increased up to 60 mg/day. The dose should be increased gradually.

Patients concurrently using inhibitors or inducers of cytochrome CYP3A4. Dose adjustment or discontinuation of the drug may be required when used concomitantly with inhibitors or inducers of cytochrome CYP3A4.

The drug should be discontinued gradually, especially after prolonged use of high doses.

Children. Do not administer the drug to children.

Overdose.

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

Treatment. Emergency measures should primarily aim at eliminating the drug from the body and restoring stable hemodynamics. After oral intake, complete gastric evacuation is recommended, if necessary in combination with gastric and small intestine lavage. In case of bradycardia, β-sympathomimetics are recommended. For life-threatening slowing of heart rate, artificial cardiac pacing is recommended. Arterial hypotension due to cardiogenic shock and vasodilation may be treated with calcium preparations (10–20 ml of 10% calcium chloride or calcium gluconate solution administered slowly intravenously, repeated if necessary). Serum calcium levels may reach the upper limit of normal or be slightly elevated. If calcium administration is insufficiently effective, sympathomimetics such as dopamine or noradrenaline should 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. Since nifedipine is highly protein-bound and has a relatively small volume of distribution, hemodialysis is ineffective; however, plasmapheresis is recommended.

Side effects.

Blood and lymphatic system disorders: anemia, leukopenia, thrombocytopenia (sometimes with purpura), agranulocytosis.

Nervous system and psychiatric disorders: headache, migraine, dizziness/vertigo, tremor, para-/dy-/hypesthesia, sleep disorders, somnolence, feelings of anxiety.

Eye disorders: visual disturbances, eye pain.

Cardiovascular system disorders: tachycardia, palpitations, arterial hypotension, edema, vasodilation, hyperemia, collapse, chest pain (including typical angina attacks), loss of consciousness.

Respiratory, thoracic and mediastinal disorders: epistaxis, nasal congestion, dyspnea.

Gastrointestinal disorders: nausea, vomiting, dyspepsia, diarrhea, constipation, flatulence, discomfort/abdominal pain, abdominal pain, intestinal obstruction, intestinal ulcer, gastroesophageal sphincter insufficiency, bezoar, dry mouth, gingival hyperplasia, dysphagia.

Hepatobiliary disorders: transient increase in liver enzyme activity, jaundice, cholestasis.

Metabolism and nutrition disorders: hyperglycemia.

Renal and urinary disorders: polyuria, dysuria, in patients with renal insufficiency – worsening of kidney function.

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

Reproductive system and breast disorders: erectile dysfunction, gynecomastia (in elderly men).

Immune system, skin and subcutaneous tissue disorders: hypersensitivity reactions, including rash, pruritus, urticaria, allergic edema/angioedema, including laryngeal edema; anaphylactic/anaphylactoid reactions; erythema, photosensitivity, purpura, exfoliative dermatitis, toxic epidermal necrolysis (Lyell's syndrome).

Other: malaise, increased fatigue, chills, nonspecific pain; prolonged use may lead to fever.

In patients with malignant hypertension and hypovolemia undergoing hemodialysis, significant decrease in arterial pressure due to vasodilation may occur.

Shelf life. 3 years.

Storage conditions. Store in original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging. Tablets № 10x5 in blisters in a box.

Prescription status. Prescription only.

Manufacturer. LIMITED LIABILITY COMPANY "CORPORATION "ZDOROV'YA".

Manufacturer's address and location of business activity. 22, Shevchenka Street, Kharkiv, Kharkiv region, 61013, Ukraine.