Nifedipine-darnitsa

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT NIFEDIPINE-DARNITSA (NIFEDIPINE-DARNITSA)

Composition:

active substance: nifedipine;

1 tablet contains 10 mg of nifedipine;

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

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: film-coated tablets, orange-colored, round-shaped with a biconvex surface.

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

Pharmacological properties.

Pharmacodynamics.

Nifedipine – the active substance of the medicinal product – is a selective calcium channel blocker, a dihydropyridine derivative. It has 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 circulation. 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 the excretion of sodium and fluid from the body. In Raynaud's syndrome, the drug may prevent or alleviate vasospasm in limb vessels.

Pharmacokinetics.

After oral administration, nifedipine is rapidly and almost completely absorbed. Due to presystemic metabolism in the liver, its bioavailability is about 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 are pharmacologically inactive. The drug is excreted from the body primarily as metabolites through the kidneys and approximately 5–15% through the intestine with bile. A negligible amount of unchanged substance (less than 0.1%) has 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 pectoris, vasospastic angina (Prinzmetal's angina).

Contraindications.

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

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, medicinal products 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 metabolism (after oral administration) or clearance of nifedipine.

Although in vivo interaction studies with these medicinal products have not been conducted, a potential increase in plasma concentration of nifedipine may occur when used concomitantly. Therefore, blood pressure should be monitored, and a reduction in the dose of nifedipine may be necessary.

The antihypertensive effect of nifedipine may be enhanced when used concomitantly with other antihypertensive agents and tricyclic antidepressants.

Medicinal products affecting the efficacy of nifedipine

With quinupristin/dalfopristin, cimetidine, cisapride – inhibition of cytochrome P450 3A4 increases plasma concentration of nifedipine; when used concomitantly, blood pressure monitoring is recommended and dose reduction of nifedipine may be required.

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 interaction studies between these medicinal products and nifedipine have not been conducted. It is known that these agents inhibit in vitro the cytochrome P450 3A4-mediated metabolism of nifedipine; therefore, when used concomitantly, an increase in plasma concentration and reduced elimination of nifedipine cannot be excluded. Blood pressure monitoring is recommended and dose reduction of nifedipine may be necessary.

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

With rifampicin – induction of cytochrome P450 3A4 significantly reduces bioavailability and efficacy of nifedipine; concomitant use is contraindicated.

With phenytoin – induction of cytochrome P450 3A4 reduces bioavailability and efficacy of nifedipine; when used concomitantly, clinical response to nifedipine therapy should be monitored and dose increase may be required. If nifedipine dose was increased during concomitant use, dose reduction should be considered after discontinuation of phenytoin.

With inducers of the cytochrome P450 3A4 system, such as carbamazepine, phenobarbital, valproic acid – clinical interaction studies between these medicinal products and nifedipine have not been conducted. It is known that these agents, via induction of cytochrome P450 3A4, reduce plasma concentration of the structurally similar calcium channel blocker nimodipine; therefore, a similar effect on nifedipine cannot be excluded.

With cimetidine and ranitidine – inhibition of cytochrome P450 3A4 by cimetidine/ranitidine increases plasma concentration of nifedipine and may enhance its antihypertensive effect. Cimetidine acts as an inhibitor of the CYP3A4 isoenzyme. Nifedipine should be administered cautiously in patients already receiving cimetidine, and dosage should be increased more gradually.

With cisapride – concomitant use of cisapride and nifedipine may increase plasma concentration of nifedipine. Therefore, continuous blood pressure monitoring is required and dose reduction of nifedipine may be necessary.

With diltiazem – reduces metabolism and clearance of nifedipine, thereby increasing its plasma concentration. Therefore, concomitant use of nifedipine with diltiazem should be cautious, and dose reduction of nifedipine may be required.

With hypotensive agents (diuretics, α- and β-adrenoblockers, ACE inhibitors, calcium receptor antagonists, AT-1 receptor antagonists, PDE-5 inhibitors, α-methyldopa, magnesium sulfate) – enhanced hypotensive effect may occur. When nifedipine is used concomitantly with β-adrenoblockers, careful patient monitoring is required, as isolated cases of worsening heart failure have been reported.

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

Concomitant use of nifedipine and tricyclic antidepressants may increase plasma concentrations of these drugs and enhance the antihypertensive effect of nifedipine.

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

Nifedipine may potentiate the toxic effect of magnesium sulfate, leading to neuromuscular blockade. Concomitant use of nifedipine and magnesium sulfate is not recommended due to the risk of life-threatening effects.

In patients receiving 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.

With theophylline – the need for concomitant use of theophylline and nifedipine should be carefully evaluated, as plasma concentration of theophylline may increase during concomitant administration.

With digoxin – possible reduction in digoxin clearance and increased plasma concentration; patients should be monitored for signs of digoxin overdose, and dose adjustment should be made based on plasma digoxin levels if necessary.

With amiodarone – certain calcium channel blockers may enhance the negative inotropic effect of antiarrhythmic agents such as amiodarone. However, information on interaction specifically with nifedipine is lacking.

With quinidine – decreased plasma concentration of quinidine has been reported, and a sharp increase in quinidine concentration upon discontinuation of nifedipine; plasma concentration of quinidine should be monitored and dose adjusted if necessary. There have also been reports of increased plasma concentration of nifedipine when used concomitantly, although no changes in nifedipine pharmacokinetics were observed. Therefore, careful blood pressure monitoring is required when initiating quinidine therapy in patients receiving nifedipine. Dose reduction of nifedipine may be necessary.

With tacrolimus – increased plasma concentration of tacrolimus has been reported due to its metabolism via the cytochrome P450 3A4 system. Published data suggest that in some cases, the dose of tacrolimus may be reduced when used concomitantly with nifedipine. Plasma concentration of tacrolimus should be monitored and dose adjusted if necessary.

Concomitant use of vincristine may reduce vincristine elimination, potentially leading to adverse effects; dose reduction should be considered.

With cephalosporins (e.g., cefixime) – increased bioavailability and plasma levels of cephalosporins.

Other forms of interaction

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

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

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

Special precautions for use.

The medicinal product can be used in combination with other antihypertensive agents. However, postural arterial hypotension may occur and should be taken into account.

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

The medicinal product should not be used in patients with acute attacks of stable angina pectoris.

There are limited data suggesting that in patients with essential hypertension or chronic stable angina pectoris, dose-dependent increased risk of cardiovascular complications (e.g., myocardial infarction) and mortality may occur. Therefore, nifedipine is recommended for treatment of patients with essential hypertension or chronic stable angina pectoris only when therapy with other agents is inappropriate.

The medicinal product should not be used if there is a possible association between prior nifedipine use and ischemic pain. Within 1–4 hours after initiation of nifedipine administration, some patients have reported mild ischemic pain. Although coronary steal syndrome has not been confirmed, treatment with nifedipine 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 down digoxin elimination. Concomitant administration of nifedipine with digoxin may increase digoxin concentration and may lead to adverse reactions associated with elevated levels of cardiac glycosides.

The medicinal product should be used with caution in patients with marked arterial hypotension (systolic pressure below 90 mm Hg), severe heart failure, severe cerebral circulation disorders, diabetes mellitus, or impaired liver function. Patient monitoring is recommended, and nifedipine dosage adjustment may be necessary.

The medicinal product should be used with particular caution in patients with chronic renal failure undergoing hemodialysis, in cases of malignant arterial hypertension or hypovolemia, since vasodilation may cause a significant drop in arterial pressure.

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

Medicinal products 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.

Arterial pressure should be monitored and nifedipine dosage adjusted if necessary.

The medicinal product should be used with caution in patients with existing severe narrowing of the gastrointestinal tract due to the possibility of obstructive symptoms. Obstructive symptoms have been reported even in the absence of prior gastrointestinal disorders. Bezoar formation is possible, 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 an ileostomy (intestinal reservoir after proctocolectomy).

Excipients

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

Use during pregnancy or breastfeeding.

Pregnancy.

The use of nifedipine is contraindicated during pregnancy.

Animal studies have shown embryotoxic, fetotoxic, and teratogenic effects of the medicinal product, as well as negative effects on reproductive function. Nifedipine should not be used in women who are planning pregnancy in the near future.

There are no adequate and well-controlled studies on the safety of the medicinal product in pregnant women. From available clinical data, a specific prenatal risk has not been established. However, increased incidence of perinatal asphyxia, cesarean deliveries, preterm deliveries, and intrauterine growth retardation has been reported. It remains unclear whether these events are due to arterial hypertension, its treatment, or a specific effect of the medicinal product. Available information is insufficient to exclude serious adverse effects on the fetus or newborn.

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

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

Breastfeeding.

Breastfeeding should be discontinued during treatment with the medicinal product.

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

Fertility.

In individual in vitro experiments, an association has been observed between the use of calcium channel blockers, particularly nifedipine, and reversible biochemical changes in spermatozoa that impair their fertilizing capacity. If in vitro fertilization attempts are unsuccessful and no other explanation is found, calcium channel blockers, particularly nifedipine, may be considered as a possible cause.

Ability to influence reaction speed when driving or operating machinery.

Treatment with this medicinal product requires continuous medical supervision. Adverse reactions may occur during treatment; due to various individual responses to the medicinal product affecting reaction speed when driving or operating machinery, or performing tasks requiring unsupported body posture, such activities may be impaired. These warnings apply particularly at the beginning of treatment, during dose escalation, when switching to another medicinal product, or when consuming alcohol.

Method of Administration and Dosage

The medicinal product should be administered orally to adults. Tablets should be taken at the same time each day, regardless of food intake, without chewing and swallowed with sufficient fluid (except grapefruit juice). Food intake together with the tablet leads to delayed, but not reduced, absorption.

The recommended interval between doses of the medicinal product is 12 hours (but not less than 6 hours).

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

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

Arterial Hypertension

Administer the medicinal product at a dose of 20 mg twice daily.

Ischemic Heart Disease

Administer the medicinal product 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.

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

Patients concurrently using inhibitors or inducers of cytochrome CYP3A4

When used concomitantly with inhibitors or inducers of cytochrome CYP3A4, dose adjustment or discontinuation of the medicinal product may be required.

Patients with hepatic impairment require close monitoring, and dose reduction of the medicinal product may be necessary.

Due to the potential risk of rebound syndrome, the medicinal product should be discontinued gradually, especially after prolonged treatment or use of high doses.

Tablets should not be divided, as the protective coating no longer ensures protection from light exposure in such cases.

Children

The medicinal product should not be used in children, as the safety and efficacy of nifedipine in pediatric patients (under 18 years of age) have not been established.

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 focus on eliminating the medicinal product from the body and restoring stable hemodynamics. After oral administration, complete gastric evacuation is recommended, if necessary combined with gastric and small bowel lavage.

Administration of activated charcoal should be considered. In cases of intoxication caused by prolonged-release medicinal products, efforts should be made to eliminate 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 potentially beneficial to administer activated charcoal later in cases of overdose with prolonged-release drugs, there is no evidence to confirm this.

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

After ingestion of a clinically significant amount of a slowly eliminated medicinal product, 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. Due to the high degree of plasma protein binding and relatively small volume of distribution of nifedipine, hemodialysis is ineffective; however, plasmapheresis is recommended.

In case of bradycardia, β-sympathomimetics or atropine are recommended. For 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, sympathomimetics such as dopamine, dobutamine, epinephrine, or norepinephrine should be used. Doses of these medicinal products should be titrated according to the therapeutic response achieved. Additional fluid administration should be approached with extreme caution, as it may increase the risk of cardiac overload. Due to the high degree of plasma protein binding and relatively small volume of distribution of nifedipine, hemodialysis is ineffective; however, plasmapheresis is recommended.

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

Adverse reactions.

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

Eye disorders: mild, transient visual disturbances, visual impairment, eye pain, excessive tearing, amblyopia.

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

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

Hepatobiliary disorders: liver function abnormalities, transient increase in liver enzyme activity, jaundice, intrahepatic cholestasis, elevated γ-glutamyltransferase levels.

Renal and urinary disorders: polyuria, dysuria, in patients with renal insufficiency – worsening of kidney function, increased frequency of urination, increased daily urine output, nocturia.

Metabolism and nutritional disorders: hyperglycemia (especially in patients with diabetes mellitus).

Nervous system disorders: headache, migraine, dizziness/vertigo, tremor, para-/dy-/hypesthesia, hyperesthesia, sleep disorders, insomnia, somnolence.

Psychiatric disorders: anxiety, mood changes, nervousness.

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

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

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

Skin and subcutaneous tissue disorders: rash, pruritus, urticaria, facial swelling, 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, photosensitivity, photodermatitis, purpura, exfoliative dermatitis, toxic epidermal necrolysis (Lyell’s syndrome).

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

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

General disorders: general weakness, malaise, increased fatigue, apathy, increased sweating, chills, non-specific pain, fever may occur with prolonged use.

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

Shelf life. 2 years.

Storage conditions.

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

Packaging.

10 tablets in a blister pack; 5 blister packs in a carton.

Prescription category. Prescription only.

Manufacturer: JSC "Pharmaceutical Company "Darnytsia".

Manufacturer's address and place of business.

13, Borispilska Street, Kyiv, 02093, Ukraine.