Nicardia® retard

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT NIKARDIA® RETARD (NICARDIA® RETARD)

Composition:

Active substance: nifedipine;

1 tablet contains 20 mg of nifedipine;

Excipients: hypromellose; microcrystalline cellulose; lactose monohydrate; calcium hydrogen phosphate dihydrate; corn starch; magnesium stearate; Tabcoat Orange 2115 [hypromellose; polyethylene glycol; talc; titanium dioxide (E 171), Yellow West FCF (E 110)].

Pharmaceutical form. Film-coated prolonged-release tablets.

Main physicochemical properties: orange, round, biconvex, film-coated tablets with a break line on one side.

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

Pharmacological properties.

Pharmacodynamics.

Nicardia® Retard exhibits vasodilatory, antianginal, and antihypertensive effects. The active ingredient of the medicinal product, nifedipine, is a derivative of 1,4-dihydropyridine and a selective blocker of L-type calcium channels. It inhibits calcium ion influx into cardiomyocytes and smooth muscle cells of coronary and peripheral arteries. At high doses, it also suppresses the release of calcium ions from intracellular stores. Nifedipine dilates peripheral arteries, reduces total peripheral vascular resistance, and lowers arterial pressure and myocardial load, thereby improving myocardial function, decreasing myocardial oxygen demand, and reducing the force of cardiac contractions. It enhances coronary blood flow, improves perfusion of ischemic myocardial areas without causing a "steal" phenomenon. It also increases renal blood flow and induces moderate natriuresis.

Pharmacokinetics.

Nifedipine is highly absorbed—approximately 90%. Bioavailability ranges from 43% to 77%. It undergoes a pronounced first-pass effect in the liver. Bioavailability increases when taken with food. The active substance is gradually released into systemic circulation, with maximum concentration reached within 1.2–4 hours after administration. Plasma protein binding is high, ranging from 92% to 98%. Nifedipine is metabolized in the liver. No active metabolites have been identified.

After oral administration, the therapeutic effect begins within 20 minutes and lasts for 24 hours.

The elimination half-life ranges from 3.8 to 16.9 hours. Nifedipine is excreted primarily by the kidneys as inactive metabolites (70–80% of the dose). Nifedipine does not accumulate in the body. It crosses the blood-brain barrier and is excreted into breast milk in small amounts. Prolonged use of the drug (over 2–3 months) may lead to the development of tolerance.

Clinical Characteristics.

Indications.

• Prophylaxis of stable exertional angina;
• treatment of arterial hypertension.

Contraindications.

• Hypersensitivity to nifedipine or to other dihydropyridines — due to possible risk of cross-reactivity;
• hypersensitivity to other components of the medicinal product;
• secondary prevention of myocardial infarction;
• cardiogenic shock;
• unstable angina during and within 4 weeks following myocardial infarction;
• acute angina attack;
• treatment of malignant hypertension;
• high-grade aortic stenosis;
• use in combination with rifampicin (due to inability to achieve effective plasma levels of nifedipine as a result of enzyme induction).

Interaction with other medicinal products and other types of interactions.

Medicinal products affecting nifedipine.

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 clearance of nifedipine (see section "Special precautions for use").

The extent and duration of interaction should also be considered when used concomitantly with the following drugs:

Hepatic microsomal enzyme inducers (e.g., rifampicin) induce the cytochrome P450 3A4 system and thereby significantly reduce the bioavailability of nifedipine, thus decreasing its efficacy. Therefore, the combination of nifedipine with rifampicin is contraindicated (see section "Contraindications").

When used concomitantly with inhibitors of the cytochrome P450 3A4 system, blood pressure should be monitored and, if necessary, the dose of nifedipine should be reduced. In most cases, there are currently no official studies to evaluate the interaction between nifedipine and these medicinal products.

Medicinal products that enhance the effect of nifedipine:

macrolides (e.g., erythromycin);

anti-HIV protease inhibitors (e.g., ritonavir);

azole antifungal agents (e.g., ketoconazole);

fluoxetine;

nefazodone;

quinupristin/dalfopristin;

cisapride;

valproic acid;

cimetidine;

diltiazem.

When used concomitantly with inducers of the cytochrome P450 3A4 system, the patient's response to nifedipine should be monitored and, if necessary, the dose of nifedipine should be increased. When the concomitant drug is discontinued, the dose of nifedipine should be reduced.

Medicinal products that reduce the effect of nifedipine:

rifampicin;

phenytoin;

carbamazepine;

phenobarbital.

Effect of nifedipine on other medicinal products.

When used concomitantly with antihypertensive agents, nifedipine may enhance the antihypertensive effect.

In isolated cases, worsening of heart failure has been reported when used concomitantly with β-blockers.

During concomitant administration of nifedipine with theophylline or digoxin, serum concentrations of theophylline or digoxin may increase. Monitoring of serum theophylline or digoxin concentrations is recommended, and dosage adjustment may be necessary.

Nifedipine reduces plasma concentrations of quinidine when used concomitantly; upon discontinuation of nifedipine, plasma concentrations of quinidine increase sharply. When initiating nifedipine treatment in patients already taking quinidine, particular attention should be paid to adverse effects of nifedipine. After adding or stopping nifedipine, serum quinidine concentrations should be checked and quinidine dosage adjusted accordingly. Blood pressure should be carefully monitored, and if necessary, the dose of nifedipine should be reduced.

Tacrolimus is metabolized by the cytochrome P450 3A4 system. When nifedipine is used concomitantly with tacrolimus, monitoring of tacrolimus plasma concentrations is recommended, and the dose of tacrolimus should be reduced if necessary.

Interaction with food.

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 metabolism during "first-pass" 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.

Other interactions.

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

Special precautions for use.

Nicardia® Retard is not a β-blocker and therefore does not protect against the risk of abrupt withdrawal of β-blockers. β-blockers should be tapered gradually over 8–10 days. Nicardia® Retard may be used concomitantly with β-blockers and other antihypertensive agents; however, postural hypotension due to additive effects should be considered. Nicardia® Retard does not prevent rebound effects after discontinuation of other antihypertensive drugs.

Caution is required when prescribing Nicardia® Retard to patients with significantly reduced arterial blood pressure (systolic BP below 90 mm Hg), severe heart failure, patients with malignant hypertension and pronounced cardiac insufficiency, marked bradycardia and/or tachycardia, sick sinus syndrome, patients who have had myocardial infarction with left ventricular dysfunction, severe aortic or mitral stenosis, obstructive hypertrophic cardiomyopathy with left ventricular outflow tract obstruction, severe disturbances of cerebral circulation, gastrointestinal obstruction, as well as elderly patients.

Nicardia® Retard should be used with caution in patients with low cardiac reserve due to the potential for worsening heart failure.

Patients with diabetes, hypovolemia, and pulmonary hypertension should be under continuous medical supervision during treatment.

Treatment with nifedipine in patients with diabetes may require adjustment of antidiabetic therapy. The drug should be prescribed with particular caution to patients undergoing hemodialysis, those with malignant hypertension, or hypovolemia, as vasodilation may cause a significant drop in arterial pressure.

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 (see section "Interaction with other medicinal products and other forms of interactions").

Examples of drugs that are weak or moderate inhibitors of the cytochrome P450 3A4 system and may increase plasma concentrations of nifedipine include:

− 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 dose reduction of nifedipine should be considered if necessary.

Isolated cases of myocardial infarction have been reported, although these events cannot be clearly distinguished from the natural course of the underlying disease.

Nicardia® Retard should not be used for the prevention of myocardial infarction.

The medicinal product contains lactose and therefore should not be administered to patients with lactase deficiency, galactosemia, galactose intolerance, or glucose-galactose malabsorption syndrome.

During treatment with nifedipine, direct Coombs test results and tests for antinuclear antibodies may be positive. Nifedipine may also affect certain laboratory parameters and tests (alkaline phosphatase – ALP, lactate dehydrogenase – LDH, alanine aminotransferase – ALT, aspartate aminotransferase – AST), including elevated alkaline phosphatase levels, increased serum urea and creatinine concentrations. These changes are not necessarily associated with clinical signs (although cases of cholestasis and jaundice have been reported). Clinically insignificant decreases in platelet count and prolonged bleeding time may occur in some patients.

Fertility.

Some in vitro experiments have demonstrated 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, particularly nifedipine, may be considered as a possible cause.

Use during pregnancy or breastfeeding.

Pregnancy

The use of nifedipine is contraindicated during pregnancy.

Use of nifedipine during pregnancy requires careful risk-benefit assessment. Treatment with the drug should be considered only if all other treatment strategies are either contraindicated or have proven ineffective. There are no adequate and well-controlled studies on the use of the drug in pregnant women.

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

Based on available clinical data, a specific perinatal risk has not been identified. However, increased incidences of perinatal asphyxia, cesarean section, preterm delivery, and intrauterine growth retardation have been reported. It is unclear whether these are related to arterial hypertension and its treatment or to the drug's effect.

When the drug is used concomitantly with intravenous administration of magnesium sulfate, careful monitoring of blood pressure is required due to the possibility of significant hypotension, which may harm both the mother and the fetus.

Breastfeeding.

Nifedipine passes into breast milk. The concentration of nifedipine in breast milk is comparable to that in blood serum. To minimize exposure to the infant, breastfeeding should be delayed for 3–4 hours after administration of immediate-release nifedipine formulations.

Ability to affect reaction speed when driving or operating machinery.

Treatment with this medicinal product requires continuous medical supervision. Nifedipine may cause hypotension, drowsiness, and dizziness (see section "Adverse reactions"); therefore, patients should avoid driving or operating machinery during treatment with Nicardia® Retard.

Dosage and Administration

The dosage regimen is determined individually, depending on the severity of the disease and the patient's response to therapy.

The usual initial dose of nifedipine is 10 mg every 12 hours. If necessary, the dose may be increased according to the patient's response to treatment up to 40 mg every 12 hours or up to a maximum daily dose of 80 mg.

Concomitant use of the drug with inhibitors or inducers of the cytochrome CYP3A4 system may require dose adjustment of nifedipine or discontinuation of the drug.

Patients should swallow the tablets whole with a small amount of water, regardless of food intake.

Elderly patients (aged 65 years and older)

Due to pharmacokinetic changes associated with Nicardia® Retard in elderly patients, lower doses may be required.

Patients with hepatic impairment

Nifedipine is primarily metabolized in the liver. Patients with impaired liver function require close monitoring, and dose reduction of the drug may be necessary.

Patients with renal impairment

Based on pharmacokinetic data, dose adjustment is not required.

Children. Nicardia® Retard is contraindicated in children.

Overdose.

Symptoms: arterial hypotension, headache, dizziness, nausea, confusion, disturbances of consciousness up to coma, lethargy, facial skin hyperemia, peripheral vasodilation with prolonged and pronounced reduction in arterial pressure, vomiting, somnolence, arrhythmia, inhibition of sinus node function, bradycardia, bradyarrhythmia, tachycardia, collapse, hyperglycemia, metabolic acidosis, cardiac failure, hypoxia, cardiogenic shock with pulmonary edema, seizures. Symptoms typically last several hours. Symptoms may appear only 3–4 hours after ingestion of an excessive dose.

Treatment: emergency measures should be directed toward elimination of the drug from the body and restoration of stable hemodynamics. Gastric lavage in combination with intestinal lavage (to prevent absorption of the active substance) and administration of sorbents is recommended.

Administration of activated charcoal (50 g for adults, 1 g/kg for children) within 1 hour after ingestion of a potentially toxic amount.

There is no evidence that late administration of activated charcoal may be beneficial after ingestion of prolonged-release (modified-release) formulations.

As an alternative, gastric lavage in adults should be considered within 1 hour after ingestion of potentially life-threatening doses.

Administration of activated charcoal every 4 hours and a single dose of an osmotic laxative (e.g., sorbitol, lactulose, or magnesium sulfate).

After administration of high doses of the drug, asymptomatic patients should be observed for at least 4 hours and for 12 hours after administration of a prolonged-release formulation.

Arterial hypotension followed by cardiogenic shock and arterial vasodilation may be treated with calcium (10–20 mL of 10% calcium gluconate solution administered intravenously over 5–10 minutes). If effects are insufficient, treatment may be continued with ECG monitoring. If blood pressure does not adequately respond to calcium, vasoconstrictor sympathomimetics such as dopamine or norepinephrine should be administered. Dosing of these agents should be adjusted according to the patient's response.

Symptomatic bradycardia may be treated with β-sympathomimetics. In case of life-threatening slowing of heart rate, artificial cardiac pacing is recommended.

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

Additional fluid volumes should be administered cautiously to avoid cardiac overload.

Adverse Reactions

Adverse reactions that may occur during the use of nifedipine are classified by frequency: very common (> 1/10), common (> 1/100, < 1/10), uncommon (> 1/1000, < 1/100), rare (> 1/10,000, < 1/1000), very rare (< 1/10,000), and not known (cannot be estimated from available data). Within each frequency group, adverse reactions are listed in order of decreasing severity.

Adverse reactions are listed by organ system.

Blood and lymphatic system disorders:
Rare: anemia, leukopenia, thrombocytopenia, thrombocytopenic purpura, thrombocytopenic microangiopathy;
Not known: asymptomatic agranulocytosis, aplastic anemia.

Immune system disorders:
Uncommon: allergic edema (angioedema, including laryngeal edema and facial swelling);
Rare: pruritus, rash, urticaria, anaphylactoid reaction, autoimmune hepatitis;
Not known: anaphylactic/anaphylactoid reaction.

Psychiatric disorders:
Uncommon: anxiety reactions, anxiety, sleep disorders;
Rare: mood changes, nervousness;
Not known: depression, paranoid syndrome, decreased libido.

Nervous system disorders:
Common: headache;
Uncommon: migraine, dizziness, increased fatigue, asthenia, impaired balance, vertigo, increased excitability;
Rare: paresthesia in limbs, tremor, dysesthesia, extrapyramidal (parkinsonism-like) disorders (ataxia, mask-like face, shuffling gait, joint stiffness in arms and legs, hand and finger tremor, swallowing difficulty), usually observed after prolonged oral administration of the drug at high doses;
Not known: somnolence, hypesthesia, lethargy.

Eye disorders:
Uncommon: visual disturbances, decreased visual acuity;
Not known: eye pain, transient blindness at peak serum nifedipine concentration, transient retinal ischemia, excessive lacrimation.

Ear and labyrinth disorders:
Very rare: tinnitus.

Cardiac and vascular disorders:
Common: peripheral edema, excessive vasodilation (asymptomatic decrease in blood pressure, flushing, arterial hypotension, symptomatic hypotension, orthostatic hypotension, chest pain, cardiac conduction disturbances, facial and trunk skin hyperemia, sensation of warmth, burning sensation);
Uncommon: tachycardia, palpitations, arrhythmia, excessive increase in blood pressure (rare), syncope;
Not known: development or worsening of heart failure (in most cases, exacerbation of pre-existing heart failure), episodes of asymptomatic myocardial ischemia, worsening of existing myocardial ischemia. In some patients, particularly those with severe obstructive coronary artery disease, episodes of angina may occur at the beginning of treatment or with dose escalation, and even myocardial infarction (requires discontinuation of the drug), loss of consciousness (collapse), erythromelalgia.

In patients with malignant hypertension and hypovolemia undergoing hemodialysis, significant hypotension may occur due to vasodilation.

Respiratory system disorders:
Uncommon: epistaxis, nasal congestion;
Not known: dyspnea, cough, bronchial muscle spasm up to life-threatening respiratory distress, which resolves after discontinuation of treatment.

Gastrointestinal disorders:
Common: constipation;
Uncommon: epigastric discomfort, abdominal pain, dry mouth, decreased appetite, loss of appetite, dyspepsia, nausea, flatulence, belching, sensation of stomach fullness, gastrointestinal pain;
Rare: gingival hyperplasia (bleeding, pain, swelling of gums), black stools, heartburn, taste disturbances;
Not known: diarrhea, vomiting, gastroesophageal sphincter insufficiency, bezoar, dysphagia, intestinal ulceration, intestinal obstruction.

Hepatobiliary disorders:
Uncommon: transient increase in transaminase activity, allergic hepatitis;
Not known: jaundice, cholestasis.

Skin and subcutaneous tissue disorders:
Uncommon: erythema, Mitchell’s disease, skin hypersensitivity reactions such as pruritus, exanthema, skin and mucous membrane swelling, increased sweating, excessive sweating, chills, photosensitivity dermatitis, Stevens-Johnson syndrome, alopecia;
Not known: toxic epidermal necrolysis, purpura, photosensitivity reactions, exfoliative dermatitis, polymorphic erythema.

Musculoskeletal and connective tissue disorders:
Uncommon: muscle cramps, joint swelling;
Not known: arthralgia, myalgia, back pain, gout, arthritis with presence of positive antinuclear antibodies.

Renal and urinary disorders:
Uncommon: transient decrease in kidney function in case of renal insufficiency, increased daily urine volume (polyuria), dysuria, nocturia, hematuria, worsening of kidney function (in patients with renal insufficiency);
Not known: increased frequency of urination.

Reproductive system and breast disorders:
Uncommon: erectile dysfunction, impotence;
Not known: reversible gynecomastia (symptoms resolve after discontinuation of nifedipine).

Metabolism and nutrition disorders:
Not known: hyperglycemia (especially in patients with diabetes mellitus), weight gain.

Other:
Uncommon: chills, warmth sensation, nasal congestion, epistaxis, malaise, non-specific pain, increased temperature;
Rare: visual disturbances (including transient loss of vision), gynecomastia (observed in elderly patients, but completely resolves after discontinuation of the drug), galactorrhea, hyperglycemia, pulmonary edema, dyspnea, cough, wheezing, vertigo, migraine, dyspnea, weight gain, erectile dysfunction, feeling unwell, non-specific pain.

Shelf life. 3 years.

Storage conditions. Store in original packaging at a temperature not exceeding 30 °C. Keep out of reach of children.

Packaging. 10 tablets per blister, 3 or 10 blisters per carton.

Prescription status. Prescription only.

Manufacturer. Unique Pharmaceuticals Laboratories (a division of J. B. Chemicals and Pharmaceuticals Ltd.).

Manufacturer's address and place of business.
Plot No. 215–219, G.I.D.C. Industrial Area, Panoli – 394116, Bharuch District, India.