INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KORINFAR® (CORINFAR®)

Composition:

Active substance: nifedipine;

1 tablet contains nifedipine 10 mg;

Excipients: lactose monohydrate, potato starch, microcrystalline cellulose, povidone, magnesium stearate, hypromellose, macrogol 6000, macrogol 35000, quinoline yellow (E 104), titanium dioxide (E 171), talc.

Pharmaceutical form. Prolonged-release tablets.

Main physicochemical properties: yellow, biconvex, round tablets, film-coated, with bevelled, undamaged edges and uniform appearance.

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

Pharmacological Properties

Pharmacodynamics

Nifedipine is a calcium antagonist that inhibits calcium ion influx into myocardial cells, smooth muscle cells of coronary arteries, and peripheral capillaries. Nifedipine dilates coronary arteries and reduces smooth muscle tone in coronary vessels, thereby increasing oxygen supply. At the same time, it reduces total peripheral vascular resistance (afterload), thus reducing cardiac workload. By decreasing myocardial work, it reduces oxygen demand. Normalization of arterial pressure occurs due to dilation of systemic arteries and arterioles, as well as due to reduced total peripheral vascular resistance.

Especially during the initial phase of treatment, heart rate and cardiac volume may increase due to activation of the baroreceptor reflex. With long-term nifedipine therapy, heart rate and cardiac volume return to pre-treatment levels.

Pharmacokinetics

Absorption

After oral administration, nifedipine is rapidly and almost completely absorbed. The bioavailability of nifedipine is 50\–60%.

The release of nifedipine from prolonged-release tablets is slower, reaching peak plasma concentration 2\–4 hours after administration; its effect lasts for 10\–12 hours.

Distribution

Nifedipine is bound to plasma proteins, primarily albumin, by 94\–99%. The volume of distribution of nifedipine is 1.32 L/kg. Animal studies have demonstrated that released nifedipine distributes to all organs and tissues. Concentrations in cardiac muscle were higher than in skeletal muscle. Neither nifedipine nor its metabolites accumulate in tissues.

The bioavailability of nifedipine is higher in patients with moderate renal impairment due to lower plasma protein binding. Nifedipine passes into breast milk.

Metabolism

Nifedipine is almost completely metabolized in the liver via the cytochrome P450 isoenzyme CYP3A4. The metabolites are pharmacologically inactive. In patients with impaired liver function, metabolism is somewhat slowed.

Excretion

Approximately 80% of metabolites are excreted in urine, the remainder in feces. Only a negligible amount of unchanged nifedipine is excreted in urine. The elimination half-life after oral administration of a prolonged-release tablet is 8\–10 hours; it may be slightly prolonged in patients with renal insufficiency. In patients with impaired liver function, the elimination half-life is significantly prolonged and clearance is markedly reduced.

Clinical characteristics.

Indications.

Essential hypertension.

Angina pectoris (mainly vasospastic and chronic stable angina).

Contraindications.

Hypersensitivity to nifedipine or to any other component of the medicinal product;
cardiogenic shock;
unstable angina;
acute myocardial infarction (within the first 4 weeks);
acute angina attack;

− secondary prevention of myocardial infarction;

− malignant hypertension (safety of the drug use has not been studied);

high-grade aortic stenosis;

− ileostomy or colostomy;

concomitant use of rifampicin (due to the impossibility of achieving effective plasma levels of nifedipine as a result of enzyme induction);

‒ pregnancy period.

Interaction with other medicinal products and other forms of interactions.

Medicinal products affecting the efficacy of nifedipine

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" effect (after oral administration) or clearance of nifedipine. Although no in vivo studies on the interaction of these drugs have been conducted, there is a potential for increased plasma concentration of nifedipine when used concomitantly. Therefore, blood pressure should be monitored — dose reduction of nifedipine may be required.

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

When using nifedipine together with the following medicinal products, the extent and duration of interaction should be taken into account.

Rifampicin

Rifampicin significantly induces the cytochrome P450 3A4 system. When used concomitantly with rifampicin, the bioavailability of nifedipine is markedly reduced, thus weakening its efficacy. Therefore, the combination of nifedipine with rifampicin is contraindicated.

When using the following weak or moderate inhibitors of the cytochrome P450 3A4 system concomitantly, blood pressure should be monitored and, if necessary, the dose of nifedipine should be reduced.

Macrolide antibiotics (e.g., erythromycin)

No studies on the interaction between nifedipine and macrolide antibiotics have been conducted. Certain macrolide antibiotics inhibit cytochrome P450 3A4-mediated metabolism of other drugs. Therefore, an increased plasma concentration of nifedipine cannot be excluded when both drugs are used concomitantly.

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

HIV protease inhibitors (e.g., ritonavir)

No clinical study on the interaction between nifedipine and certain HIV protease inhibitors has been conducted. It is known that drugs in this class inhibit the cytochrome P450 3A4 system. In addition, these drugs inhibit in vitro cytochrome P450 3A4-mediated metabolism of nifedipine. When used concomitantly with nifedipine, a significant increase in plasma concentration of nifedipine due to reduced first-pass metabolism and decreased elimination rate cannot be excluded.

Azole antifungal agents (e.g., ketoconazole)

No formal clinical study on the interaction between nifedipine and certain azole antifungal agents has been conducted. It is known that drugs in this class inhibit the cytochrome P450 3A4 system. When administered orally concomitantly with nifedipine, a significant increase in systemic bioavailability of nifedipine due to reduced first-pass metabolism cannot be excluded.

Fluoxetine

No clinical study on the interaction between nifedipine and fluoxetine has been conducted. It is known that fluoxetine inhibits in vitro cytochrome P450 3A4-mediated metabolism of nifedipine. When both drugs are used concomitantly, an increased plasma concentration of nifedipine cannot be excluded.

Nefazodone

No clinical study on the interaction between nifedipine and nefazodone has been conducted. It is known that nefazodone inhibits in vitro cytochrome P450 3A4-mediated metabolism of other drugs. When both drugs are used concomitantly, an increased plasma concentration of nifedipine cannot be excluded. If nefazodone is used concomitantly with nifedipine, blood pressure should be monitored and, if necessary, the possibility of reducing the nifedipine dose should be considered.

Quinupristin/dalfopristin

Concomitant use of quinupristin/dalfopristin and nifedipine may lead to increased plasma concentration of nifedipine. Therefore, continuous monitoring of blood pressure is required — dose reduction of nifedipine may be necessary.

Valproic acid

No formal clinical study investigating the potential interaction between nifedipine and valproic acid has been conducted. It is known that valproic acid increases plasma concentrations of the structurally similar calcium channel blocker nimodipine due to enzyme inhibition. Therefore, an increase in plasma concentration of nifedipine and enhanced efficacy cannot be excluded.

Cimetidine, ranitidine

Due to inhibition of cytochrome P450 3A4, cimetidine/ranitidine increases plasma concentrations 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 taking cimetidine, and its dose should be increased more gradually.

Additional studies

Cisapride*

Concomitant use of cisapride and nifedipine may lead to increased plasma concentration of nifedipine. Therefore, continuous monitoring of blood pressure is required — dose reduction of nifedipine may be necessary.

Antiepileptic drugs inducing the cytochrome P450 3A4 system, such as phenytoin, carbamazepine, and phenobarbital

Phenytoin induces the cytochrome P450 3A4 system. When used concomitantly with phenytoin, the bioavailability of nifedipine is reduced and its efficacy weakened. When both drugs are used concomitantly, the clinical response to nifedipine therapy should be monitored and, if necessary, the dose of nifedipine should be increased. If the dose of nifedipine was increased during concomitant use, upon discontinuation of phenytoin, the possibility of reducing the nifedipine dose should be considered.

No formal clinical studies on the interaction between nifedipine and carbamazepine or phenobarbital have been conducted. It is known that both drugs reduce plasma concentrations of the structurally similar calcium channel blocker nimodipine due to enzyme induction. Therefore, a decrease in plasma concentration of nifedipine and reduced efficacy cannot be excluded.

Diltiazem* reduces the breakdown and clearance of nifedipine, thereby increasing its plasma concentration. Therefore, nifedipine should be used cautiously concomitantly with diltiazem, and dose reduction of nifedipine may be required.

Effect of nifedipine on other medicinal products

Antihypertensive agents

Nifedipine may enhance the hypotensive effect of concomitantly administered antihypertensive agents, such as:

diuretics;
β-blockers;
ACE inhibitors (angiotensin-converting enzyme);
AT1-receptor antagonists;
other calcium channel blockers;
α-blockers;
PDE-5 inhibitors (phosphodiesterase-5);
α-methyldopa;
magnesium sulfate.

When nifedipine is used concomitantly with antianginal agents, the effect on blood pressure and heart rate is increased.

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

Concomitant use of nifedipine and tricyclic antidepressants may lead to increased plasma concentrations of these drugs and enhanced antihypertensive effect of nifedipine.

In patients treated with nifedipine, fentanyl may cause arterial hypotension. Nifedipine intake should be avoided for at least 36 hours before a planned surgery using fentanyl-based anesthesia.

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

In patients taking coumarin-based anticoagulants, prolonged prothrombin time has been observed after adding nifedipine. The clinical significance of this interaction has not been fully studied.

Nifedipine may alter bronchial reactivity to methacholine. Nifedipine should be discontinued (if possible) before a non-specific bronchoprovocation test using methacholine.

When nifedipine is used concomitantly with β-blockers, careful monitoring of the patient is required, as concomitant use may lead to significant reduction in blood pressure; isolated cases of heart failure have also been reported.

Theophylline

The rationale for using theophylline with nifedipine should be evaluated, as plasma concentration of theophylline may increase when used concomitantly with nifedipine.

Digoxin

Concomitant use of nifedipine with digoxin may lead to reduced digoxin clearance, resulting in increased digoxin plasma concentration. Monitoring of digoxin plasma concentration is recommended, along with observation for signs of digoxin overdose, and dose adjustment as needed based on digoxin plasma levels.

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.

Quinidine

In individual cases, decreased quinidine levels were observed when used concomitantly with nifedipine, and a sharp increase in plasma quinidine concentration occurred upon discontinuation of nifedipine. Therefore, when starting or stopping nifedipine, monitoring of plasma quinidine concentration is recommended, and dose adjustment of quinidine may be necessary. Increased plasma concentration of nifedipine has been reported when both drugs are used concomitantly, although no changes in nifedipine pharmacokinetics were noted.

Therefore, blood pressure should be carefully monitored when quinidine is added to nifedipine therapy. If necessary, the dose of nifedipine should be reduced.

Tacrolimus

It is known that tacrolimus is metabolized via the cytochrome P450 3A4 system. Published data indicate that in individual cases, the dose of tacrolimus may be reduced when used concomitantly with nifedipine. When both drugs are used concomitantly, monitoring of tacrolimus plasma concentration is recommended, and if necessary, the possibility of reducing the tacrolimus dose should be considered.

When used concomitantly with vincristine, reduced elimination of vincristine may occur, potentially leading to adverse effects — dose reduction should be considered. When used concomitantly with cephalosporins (e.g., cefixime), increased bioavailability and plasma levels of cephalosporin occur.

Other forms of interactions

Grapefruit juice

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

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

Nifedipine use 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).

Special precautions for use.

Nifedipine should be used with caution in patients with severe arterial hypotension (systolic blood pressure below 90 mm Hg) or severe heart failure.

Patients with impaired liver function require careful monitoring; in severe cases, dose reduction may be necessary.

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.

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

macrolide antibiotics (e.g., erythromycin);
HIV protease inhibitors (e.g., ritonavir);
azole antifungal agents (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.

Patients receiving nifedipine together with β-adrenoreceptor blockers should be closely monitored, as this combination may lead to a pronounced decrease in blood pressure and, in some cases, to the development of heart failure.

Nifedipine should be used with caution in patients with low cardiac reserve. In addition, in some cases, nifedipine administration has led to exacerbation of heart failure.

Nifedipine may slow the elimination of digoxin. Concomitant use of nifedipine with digoxin may increase digoxin plasma concentrations and lead to adverse reactions associated with cardiac glycosides.

Particular attention should be paid to dosing if symptoms of heart failure occur.

Within 1–4 hours after starting nifedipine, 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.

As with other non-deformable materials, caution is required when administering the tablet formulation in patients with marked narrowing of the gastrointestinal tract due to the risk of obstructive symptoms. Very rarely, bezoar formation may occur, which might require surgical intervention.

In isolated cases, obstructive symptoms have been reported in patients without prior gastrointestinal disorders.

The drug is contraindicated in patients with an ileostomy (intestinal pouch after proctocolectomy).

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

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

Particular caution is required when prescribing the drug to patients with chronic renal failure undergoing hemodialysis, or those with malignant hypertension or hypovolemia, as vasodilation may cause a significant drop in blood pressure. Nifedipine use in patients with diabetes may require adjustment of blood glucose levels.

In patients with lactose intolerance, it should be noted that each prolonged-release tablet contains 15.8 mg of lactose monohydrate. The drug is contraindicated in patients with rare hereditary conditions such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

Grapefruit juice inhibits the metabolism of nifedipine, leading to increased plasma concentrations.

Use during pregnancy or breastfeeding.

Pregnancy. The use of nifedipine is contraindicated during pregnancy.

There are no adequate and well-controlled studies on the safety of nifedipine in pregnant women.

Animal studies have shown embryotoxicity, fetotoxicity, teratogenicity, and adverse effects on reproductive function. Nifedipine should not be used in women who are planning pregnancy in the near future.

From available clinical data, a specific prenatal risk has not been established. However, increased rates of perinatal asphyxia, cesarean sections, prematurity, and intrauterine growth retardation have been reported. It is unclear whether these outcomes are related to hypertension, its treatment, or the specific effect of nifedipine.

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

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

Breastfeeding. Nifedipine is not recommended during breastfeeding. Nifedipine is excreted into breast milk, and its concentration in milk is nearly equivalent to that in maternal plasma. The effect of small amounts of absorbed nifedipine on the infant is unknown; therefore, breastfeeding should be discontinued if nifedipine is required during lactation.

Fertility. In isolated in vitro experiments, reversible biochemical changes in spermatozoa impairing their fertilizing capacity have been associated with calcium channel blockers, including nifedipine. If in vitro fertilization attempts fail without other explanations, calcium channel blockers such as nifedipine may be considered a possible contributing factor.

Ability to affect reaction speed when driving or operating machinery.

Treatment with this medicinal product requires ongoing medical supervision. Due to individual responses to the drug, the ability to drive or operate machinery may be impaired. These precautions are particularly relevant during the initial treatment period, dose escalation, switching to another drug, or alcohol consumption.

Dosage and Administration.

The dosage regimen should be individually determined, 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 gradually increased.

Prolonged-release film-coated tablets of Corinfar 10 mg (i.e., containing a low dose of nifedipine) are primarily prescribed to patients with arterial hypertension and severe cerebrovascular disease, as well as to patients with increased sensitivity to nifedipine, low body weight, or those receiving antihypertensive medications.

The usual initial and maintenance dose of the drug in all cases is 1 tablet twice daily. If necessary, the dose may be increased to 2–4 tablets twice daily. The maximum daily dose of the drug must not exceed 80 mg.

Patients with hepatic insufficiency require close monitoring, and a dose reduction of the drug may be necessary.

The tablets should be taken without chewing, after meals, with sufficient fluid (except grapefruit juice), preferably in the morning and evening at the same time each day.

Food intake together with the tablet leads to delayed, but not reduced, absorption.

The interval between doses should be no less than 4 hours. The recommended interval between doses is 12 hours (morning and evening). The duration of treatment is determined by the physician.

Due to the possibility of rebound syndrome, therapy with this drug should be discontinued gradually, especially in cases of high-dose administration and long-term treatment.

Prolonged-release tablets must not be divided, as the protective coating no longer ensures protection from light exposure in such cases.

Children.

The safety and efficacy of nifedipine in children (under 18 years of age) have not been established; therefore, nifedipine should not be prescribed to children.

Overdose.

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

Treatment. The most important therapeutic measures are elimination of the drug from the body and restoration of cardiovascular stability.

After oral administration, complete gastric evacuation is recommended, if necessary, in combination with lavage of the small intestine. Administration of activated charcoal should be considered. In cases of intoxication caused by sustained-release formulations, 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 reasonable to assume benefit from later administration of activated charcoal in cases of overdose with prolonged-release drugs, it should be noted that there is no evidence to confirm this.

In the treatment of life-threatening overdose in adults, gastric lavage should be considered as an alternative within 1 hour after ingestion of a potentially toxic dose.

After ingestion of a clinically significant amount of a slowly eliminated drug, administration of one dose of an osmotic laxative (e.g., sorbitol, lactulose, or magnesium sulfate) within 4 hours, along with activated charcoal, should be considered.

When using laxatives, it should be kept in mind that calcium antagonists may cause decreased intestinal muscle tone up to intestinal atony. Since nifedipine is highly protein-bound in plasma and has a relatively small volume of distribution, hemodialysis is ineffective; however, plasmapheresis is recommended.

Bradycardia can be treated with β-sympathomimetics. In cases of 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 become slightly elevated. If calcium administration is insufficiently effective, dopamine, dobutamine, epinephrine, or norepinephrine should be used. Doses of these agents should be adjusted according to the therapeutic response achieved. Additional fluid administration should be approached with extreme caution, as it increases the risk of cardiac overload.

Symptomatic bradycardia can be treated with atropine, β-sympathomimetics, or, if necessary, temporary cardiac pacing.

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

Side effects

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

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

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

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

Nervous system disorders: headache, dizziness, migraine, tremor, paresthesia, dysesthesia, hypoesthesia, hyperesthesia, somnolence, insomnia, vertigo.

Psychiatric disorders: anxiety reactions, sleep disorders, mood changes, nervousness.

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

Cardiac and vascular disorders: flushing, palpitations, tachycardia, angina pectoris, edema (including peripheral edema), vasodilation, loss of consciousness, arterial hypotension, symptomatic hypotension, orthostatic hypotension, myocardial infarction, chest pain, erythromelalgia—especially at the beginning of treatment.

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

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

Gastrointestinal disorders: constipation, gastrointestinal dysfunction such as dyspepsia, diarrhea, abdominal pain, flatulence, nausea, vomiting, dry mouth, gingival hyperplasia, gastroesophageal sphincter insufficiency, sensation of stomach fullness, gastric disorders, bloating, belching, loss of appetite, gastrointestinal tract pain, bezoar, dysphagia, intestinal ulcer, intestinal obstruction.

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

Skin and subcutaneous tissue disorders: 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, increased sweating, urticaria, photo dermatitis, palpable purpura, toxic epidermal necrolysis, exfoliative dermatitis, photosensitivity reaction.

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

Renal and urinary disorders: transient decrease in kidney function in cases of renal insufficiency; increased frequency of urination, increased daily urine output, polyuria, dysuria, nocturia.

Reproductive system and breast disorders: gynecomastia (the process is reversible, symptoms resolve after discontinuation of nifedipine), erectile dysfunction.

General disorders: general weakness, increased fatigue, apathy, malaise, fever, nonspecific pain, chills.

Shelf life. 3 years.

Storage conditions. Store at temperatures not exceeding 25 °C in the original packaging to protect from light. Keep out of reach of children.

Packaging.

10 tablets per blister, 3 blisters per carton; 50 or 100 tablets per bottle, 1 bottle per carton.

Prescription status. Prescription only.

Manufacturer. PLIVA Hrvatska d.o.o.

Manufacturer's address and location of business operations.

Prilaz baruna Filipovića 25, 10000 Zagreb, Croatia.