Instructions for use Corinfar retard prolonged-release tablets 20 mg blister No. 30
Composition
active ingredient: nifedipine;
1 tablet contains nifedipine 20 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.
Dosage form
Extended-release tablets.
Main physicochemical properties: yellow, biconvex, round tablets, film-coated, with beveled, undamaged edges and uniform appearance.
Pharmacotherapeutic group
Selective calcium antagonists with a predominant effect on blood vessels. Dihydropyridine derivatives. Nifedipine. ATX code C08C A05.
Pharmacodynamics
Nifedipine is a 1,4-dihydropyridine calcium antagonist. Calcium antagonists reduce the influx of calcium ions through slow calcium channels into cells. Nifedipine acts mainly on the smooth muscles of the coronary arteries and peripheral arteries under pressure. This effect causes vasodilation and normalization of blood pressure. In therapeutic doses, nifedipine has practically no direct effect on the myocardium.
Nifedipine helps dilate coronary arteries and reduce peripheral vascular resistance, which improves blood circulation.
At the beginning of therapy with calcium antagonists, a reflex increase in heart rate and cardiac output is possible. However, this increase is not sufficient to compensate for the vasodilation.
In the case of long-term therapy with nifedipine, heart rate and cardiac output return to pre-therapeutic values.
A significant decrease in blood pressure with the use of nifedipine is observed in patients suffering from arterial hypertension.
Pharmacokinetics
Nifedipine is rapidly and almost completely absorbed when administered orally on an empty stomach. Nifedipine undergoes a first-pass effect through the liver, so the systemic bioavailability of the drug when administered orally is 50-70%. The maximum concentration of nifedipine in the blood plasma is reached after approximately 15 minutes after administration of a solution of nifedipine and after 30-85 minutes after administration of the drug in the form of prolonged-release tablets. 95-98% of nifedipine is bound to plasma proteins (albumin). The average volume of distribution of nifedipine (Vss) is 0.77-1.12 l/kg. Nifedipine is almost completely metabolized in the liver (first-pass effect), mainly due to the oxidative process. The metabolites formed as a result of this process do not have pharmacodynamic activity. Neither the unchanged substance nor the metabolites M-1 are excreted by the kidneys (< 0.1% of the administered dose). Approximately 50% of the administered dose is excreted in the urine as the polar metabolites M-2 and M-3 (partly in bound form), almost completely excreted within 24 hours. The remainder is excreted in the feces.
The half-life is 1.7 to 3.4 hours.
Accumulation of the drug in the body during long-term treatment with therapeutic doses has not been described. With reduced liver function, a clear prolongation of the half-life of the active substance and a decrease in total plasma clearance are observed. If necessary, in such cases, the dose of the drug is reduced.
Indication
Chronic stable angina; vasospastic angina (Prinzmetal's angina, variant angina); essential hypertension.
Contraindication
Hypersensitivity to nifedipine or any other component of the drug; cardiogenic shock; unstable angina; acute myocardial infarction (within the first 4 weeks); treatment of acute angina; secondary prevention of myocardial infarction; safety of the drug has not been studied for the treatment of malignant hypertension; high-grade aortic stenosis; ileostomy or colostomy; concomitant use of rifampicin (due to the inability to achieve effective levels of nifedipine in the blood plasma due to enzyme induction); pregnancy.
Interaction with other medicinal products and other types of interactions
Drugs that affect the effectiveness of nifedipine
Nifedipine is metabolized by the cytochrome P450 3A4 system, which is located in the intestinal mucosa and liver. Therefore, drugs that inhibit or induce this enzyme system may alter the "first pass" (after oral administration) or clearance of nifedipine.
When using nifedipine together with the following drugs, the degree and duration of interaction should be taken into account.
Rifampicin
Rifampicin significantly induces the cytochrome P450 3A4 system. When used simultaneously with rifampicin, the bioavailability of nifedipine is significantly reduced and, thus, its efficacy is reduced. In view of this, the use of the combination of nifedipine with rifampicin is contraindicated.
When concomitantly using the following weak or moderate inhibitors of the cytochrome P450 3A4 system, blood pressure should be monitored and, if necessary, a reduction in the nifedipine dose should be considered.
No interaction studies have been conducted between nifedipine and macrolide antibiotics. Certain macrolide antibiotics inhibit the cytochrome P450 3A4-mediated metabolism of other drugs. Therefore, an increase in nifedipine plasma concentrations cannot be excluded when both drugs are administered simultaneously.
Azithromycin, which is structurally similar to members of the macrolide class of antibiotics, does not inhibit CYP3A4.
Anti-HIV protease inhibitors (e.g. ritonavir)
No clinical studies have been conducted to investigate the potential for interaction between nifedipine and anti-HIV protease inhibitors. Drugs of this class are known to inhibit the cytochrome P450 3A4 system. In addition, drugs of this class inhibit the cytochrome P450 3A4-mediated metabolism of nifedipine in vitro. When used simultaneously with nifedipine, a significant increase in nifedipine plasma concentrations cannot be excluded due to a decrease in first-pass metabolism and a decrease in the rate of elimination from the body.
Azole antifungals (e.g. ketoconazole)
No formal clinical study has been conducted to investigate the potential for interaction between nifedipine and azole antifungals. Drugs of this class are known to inhibit the cytochrome P450 3A4 system. When administered orally with nifedipine, a significant increase in the systemic bioavailability of nifedipine due to a decrease in first-pass metabolism cannot be excluded.
Fluoxetine
No clinical study has been conducted to investigate the potential for interaction between nifedipine and fluoxetine. Fluoxetine is known to inhibit the cytochrome P450 3A4-mediated metabolism of nifedipine in vitro. With simultaneous use of both drugs, an increase in nifedipine plasma concentrations cannot be excluded.
Nefazodone
No clinical studies have been conducted to investigate the potential for interaction between nifedipine and nefazodone. Nefazodone is known to inhibit the cytochrome P450 3A4-mediated metabolism of other drugs in vitro. When both drugs are used simultaneously, an increase in nifedipine plasma concentrations cannot be excluded.
Quinupristin/dalfopristin
Due to inhibition of cytochrome P450 3A4, the use of these drugs simultaneously with nifedipine may lead to an increase in the concentration of nifedipine in the blood plasma and an increase in the antihypertensive effect.
Valproic acid
No formal clinical study has been conducted to investigate the potential for interaction between nifedipine and valproic acid. Valproic acid is known to increase plasma concentrations of the structurally related calcium channel blocker nimodipine due to enzyme inhibition. Therefore, an increase in nifedipine plasma concentrations and increased efficacy cannot be excluded.
Cimetidine, ranitidine
Due to inhibition of cytochrome P450 3A4, cimetidine/ranitidine increases the plasma concentration of nifedipine and may enhance the antihypertensive effect. Cimetidine acts as an inhibitor of the cytochrome isoenzyme CYP3A4. Nifedipine should be administered with caution to patients already taking cimetidine, and its dosage should be increased more gradually.
Tricyclic antidepressants, vasodilators
In the case of combining nifedipine with tricyclic antidepressants and vasodilators, the hypotensive effect may be enhanced.
Additional research
Cisapride
Concomitant use of cisapride and nifedipine may lead to an increase in the concentration of nifedipine in the blood plasma.
Antiepileptic drugs that induce the cytochrome P450 3A4 system, such as phenytoin, carbamazepine, and phenobarbital
Phenytoin induces the cytochrome P450 3A4 system. When used simultaneously with phenytoin, the bioavailability of nifedipine is reduced and the efficacy is reduced. When using both drugs simultaneously, it is necessary to monitor the clinical response to nifedipine therapy and, if necessary, consider increasing the nifedipine dose. In the event of an increase in the nifedipine dose during the simultaneous use of both drugs, when phenytoin is discontinued, a reduction in the nifedipine dose should be considered.
No formal clinical studies have been conducted on the potential interaction of nifedipine with carbamazepine or phenobarbital. Both drugs are known to reduce plasma concentrations of the structurally similar calcium channel blocker nimodipine due to enzyme induction. Therefore, a decrease in nifedipine plasma concentrations and reduced efficacy cannot be excluded.
Diltiazem reduces the biotransformation of nifedipine, which may require a dose reduction.
Effect of nifedipine on other drugs
Antihypertensive drugs
Nifedipine may increase the hypotensive effect of concomitantly used antihypertensive drugs, such as:
diuretics; β-adrenergic blockers; ACE (angiotensin-converting enzyme) inhibitors; AT1 receptor antagonists; other calcium channel blockers; α-adrenergic blockers; PDE-5 (phosphodiesterase-5) inhibitors; α-methyldopa; magnesium sulfate.
Fentanyl may cause hypotension in patients treated with nifedipine. Nifedipine should be withheld for at least 36 hours prior to elective surgery with fentanyl-based anesthesia.
Nifedipine may lead to magnesium sulfate toxicity, which causes neuromuscular blockade. The simultaneous use of nifedipine and magnesium sulfate is not recommended, as it is dangerous and can threaten the patient's life.
In patients taking coumarin-based anticoagulants, prolongation of prothrombin time has been observed after the addition of nifedipine. The significance of this interaction has not been fully investigated.
Nifedipine may alter bronchial responsiveness to methacholine. Nifedipine should be discontinued (if possible) before nonspecific methacholine challenge testing.
When nifedipine is used concomitantly with β-adrenergic blockers, careful monitoring of the patient's condition is required, as isolated cases of heart failure have been reported.
Digoxin, theophylline
When nifedipine is taken simultaneously with theophylline or digoxin, the concentration of theophylline or digoxin in the blood plasma may increase. It is recommended to monitor the concentration of theophylline or digoxin in the blood plasma, observe patients for symptoms of digoxin overdose and, if necessary, adjust the dose according to the concentration of digoxin in the blood plasma.
Quinidine
When nifedipine and quinidine are used simultaneously, in some cases a decrease in quinidine levels has been observed, and when nifedipine is discontinued, a sharp increase in quinidine plasma concentrations has been observed. Therefore, when nifedipine is used simultaneously or discontinued, it is recommended to monitor quinidine plasma concentrations and, if necessary, adjust the quinidine dose. Sometimes an increase in nifedipine plasma concentrations has been reported when both drugs are used simultaneously, but there have been cases when no changes in nifedipine pharmacokinetics have been observed.
Therefore, blood pressure should be carefully monitored when quinidine is included in the nifedipine regimen. If necessary, the nifedipine dose should be reduced.
Tacrolimus
Tacrolimus is known to be metabolised via the cytochrome P450 3A4 system. Published data suggest that in some cases the dose of tacrolimus may need to be reduced when co-administered with nifedipine. Plasma tacrolimus concentrations should be monitored when both drugs are co-administered and a reduction in the tacrolimus dose should be considered if necessary.
With simultaneous use of vincristine, a decrease in the excretion of vincristine is observed, therefore, the severity of adverse reactions may increase, which requires a dose reduction; cephalosporins (e.g. cefixime) - an increase in cephalosporin levels in blood plasma.
Other types of interactions
Grapefruit juice
Grapefruit juice inhibits the cytochrome P450 3A4 system. The use of grapefruit juice while taking nifedipine leads to an increase in the concentration of the drug in the blood plasma and an increase in the duration of action of nifedipine due to a decrease in metabolism during the "first pass" or a decrease in clearance. As a result, the antihypertensive effect of the drug may be enhanced. After regular consumption of grapefruit juice, this effect may persist for at least 3 days after the last consumption of the juice.
Therefore, grapefruit/grapefruit juice should be avoided during nifedipine therapy.
The use of nifedipine may lead to falsely elevated results in spectrophotometric determination of the concentration of vanillylmandelic acid in urine (however, this effect is not observed when using the high-performance liquid chromatography method).
Application features
The drug should be used with caution in cases of severe arterial hypotension (systolic blood pressure below 90 mm Hg) and severe heart failure.
Patients with impaired liver function require close monitoring, and in some cases a 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" or clearance of nifedipine.
Drugs that are weak or moderate inhibitors of the cytochrome P450 3A4 system and may lead to an increase in nifedipine plasma concentrations include, for example:
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, if necessary, a dose reduction of nifedipine should be considered.
It is necessary to carefully monitor the condition of the patient who simultaneously takes nifedipine with β-adrenergic blockers, as this can lead to a sharp decrease in blood pressure, and in some cases the development of heart failure has been observed.
Nifedipine may slow the excretion of digoxin. Concomitant administration of nifedipine with digoxin may lead to an increase in digoxin concentrations and may lead to adverse reactions when the concentration of cardiac glycosides is increased.
Some patients have complained of mild ischemic pain within 1–4 hours of starting nifedipine. Although there is no evidence of a steal syndrome, nifedipine should be discontinued in patients who experience such symptoms.
As with other non-deformable materials, caution should be exercised when administering the medicinal product to patients with severe narrowing of the gastrointestinal tract due to the possibility of obstructive symptoms. Very rarely, bezoars may occur, which may require surgical intervention.
In isolated cases, obstructive symptoms have been described in the absence of a history of gastrointestinal disorders.
The drug should not be used in patients with an ileostomy (after proctocolectomy).
The use of the medicinal product may lead to false-positive results in X-ray examinations using barium contrast media (e.g. filling defects interpreted as polyps).
The drug should not be used if there is a possible connection between previous use of nifedipine and ischemic pain. In patients with angina pectoris, attacks may occur more frequently, and their duration and intensity may increase, especially at the beginning of treatment.
Nifedipine should not be used in patients with an acute attack of stable angina.
The use of nifedipine in patients with diabetes may require treatment adjustment.
The drug should be administered with particular caution to patients with chronic renal failure, on hemodialysis, in conditions of malignant arterial hypertension or hypovolemia, since dilation of blood vessels may cause a significant decrease in blood pressure in them.
If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine. This medicine contains 31.6 mg of lactose monohydrate per prolonged-release tablet. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Grapefruit juice inhibits the metabolism of nifedipine, which leads to an increase in its concentration in blood plasma.
Ability to influence reaction speed when driving vehicles or other mechanisms
Therapy with this drug requires constant medical supervision. Due to the individual reaction of the body to the drug, the ability to drive or operate other mechanisms may be impaired. These precautions mainly concern the initial period of therapy, the period of increasing the dose of the drug, switching to another drug and cases of alcohol consumption.
Use during pregnancy or breastfeeding
Pregnancy. The use of nifedipine is contraindicated during pregnancy, except in cases where nifedipine therapy is absolutely necessary due to the clinical condition of the mother: only in the case of severe arterial hypertension, when all other treatment tactics are either not indicated or have been ineffective. The results of adequate and well-controlled studies of the use of the drug in pregnant women are missing. The available data are insufficient to exclude the possibility of adverse effects on the fetus and newborn.
Animal studies have shown embryotoxicity, fetotoxicity, and teratogenicity of the drug.
No specific prenatal risk has been identified from the available clinical data. Although an increase in perinatal asphyxia, cesarean section, and prematurity and intrauterine growth retardation have been reported. It is unclear whether these reports are related to hypertension, its treatment, or a specific effect of nifedipine.
Acute pulmonary edema has been reported (especially in multiple pregnancies) with intravenous calcium channel blockers, including nifedipine, to reduce labor activity and/or with concomitant use of β2-adrenergic agonists.
When using the drug simultaneously with intravenous administration of magnesium sulfate, careful monitoring of blood pressure is necessary due to the possibility of a significant decrease in blood pressure, which may harm the mother and fetus.
Fertility. In some in vitro experiments, a link has been found between the use of calcium antagonists, in particular nifedipine, and reversible biochemical changes in spermatozoa, which impair their ability to fertilize. In cases where in vitro fertilization attempts are unsuccessful, in the absence of other explanations, calcium antagonists, in particular nifedipine, may be considered as a possible cause of this phenomenon.
Method of administration and doses
The dosage regimen should be determined individually, taking into account the severity of the disease and the patient's response to the treatment used.
The recommended dose for all indications is 1 tablet 2 times a day. If necessary, the dose can be increased to 40 mg of nifedipine (i.e. 2 tablets) 2 times a day.
Depending on the individual clinical picture, the recommended dose should be increased gradually.
Patients with hepatic insufficiency require constant monitoring and may require a dose reduction.
Patients with severe cerebrovascular disease should receive low doses.
"Corinfar® retard" tablets should be swallowed without chewing, after a meal, with sufficient liquid (except grapefruit juice), preferably in the morning and evening at the same time. Taking food with the tablet slows down, but does not reduce absorption.
The duration of treatment is determined by the doctor.
Due to the possibility of rebound syndrome, therapy with the drug "Corinfar® retard" should be discontinued gradually, especially when taking the drug in high doses and with long-term treatment.
Prolonged-release tablets should not be divided, as in this case the protection against light provided by the protective coating is no longer provided.
Children
The safety and efficacy of nifedipine in children (under 18 years of age) have not been established. The drug is not for use in children.
Overdose
Symptoms of acute intoxication: impaired consciousness, up to the development of coma, hypotension, tachycardia/bradycardia, arrhythmia, hyperglycemia, metabolic acidosis, hypoxia, cardiogenic shock accompanied by pulmonary edema.
Treatment. The most important therapeutic measures are to remove the drug from the body and restore stable functioning of the cardiovascular system.
After oral administration, complete gastric emptying is recommended, if necessary in combination with small bowel lavage. Activated charcoal should be administered if necessary. In case of intoxication caused by prolonged-release preparations, efforts should be made to eliminate the drug as completely as possible from the body, including from the small intestine, to prevent absorption of the active substance. Although there is speculation about the benefit of later administration of activated charcoal in case of overdose with prolonged-release preparations, it should be noted that there is no evidence to support this.
In the treatment of life-threatening overdose in adults, gastric lavage should be considered within 1 hour of ingestion of a potentially toxic dose.
If a clinically significant amount of a slow-release drug is ingested, consideration should be given to administering 1 dose of an osmotic laxative (e.g. sorbitol, lactulose and magnesium sulfate) within four hours, with concomitant administration of activated charcoal.
When using laxatives, it should be borne in mind that calcium antagonists lead to a decrease in the tone of the intestinal muscles, up to intestinal atony. Since nifedipine is characterized by a high degree of binding to blood plasma proteins and a relatively small volume of distribution, hemodialysis is ineffective, but plasmapheresis is recommended.
Bradycardia can be treated with β-sympathomimetics. In life-threatening bradycardia, the use of an artificial pacemaker is recommended.
Arterial hypotension resulting from cardiogenic shock and vasodilation can be treated with calcium preparations (10-20 ml of 10% calcium chloride or gluconate solution administered intravenously slowly, then repeated if necessary under ECG monitoring). As a result, serum calcium levels may reach the upper limit of normal or be slightly elevated. If calcium administration is not effective enough, it is advisable to use dopamine, dobutamine, epinephrine or norepinephrine. The doses of these drugs should be determined taking into account the achieved therapeutic effect. Additional fluid administration should be approached with great caution, since this increases the risk of cardiac overload.
Patients without pronounced symptoms of intoxication should be observed for at least 4 hours after the use of an excessive dose of a short-acting drug and for at least 12 hours after the use of a prolonged-acting drug.
Adverse reactions
From the side of the hematopoietic and lymphatic systems: changes in blood count, anemia, leukopenia, thrombocytopenia and thrombotic microangiopathy, agranulocytosis, thrombocytopenic purpura.
Immune system disorders: allergic reactions, allergic edema (including laryngeal edema*), pruritus, urticaria, rash, anaphylactic/anaphylactoid reaction, angioedema, facial edema.
Nervous system: headache, dizziness, migraine, tremor, paresthesia, dysesthesia, hypoesthesia, hyperesthesia, drowsiness, vertigo.
On the part of the psyche: anxiety reactions, sleep disorders, mood changes, nervousness.
On the part of the organs of vision: slight temporary change in visual perception, visual impairment, eye pain, excessive lacrimation, amblyopia.
Cardiovascular system: hot flashes, palpitations, tachycardia, angina pectoris, edema (including peripheral edema), vasodilation, loss of consciousness, hypotension, collapse, symptomatic hypotension, orthostatic hypotension, myocardial infarction, chest pain, erythromelalgia, especially at the beginning of treatment. In patients with malignant hypertension and hypovolemia who are on hemodialysis, a significant decrease in blood pressure due to vasodilation may occur.
On the part of the respiratory system: nosebleeds, nasal congestion, dyspnea, pulmonary edema (when used by pregnant women as a tocolytic agent), cough, spasticity of the bronchial muscles, up to life-threatening shortness of breath, which disappears after discontinuation of treatment.
On the part of the digestive tract: constipation, digestive tract dysfunction such as dyspepsia, bloating, diarrhea, abdominal pain, flatulence, nausea, vomiting, dry mouth, gingival hyperplasia, gastroesophageal sphincter insufficiency, feeling of fullness of the stomach, belching, lack of appetite, gastrointestinal pain, bezoar, dysphagia, intestinal ulcer, intestinal obstruction.
From the hepatobiliary system: transient increase in transaminase activity, jaundice, liver dysfunction (intrahepatic cholestasis, increased level of
γ-glutamyl transpeptidases).
Skin and subcutaneous tissue disorders: erythema, Mitchell's disease, hypersensitivity skin reactions such as pruritus, exanthema, swelling of the skin and mucous membranes, edema or peripheral edema not caused by heart failure or weight gain, increased sweating, urticaria, photodermatitis, palpable purpura, toxic epidermal necrolysis, exfoliative dermatitis, photosensitivity reaction.
Musculoskeletal system: myalgia, arthralgia, muscle cramps, joint swelling.
On the part of the kidneys and urinary tract: temporary decrease in kidney function in case of renal failure; increased frequency of urination, increased daily urine output, polyuria, dysuria, nocturia.
From the reproductive system and mammary glands: reversible gynecomastia (symptoms disappear after discontinuation of nifedipine), erectile dysfunction.
General disorders: fatigue, apathy, asthenia, malaise, fever, nonspecific pain, chills.
*Can be life-threatening.
Expiration date
3 years.
Storage conditions
Store at a temperature not exceeding 30 °C in the original packaging in order to protect from light. Keep out of the reach of children.
Packaging
10 tablets in a blister, 3 blisters in a cardboard box.
Vacation category
According to the recipe.
Producer
PLIVA Hrvatska d.o.o.
Location of the manufacturer and its business address
Prilaz baruna Filipovića 25, 10000 Zagreb, Croatia.
