Corinfar, 10 mg 50 pcs

Pharmacotherapeutic group: slow calcium channel blocker (BMCC).

Code ATX: C08CA05

Pharmacological properties

Pharmacodynamics.

Nifedipine is a selective slow calcium channel blocker (CMCB), a 1,4-dihydropyridine derivative. It dilates coronary and peripheral arteries, reduces myocardial oxygen demand by reducing the post-load on the heart and oxygen delivery. Increases coronary blood flow, improves blood supply to ischemic zones without development of the “bypass” phenomenon, activates collaterals. By dilating peripheral arteries, it reduces total peripheral vascular resistance (TPR), myocardial tone, afterload, myocardial oxygen demand and increases duration of left ventricular (LV) diastolic relaxation. It has almost no effect on the sinoatrial and atrioventricular nodes. Does not have antiarrhythmic and proarrhythmogenic effects. Does not affect the tone of the veins. Nifedipine increases renal blood flow, causing moderate natriuresis.

It has negative chrono-, dromo- and inotropic effects accompanied by reflex activation of the sympathoadrenal system and increased heart rate (HR) in response to peripheral vasodilation. Predominantly at the beginning of therapy, heart rate and cardiac output may decrease as a result of baroreceptor reflex activation. With prolonged therapy with nifedipine, heart rate and cardiac output return to the values they had before the start of therapy.

Nifedipine has antihypertensive and antianginal effects.

In arterial hypertension, the drug reduces blood pressure (BP) due to peripheral vasodilation and reduction of PPS. Nifedipine once daily provides 24-hour control of elevated BP. In patients with normal BP, nifedipine has little or no effect on BP.

In angina, nifedipine reduces peripheral and coronary vascular resistance, which leads to increased coronary blood flow, cardiac output and stroke volume, and decreased afterload. In addition, nifedipine dilates both intact and atherosclerotically altered coronary arteries, prevents coronary artery spasm, and improves perfusion of ischemic myocardium. Nifedipine reduces the frequency of angina attacks and ischemic ECG changes, whether caused by coronary artery spasm or atherosclerosis.

Pharmacokinetics

Absorption is high (over 90%). Bioavailability is 50-70%. Simultaneous intake of food does not affect absorption. It has the effect of “first passage” through the liver.

Distribution. Maximum concentration of nifedipine (C_max) in plasma after a single oral administration of 2 tablets (corresponding to 20 mg nifedipine) is reached after 1-3 hours and its value averages 28.3 ng/ml.

It penetrates through the blood-brain and placental barriers, is excreted with breast milk. Binding with blood plasma proteins (albumin) is 95%.

In patients with impaired hepatic or renal function a significant decrease of nifedipine binding to plasma proteins is possible.

Metabolism. It is completely metabolized in the liver.

The metabolism of nifedipine is mainly carried out by the CYP3A4 isoenzyme, but also by the CYP1A2 and CYP2A6 isoenzymes.

Elimation. It is excreted by the kidneys as an inactive metabolite (60-80% of the dose taken). 20% with bile. The elimination half-life (T_1/2) is 2-5 hours.

There is no cumulative effect. Chronic renal failure, hemodialysis and peritoneal dialysis do not affect pharmacokinetics.

In patients with hepatic impairment, total clearance is decreased and T_{1/2 is increased.}

Special patient groups

Patients of advanced age

. When using nifedipine preparations in the form of prolonged/modified-release tablets, elderly patients (age > 60 years) showed increased C_max and T_1/2 compared to younger patients.

Patients with impaired liver function

Pharmacokinetic studies have shown that patients with cirrhosis have significant increases in T_1/2 and decreased total clearance of nifedipine. In patients with mild (Child-Pugh class A) and moderate (Child-Pugh class B) hepatic impairment, nifedipine clearance after oral administration was reduced by 48% and 72%, respectively, compared to patients with normal hepatic function, according to a clinical study. There was an increase in the area under the concentration-time curve (AUC) and C_mah by 93% and 64% in patients with mild hepatic impairment (Child-Pugh class A) and by 253% and 171% in patients with moderate hepatic impairment (Child-Pugh class B), respectively, compared to patients with normal hepatic function. The pharmacokinetics of nifedipine have not been studied in patients with severe hepatic impairment (Child-Pugh class C).

Patients with impaired renal function

The elimination of nifedipine may be delayed in patients with impaired renal function. Chronic renal failure, hemodialysis and peritoneal dialysis have no significant effect on the pharmacokinetics of nifedipine. There is no cumulative effect.

Children and adolescents

Pharmacokinetic studies have not been performed.

Indications

Active ingredient

Composition

How to take, the dosage

Overly after a meal, without chewing and with plenty of liquid.

The dose of the drug is adjusted by the physician individually according to the severity of the disease and the patient’s sensitivity to the drug. For patients with concomitant severe cerebrovascular disease and in elderly patients, the dose should be reduced.

Concomitant ingestion delays, but does not decrease, absorption of the active ingredient from the gastrointestinal tract.

The recommended dosage regimen for adults:

Arterial hypertension

The average daily dose is 10 mg (1 tablet) 2 to 3 times daily.

If there is insufficient clinical effect, the dose can be increased gradually to 20 mg (2 tablets) 2 times a day.

The maximum daily dose is 40 mg (4 tablets daily).

The minimum interval between doses must be at least 4 hours if 2-times prescribed.

The duration of treatment is determined by the treating physician.

Stable angina pectoris and vasospastic angina pectoris (Prinzmetal’s angina, variant angina pectoris)

The initial dose is 10 mg (1 tablet) 2 to 3 times a day. If the clinical effect is not sufficiently pronounced, the dose is gradually increased to 2 tablets (20 mg) 1 to 2 times a day. The maximum daily dose is 40 mg (4 tablets daily).

Some patients may require higher doses of nifedipine.

Increasing the daily dose of nifedipine above 120 mg is not recommended.

If a daily dose of nifedipine greater than 40 mg is required for the treatment of arterial hypertension or angina pectoris, the use of nifedipine preparations in the form of sustained release tablets in doses of 40 mg or 60 mg is recommended.

Particular patient groups

Patients in the elderly

. The pharmacokinetics of nifedipine are altered in elderly patients (over 65 years of age); therefore, the maintenance dose of the drug may be reduced compared to younger patients.

Patients with hepatic impairment

In patients with mild hepatic impairment, the dose of nifedipine should be reduced. The drug is contraindicated in patients with moderate to severe hepatic impairment (Child-Pugh grades B and C).

Patients with impaired renal function

In patients with impaired renal function, no dose adjustment of nifedipine is required

Patients with impaired renal function do not require dose adjustment.

Interaction

Pharmacokinetic interactions

Drugs affecting nifedipine metabolism

Nifedipine is metabolized by CYP3A4/5 isoenzymes, which are located in the intestinal mucosa and liver. Drugs that inhibit or induce this enzyme system may affect the “primary passage” effect through the liver (after ingestion) or the clearance of nifedipine.

Isoenzyme inducers CYP3A4 .

Rifampicin

Rifampicin is a potent inducer of the CYP3A4 isoenzyme. Concomitant use with rifampicin significantly reduces the bioavailability of nifedipine and, accordingly, its efficacy decreases. Therefore, concomitant use of nifedipine with rifampicin is contraindicated.

Antiepileptic drugs inducing CYP3A4 isoenzyme (e.g. phenytoin, carbamazepine, phenobarbital)

Phenytoin induces CYP3A4 isoenzyme. Concomitant use of nifedipine and phenytoin decreases the bioavailability of nifedipine and reduces its effectiveness. When concomitant use of this combination it is necessary to monitor the clinical response to nifedipine therapy and increase its dose, if necessary. If the dose of nifedipine is increased with concomitant use of both drugs, the dose of nifedipine should be reduced after phenytoin withdrawal.

Clinical studies on the potential interaction of nifedipine and carbamazepine or phenobarbital have not been conducted. Since both drugs reduce plasma concentrations of nimodipine, a structurally similar BMCC, the possibility of decreased plasma concentrations of nifedipine and reduced efficacy cannot be excluded.

Inhibitors of isoenzyme CYP3A4

Macrolide group antibiotics (e.g., erythromycin)

The clinical studies on the interaction of nifedipine and antibiotics of the macrolide group have not been conducted. Some macrolides are known to inhibit CYP3A4 isoenzyme. Due to this fact, it is not possible to exclude the possibility of increasing the concentration of nifedipine in blood plasma in concomitant use of nifedipine and antibiotics of macrolide group.

Asithromycin, which belongs to the group of macrolide antibiotics, does not inhibit CYP3A4 isoenzyme.

HIV protease inhibitors (e.g., ritonavir)

There have been no clinical studies on the interaction of nifedipine and HIV protease inhibitors. Drugs in this class are known to inhibit the CYP3A4 isoenzyme. In addition, drugs in this class have been shown to inhibit the metabolism of nifedipine mediated by the CYP3A4 isoenzyme under in vitro conditions. When concomitant use with nifedipine, a significant increase in plasma concentrations of nifedipine due to a decrease in the effect of “primary passage” through the liver and delayed excretion cannot be excluded.

Azoic antifungal drugs (e.g., ketoconazole)

The clinical studies on interaction of nifedipine and azole antifungal drugs have not been conducted. It is known that the drugs of this class inhibit CYP3A4 isoenzyme. When concomitant use with nifedipine a significant increase in systemic bioavailability of nifedipine is possible due to a decrease in the effect of “primary passage” through the liver.

Cimetidine and ranitidine

Cimetidine and ranitidine have been shown to inhibit CYP3A4 isoenzyme and increase nifedipine plasma concentrations (by 80% and 70%, respectively), thus increasing its antihypertensive effect.

Diltiazem

Diltiazem reduces the clearance of nifedipine. This combination should be used with caution. A reduction in the dose of nifedipine may be required.

Fluoxetine

Clinical studies to study the interaction of nifedipine and fluoxetine have not been conducted. Fluoxetine under in vitro conditions is known to inhibit the metabolism of nifedipine mediated by the action of CYP3A4 isoenzyme. Consequently, the possibility of increased plasma concentrations of nifedipine when nifedipine and fluoxetine are used concomitantly cannot be excluded.

Nefazodone

There have been no clinical studies on the interaction of nifedipine and nefazodone. Nefazodone is known to inhibit the metabolism of other drugs mediated by the action of CYP3A4 isoenzyme. Consequently, the possibility of increased plasma concentrations of nifedipine in concomitant use of nifedipine and nefazodone cannot be excluded.

Hinidine

An increase in plasma concentrations of nifedipine has been reported with quinidine. Therefore, careful monitoring of blood pressure is required when using quinidine and nifedipine concomitantly. If necessary, the dose of nifedipine should be reduced.

Quinupristine/dalfopristine

The concomitant use of quinupristine/dalfopristine may increase plasma concentrations of nifedipine.

Valproic acid

There have been no clinical studies on the interaction of nifedipine and valproic acid. Since valproic acid increases the plasma concentration of nimodipine, which is structurally similar to BMKK, the possibility of increasing the plasma concentration of nifedipine and increasing its effectiveness cannot be excluded.

Grapefruit juice

Grapefruit juice inhibits the CYP3A4 isoenzyme and inhibits nifedipine metabolism. Concomitant use of the drug with grapefruit juice leads to increased plasma concentrations of nifedipine and prolongation of its action due to a decrease in the effect of “primary passage” through the liver and reduced clearance. At the same time, the antihyperglycemic effect of nifedipine may be enhanced. With regular use of grapefruit juice this effect may persist for up to 3 days after the last use of juice. Consumption of grapefruit/grapefruit juice during treatment with nifedipine is contraindicated.

Substrates of isoenzyme CYP3A4

Substrates of CYP3A4 isoenzyme (e.g., cisapride, tacrolimus, benzodiazepines, imipramine, propafenone, terfenadine, warfarin) when used concurrently with nifedipine may act as CYP3A4 inhibitors and increase the plasma concentration of nifedipine.

Cyzapride

Concomitant use of cisapride and nifedipine may increase the plasma concentration of nifedipine.

Influence of nifedipine on other drugs

Quinidine

Nifedipine causes decreased plasma concentrations of quinidine. After nifedipine is withdrawn, there may be a sharp increase in plasma quinidine concentrations. Therefore, when using nifedipine as adjunctive therapy or withdrawing nifedipine, plasma quinidine concentrations should be monitored and, if necessary, its dose should be adjusted.

Digoxin

The concomitant use of nifedipine and digoxin may decrease digoxin clearance and therefore increase plasma concentrations of digoxin. The appearance of symptoms of glycoside overdose in a patient should be carefully monitored, and if necessary, the dose of digoxin should be reduced, taking into account its plasma concentration.

Theophylline

Nifedipine increases plasma concentrations of theophylline; therefore, plasma concentrations of theophylline should be monitored. The clinical effect of both drugs when used together does not change.

Tacrolimus

Tacrolimus is metabolized with participation of CYP3A4 isoenzyme. Recently published data indicate the possibility of increased tacrolimus concentrations in individual cases when used concomitantly with nifedipine. When concomitant use of tacrolimus and nifedipine, plasma concentrations of tacrolimus should be monitored and the dose should be reduced if necessary.

Vincristine

Nifedipine slows down excretion of vincristine from the body and may increase the side effects of vincristine. If concomitant use is necessary, the dose of vincristine is reduced.

Drugs that bind to blood proteins

Nifedipine may displace highly protein-binding drugs (including Indirect anticoagulants – coumarin and indandion derivatives, anticonvulsants, non-steroidal anti-inflammatory drugs, quinine, salicylates, sulfinpyrazone) due to which their concentration in blood plasma may increase.

Cephalosporins

The bioavailability of cephalosporins (e.g., cefixime) and nifedipine in probands was increased by 70%.

Pharmacodynamic interactions

The blood pressure lowering drugs

The antihypertensive effect of nifedipine may be enhanced when used concomitantly with antihypertensive drugs such as diuretics, beta-adrenoblockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists (ARA I), other DMARDs, alpha-adrenoblockers, phosphodiesterase-5 inhibitors, and methyldopa.

When nifedipine and beta-adrenoblockers are used concomitantly, the patient’s condition should be monitored closely, since the course of chronic heart failure may be aggravated in some cases.

The severity of BP decrease is increased with concomitant use of inhaled anesthetics and tricyclic antidepressants.

Nitrates

Concomitant use with nitrates increases tachycardia.

Antiarrhythmic agents

The DMARDs may increase the negative inotropic effect of antiarrhythmic agents such as amiodarone and quinidine. Caution should be exercised when prescribing nifedipine concomitantly with disopyramide and flecainide due to possible intensification of the negative inotropic effect.

Magnesium sulfate

Magnesium sulfate must be monitored closely in pregnant women when nifedipine is used concomitantly with intravenous magnesium sulfate due to the potential for excessive BP reduction, which poses danger to both mother and fetus.

Fentanyl

The concomitant use of nifedipine and fentanyl may result in marked arterial hypotension. If possible, it is recommended that nifedipine be withdrawn at least 36 hours prior to anesthesia with fentanyl.

Calcium preparations

Decrease the effectiveness of nifedipine.

Non-steroidal anti-inflammatory drugs (HNSAIDs)

. NSAIDs reduce the antihypertensive effect of nifedipine by inhibiting prostaglandin synthesis, as well as sodium and fluid retention in the body.

Sympathomimetics

Sympathomimetics decrease the antihypertensive effect of nifedipine.

Estrogens

Estrogens decrease the antihypertensive effect of nifedipine due to fluid retention in the body.

Lithium preparations

Lithium preparations may increase the neurotoxicity of the latter (nausea, vomiting, diarrhea, ataxia, tremor, tinnitus) when used together.

Special Instructions

Cardiovascular disease

Hypertension

Nifedipine dilates the peripheral arteries, reduces blood pressure and may in some cases cause severe arterial hypotension. It is necessary to use the drug with caution in patients who are prone to arterial hypotension, especially in patients with coronary heart disease or with cerebrovascular diseases in whom excessive reduction of BP may lead to myocardial infarction or stroke. In case of severe arterial hypotension, the dose should be reduced or nifedipine should be temporarily stopped.

The risk of arterial hypotension is higher in patients taking beta-adrenoblockers. Concomitant use of nifedipine and beta-adrenoblockers should be performed under close medical supervision, as it may cause excessive BP reduction and in some cases aggravation of chronic heart failure symptoms.

Severe arterial hypotension and/or high need for fluid replacement have been noted in patients treated with nifedipine and beta-adrenoblockers during aortocoronary bypass surgery under general anesthesia with high-dose fentanyl. If the patient requires surgery under general anesthesia during therapy, it is necessary to inform the anesthesiologist about the nature of the therapy. If surgery under general anesthesia with high doses of fentanyl is planned, it is recommended to stop Corinfar® therapy at least 36 hours prior to surgery.

Hypertension

There is no clinical experience with nifedipine in malignant arterial hypertension.

The drug Corinfar® should not be used to lower blood pressure in a hypertensive crisis.

Chronic Coronary Artery Disease

The Corinfar® drug should not be used to relieve angina attacks and for secondary prevention of cardiovascular complications in patients who have had myocardial infarction.

Unstable angina and/or myocardial infarction

.In rare cases, patients with coronary artery disease (especially with severe obstructive coronary artery disease) have experienced an increase in the frequency, duration and/or severity of angina attacks and, in isolated cases, the development of myocardial infarction after initiation of BMCCs (including nifedipine) or after increasing their dosage. The mechanism of this phenomenon is not known.

Nifedipine in immediate-release tablet form is contraindicated in acute myocardial infarction.

There is no clinical experience with nifedipine in sustained release tablet form in acute myocardial infarction and unstable angina pectoris; therefore, their use is contraindicated in these diseases.

Chronic heart failure (CHF)

BMCs (including nifedipine) should be used with extreme caution in patients with CHF. In decompensated CHF the use of Corinfar® is not recommended.

Beta-adrenoblocker withdrawal syndrome

In patients with angina pectoris, discontinuation of beta-adrenoblockers may lead to development of withdrawal syndrome (increased frequency, duration and/or severity of angina pectoris attacks), possibly due to increased sensitivity to catecholamines. Administration of nifedipine does not prevent the development of “withdrawal” syndrome of beta-adrenoblockers, and may even lead to its enhancement due to reflex release of catecholamines in response to peripheral vasodilation.

Nifedipine has no antiarrhythmic effect and does not prevent the occurrence of cardiac rhythm disturbances during abrupt withdrawal of beta-adrenoblockers. If therapy with a beta-adrenoblocker needs to be discontinued, the dose should be gradually reduced until nifedipine is prescribed.

Aortic stenosis/ mitral stenosis/hypertrophic obstructive cardiomyopathy

As with all drugs with vasodilatory effects, nifedipine should be used with caution in patients with aortic stenosis, mitral stenosis or hypertrophic obstructive cardiomyopathy. In patients with hemodynamically significant left ventricular outflow tract obstruction (e.g., severe aortic stenosis) the drug is contraindicated.

In patients with obstructive cardiomyopathy there is a risk of increased frequency, severity and duration of angina attacks after nifedipine administration. In this case, withdrawal of the drug is necessary.

Peripheral edema

Slight to moderate peripheral edema associated with peripheral arterial dilatation has been reported with nifedipine. Swelling is usually localized in the lower extremities, sometimes reduced with the use of diuretics. In patients with concomitant chronic heart failure, peripheral edema associated with nifedipine use should be carefully differentiated from symptoms of progressive left ventricular dysfunction.

Diabetes mellitus

In patients with diabetes mellitus, monitoring of plasma glucose concentrations may be required when using nifedipine preparations.

Hepatic dysfunction

.In rare cases, increased activity of some enzymes such as alkaline phosphatase, creatine phosphokinase, lactate dehydrogenase, aspartate aminotransferase (ACT) and alanine aminotransferase (AJIT), which is usually transient, but sometimes can be significantly pronounced, has been observed during nifedipine administration. The causal relationship with nifedipine intake is uncertain in most cases, but in some cases it is very likely. These changes in laboratory parameters are rarely accompanied by clinical symptomatology. However, cases of cholestasis with or without jaundice have been described, as well as rare cases of autoimmune hepatitis.

Patients with impaired liver function are closely monitored, and the drug dose is reduced and/or other dosage forms of nifedipine are used if necessary.

Renal dysfunction

The use of nifedipine in patients with impaired renal function is safe; no dose adjustment of nifedipine is required. In some cases, transient increase in serum concentrations of urea nitrogen and creatinine has been observed in patients with chronic renal insufficiency. Causal relationship with nifedipine intake is uncertain in most cases, but in some cases it is very probable.

In patients with malignant hypertension on hemodialysis, hypovolemia (decreased circulating blood volume) after dialysis procedure may enhance antihypertensive effect of nifedipine and lead to a sharp decrease of BP. In such patients, Corinfar® should be used with extreme caution, and the drug dose should be reduced if necessary.

Drug interactions

Nifedipine is metabolized by CYP3A4 isoenzyme. Drugs that inhibit or induce CYP3A4 may affect the “primary passage” effect through the liver or clearance of nifedipine.

Drugs that are mild to moderate inhibitors of the CYP3A4 isoenzyme that increase the plasma concentration of nifedipine include:

When nifedipine and the above drugs are used concomitantly, BP should be monitored and the dose of nifedipine should be adjusted if necessary. Surgical interventions/general anesthesia

Inhalational anesthetics may increase BP decrease. If a patient requires surgery under general anesthesia during therapy, the anesthesiologist should be informed that the patient is taking nifedipine.

Diagnostic tests

Positive results are possible during treatment with a direct Coombs reaction (with or without hemolytic anemia) and laboratory tests for antinuclear antibodies.

Nifedipine, like other BMCCs, inhibits platelet aggregation under in vitro conditions. A small number of clinical studies support evidence of a statistically significant decrease in platelet aggregation and increased bleeding time.

Presumably, the cause of these changes is a blockade of calcium transport across the platelet membrane. The clinical significance of this effect is unknown.

Nifedipine may cause false increases in urinary concentrations of vanillylmindalic acid when determined by spectrophotometric method, but does not affect the results of measurements using high performance liquid chromatography (HPLC).

Alcohol

Alcoholic beverages are not recommended during treatment because of the risk of excessive lowering of blood pressure.

Use in elderly patients

Caution should be exercised when using nifedipine in elderly patients because of the high likelihood of age-related renal dysfunction.

Cessation of therapy

Cessation of nifedipine preparations should be done gradually (there is a risk of withdrawal).

Influence on the ability to drive vehicles, mechanisms

In some patients, especially at the beginning of treatment, nifedipine may cause dizziness, which reduces the ability to drive vehicles or other mechanisms. Subsequently, the degree of restriction depends on the individual tolerability of nifedipine.

When treating, especially at the beginning of treatment or when changing the dose, caution should be exercised when driving vehicles and engaging in potentially hazardous activities requiring increased concentration and rapid psychomotor reactions.

In some patients, especially at the beginning of treatment or when changing the dose, caution is required.

Synopsis

Contraindications

With caution

Arterial hypotension, malignant arterial hypertension (no experience with clinical use), coronary heart disease (especially with severe obstructive coronary artery disease) or cerebrovascular disease, chronic heart failure; concomitant use with beta-adrenoblockers and other hypotensive drugs; concomitant use with cardiac glycosides; aortic stenosis, mitral stenosis, hypertrophic obstructive cardiomyopathy; diabetes mellitus; mild hepatic impairment (class A according to Child-Pugh classification); hemodialysis in patients with malignant hypertension (risk of severe arterial hypotension); concomitant use with CYP3A4 isoenzyme inhibitors and/or inducers (e.g., phenytoin, carbamazepine, phenobarbital, macrolide antibiotics, HIV protease inhibitors, ketoconazole, antidepressants, fluoxetine, valproic acid, etc.etc.); pregnancy for more than 20 weeks (the drug may be used as a “backup therapy”); older age.

Side effects

Unwanted reactions are systematized relative to each of the organ systems according to frequency of occurrence using the World Health Organization (WHO) classification as follows: Very common (≥1/10); common (≥1/100, < 1/10); infrequent (≥1/1000, < 1/100); rare (≥1/10000, < 1/1000); very rare (< 1/10000); frequency unknown (cannot be determined from available data).

Blood and lymphatic system disorders: rare – thrombocytopenia, thrombocytopenic purpura; very rare – anemia; frequency unknown – leukopenia, agranulocytosis.

Immune system disorders: infrequent – allergic reactions, edema due to an allergic reaction/angioedema (Quincke’s edema) (including laryngeal edema *); rare – skin itching, skin rash, urticaria; very rare – autoimmune hepatitis; frequency unknown – anaphylactic/anaphylactoid reactions.

Disorders of metabolism and nutrition: very rare – hyperglycemia, weight gain.

Psychiatric disorders: infrequent – anxiety, sleep disorders.

Nervous system disorders: frequent – headache, weakness; infrequent – migraine, dizziness; rare – paresthesia, dysesthesia; frequency unknown – hypoesthesia, somnolence, increased fatigue. With long-term use in high doses – paresthesia of extremities, depression, anxiety, extrapyramidal (parkinsonian) disorders (ataxia, “mask-like” face, shuffling gait, stiffness of hands and feet movements, tremors of hands and fingers, difficulty swallowing).

Visual disorders: infrequent – visual impairment (including transient loss of vision against the background of maximum concentration of nifedipine in blood plasma); frequency unknown – pain in the eye.

Chronic disorders: infrequent – tachycardia, palpitations; rare – in some patients, especially at the beginning of treatment, angina pectoris may occur, which requires discontinuation of the drug; single cases of myocardial infarction are described; frequency is unknown – arrhythmia, chest pain.

Vascular disorders: frequently – including peripheral edema, manifestations of excessive vasodilation (asymptomatic BP decrease, development or aggravation of heart failure (often aggravation of already existing), “flushes” of blood to the face, facial hyperemia, fever); rarely – marked BP decrease, fainting.

Respiratory system, chest and mediastinal disorders: infrequent – nasal bleeding, stuffy nose; rare – difficulty in breathing, cough; very rare – bronchospasm; frequency unknown – dyspnea, pulmonary edema**.

Gastrointestinal disorders:frequent – constipation; infrequent – gastrointestinal and abdominal pain, dyspepsia (nausea, diarrhea or constipation), flatulence, dry oral mucosa; rare – gum hyperplasia (bleeding, painfulness, swelling); frequency unknown – vomiting, gastroesophageal sphincter failure, increased appetite.

Hepatic and biliary tract disorders: infrequent – increased activity of “hepatic” transaminases; rarely – in long-term use – hepatic dysfunction (intrahepatic cholestasis).

Skin and subcutaneous tissue disorders: infrequent erythema; rare – exfoliative dermatitis, photodermatitis; frequency unknown – toxic epidermal necrolysis (Lyell’s syndrome), purpura.

Muscular and connective tissue disorders: infrequent – muscle cramps, joint swelling; rare – arthralgia, myalgia, frequency unknown – arthritis.

Renal and urinary tract disorders: infrequent – polyuria, dysuria; frequency unknown – worsening of renal function (in patients with renal failure).

Gender and mammary gland disorders: infrequent – erectile dysfunction; very rare – gynecomastia (in elderly patients, completely disappearing after discontinuation of the drug), galactorrhea.

General disorders and disorders at the site of administration: often – asthenia, weakness; infrequently – nonspecific pain, chills.

* may lead to a life-threatening condition

** cases have been reported when used as a tocolytic agent during pregnancy (see Use in pregnancy and during breastfeeding)

In patients on hemodialysis, with malignant arterial hypertension, or with reduced circulating blood volume, a marked decrease in BP may occur as a result of vasodilation.

Overdose

Symptoms

Nifedipine causes peripheral vasodilation with severe and possibly prolonged systemic arterial hypotension: headache, facial hyperemia, prolonged marked BP decrease, sinus node suppression, bradycardia and/or tachycardia, bradyarrhythmia. In severe poisoning – loss of consciousness, coma.

Treatment

The treatment of overdose consists of standard procedures for eliminating the drug from the body. Administration of activated charcoal, gastric lavage (if necessary – small bowel lavage), restoration of stable hemodynamic parameters are indicated.

In case of overdose with prolonged nifedipine it is necessary to ensure the most complete elimination of the drug from the body, if possible – small intestine lavage in order to prevent further absorption of the active substance. When using laxatives it should be taken into account that PBMC may cause decrease of intestinal muscle tone up to intestinal atony.

The antidote for nifedipine is calcium preparations. Intravenous injection of 10-20 ml of 10% solution of calcium chloride or calcium gluconate is indicated, followed by switching to prolonged infusion. If the administration of calcium preparations has failed to achieve a sufficient rise in BP, alpha-adrenomimetics (dopamine, norepinephrine) may be used.

In bradyarrhythmia – IV administration of atropine, beta-adrenomimetics. In life-threatening bradyarrhythmias, placement of a temporary pacemaker is recommended.

In case of development of heart failure – intravenous infusion of strophantine. Infusion therapy is recommended with caution due to the risk of volume overload of the heart.

Careful monitoring of the heart, lungs and excretory system is necessary. It is recommended to monitor glucose concentrations (insulin release may decrease) and electrolytes (potassium, calcium) in the blood.

Hemodialysis is ineffective due to the high degree of binding to plasma proteins and relatively small volume of distribution. Plasmapheresis is possible.

Pregnancy use

Pregnancy

The use of nifedipine in pregnancy before 20 weeks is contraindicated. The use of nifedipine at more than 20 weeks’ gestation is possible as a “backup therapy” for severe arterial hypertension, if the expected benefit to the mother exceeds the possible risk to the fetus.

There have been no adequately controlled studies involving pregnant women. The available information is insufficient to rule out the possibility of side effects that pose a risk to the fetus and the newborn.

In animal studies, nifedipine has been shown to be embryotoxic, fetotoxic, and teratogenic. No specific prenatal risk has been identified based on clinical data. However, there has been an increased incidence of perinatal asphyxia, cesarean section, as well as preterm birth and intrauterine fetal delay. The relationship of these reports to existing arterial hypertension, its treatment, or the specific effect of the drug is unclear.

In the use of PBMCs, including nifedipine, as a tocolytic agent during pregnancy, especially multiple pregnancies (twins or more), cases of acute pulmonary edema have been observed with intravenous administration of the drug and/or with concurrent use of beta2-adrenomimetics.

Nifedipine should not be used during pregnancy, except when the clinical condition of the woman requires treatment with nifedipine. Nifedipine may be considered as a “backup therapy” for women with severe arterial hypertension who do not respond to standard therapy.

Breast-feeding period

Nifedipine is excreted in breast milk. The concentration of nifedipine in breast milk is comparable to its concentration in the blood serum of the mother. The effect of the drug excreted with breast milk on the child is unknown. Therefore, if it is necessary to use nifedipine during lactation, it is recommended to stop breastfeeding.

Fertility

In single cases in in vitro fertilization, the use of BMCCs, including nifedipine, has been associated with reversible biochemical changes in the sperm head, which could lead to impaired sperm function. In unsuccessful attempts at in vitro fertilization and when other causes of infertility are excluded, the possibility of effects of PBMCs, including nifedipine, on sperm function should be considered.

Similarities