Nitresan®

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT NITRESAN® (NITRESAN®)

Composition:

Active substance: nitrendipine;

1 tablet contains 10 mg or 20 mg of nitrendipine;

Excipients: lactose monohydrate, maize starch, microcrystalline cellulose, magnesium stearate, povidone, sodium docusate.

Pharmaceutical form. Tablets.

Main physicochemical properties:

10 mg tablets: yellow, flat tablets with a score on one side and embossing "10" on the other side, approximately 7 mm in diameter;

20 mg tablets: yellow, flat tablets with a score on one side and embossing "20" on the other side, approximately 7 mm in diameter.

Pharmacotherapeutic group.

Selective calcium antagonists with predominant vascular action.

ATC code C08CA08.

Pharmacological properties.

Pharmacodynamics.

Nitrendipine is a selective calcium channel blocker of the 1,4-dihydropyridine type with predominant action on peripheral blood vessels, a calcium antagonist. It exhibits the following pharmacological effects: antihypertensive due to selective dilation of peripheral vessels, antianginal, nephroprotective, and vasodilatory. The mechanism of antihypertensive action is associated with inhibition of calcium ion influx through the cell membranes of vascular smooth muscle cells. By reducing intracellular calcium concentration in cells, nitrendipine decreases vascular muscle contractility, resulting in dilation of peripheral arteries; it reduces total peripheral resistance and pathologically elevated arterial pressure. Nitrendipine demonstrates a moderate natriuretic effect, particularly at the beginning of treatment.

Pharmacokinetics.

Absorption

After oral administration, nitrendipine is rapidly and completely absorbed from the gastrointestinal tract. The extent of absorption is 88%. Maximum plasma concentration (C_max) is reached within 1–3 hours after drug administration. The average C_max is approximately 6.1–19 μg/L. Due to the significant first-pass effect in the liver, the systemic bioavailability of nitrendipine is 20–30%.

Distribution

96–98% of nitrendipine is bound to plasma proteins (albumin) and therefore is not dialyzable. Nitrendipine cannot be removed by hemodialysis or peritoneal dialysis. The steady-state volume of distribution of nitrendipine is up to 5–9 L/kg of body weight.

Metabolism/elimination

After oral administration, nitrendipine undergoes extensive metabolism during its first pass through the liver (first-pass effect) and is almost completely metabolized via hepatic oxidative processes, forming inactive metabolites. Approximately 77% of an oral dose is excreted by the kidneys, less than 0.1% unchanged, and the remainder is excreted in the form of metabolites via bile and feces.

The elimination half-life of nitrendipine from plasma is approximately 8–12 hours.

No accumulation of the active substance or its metabolites occurs in the body after steady-state is achieved.

Since nitrendipine is primarily metabolized via hepatic metabolic transformations, its elimination from the body is significantly slower in patients with chronic liver disease: the biological half-life is prolonged by 2–3 times.

Dose adjustment is not required in patients with mild to moderate renal impairment.

Preclinical safety data

Preclinical safety data based on standard pharmacological studies (toxicity after single and repeated doses, genotoxicity, and carcinogenicity) do not indicate any particular hazard to humans. In reproduction studies conducted in laboratory rats and rabbits, nitrendipine was neither embryotoxic nor teratogenic. In monkeys, nitrendipine caused skeletal changes at a maternally toxic dose (100 mg/kg body weight), but not at a dose of 30 mg/kg body weight.

Clinical characteristics.

Indications.

Treatment of essential hypertension in adults.

Contraindications.

• Hypersensitivity to nitrendipine or to another calcium antagonist of the 1,4-dihydropyridine class, or to any excipient of the medicinal product;
• cardiogenic shock;
• severe aortic or subaortic valve stenosis;
• unstable angina pectoris;
• acute myocardial infarction occurred within the previous 4 weeks;
• concomitant use with rifampicin (see section "Interaction with other medicinal products and other forms of interaction");
• pregnancy and breastfeeding.

Interaction with other medicinal products and other forms of interaction.

Contraindicated combinations

Rifampicin

Rifampicin strongly induces the cytochrome P450 3A4 enzyme system. Concomitant administration of rifampicin and nitrendipine may cause a significant reduction in nitrendipine bioavailability (as well as other dihydropyridine calcium channel blockers) and weaken its antihypertensive effect; therefore, nitrendipine must not be used concomitantly with rifampicin.

Medicinal products affecting nitrendipine

Nitrendipine is metabolized by the cytochrome P450 3A4 enzyme system located in the intestinal mucosa and liver. Medicinal products that inhibit or induce this enzyme system may alter the first-pass metabolism or clearance of nitrendipine.

When co-administering the following cytochrome P450 3A4 inhibitors, arterial pressure should be monitored and, if necessary, dose reduction of nitrendipine should be considered (see section "Method of administration and dosage").

Beta-blockers and/or other antihypertensive agents

The antihypertensive effect of nitrendipine may be enhanced by beta-blockers and/or other antihypertensive drugs.

Diuretics (diuretic agents)

Concomitant use of diuretics may lead to increased urinary sodium excretion, thereby enhancing the blood pressure-lowering effect.

Other substances that reduce blood pressure

Nitrendipine may potentiate the blood pressure-lowering effect of concomitant antihypertensive agents such as:

• beta-blockers;
• angiotensin-converting enzyme (ACE) inhibitors;
• angiotensin II receptor (AT1) antagonists;
• other calcium antagonists;
• alpha-receptor blockers;
• phosphodiesterase-5 (PDE-5) inhibitors;
• alpha-methyldopa.

Muscle relaxants

The duration and intensity of action of muscle relaxants such as pancuronium or vecuronium may be increased in patients taking nitrendipine.

Cimetidine, ranitidine

Cimetidine and ranitidine (even in small amounts) may increase plasma concentrations of nitrendipine, thereby enhancing its effect (see section "Special precautions for use").

Digoxin

Concomitant use may lead to increased plasma digoxin levels and symptoms of digoxin overdose. If such combination therapy is necessary, patients should be under continuous medical supervision, with appropriate adjustment of digoxin dosage as needed.

Grapefruit juice

Grapefruit juice inhibits the oxidative metabolism of nitrendipine. Concomitant intake with the drug may increase nitrendipine plasma levels, resulting in enhanced antihypertensive effect.

The effect may persist even up to 3 days after the last intake of nitrendipine if grapefruit juice or grapefruit is consumed regularly. Therefore, consumption of grapefruit and grapefruit juice should be discontinued during nitrendipine therapy (see section "Method of administration and dosage").

Antiepileptic drugs that induce the cytochrome P450 3A4 system, such as phenytoin, phenobarbital, carbamazepine.

No detailed studies on the potential interaction between nitrendipine and anticonvulsants have been conducted. However, it is known that phenytoin, phenobarbital, and carbamazepine are potential inducers of the cytochrome P450 3A4 enzyme system. Concomitant use of these agents with structurally similar drugs to nitrendipine has significantly reduced their bioavailability. Based on these observations, a clinical reduction in nitrendipine bioavailability—and consequently, reduced efficacy—is expected. If the dose of nitrendipine has been increased due to concomitant use with phenytoin, phenobarbital, or carbamazepine, the nitrendipine dose should be reduced again after discontinuation of these anticonvulsants.

Azole antifungals (e.g., ketoconazole)

No specific studies on the potential interaction between nitrendipine and azole antifungal agents (ketoconazole, itraconazole, fluconazole) have been conducted.

It is known that these agents inhibit the cytochrome P450 3A4 enzyme system. Interactions between these agents and other dihydropyridine calcium channel blockers have been reported. Therefore, when used concomitantly with nitrendipine, a significant increase in nitrendipine bioavailability due to first-pass metabolism inhibition cannot be excluded.

If such combination therapy is necessary, patients should be under continuous medical supervision, with appropriate adjustment of nitrendipine dosage based on blood pressure monitoring.

Nefazodone

To date, no controlled studies on the potential interaction between nitrendipine and nefazodone have been conducted. This antidepressant is a potent inhibitor of cytochrome P450 3A4. Therefore, when administered concomitantly with nitrendipine, a significant increase in nitrendipine plasma concentration cannot be excluded (see section "Special precautions for use").

Fluoxetine

It is known that concomitant administration of the structurally similar dihydropyridine calcium antagonist nimodipine with the antidepressant fluoxetine leads to a 50% increase in nimodipine plasma concentration.

When co-administered, fluoxetine plasma levels were significantly reduced, but the concentration of its main metabolite, norfluoxetine, remained unchanged.

Therefore, an increase in nitrendipine plasma concentration cannot be excluded when administered concomitantly with fluoxetine (see section "Special precautions for use").

Valproic acid

To date, no controlled studies on the potential interaction between nitrendipine and valproic acid have been conducted. Since concomitant use of valproic acid with the structurally similar analogue nimodipine has been shown to increase plasma concentration and efficacy of nimodipine due to enzymatic inhibition, an increased efficacy of nitrendipine when co-administered with valproic acid cannot be excluded (see section "Special precautions for use").

Macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin, roxithromycin)

To date, no studies on the potential interaction between nitrendipine and the mentioned macrolide antibiotics have been conducted. It is known that these antibiotics inhibit the cytochrome P450 3A4 enzyme system, which metabolizes other structurally similar drugs. Therefore, an increase in nitrendipine plasma concentration when co-administered with macrolide antibiotics cannot be excluded (see section "Special precautions for use").

Although azithromycin belongs structurally to the macrolide class, it does not inhibit the cytochrome P450 3A4 system.

HIV protease inhibitors (e.g., ritonavir)

No detailed studies on the potential interaction between nitrendipine and protease inhibitors have been conducted. These agents are known to be potent inhibitors of the cytochrome P450 3A4 enzyme system. Therefore, an increase in nitrendipine plasma concentration when co-administered with protease inhibitors cannot be excluded (see section "Special precautions for use").

Quinupristin/dalfopristin

Studies conducted with another calcium channel blocker, nifedipine, have shown that concomitant use of quinupristin/dalfopristin may increase nifedipine plasma concentration (see section "Special precautions for use"). In view of this, concomitant use of quinupristin/dalfopristin with nitrendipine is recommended only with close monitoring of the patient's blood pressure and, if necessary, timely reduction of nitrendipine dosage.

Special precautions for use.

The medicinal product should be used with caution in the following patient groups.

Patients with impaired liver function and elderly patients

In patients with impaired liver function and in elderly patients (over 65 years of age), the effect of nitrendipine may be enhanced and/or prolonged, which may lead to undesirable hypotension. In such cases, treatment should be initiated with the lowest possible dose (see section "Interaction with other medicinal products and other forms of interaction"), and the patient's condition should be carefully monitored during treatment. If blood pressure is consistently reduced, replacement of the medicinal product may be necessary.

Patients with impaired cardiac function

When nitrendipine is used concomitantly with beta-blockers in patients with impaired cardiac function, careful monitoring of blood pressure is required, as sudden reduction in blood pressure may occur.

Particular attention and careful monitoring of cardiac activity are required in patients with decompensated heart failure, as well as in patients with sinus node dysfunction (sick-sinus syndrome) who are not provided with cardiac pacing support when using Nitresan®.

Angina pectoris

According to spontaneous reports, angina attacks occurred very rarely (usually at the beginning of treatment). Clinical trial data indicate that angina occurred infrequently.

Cytochrome P450 3A4 system

Nitrendipine is metabolized via the cytochrome P450 3A4 enzyme system. Medicinal products that inhibit or induce this enzyme system may alter the first-pass metabolism or elimination of nitrendipine.

The following medicinal products, known as inhibitors of the cytochrome P450 3A4 enzyme system, may increase nitrendipine plasma levels:

• macrolide antibiotics;
• protease inhibitors for HIV;
• antifungal azole agents;
• antidepressants nefazodone and fluoxetine;
• quinupristin/dalfopristin;
• valproic acid;
• cimetidine and ranitidine.

Therefore, when nitrendipine is used concomitantly with any of these medicinal products, blood pressure should be monitored. Dose reduction of nitrendipine should be considered if necessary.

Elderly patients should be particularly cautious when using higher doses of the drug.

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

The medicinal product contains less than 1 mmol of sodium (23 mg) per tablet, i.e., it is practically sodium-free.

Use during pregnancy or breastfeeding.

The medicinal product is contraindicated during pregnancy and breastfeeding.

Pregnancy

Nitresan® is contraindicated during pregnancy (see section "Contraindications").

Data on use in pregnant women are lacking or limited. In animal studies, the nitrendipine doses investigated were toxic to both the mother and offspring. This was manifested by a number of minor malformations in offspring.

Period of breastfeeding

Nitrendipine passes into breast milk. The effect of nitrendipine on the newborn/infant is unknown. Nitresan® should not be taken during breastfeeding (see section "Contraindications").

Fertility

In individual cases of in vitro fertilization, the use of calcium antagonists has been associated with reversible biochemical changes in the head of spermatozoa, which could lead to impaired sperm function. In cases where repeated in vitro fertilization has been unsuccessful and no other cause has been identified, calcium antagonists should be considered as a possible cause. Due to the potential effect on fertility, an alternative treatment option should be considered if pregnancy is planned.

Ability to influence reaction speed when driving or operating machinery.

At the beginning of treatment, when higher doses are used, during combination therapy with other antihypertensive agents, or when alcohol is consumed concurrently, it is recommended to refrain from driving vehicles and from potentially hazardous activities requiring heightened attention and rapid psychomotor reactions, as reduced attention levels may occur with lowering of blood pressure.

Administration and Dosage

The drug is intended for oral administration in adults in the morning after a meal. The tablets should be swallowed whole, without chewing, with sufficient fluid (e.g., a glass of water).

Grapefruit juice is strictly prohibited!

The active ingredient, nitrendipine, is light-sensitive; therefore, tablets should be removed from the blister pack only immediately before use.

Nitresan® 10 mg

One tablet of Nitresan® 10 mg twice daily (in the morning and evening), providing a total daily dose of 20 mg nitrendipine. If the reduction of arterial pressure is insufficient, the physician may during treatment increase the daily dose twofold and prescribe two tablets twice daily, equivalent to a total daily dose of 40 mg.

Nitresan® 20 mg

One tablet of Nitresan® 20 mg once daily (in the morning), providing a total daily dose of 20 mg nitrendipine. If the reduction of arterial pressure is insufficient, the physician may during treatment increase the daily dose twofold and prescribe one 20 mg tablet twice daily, equivalent to a total daily dose of 40 mg.

Maximum daily dose – 40 mg.

The dosage and frequency of administration are determined individually by the physician. To achieve optimal therapeutic effect, individualized dosing is recommended based on the patient's condition, response to the drug, and tolerability. The duration of treatment is determined by the patient's clinical status.

Concomitant use with CYP3A4 inhibitors or CYP3A4 inducers may necessitate dose adjustment of nitrendipine or may preclude the use of nitrendipine altogether.

Special Patient Groups

Hepatic Impairment

Nitrendipine metabolism may be slowed, leading to an undesirable reduction in arterial pressure. Since the therapeutic effect of the drug may be enhanced and/or prolonged, treatment should be initiated at lower doses (10 mg nitrendipine daily) under close medical supervision.

In cases of significant reduction in arterial pressure, even with low doses, therapy should be modified.

Renal Impairment

Patients with mild to moderate renal impairment do not require specific dose adjustments.

Children

The medicinal product is not administered to children (under 18 years of age) due to lack of data on efficacy and safety.

Overdose

Symptoms of acute intoxication

Flushing, headache, arterial hypotension (circulatory collapse), changes in heart rate (tachycardia or bradycardia).

Treatment

Eliminate the drug from the body: gastric lavage and administration of activated charcoal. Careful monitoring of vital functions is required. In cases of significant arterial hypotension, dopamine and noradrenaline should be administered. Attention should be paid to possible adverse effects of catecholamines (particularly regarding cardiac rhythm disturbances).

In case of bradycardia, intravenous administration of atropine or orciprenaline (similar to treatment of intoxication with other calcium channel blockers) is indicated. Repeated intravenous administration of 10 mL of 10% calcium gluconate or 10% calcium chloride, followed by calcium infusion, may be considered (care should be taken to avoid possible development of hypercalcemia). In such cases, catecholamines may also be effective, but at significantly higher doses. Further treatment is symptomatic.

Nitrendipine is not dialyzable; therefore, hemoperfusion and plasmapheresis are ineffective.

Adverse reactions.

Adverse reactions associated with the use of nitrendipine are classified by organ systems and frequency of occurrence: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1,000, < 1/100), rare (≥ 1/10,000, < 1/1,000), very rare (< 1/10,000), including isolated cases.

Immune system disorders:

Uncommon: allergic reactions, including skin reactions and allergic edema / angioedema.

Psychiatric disorders:

Common: feeling of anxiety.

Uncommon: sleep disturbances.

Nervous system disorders:

Common: headache (especially at the beginning of treatment, subsides over time).

Uncommon: dizziness, fatigue, migraine, hypesthesia, vertigo.

Eye disorders:

Uncommon: visual disturbances.

Ear and labyrinth disorders:

Uncommon: tinnitus.

Cardiac disorders:

Common: palpitations.

Uncommon: angina pectoris, tachycardia, arrhythmia, chest pain.

Frequency not known: myocardial infarction.

Vascular disorders:

Common: edema, vasodilation, hyperemia and skin flushing, sensation of warmth (erythema).

Uncommon: hypotension.

Respiratory system disorders:

Uncommon: dyspnea, epistaxis.

Gastrointestinal disorders:

Common: flatulence.

Uncommon: nausea, vomiting, gastrointestinal and abdominal pain, dry mouth, constipation, gingival hyperplasia, dyspepsia, gastroenteritis.

Hepatobiliary disorders:

Uncommon: liver function abnormalities (elevated levels of liver transaminases).

Renal and urinary disorders:

Uncommon: polyuria.

Musculoskeletal system disorders:

Uncommon: myalgia.

General disorders and administration site conditions:

Common: malaise.

Uncommon: unspecified pain.

Shelf life. 4 years.

Storage conditions.

Store in the original packaging, protected from light and out of reach of children, at a temperature not exceeding 25 °C.

Packaging.

10 mg tablets: 10 tablets in a blister, 2 or 3 or 6 blisters in a cardboard box.

20 mg tablets: 10 tablets in a blister, 2 or 3 or 6 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

PRO.MED.CS Praha a.s. / PRO.MED.CS Praha a.s.

Manufacturer's name and address of the place of business.

Telčská 377/1, Michle, Praha 4, 140 00, Czech Republic /
Telčská 377/1, Michle, Praha 4, 140 00, Czech Republic.