Instructions for Nitresan tablets 20 mg blister No. 30
Composition
active ingredient: nitrendipine;
1 tablet contains 10 mg or 20 mg of nitrendipine;
Excipients: lactose monohydrate, corn starch, microcrystalline cellulose, magnesium stearate, povidone, docusate sodium.
Dosage form
Pills.
Main physicochemical properties:
10 mg tablets: yellow flat tablets with a score on one side and embossed "10" on the other side, with a diameter of about 7 mm;
20 mg tablets: yellow flat tablets with a score on one side and embossed "20" on the other side, with a diameter of approximately 7 mm.
Pharmacotherapeutic group
Selective calcium antagonists with a predominant effect on blood vessels.
ATX code C08C A08.
Pharmacological properties
Pharmacodynamics.
Nitrendipine is a selective 1,4-dihydropyridine type calcium channel blocker with a predominant effect on peripheral blood vessels, a calcium antagonist. It exhibits pharmacological effects: hypotensive due to selective dilation of peripheral vessels, antianginal, nephroprotective, vasodilator. The mechanism of antihypertensive action is associated with inhibition of the influx of calcium ions through the cell membranes of smooth muscle cells of the blood vessel walls. By reducing the intracellular calcium concentration in the cells, nitrendipine reduces the contractility of vascular muscles, dilating peripheral arteries; reduces total peripheral resistance and pathologically elevated blood pressure. Nitrendipine exhibits a moderate natriuretic effect, especially at the beginning of treatment.
Pharmacokinetics.
Absorption
When administered orally, nitrendipine is rapidly and completely absorbed from the gastrointestinal tract. The degree of absorption is 88%. The maximum concentration in the blood plasma (Cmax) is reached 1-3 hours after administration of the drug. The average Cmax is approximately 6.1-19 μg/l. Taking into account the significant influence of the first passage through the liver (first-pass effect), the systemic bioavailability of nitrendipine is 20-30%.
Distribution
Nitrendipine is 96-98% bound to plasma proteins (albumin) and is therefore not dialyzable. Nitrendipine cannot be removed by hemodialysis or peritoneal dialysis. In the steady-state phase, the volume of distribution of nitrendipine is up to 5-9 l/kg body weight.
Metabolism/elimination
When administered orally, nitrendipine is extensively metabolized during the first passage through the liver (first-pass effect) and is almost completely metabolized by oxidation in the liver to form inactive metabolites. Approximately 77% of the oral dose is excreted by the kidneys, less than 0.1% in unchanged form, the rest in the form of metabolites with bile and feces.
The half-life of nitrendipine from blood plasma is approximately 8-12 hours.
No accumulation of the active substance or metabolites in the body is detected after reaching a stable state.
Since nitrendipine is mainly biotransformed through metabolic transformations in the liver, in patients with chronic liver diseases its elimination from the body is much slower: the biological half-life is slowed down by 2-3 times.
No dose adjustment is required for patients with mild to moderate renal impairment.
Preclinical safety data of the medicinal product
Preclinical safety data based on conventional pharmacological studies (single and repeated dose toxicity, genotoxicity and carcinogenicity) do not indicate any special hazard for 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.
Indication
Treatment of essential hypertension in adults.
Contraindication
Hypersensitivity to nitrendipine or to another 1,4-dihydropyridine calcium antagonist or to any auxiliary component of the drug;
cardiogenic shock;
severe aortic and subaortic valve stenosis;
unstable angina;
acute myocardial infarction that occurred within the previous 4 weeks;
simultaneous administration with rifampicin (see section "Interaction with other medicinal products and other types of interactions");
pregnancy and breastfeeding.
Interaction with other medicinal products and other types of interactions
Contraindicated combinations
Rifampicin
Rifampicin significantly stimulates the cytochrome P450 3A4 enzyme system. Concomitant use of rifampicin and nitrendipine may significantly reduce the bioavailability of nitrendipine (as well as other dihydropyridine calcium channel blockers) and weaken its antihypertensive effect, therefore nitrendipine should not be used concomitantly with rifampicin.
Drugs that affect nitrendipine
When using the following inhibitors of the cytochrome P450 3A4 system simultaneously, blood pressure should be monitored and, if necessary, a 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
Concomitant use of diuretics may lead to increased urinary sodium excretion, which enhances the blood pressure-lowering effect.
Other substances that lower blood pressure
Nitrendipine may enhance the blood pressure lowering effect of concomitant antihypertensive agents such as:
beta-blockers;
angiotensin-converting enzyme (ACE) inhibitors;
angiotensin I (AT 1) receptor antagonists;
other calcium antagonists;
alpha receptor blockers;
phosphodiesterase-5 (PDE-5) inhibitors;
alpha-methyldopa.
Muscle relaxation
The duration and intensity of interactions with muscle relaxants such as pancuronium or vecuronium may be increased in patients taking nitrendipine.
Cimetidine, ranitidine
Cimetidine and ranitidine (including small amounts) may cause an increase in the concentration of nitrendipine in the blood plasma, enhancing its effect (see section "Special instructions").
Digoxin: With simultaneous use, an increase in the level of digoxin in the blood plasma and the appearance of symptoms of overdose are possible. If it is necessary to prescribe such a combination, patients should be under constant supervision of a physician who can make appropriate adjustments to the doses of digoxin.
Grapefruit juice
Grapefruit juice inhibits the oxidative metabolism of nitrendipine. Concomitant use with the drug may cause an increase in the level of nitrendipine in the blood plasma, which is accompanied by an increase in the antihypertensive effect of nitrendipine.
With regular use of grapefruit juice or grapefruit, the effect may occur even 3 days after the last dose of nitrendipine. Therefore, grapefruit and grapefruit juice should be discontinued when taking nitrendipine (see section "Method of administration and dosage").
Antiepileptic drugs that induce the cytochrome P450 3A4 system, such as phenytoin, phenobarbital, carbamazepine.
Detailed studies of the potential interaction between nitrendipine and anticonvulsants have not been conducted. However, it is known that phenytoin, phenobarbital, carbamazepine are potential inducers of the cytochrome P450 3A4 enzyme system. The simultaneous use of these drugs and drugs similar in structure to nitrendipine significantly reduced their bioavailability. Based on these assumptions, a clinical decrease in the bioavailability of nitrendipine and, as a consequence, a decrease in the effect of nitrendipine should be expected. If the dose of nitrendipine was increased due to simultaneous use with phenytoin, phenobarbital, carbamazepine, then after discontinuation of these anticonvulsants, the dose of nitrendipine should be reduced again.
Azole antifungals (e.g., ketoconazole)
Specific studies of the potential interaction between nitrendipine and antifungals
No studies were conducted with azole drugs (ketoconazole, itraconazole, fluconazole).
These agents are known to inhibit the cytochrome P450 3A4 enzyme system. Described
interactions of these agents with other dihydropyridine calcium channel blockers. Therefore
with simultaneous oral administration with nitrendipine, a significant increase in
increased bioavailability of nitrendipine as a result of the first-pass effect.
If it is necessary to prescribe such a combination with nitrendipine, patients should be under constant supervision of a physician who can make appropriate adjustments to the doses of nitrendipine after monitoring blood pressure.
Nefazodone
No controlled studies of the potential interaction between nitrendipine and nefazodone have been conducted to date. This antidepressant is a potent inhibitor of cytochrome P450 3A4. Therefore, a significant increase in nitrendipine plasma levels cannot be excluded when administered orally with nitrendipine (see section 4.4).
Fluoxetine
It is known that simultaneous use of the structurally similar dihydropyridine calcium antagonist nimodipine with the antidepressant fluoxetine leads to a 50% increase in nimodipine plasma concentrations.
With simultaneous use, the plasma level of fluoxetine was significantly reduced, but the concentration of its main metabolite, norfluoxetine, did not change.
Therefore, the possibility of an increase in the concentration of nitrendipine in the blood plasma when used simultaneously with fluoxetine cannot be ruled out (see section "Special warnings and precautions for use").
Valproic acid
Macrolide antibiotics (e.g. erythromycin, troleandomycin, clarithromycin, roxithromycin)
To date, no studies have been conducted on the potential interaction between nitrendipine and these macrolide antibiotics. These antibiotics are known to inhibit the cytochrome P450 3A4 enzyme system, which metabolizes other drugs with a similar structure. Therefore, the possibility of increasing the plasma concentration of nitrendipine when used simultaneously with macrolide antibiotics cannot be ruled out (see section "Special warnings and precautions for use").
Although azithromycin structurally belongs to the macrolide class of antibiotics, it does not inhibit the cytochrome P450 3A4 system.
HIV protease inhibitors (e.g. ritonavir)
No detailed studies of the potential interaction between nitrendipine and protease inhibitors have been conducted. Drugs of this type have been described as potent inhibitors of the cytochrome P450 3A4 enzyme system. Therefore, the possibility of an increase in the plasma concentration of nitrendipine when used simultaneously with protease inhibitors cannot be excluded (see section "Special instructions").
Quinupristin/dalfopristin
Studies conducted with another calcium channel blocker, nifedipine, have shown that concomitant use of quinupristin/dalfopristin may increase nifedipine plasma concentrations (see section 4.4). Given this fact, it is recommended that the patient's blood pressure be monitored closely when quinupristin/dalfopristin is used with nitrendipine and that the dose of nitrendipine be reduced in a timely manner if necessary.
Application features
Use the drug with caution in these categories of patients.
Patients with hepatic impairment and elderly patients
In patients with impaired liver function and elderly patients (over 65 years of age), the effect of nitrendipine may be increased and/or prolonged, which may lead to undesirable hypotension. In such cases, treatment should be started at 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 continues to decrease, it may be necessary to replace the drug.
Patients with impaired cardiac function
When nitrendipine and beta-blockers are used simultaneously in patients with impaired cardiac function, careful monitoring of blood pressure is necessary, since a sudden decrease in blood pressure is possible.
In cases of decompensated heart failure, as well as in sick sinus syndrome, in the absence of cardiac pacing support, special attention to the patient's condition and careful monitoring of cardiac activity are necessary when using the drug Nitresan®.
Angina pectoris
According to spontaneous reports, angina attacks occurred very rarely (usually at the beginning of treatment). According to clinical studies, angina occurred infrequently.
Cytochrome P450 3A4 system
Nitrendipine is metabolized by the cytochrome P450 3A4 enzyme system. Drugs that inhibit or induce this enzyme system may modify the first-pass effect or elimination of nitrendipine.
The following drugs, known as inhibitors of the cytochrome P450 3A4 enzyme system, may increase the level of nitrendipine in the blood plasma:
macrolide antibiotics;
protease inhibitors AIDS;
azole antifungal drugs;
antidepressants nefazodone and fluoxetine;
quinupristin/dalfopristin;
valproic acid;
cimetidine and ranitidine.
Therefore, when nitrendipine is used concomitantly with one of these drugs, blood pressure should be monitored. If necessary, a reduction in the nitrendipine dose should be considered.
Elderly patients should be especially careful when using increased doses of the drug.
The drug contains lactose as an excipient, therefore patients with rare hereditary forms of galactose intolerance, lactase deficiency or glucose-galactose malabsorption syndrome should not use this drug.
This medicine contains less than 1 mmol sodium (23 mg) per tablet, i.e. essentially 'sodium-free'.
Use during pregnancy or breastfeeding
The drug is contraindicated for use during pregnancy and breastfeeding.
Pregnancy
Nitresan® is contraindicated during pregnancy (see section "Contraindications").
There are no or limited data on use in pregnant women. In animal studies, nitrendipine was toxic to both the mother and the offspring at the doses tested, resulting in a number of mild malformations in the offspring.
Breastfeeding period
Nitrendipine passes into breast milk. The effect of nitrendipine on the newborn/infant is unknown. Nitresan® should not be taken during breast-feeding (see section "Contraindications").
In isolated cases of in vitro fertilization, the use of calcium antagonists has been associated with reversible biochemical changes in the head of spermatozoa, which may lead to impaired sperm function. In men in whom repeated in vitro fertilization has not been successful and no other cause has been found, calcium antagonists should be considered as a possible cause. Given the possible effect on fertility, alternative treatment options should be considered if pregnancy is planned.
Ability to influence reaction speed when driving vehicles or other mechanisms
At the beginning of treatment or when using increased doses, or in combination therapy with other antihypertensive agents, or when drinking alcohol simultaneously, it is recommended to refrain from driving vehicles and potentially hazardous activities that require increased attention and speed of psychomotor reactions, since the level of attention may decrease with a decrease in blood pressure.
Method of administration and doses
Prescribed for adults orally in the morning after meals. The tablets should be swallowed whole, without chewing, with a sufficient amount of liquid (for example, a glass of water).
It is strictly forbidden to drink grapefruit juice!
The active ingredient nitrendipine is sensitive to light, so the tablets should be removed from the blister only before use.
Nitresan® 10 mg
1 tablet of Nitresan® 10 mg twice a day (morning and evening), which is 20 mg of nitrendipine per day. If blood pressure is not sufficiently reduced during treatment, the doctor may double the daily dose and prescribe 2 tablets twice a day, which is equivalent to a daily dose of 40 mg.
Nitresan® 20 mg
1 tablet of Nitresan® 20 mg once a day (in the morning), which is 20 mg of nitrendipine per day. If blood pressure is not sufficiently reduced during treatment, the doctor may double the daily dose and prescribe 1 tablet of 20 mg twice a day, which is equivalent to a daily dose of 40 mg.
The maximum daily dose is 40 mg.
The dose and number of doses are determined by the doctor individually. In order to achieve the maximum therapeutic effect, individual dosage of the drug is recommended depending on the patient's condition, his reaction to the drug and tolerability. The duration of treatment is determined by the patient's clinical condition.
Concomitant administration with CYP3A4 inhibitors or CYP3A4 inducers may require dose adjustment of nitrendipine or may result in the inability to use nitrendipine.
Special patient groups
Liver dysfunction
The metabolism of nitrendipine may be slowed down, leading to an undesirable decrease in blood pressure. Since the therapeutic effect of the drug may be enhanced and/or prolonged, it is recommended to start treatment with lower doses (10 mg nitrendipine per day)
under the close supervision of a doctor.
In cases of significant reduction in blood pressure, even when using low doses, treatment should be changed.
Kidney dysfunction
Patients with mild to moderate renal impairment do not require special dose adjustments.
Children.
The drug is not used in children (under 18 years of age) due to the lack of data on its effects and safe use.
Overdose
Symptoms of acute intoxication.
Hot flashes, headache, hypotension (circulatory collapse), changes in heart rate (tachycardia or bradycardia).
Treatment.
It is necessary to remove the drug from the body: wash the gastrointestinal tract, use activated charcoal. Carefully monitor the patient's vital functions. If blood pressure drops significantly, dopamine and noradrenaline should be administered. Attention should be paid to the possible negative effects of catecholamines (especially with regard to heart rhythm disturbances).
In case of bradycardia, intravenous administration of atropine or orciprenaline (similarly to the treatment of intoxication with other calcium channel blockers). Repeated intravenous administration of 10 ml of 10% calcium gluconate or 10% calcium chloride is possible, followed by calcium infusion (it is necessary to prevent the possible development of hypercalcemia). In such cases, catecholamines are also effective, but in much higher doses. Further treatment is symptomatic.
Nitrendipine is not dialyzable, so hemoperfusion and plasmapheresis will not be effective.
Adverse reactions
Adverse reactions occurring with nitrendipine are classified by organ system and frequency of occurrence: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10000, < 1/1000), very rare (< 1/10000), including isolated cases.
On the part of the immune system:
Uncommon: allergic reactions, including skin reactions and allergic oedema/angioedema.
Mental disorders:
Common: feeling anxious
Uncommon: sleep problems.
From the nervous system:
Common: headache (especially at the beginning of treatment, disappears with time).
Uncommon: dizziness, fatigue, migraine, hypoesthesia, vertigo.
On the part of the organs of vision:
Uncommon: visual disturbances.
From the side of the organs of hearing and vestibular apparatus:
Uncommon: tinnitus.
Cardiac disorders:
Uncommon: angina pectoris, tachycardia, arrhythmia, chest pain.
Frequency unknown: myocardial infarction
Vascular disorders:
Common: edema, vasodilation, hyperemia and redness of the skin, feeling of warmth (erythema).
Uncommon: hypotension
On the part of the respiratory system:
Uncommon: dyspnea, epistaxis.
From the digestive system:
Often: flatulence.
Uncommon: nausea, vomiting, gastrointestinal and abdominal pain, dry mouth, constipation, gingival hyperplasia, dyspepsia, gastroenteritis.
From the liver and biliary tract:
Uncommon: liver dysfunction (increased hepatic transaminase levels).
From the kidneys and urinary tract:
Uncommon: polyuria.
From the musculoskeletal system:
Uncommon: myalgia.
General disorders and administration site conditions:
Common: malaise.
Uncommon: unspecified pain.
Expiration date
4 years.
Storage conditions
Store in the original packaging, protected from light and out of the 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.
Vacation category
According to the recipe.
Producer
PRO.MED.CS Praha a. s. / PRO.MED.CS Prahа as
Location of the manufacturer and its business address
Telcska 377/1, Michle, Prague 4, 140 00, Czech Republic.
Address
Telcska 377/1, Michle, Prague 4, 140 00, Czech Republic.
