Normodipine

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT NORMODIPINE (NORMODIPINE)

Composition:

Active substance: amlodipine;

Each tablet contains respectively:

5 mg amlodipine (as 6.944 mg amlodipine besylate);

10 mg amlodipine (as 13.889 mg amlodipine besylate);

Excipients: magnesium stearate, sodium starch glycolate (type A), calcium hydrogen phosphate anhydrous, microcrystalline cellulose.

Pharmaceutical form. Tablets.

Main physicochemical properties: 5 mg tablets: white or almost white, elongated oval-shaped, biconvex tablets with engraving "5" on one side;

10 mg tablets: white or almost white, elongated oval-shaped, biconvex tablets with engraving "10" on one side and a score line on the other.

Pharmacotherapeutic group. Selective calcium antagonists with predominant vascular effect. ATC code C08CA01.

Pharmacological Properties.

Pharmacodynamics.

Pharmacotherapeutic group: slow calcium channel blockers, selective blocker of slow calcium channels with predominant vascular action.

Amlodipine, a dihydropyridine derivative, inhibits transmembrane influx of calcium ions (a slow calcium channel blocker or calcium ion antagonist); it also blocks transmembrane calcium ion flux into smooth muscle cells of the myocardium and blood vessels.

The antihypertensive mechanism of amlodipine is due to its direct relaxing effect on vascular smooth muscle. The exact mechanism of amlodipine's action in angina pectoris has not been fully established, but amlodipine reduces ischemia through two pathways described below:

1. Amlodipine dilates peripheral arterioles, thereby reducing total peripheral vascular resistance (afterload) against which the heart must work. Since heart rate remains unchanged, the reduction in cardiac workload decreases myocardial energy expenditure and oxygen demand.
2. The mechanism of amlodipine's action likely also includes dilation of major coronary arteries and coronary arterioles in both normal and ischemic areas of the myocardium. This dilation increases oxygen delivery to the myocardium in patients with coronary artery spasm (Prinzmetal's angina or variant angina).

In patients with arterial hypertension, administration of the drug once daily provides clinically significant reduction of arterial blood pressure over 24 hours in both supine and standing positions. Due to the slow onset of amlodipine's action, acute arterial hypotension is usually not observed.

In patients with angina, administration of a single daily dose increases total exercise duration, time to onset of angina, and time to 1 mm ST-segment depression. The drug reduces the frequency of angina attacks and decreases the need for nitroglycerin use.

Amlodipine is not associated with any adverse metabolic effects or changes in plasma lipid levels and can be used in patients with asthma, diabetes mellitus, and gout.

Pharmacokinetics.

Absorption, distribution, and plasma protein binding.

Amlodipine is well absorbed after oral administration at therapeutic doses. Peak plasma concentration is reached within 6–12 hours. Its absolute bioavailability is approximately 64–80%. The volume of distribution is approximately 21 L/kg. Approximately 97.5% of circulating amlodipine is bound to plasma proteins.

Food intake does not affect the bioavailability of amlodipine.

Metabolism/elimination.

The terminal elimination half-life is approximately 35–50 hours, allowing once-daily dosing. Amlodipine is extensively metabolized in the liver to inactive metabolites; the drug is excreted in urine as unchanged drug (10%) and metabolites (60%).

Use in hepatic impairment.

Limited clinical data are available on the use of amlodipine in patients with impaired liver function. Patients with hepatic insufficiency have reduced creatinine clearance, leading to an increase in AUC by approximately 40–60% and prolonged elimination half-life.

Use in elderly patients.

Time to reach peak plasma concentration of amlodipine is similar in younger and elderly patients. However, elderly patients have reduced amlodipine clearance, resulting in increased AUC and prolonged elimination half-life. Increased AUC and prolonged elimination half-life are also observed in patients with congestive heart failure.

Use in children and adolescents.

Marked interindividual variability has been observed. Data in children under 6 years of age are limited.

Clinical characteristics.

Indications.

• Arterial hypertension.
• Chronic stable angina.
• Vasospastic angina (Prinzmetal's angina).

Contraindications.

Amlodipine is contraindicated in patients with the following conditions:

• Hypersensitivity to amlodipine, dihydropyridine derivatives, or any other component of the medicinal product;
• Severe arterial hypotension;
• Shock (including cardiogenic shock);
• Left ventricular outflow tract obstruction (e.g., severe aortic stenosis);
• Hemodynamically unstable heart failure following acute myocardial infarction.

Interaction with other medicinal products and other forms of interaction.

Effect of other medicinal products on amlodipine.

CYP3A4 inhibitors.

Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungal agents, macrolides such as erythromycin or clarithromycin, verapamil, or diltiazem) may lead to a significant increase in amlodipine concentration, which may also increase the risk of hypotension. Clinical manifestations of these pharmacokinetic deviations may be more pronounced in elderly patients. Therefore, monitoring of clinical status and dose adjustment may be required.

Clarithromycin is a CYP3A4 inhibitor. There is an increased risk of hypotension in patients who are concomitantly taking clarithromycin and amlodipine; therefore, close monitoring is recommended in such patients.

CYP3A4 inducers.

When amlodipine is used concomitantly with known CYP3A4 inducers, plasma concentrations of amlodipine may fluctuate. For this reason, blood pressure should be monitored and dosage adjusted during and after concomitant use, especially with strong CYP3A4 inducers (e.g., rifampicin, St John's wort [Hypericum perforatum] preparations).

Concomitant use of amlodipine with grapefruit or grapefruit juice is not recommended, as it may increase the bioavailability of amlodipine in some patients, thereby enhancing its hypotensive effect.

Dantrolene (infusions): In laboratory animals, cases of ventricular fibrillation and cardiovascular collapse accompanied by hyperkalemia, resulting in death and circulatory collapse, have been observed with verapamil and intravenous dantrolene. Due to the risk of hyperkalemia, concomitant use of dantrolene and calcium channel blockers (including amlodipine) should be avoided in patients predisposed to malignant hyperthermia, as well as during treatment of malignant hyperthermia.

Effect of amlodipine on other medicinal products.

Amlodipine enhances the hypotensive effect of other antihypertensive agents used to lower blood pressure.

Tacrolimus.

There is a risk of increased blood levels of tacrolimus when used concomitantly with amlodipine, although the pharmacokinetic mechanism of this interaction is not fully understood. To avoid tacrolimus toxicity, regular monitoring of blood tacrolimus levels is required when amlodipine is used concomitantly, and dose adjustment should be made if necessary.

Cyclosporine.

In kidney transplant patients, variable increases in cyclosporine trough concentrations (on average by 0–40%) have been observed. For kidney transplant patients receiving amlodipine, monitoring of cyclosporine concentrations should be considered, and cyclosporine dosage reduced if necessary.

Simvastatin: repeated co-administration of amlodipine 10 mg with simvastatin 80 mg resulted in a 77% increase in simvastatin concentration compared to simvastatin monotherapy. It is recommended to limit the dose of simvastatin in patients taking amlodipine to 20 mg daily.

mTOR inhibitors (mammalian target of rapamycin).

mTOR inhibitors such as sirolimus, temsirolimus, and everolimus are substrates of CYP3A. Amlodipine is a weak inhibitor of CYP3A. When amlodipine is used concomitantly with mTOR inhibitors, it may potentiate their effects.

Sildenafil.

Single administration of 100 mg sildenafil in patients with essential hypertension did not affect the pharmacokinetics of amlodipine. When amlodipine and sildenafil are used concomitantly as combination therapy, each drug exerts its hypotensive effect independently of the other.

Other medicinal products.

Amlodipine does not affect the pharmacokinetics of atorvastatin, digoxin, or warfarin.

Ethanol (alcohol).

Single and repeated administration of 10 mg amlodipine did not have a significant effect on the pharmacokinetics of ethanol.

Concomitant use of amlodipine with cimetidine did not affect the pharmacokinetics of amlodipine.

Concomitant use of aluminum/magnesium-containing products (antacids) with a single dose of amlodipine did not have a significant effect on the pharmacokinetics of amlodipine.

Laboratory tests.

The effect on laboratory test parameters is unknown.

Special precautions for use.

The safety and efficacy of amlodipine in hypertensive crisis have not been established.

Patients with heart failure.

Amlodipine should be used with caution in this patient population.

In studies involving patients with heart failure (NYHA functional class III-IV), an increased incidence of pulmonary edema was observed in the amlodipine group compared to the placebo group; however, this was not associated with worsening of heart failure.

Calcium channel blockers of the “slow” type, including amlodipine, should be used with caution in patients with congestive heart failure, as they may increase the risk of cardiovascular complications and mortality rate.

Use in patients with hepatic impairment.

The elimination half-life and AUC values of amlodipine are increased in patients with hepatic impairment; recommended doses for these patients have not been established. Treatment with amlodipine should be initiated at the lowest dose, and dose escalation should be performed cautiously. In patients with severe hepatic impairment, dose titration should be slow and conducted under close medical supervision.

Use in elderly patients.

Dose escalation in elderly patients should be performed with caution (see sections "Dosage and administration" and "Pharmacokinetics").

Use in patients with renal impairment.

Amlodipine can be administered at usual doses in this patient group. Plasma concentrations of amlodipine do not correlate with the degree of renal impairment. Amlodipine is not removed by hemodialysis.

Use during pregnancy or breastfeeding.

Pregnancy. The safety of amlodipine use during pregnancy has not been established.

Use during pregnancy is recommended only if no safer alternative is available, or if the mother's condition poses a greater risk to mother and fetus than the treatment itself. Reproductive toxicity has been observed in animals at high doses.

Breastfeeding. Amlodipine is excreted into breast milk. The infant exposure, expressed as a fraction of maternal dose, has been estimated at an interquartile range of 3–7%, with a maximum of 15%. The effect of amlodipine on infants is unknown. The decision to continue or discontinue breastfeeding or to continue or discontinue amlodipine therapy should be made considering the benefits of breastfeeding for the infant and the benefits of treatment for the mother.

Fertility. Reversible biochemical changes in spermatozoa heads have been reported in some patients receiving “slow” calcium channel blockers. Clinical data on the potential effect of amlodipine on fertility are limited.

Ability to affect reaction speed when driving or operating machinery.

Amlodipine may have a minor influence on the ability to drive or operate machinery. If a patient taking amlodipine experiences dizziness, headache, increased fatigue, or nausea, these may affect the speed and quality of reactions. Caution is recommended, especially during the initial phase of treatment.

Method of Administration and Dosage

Dosage

Adults

For hypertension and angina, the usual initial dose is 5 mg once daily. Depending on the individual patient's response to treatment, this dose may be increased to a maximum dose of 10 mg daily.

For patients with arterial hypertension, Normodipine may be used in combination with a thiazide diuretic, alpha-blocker, beta-blocker, or angiotensin-converting enzyme (ACE) inhibitor. For patients with angina who do not respond adequately to treatment with nitrates and/or appropriate doses of beta-blockers, Normodipine may be used as monotherapy or in combination with other antianginal agents.

When Normodipine is co-administered with thiazide diuretics, beta-blockers, or ACE inhibitors, dosage adjustment is not required.

Special Patient Groups

Children and adolescents aged 6 to 17 years with arterial hypertension

The recommended initial dose for treating arterial hypertension in patients aged 6 to 17 years is 2.5 mg daily (in this case, an alternative medicinal product should be used). If blood pressure control is not achieved after 4 weeks of treatment, the dose may be increased to 5 mg daily. Doses exceeding 5 mg daily have not been studied in pediatric patients (see section "Pharmacokinetics").

Elderly patients

Normodipine is similarly well tolerated in both younger and elderly patients when used at comparable doses. The standard treatment regimen is recommended for elderly patients; however, dose escalation should be performed cautiously (see sections "Special Warnings and Precautions for Use" and "Pharmacokinetics").

Hepatic impairment

Recommended dosages for patients with mild or moderate hepatic impairment have not been established. Dose titration should be performed cautiously; treatment should be initiated with the lowest recommended dose (see sections "Special Warnings and Precautions for Use" and "Pharmacokinetics"). The pharmacokinetics of amlodipine in patients with severe hepatic impairment have not been studied. Treatment in patients with severe hepatic impairment should be initiated with the lowest dose of amlodipine, and dose titration should be gradual.

Renal impairment

Plasma concentrations of amlodipine do not correlate with the degree of renal impairment; therefore, standard dosing is recommended for these patients. Amlodipine is not removed by hemodialysis.

Method of Administration

Oral tablets.

This medicinal product is not available in a 2.5 mg strength. The 5 mg Normodipine tablets are not intended to be split to achieve a 2.5 mg dose.

Children

To be used in children aged 6 years and older.

The effect of amlodipine on blood pressure in patients under 6 years of age is unknown.

Overdose

Symptoms

Available data indicate that significant overdose may lead to excessive peripheral vasodilation, potentially resulting in reflex tachycardia. Cases of severe and persistent arterial hypotension have been reported, including cases progressing to shock and fatal outcomes.

Rare cases of non-cardiogenic edema following amlodipine overdose have been reported, which may present with delayed onset (24–48 hours after ingestion) and may require initiation of mechanical ventilation. Early resuscitative measures (including fluid loading) aimed at maintaining perfusion and cardiac output may act as triggering factors.

Treatment

Clinically significant hypotension due to amlodipine overdose requires active interventions to support cardiovascular function, including elevating the lower extremities, continuous monitoring of cardiac and pulmonary status, and monitoring of circulating blood volume and diuresis.

In the absence of contraindications, vasoconstrictive agents may be used to restore vascular tone and normalize blood pressure. Intravenous calcium gluconate should be administered to counteract the effects of calcium channel blockade.

In some cases, gastric lavage may be effective. Administration of activated charcoal (10 g) to healthy volunteers immediately or within 2 hours after amlodipine intake resulted in a significant reduction in drug absorption. Because amlodipine is highly protein-bound, hemodialysis is not effective.

Adverse Reactions

The most commonly observed adverse reactions during treatment were: somnolence, dizziness, headache, palpitations, hot flushes, abdominal pain, nausea, leg swelling, edema, and fatigue.

The list of adverse reactions is presented in the table below.

When treating with amlodipine, undesirable effects were observed, with frequencies categorized as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10,000 to <1/1000); very rare (<1/10,000), and not known (cannot be estimated based on available data).

* usually accompanied by cholestasis.

Isolated cases of extrapyramidal syndrome have been reported.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important and allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are encouraged to report suspected adverse reactions through the national adverse reaction reporting system.

Shelf life.

3 years.

Storage conditions.

Keep out of reach and sight of children.

Store at a temperature not exceeding 30 °C, in the original packaging to protect from light.

Packaging.

10 tablets in a blister; 3 blisters in a cardboard pack.

Prescription status.

Prescription only.

Manufacturer. Gedeon Richter Plc., Hungary.

Manufacturer's address and location of operations.

H-1103 Budapest, Demrédi street 19-21, Hungary.