Amlodipine-fitopharm

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT AMLODIPINE-PHYTOPHARM (AMLODIPINE-PHYTOPHARM)

Composition:

Active substance: amlodipine besylate;

1 tablet contains 7.45 mg of amlodipine besylate (equivalent to 5 mg of amlodipine);

Excipients: magnesium carbonate heavy, microcrystalline cellulose, potato starch, magnesium stearate, povidone, talc.

Pharmaceutical form. Tablets.

Main physicochemical characteristics: white-colored, round, flat tablets with a bevel and a division line on one side.

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

Pharmacological properties.

Pharmacodynamics.

Amlodipine is a calcium antagonist (a dihydropyridine derivative) that blocks the influx of calcium ions into myocardial and smooth muscle cells.

The antihypertensive mechanism of action of amlodipine is due to its direct vasodilating effect on vascular smooth muscle. The exact mechanism of the antianginal effect of amlodipine is not fully understood, but the following effects are believed to play a role.

1. Amlodipine dilates peripheral arterioles, thereby reducing peripheral resistance (afterload). Since heart rate remains stable, this reduction in cardiac workload leads to decreased myocardial energy consumption and oxygen demand.
2. Dilation of major coronary arteries and coronary arterioles (both normal and ischemic) may also contribute to the mechanism of action of amlodipine. This dilation increases myocardial oxygen supply in patients with coronary artery spasm (Prinzmetal’s angina or variant angina).

In patients with arterial hypertension, once-daily administration of the drug provides clinically significant reduction in arterial blood pressure over 24 hours, both in supine and standing positions. Due to the slow onset of 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. After oral administration of therapeutic doses, amlodipine is gradually absorbed into plasma. Concomitant food intake does not affect the absorption of amlodipine. The absolute bioavailability of the unchanged molecule is approximately 64–80%. Peak plasma concentration is reached within 6–12 hours after administration.

The volume of distribution is approximately 21 L/kg, and the acid dissociation constant (pKa) of amlodipine is 8.6. In vitro studies have shown that plasma protein binding of amlodipine is approximately 97.5%.

Concomitant food intake does not affect the absorption of amlodipine.

Metabolism/elimination. The elimination half-life from plasma is approximately 35–50 hours. Steady-state plasma concentration is achieved after 7–8 days of continuous drug administration. Amlodipine is primarily metabolized to inactive metabolites. Approximately 60% of the administered dose is excreted in urine, of which about 10% is unchanged amlodipine.

Elderly patients. The time to reach steady-state plasma concentrations of amlodipine is similar in elderly and adult patients. Amlodipine clearance is generally slightly reduced, which in elderly patients leads to increased area under the concentration-time curve (AUC) and prolonged elimination half-life.

Patients with renal impairment. Amlodipine is extensively biotransformed into inactive metabolites. About 10% of amlodipine is excreted unchanged in urine. Changes in plasma amlodipine concentrations do not correlate with the degree of renal impairment. Standard doses of amlodipine can be used in patients with impaired renal function. Amlodipine is not removed by dialysis.

Patients with hepatic impairment. Information on the use of amlodipine in patients with hepatic impairment is very limited. In patients with hepatic insufficiency, amlodipine clearance is reduced, resulting in prolonged elimination half-life and an increase in AUC by approximately 40–60%.

Children. Pharmacokinetic studies were conducted in 74 children aged 12 to 17 years with arterial hypertension (also including 34 patients aged 6 to 12 years and 28 patients aged 13 to 17 years), who received amlodipine at doses of 1.25–20 mg daily in one or two doses. Typical oral clearance in children aged 6 to 12 years and 13 to 17 years was 22.5 and 27.4 L/hour, respectively, in boys, and 16.4 and 21.3 L/hour, respectively, in girls. Considerable variability in exposure among individual patients was observed. Information on patients under 6 years of age is limited.

Clinical characteristics.

Indications.

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

Contraindications.

• Known hypersensitivity to dihydropyridines, amlodipine, or to 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.

Safety data are available regarding the use of amlodipine with thiazide diuretics, alpha-blockers, beta-blockers, ACE inhibitors, long-acting nitrates, sublingual nitroglycerin, nonsteroidal anti-inflammatory drugs, antibiotics, and oral hypoglycemic agents.

Data obtained from in vitro studies using human plasma indicate that amlodipine does not affect the protein binding of the investigated medicinal products (digoxin, phenytoin, warfarin, or indomethacin).

CYP3A4 inhibitors.

Concomitant use of amlodipine and 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 exposure, which may also increase the risk of hypotension. The clinical significance of such changes may be more pronounced in elderly patients. Clinical monitoring and dose adjustment may be necessary.

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

CYP3A4 inducers.

Plasma concentrations of amlodipine may change following concomitant use with known CYP3A4 inducers. Therefore, blood pressure should be monitored and dosage adjusted accordingly during and after concomitant therapy, particularly with strong CYP3A4 inducers (e.g., rifampicin, St. John’s wort).

Dantrolene (infusions).

In animals, ventricular fibrillation with fatal outcome and cardiovascular collapse associated with hyperkalemia have been observed after intravenous administration of verapamil and dantrolene. Due to the risk of hyperkalemia, it is recommended to avoid using calcium channel blockers such as amlodipine in patients susceptible to malignant hyperthermia and during treatment of malignant hyperthermia.

Effect of amlodipine on other medicinal products.

The hypotensive effect of amlodipine may potentiate the hypotensive effects of other antihypertensive agents.

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 during concomitant use with amlodipine, regular monitoring of tacrolimus blood levels is required, and dosage adjustment may be necessary.

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 used concomitantly with mTOR inhibitors, amlodipine may enhance their effects.

Cyclosporine.

Interaction studies between cyclosporine and amlodipine have not been conducted in healthy volunteers or other patient groups, except in kidney transplant patients, in whom variable increases in cyclosporine trough concentrations (on average 0–40%) have been observed. For kidney transplant patients receiving amlodipine, monitoring of cyclosporine concentrations should be considered, and cyclosporine dosage reduction may be necessary.

Simvastatin.

Concomitant administration of multiple doses of 10 mg amlodipine and 80 mg simvastatin resulted in a 77% increase in simvastatin exposure compared to simvastatin alone. For patients receiving amlodipine, the simvastatin dose should be limited to 20 mg daily.

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.

Clinical interaction studies have shown that amlodipine does not affect the pharmacokinetics of atorvastatin, digoxin, warfarin, or cyclosporine.

Ethanol (alcohol).

Single and multiple doses of 10 mg amlodipine had no significant effect on the pharmacokinetics of ethanol.

Concomitant administration of amlodipine with cimetidine had no effect on amlodipine pharmacokinetics.

Concomitant administration of aluminum/magnesium-containing products (antacids) with a single dose of amlodipine had no significant effect on amlodipine pharmacokinetics.

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 evaluated.

Patients with heart failure.

Amlodipine-Phytopharm should be used with caution in this patient group. In a long-term placebo-controlled study in patients with severe heart failure (NYHA class III and IV), the incidence of pulmonary edema was higher with amlodipine than with placebo. Calcium channel blockers, including amlodipine, should be used with caution in patients with congestive heart failure, as they may increase the risk of cardiovascular events and future mortality.

Patients with hepatic impairment.

The elimination half-life and AUC parameters of amlodipine are higher in patients with hepatic impairment; however, no specific dosage recommendations are available. Therefore, treatment in these patients should be initiated at the lowest dose. Caution should be exercised both at the start of treatment and during dose escalation. Patients with severe hepatic impairment may require slow dose titration and careful monitoring.

Elderly patients.

Dose escalation in this patient group should be performed cautiously.

Patients with renal impairment.

This patient group should receive the usual doses of the drug. Changes in amlodipine plasma concentrations do not correlate with the degree of renal impairment. Amlodipine is not removed by dialysis.

Amlodipine does not affect laboratory test results.

Concomitant use of amlodipine with grapefruit or grapefruit juice is not recommended, as in some patients bioavailability may be increased, leading to an enhanced hypotensive effect of the drug.

Fertility.

Reversible biochemical changes in the spermatozoa head have been reported in some patients receiving calcium channel blockers. Clinical data on the potential effect of amlodipine on fertility are insufficient.

Use during pregnancy or breastfeeding.

The safety of amlodipine use in pregnant women has not been established.

Amlodipine should be used during pregnancy only if safer alternatives are unavailable and the risk associated with the underlying disease outweighs the potential risk to the mother and fetus.

In animal studies, reproductive toxicity was observed with high doses.

Lactation period.

Amlodipine is excreted in breast milk. The infant dose received from the mother is estimated to be 3–7% in the interquartile range, with a maximum of 15%. The effects of amlodipine on infants are unknown. When deciding whether to continue breastfeeding or to use amlodipine, the benefit of breastfeeding for the child and the benefit of the drug for the mother should be weighed.

Ability to affect reaction speed when driving or operating machinery.

Amlodipine may have a slight or moderate effect on the ability to drive or operate machinery.

Reaction speed may be reduced if symptoms such as dizziness, headache, confusion, or nausea occur.

Caution is advised, especially at the beginning of therapy.

Method of Administration and Dosage.

Adults.

For the treatment of arterial hypertension and angina pectoris, the usual initial dose of the drug is 5 mg of amlodipine once daily. Depending on the patient's response to therapy, the dose may be increased up to the maximum dose of 10 mg once daily.

In patients with angina, the drug can be used as monotherapy or in combination with other antianginal medicinal products in cases of resistance to nitrates and/or adequate doses of beta-blockers.

There is experience with using the drug in combination with thiazide diuretics, alpha-blockers, beta-blockers, or angiotensin-converting enzyme inhibitors in patients with arterial hypertension.

There is no need for dose adjustment when the drug is used concomitantly with thiazide diuretics, beta-blockers, or angiotensin-converting enzyme inhibitors.

Children aged 6 years and older with arterial hypertension.

The recommended initial dose of the drug for this patient group is 2.5* mg once daily. If the target blood pressure level is not achieved within 4 weeks, the dose may be increased to 5 mg daily. The use of doses higher than 5 mg in this patient group has not been studied.

Elderly patients.

There is no need for dose adjustment in this patient group. Dose escalation should be performed with caution.

Patients with renal impairment.

Standard doses of the drug are recommended, as changes in amlodipine plasma concentrations are not related to the severity of renal impairment. Amlodipine is not removed by dialysis.

Patients with hepatic impairment.

Doses of the drug for patients with mild to moderate hepatic impairment have not been established; therefore, dose titration should be performed with caution, starting with the lowest dose within the recommended range (see sections "Special Warnings" and "Pharmacological Properties. Pharmacokinetics").

The pharmacokinetics of amlodipine have not been studied in patients with severe hepatic impairment. In patients with severe hepatic impairment, amlodipine therapy should be initiated at the lowest dose, with gradual dose escalation.

Tablets containing 5 mg of the drug are not intended to be split to achieve a 2.5 mg dose.

* administer amlodipine preparations at the appropriate dosage.

Children.

The drug is administered to children aged 6 years and older.

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

Overdose.

Experience with intentional overdose of the drug is limited.

Symptoms of overdose. Available data suggest that significant overdose of the drug will lead to excessive peripheral vasodilation and possibly reflex tachycardia. Cases of severe and potentially prolonged systemic arterial hypotension have been reported, including shock with fatal outcome.

Rarely, noncardiogenic pulmonary edema has been reported as a consequence of amlodipine overdose, which may present with delayed onset (24–48 hours after ingestion) and may require initiation of mechanical ventilation. Early resuscitation measures (including fluid loading) to support perfusion and cardiac output may be precipitating factors.

Treatment. Clinically significant arterial hypotension caused by amlodipine overdose requires active cardiovascular support, including continuous monitoring of cardiac and respiratory functions, elevation of the lower limbs, and monitoring of circulating fluid volume and urine output.

Vasoconstrictor agents may be used to restore vascular tone and blood pressure, provided there are no contraindications to their use. Intravenous calcium gluconate may be beneficial in counteracting the effects of calcium channel blockade.

In some cases, gastric lavage may be helpful. Administration of activated charcoal within 2 hours after ingestion of 10 mg of amlodipine significantly reduced its absorption in healthy volunteers.

Since amlodipine is highly protein-bound, dialysis is of negligible benefit.

Adverse reactions.

When amlodipine is used, the most commonly reported adverse reactions include somnolence, dizziness, headache, palpitations, flushing, abdominal pain, nausea, ankle swelling, edema, and increased fatigue.

The adverse reactions reported during the use of amlodipine are listed below by system organ classes and frequency of occurrence: 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), frequency not known (cannot be estimated based on available data).

Blood and lymphatic system disorders.

Very rare: leukopenia, thrombocytopenia.

Immune system disorders.

Very rare: allergic reactions.

Metabolism and nutrition disorders.

Very rare: hyperglycemia.

Psychiatric disorders.

Uncommon: depression, mood changes (including anxiety), insomnia.

Rare: confusion.

Nervous system disorders.

Common: somnolence, dizziness, headache (mainly at the beginning of treatment).

Uncommon: tremor, dysgeusia, syncope, hypesthesia, paresthesia.

Very rare: hypertonia, peripheral neuropathy.

Frequency not known: extrapyramidal disorders.

Eye disorders.

Common: visual disturbances (including diplopia).

Ear and labyrinth disorders.

Uncommon: tinnitus.

Cardiac disorders.

Common: palpitations.

Uncommon: arrhythmia (including bradycardia, ventricular tachycardia, and atrial fibrillation).

Very rare: myocardial infarction.

Vascular disorders.

Common: flushing.

Uncommon: arterial hypotension.

Very rare: vasculitis.

Respiratory, thoracic and mediastinal disorders.

Common: dyspnea.

Uncommon: cough, rhinitis.

Gastrointestinal disorders.

Common: abdominal pain, nausea, dyspepsia, altered intestinal peristalsis (including diarrhea and constipation).

Uncommon: vomiting, dry mouth.

Very rare: pancreatitis, gastritis, gingival hyperplasia.

Hepatobiliary disorders.

Very rare: hepatitis, jaundice, increased liver enzymes (most commonly associated with cholestasis).

Skin and subcutaneous tissue disorders.

Uncommon: alopecia, purpura, skin discoloration, increased sweating, pruritus, rash, exanthema, urticaria.

Very rare: angioneurotic edema, Stevens-Johnson syndrome, exfoliative dermatitis, erythema multiforme, Quincke's edema, photosensitivity.

Frequency not known: toxic epidermal necrolysis.

Musculoskeletal and connective tissue disorders.

Common: leg swelling, muscle cramps.

Uncommon: arthralgia, myalgia, back pain.

Renal and urinary disorders.

Uncommon: micturition disorder, nocturia, increased frequency of urination.

Reproductive system and breast disorders.

Uncommon: impotence, gynecomastia.

General disorders and administration site conditions.

Very common: edema.

Common: fatigue, asthenia.

Uncommon: chest pain, pain, malaise.

Investigations.

Uncommon: weight gain or weight loss.

Rare cases of extrapyramidal syndrome have been reported.

Children.

Amlodipine is well tolerated in children. The adverse reaction profile was similar to that observed in adults. In a study involving 268 children, the most commonly reported adverse reactions were headache, dizziness, vasodilation, epistaxis, abdominal pain, and asthenia.

Most adverse reactions were mild or moderate in severity. Severe adverse reactions (mainly headache) occurred in 7.2% of patients receiving 2.5 mg amlodipine, in 4.5% receiving 5 mg amlodipine, and in 4.6% in the placebo group. The most common reason for study discontinuation was uncontrolled hypertension. No study discontinuations were due to laboratory abnormalities. No significant changes in pulse rate were observed.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after a medicinal product is authorized is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions in accordance with applicable regulatory requirements.

Shelf life. 2 years 6 months.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.

The medicinal product must not be used after the expiry date stated on the packaging.

Packaging. 10 tablets per blister; 2 or 3 blisters per carton.

Prescription status. Prescription only.

Manufacturer. JSC "FITOPHARM".

Manufacturer's address.

2 Sybirtseva St., Bakhmut, Donetsk region, 84500, Ukraine.

Marketing Authorization Holder. JSC "FITOPHARM".

Address of the Marketing Authorization Holder.

7, Verkhovnoyi Rady Ave., Kyiv, 02100, Ukraine, floor 3, room 18.