Norvasc^® (Tablets) Instructions for Use

Marketing Authorization Holder

Viatris Specialty, LLC (USA)

Manufactured By

Pfizer Pharmaceuticals, LLC (Puerto Rico)

Packaging and Quality Control Release

PFIZER MANUFACTURING DEUTSCHLAND, GmbH (Germany)

ATC Code

C08CA01 (Amlodipine)

Active Substance

Amlodipine (Rec.INN registered by WHO)

Dosage Forms

	Norvasc®	Tablets 5 mg: 14, 30, 40 or 90 pcs.
		Tablets 10 mg: 14, 30, 40 or 90 pcs.

Dosage Form, Packaging, and Composition

Tablets white or almost white, in the shape of an emerald (octagon with uneven sides), engraved with “AML 5” and a score on one side and engraved with “Pfizer” on the other; the tablet can be divided into equal doses.

Excipients: microcrystalline cellulose, anhydrous calcium hydrogen phosphate, sodium carboxymethyl starch, magnesium stearate.

10 pcs. – blisters (3) – cardboard packs with first opening control.
10 pcs. – blisters (4) – cardboard packs with first opening control.
10 pcs. – blisters (9) – cardboard packs with first opening control.
14 pcs. – blisters (1) – cardboard packs with first opening control.

Tablets white or almost white, in the shape of an emerald (octagon with uneven sides), engraved with “AML-10” on one side and engraved with “Pfizer” on the other.

Excipients: microcrystalline cellulose, anhydrous calcium hydrogen phosphate, sodium carboxymethyl starch, magnesium stearate.

10 pcs. – blisters (3) – cardboard packs with first opening control.
10 pcs. – blisters (4) – cardboard packs with first opening control.
10 pcs. – blisters (9) – cardboard packs with first opening control.
14 pcs. – blisters (1) – cardboard packs with first opening control.

Clinical-Pharmacological Group

Calcium channel blocker

Pharmacotherapeutic Group

Calcium channel blockers; selective calcium channel blockers with predominant vascular action; dihydropyridine derivatives

Pharmacological Action

Amlodipine is an inhibitor of calcium ion influx of the dihydropyridine group (a “slow” calcium channel blocker or calcium ion antagonist); it prevents the transmembrane influx of calcium ions into cardiomyocytes and vascular smooth muscle cells.

Mechanism of action

The mechanism of the antihypertensive action of amlodipine is due to a direct relaxing effect on vascular smooth muscles. The exact mechanism by which Amlodipine relieves the symptoms of angina has not been fully established, but it is known that Amlodipine reduces the total ischemic load through the following 2 factors

• By dilating peripheral arterioles, it reduces total peripheral resistance (afterload), which the heart overcomes. Since the heart rate remains stable, such cardiac unloading reduces myocardial energy consumption and its oxygen demand;

• The mechanism of action of amlodipine may also be associated with the expansion of the main coronary arteries and coronary arterioles, both in unchanged and in 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).

Pharmacodynamic effects

In patients with arterial hypertension, taking the drug once a day provides a clinically significant reduction in blood pressure in the supine and standing positions throughout the 24-hour period. Since the effects of amlodipine develop slowly, taking the drug is not associated with the risk of acute hypotension.

In patients with stable angina, a single daily dose increases exercise tolerance, slows the development of angina attacks and “ischemic” depression of the ST segment by 1 mm, and also reduces the frequency of angina attacks and the consumption of nitroglycerin and other nitrates.

Amlodipine was not associated with any metabolic adverse events or changes in plasma lipid levels and can be used in the treatment of patients with bronchial asthma, diabetes mellitus and gout. A significant decrease in blood pressure is observed after 6-10 hours, the duration of the effect is 24 hours.

Clinical efficacy and safety

Use in patients with coronary artery disease (CAD)

The efficacy of amlodipine for preventing clinical events in patients with CAD was evaluated in an independent multicenter randomized double-blind placebo-controlled study in 1997 patients: Comparison of Amlodipine vs. Enalapril to Limit Occurrences of Thrombosis – CAMELOT. Over 2 years, 663 of these patients received Amlodipine at a dose of 5-10 mg, 673 patients received enalapril at a dose of 10-20 mg, and 655 patients received placebo in addition to standard therapy, which included statins, beta-blockers, diuretics, or aspirin. Key efficacy indicators are presented in Table 1. The results show that treatment with amlodipine was accompanied by fewer hospitalizations for angina and revascularization procedures in patients with CAD.

Table 1. Frequency of significant clinical outcomes in the CAMELOT study

Use in patients with heart failure

Hemodynamic studies and controlled clinical exercise studies in patients with heart failure of functional class II-IV according to the NYHA classification demonstrated that Amlodipine does not lead to clinical deterioration, as shown by the assessment of exercise tolerance, left ventricular ejection fraction and clinical symptoms.

A placebo-controlled study (PRAISE), designed to evaluate the use of digoxin, diuretics and ACE inhibitors in patients with heart failure of functional class III-IV according to the NYHA classification, showed that Amlodipine does not lead to an increase in the risk of mortality or combined mortality and morbidity in patients with heart failure.

In a long-term placebo-controlled follow-up study (PRAISE-2) on the use of Norvasc^® in patients with heart failure of class III and IV according to the NYHA classification without clinical symptoms or objective evidence of concomitant coronary artery disease, receiving stable doses of ACE inhibitors, cardiac glycosides and diuretics, Norvasc^® did not affect overall mortality from cardiovascular diseases. In the same patient population, the use of amlodipine was accompanied by a higher incidence of pulmonary edema.

Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)

A randomized double-blind morbidity and mortality study called the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) was conducted to compare innovative drugs – amlodipine (calcium channel blocker) at doses of 2.5-10 mg/day or lisinopril (ACE inhibitor) at doses of 10-40 mg/day as first-line therapy – with chlorthalidone (thiazide diuretic) at doses of 12.5-25 mg/day for mild or moderate arterial hypertension.

A total of 33,357 patients with arterial hypertension aged 55 years and older were randomized; patients were followed for an average of 4.9 years. Patients had at least 1 additional risk factor for CAD, including: history of myocardial infarction or stroke (>6 months before inclusion in the study) or history of other atherosclerotic cardiovascular diseases (overall 51.5%), type 2 diabetes mellitus (36.1%), HDL-C level < 35 mg/dL (11.6%), left ventricular hypertrophy diagnosed by ECG or echocardiography (20.9%), and smoking (21.9%).

The primary endpoint was a combined endpoint that included fatal CAD or non-fatal myocardial infarction. There was no significant difference between the primary endpoints for amlodipine-based therapy and chlorthalidone-based therapy (HR 0.98, 95% confidence interval (CI) 0.90-1.07, p=0.65). Among the secondary endpoints, the incidence of heart failure (a component of the combined endpoint that included cardiovascular events) was statistically significantly higher in the amlodipine group compared to the chlorthalidone group (10.2% compared to 7.7%, HR 1.38, 95% CI 1.25-1.52; p< 0.001). However, there was no significant difference in all-cause mortality rates for amlodipine-based therapy and chlorthalidone-based therapy (HR 0.96, 95% CI 0.89-1.02, p=0.20).

Use in pediatric patients (aged 6 years and older)

In a study involving 268 children aged 6 to 17 years, predominantly with secondary arterial hypertension, comparing amlodipine at doses of 2.5 mg and 5.0 mg with placebo, it was shown that both doses reduce systolic blood pressure to a greater extent than placebo, and this difference in blood pressure reduction was statistically significant. The difference between these two doses of amlodipine was not statistically significant.

The long-term effects of amlodipine therapy on the growth, puberty and general development of children and adolescents have not been studied. The long-term efficacy of amlodipine therapy in childhood in terms of reducing cardiovascular morbidity and mortality in adulthood has also not been established.

Pharmacokinetics

Absorption

After oral administration, Amlodipine is well absorbed from the gastrointestinal tract, C_max in blood serum is determined 6-12 hours after administration. Absolute bioavailability is 64-80%. C_ss in plasma is achieved after 7-8 days of therapy.

Distribution

V_d is about 21 L/kg. In vitro studies have shown that approximately 97.5% of circulating amlodipine binds to plasma proteins. Food intake does not affect the bioavailability of amlodipine.

Metabolism

The terminal T_1/2 from plasma is 35-50 hours.

Excretion

Amlodipine is extensively metabolized in the liver to form inactive metabolites, with 10% of the parent compound and 60% of the metabolites excreted in the urine.

Pharmacokinetics in special clinical cases

Elderly patients. The time to reach C_max of amlodipine in plasma is similar in elderly and young patients. In elderly patients, the clearance of amlodipine tends to decrease, leading to an increase in AUC and T_1/2, but this difference is not clinically significant. The increase in AUC and T_1/2 in patients with heart failure corresponded to the expected values for the studied age groups of patients.

Hepatic impairment. Available clinical data on the use of amlodipine in patients with impaired liver function are limited. In patients with hepatic impairment, there is a decrease in the clearance of amlodipine, leading to a prolongation of T_1/2 and an increase in AUC values by approximately 40-60%.

Use in pediatric patients. A population pharmacokinetic study was conducted with 74 pediatric patients with hypertension aged 1 to 17 years (34 patients aged 6 to 12 years and 28 patients aged 13 to 17 years) receiving Amlodipine at a dose of 1.25 to 20 mg once or twice daily. The mean oral clearance (CL/F) in children aged 6 to 12 years and adolescents aged 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. Large differences in exposure were observed among patients. Data for children under 6 years of age are limited.

Indications

• Arterial hypertension in adults (both as monotherapy and in combination with other antihypertensive agents);
• Arterial hypertension in children aged 6-17 years;
• Stable angina and vasospastic angina (Prinzmetal’s angina or variant angina) (both as monotherapy and in combination with other antianginal agents).

ICD codes

Dosage Regimen

Orally once a day.

For arterial hypertension and angina the initial dose is 5 mg, depending on the therapeutic response it can be increased to a maximum daily dose of 10 mg.

In patients with arterial hypertension, Amlodipine is used in combination with thiazide diuretics, alpha-blockers, beta-blockers or ACE inhibitors. For angina, Amlodipine can be used as monotherapy or in combination with other antianginal drugs in patients with angina that is refractory to nitrates and/or beta-blockers at an adequate dose.

No dose adjustment is required when used concomitantly with thiazide diuretics, beta-blockers and ACE inhibitors.

Special patient groups

Elderly patients

Norvasc^® is well tolerated by elderly and younger patients when used in equal doses. Dose adjustment is not required. Elderly patients are recommended to use the average therapeutic dose, and if it is necessary to increase the dose, this should be done with caution.

Patients with hepatic impairment

There are no dosing recommendations for patients with mild or moderate hepatic impairment; therefore, the dose of the drug should be selected carefully and treatment should be started at the lowest value of the dose range.

The pharmacokinetics of amlodipine in severe hepatic impairment have not been studied. In patients with severe hepatic impairment, the drug is started at the lowest dose and slowly increased by titration. Dose adjustment is usually not required.

Patients with renal impairment

Changes in amlodipine plasma concentrations do not correlate with the degree of renal impairment, so the usual dose is recommended in such patients. Amlodipine is not removed by dialysis.

Children

Children and adolescents from 6 to 17 years with arterial hypertension. The recommended antihypertensive oral dose in pediatric patients from 6 to 17 years is 2.5 mg once daily as an initial dose, increasing to 5 mg once daily if target blood pressure is not achieved after 4 weeks. The use of doses exceeding 5 mg/day in children has not been studied.

Pediatric patients under 6 years of age. The safety and efficacy of amlodipine in children aged 0 to 6 years have not been established. No data available.

Adverse Reactions

Summary of the safety profile

The most frequent adverse reactions (AR) reported during therapy were drowsiness, dizziness, headache, palpitations, flushing, abdominal pain, nausea, ankle swelling, edema and increased fatigue.

The frequency of AR is defined as: very common (≥1/10), common (from ≥1/100 to <1/10), uncommon (from ≥1/1000 to <1/100), rare (from ≥1/10000 to <1/1000), very rare (<1/10000) and frequency unknown (cannot be estimated from available data).Within each frequency group, adverse reactions are listed in descending order of severity.

Contraindications

• Hypersensitivity to amlodipine, dihydropyridine derivatives, or to any of the excipients of the used medicinal product;
• Severe arterial hypotension (systolic BP less than 90 mm Hg);
• Shock (including cardiogenic shock);
• Obstruction of the left ventricular outflow tract (including severe aortic stenosis);
• Hemodynamically unstable heart failure after acute myocardial infarction;
• Children under 6 years of age (efficacy and safety not established for arterial hypertension), for other indications the medicinal product is contraindicated in patients under 18 years of age.

Use in Pregnancy and Lactation

Pregnancy

The safety of amlodipine use in pregnant women has not been established. In animal studies, reproductive toxicity was observed at high doses.

Use during pregnancy is only possible in the absence of a safer alternative treatment option and in cases where the disease itself poses a greater risk to the mother and fetus.

Breastfeeding period

Experience with the medicinal product shows that Amlodipine is excreted in breast milk.

The proportion of the maternal dose received by the infant is estimated in the interquartile range of 3-7%, maximum 15%. The impact of amlodipine on young children is unknown. The decision to continue or discontinue breastfeeding, or to continue or discontinue amlodipine therapy should be made taking into account the benefits of breastfeeding for the child and the benefits of amlodipine therapy for the mother.

Fertility

Some patients treated with calcium channel blockers have reported cases of reversible biochemical changes in sperm heads. There is insufficient clinical data on the possible effect of amlodipine on reproductive function. In 1 rat study, adverse effects on male reproductive function were found.

Use in Hepatic Impairment

There are no dosing recommendations for patients with mild or moderate hepatic impairment; therefore, the dose of the medicinal product should be selected carefully and treatment should be started at the lowest value of the dose range. In patients with severe hepatic impairment, the medicinal product should be started at the lowest dose and slowly increased by titration. Dose adjustment is usually not required.

Use in Renal Impairment

Changes in amlodipine plasma concentrations do not correlate with the degree of renal impairment, so the usual dose is recommended for such patients. Amlodipine is not eliminated by dialysis.

Pediatric Use

Contraindication: children under 6 years of age (efficacy and safety not established for arterial hypertension), for other indications Amlodipine is contraindicated in patients under 18 years of age.

Geriatric Use

Dose adjustment is not required. Elderly patients are recommended to use the average therapeutic dose, and caution is required if a dose increase is necessary.

Special Precautions

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

Patients with heart failure

Caution should be exercised when using in patients with heart failure. In a long-term placebo-controlled study in patients with severe heart failure (NYHA class III and IV), the reported incidence of pulmonary edema was higher in the amlodipine treatment group than in the placebo group (see the “Pharmacological action” section). Calcium channel blockers, including Amlodipine, should be used with caution in patients with congestive heart failure, as they may increase the risk of future cardiovascular complications and the risk of fatal outcome.

Patients with hepatic impairment

The T_1/2 of amlodipine is prolonged and AUC values are increased in patients with hepatic impairment; dosing recommendations for such patients have not been established. In view of this, the use of amlodipine should be started at the lowest value of the recommended range, with caution both at the start of therapy and when increasing the dose. In patients with severe hepatic impairment, gradual dose increase by titration and careful monitoring of their condition may be required.

Elderly patients

In elderly patients, dose increases should be performed with caution.

Patients with renal impairment

For such patients, Amlodipine can be used at usual doses. Changes in amlodipine plasma concentrations do not correlate with the degree of renal impairment. Amlodipine is not eliminated by dialysis.

Effect on ability to drive and operate machinery

Amlodipine may have a minor or moderate effect on the ability to drive and operate machinery. If patients taking Amlodipine experience dizziness, headache, increased fatigue, or nausea, their reaction speed may be impaired. Caution is recommended, especially at the start of therapy.

Drug Interactions

Effect of other medicinal products on Amlodipine

CYP3A4 isoenzyme inhibitors

Concomitant use of amlodipine with potent or moderate CYP3A4 isoenzyme inhibitors (protease inhibitors, azole antifungals, macrolides such as erythromycin or clarithromycin, verapamil or diltiazem) may cause a significant increase in amlodipine exposure, leading to an increased risk of arterial hypotension. The clinical manifestations of these pharmacokinetic changes may be more pronounced in elderly patients. In this regard, clinical monitoring and dose adjustment of amlodipine may be necessary.

CYP3A4 inducers

When used concomitantly with known CYP3A4 isoenzyme inducers, the plasma concentration of amlodipine may vary. In this regard, it is necessary to monitor BP and assess the need for dose adjustment both during and after concomitant therapy, especially with potent CYP3A4 inducers (e.g., rifampicin, St. John’s wort).

It is not recommended to take Amlodipine concomitantly with grapefruit or grapefruit juice, as in some patients this may lead to increased bioavailability of amlodipine, which will enhance its hypotensive effects.

Dantrolene (infusion)

In animals, lethal ventricular fibrillation and cardiovascular collapse in combination with hyperkalemia were observed after verapamil administration and intravenous dantrolene administration. Due to the risk of hyperkalemia, it is recommended to avoid concomitant use of calcium channel blockers, such as Amlodipine, in patients predisposed to malignant hyperthermia and receiving treatment for malignant hyperthermia.

Effect of amlodipine on other medicinal products

The hypotensive effects of amlodipine are additive to the hypotensive effects of other medicinal products with antihypertensive properties.

Tacrolimus

When used concomitantly with amlodipine, there is a risk of increased plasma concentration of tacrolimus, but the pharmacokinetic mechanisms of this interaction are not sufficiently studied. To avoid tacrolimus toxicity when used concomitantly with amlodipine, the plasma concentration of tacrolimus in patients should be monitored and the dose of tacrolimus should be adjusted if necessary.

Mechanistic target of rapamycin (mTOR) inhibitors

MTOR inhibitors, such as sirolimus, temsirolimus, and everolimus, are substrates of the CYP3A isoenzyme. Amlodipine is a weak inhibitor of the CYP3A isoenzyme. When used concomitantly with mTOR inhibitors, Amlodipine may increase their exposure.

Cyclosporine

Interaction studies of cyclosporine and amlodipine have not been conducted in healthy volunteers or in other populations, except for patients who have undergone kidney transplantation, in whom varying increases in cyclosporine trough concentrations (on average 0-40%) were observed. Consideration should be given to monitoring cyclosporine levels in patients who have undergone kidney transplantation and are receiving Amlodipine, and the dose of cyclosporine should be reduced if necessary.

Simvastatin

Concomitant multiple administration of amlodipine 10 mg and simvastatin 80 mg leads to a 77% increase in simvastatin exposure compared to simvastatin alone. For patients taking Amlodipine, the daily dose of simvastatin should not exceed 20 mg.

In clinical drug interaction studies, Amlodipine did not affect the pharmacokinetics of atorvastatin, digoxin or warfarin.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.