Amlodipine sandoz®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT AMLIPIDINE SANDOZ® (AMLODIPINE SANDOZ®)

Composition:

Active substance: amlodipine;

One tablet contains 5 mg or 10 mg of amlodipine in the form of amlodipine besylate;

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

Pharmaceutical form. Tablets.

Main physicochemical properties:

5 mg tablets: white or almost white, elongated tablets with bevel, a groove on one side and marking "5" on the other;

10 mg tablets: white or almost white, elongated tablets with bevel, a groove on one side and marking "10" on the other.

Pharmacotherapeutic group.

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

Pharmacological Properties

Pharmacodynamics

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

The antihypertensive effect of amlodipine is due to its direct vasodilating action on vascular smooth muscle. The exact mechanism of amlodipine's antianginal effect is not fully understood; however, the following effects are considered to play a role:

• 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;
• Dilation of major coronary arteries and coronary arterioles (both normal and ischemic) may also contribute to amlodipine’s mechanism of action. 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 blood pressure over 24 hours, both in supine and standing positions. Due to the slow onset of amlodipine’s action, acute hypotension is generally not observed.

In patients with angina, once-daily dosing 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. 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; the acid dissociation constant (pKa) of amlodipine is 8.6. In vitro studies have shown that protein binding of amlodipine to plasma proteins is approximately 97.5%.

Concomitant food intake does not affect the absorption of amlodipine.

Metabolism/Excretion

The elimination half-life from plasma is approximately 35–50 hours. Steady-state plasma concentrations are 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

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

Patients with Renal Impairment

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

Patients with Hepatic Impairment

Information on amlodipine use 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 once or twice daily. Oral clearance in children aged 6 to 12 years and 13 to 17 years was typically 22.5 and 27.4 L/hour, respectively, in boys, and 16.4 and 21.3 L/hour, respectively, in girls. There is considerable inter-patient variability in exposure. Data in patients under 6 years of age are limited.

Clinical characteristics.

Indications.

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

Contraindications.

Known hypersensitivity to dihydropyridines, amlodipine, or any other component of the drug. 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.

Available data indicate safe co-administration of amlodipine with thiazide diuretics, alpha-blockers, beta-blockers, ACE inhibitors, long-acting nitrates, sublingual nitroglycerin, nonsteroidal anti-inflammatory drugs (NSAIDs), antibiotics, and oral hypoglycemic agents.

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

CYP3A4 inhibitors. Concomitant use of amlodipine and strong or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, 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 these 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 be increased, thereby enhancing its hypotensive effect.

CYP3A4 inducers. Plasma concentrations of amlodipine may change when co-administered with known CYP3A4 inducers. Therefore, blood pressure should be monitored and dose adjustments made accordingly, both during and after concomitant therapy, especially with strong CYP3A4 inducers (e.g., rifampicin, St. John’s wort).

Dantrolene (infusions). Ventricular fibrillation with fatal outcome and cardiovascular collapse due to hyperkalemia have been observed in animals following intravenous administration of verapamil and dantrolene. Due to the risk of hyperkalemia, concomitant use of calcium channel blockers such as amlodipine should be avoided in patients susceptible to malignant hyperthermia and during treatment of malignant hyperthermia.

Effect of amlodipine on other medicinal products.

The antihypertensive effect of amlodipine may enhance the hypotensive effect of other antihypertensive agents. Drug interaction studies have shown that amlodipine does not affect the pharmacokinetics of atorvastatin, digoxin, or warfarin.

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

mTOR inhibitors (mammalian target of rapamycin – 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 potentiate their effects.

Cyclosporine. No interaction studies between cyclosporine and amlodipine have been conducted in healthy volunteers or other patient groups, except in kidney transplant recipients, in whom variable increases in cyclosporine trough concentrations (on average by 0–40%) have been observed. For kidney transplant recipients receiving amlodipine, monitoring of cyclosporine concentrations should be considered, and cyclosporine dosage reduced if necessary.

Simvastatin. Concomitant administration of multiple 10 mg doses of amlodipine and 80 mg of simvastatin results in a 77% increase in simvastatin exposure compared to simvastatin alone. The recommended maximum dose of simvastatin in patients taking amlodipine is 20 mg daily.

Sildenafil. A single 100 mg dose of 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.

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 did not affect the pharmacokinetics of amlodipine.

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

Laboratory tests. The effect on laboratory test parameters is unknown.

Other medicinal products.

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

Special precautions for use.

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

Patients with heart failure.

Amlodipine should be used with caution in this patient population. Data indicate an increased frequency of pulmonary edema in patients with severe heart failure (NYHA class III and IV) treated with amlodipine. 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 mortality in the future.

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 this patient group should be initiated at the lowest dose. Caution is advised 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 with caution.

Patients with renal impairment.

Standard doses of the drug are recommended for this patient group. 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 this may increase bioavailability, leading to an enhanced hypotensive effect of the drug.

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 if the risk associated with the underlying disease exceeds the potential risk to the mother and fetus.

Reproductive toxicity was observed in animal studies with high doses.

Breastfeeding period. Amlodipine passes into breast milk. The amount of amlodipine transferred to the infant via maternal milk may range from 3–7 to 15% of the maternal dose. The effects of amlodipine on infants are unknown. When deciding whether to continue breastfeeding or to use amlodipine, the benefits of breastfeeding for the infant and the therapeutic benefits for the mother should be carefully weighed.

Fertility. Reversible biochemical changes in sperm head morphology have been reported in some patients receiving 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 or moderate effect on the ability to drive or operate machinery. Reaction speed may be reduced in the presence of symptoms such as dizziness, headache, confusion, or nausea.

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 is 5 mg 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 pectoris, the drug may be used as monotherapy or in combination with other antianginal agents in cases of resistance to nitrates and/or adequate doses of beta-blockers.

There is experience 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 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.

Tablets of 5 mg and 10 mg are suitable for splitting to obtain doses of 2.5 mg and 5 mg, respectively.

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

Use in patients with hepatic insufficiency.

Dosage recommendations for patients with mild to moderate hepatic impairment have not been established; therefore, dose titration should be performed cautiously, starting with the lowest dose (see sections "Special Warnings" and "Pharmacokinetics"). The pharmacokinetics of amlodipine have not been studied in patients with severe hepatic impairment. For such patients, amlodipine therapy should be initiated at the lowest dose with gradual dose escalation.

Children.

The drug may be 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: available data suggest that significant overdose of amlodipine may lead to excessive peripheral vasodilation and possibly reflex tachycardia. Cases of severe and potentially prolonged systemic arterial hypotension have been reported, including fatal shock.

Treatment: clinically significant hypotension due to amlodipine overdose requires active cardiovascular support, including continuous monitoring of cardiac and respiratory function, elevation of the lower limbs, and monitoring of circulating fluid volume and urine output.

Vasoconstrictors 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 to healthy volunteers within 2 hours after ingestion of 10 mg amlodipine significantly reduced its absorption.

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

Rare cases of non-cardiogenic pulmonary edema have been reported following amlodipine overdose, which may present with delayed onset (24–48 hours after ingestion) and may require mechanical ventilation. Contributing factors to the development of non-cardiogenic pulmonary edema may include early resuscitation measures (including fluid overload) aimed at maintaining perfusion and cardiac output.

Adverse Reactions

The most commonly reported adverse reactions during amlodipine use are: somnolence, dizziness, headache, palpitations (increased heart rate), flushing, abdominal pain, nausea, leg swelling, edema, and fatigue.

Adverse reactions reported during amlodipine use are listed below by system organ classes and frequency of occurrence: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10,000, < 1/1000), very rare (≤ 1/10,000), and not known (cannot be estimated from 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 – insomnia, mood changes (including anxiety), depression; 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; 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 – hypotension; very rare – vasculitis.

Respiratory, thoracic and mediastinal disorders: common – dyspnea; uncommon – rhinitis, cough.

Gastrointestinal disorders: common – abdominal pain, nausea, dyspepsia, intestinal motility disorders (including constipation and diarrhea); uncommon – vomiting, dry mouth; very rare – pancreatitis, gastritis, gingival hyperplasia.

Hepatobiliary disorders: very rare – hepatitis, jaundice, increased levels of 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, toxic epidermal necrolysis, erythema multiforme, exfoliative dermatitis, Quincke's edema, photosensitivity; 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, gynaecomastia.

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. Serious adverse reactions (mainly headache) occurred in 7.2% of patients receiving 2.5 mg amlodipine, in 4.5% of patients receiving 5 mg amlodipine, and in 4.6% in the placebo group. The most common reason for withdrawal from the study was uncontrolled hypertension. No withdrawal was due to abnormal laboratory test results. No significant changes in pulse rate were observed.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicine. Healthcare professionals should report any suspected adverse reactions in accordance with applicable regulatory requirements.

Shelf life. 3 years.

Storage conditions.

Store at temperatures not exceeding 25 °C, in the original packaging to protect from light and moisture.

Keep out of reach and sight of children.

Packaging.

15 tablets in a blister; 2 blisters (15 × 2) in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Lek Pharmaceuticals d.d.

or

Lek Pharmaceuticals d.d.

or

Lek S.A.

Address of the manufacturer and location of operations.

Verovškova 57, 1526 Ljubljana, Slovenia

or

Trimlin 2d, 9220 Lendava, Slovenia

or

Podlipje 16, Strzykow, 95-010, Poland.