Amlodipine bosnalek®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT AMLODIL BOSNALIJEK® (AMLODIL BOSNALIJEK®)

Composition:

Active substance: amlodipine;

1 capsule contains 5 mg of amlodipine (as besylate);

Excipients: maize starch, microcrystalline cellulose, anhydrous colloidal silicon dioxide, magnesium stearate;

Capsule shell composition: titanium dioxide (colorant), quinoline yellow (E 104), yellow FCF (E 110), gelatin.

Pharmaceutical form. Hard capsules.

Main physicochemical properties: hard gelatin capsules consisting of a body and a cap. Capsule color: white opaque body and yellow opaque cap. Capsule size – 3. Contents: granules ranging from almost white to yellowish-white.

Pharmacotherapeutic group. Selective calcium antagonists with predominant vascular effect. Dihydropyridine derivatives. 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 action of amlodipine is due to its direct vasodilating effect on vascular smooth muscle. The exact mechanism of amlodipine's antianginal effect is not fully understood, but the following effects are considered 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 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 arterial hypotension is usually not observed.

In patients with angina, administration of a single daily dose increases total exercise time, 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, with peak plasma concentration (Cmax) reached within 6–12 hours after administration. Absolute bioavailability is approximately 64–80%. The volume of distribution is about 21 L/kg. Plasma protein binding of amlodipine is approximately 97.5%. Concomitant food intake does not affect amlodipine absorption.

Metabolism/Excretion.

The elimination half-life from plasma is approximately 35–50 hours. Amlodipine is primarily metabolized to inactive metabolites. Approximately 60% of the administered dose is excreted in urine, of which about 10% is unchanged amlodipine.

Patients with renal impairment.

This patient group should receive standard doses of the drug. Changes in amlodipine plasma concentrations do not correlate with the degree of 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 the area under the concentration-time curve (AUC) by approximately 40–60%.

Elderly patients.

Time to reach Cmax of amlodipine in plasma is similar in elderly and younger patients. Amlodipine clearance is generally slightly reduced in elderly patients, leading to increased AUC and prolonged elimination half-life (T½) of the drug.

Children.

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, with considerable interpatient variability in exposure. Information in patients under 6 years of age is limited.

Clinical characteristics.

Indications.

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

Contraindications.

Hypersensitivity to dihydropyridines, amlodipine, or to any other component of the medicinal product.

Severe hypotension. Shock (including cardiogenic shock). Obstruction of the left ventricular outflow tract (e.g., severe aortic stenosis). Hemodynamically unstable heart failure following acute myocardial infarction.

Interaction with other medicinal products and other forms of interaction.

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 effect, 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.

CYP3A4 inducers.

Amlodipine plasma concentrations may be altered when co-administered with known CYP3A4 inducers. Therefore, blood pressure should be monitored and dosage adjusted accordingly during and after concomitant therapy, especially 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 following intravenous administration of verapamil and dantrolene.

Due to the risk of hyperkalemia, 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 is additive to the antihypertensive 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, regular monitoring of tacrolimus blood levels and, if necessary, dose adjustment are required when used concomitantly with amlodipine.

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 potentiate 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 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.

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

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

Effect of other medicinal products on amlodipine.

Available data support the safe concomitant 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 from in vitro studies using human plasma indicate that amlodipine does not affect the protein binding of tested medicinal products (digoxin, phenytoin, warfarin, or indomethacin).

Sildenafil.

Single-dose 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 antihypertensive effect independently of the other.

Other medicinal products.

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

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 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.

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 patients with severe heart failure (NYHA class III and IV), treatment with amlodipine has been associated with an increased risk of pulmonary edema. Calcium channel blockers, including amlodipine, should be administered with caution to 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 impaired liver function; however, specific dosage recommendations are not available. Therefore, treatment in these patients should be initiated at the lowest dose. Caution is advised both at the start of therapy 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.

Standard doses of the drug are recommended for this patient population. Plasma concentrations of amlodipine do not correlate with the degree of renal impairment. Amlodipine is not removed by dialysis.

Grapefruit or grapefruit juice: concomitant use with amlodipine is not recommended due to the potential for increased bioavailability of amlodipine in some patients, which may lead to enhanced hypotensive effects.

Patients with hypersensitivity or intolerance to gluten should not take this medicinal product, as corn starch is included among its excipients.

Amodil Bosnaliek**®** in gelatin capsule formulation contains the dye sunset yellow FCF (E 110), which may cause allergic reactions.

Use during pregnancy or breastfeeding.

Pregnancy period.

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

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

Breastfeeding period.

Amlodipine is excreted in breast milk. The infant's exposure via maternal milk is estimated to range between 3–7% (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 benefits of breastfeeding for the child and the benefits of treatment for the mother should be carefully weighed.

Fertility.

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

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, particularly at the beginning of therapy.

Dosage and Administration.

Adults.

For the treatment of hypertension and angina, the usual initial dose is 5 mg of amlodipine once daily. Depending on the patient's response to therapy, the dose may be increased to a maximum dose of 0. mg once daily.

There is experience with the use of the drug in combination with thiazide diuretics, alpha-blockers, beta-blockers, or angiotensin-converting enzyme (ACE) inhibitors in patients with hypertension.

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

There is no need for dose adjustment when amlodipine is used concomitantly with thiazide diuretics, beta-blockers, or ACE inhibitors.

Elderly patients.

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

Patients with hepatic impairment.

Dosage recommendations 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 (see sections "Pharmacological Properties. Pharmacokinetics" and "Special Instructions"). The pharmacokinetics of amlodipine have not been studied in patients with severe hepatic impairment. In patients with severe hepatic dysfunction, amlodipine therapy should be initiated at the lowest dose, with gradual dose escalation.

Patients with renal impairment.

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

Children.

This medicinal product is not recommended for use in children.

Overdose.

Experience with intentional overdose of the drug is limited.

Available data suggest that significant overdose may lead to excessive peripheral vasodilation and possibly reflex tachycardia. Marked and potentially prolonged systemic arterial hypotension has been reported, including shock with fatal outcome.

Rare cases of non-cardiogenic pulmonary edema following amlodipine overdose have been reported, which may have a 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) used to support perfusion and cardiac output.

Treatment: Clinically significant hypotension due to amlodipine overdose requires active cardiovascular support, including continuous monitoring of cardiac and respiratory function, elevation of the legs, 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 administration of 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 amlodipine significantly reduced its absorption in healthy volunteers.

Since amlodipine is highly protein-bound, dialysis is ineffective.

Adverse Reactions

Blood and lymphatic system disorders: leukopenia, thrombocytopenia.

Immune system disorders: allergic reactions.

Metabolism and nutrition disorders: hyperglycemia.

Psychiatric disorders: insomnia, mood changes (including anxiety), depression, confusion.

Nervous system disorders: drowsiness, dizziness, headache (mainly at the beginning of treatment). Tremor, dysgeusia, syncope, hypesthesia, paresthesia. Hypertonia, peripheral neuropathy.

Eye disorders: visual disturbances (including diplopia), tinnitus.

Cardiac disorders: palpitations, flushing. Arterial hypotension, myocardial infarction, arrhythmia (including bradycardia, ventricular tachycardia, and atrial fibrillation), vasculitis.

Respiratory, thoracic and mediastinal disorders: dyspnea, rhinitis, cough.

Gastrointestinal disorders: abdominal pain, nausea, vomiting, dyspepsia, gastrointestinal motility disorders (including constipation and diarrhea), dry mouth. Pancreatitis, gastritis, gingival hyperplasia, hepatitis, jaundice, elevated liver enzymes (most commonly associated with cholestasis).

Skin and subcutaneous tissue disorders: alopecia, purpura, skin discoloration, increased sweating, pruritus, rash, exanthema. Angioedema, erythema multiforme, urticaria, exfoliative dermatitis, Stevens-Johnson syndrome, Quincke's edema, photosensitivity, toxic epidermal necrolysis.

Musculoskeletal and connective tissue disorders: leg swelling, arthralgia, myalgia, muscle cramps, back pain.

Renal and urinary disorders: increased frequency and disturbances of urination, nocturia, impotence, gynecomastia.

General disorders: edema, increased fatigue. Chest pain, asthenia, pain, malaise, weight gain or weight loss. Rare cases of extrapyramidal syndrome have been reported.

Healthcare professionals, patients, and pharmacists are kindly requested to report any suspicion of adverse reactions or lack of therapeutic effect to the email address of Bosnalijek d.d.: [email protected].

Shelf life.

3 years.

Storage conditions.

Store out of reach of children at a temperature not exceeding 25 °C.

Packaging.

10 hard capsules in a blister, 2 blisters per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Bosnalijek d.d.

Manufacturer's address and place of business.

Yukicheva 53, 71000 Sarajevo, Bosnia and Herzegovina.