Stamlo

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

Composition:

Active substance: amlodipine;

One tablet contains amlodipine besylate equivalent to 5 mg or 10 mg of amlodipine;

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

Pharmaceutical form. Tablets.

Main physicochemical properties: white or almost white, flat tablets with bevel, a dividing line on one side and embossing "5" or "10" on the other side.

Pharmacotherapeutic group. Selective calcium antagonists with predominant vascular effect. Dihydropyridine derivatives. 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, 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 amlodipine's mechanism of action. This vasodilation 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 amlodipine’s slow onset of action, acute arterial hypotension is usually not observed. In patients with angina, once-daily dosing 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 into plasma. Concomitant food intake does not affect amlodipine absorption. 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 20 L/kg; the acid dissociation constant (pKa) of amlodipine is 8.6. In vitro studies have shown that amlodipine plasma protein binding is approximately 97.5%.

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 in the liver, forming inactive metabolites (~90%), of which approximately 60% are excreted in urine, and about 10% of amlodipine is excreted unchanged.

Elderly patients. Time to reach steady-state plasma concentrations of amlodipine is similar in elderly and adult patients. However, amlodipine clearance is reduced in elderly patients, resulting in an increase in the area under the concentration-time curve (AUC) by approximately 40–60%, which may necessitate the use of a lower initial dose.

Patients with heart failure.

In patients with heart failure, amlodipine clearance is reduced. Studies have shown an increase in AUC by approximately 40–60% in patients with moderate to severe heart failure.

Patients with hepatic impairment.

In patients with hepatic insufficiency, amlodipine clearance is reduced, leading to prolonged elimination half-life and an increase in AUC by approximately 40–60%.

Patients with renal impairment. Amlodipine is extensively biotransformed into inactive metabolites. 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 renal impairment. Amlodipine is not removed by dialysis.

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); unstable angina; use within 8 days following myocardial infarction; hemodynamically unstable heart failure after acute myocardial infarction.

Interaction with other medicinal products and other forms of interaction.

Effect of other medicinal products on amlodipine.

Available data support the safe 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 tested medicinal products (digoxin, phenytoin, warfarin, or indomethacin).

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 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 of 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).

Effect of amlodipine on other medicinal products.

The antihypertensive effect of amlodipine potentiates the antihypertensive effects of other antihypertensive agents.

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, calcium channel blockers such as amlodipine should be avoided in patients susceptible to malignant hyperthermia and during treatment of malignant hyperthermia.

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 is recommended in patients receiving concomitant amlodipine, with dose adjustment of tacrolimus as needed.

mTOR inhibitors (mammalian target of rapamycin – mTOR in mammals).

mTOR inhibitors such as sirolimus, temsirolimus, and everolimus are substrates of CYP3A. Amlodipine is a weak inhibitor of CYP3A. Concomitant use of amlodipine with mTOR inhibitors may enhance their effects.

Cyclosporine.

In a study of cyclosporine and amlodipine interaction in kidney transplant patients, variable increases in cyclosporine trough concentrations (on average by 40%) were observed. When these medicinal products are used concomitantly, cyclosporine concentrations should be monitored and the cyclosporine dose reduced as necessary.

Simvastatin.

Concomitant administration of multiple 10 mg doses of amlodipine and 80 mg of simvastatin resulted in a 77% increase in simvastatin exposure compared to simvastatin alone. In patients receiving amlodipine, the dose of simvastatin 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.

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 use of amlodipine with cimetidine had no effect on the pharmacokinetics of amlodipine.

Concomitant use 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 evaluated.

Patients with heart failure.

Amlodipine should be used with caution in this patient population. 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 future cardiovascular events and mortality.

Patients with hepatic impairment.

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

Elderly patients.

The clearance of amlodipine is reduced in elderly patients, resulting in an increase in AUC by approximately 40–60%. Dose titration in elderly patients should be performed cautiously, usually starting with the lowest dose.

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 interfere with laboratory test results.

It is not recommended to take amlodipine together with grapefruit or grapefruit juice, as in some patients this may increase bioavailability, leading to an enhanced hypotensive effect of the drug.

Fertility.

Reversible biochemical changes in the sperm head have been reported in some patients receiving calcium channel blockers. There is insufficient clinical information on the potential effect of amlodipine on fertility.

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 outweighs the potential harm of treatment to the mother and fetus.

Reproductive toxicity was observed in animal studies with high doses.

Breastfeeding period.

Amlodipine passes into breast milk. The infant exposure relative to maternal dose 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 treatment for the mother should be weighed.

Ability to influence 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 if symptoms such as dizziness, headache, confusion, or nausea occur.

Caution is advised, especially at the beginning of therapy.

Dosage and Administration

Tablets should be taken orally, independently of food intake.

Adults. The usual recommended starting dose for the treatment of hypertension and angina 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.

Children aged 6 years and older with hypertension. The recommended starting dose of amlodipine for this patient group is 2.5 mg once daily. If the desired 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, debilitated patients. Treatment in these patients is usually initiated with a lower dose (2.5 mg once daily). Dose escalation should be performed cautiously.

Patients with renal impairment. Dose adjustment is not required in this patient group.

Use in patients with hepatic impairment. Patients with hepatic impairment have reduced amlodipine clearance. Treatment is usually initiated with a lower dose (2.5 mg once daily). (See section "Special precautions").

Amlodipine 5 mg tablets may be divided in half to achieve a 2.5 mg dose.

Pediatric population.

The drug can 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 of overdose: Available data suggest that significant overdose of amlodipine leads 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.

Rare cases of non-cardiogenic pulmonary edema following amlodipine overdose have been reported, 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.

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

Vasoconstrictive 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 in healthy volunteers within 2 hours after 10 mg amlodipine intake significantly reduced its absorption.

As amlodipine is highly protein-bound, dialysis is unlikely to be effective.

Adverse reactions.

Blood and lymphatic system disorders: leucopenia, thrombocytopenia, purpura.

Immune system disorders: allergic reactions, angioedema (Quincke's edema).

Metabolism and nutrition disorders: hyperglycemia, thirst.

Psychiatric disorders: insomnia, abnormal dreams, 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, extrapyramidal syndrome, vertigo.

Eye disorders: visual disturbances (including diplopia), eye pain, conjunctivitis.

Ear and labyrinth disorders: tinnitus, chest pain, syncope.

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

Vascular disorders: flushing, arterial hypotension, vasculitis, peripheral ischemia.

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

Gastrointestinal disorders: anorexia, dysphagia, abdominal pain, nausea, vomiting, dyspepsia, intestinal motility disorders (including constipation and diarrhea), abdominal distension, dry mouth, pancreatitis, gastritis, gingival hyperplasia.

Hepatobiliary disorders: hepatitis, jaundice, increased levels of liver enzymes (most commonly associated with cholestasis).

Skin and subcutaneous tissue disorders: alopecia, purpura, skin discoloration, increased sweating, pruritus, rash, erythematous rash, maculopapular rash, exanthema, angioedema, erythema multiforme, urticaria, exfoliative dermatitis, Stevens-Johnson syndrome, photosensitivity, toxic epidermal necrolysis.

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

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

Reproductive system and breast disorders: impotence, gynecomastia.

General disorders and administration site conditions: edema, fatigue, chest pain, asthenia, pain, malaise, hot flushes, stiffness.

Other: weight increase or weight decrease.

Rare cases of extrapyramidal syndrome development have been reported.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after marketing authorization is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions in accordance with national regulatory requirements.

Shelf life. 3 years.

Storage conditions.

Store in a light-protected, child-resistant place at a temperature not exceeding 25 °C.

Packaging.

10 tablets in a strip or blister, 2 or 3 strips or blisters in a carton.

Prescription status.

Prescription only.

Manufacturer.

Dr. Reddy’s Laboratories Ltd, FTZ – II.

Manufacturer's address and site of operations.

Survey Nos. 42R, 43, 44R, 45R, 46R, 53, 54, 83, Bachupally, Bachupally Mandal, Medchal Malkajgiri District – 500090, Telangana State, India.