Semlopin

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT SEMPLIN® (SAMLOPIN®)

Composition:

active substance: S(-) amlodipine besylate;

1 tablet contains S(-) amlodipine besylate equivalent to S(-) amlodipine 2.5 mg or 5 mg;

excipients: microcrystalline cellulose, calcium hydrogen phosphate dihydrate, iron oxide yellow (E 172), colloidal anhydrous silicon dioxide, sodium starch glycolate (type A), magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: light-yellow, round, flat-cylindrical tablets with bevelled edges and the logo «K» on one side.

Pharmacotherapeutic group. Selective calcium antagonists with predominant vascular effect.

ATC code C08CA01.

Pharmacological Properties

Pharmacodynamics

Amlodipine is a racemic mixture of S(-) and R(+) isomers. S(-) amlodipine is the active chiral form of amlodipine—a calcium antagonist (a dihydropyridine derivative) that blocks calcium ion influx into myocardial and vascular smooth muscle cells.

The antihypertensive mechanism of amlodipine is due to its direct vasodilatory effect 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 expenditure 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 arterial blood pressure over 24 hours, both in supine and standing positions. Due to the slow onset of amlodipine’s action, acute 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, 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 21 L/kg; 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%.

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 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 younger adult patients. Amlodipine clearance is generally slightly reduced in the elderly, resulting in 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 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 liver dysfunction, amlodipine clearance is reduced, leading to prolonged elimination half-life and an increase in AUC by approximately 40–60%.

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.

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, antibiotics, and oral hypoglycemic agents.

In vitro studies using human plasma have shown that amlodipine does not affect the protein binding of tested medicinal products (digoxin, phenytoin, warfarin, or indomethacin).

Inhibitors of CYP3A4.

Concomitant administration of amlodipine and strong or moderately potent 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 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.

Inducers of CYP3A4.

Plasma concentrations of amlodipine may be altered following concomitant administration with known CYP3A4 inducers. Therefore, blood pressure should be monitored and the dose 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 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.

Effect of amlodipine on other medicinal products.

The antihypertensive effect of amlodipine may be potentiated by other antihypertensive agents. Amlodipine does not affect the pharmacokinetics of atorvastatin, digoxin, or warfarin.

Tacrolimus.

There is a risk of increased blood levels of tacrolimus when administered 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 and, if necessary, dose adjustment are required.

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. Concomitant administration of amlodipine may lead to increased exposure to mTOR inhibitors.

Cyclosporine.

Interaction studies between cyclosporine and amlodipine have not been conducted in healthy volunteers or other groups, except in kidney transplant patients, in whom variable increases in cyclosporine trough concentrations (on average by 0–40%) have been observed. In 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. 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 were used concomitantly as combination therapy, each drug exerted 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 repeated administration 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 evaluated.

Patients with heart failure.

Amlodipine should be used with caution in this patient population. An increased incidence of pulmonary edema has been observed 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 impaired liver function; dosage recommendations are not available. Therefore, treatment in these patients should be initiated at the lowest dose. Caution is required 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 population. 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.

Sodium.

This medicinal product contains less than 1 mmol of sodium (23 mg) per tablet, i.e. it is practically sodium-free.

Use during pregnancy or breastfeeding.

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

Amlodipine should be used during pregnancy only when no safer alternative exists and when 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 is excreted in breast milk. The amount of amlodipine that may be transferred to the infant through maternal breast milk may range from 3–7% to 15% of the maternal dose. The effect of amlodipine on neonates is unknown. When deciding whether to continue breastfeeding or to administer amlodipine, the benefits of breastfeeding for the child and the benefits of treatment for the mother should be weighed.

Fertility.

Reversible biochemical changes in the sperm head have been reported in some patients treated with 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 influence 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 of Cemlopine® is 2.5 mg of S(-) amlodipine once daily. Depending on the patient's response to therapy, the dose may be increased to the maximum dose of 5 mg of S(-) amlodipine once daily.

Cemlopine® may be used in patients with angina either 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 the use of the drug in combination with thiazide diuretics, alpha-blockers, beta-blockers, or ACE inhibitors in patients with arterial hypertension.

There is no need for dose adjustment when co-administering the drug with thiazide diuretics, beta-blockers, or ACE inhibitors.

Elderly Patients.

There is no need for dose adjustment in this patient population. 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 insufficiency. Amlodipine is not removed by dialysis.

Use in 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 Warnings and Precautions for Use").

The pharmacokinetics of amlodipine have not been studied in patients with severe hepatic impairment. In patients with severe hepatic impairment, treatment with amlodipine should be initiated at the lowest dose and gradually increased.

The 2.5 mg tablets of Cemlopine® are not intended to be divided in half to achieve a 1.25 mg dose.

The 5 mg tablets of Cemlopine® are not intended to be divided in half to achieve a 2.5 mg dose.

Children.

The safety of S(-) amlodipine use in children has not been established. The drug is contraindicated for use in this age group.

Overdose.

Experience with intentional amlodipine overdose is limited.

Symptoms of overdose: available data suggest that a significant overdose of amlodipine would lead to excessive peripheral vasodilation and possibly reflex tachycardia. Cases of marked and potentially prolonged systemic hypotension have 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) aimed at maintaining perfusion and cardiac output.

Treatment: clinically significant hypotension caused by 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 arterial 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.

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

Adverse reactions.

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

The adverse reactions observed during amlodipine administration are listed below by system organ class and frequency of occurrence: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (≤ 1/10,000), not known (cannot be estimated from available data).

Blood and lymphatic system disorders: Very rare — leukopenia, thrombocytopenia. Not known — purpura, anemia, agranulocytosis.

Immune system disorders: Very rare — allergic reactions.

Metabolism and nutrition disorders: Very rare — hyperglycemia. Not known — thirst.

Psychiatric disorders: Uncommon — depression, mood changes (including anxiety), insomnia. Rare — confusion. Not known — restlessness, loss of consciousness, sleep disturbances, depersonalization.

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 syndrome.

Eye disorders: Common — visual disturbances (including diplopia). Not known — conjunctivitis, eye pain.

Ear and labyrinth disorders: Uncommon — tinnitus. Not known — ear noise.

Cardiac disorders: Common — palpitations. Uncommon — arrhythmia (including bradycardia, ventricular tachycardia, and atrial fibrillation). Very rare — myocardial infarction. Not known — tachycardia, angina attacks, orthostatic (postural) hypotension, collapse, chest pain.

Vascular disorders: Common — flushing. Uncommon — arterial hypotension. Very rare — vasculitis. Not known — peripheral ischemia.

Respiratory, thoracic and mediastinal disorders: Common — dyspnea. Uncommon — rhinitis, cough. Not known — epistaxis.

Gastrointestinal disorders: Common — abdominal pain, nausea, dyspepsia, intestinal motility disorders (including constipation and diarrhea). Uncommon — vomiting, dry mouth. Very rare — pancreatitis, gastritis, gingival hyperplasia. Not known — anorexia, loss of appetite, epigastric discomfort, flatulence, intestinal dysfunction, dysphagia, taste disturbances.

Hepatobiliary disorders: Very rare — hepatitis, including fulminant hepatitis, jaundice, increased liver enzymes (most commonly associated with cholestasis). Not known — hyperbilirubinemia, liver function abnormalities.

Skin and subcutaneous tissue disorders: Uncommon — alopecia, purpura, skin discoloration, increased sweating, pruritus, rash, exanthema, urticaria. Very rare — angioedema, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, Quincke's edema, photosensitivity. Not known — skin pigmentation disorders, erythematous rash, maculopapular rash, toxic epidermal necrolysis.

Musculoskeletal and connective tissue disorders: Common — ankle swelling, muscle cramps. Uncommon — arthralgia, myalgia, back pain. Not known — muscle rigidity.

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

Reproductive system and breast disorders: Uncommon — impotence, gynecomastia. Not known — sexual dysfunction.

General disorders and administration site conditions: Very common — edema. Common — increased fatigue, asthenia. Uncommon — chest discomfort, pain, malaise.

Investigations: Uncommon — weight gain or weight loss.

Rare cases of extrapyramidal syndrome have been reported.

Reporting of 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 and patients, or their legal representatives, should report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life.

3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of the reach and sight of children.

Packaging.

14 tablets in blisters; 2, 4, or 6 blisters in a cardboard package.

Prescription status.

Prescription only.

Manufacturer.

LLC "KUSUM PHARM".

Manufacturer's address and place of business.

54 Skryabina Street, Sumy, Sumy region, 40020, Ukraine.

or

Manufacturer.

KUSUM HEALTHCARE PVT LTD.

Manufacturer's address and place of business.

SP-289 (A), RIICO Industrial Area, Chopanki, Bhiwadi, Dist. Alwar (Rajasthan), India.

or

Manufacturer.

LLC "GLEDFARM LTD".

Manufacturer's address and place of business.

54 Davydovskoho Hryhoriya Street, Sumy, Sumy region, 40020, Ukraine.