Amlodipine-ZT (Tablets) Instructions for Use

Marketing Authorization Holder

Pharmaceutical Company Zdorovye, LLC (Ukraine)

ATC Code

C08CA01 (Amlodipine)

Active Substance

Amlodipine (Rec.INN registered by WHO)

Dosage Form

Amlodipine-ZT

Tablets 5 mg: 10 or 30 pcs.

Dosage Form, Packaging, and Composition

10 pcs. – blister packs (1) – cardboard packs.
10 pcs. – blister packs (2) – cardboard packs.
10 pcs. – blister packs (3) – cardboard packs.
15 pcs. – blister packs (1) – cardboard packs.
5 kg – polyethylene bags (1) – containers.
10 kg – polyethylene bags (1) – containers.
15 kg – polyethylene bags (1) – containers.
20 kg – polyethylene bags (1) – containers.
25 kg – polyethylene bags (1) – containers.
50 kg – polyethylene bags (1) – containers.

Clinical-Pharmacological Group

Calcium channel blocker

Pharmacotherapeutic Group

BMCC (Bone Mineral Crystal Complex)

Pharmacological Action

A dihydropyridine derivative – a second-generation slow calcium channel blocker (CCB), has antianginal and antihypertensive action. It blocks calcium channels, reduces the transmembrane transition of calcium ions into the cell (more so in vascular smooth muscle cells than in cardiomyocytes).

The antianginal action is due to the dilation of coronary and peripheral arteries and arterioles: in angina, it reduces the severity of myocardial ischemia; by dilating peripheral arterioles, it reduces total peripheral vascular resistance, reduces cardiac afterload, and reduces myocardial oxygen demand. By dilating coronary arteries and arterioles in unchanged and ischemic areas of the myocardium, it increases oxygen supply to the myocardium (especially in vasospastic angina); prevents spasm of the coronary arteries (including that caused by smoking). In patients with stable angina, a single daily dose increases exercise tolerance, increases the time to onset of angina attack and ischemic ST-segment depression, and reduces the frequency of angina attacks and the consumption of nitroglycerin and other nitrates.

It has a long-term dose-dependent antihypertensive effect. The antihypertensive action is due to a direct vasodilatory effect on vascular smooth muscles. In arterial hypertension, a single dose provides a clinically significant reduction in blood pressure over 24 hours (in the supine and standing positions). Orthostatic hypotension is quite rare when amlodipine is prescribed. It does not cause a reduction in left ventricular ejection fraction. It reduces the degree of left ventricular myocardial hypertrophy. It does not affect myocardial contractility and conductivity, does not cause a reflex increase in heart rate, inhibits platelet aggregation, increases glomerular filtration rate, and has a weak natriuretic effect. In diabetic nephropathy, it does not increase the severity of microalbuminuria. It does not have any adverse effect on metabolism and plasma lipid concentrations and can be used in the therapy of patients with bronchial asthma, diabetes mellitus, and gout. A significant reduction in blood pressure is observed after 6-10 hours, the duration of the effect is 24 hours.

In patients with cardiovascular diseases (including coronary atherosclerosis with single-vessel disease and up to stenosis of three or more arteries, atherosclerosis of the carotid arteries), who have had myocardial infarction, percutaneous transluminal coronary angioplasty (PTCA) or patients with angina, the use of amlodipine prevents the development of carotid intima-media thickening, reduces mortality from myocardial infarction, stroke, PTCA, coronary artery bypass grafting, which leads to a decrease in the number of hospitalizations for unstable angina and reduces the progression of chronic heart failure (CHF); reduces the frequency of interventions aimed at restoring coronary blood flow.

It does not increase the risk of death or the development of complications and fatal outcomes in patients with CHF (III-IV functional class according to the NYHA classification) against the background of therapy with digoxin, diuretics, and ACE inhibitors. In patients with CHF (III-IV functional class according to the NYHA classification) of non-ischemic etiology, there is a possibility of pulmonary edema when using amlodipine.

Pharmacokinetics

After oral administration, Amlodipine is slowly absorbed from the gastrointestinal tract. The mean absolute bioavailability is 64%, C_max in blood serum is observed after 6-9 hours. C_ss is achieved after 7-8 days of therapy.

Food intake does not affect the absorption of amlodipine. The mean V_d is 21 L/kg of body weight, indicating that most of the drug is in the tissues, and a smaller part is in the blood. Most of the drug in the blood (95%) is bound to plasma proteins. Amlodipine undergoes slow but active metabolism in the liver in the absence of a significant first-pass effect. Metabolites do not have significant pharmacological activity.

After a single dose, T_1/2 ranges from 31 to 48 hours, with repeated administration, T_1/2 is approximately 45 hours. About 60% of the orally administered dose is excreted by the kidneys mainly as metabolites, 10% – unchanged, and 20-25% – through the intestine with bile. The total clearance of amlodipine is 0.116 ml/s/kg (7 ml/min/kg, 0.42 L/h/kg).

In elderly patients (over 65 years), the elimination of amlodipine is slowed (T_1/2 – 65 hours) compared to young patients, but this difference is not clinically significant. The prolongation of T_1/2 in patients with hepatic insufficiency suggests that with long-term use, the accumulation of the drug in the body will be higher (T_1/2 – up to 60 hours). Renal failure does not significantly affect the kinetics of amlodipine.

Amlodipine penetrates the blood-brain barrier. It is not removed by hemodialysis.

Indications

• Arterial hypertension (in monotherapy or in combination with other antihypertensive agents);
• Stable exertional angina and vasospastic angina (in monotherapy or in combination with other antianginal agents).

ICD codes

Dosage Regimen

Orally, 1 time/day, with a sufficient amount of water (100 ml).

For arterial hypertension and angina the initial dose of Amlodipine-ZT, 5 mg tablets is 1 tab. (5 mg) 1 time/day. If necessary, the daily dose can be increased to 2 tabs. (10 mg) in 1 dose.

In elderly patients Amlodipine-ZT, 5 mg tablets are recommended to be used at the average therapeutic dose, dose adjustment is not required.

In patients with impaired liver function despite the fact that the T_1/2 of amlodipine, like all CCBs, increases, dose adjustment is usually not required.

In patients with renal failure it is recommended to use Amlodipine-ZT, 5 mg tablets in usual doses, however, a possible slight increase in T_1/2 should be taken into account.

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

Adverse Reactions

The frequency of adverse reactions listed below was determined according to the following (World Health Organization classification): very common – more than 1/10, common – from more than 1/100 to less than 1/10, uncommon – from more than 1/1000 to less than 1/100, rare – from more than 1/10,000 to less than 1/1000, very rare – less than 1/10,000, including isolated reports.

From the central nervous system: common – headache, dizziness, increased fatigue, drowsiness; uncommon – asthenia, general malaise, hypoesthesia, paresthesia, peripheral neuropathy, tremor, insomnia, mood lability, unusual dreams, increased excitability, depression, anxiety; very rare – migraine, increased sweating, apathy, agitation, ataxia, amnesia.

From the digestive system : common – nausea, abdominal pain; uncommon – vomiting, constipation or diarrhea, flatulence, dyspepsia, anorexia, dry oral mucosa, thirst; rare – gingival hyperplasia, increased appetite; very rare – pancreatitis, gastritis, jaundice (due to cholestasis), hyperbilirubinemia, increased activity of hepatic transaminases, hepatitis.

From the cardiovascular system common – palpitations, peripheral edema (ankles and feet), flushing; uncommon – excessive decrease in blood pressure; very rare – fainting, shortness of breath, vasculitis, orthostatic hypotension, development or worsening of the course of CHF, heart rhythm disturbances (including bradycardia, ventricular tachycardia and atrial fibrillation), myocardial infarction, chest pain.

From the hematopoietic system very rare – thrombocytopenic purpura, leukopenia, thrombocytopenia.

From the genitourinary system uncommon – frequent urination, painful urination, nocturia, impotence; very rare – dysuria, polyuria.

From the respiratory system uncommon – rhinitis; very rare – cough.

From the musculoskeletal system uncommon – muscle cramps, myalgia, arthralgia, back pain, arthrosis; rare – myasthenia.

From the skin rare – dermatitis; very rare – alopecia, xeroderma, cold sweat, skin pigmentation disorder.

Allergic reactions : skin itching, rash (including erythematous, maculopapular rash, urticaria), angioedema, multiforme erythema.

Other uncommon – ringing in the ears, diplopia, accommodation disorder, xerophthalmia, conjunctivitis, eye pain, chills, nosebleed, gynecomastia; very rare – parosmia, hyperglycemia.

Contraindications

• Severe arterial hypotension (systolic blood pressure less than 90 mm Hg);
• Unstable angina (except for Prinzmetal’s angina);
• Clinically significant aortic stenosis;
• Lactase deficiency, lactose intolerance, glucose-galactose malabsorption;
• Age under 18 years (efficacy and safety not established);
• Hypersensitivity to amlodipine, other dihydropyridine derivatives and other components of the drug.

With caution impaired liver function, sick sinus syndrome (severe bradycardia, tachycardia), CHF of non-ischemic etiology III-IV functional class according to the NYHA classification, arterial hypotension, aortic stenosis, mitral stenosis, hypertrophic obstructive cardiomyopathy, acute myocardial infarction (and within 1 month after myocardial infarction), old age.

Use in Pregnancy and Lactation

The safety of using Amlodipine-ZT during pregnancy has not been established, so use during pregnancy is only possible if the benefit to the mother outweighs the potential risk to the fetus.

There are no data indicating the excretion of amlodipine in breast milk. However, it is known that other CCBs – dihydropyridine derivatives, are excreted in breast milk. Therefore, if it is necessary to use Amlodipine-ZT during lactation, the issue of discontinuing breastfeeding should be decided.

Use in Hepatic Impairment

With caution: impaired liver function.

In patients with impaired liver function, despite the fact that the T_1/2 of amlodipine, like all CCBs, increases, dose adjustment is usually not required.

Use in Renal Impairment

In patients with renal failure, it is recommended to use Amlodipine-ZT, 5 mg tablets in usual doses, however, a possible slight increase in T_1/2 should be taken into account.

Pediatric Use

Contraindicated

• Age under 18 years (efficacy and safety not established).

Geriatric Use

In elderly patients Amlodipine-ZT, 5 mg tablets are recommended to be used at the average therapeutic dose, dose adjustment is not required.

In elderly patients, T_1/2 may increase and the clearance of the drug may decrease. Dose changes are not required, but more careful monitoring of patients in this category is necessary.

Special Precautions

During therapy with Amlodipine-ZT, it is necessary to control body weight and salt intake, and an appropriate diet is indicated.

It is necessary to maintain oral hygiene and be observed by a dentist (to prevent soreness, bleeding and gingival hyperplasia).

In elderly patients, T_1/2 may increase and the clearance of the drug may decrease. Dose changes are not required, but more careful monitoring of patients in this category is necessary.

Patients with low body mass index and patients with severe liver dysfunction may require a lower dose of the drug.

The efficacy and safety of using Amlodipine-ZT in hypertensive crisis have not been established.

Although CCBs do not have a withdrawal syndrome, it is advisable to discontinue treatment with Amlodipine-ZT by gradually reducing the dose of the drug.

Effect on ability to drive vehicles and operate machinery

Although no negative effect on the ability to drive a car or other complex machinery was observed while taking Amlodipine-ZT, however, due to the possible excessive decrease in blood pressure, development of dizziness, drowsiness and other adverse reactions, caution should be exercised in the listed situations, especially at the beginning of treatment and when increasing the dose.

Overdose

Symptoms pronounced decrease in blood pressure with possible development of reflex tachycardia and excessive peripheral vasodilation (risk of developing pronounced and persistent arterial hypotension, including with the development of shock and fatal outcome).

Treatment gastric lavage, intake of activated charcoal (especially in the first 2 hours after overdose), maintenance of cardiovascular function, elevated position of the lower extremities, monitoring of heart and lung function indicators, control of circulating blood volume and diuresis. To restore vascular tone – use of vasoconstrictors (in the absence of contraindications to their use); to eliminate the consequences of calcium channel blockade – intravenous administration of calcium gluconate. Hemodialysis is ineffective.

Drug Interactions

Amlodipine can be safely used for the therapy of arterial hypertension together with thiazide diuretics, alpha-blockers, beta-blockers or ACE inhibitors.

In patients with stable angina, Amlodipine can be combined with other antianginal agents, for example, with long-acting or short-acting nitrates, beta-blockers.

Unlike other CCBs, no clinically significant interaction of amlodipine (second generation CCB) was found when used concomitantly with NSAIDs, including indomethacin.

Enhancement of the antianginal and antihypertensive action of CCBs is possible with simultaneous use with thiazide and loop diuretics, ACE inhibitors, beta-blockers and nitrates, as well as enhancement of their antihypertensive action when used together with alpha₁-blockers.

Although a negative inotropic effect was usually not observed in studies of amlodipine, nevertheless, some CCBs may enhance the severity of the negative inotropic effect of antiarrhythmic drugs that cause QT interval prolongation (for example, amiodarone and quinidine).

A single dose of 100 mg of sildenafil in patients with essential hypertension does not affect the pharmacokinetic parameters of amlodipine.

Repeated use of amlodipine at a dose of 10 mg and atorvastatin at a dose of 80 mg is not accompanied by significant changes in the pharmacokinetic parameters of atorvastatin.

Ethanol (beverages containing alcohol): Amlodipine with single and repeated use at a dose of 10 mg does not affect the pharmacokinetics of ethanol.

Antiviral agents (ritonavir) increase plasma concentrations of CCBs, including amlodipine.

Antipsychotics and isoflurane – enhancement of the antihypertensive effect of dihydropyridine derivatives.

Calcium preparations may reduce the effect of CCBs.

With simultaneous use of amlodipine with lithium preparations, an increase in the manifestation of neurotoxicity (nausea, vomiting, diarrhea, ataxia, tremor, tinnitus) is possible.

Amlodipine does not change the pharmacokinetics of cyclosporine.

It does not affect the serum concentration of digoxin and its renal clearance.

It does not significantly affect the action of warfarin (prothrombin time).

Cimetidine does not affect the pharmacokinetics of amlodipine.

In in vitro studies, Amlodipine does not affect the plasma protein binding of digoxin, phenytoin, warfarin and indomethacin.

Grapefruit juice: simultaneous single intake of 240 mg of grapefruit juice and 10 mg of amlodipine orally is not accompanied by a significant change in the pharmacokinetics of amlodipine.

Aluminum- or magnesium-containing antacids: their single intake does not significantly affect the pharmacokinetics of amlodipine.

Storage Conditions

Store the drug in a dry, light-protected place, at a temperature not exceeding 25°C (77°F). Keep out of reach of children.

Shelf Life

Shelf life – 3 years. Do not use after the expiration date stated on the packaging.

Dispensing Status

The drug is dispensed by prescription.

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.