AMOSTAT 10mg TABLETS

Composition

active substance:

1 tablet contains 13.90 mg or 6.95 mg amlodipine besylate (in terms of amlodipine 10 mg or 5 mg);

ATC code

C Drugs affecting the cardiovascular system C08 Calcium antagonists C08C Selective calcium antagonists with a predominant effect on blood vessels C08CA Dihydropyridine derivatives C08CA01 Amlodipine

Pharmacotherapeutic group

Selective calcium antagonists with a predominant effect on blood vessels. Derivatives of dihydropyridine.

Pharmacological properties

Pharmacodynamics.

Amlodipine is a calcium antagonist (dihydropyridine derivative) that blocks the flow of calcium ions into the myocardium and smooth muscle cells. The mechanism of the hypotensive action of amlodipine is due to a direct relaxing effect on vascular smooth muscles. The exact mechanism of the antianginal effect of amlodipine is not well understood, but the following effects play a role. Amlodipine dilates peripheral arterioles and thus reduces peripheral resistance (afterload). Since the heart rate remains stable, reducing the load on the heart leads to a decrease in energy consumption and myocardial oxygen demand. Dilation of the main coronary arteries and coronary arterioles (normal and ischemic) may also play a role in the mechanism of action of amlodipine. This expansion increases myocardial oxygen saturation in patients with coronary artery spasm (Prinzmetal’s angina or variant angina). In patients with arterial hypertension, the use of the drug once a day provides a clinically significant decrease in blood pressure within 24 hours in both supine and standing positions. Due to the slow onset of action of amlodipine, acute arterial hypotension is usually not observed. In patients with angina pectoris, when using one daily dose of the drug, the total time of physical activity, the time to the onset of angina pectoris, and the time up to 1 mm of ST segment depression increase. The drug reduces the frequency of angina attacks and reduces the need for nitroglycerin. Amlodipine is not associated with any metabolic side effects or changes in plasma lipids 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 the blood plasma. The absolute bioavailability of the unchanged molecule is approximately 64-80%. The maximum concentration in blood plasma is reached within 6-12 hours after application. The volume of distribution is approximately 21 l / kg; the acid dissociation constant (pKa) of amlodipine is 8.6. Plasma protein binding of amlodipine is approximately 97.5%. The simultaneous consumption of food does not affect the absorption of amlodipine.

Metabolism / excretion.

The plasma half-life is approximately 35-50 hours. Equilibrium concentration in blood plasma is achieved after 7-8 days of continuous use of the drug. Amlodipine is mainly metabolized to form inactive metabolites. About 60% of the administered dose is excreted in the urine, approximately 10% of which is unchanged amlodipine.

Therapeutic indications

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

Posology and method of administration

Adults. For the treatment of arterial hypertension and angina pectoris, the usual initial dose of AMOSTAT  is 5 mg once a day. Depending on the patient’s response to therapy, the dose can be increased to a maximum dose of 10 mg once a day. In patients with angina pectoris, the drug can be used as monotherapy or in combination with other antianginal drugs with resistance to nitrates and / or adequate doses of beta-blockers. There is experience of 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 to select a dose of the drug when used simultaneously with thiazide diuretics, beta-blockers and angiotensin-converting enzyme inhibitors. Children over 6 years of age with arterial hypertension. The recommended initial dose of AMOSTAT  for this category of patients is 2.5 mg once a day (use in an appropriate dosage). If the required blood pressure level is not reached within 4 weeks, the dose can be increased to 5 mg per day. The use of the drug in doses above 5 mg for this category of patients has not been studied. Elderly patients. There is no need to select a dose for this category of patients. Increasing the dose should be done with caution. Patients with impaired renal function. It is recommended to use the usual doses of the drug, since changes in the concentration of amlodipine in the blood plasma are not associated with the severity of renal failure. Amlodipine is not excreted by dialysis. Patients with hepatic impairment. Doses of the drug for use in patients with mild to moderate hepatic impairment have not been established, therefore, dose selection should be carried out with caution and use should be started with the lowest dose (see section “Peculiarities of use” and “Pharmacological properties. Pharmacokinetics”). The pharmacokinetics of amlodipine have not been studied in patients with severe hepatic impairment. For patients with severe hepatic impairment, the use of amlodipine should be started at the lowest dose and gradually increased. Children. The drug should be used in children from 6 years of age. The effect of amlodipine on blood pressure in patients under 6 years of age is unknown.

Overdose

Experience with intentional drug overdose is limited. Overdose symptoms: the available information suggests that a significant overdose of AMOSTAT  will lead to excessive peripheral vasodilation and, possibly, reflex tachycardia. The development of significant and possibly prolonged systemic hypotension, including fatal shock, has been reported. Treatment: clinically significant hypotension caused by an overdose of amlodipine requires active support for the activity of the cardiovascular system, including frequent monitoring of cardiac and respiratory functions, raising the limbs, monitoring the volume of circulating fluid and urination. To restore vascular tone and blood pressure, vasoconstrictor drugs can be used, making sure that there are no contraindications to their use. Intravenous administration of calcium gluconate may be helpful in mitigating the effects of calcium channel blockade. In some cases, gastric lavage may be helpful. The use of activated charcoal in healthy volunteers within 2 hours after administration of 10 mg of amlodipine significantly reduced the level of its absorption. Since amlodipine is highly protein bound, the dialysis effect is negligible.

Special Conditions

Elderly patients.

The time to reach equilibrium plasma concentrations of amlodipine is similar in elderly patients and in adult patients. The clearance of amlodipine is usually slightly reduced, which in elderly patients leads to an increase in the area under the concentration / time curve (AUC) and the half-life of the drug.

Patients with impaired renal function.

Amlodipine is extensively biotransformed to inactive metabolites. 10% of amlodipine is excreted unchanged in the urine. Changes in the concentration of amlodipine in blood plasma do not correlate with the degree of renal dysfunction. Patients with impaired renal function can be treated with usual doses of amlodipine. Amlodipine is not removed by dialysis.

Patients with impaired liver function.

Information on the use of amlodipine in patients with impaired liver function is very limited. In patients with hepatic impairment, the clearance of amlodipine is reduced, which leads to an increase in the half-life and an increase in AUC by approximately 40-60%.

Children.

Usually, oral clearance for children from 6 to 12 years old and from 13 to 17 years old was 22.5 and 27.4 l / h, respectively, for boys and 16.4 and 21.3 l / h, respectively, for girls. There is significant variability in exposure between patients. Information for patients under 6 years of age is limited.

Fertility

It has been reported about reversible biochemical changes in the sperm head in some patients with the use of calcium channel blockers. There is insufficient clinical information regarding the potential effect of amlodipine on fertility. This medicinal product contains less than 1 mmol sodium (less than 23 mg), which is essentially free of sodium.

Pregnancy.

The safety of using amlodipine in women during pregnancy has not been established. It is recommended to use amlodipine during pregnancy only in cases where there is no safer alternative, and the risk associated with the disease itself outweighs the possible harm from treatment for the mother and fetus. Reproductive toxicity has been observed in animal studies with high doses.

Breastfeeding period.

Amlodipine has been identified in babies who were breastfed while their mothers were using the drug. The proportion of the mother’s initial dose received by the infant was estimated in the middle range as 3–7%, with a maximum of 15%. The effect of amlodipine in infants is unknown. When deciding whether to continue breastfeeding or to use amlodipine, it is necessary to evaluate the benefits of breastfeeding for the child and the benefits of using the drug for the mother.

Contraindications

• Known hypersensitivity to dihydropyridines, amlodipine, or any other component of the drug.
• Arterial hypotension of severe degree.
• Shock (including cardiogenic shock).
• Left ventricular outflow tract obstruction (eg, severe aortic stenosis).
• Hemodynamically unstable heart failure after acute myocardial infarction.

Interaction with other medicinal products

The effect of other drugs on amlodipine.

There is evidence for the safe use of amlodipine with thiazide diuretics, alpha-blockers, beta-blockers, ACE inhibitors, long-acting nitrates, sublingual nitroglycerin, non-steroidal anti-inflammatory drugs, antibiotics, oral hypoglycemic drugs. The data obtained in the course of in vitro studies of human blood plasma indicate the absence of the effect of amlodipine on binding to blood proteins of the studied drugs (digoxin, phenytoin, warfarin or indomethacin).

CYP3A4 inhibitors.

The simultaneous use of amlodipine and CYP3A4 inhibitors of powerful or moderate action (protease inhibitors, azole antifungals, macrolides such as erythromycin or clarithromycin, verapamil or diltiazem) can lead to a significant increase in amlodipine exposure, which also increases the risk of hypotension. The clinical significance of such changes may be more pronounced in elderly patients. Clinical observation of the patient’s condition and dose selection may be necessary. It is not recommended to simultaneously use amlodipine and grapefruit or grapefruit juice, since in some patients the bioavailability of amlodipine may increase, which, in turn, leads to an increase in the hypotensive effect.

CYP3A4 inductors.

There is no information on the effect of CYP3A4 inducers on amlodipine. The simultaneous use of amlodipine and substances that are inducers of CYP3A4 (for example, rifampicin, St. John’s wort) can lead to a decrease in the concentration of amlodipine in the blood plasma, therefore, such combinations should be used with caution.

Dantrolene (infusion).

Fatal ventricular fibrillation and cardiovascular collapse associated with hyperkalemia were observed in animals after intravenous verapamil and dantrolene were administered. Due to the risk of hyperkalemia, it is recommended to avoid the use of calcium channel blockers, such as amlodipine, in patients prone to malignant hyperthermia and in the treatment of malignant hyperthermia.

The effect of amlodipine on other medicines.

The hypotensive effect of amlodipine is potentiated by the hypotensive effect of other antihypertensive drugs.

Tacrolimus.

There is a risk of increased blood levels of tacrolimus when used concomitantly with amlodipine, but the pharmacokinetic mechanism of this interaction has not been fully established. To avoid tacrolimus toxicity, with concomitant use of amlodipine in patients using tacrolimus, tacrolimus blood levels should be regularly monitored and the tacrolimus dosage adjusted if necessary.

MTOR inhibitors (mammalian target of rapamycin – mammalian targets of rapamycin).

MTOR inhibitors such as sirolimus, temsirolimus and everolimus are substrates for CYP3A. Amlodipine is a weak inhibitor of CYP3A. With the simultaneous use of amlodipine with mTOR inhibitors, it can enhance the effect of the latter.

Cyclosporine .

Studies of the interaction of cyclosporine and amlodipine when used in healthy volunteers or in other groups have not been conducted, with the exception of the use in patients with kidney transplants, who showed a variable increase in the residual concentration of cyclosporine (on average by 0-40%). For patients with kidney transplants using amlodipine, monitoring of cyclosporine concentrations should be considered and, if necessary, the dose of cyclosporine should be reduced.

Simvastatin .

The simultaneous use of multiple doses of amlodipine 10 mg and simvastatin at a dose of 80 mg led to an increase in simvastatin exposure by 77% compared to the use of simvastatin alone. For patients using amlodipine, the dose of simvastatin should be limited to 20 mg per day.

Sildenafil.

Single use of 100 mg of sildenafil in patients with essential hypertension did not affect the pharmacokinetics of amlodipine. With a single use of amlodipine and sildenafil as a combination therapy, each of the drugs showed a hypotensive effect independently of the other.

Side effects

When using amlodipine, the most commonly reported adverse reactions were: drowsiness, dizziness, headache, increased heart rate, hot flashes, abdominal pain, nausea, swelling of the legs, edema and fatigue. Adverse reactions reported with the use of amlodipine are listed below by system and organ class and by frequency of occurrence: very often (≥ 1/10), often (from ≥ 1/100 to <1/10), infrequently (from ≥ 1 / 1000 to ≤ 1/100), rarely (from ≥ 1/10000 to ≤ 1/1000), very rarely (≤ 1/10000). On the part of the blood and lymphatic system. Very rare: leukocytopenia, thrombocytopenia. From the immune system. Very rare: allergic reactions. From the side of metabolism and nutritional disorders . Very rare: hyperglycemia. Mental disorders. Uncommon: depression, mood changes (including anxiety), insomnia. Rarely: confusion of consciousness. From the nervous system. Often: drowsiness, dizziness, headache (mainly at the beginning of treatment). Uncommon: tremor, dysgeusia, syncope, hypesthesia, paresthesia. Very rare: hypertonicity, peripheral neuropathy. On the part of the organs of vision. Often: visual impairment (including diplopia). On the part of the hearing organs and the labyrinth . Uncommon: ringing in the ears. From the side of the heart. Often: increased heart rate. Uncommon: arrhythmias (including bradycardia, ventricular tachycardia, and atrial fibrillation). Very rare: myocardial infarction. From the side of the vessels. Often: hot flashes. Uncommon: arterial hypotension. Very rare: vasculitis. Respiratory, thoracic and mediastinal disorders. Often: dyspnea. Uncommon: cough, rhinitis. From the gastrointestinal tract. Often: abdominal pain, nausea, dyspepsia, impaired intestinal motility (including diarrhea and constipation). Uncommon: vomiting, dry mouth. Very rare: pancreatitis, gastritis, gingival hyperplasia. From the hepatobiliary system. Very rare: hepatitis, jaundice, increased levels of liver enzymes (most often associated with cholestasis). On the part of the skin and subcutaneous tissue. Uncommon: alopecia, purpura, discoloration of the skin, increased sweating, itching, rash, exanthema, urticaria. Very rare: angioedema, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, Quincke’s edema, photosensitivity. From the musculoskeletal and connective tissues. Often: swelling of the legs, muscle cramps. Uncommon: arthralgia, myalgia, back pain. From the kidneys and urinary tract. Uncommon: violation of urination, nocturia, increased frequency of urination. On the part of the reproductive system and mammary glands. Uncommon: impotence, gynecomastia. General disorders and conditions at the injection site. Very common: edema. Often: increased fatigue, asthenia. Uncommon: chest pain, pain, malaise. Study. Uncommon: increase or decrease in body weight. Exceptional cases of extrapyramidal syndrome have been reported.

Package available in the  Republic of Yemen

30 tablets