Amzaar - instructions for use, doses, side effects, contraindications

Active substanceAmlodipine + LosartanAmlodipine + Losartan

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Amsaar

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MSD FARMASYUTIKALS, LLC Russia

Lortense

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KRKA-RUS, LLC Russia

Dosage form: & nbspfilm coated tablets

Composition:

1 film-coated tablet contains

Dosage of 5 mg + 50 mg

Active substances: Amlodipine camzilate 7.84 mg (in terms of amlodipine 5.00 mg) and potassium losartan 50.00 mg.

Excipients: butyl hydroxytoluene 0.10 mg, sodium carboxymethyl starch 17.00 mg, microcrystalline cellulose 265.10 mg, mannitol 40.00 mg, povidone-K30 5.00 mg, crospovidone 12.00 mg, magnesium stearate 3.00 mg; the membrane (hypromellose-2910 8.00 mg, giprolose 2.00 mg, titanium dioxide 1.80 mg, talc 0.20 mg).

Dosage 5 mg + 100 mg

Active substances: Amlodipine camzilate 7.84 mg (in terms of amlodipine 5.00 mg) and potassium losartan 100.00 mg.

Excipients: butyl hydroxytoluene 0.10 mg, sodium carboxymethyl starch 17.00 mg, microcrystalline cellulose 407.10 mg, mannitol 40.00 mg, povidone-K30 5.00 mg, crospovidone 18.00 mg, magnesium stearate 5.00 mg; shell (hypromellose-2910 12.00 mg, giprolose 3.00 mg, titanium dioxide 2.70 mg, talc 0.30 mg, iron-oxide dye yellow 0.045 mg, iron-oxide red oxide 0.045 mg).

Description:

Dosage of 5 mg + 50 mg: white or almost white oblong biconvex tablets covered with a film sheath, engraved with "AT1" on one side of the tablet.

Dosage of 5 mg + 100 mg: pink or light pink oblong biconvex tablets, covered with a film sheath, engraved with "AT2" on one side of the tablet.

Pharmacotherapeutic group:Hypotensive combined (blocker of "slow" calcium channels + angiotensin II receptor antagonist)

ATX: & nbsp

C.08.C.A.01 Amlodipine

C.09.C.A.01 Losartan

Pharmacodynamics:

The drug Amzaar

The results of two studies of bioequivalence involving healthy volunteers showed that Amzaar in doses of 5 mg + 50 mg and 5 mg + 100 mg bioequivalent to the combined use of appropriate doses of amlodipine camsylate and losartan potassium in the form of individual tablets.

Amlodipine

The bioequivalence of amlodipine besylate and amlodipine-camsylate was evaluated in a randomized, blind cross-over comparison study involving healthy volunteers. The results obtained in the study showed that 5 mg amlodipine camsilate tablets are bioequivalent to 5 mg amlodipine besylate tablets.

Mechanism of action

The drug Amzaar

Amzaar contains two active substances with a complementary mechanism of action to improve blood pressure control (BP) in patients with arterial hypertension (AH): losartan potassium, angiotensin receptor antagonist II (APA II), and amlodipine, blocker of "slow" calcium channels (BCCI). Losartan blocks the vasoconstrictive effect of angiotensin II and stimulation by the latter of aldosterone release by selective inhibition of angiotensin binding II with receptors AT1 in many tissues. Amlodipine is a vasodilator of peripheral arteries, which acts directly on the smooth muscles of the vessels, which leads to a decrease in peripheral resistance of blood vessels and a decrease in blood pressure.

Losartan

Angiotensin II is a potent vasoconstrictor, the main active hormone of the renin-angiotensin-aldosterone system (RAAS), as well as the crucial pathophysiological link in the development of hypertension. Angiotensin II communicates with AT1receptors found in many tissues (in the smooth muscle tissues of the vessels, in the adrenal gland, kidneys and heart), and performs several important biological functions, including vasoconstriction and aldosterone release. Besides, angiotensin II stimulates proliferation of smooth muscle cells. AT2 receptors are the second type of receptor with which angiotensin II binds, but its role in the regulation of cardiovascular function is unknown.

Losartan is a selective antagonist of AT1 receptors of angiotensin II, highly effective when ingested. Losartan and its pharmacologically active carboxylated metabolite (E-3174) as in vitro, and in vivo block all the physiological effects of angiotensin II, regardless of its source or pathway of synthesis. Unlike some peptide angiotensin II antagonists losartan does not possess the properties of an agonist.

Losartan selectively binds to AT1 receptors and does not bind or block receptors of other hormones and ion channels, which play an important role in regulating the function of the cardiovascular system. Besides, losartan does not inhibit angiotensin-converting enzyme (ACE, kininase II), responsible for the destruction of bradykinin. Consequently, effects that are not directly related to the blockade ATi-receptors, such as increased bradykinin-mediated effects or development of edema (losartan 1.7%, placebo 1.9%), are not related to the action of losartan.

Amlodipine

Amlodipine is a dihydropyridine calcium antagonist (calcium ion antagonist or "slow" channel blocker) that inhibits the transmembrane entry of calcium ions into smooth muscle cells of the blood vessels and cardiomyocytes. Experimental data suggest that amlodipine binds both to dihydropyridine and non-dihydropyridine binding sites on the receptors of "slow" calcium channels. The process of contraction of the myocardium and smooth muscles of the vessels depends on the transmembrane entry into the cell of extracellular calcium ions through specific ion channels. Amlodipine selectively inhibits the transmembrane calcium intake, more affecting the smooth muscle cells of the blood vessels than the cardiomyocytes.

In vitro it is possible to detect a negative inotropic effect, however, in studies on intact animals using amlodipine in therapeutic doses, this effect has not been revealed. Amlodipine does not affect the content of calcium in the blood serum. Within the physiological range, pH amlodipine is an ionized compound (pKa = 8.6), and its kinetic interaction with the calcium channel receptor is characterized by a gradual association and dissociation with the receptor binding site, which leads to a gradual development of the effect.

Amlodipine is a vasodilator of peripheral arteries acting directly on the smooth muscles of the vessels,which leads to a decrease in peripheral resistance of blood vessels and a decrease in blood pressure.

Pharmacodynamics

The drug Amzaar

It is shown that Amzaar effectively reduces blood pressure. how losartan, and amlodipine reduce blood pressure by decreasing peripheral resistance. Blocking the calcium entry into the cell and reducing the vasoconstrictive effect due to exposure to angiotensin II, are complementary mechanisms.

Losartan

Losartan suppresses an increase in systolic and diastolic BP with angiotensin infusion II. At the moment of reaching the maximum concentration (C_m_Oh) losartan in blood plasma after taking losartan in a dose of 100 mg the above-mentioned effect of angiotensin II is suppressed by approximately 85%, and 24 hours after a single and multiple doses - by 26-39%.

During the administration of losartan, the elimination of negative feedback, consisting of angiotensin inhibition II secretion of renin, leads to an increase in plasma renin activity (ARP). The increase in ARP leads to an increase in the concentration of angiotensin II in the blood plasma. With prolonged (6-week) treatment of patients with AH losartan at a dose of 100 mg / day, there was a 2-3-fold increase in the concentration of angiotensin II in blood plasma at the time of reaching C_max losartan. In some patients, an even greater increase in angiotensin II, especially with a short duration of treatment (2 weeks). Despite this, during treatment, the antihypertensive effect and the decrease in plasma aldosterone concentration were manifested at 2 and 6 weeks of therapy, which indicates an effective blockade of angiotensin receptors II. After cancellation of losartan, APP and angiotensin concentration II decreased within 3 days to the values observed before the start of losartan. Because the losartan is a specific antagonist of AT1-receptors of angiotensin II, it does not inhibit ACE (kinase II) - an enzyme that inactivates bradykinin. A study comparing the effects of losartan in doses of 20 mg and 100 mg with the effects of an ACE inhibitor on the effect on angiotensin I, angiotensin II and Bradykinin, showed that losartan blocks the effects of angiotensin I and angiotensin II, without affecting the effects of bradykinin. This is due to the specific mechanism of action of losartan. The ACE inhibitor blocked the response to angiotensin I and increased the severity of the effects,caused by the action of bradykinin, without affecting the severity of the response to angiotensin II, which demonstrates the pharmacodynamic difference between losartan and ACE inhibitors.

The concentration of losartan and its active metabolite in the blood plasma, as well as the antihypertensive effect of losartan increase with increasing dose of the drug. As losartan and its active metabolite are antagonists of angiotensin II receptors, they both contribute to the antihypertensive effect.

In a study with a single dose of losartan in a dose of 100 mg, in which healthy volunteers (men) were included, taking the drug inward under high and low-fat diet conditions did not affect the glomerular filtration rate (GFR), the effective renal plasma flow and the filtration fraction. Losartan had a natriuretic effect that was more pronounced with a low-sal diet and, apparently, was not associated with the suppression of early sodium reabsorption in the proximal renal tubules. Losartan also caused a transient increase in the excretion of uric acid by the kidneys.

In patients with AH, proteinuria (not less than 2 g / 24 h), without diabetes mellitus and taking losartan for 8 weeks at a dose of 50 mg with a gradual increase to 100 mg, there was a significant decrease in proteinuria (by 42%), fractional excretion of albumin and immunoglobulins (IgG). In these patients losartan stabilized GFR and reduced the filtration fraction.

In postmenopausal women with AH, who took losartan in a dose of 50 mg for 4 weeks, there was no effect of therapy on the renal and systemic levels of prostaglandins.

Losartan does not affect vegetative reflexes and does not have a lasting effect on the concentration of noradrenaline in the blood plasma.

In patients with AH losartan in doses up to 150 mg / day did not cause clinically significant changes in the concentration of fasting triglycerides, total cholesterol and high-density lipoprotein cholesterol. In the same doses losartan did not affect the concentration of glucose in the blood on an empty stomach.

Generally losartan caused a decrease in the concentration of uric acid in the blood serum (usually less than 0.4 mg / dL), which persisted with long-term treatment. In controlled clinical trials involving patients with hypertension, there were no cases of drug withdrawal due to an increase in creatinine concentration or serum potassium levels.

In a 12-week parallel study, which included patients with left ventricular failure (II-IV functional class by classification NYHA), most of whom took diuretics and / or cardiac glycosides, compared the effects of losartan at doses of 2.5, 10, 25 and 50 mg / day with placebo. At doses of 25 and 50 mg / day, the drug exhibited positive hemodynamic and neurohormonal effects that persisted throughout the study. Hemodynamic effects included an increase in the cardiac index and a decrease in the wedge pressure in the pulmonary capillaries, as well as a reduction in total peripheral vascular resistance, mean systemic arterial pressure, and heart rate (HR). The incidence of arterial hypotension in these patients depended on the dose of the drug. Neurohormonal effects included a decrease in the concentration of aldosterone and norepinephrine in the blood.

Amlodipine

Hemodynamics

In patients with hypertension after taking in therapeutic doses amlodipine causes vasodilation, which leads to a decrease in blood pressure in the prone and standing positions. This decrease in blood pressure is not accompanied by significant changes in heart rate or catecholamine concentration in blood plasma with long-term admission.Despite the fact that in studies on the evaluation of hemodynamics with the participation of patients with stable angina pectoris with a single intravenous administration of amlodipine, there was a decrease in blood pressure and an increase in heart rate, within the framework of clinical studies, repeated ingestion of amlodipine did not lead to clinically significant changes in heart rate or blood pressure in normotensive patients with angina pectoris.

With prolonged ingestion once a day, the antihypertensive effect persists for at least 24 hours. Amlodipine concentration in the blood plasma correlates with antihypertensive action in both young and elderly patients. The magnitude of BP reduction when taking amlodipine also correlates with the severity of BP elevation before treatment. Thus, in patients with moderate-to-moderate arterial hypertension (diastolic pressure 105-114 mm Hg), a greater antihypertensive effect was observed by approximately 50% than in patients with AH of mild severity (diastolic pressure 90-104 mm Hg. ). In patients with normal blood pressure, there was no clinically significant change in blood pressure (+ 1 / -2 mm Hg).

In patients with hypertension and normal renal function, the administration of amlodipine at therapeutic doses led to a decrease in the resistance of the kidney vessels,increased GFR and effective renal plasma flow without changing the filtration fraction or proteinuria.

As with other BCCI, the hemodynamic parameters of heart function at rest and under load (or pacing) in patients with normal function ventricles amlodipine, generally showed a slight increase in the cardiac index without a significant change in the rate of increase in pressure in the cavity of the left ventricle at the beginning of the period of exile (dP/dt) or end-diastolic pressure or volume of the left ventricle. In studies on the evaluation of hemodynamic parameters amlodipine did not have a negative inotropic effect when applied in therapeutic doses in healthy volunteers, even with simultaneous use with beta-blockers. However, similar results were observed in healthy volunteers or in patients with heart failure in the stage of compensation with the use of drugs with a pronounced negative inotropic effect.

Electrophysiological effects

Amlodipine did not affect the function of the sinoatrial node or atrioventricular conduction in healthy volunteers.In patients with chronic stable angina, intravenous administration of 10 mg of amlodipine had no significant effect on AH and H-V conduction and recovery time of the sinus node after pacing. Similar results were obtained in patients who simultaneously took amlodipine and beta-blockers. In clinical studies in which patients with hypertension or angina took amlodipine simultaneously beta-adrenoblockers, there was no undesirable effect on electrocardiographic parameters. In clinical studies with patients only with angina, amlodipine therapy did not affect the electrocardiographic intervals and did not cause atrioventricular blockade to a greater extent.

Pharmacokinetics:

Suction

Losartan

Ingestion losartan is well absorbed and metabolized by "primary passage" through the liver to form an active carboxylated metabolite and inactive metabolites. Systemic bioavailability of losartan in tablet form is about 33%. The average maximum concentrations of losartan and its active metabolite are reached after 1 hour and 3-4 hours, respectively.When losartan was taken during the usual meal, there was no clinically significant effect on the profile of losartan concentration in the blood plasma.

Amlodipine

After oral administration at therapeutic doses of C_m_Oh Amlodipine in blood plasma is achieved in 6-12 hours. The absolute bioavailability of amlodipine ranges from 64% to 90% of the dose. Eating food does not affect the bioavailability of amlodipine.

Distribution

Losartan

Lozartan and its active metabolite bind to plasma proteins (mainly albumin) by at least 99%. The volume of distribution of losartan is 34 liters. Studies in rats have shown that losartan practically does not penetrate the blood-brain barrier.

Amlodipine

Studies have shown that in patients with hypertension, approximately 93% of the circulating drug binds to plasma proteins.

Metabolism

Losartan

Approximately 14% of the dose of losartan for intravenous administration or ingestion is converted into its active metabolite. After ingestion or intravenous administration of radiolabeled radiolabel (¹⁴FROM losartan) radioactivity of circulating blood plasma, primarily due to the presence in it of losartan and its active metabolite.Low conversion efficiency of losartan in its active metabolite was observed in approximately 1% of the patients participating in the study. In addition to the active metabolite, biologically inactive metabolites are formed, including two basic metabolites formed as a result of hydroxylation of the butyl side chain, and one secondary - N-2-tetrazole-glucuronide.

Amlodipine

Amlodipine is intensively (about 90%) metabolized into inactive metabolites in the liver. The kidneys deduce 10% of the dose in the form of unchanged amlodipine and 60% in the form of metabolites.

Excretion

Losartan

The plasma clearance of losartan and its active metabolite is about 600 ml / min and 50 ml / min, respectively. The renal clearance of losartan and its active metabolite is approximately 74 ml / min and 26 ml / min, respectively. When taking losartan, about 4% of the dose is excreted by the kidneys unchanged and about 6% of the dose is excreted by the kidneys as an active metabolite. Losartan and its active metabolite have linear pharmacokinetics when administered to losartan in doses up to 200 mg.

After oral administration, the plasma concentrations of losartan and its active metabolite decrease polyexponentially with a final phase of the half-life of about 2 and 6-9 hours, respectively.When the dosing regimen of the drug is 100 mg once a day, there is no significant accumulation in the blood plasma of either losartan or its active metabolite.

The excretion of losartan and its metabolites is carried out by the kidneys and through the intestine with bile. After oral administration ¹⁴With losartan in men, about 35% of radioactivity is found in urine and 58% in feces. After intravenous administration ¹⁴With losartan in men, approximately 43% of radioactivity is found in urine and 50% in feces.

Amlodipine

Excretion of amlodipine from the blood plasma occurs in two phases, the final phase of the half-life is about 30-50 hours. The equilibrium concentration of amlodipine in plasma is reached after 7-8 days with daily intake.

Pharmacokinetics in specific patient groups

The drug Amzaar

The drug Amsaar has not been studied in any special groups of patients due to a good study of the active substances of the drug, losartan and amlodipine. Losartan should be used with caution in the violation of kidney and liver. It is contraindicated in pregnancy and during breastfeeding. There have been no separate studies involving patients of childhood and elderly patients. Amlodipine should be used with caution in case of impaired liver function. It is contraindicated in the unstable course of cardiovascular diseases, as well as during pregnancy and during breastfeeding.

Losartan

Elderly patients

The concentrations of losartan and its active metabolite in blood plasma in elderly male patients with AH do not significantly differ from these indices in young male patients with AH.

Floor

Concentrations of losartan in the blood plasma in women with AH were 2 times higher than the corresponding values in men with AH. The concentrations of active metabolite in men and women did not differ. This apparent pharmacokinetic difference, however, has no clinical significance.

Patients with impaired hepatic function

When losartan was administered orally to patients with mild and moderate alcoholic cirrhosis, the concentrations of losartan and its active metabolite in blood plasma were respectively 5 and 1.7 times higher than in young healthy male volunteers.

Patients with impaired renal function

Concentrations of losartan in blood plasma in patients with creatinine clearance above 10 ml / min did not differ from those in patients with unchanged renal function. The value of the area under the curve "concentration-time" (AUC) losartan in patients on hemodialysis was approximately 2 times greater than the value AUC losartan in patients with normal renal function. The concentrations of the active metabolite in the blood plasma did not change in patients with impaired renal function or patients on hemodialysis. Losartan and its active metabolite is not output by the hemodialysis procedure.

Amlodipine

Patients with impaired renal function

Renal dysfunction does not significantly affect the pharmacokinetic parameters of amlodipine, so patients with renal insufficiency can be assigned the usual initial dose of amlodipine.

Elderly patients and patients with impaired liver function

In elderly patients and patients with hepatic insufficiency, clearance of amlodipine is reduced, which leads to an increase AUC by about 40-60%. Such patients may require a lower initial dose of amlodipine. A similar increase AUC was observed in patients with moderate or severe heart failure.

Children and teens

Pharmacokinetic studies involving patients with AH at the age of 6 to 17 years who took amlodipine in a dose of 1.25 mg to 20 mg, showed that the body weight corrected clearance and the volume of amlodipine distribution were comparable to those in adult patients.

Indications:Arterial hypertension (patients who are shown combined therapy).

Contraindications:

Hypersensitivity to any of the components of the drug.

Pregnancy and the period of breastfeeding.

Age to 18 years (efficacy and safety of use not established).

Simultaneous use with aliskiren or aliskirenoderzhaschimi drugs in patients with diabetes mellitus and / or renal dysfunction (GFR less than 60 ml / min / 1.73 m²) (see INTERACTION WITH OTHER DRUGS).

Severe liver dysfunction (no experience of use).

Shock (including cardiogenic shock).

Obstruction of the outflow tract of the left ventricle (eg, severe aortic stenosis).

Hemodynamically unstable heart failure after acute myocardial infarction.

Use in patients with impaired renal function (creatinine clearance less than 20 ml / min) or patients on hemodialysis.

Carefully:

Bilateral stenosis of the renal arteries or stenosis of the artery of a single kidney; hyperkalemia; condition after kidney transplantation (no experience of application); aortic or mitral stenosis; hypertrophic obstructive cardiomyopathy; heart failure with concomitant severe impairment of kidney function; severe heart failure (IV functional class by classification NYHA); heart failure with life-threatening arrhythmias; cardiac ischemia; cerebrovascular diseases; primary hyperaldosteronism; angioedema in history; abnormal liver function; unstable angina or myocardial infarction.

Patients with reduced circulating blood volume (eg, receiving treatment with large doses of diuretics) - symptomatic arterial hypotension may occur.

Pregnancy and lactation:

Amzaar is contraindicated in pregnancy and during breastfeeding.

Pregnancy

Losartan

Medicines that directly affect RAAS can cause serious damage and death of the developing fetus,so when diagnosing a pregnancy, Amzaar should be immediately withdrawn and, if necessary, an alternative hypotensive therapy is prescribed.

Although there is no experience with the use of Amzaar in pregnant women, preclinical studies in animals have shown that the administration of losartan leads to the development of serious embryonic and neonatal injuries and the death of the fetus or offspring. It is believed that the mechanism of these phenomena is due to the impact on the RAAS.

Renal perfusion in the fetus, depending on the development of RAAS, appears in the second trimester, so the risk for the fetus increases if the drug Amsaar is used in the second or third trimester of pregnancy.

The use of drugs that affect RAAS in the second and third trimester of pregnancy reduces the function of the kidneys of the fetus and increases the incidence and mortality of the fetus and newborn. The development of oligohydramnion can be associated with fetal lung hypoplasia and skeletal deformities. Possible adverse events in newborns include hypoplasia of the skull bones, anuria, arterial hypotension, renal failure and death.

The above undesirable outcomes are usually due to the use of drugs that affect RAAS in the second and third trimester of pregnancy. Most epidemiological studies on the development of fetal anomalies after the use of antihypertensive drugs in the first trimester of pregnancy have not revealed differences between drugs that affect RAAS and other antihypertensive drugs. When prescribing antihypertensive therapy for pregnant women, it is important to optimize the possible outcomes for the mother and fetus.

If it is not possible to select alternative therapy in place of drugs that affect RAAS, it is necessary to inform the patient about the possible risk of therapy for the fetus. It is necessary to conduct periodic ultrasound examinations to assess the intra-amniotic space. If oligohydramnion is detected, it is necessary to stop taking Amzaar, unless it is vital for the mother. Depending on the week of pregnancy, appropriate fetal tests are necessary.Patients and physicians should be aware that the oligohydramnios may not be detected until irreversible damage to the fetus occurs. It is necessary to closely monitor the newborns whose mothers took the drug Amzaar during pregnancy, in order to control arterial hypotension, oliguria and hyperkalemia.

Amlodipine

Adequate and controlled studies of the use of amlodipine in pregnant women have not been conducted.

Breastfeeding period

It is not known whether losartan and amlodipine with breast milk. Since many drugs are excreted in breast milk and there is a risk of developing potential adverse effects in a breastfed infant, a decision should be made to stop breastfeeding or to discontinue the drug, taking into account the need for its use for the mother.

Fertility

Losartan

There is no clinical evidence of the effect of losartan on fertility.

Amlodipine

Reversible biochemical changes in the head of spermatozoa were observed in some patients taking BCCC. There is insufficient clinical data to assess the possible effects of amlodipine on fertility.

Dosing and Administration:

The drug Amzaar is taken orally regardless of the time of ingestion. It is recommended to drink the product with sufficient water.

The drug Amzaar can be taken in combination with other antihypertensive drugs. Patients who have not achieved adequate control of blood pressure in the application of losartan or amlodipine monotherapy, can upgrade to combined therapy with Amzaar.

The recommended dose of Amzaar is 1 tablet once a day.

The maximum recommended dose of Amzaar is 5 mg + 100 mg once a day.

Preparation Amzaar 5 mg + 50 mg is prescribed for patients who have not achieved adequate BP control with amlodipine 5 mg or losartan 50 mg monotherapy.

The preparation at a dose of 5mg Amzaar + 100mg administered to patients who have not achieved adequate BP control in the application of losartan in a dose of 100 mg or preparation Amzaar 5 mg + 50 mg.

Patients receiving the combination therapy with amlodipine and losartan as separate medicaments may switch to receive a combined preparation Amzaar (fixed dose combination containing the same doses of amlodipine and losartan) to improve adherence to therapy.

Use in patients with impaired renal function

In patients with impaired renal function (KK 20-50 ml / min), dose adjustment is not required. Patients with moderate renal impairment are not recommended. Amzaar is contraindicated in patients with severe renal dysfunction or hemodialysis patients.

In the therapeutic need to use Amzaar in patients with reduced circulating blood volume (BCC), patients with impaired liver function, or elderly patients, individual doses of the active ingredients (i.e., amlodipine and losartan) should be individually pre-determined prior to the use of a combination drug with fixed doses of active substances. Use in patients with reduced BCC

In patients with reduced BCC (eg, receiving treatment with large doses of diuretics) the recommended initial dose of losartan is 25 mg once a day (see SPECIAL INSTRUCTIONS). Since Amzar has no dosage containing losartan 25 mg, this dose should be given in monotherapy with losartan. Use in patients with impaired liver function

Use of Amzaar is not recommended in patients with a history of liver failure, requiring low-dose losartan (i.e., 25 mg once daily).

The recommended doses of amlodipine in patients with impaired liver function of mild and moderate severity have not been studied. Contraindicated use of the drug Amzaar in patients with severe impairment of liver function.

Application in elderly patients

In elderly patients, because of reduced clearance, amlodipine therapy is usually recommended starting at a dose of 2.5 mg once a day. Since Amzar has no dosage containing amlodipine 2.5 mg, this dose should be given in monotherapy with amlodipine.

Application in children and adolescents

Since the effectiveness and safety of the use of Amzaar in patients under 18 years of age have not been studied, the use of Amzaar in this group of patients is contraindicated.

Side effects:

The drug Amzaar

The safety of Amzaar was evaluated in clinical trials for 8 weeks with the participation of 646 patients with AH, of which 325 patients took combination therapy amlodipine + losartan. In the course of clinical studies, the following adverse events were observed, which were evaluated by the investigators as possible, probably or definitely associated with taking the drug (frequent> 1% and <10%, infrequent> 0.1% and <1%).

From the nervous system Frequent: dizziness, headache. Infrequent: drowsiness.

General disorders Infrequent: weakness, discomfort in the chest, chest pain, a sense of rapid saturation, peripheral edema.

From the gastrointestinal tract Infrequent: abdominal discomfort, dyspepsia, nausea, reflux esophagitis.

From the skin and subcutaneous tissue Infrequent: itchy skin (generalized), urticaria (generalized).

From the heart Infrequent: a feeling of palpitations.

From the side of the vessels Infrequent: "tides" of blood to the skin of the face, orthostatic hypotension.

On the part of the respiratory system, the organs of the thorax and the mediastinum Infrequent: shortness of breath.

From the side of the hearing organ and labyrinthine disorders Infrequent: vertigo.

From the side of the kidneys and urinary tract Infrequent: pollakiuria.

The following undesirable phenomena were observed when using the active substances included in the preparation Amsaar in monotherapy.

Losartan

Because clinical trials are conducted under different conditions, the frequency of adverse reactions observed in clinical studies of a single drug can not be directly compared with the frequency of adverse reactions observed in clinical studies of another drug and it can not reflect the frequency observed in clinical practice.

Generally losartan well tolerated by patients with AH. Adverse events are mild and transient and do not require withdrawal of therapy. The total incidence of adverse events with losartan is comparable to that for placebo. In controlled clinical trials, the frequency of discontinuation of therapy due to clinically significant adverse events was 2.3% in the group of patients taking losartan, and 3.7% in the group of patients taking placebo. In controlled clinical trials of losartan in patients with hypertension, the only undesirable treatment-related response observed more often than with placebo was dizziness observed in treatment groups with losartan at a frequency of 1% or more.In addition, less than 1% of patients had dose-dependent orthostatic reactions. Rarely (> 0.01% and <0.1% of cases) reported skin rash, but the incidence was less than with placebo.

In double-blind, controlled clinical trials,> 1% of patients with AH experienced the following adverse events with losartan (n = 2085) or placebo (n = 535), regardless of their association with treatment.

General disorders: pain in the stomach area of 1.7% (placebo 1.7%); weakness and fatigue 3.8% (3.9%); chest pain 1.1% (2.6%); peripheral edema 1.7% (1.9%).

From the cardiovascular system: a palpitation of 1.0% (placebo 0.4%); tachycardia 1.0% (1.7%).

From the digestive system: diarrhea 1.9% (placebo 1.9%); indigestion 1.1% (1.5%); nausea 1.8% (2.8%).

From the musculoskeletal system: back pain 1.6% (placebo 1.1%); muscle spasms 1.0% (1.1%).

From the central nervous system: dizziness 4.1% (placebo 2.4%); headache 14.1% (17.2%); insomnia 1,1% (0,7%).

From the respiratory system: cough 3.1% (placebo 2.6%); edema of the nasal mucous membrane 1.3% (1.1%); pharyngitis 1.5% (2.6%); Sinusitis 1.0% (1.3%); upper respiratory tract infection 6.5% (5.6%).

Controlled clinical studies have shown that losartan mainly well tolerated by patients with hypertrophy and left ventricular hypertrophy. The most frequent undesirable reactions associated with the use of losartan were systemic and non-systemic dizziness, asthenia / weakness.

In this study, in patients without diabetes mellitus, the incidence of new cases of diabetes was lower with losartan compared to atenolol (p <0.001). Since there was no placebo group in this study, it is not known whether this is a positive effect of losartan or an undesirable phenomenon of atenolol.

Controlled clinical studies have shown that losartan mainly well tolerated by patients with type 2 diabetes and proteinuria. The most frequent adverse reactions associated with the use of losartan were dizziness, asthenia / weakness, marked decrease in blood pressure and hyperkalemia (see SPECIAL INSTRUCTIONS).

The following undesirable reactions were observed in clinical practice during post-marketing period.

Hypersensitivity reactions: in patients taking losartan, anaphylactic reactions, angioedema with involvement of the larynx and pharynx causing airway obstruction, and / or angioedema of the face, lips, throat and / or tongue were rarely observed. Some of these patients had a history of angioneurotic edema following the administration of other drugs, including ACE inhibitors. Rarely reported on the occurrence of vasculitis, including purple Shenlaine-Genoh.

From the digestive system: hepatitis (rarely), a violation of the liver, vomiting.

General disorders: a feeling of general discomfort.

On the part of the blood system: anemia, thrombocytopenia (rarely).

From the musculoskeletal system: myalgia, arthralgia.

From the central nervous system: migraine, dysgeusia.

From the genitals and the breast: erectile dysfunction / impotence. From the respiratory system: cough.

From the skin: urticaria, itching, redness of the skin, photosensitization.

Amlodipine besylate

Since clinical trials are conducted under different conditions, the frequency of adverse reactions,observed in clinical studies of a single drug, can not be directly compared with the frequency of adverse reactions observed in clinical studies of another drug, and it can not reflect the frequency observed in clinical practice.

The safety of amlodipine besylate has been evaluated in clinical trials involving more than 11,000 patients. In general, treatment with amlodipine besylate in a dosage of up to 10 mg once a day was well tolerated. The majority of undesirable phenomena observed during amlodipine besylate therapy were of mild or moderate severity. In controlled clinical trials that directly compare amlodipine besylate therapy at a dosage of up to 10 mg once daily from placebo, amlodipine besylate therapy was withdrawn because of adverse events in only 1.5% of patients, which is not significantly different from the placebo group (about 1 %). The most frequent (> 1% and <10%) adverse events are headache and swelling.

The following frequency (%) of dose-dependent undesirable events was observed:

Unwanted phenomenon	2.5 mg	5.0 mg	10.0 mg	Placebo
Edema	1,8	3,0	10,8	0,6
Dizziness	1,1	3,4	3,4	1,5
Tides	0,7	1,4	2,6	0,0
Heart palpitations	0,7	1,4	4,5	0,6

Other adverse events that were observed in the placebo-controlled clinical trials of more than 1.0% of patients and did not have a clear link with the dose:

Unwanted phenomenon	Amlodipine besylate (%)	Placebo (%)
Headache	7,3	7,8
Increased fatigue	4,5	2,8
Nausea	2,9	1,9
Abdominal pain	1,6	0,3
Drowsiness	1,4	0,6

Some adverse events appears to be associated with taking amlodipine besylate and dose were more common in women than in men:

Undesirable	Amlodipine besylate		Placebo
phenomenon	Men (%)	Women (%)	Men (%)	Women (%)
Edema	5,6	14,6	1,4	5,1
Tides	1,5	4,5	0,3	0,9
Feeling palpitation	1,4	3,3	0,9	0,9
Drowsiness	1,3	1,6	0,8	0,3

The following undesirable phenomena are often (>0,1% and < 1%) observed in patients treated in controlled clinical trials or in the open research environment or in the post-registration period, applications where a causal relationship is unknown (indicated in order to inform about a possible causal relationship):

From the cardiovascular system: arrhythmia (including ventricular tachycardia and atrial fibrillation), bradycardia, chest pain, marked reduction in blood pressure, ischemic peripheral vascular disease, syncope, tachycardia, postural dizziness, postural hypotension, vasculitis.

From the central and peripheral nervous system: hypoesthesia, peripheral neuropathy, paresthesia, tremor, vertigo.

From the digestive system: anorexia, constipation, dyspepsia *, dysphagia, diarrhea, flatulence, pancreatitis, vomiting, gingival hyperplasia.

General disorders: allergic reaction, asthenia *, back pain, "tides" of blood to the skin of the face, malaise, pain, stiffness, weight gain, weight loss. From the side of the musculoskeletal system: arthralgia, arthrosis, muscle cramps *, myalgia.

Disorders of the psyche: sexual dysfunction (in men and women), insomnia, increased excitability, depression, unusual dreams, anxiety, depersonalization.

From the respiratory system: shortness of breath *, nosebleeds.

From the skin: angioedema, erythema multiforme, skin itch *, skin rash *, erythematous rash, maculopapular rash.

From the sense organs: impaired vision, conjunctivitis, diplopia, pain in the eye, ringing in the ears.

From the urinary system: frequent urination, impaired urination, nocturia.

From the side of the autonomic nervous system: dryness of the oral mucosa, increased sweating.

From the side of metabolism and nutrition: hyperglycemia, thirst.

From the hematopoiesis: leukopenia, purpura, thrombocytopenia.

* These adverse events were observed in less than 1% in placebo-controlled studies, but their incidence was from 1% to 2% in all studies with repeated use of amlodipine.

The following undesirable phenomena were observed very rarely (<0.1%): heart failure, rhythm disturbances, extrasystole, skin depigmentation, urticaria, dry skin, alopecia, dermatitis, muscle weakness, muscle twitching, ataxia, increased blood pressure, migraine, and moisture of the skin, apathy, agitation, amnesia, gastritis, increased appetite, frequent unformed stool, cough, rhinitis, dysuria, polyuria, parosmia, taste disorder, accommodation disorder and xerophthalmia.

Other adverse events have been observed sporadically, and it is impossible to establish a causal relationship with medication or concomitant diseases, such as myocardial infarction and angina pectoris.

The following undesirable phenomena were also observed in the post-marketing period of observation.Since these unwanted reactions were obtained voluntarily from a population of unknown size, it is not always possible to establish their frequency reliably or to establish a cause-and-effect relationship with the taking of the drug. An undesirable phenomenon that was rarely observed in the post-registration period of observation without an established cause-effect relationship: gynecomastia. During post-registration period of observation, amlodipine besylate received jaundice and increased activity of "hepatic" enzymes (mostly caused by cholestasis or hepatitis), in some cases quite severe and requiring hospitalization.

Amlodipine besylate was safely used in patients with chronic obstructive pulmonary disease, compensated for chronic heart failure, coronary artery disease, peripheral arterial disease, diabetes mellitus, and lipid profile disorder.

Laboratory indicators

The drug Amzaar

In some patients, at 8 weeks of simultaneous administration of amlodipine and losartan, palpitation decreased, but it was not clinically significant.

Some patients showed an increase in creatinine in the blood and an increase in the activity of "liver" enzymes, but no specific laboratory monitoring is required.

Losartan

In controlled clinical trials in patients with hypertension, clinically significant changes in baseline laboratory indicators were rarely associated with losartan. In 1,5% of patients, hyperkalemia was observed (serum potassium more than 5.5 meq / l). In a clinical study in patients with type 2 diabetes mellitus with proteinuria, hyperkalemia developed in 9.9% of patients taking losartan, and 3.4% of patients taking placebo (see SPECIAL INSTRUCTIONS). Increased activity of alanine aminotransferase (ALT) was observed in rare cases and usually returned to normal after the abolition of therapy.

Amlodipine

There were no clinically significant changes in standard laboratory indicators associated with amlodipine therapy. There were no clinically significant changes in serum potassium levels, serum glucose concentrations, triglyceride concentrations, total cholesterol, high-density lipoprotein cholesterol, uric acid, blood urea nitrogen, or creatinine.

Overdose:

The drug Amzaar

There are no data on an overdose of Amzaar. Overdoses with amlodipine and losartan are described.

Losartan

Information on overdose is limited. The most likely manifestation of an overdose is a marked decrease in blood pressure and tachycardia; Bradycardia can occur due to parasympathetic (vagal) stimulation.

Treatment: symptomatic therapy.

Lozartan and its active metabolite are not excreted by hemodialysis.

Amlodipine

Symptoms: Overdose can lead to excessive peripheral vasodilation with a marked decrease in blood pressure and the possible development of reflex tachycardia. A pronounced and prolonged systemic hypotensive effect has been reported up to a fatal shock.

Treatment: if necessary, gastric lavage is indicated. Taking activated charcoal by healthy volunteers directly or within 2 hours after ingestion of 10 mg of amlodipine reduced the absorption of the latter. In the case of a significant overdose of amlodipine, it is necessary to actively monitor hemodynamic and respiratory parameters. Frequent measurement of blood pressure is necessary.When arterial hypotension occurs, it is necessary to provide support for hemodynamics, including the elevated position of the limbs and the adequate introduction of fluids. If arterial hypotension remains resistant to these conservative measures, consideration should be given to the introduction of vasoconstrictive drugs (eg, phenylephrine), taking into account bcc and diuresis. To eliminate calcium channel blockade, intravenous calcium gluconate is effective. Because the amlodipine binds well to plasma proteins, the procedure for hemodialysis is ineffective.

Interaction:

The drug Amzaar

Amzaar drug drug interactions were not studied with other drugs. The study of drug interactions of the active substances that make up Amzaar is described below.

Losartan

In clinical studies on pharmacokinetic interactions of drugs, clinically significant interactions of losartan with hydrochlorothiazide, digoxin, warfarin, cimetidine, and phenobarbital have not been identified. Rifampicin, being an inducer of the metabolism of drugs, reduces the concentration of the active metabolite of losartan in the blood. In clinical studies, the use of two inhibitors of the isoenzyme P450-O4: ketoconazole and erythromycin was studied. Ketoconazole did not affect the metabolism of losartan to the active metabolite after intravenous administration of losartan. Erythromycin did not have a clinically significant effect when taking losartan inside. Fluconazole, inhibitor of the isoenzyme P450 2C9, reduced the concentration of the active metabolite of losartan, however the pharmacodynamic significance of the simultaneous use of losartan and inhibitors of the isoenzyme P450 2C9 has not been studied. It was shown that in patients not metabolizing losartan in the active metabolite, there is a very rare and specific defect in the isoenzyme P450 2C9. These data suggest that the metabolism of losartan to the active metabolite is carried out by the P450 2C9 isoenzyme, rather than the P450 isoenzyme ZA4.

The simultaneous use of losartan, as well as other drugs that block angiotensin II or its effects, with potassium-sparing diuretics (eg, spironolactone, triamterene,amiloride), potassium-containing additives or potassium salts can lead to an increase in potassium in the blood serum.

As with the use of other drugs that affect the excretion of lithium, losartan can reduce the excretion of lithium, so when lithium and ARA II are used simultaneously, the concentration of lithium in serum should be monitored carefully.

Non-steroidal anti-inflammatory drugs (NSAIDs), including selective inhibitors of cyclooxygenase-2 (COX-2), can reduce the effect of diuretics and other antihypertensive agents. As a result, the antihypertensive effect of APA II or ACE inhibitors may be weakened when used simultaneously with NSAIDs, including selective COX-2 inhibitors.

In some patients with impaired renal function (eg, in elderly patients or patients with dehydration, including those taking diuretics) receiving NSAID therapy, including selective COX-2 inhibitors, concomitant use of ARA II or ACE inhibitors may cause further impairment of function kidney, including the development of acute renal failure.These effects are usually reversible, so the simultaneous use of these medicines should be done with caution in patients with impaired renal function.

Double blockade of RAAS with the use of ARA II, ACE inhibitors or aliskiren (renin inhibitor) is associated with an increased risk of arterial hypotension, syncope, hyperkalemia and renal dysfunction (including acute renal failure) compared with monotherapy. Regular monitoring of blood pressure, kidney function and electrolyte content in the blood are necessary for patients taking both Amsaar and other medicines that affect RAAS. Amzaar should not be used concomitantly with aliskiren or aliskiren-containing drugs in patients with diabetes mellitus and / or renal dysfunction (GFR less than 60 ml / min / 1.73 m2).

Amlodipine

Research data in vitro

Research data in vitro showed that amlodipine does not affect the binding of digoxin, phenytoin, warfarin and indomethacin to plasma proteins.

Cimetidine

The simultaneous use of amlodipine and cimetidine does not affect the pharmacokinetics of amlodipine.

Grapefruit juice

Simultaneous intake of 240 ml of grapefruit juice with a single oral intake of amlodipine at a dose of 10 mg in healthy volunteers did not have a significant effect on the pharmacokinetics of amlodipine.

Antacids containing magnesium or aluminum hydroxide

Simultaneous administration of an antacid containing magnesium or aluminum hydroxide with a single dose of amlodipine did not significantly affect the pharmacokinetics of amlodipine.

Sildenafil

A single dose of sildenafil in a dose of 100 mg in patients with AH did not affect the pharmacokinetics of amlodipine. When taking amlodipine simultaneously with sildenafil, each of the drugs independently had its own antihypertensive effect.

Atorvastatin

Simultaneous multiple administration of amlodipine in a dose of 10 mg with atorvastatin at a dose of 80 mg did not lead to significant changes in the equilibrium pharmacokinetic parameters of atorvastatin.

Simvastaty

Simultaneous multiple administration of amlodipine in a dose of 10 mg with simvastatin at a dose of 80 mg resulted in an increase of 77% in the exposure of simvastatin compared with the use of simvastatin in monotherapy. The dose of simvastatin with simultaneous application with amlodipine should not exceed 20 mg once a day.

Digoxin

Simultaneous administration of amlodipine and digoxin did not lead to a change in digoxin concentration in the blood or renal clearance of digoxin in healthy volunteers.

Ethanol (alcohol)

Single and multiple administration of amlodipine at a dose of 10 mg did not significantly affect the pharmacokinetics of ethanol.

Warfarin

The simultaneous administration of amlodipine and warfarin does not affect the increase in prothrombin time in response to the use of warfarin.

Inhibitor inhibitors CYP3A4

In elderly patients with hypertension, simultaneous use of diltiazem in a daily dose of 180 mg and amlodipine at a dose of 5 mg resulted in an increase AUC amlodipine in 1,6 times. In healthy volunteers, simultaneous use of erythromycin and amlodipine does not significantly affect AUC Amlodipine, however, strong inhibitors of isoenzyme CYP3A4 (eg, ketoconazole, itraconazole, ritonavir) can greatly increase the concentration of amlodipine in the blood plasma. With the simultaneous use of amlodipine and isoenzyme inhibitors CYP3A4 should regularly monitor the symptoms of arterial hypotension and swelling.

Inductors of isoenzyme CYP3A4

There is no data on the significant effect of isoenzyme inducers CYP3A4 on pharmacokinetic parameters of amlodipine. It is necessary to monitor the adequacy of the clinical response in patients with simultaneous use of amlodipine and isoenzyme inducers CYP3A4.

Special instructions:

The drug Amzaar

Arterial hypotension

In patients with reduced BCC (eg, receiving treatment with large doses of diuretics) or with severe aortic stenosis, symptomatic arterial hypotension may occur. Correction of such conditions should be performed prior to the appointment of Amzaar or to start treatment with a lower dose of Amzaar (see METHOD OF APPLICATION AND DOSES). Acute hypotension is unlikely in connection with the gradual onset of the drug.

Impaired liver function

On the basis of pharmacokinetic data, which showed a significant increase in the concentration of losartan in the blood plasma in patients with cirrhosis, patients with a history of liver dysfunction should be prescribed lower doses of losartan (see Pharmacokinetics, Pharmacokinetics, METHOD OF APPLICATION AND DOSES).

Because the amlodipine mainly metabolized in the liver and half-life in patients with impaired liver function is 56 hours, with the appointment of amlodipine

patients with severe hepatic insufficiency titration of the dose should be carried out gradually.

Losartan

Hypersensitivity reactions

Patients with an angioneurotic edema in the anamnesis (edema of the face, lips, pharynx / larynx and / or tongue) need control of the drug (see ADVERSE EFFECTS).

Embryotoxicity

Violation of the water-electrolyte balance

Violation of the water-electrolyte balance is characteristic of patients with impaired renal function with or without diabetes mellitus, therefore careful monitoring of these patients is necessary.In clinical studies involving patients with type 2 diabetes mellitus with proteinuria, the incidence of hyperkalemia was greater in the group taking losartan, than in the group taking placebo. Several patients discontinued therapy due to hyperkalemia (see SIDE EFFECTS, Laboratory indicators).

When taking losartan, patients should not take potassium preparations or potassium-containing substitutes for edible salt without first consulting with the doctor.

Aortic or mitral stenosis, hypertrophic obstructive cardiomyopathy

Like all drugs with a vasodilating effect, ARA II should be given with caution to patients with aortic or mitral stenosis or hypertrophic obstructive cardiomyopathy.

Ischemic heart disease and cerebrovascular disease

Like all drugs that have a vasodilating effect, ARA II should be administered with caution to patients with ischemic heart disease or cerebrovascular diseases, as excessive reduction in blood pressure in patients of this group can lead to the development of myocardial infarction or stroke.

Chronic heart failure (CHF)

As with the use of other drugs that have an effect on RAAS, patients with CHF and with or without renal dysfunction have a risk of developing severe hypotension or acute renal failure.

Since there is insufficient experience with losartan in patients with heart failure and concomitant severe impairment of renal function, in patients with severe heart failure (IV functional class by classification NYHA), as well as in patients with heart failure and symptomatic life-threatening arrhythmias, losartan should be administered with caution to patients in these groups.

Primary hyperaldosteronism

Since patients with primary hyperaldosteronism, as a rule, do not have a positive response to therapy with antihypertensive agents that act by inhibiting RAAS, the use of losartan is not recommended in patients in this group.

Impaired liver function

Data from pharmacokinetic studies indicate that the concentration of losartan in the blood plasma in patients with cirrhosis increases significantly, so patients with a history of liver disease should be prescribed losartan in a lower dose.There is no experience with losartan in patients with severe hepatic impairment, so the drug should not be used in patients of this group (see PHARMACOLOGICAL PROPERTIES, Pharmacokinetics, CONTRAINDICATIONS, APPLICATION METHOD AND DOSES).

Impaired renal function

Due to inhibition of RAAS in some predisposed patients, renal function changes, including renal failure, were observed. These changes may occur after discontinuation of treatment.

Some drugs that affect RAAS can increase the concentration of urea in the blood and serum creatinine in patients with bilateral stenosis of the renal arteries or stenosis of the renal artery of a single kidney. It has been reported that similar effects occur when taking losartan. Similar violations of kidney function can be reversible after the abolition of therapy.

Losartan should be used with caution in patients with bilateral stenosis of the renal arteries or stenosis of the renal artery of a single kidney.

Amlodipine

Unstable angina and myocardial infarction

After initiating therapy or increasing the dose of amlodipine, unstable angina and acute myocardial infarction may develop, especially in patients with severe hypertrophic obstructive cardiomyopathy.

Special patient groups

Children and teens

The effectiveness and safety of the use of Amzaar in children and adolescents under 18 years are not established.

If newborns whose mothers took Amzaar during pregnancy, oliguria or hypotension develop, symptomatic therapy is needed to maintain blood pressure and renal perfusion. You may need a blood transfusion or dialysis to prevent the development of arterial hypotension and / or maintain kidney function.

Elderly patients

Clinical studies have not revealed any specificities regarding the safety and effectiveness of losartan in elderly patients (over 65 years of age). In elderly patients due to reduced clearance, leading to an increase AUC Amlodipine by approximately 40-60%, amlodipine therapy is usually recommended starting at a dose of 2.5 mg once a day. Since Amzar has no dosage containing amlodipine 2.5 mg, this dose should be given in monotherapy with amlodipine.

Effect on the ability to drive transp. cf. and fur:

No studies have been conducted to assess the effect on ability to drive vehicles and work with mechanisms, but some of the undesirable effects observed with the use of Amzaar may affect the ability to drive vehicles and work with mechanisms (see ADVERSE EFFECTS).

Form release / dosage:

Tablets film-coated 5 mg + 50 mg or 5 mg + 100 mg.

Packaging:

For 10 tablets in a blister of PA / Al / PVC and aluminum foil or 300 tablets per vial of HDPE, hermetically sealed with a screw cap of PP, containing silica gel under a PE membrane and equipped with a first-opening control ring.

For 1 or 3 blisters or 1 bottle, together with the instructions for use are placed in a cardboard box.

Storage conditions:

Store at a temperature not exceeding 30 ° C.

Keep out of the reach of children.

Shelf life:

2 years (in blisters), 3 years (in vials).

Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:LP-001481

Date of registration:06.02.2012

The owner of the registration certificate:MSD FARMASYUTIKALS, LLC MSD FARMASYUTIKALS, LLC Russia

Manufacturer: & nbsp

HANMI PHARM., Co., Ltd. The Republic of Korea

Information update date: & nbsp11.12.2014

Illustrated instructions

Instructions

Amsaar (Amzaar)