Amlodipine + Olmesartan medoxomil Sandoz^® (Tablets) Instructions for Use

Marketing Authorization Holder

Sandoz, d.d. (Slovenia)

Manufactured By

Novartis Pharmaceutical Manufacturing LLC (Slovenia)

ATC Code

C09DB02 (Amlodipine and olmesartan medoxomil)

Active Substances

Amlodipine (Rec.INN registered by WHO)

Olmesartan medoxomil (Rec.INN registered by WHO)

Dosage Forms

	Amlodipine + Olmesartan medoxomil Sandoz®	Film-coated tablets 5 mg+20 mg: 28 pcs.
		Film-coated tablets 5 mg+40 mg: 28 pcs.
		Film-coated tablets 10 mg+40 mg: 28 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets, engraved with “20 5” on one side, white or almost white, round, biconvex.

Excipients: lactose monohydrate, croscarmellose sodium, corn starch pregelatinized, silicified microcrystalline cellulose, magnesium stearate, partially hydrolyzed polyvinyl alcohol (E1203), titanium dioxide (E171), macrogol/PEG 3350 (E1521), talc (E553b).

14 pcs. – Al/Al blisters (2) – cardboard packs with an insert.

Film-coated tablets, engraved with “40 5” on one side, yellow, round, biconvex.

Excipients: lactose monohydrate, croscarmellose sodium, corn starch pregelatinized, silicified microcrystalline cellulose, magnesium stearate, partially hydrolyzed polyvinyl alcohol (E1203), titanium dioxide (E171), macrogol/PEG 3350 (E1521), talc (E553b), yellow iron oxide (E172).

14 pcs. – Al/Al blisters (2) – cardboard packs with an insert.

Film-coated tablets, engraved with “40 10” on one side, pink, round, biconvex.

Excipients: lactose monohydrate, croscarmellose sodium, corn starch pregelatinized, silicified microcrystalline cellulose, magnesium stearate, partially hydrolyzed polyvinyl alcohol (E1203), titanium dioxide (E171), macrogol/PEG 3350 (E1521), talc (E553b), yellow iron oxide (E172), red iron oxide (E172).

14 pcs. – Al/Al blisters (2) – cardboard packs with an insert.

Clinical-Pharmacological Group

Combined antihypertensive drug (slow calcium channel blocker + angiotensin II receptor antagonist)

Pharmacotherapeutic Group

Agents acting on the renin-angiotensin system; angiotensin II receptor antagonists, combinations; angiotensin II receptor antagonists and calcium channel blockers

Pharmacological Action

A combined antihypertensive drug containing the angiotensin II receptor antagonist olmesartan medoxomil and the slow calcium channel blocker amlodipine. The combination of the two active substances has a synergistic antihypertensive effect, resulting in a greater reduction in blood pressure than when each is taken separately.

In an 8-week double-blind, randomized, placebo-controlled study involving 1940 patients, it was shown that the antihypertensive effect of the drug usually develops within the first 2 weeks of therapy. As shown in three studies, when the drug was applied once daily, the antihypertensive effect of the drug was maintained for 24 hours, with the trough-to-peak ratio for systolic blood pressure (SBP) and diastolic blood pressure (DBP) ranging from 71% to 82%. The antihypertensive effect was confirmed by ambulatory blood pressure monitoring and did not depend on age and gender, as well as on the presence of diabetes mellitus in patients. In two open-label, non-randomized extension studies, sustained efficacy of the drug at a dose of 5 mg+40 mg was shown for 49-67% of patients over one year of use.

In a double-blind, randomized, placebo-controlled study, the addition of amlodipine at a dose of 5 mg with insufficient efficacy of prior (for 8 weeks) monotherapy with olmesartan medoxomil at a dose of 20 mg led after 8 weeks to a reduction in SBP and DBP by 16.2 and 10.6 mm Hg (p=0.0006), respectively. The proportion of patients who achieved target blood pressure values (<140/90 mm Hg for patients without diabetes and <130/80 mm Hg for patients with diabetes) was 44.5% with combination therapy with olmesartan medoxomil 20 mg and amlodipine 5 mg compared to 28.5% with monotherapy with 20 mg olmesartan medoxomil.

In another study, the addition of 20 mg (40 mg) olmesartan medoxomil with insufficient efficacy of prior monotherapy with amlodipine 5 mg (for 8 weeks) led after 8 weeks to a reduction in SBP and DBP by 15.3 and 9.3 mm Hg, respectively (addition of 40 mg olmesartan medoxomil – by 16.7 and 9.5 mm Hg). In patients who continued to receive amlodipine monotherapy at a dose of 5 mg, SBP and DBP decreased by 9.9 and 5.7 mm Hg, respectively, after 8 weeks.

The proportion of patients who achieved target blood pressure values (<140/90 mm Hg for patients without diabetes and <130/80 mm Hg for patients with diabetes) was 29.9% in the amlodipine 5 mg monotherapy group, 53.5% in the combination drug 5 mg+20 mg group, and 50.5% in the combination drug 5 mg+40 mg group.

In an 8-week double-blind, randomized, placebo-controlled study involving 1940 patients (71% Caucasian and 29% other races), the use of the drug (at any combination of its component doses) resulted in a significantly greater reduction in SBP and DBP compared to monotherapy. The degree of SBP/DBP reduction depended on the amlodipine/olmesartan medoxomil doses used: -24/-14 mm Hg (5 mg+20 mg), -25/-16 mm Hg (5 mg+40 mg) and -30/-19 mm Hg (10 mg+40 mg).

When using the drug at a dose of 5 mg+40 mg, an additional reduction in sitting SBP/DBP of 2.5/1.7 mm Hg was observed compared to the use of the drug at a dose of 5 mg+20 mg. Similarly, the use of the drug at a dose of 10 mg+40 mg led to an additional reduction in sitting SBP/DBP of 4.7/3.5 mm Hg compared to the use of the drug at a dose of 5 mg+40 mg. The proportion of patients who achieved target blood pressure values (<140/90 mm Hg for patients without diabetes and <130/80 mm Hg for patients with diabetes) was 42.5%, 51% and 49.1% for the drug at doses of 5 mg+20 mg, 5 mg+40 mg and 10 mg+40 mg, respectively.

Amlodipine

Amlodipine is a slow calcium channel blocker that blocks the transmembrane influx of calcium ions into cardiomyocytes and vascular smooth muscle cells through voltage-gated L-type channels. Experimental data indicate that amlodipine interacts with both dihydropyridine and non-dihydropyridine binding sites. Amlodipine has relative vasoselectivity and exerts a greater effect on vascular smooth muscle cells than on cardiomyocytes. The mechanism of the antihypertensive action of amlodipine is associated with a direct relaxing effect on vascular smooth muscle, causing a decrease in peripheral vascular resistance and a reduction in blood pressure.

Amlodipine causes a dose-dependent, long-term reduction in blood pressure in patients with arterial hypertension. There are no data on the development of arterial hypotension after the first dose of amlodipine, on tachyphylaxis during long-term treatment, or on a withdrawal syndrome.

When used in therapeutic doses in patients with arterial hypertension, amlodipine causes vasodilation, leading to a decrease in blood pressure (in the supine, sitting, and standing positions). With long-term use, the reduction in blood pressure is not accompanied by a significant change in heart rate and plasma catecholamine concentrations. In arterial hypertension in patients with normal renal function, the use of amlodipine in therapeutic doses leads to a decrease in renal vascular resistance, an increase in GFR and an increase in effective renal blood flow without changing the filtration fraction and the level of proteinuria.

In hemodynamic studies in patients with heart failure, as well as in clinical studies involving patients with heart failure (NYHA class II-IV) during stress testing, amlodipine did not worsen the condition of patients, as assessed by exercise tolerance, left ventricular ejection fraction, as well as clinical signs and symptoms.

In a placebo-controlled study (PRAISE) involving patients with heart failure (NYHA class III-IV) receiving digoxin, diuretics and ACE inhibitors, it was shown that amlodipine did not increase the risk of complications and/or mortality (overall and from cardiovascular causes) in patients with heart failure.

In a long-term placebo-controlled study (PRAISE-II) involving patients with heart failure (NYHA class III-IV) without clinical symptoms or objective evidence of coronary artery disease, taking ACE inhibitors, digoxin and diuretics, it was shown that the use of amlodipine had no effect on overall mortality and mortality from cardiovascular causes.

In a double-blind randomized study (ALLHAT), the efficacy of amlodipine at a dose of 2.5-10 mg/day or lisinopril at a dose of 10-40 mg/day as first-line therapy was compared, and the use of the thiazide diuretic chlorthalidone at a dose of 12.5-25 mg/day for mild to moderate arterial hypertension. A total of 33,357 patients with hypertension aged 55 years and older were included in the study and followed for an average of 4.9 years. The combined primary endpoint included fatal outcomes in patients with coronary artery disease or nonfatal myocardial infarction. No statistically significant differences in the effect on the primary study endpoint were noted between the amlodipine and chlorthalidone groups. No significant difference in all-cause mortality was observed between these groups either.

Olmesartan medoxomil

Olmesartan medoxomil is a potent specific angiotensin II receptor antagonist (type AT₁). Angiotensin II is the primary vasoactive component of the RAAS and plays a significant role in the pathophysiology of arterial hypertension by acting on AT₁ receptors. Olmesartan, by preventing the binding of angiotensin II to AT₁ receptors in tissues (including vascular smooth muscle and adrenal glands), blocks its vasoconstrictive action, as well as the effects associated with the influence of angiotensin II on aldosterone secretion. The specific antagonism of olmesartan to AT₁ receptors leads to an increase in the activity of renin, angiotensin I and II in the blood plasma, and also contributes to a decrease in the plasma concentration of aldosterone.

In arterial hypertension, olmesartan medoxomil causes a dose-dependent, long-term reduction in blood pressure. There are no data on the development of arterial hypotension after the first dose of olmesartan medoxomil, on tachyphylaxis during long-term treatment, or on a withdrawal syndrome.

Taking olmesartan medoxomil once daily provides effective and smooth blood pressure reduction over 24 hours. Dividing the daily dose into two doses has an antihypertensive effect similar to that achieved when taking the same daily dose at once. The antihypertensive effect of olmesartan medoxomil usually occurs within 2 weeks, and the maximum effect develops approximately 8 weeks after the start of therapy.

In the randomized ROADMAP study involving 4447 patients with type 2 diabetes, normoalbuminuria and at least one additional cardiovascular risk factor, the ability of olmesartan to increase the time to the onset of microalbuminuria was evaluated. During the study (median follow-up was 3.2 years), patients took olmesartan or placebo in addition to other antihypertensive agents (excluding ACE inhibitors or other angiotensin II receptor antagonists). The study showed a 23% reduction in risk for the primary endpoint (time to onset of microalbuminuria) in favor of olmesartan (HR 0.770; 95.1% CI: 0.630-0.941; p=0.0104). Cardiovascular complications (secondary endpoints) were reported in 96 patients (4.3%) in the olmesartan group and 94 patients (4.2%) in the placebo group.

In the randomized ORIENT study conducted in Japan and China, the effect of olmesartan on renal and cardiovascular outcomes was studied in 577 patients with type 2 diabetes and overt nephropathy. During the study (median follow-up was 3.1 years), patients received olmesartan or placebo in addition to other antihypertensive drugs, including ACE inhibitors.

The primary combined endpoint (time to event, whichever occurred first: doubling of plasma creatinine concentration, development of end-stage chronic kidney disease, death from all causes) was recorded in 116 patients in the olmesartan group (41.1%) and 129 patients in the placebo group (45.4%) (HR 0.97; 95% CI: 0.75-1.24; p=0.791).

Pharmacokinetics

After oral administration of the drug, the C_max of olmesartan and amlodipine in plasma is reached after 1.5-2 hours and 6-8 hours, respectively. The rate and extent of absorption of olmesartan medoxomil and amlodipine in the combined drug correspond to the rate and extent of absorption of these components as monodrugs. Simultaneous food intake does not affect the bioavailability of olmesartan medoxomil and amlodipine.

Amlodipine

After oral administration in therapeutic doses, amlodipine is well absorbed, the time to reach C_max is 6-12 hours after administration. Absolute bioavailability is about 64-80%. V_d is about 21 L/kg. Plasma protein binding in vitro for circulating amlodipine is approximately 97.5%. Simultaneous food intake does not significantly affect the absorption of amlodipine.

Amlodipine is extensively metabolized in the liver to form inactive metabolites, 10% of the parent substance and 60% of metabolites are excreted by the kidneys.

After a single dose, T_1/2 from plasma in the terminal phase is about 35-50 hours.

Olmesartan medoxomil

Olmesartan medoxomil is a prodrug. It is rapidly converted to a pharmacologically active metabolite by the action of enzymes (esterases) in the intestinal mucosa and portal blood during absorption from the gastrointestinal tract. Olmesartan medoxomil in unchanged form or with an intact medoxomil fragment is not detected in plasma and/or feces. The bioavailability of olmesartan averages 25.6%. Simultaneous food intake does not significantly affect the bioavailability of olmesartan, so olmesartan medoxomil can be taken regardless of meals.

C_max of olmesartan in plasma is reached on average 2 hours after oral administration of olmesartan medoxomil and increases approximately linearly with an increase in a single dose up to 80 mg.

Olmesartan is characterized by a high degree of binding to plasma proteins (99.7%), but the potential for clinically significant displacement of the binding value when olmesartan interacts with other highly bound and simultaneously used drugs is low (as evidenced by the absence of clinically significant interaction between olmesartan and warfarin). The degree of binding of olmesartan to blood cells is insignificant. The mean V_d after IV administration is low (16-29 L).

Steady state is reached after the first few doses of the drug, after 14 days of repeated use no further accumulation is observed.

Total plasma clearance is usually 1.3 L/h (coefficient of variation – 19%) and is relatively low compared to hepatic blood flow (approximately 90 L/h).

Olmesartan is eliminated by two routes. After a single oral dose of ¹⁴C-labeled olmesartan medoxomil, 10-16% of the radioactive substance was excreted by the kidneys (most within 24 hours after taking olmesartan medoxomil), the remaining radioactive substance was excreted through the intestine. Taking into account the systemic bioavailability of 25.6%, it can be calculated that approximately 40% of the absorbed olmesartan is excreted through the kidneys, and about 60% through the hepatobiliary system. The excreted radioactive substance was represented by olmesartan. No other metabolites were found. Enterohepatic recirculation of olmesartan is minimal. The T_1/2 of olmesartan is 10-15 hours after multiple oral doses. Renal clearance is approximately 0.5-0.7 L/h and does not depend on the dose of the drug.

No clinically significant differences in the pharmacokinetic parameters of olmesartan depending on gender were found.

Pharmacokinetics in special patient groups

The time to reach C_max of amlodipine in plasma does not differ between elderly patients and young patients. In elderly patients, there is a tendency to decrease the clearance of amlodipine, which leads to an increase in AUC and a prolongation of T_1/2.

In elderly (65-75 years) and very elderly (75 years and older) patients with arterial hypertension, the steady-state AUC for olmesartan is 35% and approximately 44% higher, respectively, compared to the AUC of olmesartan in younger patients, which may be partly due to age-related decline in renal function.

Renal failure does not significantly affect the pharmacokinetics of amlodipine. Changes in amlodipine plasma concentrations do not correlate with the degree of renal impairment. Amlodipine is not removed from the body by dialysis.

Compared with healthy volunteers, in patients with mild, moderate and severe renal impairment, the AUC of olmesartan increases by approximately 62%, 82% and 179%, respectively.

Clinical experience with amlodipine in patients with hepatic impairment is limited. In these patients, a decrease in amlodipine clearance and a prolongation of T_1/2 are observed, leading to an increase in AUC of approximately 40-60%.

After a single oral dose, the AUC values of olmesartan were 6% and 65% higher in patients with mild and moderate hepatic impairment, respectively, compared with healthy volunteers. The unbound fraction of olmesartan 2 hours after oral administration of a single dose of the drug in healthy volunteers, in patients with mild and moderate hepatic impairment was 0.26%, 0.34% and 0.41%, respectively. With multiple oral administration, the AUC of olmesartan in patients with moderate hepatic impairment was 65% higher than in healthy control volunteers. The mean C_max values of olmesartan in patients with hepatic impairment and healthy volunteers were similar. Since most of the olmesartan is excreted through the hepatobiliary system, the use of the drug in patients with biliary tract obstruction is contraindicated.

Indications

Essential hypertension (when monotherapy with olmesartan medoxomil or amlodipine is ineffective).

ICD codes

Dosage Regimen

The drug is taken orally, once a day, at the same time, regardless of meals, without chewing, with a sufficient amount of liquid (for example, a glass of water).

Before prescribing the combination drug, it is recommended to preliminarily titrate the doses of each active substance separately (olmesartan medoxomil and amlodipine).

The recommended dose is 1 tablet of the drug containing 5 mg of amlodipine and 20 mg of olmesartan medoxomil.

If there is no adequate reduction in blood pressure while taking the combination drug at a dose of 5 mg+20 mg, the drug at a dose of 5 mg+40 mg (1 tablet)/day may be used.

If there is no adequate reduction in blood pressure while taking the combination drug at a dose of 5 mg+40 mg, the drug at a dose of 10 mg+40 mg (1 tablet)/day may be used.

The maximum daily dose of olmesartan medoxomil is 40 mg. The maximum daily dose of amlodipine is 10 mg.

In patients aged 65 years and older with normal renal function, no dose adjustment of the drug is required. When increasing the dose of olmesartan medoxomil to the maximum (40 mg/day) in elderly patients, careful blood pressure monitoring should be carried out.

When using the drug in patients with mild to moderate renal impairment (creatinine clearance 20-60 ml/min), periodic monitoring of plasma potassium and creatinine levels is recommended. The maximum dose of olmesartan medoxomil for patients with mild to moderate renal impairment is 20 mg once a day, since experience with higher doses in this category of patients is limited. In patients with severe renal impairment (creatinine clearance less than 20 ml/min), the use of the drug is contraindicated.

In patients with mild or moderate hepatic impairment (less than 9 points on the Child-Pugh scale), the drug should be used with caution. In mild or moderate hepatic impairment, the maximum dose of olmesartan medoxomil is 20 mg once a day. The use of amlodipine in patients with impaired liver function should be started at the minimum dose (5 mg). With simultaneous use with diuretics and/or other antihypertensive drugs in patients with impaired liver function, careful monitoring of blood pressure and renal function is recommended. The use of the drug is contraindicated in patients with severe hepatic impairment (more than 9 points on the Child-Pugh scale) (no experience of use).

Adverse Reactions

Possible side effects are listed below according to the WHO classification in descending order of frequency: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1000), very rare, including isolated reports (<1/10,000), frequency unknown (cannot be estimated from the available data).

Combination of amlodipine and olmesartan medoxomil

Immune system disorders rare – allergic reactions, hypersensitivity reactions, urticaria.

Nervous system disorders common – dizziness, headache; uncommon – hypoesthesia, paresthesia, postural dizziness, somnolence; rare – syncope.

Psychiatric disorders uncommon – decreased libido.

Cardiac and vascular disorders uncommon – palpitations, tachycardia, marked decrease in blood pressure, orthostatic hypotension; rare – flushing.

Respiratory, thoracic and mediastinal disorders uncommon – cough, dyspnea.

Ear and labyrinth disorders uncommon – vertigo.

Gastrointestinal disorders uncommon – dry mouth, abdominal pain, constipation, diarrhea, dyspepsia, nausea, vomiting.

Renal and urinary disorders uncommon – pollakiuria.

Reproductive system and breast disorders uncommon – erectile dysfunction/impotence.

Skin and subcutaneous tissue disorders uncommon – skin rash.

Musculoskeletal and connective tissue disorders uncommon – back pain, muscle cramps, limb pain.

General disorders and administration site conditions common – increased fatigue, peripheral edema, soft tissue edema; uncommon – asthenia; rare – facial edema.

Investigations uncommon – increase/decrease in plasma potassium levels, increase in plasma uric acid concentration, increase in plasma creatinine concentration, increased GGT activity.

Amlodipine (monotherapy)

Blood and lymphatic system disorders: very rare – leukopenia, thrombocytopenia, thrombocytopenic purpura.

Immune system disorders very rare – hypersensitivity reactions, angioedema, urticaria.

Metabolism and nutrition disorders very rare – increased blood glucose levels.

Psychiatric disorders uncommon – depression, insomnia, irritability, mood swings (including anxiety); rare – confusion.

Nervous system disorders common – dizziness, headache, somnolence; uncommon – taste perversion, sleep disorder, hypoesthesia, paresthesia, syncope, tremor, ataxia, amnesia, peripheral neuropathy; very rare – hypertonia, parosmia, apathy, agitation.

Eye disorders uncommon – visual impairment (including diplopia), xerophthalmia, conjunctivitis, eye pain.

Ear and labyrinth disorders uncommon – tinnitus.

Cardiac and vascular disorders common – flushing, palpitations; uncommon – angina pectoris (including exacerbation of coronary artery disease), marked decrease in blood pressure; very rare – cardiac arrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation), development or worsening of chronic heart failure, orthostatic hypotension, myocardial infarction, vasculitis.

Respiratory, thoracic and mediastinal disorders uncommon – dyspnea, rhinitis, epistaxis; very rare – cough.

Gastrointestinal disorders common – abdominal pain, nausea; uncommon – functional bowel disorders (including diarrhea and constipation), dry mouth, dyspepsia, vomiting; very rare – gastritis, gingival hyperplasia, pancreatitis, increased liver enzymes (mostly in the context of cholestasis), hepatitis, jaundice, hyperbilirubinemia.

Skin and subcutaneous tissue disorders uncommon – alopecia, exanthema, hyperhidrosis, pruritus, skin rash (including hemorrhagic), skin pigmentation disorders; very rare – erythema multiforme, exfoliative dermatitis, photosensitivity, Stevens-Johnson syndrome.

Musculoskeletal and connective tissue disorders uncommon – arthralgia, back pain, myalgia, muscle cramps; rare – myasthenia.

Renal and urinary disorders uncommon – frequent urination, painful urination, nocturia; very rare – dysuria, polyuria.

Reproductive system and breast disorders uncommon – erectile dysfunction/impotence, gynecomastia.

General disorders and administration site conditions common – increased fatigue, edema, ankle edema; uncommon – asthenia, chest pain, malaise, pain of unspecified localization, decrease/increase in body weight.

Isolated cases of extrapyramidal syndrome have also been reported in patients taking Amlodipine.

Olmesartan medoxomil (monotherapy)

Blood and lymphatic system disorders uncommon – thrombocytopenia.

Immune system disorders uncommon – anaphylactic reactions, allergic dermatitis, urticaria; rare – angioedema.

Metabolism and nutrition disorders common – increased plasma triglycerides, increased plasma uric acid; rare – hyperkalemia.

Nervous system disorders common – dizziness, headache.

Cardiac and vascular disorders uncommon – angina pectoris; rare – marked decrease in blood pressure.

Respiratory, thoracic and mediastinal disorders common – pharyngitis, rhinitis, bronchitis, cough.

Ear and labyrinth disorders uncommon – vertigo.

Gastrointestinal disorders common – diarrhea, dyspepsia, gastroenteritis, abdominal pain, nausea, increased liver enzymes; uncommon – vomiting; very rare – sprue-like enteropathy.

Renal and urinary disorders common – hematuria, urinary tract infections; rare – acute renal failure, renal failure.

Skin and subcutaneous tissue disorders uncommon – exanthema, skin rash, pruritus.

Musculoskeletal and connective tissue disorders common – bone pain, arthritis; uncommon – myalgia; rare – muscle cramps.

General disorders and administration site conditions common – back pain, chest pain, peripheral edema, flu-like symptoms, increased fatigue, pain of unspecified localization; uncommon – facial edema, asthenia, malaise; rare – somnolence.

Investigations common – increased blood urea, increased CPK activity; rare – increased plasma creatinine concentration.

Isolated cases of rhabdomyolysis, which were temporally related to the intake of angiotensin II receptor antagonists, have also been reported.

Contraindications

Severe hepatic impairment (more than 9 points on the Child-Pugh scale); biliary obstruction and cholestasis; severe renal impairment (creatinine clearance less than 20 ml/min, no clinical experience); condition after kidney transplantation (no clinical experience); conditions accompanied by a significant impairment of blood outflow from the left ventricle (for example, severe aortic stenosis); severe arterial hypotension (SBP less than 90 mm Hg); shock (including cardiogenic); hemodynamically unstable heart failure after myocardial infarction; simultaneous use with aliskiren and aliskiren-containing drugs in patients with diabetes mellitus and/or impaired renal function (GFR less than 60 ml/min/1.73 m² body surface area); pregnancy; breastfeeding period; age under 18 years (efficacy and safety not established); hypersensitivity to olmesartan medoxomil, amlodipine and other dihydropyridine derivatives or to other components of the drug.

With caution aortic and mitral stenosis; hypertrophic obstructive cardiomyopathy; simultaneous use with lithium preparations; hyperkalemia, hyponatremia; hypovolemia (including due to diarrhea, vomiting or simultaneous use of diuretics), as well as in patients on a salt-restricted diet; mild to moderate renal impairment (creatinine clearance 20-60 ml/min); primary aldosteronism; renovascular hypertension (bilateral renal artery stenosis or stenosis of the artery of a solitary kidney); other conditions accompanied by activation of the RAAS; chronic heart failure (NYHA class III-IV); chronic forms of coronary artery disease; acute forms of coronary artery disease (acute myocardial infarction, including within one month after it; unstable angina); sick sinus syndrome; arterial hypotension; cerebrovascular diseases; mild to moderate hepatic impairment (less than 9 points on the Child-Pugh scale); age over 65 years; use in patients of Black race.

Use in Pregnancy and Lactation

There are no data on the use of the drug during pregnancy. However, due to reports of severe teratogenic effects of drugs that act directly on the RAAS, the use of the drug during pregnancy is contraindicated.

If angiotensin II receptor antagonists are used in the second and third trimesters of pregnancy, an ultrasound examination should be performed to assess fetal renal function and skull ossification. Newborns whose mothers took angiotensin II receptor antagonists should be observed for the possible development of arterial hypotension and impaired renal function.

Data obtained from observations of a limited number of pregnant women did not show that Amlodipine or other slow calcium channel blockers have a negative effect on the fetus. However, there is a risk of increased duration of labor.

Patients planning pregnancy are recommended to be switched to antihypertensive drugs of other groups, the safety of which during pregnancy has been proven, except in cases where the drug is prescribed for vital indications. If pregnancy occurs during therapy with the combination drug, it should be discontinued immediately and, if necessary, alternative treatment with a proven safety profile for use during pregnancy should be prescribed.

It has been shown that olmesartan medoxomil passes into breast milk in rats, but similar data for humans are not available. Due to the lack of reliable data, the use of the drug during breastfeeding is contraindicated.

Use in Hepatic Impairment

The use of the drug is contraindicated in severe hepatic impairment (more than 9 points on the Child-Pugh scale); biliary obstruction and cholestasis.

With caution mild to moderate hepatic impairment (less than 9 points on the Child-Pugh scale).

Use in Renal Impairment

The use of the drug is contraindicated in severe renal impairment (creatinine clearance less than 20 ml/min, no clinical experience); condition after kidney transplantation (no clinical experience).

With caution mild to moderate renal impairment (creatinine clearance 20-60 ml/min).

Pediatric Use

The use of the drug is contraindicated under the age of 18 years (efficacy and safety not established).

Geriatric Use

The drug should be prescribed with caution to patients over 65 years of age.

Special Precautions

In patients with chronic heart failure, in whom renal function may depend to a significant extent on the activity of the RAAS (for example, in patients with bilateral renal artery stenosis or stenosis of the artery of a solitary functioning kidney), the use of drugs affecting the RAAS (for example, angiotensin II receptor antagonists) may lead to the development of acute arterial hypotension, oliguria, azotemia or, in rare cases, acute renal failure. Thus, the drug should be used with caution in patients with heart failure.

Since the drug contains Amlodipine, it, like other vasodilators, should be used with caution in patients with aortic and/or mitral stenosis, as well as in patients with hypertrophic obstructive cardiomyopathy.

Slow calcium channel blockers should be used with caution in patients with chronic heart failure, as there is evidence that they may increase the risk of cardiovascular complications and mortality. However, studies in patients with heart failure have shown that Amlodipine does not increase the risk of complications and/or mortality.

In a long-term placebo-controlled study of amlodipine in patients with severe heart failure (NYHA class III and IV), an increased number of reports of pulmonary edema was noted in the amlodipine group compared to the placebo group.

As with the use of any antihypertensive drugs, an excessive decrease in blood pressure in patients with coronary artery disease and cerebrovascular diseases may lead to the development of myocardial infarction or ischemic stroke.

In patients with hypovolemia and/or hyponatremia resulting from intensive diuretic therapy, dietary salt restriction, diarrhea or vomiting, symptomatic arterial hypotension may occur, especially after taking the first dose of the drug. These conditions should be corrected before prescribing the drug, or the patient should be carefully monitored at the initial stage of therapy.

As with the use of other angiotensin II receptor antagonists and ACE inhibitors, hyperkalemia may develop during the use of the drug, especially in patients with impaired renal function and/or heart failure. When prescribing the drug to patients in this group, careful monitoring of plasma potassium and creatinine levels is recommended.

There is no experience with the use of the drug in patients who have recently undergone kidney transplantation or in patients with end-stage renal disease (creatinine clearance less than 12 ml/min).

In patients with hepatic impairment, the effects of amlodipine and olmesartan medoxomil may be enhanced. The drug should be prescribed with caution to patients with mild or moderate hepatic impairment (less than 9 points on the Child-Pugh scale). In patients with moderate hepatic impairment, the dose of olmesartan medoxomil should not exceed 20 mg. In patients with hepatic impairment, the use of amlodipine should be started at the lowest dose and caution should be exercised both at the beginning of treatment and when increasing the dose.

The drug should be used with caution simultaneously with potassium supplements, potassium-sparing diuretics, salt substitutes containing potassium or other drugs that can increase potassium levels (heparin); regular monitoring of blood potassium levels is recommended in this case.

Patients with primary aldosteronism usually do not respond to antihypertensive drugs that suppress the RAAS. Therefore, prescribing the drug is not advisable for patients of this category.

As with the use of other angiotensin II receptor antagonists, the antihypertensive effect of the drug in Black patients may be somewhat less than in other patients, possibly due to the higher prevalence of low renin levels in this population.

Cases have been reported where patients taking slow calcium channel blockers experienced reversible biochemical changes in the sperm head. There is insufficient clinical data regarding the potential impact of amlodipine on fertility.

Given the presence of amlodipine in the composition, during the use of the drug, monitoring of the following parameters is necessary: body weight, amount of salt consumed, oral hygiene and observation by a dentist (to prevent soreness, bleeding and gingival hyperplasia).

In very rare cases, the development of severe chronic diarrhea accompanied by significant weight loss has been reported in patients taking olmesartan medoxomil for several months to several years. It is possible that these effects are based on a local delayed hypersensitivity reaction. Biopsy results in these cases often showed villous atrophy. In the event of the symptoms described above during treatment with olmesartan medoxomil, other possible causes of diarrhea should be excluded. If no possible causes can be identified, the use of preparations containing olmesartan medoxomil should be discontinued.

If biopsy confirms the presence of a sprue-like enteropathy, treatment with preparations containing olmesartan medoxomil should not be resumed, even after the symptoms have disappeared.

Effect on the ability to drive vehicles and operate machinery

While being treated with the drug, caution should be exercised when driving vehicles and other mechanisms, and when engaging in potentially hazardous activities that require increased concentration and speed of psychomotor reactions (since the development of such side effects as headache, dizziness, nausea, and increased fatigue is possible, especially at the beginning of treatment).

Drug Interactions

The antihypertensive effect of the drug may be enhanced when used concomitantly with other antihypertensive drugs (for example, alpha-blockers, diuretics).

Amlodipine

When amlodipine and other antihypertensive drugs are used concomitantly, their antihypertensive effects are additive.

Concomitant use of amlodipine with strong or moderate inhibitors of the CYP3A4 isoenzyme (protease inhibitors, azole antifungals, macrolides such as erythromycin or clarithromycin, verapamil or diltiazem) may significantly increase the plasma concentration of amlodipine. The clinical manifestations of this interaction may be more pronounced in elderly patients, which may require additional patient monitoring and dose adjustment.

It should be taken into account that concomitant use with inducers of the CYP3A4 isoenzyme (such as rifampicin, St. John’s wort) may decrease the plasma concentration of amlodipine. Amlodipine should be used with caution concomitantly with inducers of the CYP3A4 isoenzyme.

In animal studies, after administration of a slow calcium channel blocker (verapamil) and intravenous dantrolene (a drug for the treatment of malignant hyperthermia) against the background of hyperkalemia, cases of ventricular fibrillation and the development of cardiovascular failure with a fatal outcome were noted. Due to the risk of hyperkalemia, in patients prone to malignant hyperthermia, as well as during the use of dantrolene for malignant hyperthermia, it is recommended to avoid the use of slow calcium channel blockers, such as Amlodipine.

Although a negative inotropic effect is generally not observed with the use of amlodipine, some slow calcium channel blockers may enhance the negative inotropic effect of antiarrhythmic drugs that cause QT interval prolongation (for example, amiodarone, quinidine).

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

Single and repeated administration of amlodipine 10 mg does not affect the pharmacokinetics of ethanol.

Antiviral agents (for example, ritonavir) increase the plasma concentrations of slow calcium channel blockers, including amlodipine.

Antipsychotics and isoflurane enhance the antihypertensive effect of dihydropyridine-derived slow calcium channel blockers.

Calcium preparations may reduce the effect of slow calcium channel blockers.

Cimetidine does not affect the pharmacokinetics of amlodipine.

Concomitant use of aluminum- or magnesium-containing antacids does not significantly affect the pharmacokinetics of amlodipine.

In clinical drug interaction studies, no effect of amlodipine on the pharmacokinetics of atorvastatin, digoxin, warfarin, or cyclosporine was noted.

Long-term concomitant use of amlodipine (10 mg) and simvastatin (80 mg) led to a 77% increase in the plasma concentration of simvastatin compared to taking simvastatin alone. The dose of simvastatin in patients taking Amlodipine should not exceed 20 mg/day.

Concomitant use of amlodipine and grapefruit juice is not recommended, as an increase in bioavailability and enhancement of the antihypertensive effect of amlodipine is possible in some patients.

When used concomitantly, Amlodipine may enhance the toxic effect of tacrolimus or cyclosporine, therefore, it is necessary to monitor the plasma concentration of cyclosporine and tacrolimus and adjust the dose if necessary.

Olmesartan medoxomil

Concomitant use with potassium-sparing diuretics, potassium preparations, potassium-containing salt substitutes, or other drugs that increase plasma potassium levels (for example, NSAIDs (including selective COX-2 inhibitors), immunosuppressants (for example, cyclosporine or tacrolimus), trimethoprim, ACE inhibitors, heparin) is not recommended. If concomitant use of these drugs and olmesartan medoxomil is necessary, careful monitoring of plasma potassium levels is required.

Clinical trial data show that dual blockade of the RAAS with the concomitant use of ACE inhibitors, angiotensin II receptor antagonists, or aliskiren is associated with a higher incidence of adverse effects such as arterial hypotension, hyperkalemia, and decreased renal function (including the development of acute renal failure) than with the use of only one drug acting on the RAAS. Therefore, the concomitant use of ACE inhibitors, angiotensin II receptor antagonists, or aliskiren is not recommended.

Concomitant use of olmesartan medoxomil and drugs containing aliskiren is contraindicated in patients with diabetes and renal failure (with GFR less than 60 ml/min/1.73²m body surface area).

In patients with diabetic nephropathy, ACE inhibitors and angiotensin II receptor antagonists should not be used concomitantly.

When concomitant use of two agents affecting the RAAS is necessary, their use should be under medical supervision and accompanied by regular monitoring of renal function, blood pressure, and plasma electrolyte levels.

When used concomitantly with antacids (magnesium and aluminum hydroxide), a moderate decrease in the bioavailability of olmesartan medoxomil is observed.

When used concomitantly, olmesartan medoxomil does not have a clinically significant effect on the pharmacokinetics and pharmacodynamics of warfarin or the pharmacokinetics of digoxin.

Concomitant use of olmesartan medoxomil with pravastatin in healthy volunteers did not have clinically significant effects on the pharmacokinetics of either drug.

There are reports of a reversible increase in plasma lithium concentration and manifestation of toxicity with the concomitant use of lithium preparations with ACE inhibitors and angiotensin II receptor antagonists, therefore, the use of olmesartan medoxomil in combination with lithium preparations is not recommended. If the use of the corresponding combination therapy is necessary, regular monitoring of plasma lithium concentration is recommended.

No clinically significant inhibitory effect of olmesartan on the CYP1A1/2, CYP2A6, CYP2C8/9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 isoenzymes was detected in vitro; a minimal or zero inducing effect was noted in relation to rat cytochrome P450, suggesting the absence of clinically significant interaction when olmesartan medoxomil is used concomitantly with drugs metabolized by the aforementioned cytochrome P450 system isoenzymes.

Concomitant use of NSAIDs, including non-selective NSAIDs, selective COX-2 inhibitors, acetylsalicylic acid (in a dose of more than 3 g/day), and angiotensin II receptor antagonists may increase the risk of acute renal failure, therefore, monitoring of renal function is recommended, especially at the beginning of use, as well as regular intake of a sufficient amount of fluid by the patient.

At the same time, concomitant use of NSAIDs and angiotensin II receptor antagonists may lead to a weakening of the antihypertensive effect of angiotensin II receptor antagonists, resulting in a partial loss of their therapeutic efficacy.

Concomitant use of colesevelam hydrochloride (a bile acid sequestrant) and olmesartan medoxomil results in a weakening of the systemic effect of olmesartan medoxomil, a decrease in its C_{max and}T_1/2. Administration of olmesartan medoxomil at least 4 hours before administration of colesevelam hydrochloride attenuates this interaction. Olmesartan medoxomil should be taken at least 4 hours before taking colesevelam hydrochloride.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

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.