Olmesar a 40/10

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT Olmesar A 20/5 / Olmesar A 20/5

Olmesar A 40/5 / Olmesar A 40/5
Olmesar A 40/10 / Olmesar A 40/10

Composition:

Active substances: olmesartan medoxomil; amlodipine besylate;

Olmesar A 20/5:

1 tablet contains olmesartan medoxomil 20 mg and amlodipine besylate 6.944 mg (equivalent to amlodipine 5 mg);

Olmesar A 40/5:

1 tablet contains olmesartan medoxomil 40 mg and amlodipine besylate 6.944 mg (equivalent to amlodipine 5 mg);

Olmesar A 40/10:

1 tablet contains olmesartan medoxomil 40 mg and amlodipine besylate 13.888 mg (equivalent to amlodipine 10 mg);

Excipients:

microcrystalline cellulose silicified, colloidal anhydrous silicon dioxide, pregelatinized starch, sodium croscarmellose, magnesium stearate;

film coating:

Olmesar A 20/5:

Opadry II White 85F18422 (partially hydrolyzed polyvinyl alcohol, macrogol, talc, titanium dioxide (E 171));

Olmesar A 40/5:

Opadry II Yellow 85F82567 (partially hydrolyzed polyvinyl alcohol, macrogol, talc, titanium dioxide (E 171), yellow iron oxide (E 172));

Olmesar A 40/10:

Opadry II Brown 85F26912 (partially hydrolyzed polyvinyl alcohol, macrogol, talc, titanium dioxide (E 171), yellow iron oxide (E 172), red iron oxide (E 172)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties.

Olmesar A 20/5:

white, round, biconvex film-coated tablets, embossed with "L75" on one side and smooth on the other;

Olmesar A 40/5:

light yellow, rounded, biconvex film-coated tablets, embossed with "L77" on one side and smooth on the other;

Olmesar A 40/10:

red (brown-red), round, biconvex film-coated tablets, embossed with "L78" on one side and smooth on the other.

Pharmacotherapeutic group. Angiotensin II antagonists and calcium channel blockers.

ATC code C09D B02.

Pharmacological properties.

Pharmacodynamics.

Olmesar A is a combination medicinal product containing olmesartan medoxomil – an angiotensin II receptor antagonist – and amlodipine besylate – a calcium channel blocker. The combination of these two active substances demonstrates a synergistic effect, resulting in greater reduction of arterial pressure than either active substance alone.

In an 8-week, double-blind, randomized, placebo-controlled factorial study involving 1940 patients (71% of patients were Caucasian and 29% belonged to other races), treatment with Olmesar A resulted in significantly greater reductions in diastolic and systolic blood pressure compared to monotherapy with the respective components. The mean reduction in systolic/diastolic blood pressure was dose-dependent: 24/14 mm Hg (20 mg/5 mg), 25/16 mm Hg (40 mg/5 mg), and 30/19 mm Hg (40 mg/10 mg).

The medicinal product Olmesar A 40/5 reduced seated systolic/diastolic blood pressure by an additional 2.5/1.7 mm Hg compared to Olmesar A 20/5. Similarly, Olmesar A 40/10 reduced seated systolic/diast polic blood pressure by an additional 4.7/3.5 mm Hg compared to Olmesar A 40/5.

The proportion of patients who achieved target blood pressure values (<140/90 mm Hg in patients without diabetes mellitus and <130/80 mm Hg in diabetic patients) was 42.5%, 51.0%, and 49.1% for Olmesar A 20/5, Olmesar A 40/5, and Olmesar A 40/10, respectively.

The main antihypertensive effect of Olmesar A was generally achieved within the first 2 weeks of therapy.

In a second double-blind, randomized, placebo-controlled study, the efficacy of adding amlodipine to the treatment regimen was evaluated in Caucasian patients who had an inadequate response to monotherapy with olmesartan medoxomil 20 mg over 8 weeks.

In patients who continued to receive only olmesartan medoxomil 20 mg, systolic/diastolic blood pressure decreased by 10.6/7.8 mm Hg over the subsequent 8 weeks. When 5 mg amlodipine was added, a reduction in systolic/diastolic blood pressure of 16.2/10.6 mm Hg was achieved over 8 weeks (p=0.0006).

The proportion of patients who achieved target blood pressure values (<140/90 mm Hg in non-diabetic patients and <130/80 mm Hg in diabetic patients) was 44.5% for Olmesar A 20/5 compared to 28.5% for 20 mg olmesartan medoxomil.

Further studies evaluated the efficacy of adding various doses of olmesartan medoxomil to the treatment regimen in Caucasian patients with an inadequate response to monotherapy with amlodipine 5 mg over 8 weeks.

In patients who continued to receive only 5 mg amlodipine, systolic/diastolic blood pressure decreased by 9.9/5.7 mm Hg over the subsequent 8 weeks. Adding 20 mg olmesartan medoxomil resulted in a reduction in systolic/diastolic blood pressure of 15.3/9.3 mm Hg, and adding 40 mg olmesartan medoxomil resulted in a reduction of 16.7/9.5 mm Hg (p<0.0001).

The proportion of patients who achieved target blood pressure values (<140/90 mm Hg in non-diabetic patients and <130/80 mm Hg in diabetic patients) was 29.9% in the amlodipine 5 mg monotherapy group, 53.5% in the Olmesar A 20/5 group, and 50.5% in the Olmesar A 40/5 group.

Randomized data comparing the outcomes of combination therapy with Olmesar A at medium doses versus dose escalation of amlodipine or olmesartan medoxomil as monotherapy in patients with uncontrolled arterial hypertension are lacking.

Results from three studies confirm that the antihypertensive effect of Olmesar A administered once daily persisted over a 24-hour dosing interval, with the ratio between minimum and maximum systolic and diastolic blood pressure values ranging from 71% to 82%. The 24-hour efficacy of the drug was confirmed by ambulatory blood pressure monitoring.

The antihypertensive effect of Olmesar A was independent of age, sex, and the presence of diabetes mellitus in patients.

In two open-label, non-randomized, extension studies, sustained efficacy of Olmesar A 40/5 was demonstrated in 49–67% of patients after one year of treatment.

Olmesartan medoxomil (active substance in Olmesar A)

Olmesartan medoxomil, contained in Olmesar A, is a selective antagonist of angiotensin II type 1 (AT1) receptors. In the body, olmesartan medoxomil is rapidly converted into the pharmacologically active metabolite olmesartan by esterases in the intestinal mucosa and portal blood during absorption in the gastrointestinal tract. Unconverted olmesartan medoxomil or the medoxomil side chain are not detected in plasma or excretory products. The mean absolute bioavailability of olmesartan as tablets is 25.6%.

The mean peak plasma concentration (Cmax) of olmesartan is reached approximately 2 hours after oral administration. Plasma concentrations of olmesartan increase approximately linearly with increasing single doses up to 80 mg.

Food has minimal effect on the bioavailability of olmesartan; therefore, olmesartan medoxomil can be administered independently of food intake.

No clinically significant differences in the pharmacokinetics of olmesartan related to sex have been observed. Olmesartan is highly bound to plasma proteins (99.7%), but the risk of clinically significant competitive interactions with other highly protein-bound drugs is low, as confirmed by the absence of interaction between olmesartan medoxomil and warfarin. Olmesartan is extensively bound to blood cells. The mean volume of distribution after intravenous administration is low (16–29 L).

Metabolism and elimination

Total plasma clearance of olmesartan is typically 1.3 L/hour (coefficient of variation 19%) and is relatively low compared to hepatic blood flow (approximately 90 L/hour). After a single oral dose of radiolabeled 14C-olmesartan medoxomil, 10–16% of radioactivity was observed in urine (mostly within 24 hours after administration), and the remainder was excreted in feces. Based on systemic availability of 25.6%, it can be calculated that absorbed olmesartan is eliminated both renally (approximately 40%) and via the hepatobiliary system (approximately 60%). All detected radioactivity was identified as olmesartan. No other significant metabolites have been identified. Enterohepatic recirculation of olmesartan is minimal. Since the majority of olmesartan is excreted via bile, its use is contraindicated in patients with biliary obstruction (see section "Contraindications").

The terminal elimination half-life of olmesartan after multiple oral doses ranges from 10 to 15 hours. Steady state is reached after the first few doses, and no further accumulation occurs after 14 days of multiple dosing. Renal clearance is approximately 0.5–0.7 L/hour and is dose-independent.

Drug interactions

Bile acid-binding drug colesevelam

Concomitant administration of 40 mg olmesartan medoxomil and 3750 mg colesevelam hydrochloride in healthy volunteers resulted in a 28% reduction in Cmax and a 39% reduction in the area under the plasma concentration-time curve (AUC) for olmesartan. A smaller effect, with reductions in Cmax and AUC of 4% and 15%, respectively, was observed when olmesartan medoxomil was administered 4 hours before colesevelam hydrochloride (see section "Interaction with other medicinal products and other forms of interaction").

Amlodipine (active substance in Olmesar A)

Amlodipine, contained in Olmesar A, is a calcium channel blocker that inhibits transmembrane influx of calcium ions through voltage-dependent L-type channels in the heart and vascular smooth muscle. Experimental data indicate that amlodipine interacts with both dihydropyridine binding sites and other sites. Amlodipine has relative vasoselectivity and primarily affects vascular smooth muscle cells rather than cardiomyocytes. The antihypertensive effect of amlodipine is due to direct relaxation of arterial smooth muscle cells, leading to reduced peripheral vascular resistance and, consequently, reduced arterial pressure.

In arterial hypertension, amlodipine induces a prolonged, dose-dependent reduction in blood pressure. No post-first-dose hypotension, tachyphylaxis during long-term treatment, or rebound hypertension after discontinuation has been observed.

After administration in therapeutic doses, amlodipine effectively reduces blood pressure in supine, seated, and standing positions in patients with arterial hypertension. Long-term use of amlodipine is not associated with significant changes in heart rate or plasma catecholamine levels. In patients with arterial hypertension and normal renal function, therapeutic doses of amlodipine reduce renal vascular resistance and increase glomerular filtration rate (GFR) and effective renal plasma flow, without altering filtration fraction or inducing proteinuria.

Hemodynamic studies in patients with heart failure, as well as clinical stress testing studies in patients with heart failure (NYHA classes II–IV), showed that amlodipine did not worsen the condition of study participants, as assessed by exercise tolerance, left ventricular ejection fraction, and clinical signs and symptoms.

In a placebo-controlled study (PRAISE) involving patients with heart failure (NYHA classes III–IV) receiving digoxin, diuretics, and ACE inhibitors, amlodipine was shown not to increase the risk of mortality or morbidity in patients with heart failure.

In a subsequent long-term, placebo-controlled study (PRAISE-2) involving patients with heart failure (NYHA III and IV) without clinical or objective evidence of ischemic heart disease (IHD), receiving ACE inhibitors, digitalis, and diuretics at stable doses, amlodipine did not affect overall mortality or cardiovascular mortality. In this patient group, an increased incidence of pulmonary edema was observed with amlodipine, but no statistically significant differences in the frequency of worsening heart failure compared to placebo were observed.

Preventive therapy of myocardial infarction (ALLHAT)

A double-blind, randomized study on morbidity and mortality, "Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial" (ALLHAT), was conducted to compare new antihypertensive therapies: amlodipine 2.5–10 mg daily (calcium channel blocker) or lisinopril 10–40 mg daily (ACE inhibitor) as first-line therapy versus the thiazide diuretic chlorthalidone 12.5–25 mg daily in mild to moderate hypertension.

All 33,357 hypertensive patients aged 55 years or older were randomized and followed for a mean of 4.9 years. Patients had at least one additional risk factor for IHD, including prior myocardial infarction or stroke (more than 6 months before enrollment) or other atherosclerotic cardiovascular diseases (51.5% total), type 2 diabetes (36.1%), high-density lipoprotein (HDL) cholesterol <35 mg/dL (11.6%), left ventricular hypertrophy diagnosed by electrocardiography or echocardiography (20.9%), or current smoking (21.9%).

The primary endpoint was a composite of fatal IHD or non-fatal myocardial infarction. No significant differences in the primary endpoint were observed between amlodipine and chlorthalidone therapy: OR 0.98, 95% CI (0.90–1.07); p=0.65. Regarding secondary endpoints, the incidence of heart failure (a component of the composite cardiovascular endpoint) was significantly higher in the amlodipine group compared to the chlorthalidone group (10.2% vs. 7.7%, OR 1.38, 95% CI [1.25–1.52]; p<0.001). However, no significant differences in all-cause mortality were observed between amlodipine and chlorthalidone therapy (OR 0.96, 95% CI [0.89–1.02]; p=0.20).

Other information

Concomitant use of ACE inhibitors and angiotensin II receptor blockers was investigated in two large-scale, randomized, controlled trials (ONTARGET [ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial] and VA NEPHRON-D [The Veterans Affairs Nephropathy in Diabetes]).

ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular disease or type 2 diabetes with evidence of target organ damage. VA NEPHRON-D was a study conducted in patients with type 2 diabetes and diabetic nephropathy. The data from these studies did not demonstrate a significant beneficial effect on renal and/or cardiovascular outcomes or mortality, while an increased risk of hyperkalemia, acute kidney injury, and/or hypotension was observed compared to monotherapy. Given the similar pharmacodynamic properties, these results are also applicable to other ACE inhibitors and angiotensin II receptor blockers.

Concomitant use of ACE inhibitors and angiotensin II receptor blockers is contraindicated in patients with diabetic nephropathy.

ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a study designed to detect a positive effect of adding aliskiren to standard therapy with ACE inhibitors or angiotensin II receptor blockers in patients with type 2 diabetes and chronic kidney disease, cardiovascular disease, or both. The study was terminated early due to an increased risk of adverse outcomes. Cardiovascular mortality and stroke incidence were higher in the aliskiren group than in the placebo group, and reports of adverse events and serious adverse events (hyperkalemia, arterial hypotension, and renal function impairment) were more frequent in the aliskiren group than in the placebo group.

Pharmacokinetics.

After oral administration of Olmesar A, maximum plasma concentrations (Cmax) of olmesartan medoxomil and amlodipine are reached within 1.5–2 hours and 6–8 hours, respectively. The rate and extent of absorption of the two active substances in Olmesar A correspond to the rate and extent of absorption when administered separately. The bioavailability of olmesartan and amlodipine in Olmesar A is not affected by food intake.

Olmesartan medoxomil (active substance in Olmesar A)

Absorption and distribution

Olmesartan medoxomil is a prodrug. It is rapidly converted to the pharmacologically active metabolite olmesartan by esterases in the intestinal mucosa and portal blood during absorption in the gastrointestinal tract. Unconverted olmesartan medoxomil or the medoxomil side chain are not detected in plasma or excretory products. The mean absolute bioavailability of olmesartan as tablets is 25.6%.

The mean peak plasma concentration of olmesartan is reached approximately 2 hours after oral administration. Plasma concentrations of olmesartan increase approximately linearly with increasing single doses up to 80 mg.

Food has minimal effect on the bioavailability of olmesartan; therefore, olmesartan medoxomil can be administered independently of food intake.

No clinically significant differences in the pharmacokinetics of olmesartan related to sex have been observed. Olmesartan is highly bound to plasma proteins (99.7%), but the risk of clinically significant competitive interactions with other highly protein-bound drugs is low, as confirmed by the absence of interaction between olmesartan medoxomil and warfarin. Olmesartan is extensively bound to blood cells. The mean volume of distribution after intravenous administration is low (16–29 L).

Metabolism and elimination

Total plasma clearance of olmesartan is typically 1.3 L/hour (coefficient of variation 19%) and is relatively low compared to hepatic blood flow (approximately 90 L/hour). After a single oral dose of radiolabeled 14C-olmesartan medoxomil, 10–16% of radioactivity was observed in urine (mostly within 24 hours after administration), and the remainder was excreted in feces. Based on systemic availability of 25.6%, it can be calculated that absorbed olmesartan is eliminated both renally (approximately 40%) and via the hepatobiliary system (approximately 60%). All detected radioactivity was identified as olmesartan. No other significant metabolites have been identified. Enterohepatic recirculation of olmesartan is minimal. Since the majority of olmesartan is excreted via bile, its use is contraindicated in patients with biliary obstruction (see section "Contraindications").

The terminal elimination half-life of olmesartan after multiple oral doses ranges from 10 to 15 hours. Steady state is reached after the first few doses, and no further accumulation occurs after 14 days of multiple dosing. Renal clearance is approximately 0.5–0.7 L/hour and is dose-independent.

Drug interactions

Bile acid-binding drug colesevelam

Concomitant administration of 40 mg olmesartan medoxomil and 3750 mg colesevelam hydrochloride in healthy volunteers resulted in a 28% reduction in Cmax and a 39% reduction in the area under the plasma concentration-time curve (AUC) for olmesartan. A smaller effect, with reductions in Cmax and AUC of 4% and 15%, respectively, was observed when olmesartan medoxomil was administered 4 hours before colesevelam hydrochloride (see section "Interaction with other medicinal products and other forms of interaction").

Amlodipine (active substance in Olmesar A)

Absorption and distribution

After oral administration in therapeutic doses, amlodipine is well absorbed, reaching peak plasma concentration (Cmax) 6–12 hours after administration. The absolute bioavailability of unchanged compound is approximately 64–80%. The volume of distribution is approximately 21 L/kg. In vitro studies showed that approximately 97.5% of circulating amlodipine is bound to plasma proteins. Food intake does not affect the absorption of amlodipine.

Metabolism and elimination

The elimination half-life from plasma ranges from 35 to 50 hours and remains unchanged with daily single-dose administration. Amlodipine is extensively metabolized to inactive metabolites. Approximately 60% of the administered dose is excreted in urine, of which 10% is unchanged.

Olmesartan medoxomil and amlodipine (active substances in Olmesar A)

Special patient groups

Children (under 18 years of age)

Pharmacokinetic data in children are lacking.

Elderly patients (aged 65 years and older):

It has been demonstrated that in elderly (65–75 years) and very elderly (aged 75 years and older) patients with arterial hypertension, the steady-state AUC of olmesartan is approximately 35% and 44% higher, respectively, compared to younger patients (see section "Dosage and administration"). This can be explained by the presence of moderate renal impairment in these patients. However, the same dosage regimen is recommended for elderly patients as for other patients, although dose escalation should be done cautiously.

The time to reach Cmax of amlodipine in plasma is the same in elderly and younger patients. In elderly patients, there is a tendency toward reduced clearance of amlodipine, leading to increased AUC and prolonged elimination half-life. Increased AUC and prolonged elimination half-life in patients with congestive heart failure are consistent with expectations for this age group (see section "Special precautions for use").

Renal impairment

In patients with impaired renal function, steady-state AUC was approximately 62%, 82%, and 179% higher in cases of mild, moderate, and severe impairment, respectively, compared to healthy volunteers (see sections "Special precautions for use" and "Dosage and administration").

Amlodipine is extensively metabolized to inactive metabolites. 10% of the substance is excreted unchanged in urine. Changes in amlodipine plasma concentration do not correlate with the degree of renal impairment. Amlodipine can be administered at usual doses to such patients. Amlodipine is not removed by hemodialysis.

Hepatic impairment

After a single oral dose, AUC values of olmesartan were 6% and 65% higher in patients with mild or moderate hepatic impairment, respectively, compared to healthy volunteers. The unbound fraction of olmesartan 2 hours after administration in healthy volunteers and patients with mild or moderate hepatic impairment was 0.26%, 0.34%, and 0.41%, respectively. With repeated dosing, the mean AUC of olmesartan in patients with moderate hepatic impairment was 65% higher than in healthy volunteers. Mean Cmax values of olmesartan in patients with hepatic impairment and healthy volunteers were similar. Olmesartan medoxomil has not been evaluated in patients with severe hepatic impairment (see sections "Special precautions for use" and "Dosage and administration").

Only very limited clinical data are available on the use of amlodipine in patients with severe hepatic impairment. In patients with hepatic impairment, reduced clearance and prolonged elimination half-life of amlodipine lead to an increase in AUC by approximately 40–60% (see sections "Special precautions for use" and "Dosage and administration").

Preclinical safety data

Based on the preclinical toxicity profile of each active substance, increased toxicity for the combination product is not expected, as these substances affect different organs: olmesartan medoxomil acts on the kidneys, and amlodipine acts on the heart.

In a 3-month toxicity study of the combination product olmesartan medoxomil/amlodipine in rats with repeated oral administration, the following changes were observed: decreased erythrocyte parameters and kidney changes (both effects may be caused by olmesartan medoxomil), intestinal changes (lumen dilation and diffuse thickening of the mucosa of the ileum and colon), adrenal gland changes (hypertrophy of glomerular zone cells and vacuolization of fasciculate zone cells), and mammary duct hypertrophy, which may be caused by amlodipine. These changes do not supplement previously obtained toxicity data on individual components and do not indicate new toxic effects or synergistic toxicity.

Olmesartan medoxomil (active substance in Olmesar A)

In chronic toxicity studies in rats and dogs, effects of olmesartan medoxomil were similar to those of other AT1 receptor antagonists and ACE inhibitors: increased blood urea nitrogen (BUN) and creatinine levels, reduced heart weight, decreased erythrocyte parameters (erythrocyte count, hemoglobin, hematocrit), histological signs of kidney damage (regenerative kidney epithelial lesions, thickening of the basal membrane, tubular dilation). These adverse reactions, caused by the pharmacological action of olmesartan medoxomil, were also observed in preclinical studies with other AT1 receptor antagonists and ACE inhibitors and may be reduced by oral administration of sodium chloride. In both animal species, increased plasma renin activity and hypertrophy/hyperplasia of renal juxtaglomerular cells were observed. These changes, typical of the class of ACE inhibitors and other AT1 receptor antagonists, are likely not clinically significant.

Similar to other AT1 receptor antagonists, olmesartan medoxomil increases the frequency of chromosomal breaks in in vitro cell cultures. However, similar effects were reproduced in several in vivo studies where olmesartan medoxomil was administered orally at very high doses up to 2000 mg/kg. Overall, comprehensive genotoxicity studies suggest that genotoxic effects of olmesartan are unlikely at clinical use.

In a 2-year study in rats or a 6-month carcinogenicity study in transgenic mice, no carcinogenic properties of olmesartan medoxomil were detected.

In reproductive organ toxicity studies in rats, olmesartan medoxomil did not affect fertility and had no teratogenic effects. As with other angiotensin II receptor antagonists, after exposure to olmesartan medoxomil, offspring survival was reduced, and female rats receiving the drug in late pregnancy and during lactation showed renal pelvis dilation. Like other antihypertensive drugs, olmesartan medoxomil was more toxic to pregnant rabbits than to pregnant rats but did not exert fetotoxic effects.

Amlodipine (active substance in Olmesar A)

Reproductive toxicity

Reproductive function studies in rats and mice revealed delayed onset of labor, prolonged labor duration, and reduced offspring survival at doses approximately 50 times higher than the maximum recommended human dose based on body weight (mg/kg).

Impairment of fertility

No effect on fertility was observed in rats receiving amlodipine (males for 64 days, females for 14 days before mating) at doses up to 10 mg/kg/day (8 times* the maximum recommended human dose of 10 mg, normalized to mg/m²). In another study, male rats receiving amlodipine besylate for 30 days at doses comparable to the human dose normalized to mg/m² showed reduced plasma follicle-stimulating hormone and testosterone concentrations, reduced sperm density, and decreased numbers of mature spermatids and Sertoli cells.

Carcinogenesis, mutagenesis

Two-year carcinogenicity studies in rats and mice receiving amlodipine in feed at concentrations calculated to reproduce doses of 0.5, 1.25, and 2.5 mg/kg/day did not reveal signs of carcinogenicity. The highest dose (equivalent in mice to the maximum recommended dose of 10 mg normalized to mg/m², and in rats twice the maximum recommended dose) was close to the maximum tolerated dose in mice but not in rats.

Mutagenicity studies did not reveal any drug-related effects at the gene or chromosome level.

*Assuming a patient body weight of 50 kg.

Clinical characteristics.

Indications.

Treatment of essential hypertension.

The medicinal product Olmesar A is indicated for patients in whom monotherapy with olmesartan medoxomil or amlodipine does not provide adequate control of arterial pressure (see sections "Pharmacodynamics" and "Method of administration and dosage").

Contraindications.

• Hypersensitivity to the active substances, dihydropyridine derivatives, or to any of the excipients of the medicinal product (see section "Composition").
• Pregnancy and planned pregnancy (see sections "Contraindications" and "Use in pregnancy or lactation").
• Severe hepatic impairment and biliary obstruction (see section "Pharmacokinetics").
• Concomitant use of Olmesar A and medicinal products containing aliskiren is contraindicated in patients with diabetes mellitus or renal impairment (eGFR <60 mL/min/1.73 m²) (see sections "Pharmacodynamics**"** and "Interaction with other medicinal products and other forms of interaction").

Due to the presence of amlodipine, Olmesar A is also contraindicated in patients with:

• Severe arterial hypotension;
• Shock (including cardiogenic shock);
• Impaired outflow from the left ventricle (e.g., in severe aortic stenosis);
• Hemodynamically unstable heart failure following acute myocardial infarction.

Interaction with other medicinal products and other forms of interaction.

Potential interactions caused by combination with the medicinal product Olmesar A

Caution should be exercised when co-administering

Other antihypertensive agents

The antihypertensive effect of Olmesar A may be enhanced when used concomitantly with other antihypertensive medicinal products (e.g., alpha-blockers, diuretics).

Potential interactions related to the olmesartan medoxomil component of Olmesar A

Concomitant use is not recommended

ACE inhibitors, angiotensin II receptor blockers, or aliskiren

Clinical trial data show that dual blockade of the renin-angiotensin-aldosterone system (RAAS), associated with concomitant use of ACE inhibitors and angiotensin II receptor blockers or aliskiren, leads to increased frequency of adverse events such as arterial hypotension, hyperkalemia, and impaired renal function (including acute renal failure), compared to use of a single RAAS-acting medicinal product (see sections "Pharmacodynamics", "Contraindications", and "Special precautions for use").

Medicinal products affecting potassium levels

Concomitant use with potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, or other medicinal products that may increase potassium levels (e.g., heparin, ACE inhibitors) may lead to increased serum potassium concentration (see section "Special precautions for use"). When prescribing medicinal products affecting potassium levels in combination with Olmesar A, monitoring of serum potassium concentration is recommended.

Lithium preparations

Increased serum lithium concentrations and lithium toxicity have been observed rarely when lithium is used concomitantly with ACE inhibitors and angiotensin II receptor antagonists. Therefore, concomitant use of Olmesar A and lithium preparations is not recommended (see section "Special precautions for use"). If concomitant use of Olmesar A and lithium preparations is necessary, regular monitoring of serum lithium levels is recommended.

Concomitant use requires caution

Nonsteroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors, acetylsalicylic acid (>3 g/day), and non-selective NSAIDs

When angiotensin II antagonists are administered concomitantly with NSAIDs, the antihypertensive effect may be attenuated. In addition, concomitant use of angiotensin II antagonists and NSAIDs may increase the risk of renal impairment and lead to increased serum potassium concentration. Therefore, during such combination therapy, initial regular assessment of renal function is recommended, along with ensuring adequate hydration of the patient.

The bile acid sequestrant medicinal product colesevelam

Concomitant use of the bile acid sequestrant colesevelam hydrochloride reduces systemic exposure and Cmax of olmesartan in plasma, as well as shortens its elimination half-life. Administration of olmesartan medoxomil at least 4 hours before colesevelam hydrochloride reduces the effect of this drug interaction. Administration of olmesartan medoxomil at least 4 hours before colesevelam hydrochloride should be considered (see section "Pharmacokinetics").

Additional information

A moderate reduction in the bioavailability of olmesartan medoxomil has been observed after treatment with antacids (magnesium and aluminum hydroxides).

Olmesartan medoxomil has no significant effect on the pharmacokinetics and pharmacodynamics of warfarin or on the pharmacokinetics of digoxin. Concomitant administration of olmesartan medoxomil with pravastatin does not result in clinically significant changes in the pharmacokinetics of these drugs in healthy volunteers.

No clinically significant inhibitory effect of olmesartan on human cytochrome P450 enzymes 1A1/2, 2A6, 2C8/9, 2C19, 2D6, 2E1, and 3A4 has been observed in vitro. Minimal or no induction of rat cytochrome P450 activity has been observed. Therefore, clinically significant interactions between olmesartan and medicinal products metabolized by the aforementioned cytochrome P450 enzymes are not expected.

Potential interactions related to the amlodipine component of Olmesar A

Effect of other medicinal products on amlodipine

CYP3A4 inhibitors

When amlodipine is used concomitantly with strong or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides such as erythromycin or clarithromycin, verapamil, or diltiazem), the effect of amlodipine may be significantly enhanced, which may also increase the risk of hypotension. Clinical manifestations of these pharmacokinetic variations may be more pronounced in elderly patients. There is an increased risk of hypotension. Careful monitoring of patients is recommended. Clinical observation and dose adjustment may therefore be required.

CYP3A4 inducers

When known CYP3A4 inducers are used concomitantly, plasma concentrations of amlodipine may vary. Therefore, blood pressure should be monitored and dosage adjusted both during and after concomitant therapy, particularly with strong CYP3A4 inducers (such as rifampicin, St. John’s wort).

Consumption of amlodipine with grapefruit or grapefruit juice is not recommended, as it may increase the bioavailability of the drug in some patients, resulting in enhanced hypotensive effect.

Dantrolene (infusion): In animal studies, ventricular fibrillation and cardiovascular collapse with fatal outcome were observed after verapamil administration and intravenous dantrolene infusion, due to the development of hyperkalemia. Due to the risk of hyperkalemia in patients predisposed to malignant hyperthermia, and during treatment of malignant hyperthermia, concomitant use of calcium channel blockers such as amlodipine should be avoided.

Effect of amlodipine on other medicinal products

The antihypertensive effect of amlodipine is additive to the antihypertensive effects of other blood pressure-lowering agents.

In clinical drug interaction studies, amlodipine did not affect the pharmacokinetics of atorvastatin, digoxin, or warfarin.

Simvastatin. Concomitant administration of multiple 10 mg doses of amlodipine and 80 mg of simvastatin resulted in a 77% increase in simvastatin exposure compared to simvastatin alone. The simvastatin dose in patients taking amlodipine should not exceed 20 mg daily.

Tacrolimus. There is a risk of increased blood levels of tacrolimus when used concomitantly with amlodipine. To avoid tacrolimus toxicity during concomitant use with amlodipine, regular monitoring of blood tacrolimus levels is required, and dose adjustment may be necessary.

mTOR inhibitors (mammalian target of rapamycin).

mTOR inhibitors such as sirolimus, temsirolimus, and everolimus are substrates of CYP3A. Amlodipine is a weak inhibitor of CYP3A. When mTOR inhibitors are used concomitantly with amlodipine, the effects of mTOR inhibitors may be increased.

Cyclosporine. In a prospective clinical study involving kidney transplant patients, co-administration of amlodipine with cyclosporine resulted in an average 40% increase in cyclosporine trough levels. Concomitant use of Olmesar A with cyclosporine may enhance the effect of cyclosporine. When cyclosporine is used concomitantly with amlodipine, monitoring of cyclosporine trough levels should be considered, and cyclosporine dosage may need to be reduced if necessary.

Special precautions for use.

Patients with hypovolemia or sodium deficiency

Symptomatic hypotension may occur in patients with hypovolemia and/or hyponatremia resulting from intensive diuretic therapy, dietary salt restriction, diarrhea, or vomiting—especially after the first dose. It is recommended to correct these conditions prior to initiating Olmesar A or to closely monitor the patient at the beginning of treatment.

Other conditions associated with RAAS activation

Patients in whom vascular tone and renal function are highly dependent on the activity of the renin-angiotensin-aldosterone system (RAAS)—such as patients with severe congestive heart failure or renal disease, including renal artery stenosis—may experience acute hypotension, azotemia, oliguria, or rarely acute renal failure when treated with drugs affecting this system (such as angiotensin II receptor antagonists).

Renovascular hypertension

The use of drugs affecting the RAAS in patients with bilateral renal artery stenosis or stenosis of the artery of a solitary functioning kidney is associated with an increased risk of severe hypotension and renal failure.

Renal impairment and kidney transplantation

Periodic monitoring of serum potassium and creatinine concentrations is recommended in patients with renal impairment treated with Olmesar A. The use of this drug is not recommended in patients with severe renal impairment (creatinine clearance <20 mL/min). There is no experience with the use of Olmesar A in patients who have recently undergone kidney transplantation or in patients with end-stage renal failure (e.g., creatinine clearance <12 mL/min) (see sections "Pharmacokinetics" and "Dosage and administration").

Dual blockade of the RAAS

Evidence indicates that concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren increases the risk of hypotension, hyperkalemia, and decreased renal function (including acute renal failure). Therefore, dual blockade of the RAAS by combining ACE inhibitors with angiotensin II receptor blockers or aliskiren is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

If dual RAAS blockade is considered absolutely necessary, it should be performed only under specialist supervision and with close monitoring of renal function, electrolyte levels, and blood pressure.

The concomitant use of ACE inhibitors and angiotensin II receptor blockers is contraindicated in patients with diabetic nephropathy.

Hepatic impairment

Exposure to amlodipine and olmesartan medoxomil is increased in patients with hepatic impairment (see section "Pharmacokinetics"). Olmesar A should be used with caution in patients with mild to moderate hepatic impairment. In patients with moderate hepatic impairment, the dose of olmesartan medoxomil should not exceed 20 mg (see section "Dosage and administration"). Amlodipine should be initiated at the lowest dose in patients with hepatic impairment, and caution should be exercised both at the beginning of treatment and when increasing the dose. Olmesar A is contraindicated in patients with severe hepatic impairment (see section "Contraindications").

Hyperkalemia

As with other angiotensin II antagonists and ACE inhibitors, hyperkalemia may occur during treatment with Olmesar A, particularly in patients with renal impairment and/or heart failure (see section "Interaction with other medicinal products and other forms of interactions"). Frequent monitoring of serum potassium levels is recommended in these high-risk patients.

The drug should be used cautiously in combination with potassium supplements, potassium-sparing diuretics, potassium-containing salt substitutes, or other medicinal products that may increase potassium levels (e.g., heparin); regular monitoring of blood potassium levels is recommended in such cases.

Lithium preparations

As with other angiotensin II antagonists, concomitant use of Olmesar A® and lithium preparations is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Aortic or mitral valve stenosis; obstructive hypertrophic cardiomyopathy

Due to the presence of amlodipine in Olmesar A, as with other vasodilating agents, particular caution is recommended when prescribing to patients with aortic or mitral valve stenosis or obstructive hypertrophic cardiomyopathy.

Primary hyperaldosteronism

Patients with primary hyperaldosteronism generally do not respond to antihypertensive drugs that inhibit the renin-angiotensin system. Therefore, the use of Olmesar A is not recommended in such patients.

Heart failure

Due to suppression of the angiotensin-aldosterone system, renal function may be impaired in susceptible patients. In patients with severe heart failure, in whom renal function may depend on RAAS activity, treatment with ACE inhibitors and angiotensin II receptor antagonists may be associated with oliguria and/or progressive azotemia and (rarely) acute renal failure and/or death.

Treatment in patients with heart failure should be conducted with caution. In a long-term placebo-controlled study of amlodipine in patients with severe heart failure (NYHA III and IV), the incidence of pulmonary edema was higher in the amlodipine group compared to the placebo group (see section "Pharmacodynamics"). Calcium channel blockers, including amlodipine, should be used with caution in patients with congestive heart failure, as these drugs may increase the risk of future cardiovascular events and mortality.

Sprue-like enteropathy

Very rarely, severe chronic diarrhea with substantial weight loss has been reported, developing several months or years after initiation of treatment in patients taking olmesartan. The cause is likely a localized delayed hypersensitivity reaction. Intestinal mucosal biopsies in such patients often show villous atrophy. If these symptoms occur in a patient during olmesartan therapy and no other obvious cause is evident, olmesartan should be discontinued immediately and not restarted. If diarrhea persists for more than one week after discontinuation of the drug, consultation with an appropriate specialist (e.g., a gastroenterologist) should be considered.

Ethnic differences

As with other angiotensin II receptor antagonists, the antihypertensive effect of Olmesar A may be somewhat less in black patients compared to other patients, possibly due to a higher prevalence of low renin levels in this population.

Elderly patients

Dosage increases in elderly patients should be made cautiously (see section "Pharmacokinetics").

Pregnancy

Angiotensin II receptor antagonists should not be initiated during pregnancy. If angiotensin II receptor antagonist therapy must be continued and a patient plans pregnancy, alternative antihypertensive drugs with a well-established safety profile during pregnancy should be used. If pregnancy is diagnosed, treatment with angiotensin II receptor antagonists should be discontinued immediately and alternative therapy initiated if necessary (see sections "Contraindications" and "Use in pregnancy or lactation").

Other

As with any antihypertensive agent, excessive reduction of blood pressure in patients with ischemic heart disease or cerebrovascular disease may lead to myocardial infarction or stroke.

This medicinal product contains less than 1 mmol sodium (23 mg) per film-coated tablet and is therefore considered essentially "sodium-free."

Use during pregnancy or breastfeeding.

Pregnancy (see section "Contraindications")

There are no data on the use of Olmesar A in pregnant women. Reproductive toxicity studies of Olmesar A in animals have not been conducted.

Olmesartan medoxomil (active ingredient of Olmesar A)

Angiotensin II antagonists are contraindicated in pregnant women and women planning pregnancy (see sections "Contraindications" and "Special precautions for use").

Epidemiological data on the teratogenic risk of ACE inhibitors during the first trimester of pregnancy do not allow definitive conclusions, but such risks cannot be entirely excluded. A similar risk may be assumed for angiotensin II receptor antagonists, as controlled epidemiological studies on these drugs have not been conducted. If angiotensin II receptor antagonist therapy must be continued and a patient plans pregnancy, alternative antihypertensive drugs with a well-established safety profile during pregnancy should be used.

Upon diagnosis of pregnancy, angiotensin II receptor antagonists should be discontinued immediately and alternative treatment initiated if necessary.

During the second and third trimesters of pregnancy, angiotensin II receptor antagonists have toxic effects on the fetus (renal dysfunction, oligohydramnios, delayed skull ossification) and the newborn (renal failure, arterial hypotension, hyperkalemia) (see section "Non-clinical safety data").

If angiotensin II receptor antagonists are used during the second or third trimester of pregnancy, renal function and skull ossification in the fetus should be monitored by ultrasound. Newborns whose mothers took angiotensin II receptor antagonists should be monitored for possible arterial hypotension (see sections "Contraindications" and "Special precautions for use").

Amlodipine (active ingredient of Olmesar A)

Data from limited observations in pregnant women do not indicate that amlodipine or other calcium channel blockers have harmful effects on the fetus. However, there is a risk of prolonged labor.

Given the above, Olmesar A is contraindicated in pregnant women or women planning pregnancy (see sections "Contraindications" and "Special precautions for use").

Lactation

Olmesartan is excreted in the milk of lactating rats. However, it is unknown whether olmesartan is excreted in human breast milk. Amlodipine is excreted in human breast milk. The infant's intake of the maternal dose has been estimated at an interquartile range of 3–7%, with a maximum of 15%. The effect of amlodipine on the infant is unknown. Olmesar A is not recommended during breastfeeding. Alternative therapies with a better-established safety profile during breastfeeding should be preferred, especially when breastfeeding newborns or preterm infants.

Fertility

Reversible biochemical changes in the sperm head have been reported in some patients taking calcium channel blockers. Clinical data on the potential effect of amlodipine on fertility are insufficient. Adverse effects on male fertility were observed in rat studies (see section "Non-clinical safety data").

Ability to affect reaction speed when driving or operating machinery.

Olmesar A may have a minor or moderate influence on the ability to drive or operate machinery.

Occasionally, patients taking antihypertensive agents may experience headache, dizziness, nausea, and increased fatigue, which may impair reaction time. Caution is advised, especially at the beginning of treatment.

Method of Administration and Dosage

Adults

The recommended dose of Olmesar A is 1 tablet per day.

Olmesar A 20/5 may be prescribed to patients who have shown inadequate response to monotherapy with olmesartan medoxomil at a dose of 20 mg or amlodipine at a dose of 5 mg.

The medicinal product Olmesar A 40/5 may be prescribed to patients who have shown inadequate response to Olmesar A 20/5.

The medicinal product Olmesar A 40/10 may be prescribed to patients who have shown inadequate response to Olmesar A 40/5.

Prior to prescribing a fixed-dose combination product, stepwise dose titration of each component as monotherapy is recommended. If necessary, direct substitution of monotherapy agents with the combination product is possible.

For convenience, patients receiving olmesartan medoxomil and amlodipine as separate tablets may be switched to Olmesar A tablets containing these components in equivalent doses.

Olmesar A may be taken independently of food intake.

Elderly Patients (aged 65 years and older)

Generally, dose adjustment is not required for elderly patients; however, dose escalation should be performed cautiously (see sections "Pharmacokinetics" and "Special Warnings and Precautions for Use").

When increasing the dose of olmesartan medoxomil to the maximum (40 mg per day), careful monitoring of arterial blood pressure is required.

Renal Impairment

The maximum dose of olmesartan medoxomil in patients with mild to moderate renal impairment (creatinine clearance 20–60 mL/min) is 20 mg once daily, as experience with higher doses in this patient group is limited. Olmesar A is not recommended for patients with severe renal impairment (creatinine clearance <20 mL/min) (see sections "Pharmacokinetics" and "Special Warnings and Precautions for Use").

When administering the drug to patients with moderate renal impairment, monitoring of potassium and creatinine concentrations is recommended.

Hepatic Impairment

Olmesar A should be prescribed with caution to patients with mild to moderate hepatic impairment (see sections "Pharmacokinetics" and "Special Warnings and Precautions for Use").

In patients with moderate hepatic impairment, olmesartan medoxomil should be initiated at a dose of 10 mg once daily. The maximum dose in such patients should not exceed 20 mg once daily. In patients with hepatic impairment receiving concomitant therapy with diuretics and/or other antihypertensive agents, careful monitoring of blood pressure and renal function is recommended. There is no clinical experience with olmesartan medoxomil in patients with severe hepatic impairment.

As with all calcium antagonists, the elimination half-life of amlodipine is prolonged in patients with hepatic dysfunction; dosage recommendations have not been established. Therefore, Olmesar A should be administered with caution in such patients. The pharmacokinetics of amlodipine in patients with severe hepatic impairment have not been studied. Amlodipine administration in patients with severe hepatic impairment should be initiated at the lowest dose with gradual dose escalation. Olmesar A is contraindicated in patients with severe hepatic impairment (see section "Contraindications").

Method of Administration

Tablets should be swallowed whole with sufficient liquid (e.g., a glass of water). Tablets should not be chewed. The drug should be taken daily at the same time.

Children

The safety and efficacy of Olmesar A in children and adolescents (under 18 years of age) have not been established. Data are lacking.

Overdose

Symptoms

Cases of Olmesar A overdose have not been reported. The most likely effects of olmesartan medoxomil overdose are hypotension and tachycardia; bradycardia may also occur in case of parasympathetic stimulation (vagus nerve). Amlodipine overdose may lead to excessive peripheral vasodilation, resulting in marked hypotension and possibly reflex tachycardia. There have been reports of prolonged, severe generalized hypotension progressing to shock with fatal outcome.

Rare cases of non-cardiogenic pulmonary edema have been reported following amlodipine overdose, which may present with delayed onset (24–48 hours after ingestion) and may require mechanical ventilation. Contributing factors to the development of non-cardiogenic pulmonary edema may include early resuscitation measures (including fluid overload) aimed at maintaining perfusion and cardiac output.

Treatment

If the drug has been recently ingested, gastric lavage is indicated. In healthy volunteers, administration of activated charcoal immediately or within 2 hours after oral intake of amlodipine significantly reduces its absorption.

In case of clinically significant hypotension due to Olmesar A overdose, active cardiovascular support is required, including careful monitoring of cardiac and pulmonary function, elevation of the lower limbs, monitoring of circulating blood volume and diuresis. Vasoconstrictors may be useful to restore vascular tone and arterial pressure, provided there are no contraindications. Intravenous calcium gluconate is recommended to counteract calcium channel blockade.

Since amlodipine is highly protein-bound, elimination via dialysis is unlikely. There is no information available on the possibility of removing olmesartan via dialysis.

Adverse reactions

The most common adverse reactions observed during administration of Olmesar A were peripheral edema (11.3%), headache (5.3%), and dizziness (4.5%).

Adverse reactions observed during clinical studies and post-marketing safety monitoring, as well as spontaneously reported adverse reactions, are listed in the table below. Additionally, the table includes adverse reactions observed with each of the active components of the medicinal product administered separately (olmesartan medoxomil and amlodipine), taking into account their established safety profiles.

The following terminology was used to classify the frequency of adverse reactions: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10000 to < 1/1000); very rare (< 1/10000); frequency not known (cannot be estimated from the available data).

Organs or organ systems (by MedDRA)	Adverse reactions	Frequency
		Olmesartan/amlodipine combination	Olmesartan	Amlodipine
Blood and lymphatic system	Leukopenia			Very rare
	Thrombocytopenia		Uncommon	Very rare
Immune system	Allergic reactions/hypersensitivity reactions	Uncommon		Very rare
	Anaphylactic reaction		Uncommon
Metabolism and nutrition disorders	Hypoglycemia			Very rare
	Hyperkalemia	Uncommon	Uncommon
	Hypertriglyceridemia		Common
	Hyperuricemia		Common
Psychiatric disorders	Confusion			Uncommon
	Depression			Uncommon
	Insomnia			Uncommon
	Irritability			Uncommon
	Decreased libido	Uncommon
	Mood changes, including anxiety			Uncommon
Nervous system disorders	Dizziness	Common	Common	Common
	Dysgeusia			Uncommon
	Headache	Common	Common	Common (especially at the beginning of treatment)
	Hypertonia			Very rare
	Hypoaesthesia	Uncommon		Uncommon
	Lethargy	Uncommon
	Paraesthesia	Uncommon		Uncommon
	Peripheral neuropathy			Very rare
	Postural dizziness	Uncommon
	Sleep disturbance			Uncommon
	Somnolence			Common
	Syncope	Uncommon		Uncommon
	Tremor			Uncommon
	Extrapyramidal disorders			Unknown
Eye disorders	Visual disturbance (including diplopia)			Common
Ear and labyrinth disorders	Tinnitus			Uncommon
	Dizziness	Uncommon	Uncommon
Cardiac disorders	Angina pectoris		Uncommon	Uncommon (including exacerbation)
	Arrhythmia (including bradycardia, ventricular tachycardia, atrial fibrillation)			Uncommon
	Myocardial infarction			Very rare
	Pounding heartbeat	Uncommon		Common
	Tachycardia	Uncommon
Vascular disorders	Arterial hypotension	Uncommon	Uncommon	Uncommon
	Orthostatic hypotension	Uncommon
	Flushing	Uncommon		Common
	Vasculitis			Very rare
Respiratory system disorders	Bronchitis		Common
	Cough	Uncommon	Common	Uncommon
	Dyspnea	Uncommon		Common
	Pharyngitis		Common
	Rhinitis		Common	Uncommon
Gastrointestinal disorders	Abdominal pain		Common	Common
	Intestinal dysfunction (including constipation and diarrhea)			Common
	Constipation	Uncommon
	Diarrhea	Uncommon	Common
	Dry mouth	Uncommon		Uncommon
	Dyspepsia	Uncommon	Common	Common
	Gastritis			Very rare
	Gastroenteritis		Common
	Gingival hyperplasia			Very rare
	Nausea	Uncommon	Common	Common
	Pancreatitis			Very rare
	Upper abdominal pain	Uncommon
	Vomiting	Uncommon	Uncommon	Uncommon
	Coeliac disease-like enteropathy (see section "Special warnings and precautions for use")		Very rare

On the part of the liver and biliary tract	Elevation of liver enzymes		Common	Very rare (mostly in the context of cholestasis)
	Hepatitis			Very rare
	Jaundice			Very rare
	Autoimmune hepatitis*		Unknown
On the part of the skin and its appendages	Alopecia			Uncommon
	Angioneurotic edema		Uncommon	Very rare
	Allergic dermatitis		Uncommon
	Polymorphic erythema			Very rare
	Exanthema		Uncommon	Uncommon
	Exfoliative dermatitis			Very rare
	Increased sweating			Uncommon
	Photosensitization			Very rare
	Itching		Uncommon	Uncommon
	Hemorrhagic rash			Uncommon
	Quincke's edema			Very rare
	Rash	Uncommon	Uncommon	Uncommon
	Skin color change			Uncommon
	Stevens-Johnson syndrome			Very rare
	Toxic epidermal necrolysis			Unknown
	Urticaria	Uncommon	Uncommon	Uncommon
On the part of the musculoskeletal system and connective tissue	Calf swelling			Common
	Arthralgia			Uncommon
	Arthritis		Common
	Back pain	Uncommon	Common	Uncommon
	Muscle spasm	Uncommon	Uncommon	Common
	Myalgia		Uncommon	Uncommon
	Limb pain	Uncommon
	Bone pain		Common
On the part of the kidneys and urinary tract	Acute renal failure		Uncommon
	Hematuria		Common
	Increased frequency of urination			Uncommon
	Urination disorder			Uncommon
	Nocturia			Uncommon
	Polakiuria	Uncommon
	Renal failure		Uncommon
	Urinary tract infections		Common
On the part of the reproductive system and mammary glands	Erectile dysfunction/impotence	Uncommon		Uncommon
	Gynecomastia			Uncommon
General disorders	Asthenia	Uncommon	Uncommon	Common
	Chest pain		Common	Uncommon
	Facial swelling	Uncommon	Uncommon
	Fatigue	Common	Common	Common
	Influenza-like conditions		Common
	Somnolence		Uncommon
	Malaise		Uncommon	Uncommon
	Edema	Common		Very common
	Pain		Common	Uncommon
	Peripheral edema	Common	Common
	Soft tissue swelling	Common
Results of additional investigations	Elevated blood creatinine levels	Uncommon	Uncommon
	Elevated blood creatine phosphokinase levels		Common
	Decreased blood potassium levels	Uncommon
	Elevated blood urea levels		Common
	Elevated blood uric acid levels	Uncommon
	Elevated blood gamma-glutamyl transferase levels	Uncommon
	Decreased body weight			Uncommon
	Increased body weight			Uncommon

*During the post-marketing period, cases of autoimmune hepatitis with a latency period of several months to years have been reported, which were reversible upon discontinuation of olmesartan.

Several cases of rhabdomyolysis, temporally associated with the use of angiotensin II receptor blockers, have been reported. In patients treated with amlodipine, several cases of extrapyramidal disorder have been reported.

Reporting of possible adverse reactions

Reporting of possible adverse reactions after marketing authorization of the medicinal product is important. This enables ongoing monitoring of the benefit-risk balance of the medicinal product.

Reporting of adverse reactions after marketing authorization of the medicinal product is of great importance. This allows continuous monitoring of the benefit-risk balance of this medicinal product. Healthcare professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy of the medicinal product via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life.

3 years.

Storage conditions.

Store at temperatures not exceeding 25 °C in the original packaging. Keep out of reach and sight of children.

Packaging.

10 tablets per blister, 3 or 9 blisters per cardboard pack.

Prescription status. Prescription only.

Manufacturer.

Macleods Pharmaceuticals Limited.

Manufacturer's address and location of its business operations.

Village Theda, P.O. Lodhiamaira, Tehsil Baddi, District Solan, Himachal Pradesh, 174101, India.