Olmesar a 20/5

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 5 mg of amlodipine);

Olmesar A 40/5:

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

Olmesar A 40/10:

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

Excipients:

microcrystalline silicified cellulose, anhydrous colloidal 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, oval, 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 C09DB02.

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 and provides a greater reduction in arterial pressure than each active substance alone.

In an 8-week, double-blind, randomized, placebo-controlled factorial study involving 1490 patients (71% of patients were Caucasian and 29% were of 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 average 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).

Olmesar A 40/5 reduced seated systolic/diastolic blood pressure an additional 2.5/1.7 mm Hg compared to Olmesar A 20/5. Similarly, Olmesar A 40/10 reduced seated systolic/diastolic blood pressure 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 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 is typically 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 with inadequate response to monotherapy with olmesartan medoxomil 20 mg over 8 weeks.

In patients who continued receiving only olmesartan medoxomil 20 mg, systolic/diastolic blood pressure decreased by 10.6/7.8 mm Hg over the next 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 different doses of olmesartan medoxomil to the treatment regimen in Caucasian patients with inadequate response to monotherapy with amlodipine 5 mg over 8 weeks.

In patients who continued receiving only 5 mg amlodipine, systolic/diastolic blood pressure decreased by 9.9/5.7 mm Hg over the next 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 and olmesartan during 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 of minimum to maximum systolic and diastolic blood pressure 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 and gender, as well as the presence of diabetes in patients.

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

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 its pharmacologically active metabolite, olmesartan. Angiotensin II is the primary vasoactive hormone of the renin-angiotensin-aldosterone system (RAAS) and plays a key role in the pathophysiology of arterial hypertension. Angiotensin II causes vasoconstriction, stimulates the synthesis and release of aldosterone, promotes cardiac stimulation, and induces renal sodium reabsorption. Olmesartan inhibits the vasoconstrictive and aldosterone-secreting effects of angiotensin II by blocking AT1 receptors in tissues, including vascular smooth muscle and adrenal glands. The action of olmesartan is independent of the source and pathway of angiotensin II synthesis. Selective antagonism of angiotensin II AT1 receptors leads to increased plasma renin levels and concentrations of angiotensin I and angiotensin II, as well as a slight decrease in plasma aldosterone levels. In arterial hypertension, olmesartan medoxomil induces a prolonged, dose-dependent reduction in arterial pressure.

No post-dose hypotension after the first dose, signs of tachyphylaxis during prolonged use, or rebound hypertension after discontinuation were observed.

When administered once daily to patients with arterial hypertension, olmesartan medoxomil provides effective and smooth blood pressure reduction over the 24-hour dosing interval.

The antihypertensive effect was similar when the drug was administered once or twice daily at the same total daily dose. Maximum blood pressure reduction was achieved after 8 weeks of treatment, although a significant antihypertensive effect was observed as early as 2 weeks after initiation of therapy.

The effect of olmesartan medoxomil on morbidity and mortality has not been established.

A randomized study of olmesartan use for the prevention of diabetic microalbuminuria (ROADMAP), conducted in 4447 patients with type 2 diabetes with normal albuminuria levels and at least one additional cardiovascular risk factor, aimed to determine whether olmesartan therapy could delay the onset of microalbuminuria. During a mean follow-up period of 3.2 years, patients received olmesartan or placebo in addition to other antihypertensive agents, excluding angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs).

The primary endpoint of the study demonstrated a significant reduction in the risk of time to onset of microalbuminuria in favor of olmesartan. However, after adjustment for differences in blood pressure (BP), this risk reduction was no longer statistically significant. Microalbuminuria developed in 8.2% (178 of 2160) of patients in the olmesartan group and in 9.8% (210 of 2139) in the placebo group.

In the secondary endpoint, cardiovascular events occurred in 96 patients (4.3%) receiving olmesartan and in 94 patients (4.2%) receiving placebo. Cardiovascular mortality was higher in the olmesartan group compared to the placebo group (15 patients (0.7%) vs. 3 patients (0.1%)), despite similar rates of non-fatal stroke (14 patients (0.6%) vs. 8 patients (0.4%)), non-fatal myocardial infarction (17 patients (0.8%) vs. 26 patients (1.2%)), and non-cardiovascular mortality (11 patients (0.5%) vs. 12 patients (0.5%)). Overall mortality was higher in the olmesartan group (26 patients (1.2%) vs. 15 patients (0.7%)), primarily due to higher cardiovascular mortality.

In the ORIENT trial (The Olmesartan Reducing Incidence of End-stage Renal Disease in Diabetic Nephropathy Trial), the effect of olmesartan on renal and cardiovascular outcomes was studied in 577 randomized patients in Japan and China with type 2 diabetes and overt nephropathy. During a mean follow-up period of 3.1 years, patients received olmesartan or placebo in addition to other antihypertensive agents, including ACE inhibitors.

The primary composite endpoint (time to first occurrence of doubling of serum creatinine, end-stage renal disease, or death from any cause) was reached in 116 patients in the olmesartan group (41.1%) and in 129 patients receiving placebo (45.4%) (HR 0.97 (95% CI 0.75–1.24); p=0.791). The secondary composite cardiovascular endpoint was reached in 40 patients receiving olmesartan (14.2%) and in 53 patients receiving placebo (18.7%). This composite cardiovascular endpoint included cardiovascular mortality in 10 (3.5%) patients receiving olmesartan and in 3 (1.1%) patients receiving placebo; overall mortality was 19 (6.7%) and 20 (7.0%), non-fatal stroke was 8 (2.8%) and 11 (3.9%), and non-fatal myocardial infarction was 3 (1.1%) and 7 (2.5%), respectively.

Amlodipine (active substance in Olmesar A)

Amlodipine, contained in Olmesar A, is a calcium channel blocker that inhibits transmembrane calcium ion influx through voltage-dependent L-type channels in the heart and 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 its direct relaxing action on 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 arterial pressure. No post-dose hypotension after the first dose, signs of tachyphylaxis during prolonged treatment, or rebound hypertension after discontinuation were observed.

After oral administration at therapeutic doses in patients with arterial hypertension, amlodipine provides effective blood pressure reduction in supine, seated, and standing positions. 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 causing proteinuria.

In hemodynamic studies in patients with heart failure and clinical studies with stress testing in heart failure (NYHA classes II–IV), 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) of amlodipine in patients with heart failure (NYHA III and IV) without clinical symptoms or objective evidence of ischemic heart disease (IHD), receiving ACE inhibitors, digitalis, and diuretics at constant doses, amlodipine did not affect overall mortality or cardiovascular-specific mortality. In this patient group, an increased incidence of pulmonary edema associated with amlodipine use was observed, but no statistically significant differences in the frequency of heart failure exacerbation compared to placebo were noted.

Preventive therapy of myocardial infarction (ALLHAT)

A double-blind, randomized study on morbidity and mortality titled "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 (>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

Combination therapy with ACE inhibitors and angiotensin II receptor blockers was evaluated 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 showed no significant beneficial effect on renal and/or cardiovascular outcomes or mortality, whereas an increased risk of hyperkalemia, acute kidney injury, and/or hypotension was observed compared to monotherapy. Given the similarity in pharmacodynamic properties, these results are also applicable to other ACE inhibitors and angiotensin II receptor blockers.

Combination therapy with 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 evaluate the 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 are equivalent to their 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 into its 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 excreta. The mean absolute bioavailability of olmesartan as tablets is 25.6%.

Mean plasma Cmax of olmesartan is reached approximately 2 hours after oral administration. Plasma olmesartan concentrations 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 olmesartan pharmacokinetics based on gender have been identified. 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 small compared to hepatic blood flow (approximately 90 L/hour). After a single oral dose of radiolabeled (14C) olmesartan medoxomil, 10–16% of radioactivity was recovered in urine (mostly within 24 hours after administration), with the remainder excreted in feces. Based on systemic availability of 25.6%, it can be calculated that absorbed olmesartan is eliminated both renally (approximately 40%) and hepatobiliary (approximately 60%). All detected radioactivity was identified as olmesartan. No other significant metabolites were found. 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 achieved 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

Drug binding bile acids – 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 4% and 15% reductions in Cmax and AUC, respectively, was observed when olmesartan medoxomil was administered 4 hours before colesevelam hydrochloride. The elimination half-life of olmesartan was reduced by 50–52%, regardless of whether the drugs were administered together or olmesartan 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 at therapeutic doses, amlodipine is well absorbed, with peak blood concentrations (Cmax) reached 6–12 hours after administration. Absolute bioavailability of the unchanged compound is approximately 64–80%. The volume of distribution is approximately 21 L/kg. In vitro studies have shown 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 (≥75 years) 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 performed with caution.

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 amlodipine clearance, leading to increased AUC and prolonged elimination half-life. The increased AUC and prolonged elimination half-life in patients with congestive heart failure are consistent with predictions for this age group (see section "Special warnings and precautions for use").

Renal impairment

In patients with renal impairment, 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 warnings and precautions for use" and "Dosage and administration").

Amlodipine is extensively metabolized to inactive metabolites. 10% of the drug is excreted unchanged in urine. Changes in plasma amlodipine concentration do not correlate with the degree of renal impairment. Amlodipine can be administered at usual doses to these 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 was 0.26%, 0.34%, and 0.41% in healthy volunteers and patients with mild or moderate hepatic impairment, 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 were similar in patients with hepatic impairment and healthy volunteers. Olmesartan medoxomil has not been evaluated in patients with severe hepatic impairment (see sections "Special warnings and 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, amlodipine clearance is reduced and elimination half-life is prolonged, leading to an increase in AUC of approximately 40–60% (see sections "Special warnings and 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 renal changes (both effects possibly caused by olmesartan medoxomil), intestinal changes (lumen dilation and diffuse thickening of the mucosa of the ileum and colon), adrenal gland changes (glomerular zone cell hypertrophy and vacuolization of fasciculate zone cells), and mammary duct hypertrophy, possibly caused by amlodipine. These changes do not supplement previously obtained data on the toxicity of 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, the 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), and histological signs of kidney damage (regenerative lesions of renal epithelium, thickening of the basement 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 testing data suggest that genotoxic effects of olmesartan are unlikely at clinical use.

In a 2-year rat study 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, offspring survival was reduced after exposure to olmesartan medoxomil, 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 exhibit fetotoxic effects.

Amlodipine (active substance in Olmesar A)

Reproductive toxicity

Reproductive function studies in rats and mice showed delayed delivery, prolonged labor, 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 decreased plasma levels of follicle-stimulating hormone and testosterone, 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 provide 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 twice the maximum recommended dose in rats) was close to the maximum tolerated dose in mice but not in rats.

Mutagenicity studies did not reveal 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 during pregnancy or breastfeeding").
• 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 types of interactions").

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

• severe arterial hypotension;
• shock (including cardiogenic shock);
• left ventricular outflow tract obstruction (e.g., severe aortic stenosis);
• hemodynamically unstable heart failure following acute myocardial infarction.

Interaction with other medicinal products and other types of interactions.

Potential interactions caused by combination with the medicinal product Olmesar A

Caution is advised 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 Olmesar A component olmesartan medoxomil

Concomitant use is not recommended

ACE inhibitors, angiotensin II receptor blockers, or aliskiren

Clinical trial data show that dual blockade of the RAAS system associated with concomitant use of ACE inhibitors and angiotensin II receptor blockers or aliskiren leads to an increased frequency of adverse events such as arterial hypotension, hyperkalemia, and impaired renal function (including acute renal failure), compared to use of a single medicinal product acting on the RAAS (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-containing medicinal products

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-containing products is not recommended (see section "Special precautions for use"). If concomitant use of Olmesar A and lithium is necessary, regular monitoring of serum lithium levels is recommended.

Concomitant use requires caution

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

When angiotensin II antagonists are co-administered with NSAIDs, attenuation of the antihypertensive effect may occur. In addition, concomitant use of angiotensin II antagonists and NSAIDs may increase the risk of impaired renal function and lead to increased serum potassium concentration. Therefore, when such combination therapy is used, initial regular assessment of renal function and adequate hydration of the patient are recommended.

Medicinal product colesevelam, a bile acid sequestrant

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

Additional information

A moderate reduction in 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 inductive effect on rat cytochrome P450 activity has been noted. Therefore, clinically significant interactions between olmesartan and medicinal products metabolized by the aforementioned cytochrome P450 enzymes are not expected.

Potential interactions related to the Olmesar A component amlodipine

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. Therefore, clinical observation and dose adjustment may 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, especially with strong CYP3A4 inducers (such as rifampicin, St. John's wort).

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

Dantrolene (infusion): in animal studies, ventricular fibrillation and cardiovascular collapse with fatal outcome were observed after administration of verapamil and intravenous dantrolene 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 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 per day.

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 and, if necessary, dose adjustment are required.

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, increased effects of mTOR inhibitors may occur.

Cyclosporine. In a prospective clinical study involving kidney transplant patients, concomitant use of amlodipine with cyclosporine resulted in an average 40% increase in the minimum cyclosporine blood concentration. Concomitant use of Olmesar A with cyclosporine may enhance the effect of cyclosporine. When used concomitantly with amlodipine, monitoring of the minimum cyclosporine blood concentration 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, particularly after the first dose. It is recommended to correct these conditions prior to initiating Olmesar A or to closely monitor patients at the beginning of treatment.

Other conditions associated with activation of the RAAS

Patients in whom vascular tone and renal function are largely dependent on RAAS activity (e.g., 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

Use of drugs affecting the RAAS in patients with bilateral renal artery stenosis or stenosis of the artery of a single 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 receiving Olmesar A. The use of this drug is not recommended in severe renal impairment (creatinine clearance < 20 mL/min). Experience with 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) is lacking (see sections "Pharmacokinetics" and "Dosage and administration").

Dual blockade of the RAAS

Evidence indicates that concomitant use of ACE inhibitors, angiotensin II receptor antagonists, 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 antagonists or aliskiren is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

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

Concomitant use of ACE inhibitors and angiotensin II receptor antagonists 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 during dose escalation. Olmesar A is contraindicated in patients with severe hepatic impairment (see section "Contraindications").

Intestinal angioedema

Cases of intestinal angioedema have been reported in patients taking angiotensin II receptor antagonists, [including olmesartan medoxomil] (see section "Undesirable effects"). These patients presented with abdominal pain, nausea, vomiting, and diarrhea. Symptoms resolved after discontinuation of angiotensin II receptor antagonists. If intestinal angioedema is diagnosed, Olmesar A should be discontinued and appropriate monitoring initiated until complete resolution of symptoms.

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 interaction"). Patients in this risk group should have frequent monitoring of serum potassium levels.

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.

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 advised when prescribing to patients with aortic or mitral valve stenosis or obstructive hypertrophic cardiomyopathy.

Primary hyperaldosteronism

Patients with primary hyperaldosteronism usually do not respond to antihypertensive drugs that suppress the renin-angiotensin system. Therefore, 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.

Patients with heart failure should be treated 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 placebo (see section "Pharmacodynamics"). Calcium channel blockers, including amlodipine, should be used cautiously in patients with congestive heart failure, as these drugs may increase the risk of cardiovascular events and mortality.

Sprue-like enteropathy

In very rare cases, severe chronic diarrhea with substantial weight loss, developing several months to years after initiation of treatment in patients taking olmesartan, has been reported. 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 treatment and no other obvious cause is identified, olmesartan should be discontinued immediately and not restarted. If diarrhea persists for more than one week after discontinuation, 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

Dose escalation in elderly patients should be performed cautiously (see section "Pharmacokinetics").

Pregnancy

Angiotensin II receptor antagonists should not be initiated during pregnancy. If angiotensin II antagonist therapy must be continued and the patient is planning pregnancy, alternative antihypertensive agents 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 during pregnancy or breastfeeding").

Other

As with any antihypertensive agents, 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")

Data on the use of Olmesar A in pregnant women are lacking. Reproductive toxicity studies of Olmesar A in animals have not been conducted.

Olmesartan medoxomil (active ingredient of Olmesar A)

Use of angiotensin II antagonists is contraindicated in pregnant women and women planning pregnancy (see sections "Contraindications" and "Special precautions for use").

Epidemiological data on teratogenic risk of ACE inhibitors in the first trimester of pregnancy do not allow definitive conclusions, but such risk cannot be entirely excluded. A similar risk for angiotensin II receptor antagonists is plausible, as controlled epidemiological studies on these drugs have not been conducted. If angiotensin II antagonist therapy must be continued and the patient is planning pregnancy, alternative antihypertensive agents 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 therapy initiated if necessary.

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

If angiotensin II receptor antagonists are taken during the second or third trimester of pregnancy, monitoring of fetal renal function and skull ossification by ultrasound is required. Newborns whose mothers received 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 harmful effects of amlodipine or other calcium channel antagonists on fetal health. However, there is a risk of prolonged duration of labor.

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

Breastfeeding period

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 exposure to 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, and alternative therapies with better-established safety profiles during breastfeeding should be preferred, especially when breastfeeding newborns or preterm infants.

Fertility

Cases of 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. In rat studies, adverse effects on male fertility were observed (see section "Non-clin游戏副本 safety data").

Ability to influence 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 receiving antihypertensive agents may experience headache, dizziness, nausea, and increased fatigue, which may impair reaction time. Caution should be exercised, particularly at the beginning of treatment.

Method of Administration and Dosage

Adults

The recommended dose of Olmesar A is 1 tablet daily.

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

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

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

Prior to initiating combination therapy with fixed-dose active components, it is recommended to titrate the doses of each component individually as monotherapies. If necessary, direct substitution of monotherapies 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)

Dosage adjustment is generally not required in elderly patients; however, dose escalation should be performed cautiously (see sections "Pharmacokinetics" and "Special Warnings").

When increasing the dose of olmesartan medoxomil to the maximum (40 mg daily), 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 in patients with severe renal impairment (creatinine clearance < 20 mL/min) (see sections "Pharmacokinetics" and "Special Warnings").

In patients with moderate renal impairment, monitoring of serum potassium and creatinine concentrations is recommended during treatment.

Hepatic impairment

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

In patients with moderate hepatic impairment, the initial dose of olmesartan medoxomil should be 10 mg once daily. The maximum dose in such patients should not exceed 20 mg once daily. When concomitant therapy with diuretics and/or other antihypertensive agents is used, careful monitoring of blood pressure and renal function is recommended in patients with hepatic impairment. There is no 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 used 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 begin with the lowest dose and be titrated slowly upward. Olmesar A is contraindicated in patients with severe hepatic impairment (see section "Contraindications").

Method of administration

Tablets should be swallowed whole with sufficient fluid (e.g., a glass of water). Tablets must not be chewed. The medication 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.

Rarely, non-cardiogenic pulmonary edema has been reported as a consequence of 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 supporting perfusion and cardiac output.

Treatment

If ingestion was recent, gastric lavage is indicated. In healthy volunteers, administration of activated charcoal immediately or within 2 hours after oral intake of amlodipine significantly reduces absorption of the substance.

In cases 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, control of circulating blood volume and diuresis. Vasoconstrictors may be useful to restore vascular tone and blood pressure, provided there are no contraindications. Intravenous calcium gluconate is recommended to reverse 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%).

The adverse reactions observed during clinical and post-marketing safety studies with Olmesar A, as well as spontaneous reports, 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 (≥ 1/10,000 to < 1/1000); very rare (< 1/10,000); frequency not known (cannot be estimated from the available data).

Organ Class (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	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
	Hypoesthesia	Uncommon		Uncommon
	Lethargy	Uncommon
	Paresthesia	Uncommon		Uncommon
	Peripheral neuropathy			Very rare
	Postural dizziness	Uncommon
	Sleep disturbance			Uncommon
	Somnolence			Common
	Syncope	Rare		Uncommon
	Tremor			Uncommon
	Extrapyramidal disorders			Not known
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
	Palpitations	Uncommon		Common
	Tachycardia	Uncommon
Vascular disorders	Arterial hypotension	Uncommon	Rare	Uncommon
	Orthostatic hypotension	Uncommon
	Flushing	Rare		Common
	Vasculitis			Very rare
Respiratory, thoracic and mediastinal 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
	Intestinal angioedema		Rare
	Coeliac-like enteropathy (see section "Special warnings and precautions for use")		Very rare
Hepatobiliary disorders	Elevated liver enzymes		Common	Very rare (mostly in the context of cholestasis)
	Hepatitis			Very rare
	Jaundice			Very rare
	Autoimmune hepatitis*		Not known
Skin and subcutaneous tissue disorders	Alopecia			Uncommon
	Angioedema		Rare	Very rare
	Allergic dermatitis		Uncommon
	Polymorphic erythema			Very rare
	Exanthema		Uncommon	Uncommon
	Exfoliative dermatitis			Very rare
	Increased sweating			Uncommon
	Photosensitization			Very rare
	Pruritus		Uncommon	Uncommon
	Hemorrhagic rash			Uncommon
	Quincke's edema			Very rare
	Rash	Uncommon	Uncommon	Uncommon
	Skin discoloration			Uncommon
	Stevens-Johnson syndrome			Very rare
	Toxic epidermal necrolysis			Not known
	Urticaria	Rare	Uncommon	Uncommon
Musculoskeletal and connective tissue disorders	Leg swelling			Common
	Arthralgia			Uncommon
	Arthritis		Common
	Back pain	Uncommon	Common	Uncommon
	Muscle spasm	Uncommon	Rare	Common
	Myalgia		Uncommon	Uncommon
	Limb pain	Uncommon
	Bone pain		Common
Renal and urinary disorders	Acute renal failure		Rare
	Hematuria		Common
	Increased frequency of urination			Uncommon
	Urination disorder			Uncommon
	Nocturia			Uncommon
	Polakiuria	Uncommon
	Renal failure		Rare
	Urinary tract infections		Common
Reproductive system and breast disorders	Erectile dysfunction/impotence	Uncommon		Uncommon
	Gynaecomastia			Uncommon
General disorders	Asthenia	Uncommon	Uncommon	Common
	Chest pain		Common	Uncommon
	Facial swelling	Rare	Uncommon
	Fatigue	Common	Common	Common
	Influenza-like symptoms		Common
	Somnolence		Rare
	Malaise		Uncommon	Uncommon
	Edema	Common		Very common
	Pain		Common	Uncommon
	Peripheral edema	Common	Common
	Soft tissue swelling	Common
Investigations	Increased blood creatinine	Uncommon	Rare
	Elevated blood creatine phosphokinase		Common
	Decreased blood potassium	Uncommon
	Elevated blood urea		Common
	Elevated blood uric acid	Uncommon
	Elevated blood gamma-glutamyltransferase	Uncommon
	Decreased body weight			Uncommon
	Increased body weight			Uncommon

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

Several cases of rhabdomyolysis, temporally associated with the use of angiotensin II receptor blockers, have been reported. There have also been several reports of extrapyramidal syndrome in patients taking amlodipine.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after a medicinal product is authorized is important. It allows continued monitoring of the benefit-risk balance of the medicinal product.

Reporting of suspected adverse reactions after marketing authorization of a medicinal product is of significant importance. It enables ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of therapeutic efficacy 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 pack, 3 or 9 blister packs per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Macleods Pharmaceuticals Limited.

Manufacturer's address and site of operations.

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