Olme stad a

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT OLMESTAD A (OLMESTAD A)

Composition:

Active substances: olmesartan medoxomil/amlodipine besylate;

One film-coated tablet contains olmesartan medoxomil 20 mg, amlodipine besylate 6.935 mg, equivalent to amlodipine 5 mg; or olmesartan medoxomil 40 mg, amlodipine besylate 13.87 mg, equivalent to amlodipine 10 mg;

Excipients: microcrystalline cellulose, crospovidone (type A), colloidal anhydrous silicon dioxide, magnesium stearate, lactose monohydrate;

Tablet coating:

for dosage 20/5 mg: Opadry II 32F280008 white, purified water. Opadry II 32F280008 white consists of: hypromellose, lactose monohydrate, polyethylene glycol, titanium dioxide (E 171);

for dosage 40/10 mg: Opadry II 32F250011 red, purified water. Opadry II 32F250011 red consists of: hypromellose, lactose monohydrate, polyethylene glycol, titanium dioxide (E 171), iron oxide red (E 172), iron oxide black (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

for dosage 20/5 mg: white, round, biconvex, film-coated tablets;

for dosage 40/10 mg: reddish-brown, round, biconvex, film-coated tablets.

Pharmacotherapeutic group.

Cardiovascular system. Medicinal products affecting the renin-angiotensin system. Combinations of angiotensin II receptor blockers. Angiotensin II antagonists and calcium channel blockers. ATC code C09DB02.

Pharmacological Properties.

Pharmacodynamics.

Olmesartan 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 contributes to a greater reduction in arterial pressure than each 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 Olmesartan 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) and 30/19 mm Hg (40 mg/10 mg). 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% and 49.1% for Olmesartan A 20/5 mg and Olmesartan A 40/10 mg, respectively.

The main antihypertensive effect of Olmesartan A is usually 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 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 the combination 20 mg/5 mg compared to 28.5% for 20 mg olmesartan medoxomil. In subsequent studies, the efficacy of adding various doses of olmesartan medoxomil to the treatment regimen was evaluated in Caucasian patients with inadequate response to monotherapy with amlodipine 5 mg over 8 weeks. In patients who continued receiving only amlodipine 5 mg, 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 monotherapy group at a dose of 5 mg and 53.5% in the Olmesartan A 20/5 mg group.

There are no randomized data available for patients with uncontrolled hypertension allowing comparison of the outcomes of combination therapy with Olmesartan A at medium doses versus the effect of increasing the dose of amlodipine and olmesartan during monotherapy.

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

The antihypertensive effect of Olmesartan A did not depend on age or gender, nor on the presence of diabetes mellitus in patients.

Olmesartan medoxomil (active substance of Olmesartan A)

Olmesartan medoxomil, contained in Olmesartan 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. Angiotensin II is the primary vasoactive hormone of the renin-angiotensin-aldosterone system (RAAS), playing a key role in the pathophysiology of arterial hypertension. Angiotensin II causes vasoconstriction, stimulates the synthesis and release of aldosterone, has cardiostimulatory effects, and promotes renal sodium reabsorption. Olmesartan inhibits the vasoconstrictive and aldosterone-secreting effects of angiotensin II by blocking AT1 receptors in tissues, including vascular smooth muscles and adrenal glands. The action of olmesartan does not depend on the source or pathway of angiotensin II synthesis. Selective antagonism of angiotensin II AT1 receptors leads to an increase in 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 causes a prolonged, dose-dependent reduction in blood pressure. No episodes of arterial hypotension after the first dose, signs of tachyphylaxis during prolonged use, or rebound hypertension after discontinuation have been reported.

When olmesartan medoxomil is administered once daily to patients with arterial hypertension, effective and smooth reduction in blood pressure occurs over the 24-hour interval between doses.

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

The effect of olmesartan medoxomil on morbidity and mortality has not been established. A randomized trial of olmesartan use for prevention of diabetic microalbuminuria (ROADMAP), involving 4447 patients with type 2 diabetes with normal albuminuria levels and at least one additional cardiovascular risk factor, was conducted to determine whether olmesartan therapy could delay the onset of microalbuminuria. During the observation period with a median of 3.2 years, patients received olmesartan or placebo in addition to other antihypertensive agents, except 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. After adjustment for differences in blood pressure, this risk reduction was no longer statistically significant. Microalbuminuria developed in 8.2% (178 out of 2160) of patients in the olmesartan group and in 9.8% (210 out 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. The frequency of fatal cardiovascular events was higher in the olmesartan group compared to the placebo group (15 patients (0.7%) vs. 3 patients (0.1%)), despite similar frequencies 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 fatal events (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 the observation period with a median 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 of Olmesartan A)

Amlodipine, contained in Olmesartan 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 affects vascular smooth muscle cells more than cardiomyocytes. The antihypertensive effect of amlodipine is due to direct relaxation of vascular smooth muscle cells, leading to reduced peripheral vascular resistance and, consequently, reduced blood pressure.

In arterial hypertension, amlodipine causes prolonged, dose-dependent reduction in blood pressure. No episodes of arterial hypotension after the first dose, signs of tachyphylaxis during prolonged treatment, or rebound hypertension after discontinuation have been observed.

After administration in therapeutic doses, amlodipine effectively reduces blood pressure in patients with arterial hypertension in supine, sitting, 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, amlodipine in therapeutic doses reduces renal vascular resistance and increases glomerular filtration rate (GFR) and effective renal plasma flow without changing 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 trial (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 fatal outcomes or combined risk of mortality and morbidity in patients with heart failure. In a subsequent long-term placebo-controlled trial (PRAISE-2) involving patients with heart failure (NYHA III and IV) without clinical symptoms or objective evidence of ischemic heart disease, treated with ACE inhibitors, digitalis preparations, and diuretics at constant doses, amlodipine did not affect overall mortality or cardiovascular mortality specifically. In this patient group, an increased incidence of pulmonary edema associated with amlodipine intake was observed, 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 trial of morbidity and mortality called "Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial" (ALLHAT) was conducted to compare new types of drug therapy: 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 arterial hypertension. All 33,357 patients with arterial hypertension aged 55 years and older were randomized and followed for a median of 4.9 years. Patients had at least one additional risk factor for ischemic heart disease (IHD), including prior myocardial infarction or stroke (more than 6 months before enrollment) or presence of other atherosclerotic cardiovascular diseases (total 51.5%), type 2 diabetes (36.1%), high-density lipoprotein cholesterol (HDL-C) level < 35 mg/dL (11.6%), left ventricular hypertrophy diagnosed by electrocardiography or echocardiography (20.9%), or current smoking (21.9%).

The primary endpoint of the study was a combination of fatal IHD or non-fatal myocardial infarction. No significant differences regarding the primary endpoint were observed between amlodipine and chlorthalidone therapy: HR 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%, HR 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 studied 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 trial involving patients with a history of cardiovascular or cerebrovascular disease or type 2 diabetes with evidence of target organ damage. VA NEPHRON-D was a trial involving patients with type 2 diabetes and diabetic nephropathy. The data from these trials did not show 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 similarity of 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 trial conducted 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. This trial was terminated prematurely due to an increased risk of adverse outcomes. Cardiovascular mortality and incidence of stroke were higher in the group receiving aliskiren than in the placebo group, and reports of adverse reactions, including serious ones (hyperkalemia, arterial hypotension, and renal function impairment), were more frequent in the aliskiren group than in the placebo group.

Pharmacokinetics.

After oral administration of Olmesartan 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 Olmesartan A correspond to their rate and absorption when administered separately. The bioavailability of olmesartan medoxomil and amlodipine in the medicinal product Olmesartan A is independent of food intake.

Olmesartan medoxomil (active substance of Olmesartan A)

Absorption and distribution

Olmesartan medoxomil is a prodrug. It 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 group are not detected in plasma or excreted products. The mean absolute bioavailability of olmesartan in tablet form is 25.6%.

The mean Cmax of olmesartan in plasma is reached approximately 2 hours after oral administration. Plasma olmesartan concentration increases 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 drugs that are highly protein-bound is low, as evidenced by the absence of such interactions between olmesartan medoxomil and warfarin. Olmesartan is minimally 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 by the kidneys (approximately 40%) and via the hepatobiliary system (approximately 60%). All detected radioactivity was identified as olmesartan. No other significant metabolites were found. Intestinal-hepatic recirculation of olmesartan is minimal. Since the majority of olmesartan is excreted in bile, its use is contraindicated in patients with biliary obstruction (see section "Contraindications").

The terminal 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 is observed after 14 days of multiple dosing. Renal clearance is approximately 0.5–0.7 L/hour and does not depend on the drug dose.

Drug interactions

Drug Colesevelam, a bile acid sequestrant

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 concentration-time curve (AUC) for olmesartan. A lesser effect, with reductions in Cmax and AUC of 4% and 15%, respectively, was observed when olmesartan medoxomil was administered 4 hours before colesevelam hydrochloride. The 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 types of interactions").

Amlodipine (active substance of Olmesartan A)

Absorption and distribution

After oral administration of therapeutic doses of amlodipine, it is well absorbed, and its Cmax in blood is reached within 6–12 hours. Absolute bioavailability is approximately 64–80%. The volume of distribution is approximately 21 L/kg. In vitro studies have shown that nearly 97.5% of circulating amlodipine is bound to plasma proteins.

Food intake does not affect the absorption process of amlodipine.

Metabolism and elimination

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

Olmesartan medoxomil and amlodipine (active substances of Olmesartan A)

Special patient groups

Children (under 18 years of age)

There are no data on pharmacokinetics in children.

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 greater by 35% and approximately 44%, 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 dosing regimen is recommended for elderly patients as for younger patients, but dose escalation should be done with caution. The time to reach maximum plasma concentration of amlodipine 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 half-life. The increase in AUC and prolonged half-life in patients with congestive heart failure corresponded to predictions for this age group (see section "Special 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 "Dosage and administration" and "Special precautions for use").

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 to such patients at usual doses. 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 multiple 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, a reduction in amlodipine clearance and prolonged half-life is observed, leading 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 combined 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 combined olmesartan medoxomil/amlodipine product 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 complement previously obtained data on the toxicity of individual components and do not indicate the emergence of new toxic effects or synergistic toxicity.

Olmesartan medoxomil (active substance of Olmesartan 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, reduced erythrocyte parameters (erythrocyte count and hemoglobin, hematocrit), 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 can 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 at very high oral doses up to 2000 mg/kg. Overall, comprehensive genotoxicity studies indicate 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 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 dilatation of renal pelvises was observed in females receiving the drug in late pregnancy and during lactation. 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 of Olmesartan A)

Reproductive toxicity

Reproductive function studies in rats and mice revealed 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 based on mg/m²). In another study, in which male rats received amlodipine besylate for 30 days at doses comparable to the human dose based on mg/m², a reduction in plasma follicle-stimulating hormone and testosterone concentrations, as well as reduced sperm density, decreased number of mature spermatids, and Sertoli cells, was observed.

Carcinogenesis, mutagenesis

Two-year carcinogenicity studies in rats and mice receiving amlodipine in food at concentrations calculated to reproduce doses of 0.5 mg/kg/day, 1.25 mg/kg/day, 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 based on 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 Olmestad A is indicated for patients whose arterial blood pressure is not adequately controlled with monotherapy using olmesartan medoxomil or amlodipine (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 "Special instructions for use" and "Use during pregnancy or breastfeeding").

Severe hepatic impairment and biliary obstruction (see section "Pharmacokinetics").

Concomitant use of Olmestad 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 in its composition, Olmestad A is also contraindicated in patients with:

− severe arterial hypotension;

− shock (including cardiogenic shock);

− impaired outflow of blood 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 types of interactions.

Potential interactions caused by combination with Olmestad A

Caution should be exercised when co-administering

Other antihypertensive agents

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

Potential interactions related to the active substance of Olmestad A, olmesartan medoxomil

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 the combined use of ACE inhibitors and angiotensin II receptor blockers or aliskiren, leads to an increased incidence of adverse reactions such as arterial hypotension, hyperkalemia, and decreased renal function (including acute renal failure), compared to using a single medicinal product acting on the RAAS (see sections "Pharmacodynamics", "Contraindications", and "Special instructions 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 instructions for use"). When prescribing medicinal products that affect potassium levels in combination with Olmestad A, monitoring of serum potassium concentration is recommended.

Lithium-containing preparations

Rarely, concomitant use of lithium with angiotensin II receptor antagonists has been associated with reversible increases in serum lithium concentration and lithium toxicity. Therefore, concomitant use of Olmestad A and lithium preparations is not recommended (see section "Special instructions for use"). If concomitant use of Olmestad A and lithium preparations is necessary, regular monitoring of serum lithium levels is recommended.

Co-administration requires caution

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

When angiotensin II antagonists are co-administered with NSAIDs, the antihypertensive effect may be attenuated. Furthermore, concomitant use of angiotensin II antagonists and NSAIDs may increase the risk of renal function impairment and lead to increased serum potassium concentration. Therefore, during such combination therapy, renal function should be regularly assessed, and adequate hydration of the patient should be ensured.

Cholestyramine, a bile acid-binding medicinal product

Concomitant use of cholestyramine hydrochloride, a bile acid-binding agent, 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 cholestyramine hydrochloride reduces the effect of this drug interaction. Consideration should be given to administering olmesartan medoxomil at least 4 hours before cholestyramine hydrochloride (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 either drug 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, and minimal or no induction of 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 active substance of Olmestad A, 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 arterial hypotension. Clinical manifestations of such pharmacokinetic changes may be more pronounced in elderly patients. The risk of arterial hypotension is increased. Careful monitoring of patients is recommended. 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 when strong CYP3A4 inducers (rifampicin, St. John's wort) are used.

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

Dantrolene (infusion)

In laboratory 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. Given the risk of hyperkalemia in patients predisposed to malignant hyperthermia or 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 doses 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 per day.

Tacrolimus

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

Mechanistic target of rapamycin (mTOR) inhibitors: 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, exposure to mTOR inhibitors may increase.

Cyclosporine

In a prospective clinical study involving kidney transplant patients, co-administration of amlodipine with cyclosporine resulted in an average 40% increase in the minimum blood concentration of cyclosporine. Concomitant use of Olmestad A and cyclosporine may enhance the effect of cyclosporine. When cyclosporine is used concomitantly with amlodipine, monitoring of the minimum blood concentration of cyclosporine 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 treatment with Olmesartad A or to closely monitor the patient at the beginning of therapy.

Other conditions associated with activation of the RAAS

Patients in whom vascular tone and renal function largely depend on the activity of the renin-angiotensin-aldosterone system (RAAS) (e.g., patients with severe congestive heart failure or renal disease, including renal artery stenosis) may experience acute arterial hypotension, azotemia, oliguria, and 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 single functioning kidney is associated with an increased risk of severe arterial hypotension and renal failure.

Renal impairment and kidney transplantation

Periodic monitoring of serum potassium and creatinine levels is recommended in patients with renal impairment receiving Olmesartad A. The use of Olmesartad A is not recommended in patients with severe renal impairment (creatinine clearance < 20 mL/min). There is no experience with the use of Olmesartad 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

Combination therapy with ACE inhibitors, angiotensin II receptor blockers, or aliskiren has been shown to increase the risk of arterial hypotension, hyperkalemia, and impaired renal function (including acute renal failure). Therefore, dual blockade of the RAAS with concomitant use of ACE inhibitors and angiotensin II receptor blockers or aliskiren is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

If dual blockade therapy is absolutely necessary, it should be administered 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 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"). Olmesartad A should be used with caution in patients with mild to moderate hepatic impairment. For patients with moderate hepatic impairment, the dose of olmesartan medoxomil should not exceed 20 mg (see section "Dosage and administration"). Amlodipine therapy in patients with hepatic impairment should be initiated at the lowest dose, and caution should be exercised both at the start of treatment and when increasing the dose. Olmesartad 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 Olmesartad A, particularly in patients with renal impairment and/or heart failure (see section "Interaction with other medicinal products and other forms of interaction"). Frequent monitoring of serum potassium levels is recommended in these high-risk patients.

The drug should be used with caution 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 Olmesartad 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

As with all vasodilating agents, particular caution is recommended when prescribing Olmesartad A to patients with aortic or mitral valve stenosis or obstructive hypertrophic cardiomyopathy due to the presence of amlodipine in the formulation.

Primary hyperaldosteronism

Patients with primary hyperaldosteronism usually do not respond to antihypertensive drugs that suppress the renin-angiotensin system. Therefore, the use of Olmesartad 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, rarely with 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 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 significant weight loss has been reported, developing several months or years after initiation of treatment in patients taking olmesartan. The cause is likely a delayed local hypersensitivity reaction. Intestinal biopsies in such patients often show villous atrophy. If these symptoms occur in a patient during olmesartan therapy 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 Olmesartad A may be somewhat lower 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 antagonists are contraindicated during pregnancy. If angiotensin II antagonist therapy must be continued and a patient plans pregnancy, alternative antihypertensive agents with a well-established safety profile during pregnancy should be used. If pregnancy is confirmed during treatment with angiotensin II antagonists, therapy should be discontinued immediately and, if necessary, replaced with another medicinal product (see sections "Contraindications" and "Use during pregnancy or breastfeeding").

Other

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

Important information about excipients

Olmesartad A contains less than 1 mmol of sodium (23 mg) per film-coated tablet and is therefore considered essentially "sodium-free."

If intolerance to certain sugars is known, consult a physician before taking this medicinal product.

Use during pregnancy or breastfeeding

Pregnancy (see section "Contraindications")

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

Olmesartan medoxomil (active ingredient of Olmesartad 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 in the first trimester of pregnancy do not allow definitive conclusions, but such risks cannot be entirely excluded. A similar risk for angiotensin II receptor antagonists is assumed, as controlled epidemiological studies on these drugs have not been conducted. If angiotensin II antagonist therapy must be continued and a patient plans pregnancy, alternative antihypertensive agents with a well-established safety profile during pregnancy should be used. If pregnancy is confirmed during treatment with angiotensin II antagonists, therapy should be discontinued immediately and, if necessary, replaced with another medicinal product.

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 "Preclinical safety data").

If angiotensin II receptor antagonists are used during the second or third trimester of pregnancy, fetal renal function and skull ossification should be monitored by ultrasound. 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 Olmesartad A)

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

Given the above, Olmesartad A is not recommended during the first trimester of pregnancy and is contraindicated during the second and third trimesters of pregnancy (see sections "Contraindications" and "Special precautions for use").

Breastfeeding period

Olmesartan is excreted into the milk of lactating rats. It is unknown whether olmesartan passes into human breast milk.

Amlodipine is excreted into human breast milk. The infant's intake of the maternal dose was estimated at an interquartile range of 3–7%, with a maximum of 15%. The effect of amlodipine on the infant is unknown.

The use of Olmesartad A during breastfeeding is not recommended. 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 receiving 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 "Preclinical safety data").

Ability to influence reaction speed when driving or operating machinery

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

Occasionally, patients taking antihypertensive agents may experience headache, dizziness, nausea, and increased fatigue, which may impair reaction ability. Caution should be exercised, especially at the beginning of treatment.

Method of Administration and Dosage

Adults

The recommended dose of Olmestad A is 1 tablet daily.

Olmestad A 20/5 mg may be prescribed to patients who have an inadequate response to monotherapy with olmesartan medoxomil 20 mg or amlodipine 5 mg. Olmestad A 40/10 mg may be prescribed to patients who have an inadequate response to Olmestad A 20/5 mg.

Prior to initiating fixed-dose combination therapy, it is recommended to titrate the doses of the individual components as monotherapies. 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 Olmestad A tablets containing equivalent doses of these components.

Olmestad 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 and Precautions for Use").

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. Olmestad A is not recommended in patients with severe renal impairment (creatinine clearance < 20 mL/min) (see sections "Pharmacokinetics" and "Special Warnings and Precautions for Use").

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

Hepatic Impairment

Olmestad A should be used with caution in patients with mild to moderate hepatic impairment (see sections "Pharmacokinetics" and "Special Warnings and Precautions for Use"). 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 the use of olmesartan medoxomil in patients with severe hepatic impairment.

As with all calcium channel antagonists, the elimination half-life of amlodipine is prolonged in patients with hepatic dysfunction; dosage recommendations have not been established. Therefore, Olmestad A should be administered with caution in these patients. The pharmacokinetics of amlodipine in patients with severe hepatic impairment have not been studied. Amlodipine therapy in patients with severe hepatic impairment should be initiated at the lowest dose, with gradual dose escalation. Olmestad 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 should not be chewed. The medication should be taken daily at the same time.

Children

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

Overdose

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

Rare cases of non-cardiogenic pulmonary edema have been reported as a consequence of amlodipine overdose, which may present with delayed onset (24–48 hours after oral administration) and may require mechanical ventilation. Early resuscitation measures (including fluid loading) aimed at maintaining perfusion and cardiac output may act as triggering factors.

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

In the event of clinically significant arterial hypotension due to Olmestad A overdose, active cardiovascular support is required, including careful monitoring of cardiac and pulmonary function, elevation of the lower limbs, and monitoring of circulating blood volume and diuresis. Vasopressor agents may be useful to restore vascular tone and blood 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 removal of olmesartan by dialysis.

Adverse reactions

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

Adverse reactions observed during clinical trials and post-marketing safety studies, as well as those reported spontaneously, are listed in the table below. Additionally, the table includes adverse reactions observed with each of the active components of the drug 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 available data).

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

There have been several reports of rhabdomyolysis occurring temporally in association with angiotensin II receptor blockers. Extrapyramidal syndrome has been reported in some patients treated with amlodipine.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after a medicine is authorized is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals and patients are encouraged to report any suspected adverse reactions and lack of efficacy to the State Expert Centre of the Ministry of Health of Ukraine via the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

Keep out of the reach of children. This medicinal product does not require special storage conditions. Store in the original packaging to protect from moisture.

Packaging.

10 tablets in a blister; 3 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

STADA Arzneimittel AG (batch release).

Manufacturer’s address and place of business.

Stadastrasse 2-18, 61118 Bad Vilbel, Germany.