Olme stad

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

Composition:

active substance: olmesartan medoxomil;

1 film-coated tablet contains olmesartan medoxomil 10 mg or 20 mg or 40 mg;

excipients: microcrystalline cellulose, crospovidone, colloidal anhydrous silicon dioxide, magnesium stearate, lactose monohydrate;

coating: Opadry White 03B28796, purified water; Opadry White consists of hypromellose, polyethylene glycol, titanium dioxide (E 171).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

for 10 mg dosage: white, round, biconvex film-coated tablets, 6 mm in diameter;

for 20 mg dosage: white, round, biconvex film-coated tablets, 8 mm in diameter;

for 40 mg dosage: white, oval, biconvex film-coated tablets, 15 mm in length and 6 mm in width.

Pharmacotherapeutic group.

Angiotensin II receptor blockers. ATC code: C09C A08.

Pharmacological properties.

Pharmacodynamics.

Olmesartan medoxomil is an orally active, selective antagonist of angiotensin II receptors (type AT1). It is expected to block all actions of angiotensin II mediated by AT1 receptors, regardless of the source or pathway of angiotensin II synthesis. Selective antagonism of angiotensin II AT1 receptors leads to a reduction in plasma renin levels and concentrations of angiotensin I and II, as well as a slight decrease in plasma aldosterone concentration.

Angiotensin II is the primary vasoactive hormone of the renin-angiotensin-aldosterone system (RAAS), playing a significant role in the pathophysiology of arterial hypertension via type 1 (AT1) receptors.

Clinical efficacy and safety

In arterial hypertension, olmesartan medoxomil induces a dose-dependent, sustained reduction in blood pressure. There are no data indicating arterial hypotension after the first dose, tachyphylaxis during long-term treatment, or withdrawal syndrome after abrupt discontinuation of therapy.

Administration of olmesartan medoxomil once daily provides effective and gradual blood pressure reduction over 24 hours. When the daily dose is administered once daily, the extent of blood pressure reduction is the same as when the same daily dose is divided into two doses throughout the day.

With continuous treatment, maximum blood pressure reduction is achieved by week 8 after initiation of therapy, although a significant antihypertensive effect is observed as early as 2 weeks after starting treatment.

When used concomitantly with hydrochlorothiazide, an additional blood pressure reduction is observed, and the combination is well tolerated.

The effect of olmesartan medoxomil on morbidity and mortality is not yet known. In a randomized trial of olmesartan for the prevention of diabetic microalbuminuria (Randomised Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP)), involving 4,447 patients with type 2 diabetes, normoalbuminuria, and at least one additional cardiovascular risk factor, the potential of olmesartan to delay the onset of microalbuminuria was studied. Over a median follow-up period 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). For the primary endpoint, a statistically significant reduction in the primary endpoint (time to onset of microalbuminuria) was demonstrated in the olmesartan group. However, after adjustment for differences in blood pressure, this risk reduction was no longer statistically significant. Microalbuminuria developed in 8.2% (178 out of 2,160) of patients in the olmesartan group and in 9.8% (210 out of 2,139) in the placebo group.

For secondary cardiovascular endpoints, 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 with olmesartan than with placebo (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 with olmesartan was numerically higher (26 patients (1.2%) vs. 15 patients (0.7%)), primarily due to a higher number of fatal cardiovascular events.

In the Olmesartan Reducing Incidence of End-stage Renal Disease in Diabetic Nephropathy Trial (ORIENT), the effects of olmesartan on the kidneys and cardiovascular system were studied in 577 randomized Japanese and Chinese patients with type 2 diabetes and overt nephropathy. Over a median 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 doubling of serum creatinine concentration, end-stage renal disease, or death from any cause) occurred in 116 patients in the olmesartan group (41.1%) and in 129 patients in the placebo group (45.4%) (HR 0.97 (95% confidence interval (CI) 0.75–1.24); p = 0.791). The secondary composite cardiovascular endpoint occurred in 40 patients receiving olmesartan (14.2%) and in 53 patients receiving placebo (18.7%). This composite cardiovascular endpoint included death due to cardiovascular causes in 10 (3.5%) patients receiving olmesartan vs. 3 (1.1%) patients receiving placebo, overall mortality (19 patients (6.7%) vs. 20 patients (7.0%)), non-fatal stroke in 8 (2.8%) vs. 11 (3.9%), and non-fatal myocardial infarction in 3 (1.1%) vs. 7 (2.5%) patients, respectively.

Pediatric population

The antihypertensive effects of olmesartan medoxomil in children and adolescents were evaluated in a randomized, double-blind, placebo-controlled trial involving 302 patients with arterial hypertension aged 6 to 17 years. The study population consisted of non-Black patients (112 patients) and a racially mixed group (190 patients, including 38 non-Black patients).

The cause of arterial hypertension was predominantly essential hypertension (87% in the non-Black group and 67% in the mixed group). Patients with body weight from 20 kg to < 35 kg were randomized to receive either 2.5 mg olmesartan medoxomil (low dose) or 20 mg (high dose) once daily, while patients with body weight ≥ 35 kg were randomized to receive either 5 mg (low dose) or 40 mg (high dose) once daily. At weight-adjusted doses, olmesartan medoxomil significantly reduced both systolic and diastolic blood pressure. Olmesartan medoxomil at low and high doses reduced systolic blood pressure by 6.6 mm Hg and 11.9 mm Hg, respectively (from baseline). This effect was also observed during the 2-week washout phase in additional randomized groups, during which both mean systolic and diastolic blood pressure showed statistically significant rebound in the placebo group compared to the olmesartan medoxomil group. In the pediatric population, treatment was effective for both primary and secondary arterial hypertension. As in adult patients, blood pressure reduction in non-Black children was less pronounced.

In the same study, 59 patients aged 1 to 5 years with body weight ≥ 5 kg received 0.3 mg/kg olmesartan medoxomil once daily for 3 weeks in an open-label phase, then were randomized in a double-blind phase to receive either olmesartan medoxomil or placebo. After 2 weeks of washout, mean systolic/diastolic blood pressure at the lower limit was 3/3 mm Hg lower in the group randomized to receive olmesartan medoxomil; this difference in blood pressure values was not statistically significant (95% CI from -2 to 7 / from -1 to 7).

Additional information

ONTARGET (Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and the VA NEPHRON-D (Veterans Affairs Nephropathy in Diabetes) trial investigated the use of combined ACE inhibitors and angiotensin II receptor blockers.

ONTARGET included patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes with evidence of complications. VA NEPHRON-D included patients with type 2 diabetes and diabetic nephropathy.

These trials showed that, compared to monotherapy, combined therapy did not provide significant benefit in terms of renal and/or cardiovascular outcomes and mortality, but increased the risk of hyperkalemia, acute kidney injury, and/or arterial hypotension. Given the similar pharmacodynamic properties of ACE inhibitors and angiotensin II receptor blockers, these conclusions apply to other agents in these drug classes. Therefore, patients with diabetic nephropathy should not use ACE inhibitors and angiotensin II receptor blockers concomitantly. The ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints) study investigated the benefit 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 study was prematurely terminated due to an increased risk of adverse reactions. Compared to the placebo group, patients in the aliskiren group had numerically higher rates of death from cardiovascular causes and stroke, and adverse reactions, including serious adverse reactions (hyperkalemia, arterial hypotension, and renal function impairment), were more frequent in the aliskiren group.

Pharmacokinetics.

Absorption and distribution

Olmesartan medoxomil is a prodrug. It is rapidly converted to the pharmacologically active metabolite olmesartan by esterases in the intestinal mucosa and portal circulation during absorption from the gastrointestinal tract. Unmetabolized olmesartan medoxomil or unchanged medoxomil side chain has not been detected in plasma or excretions. The mean absolute bioavailability of olmesartan from the tablet formulation is 25.6%.

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

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

Clinically relevant differences in the pharmacokinetics of olmesartan between different sexes have not been observed.

Olmesartan is highly bound to plasma proteins (99.7%), but the potential for clinically significant displacement from protein binding due to interaction with other highly protein-bound drugs is low (as confirmed by the absence of clinically significant interaction between olmesartan medoxomil and warfarin). Binding of olmesartan to blood cells is negligible. The mean volume of distribution after intravenous administration is low (16–29 L).

Metabolism and elimination

Total plasma clearance was generally 1.3 L/h (CV, 19%) and was relatively slow compared to hepatic blood flow (approximately 90 L/h). After administration of a single oral dose of radiolabeled 14C-olmesartan medoxomil, 10–16% of the administered radioactivity was recovered in urine (mainly within 24 hours after dosing), with the remainder excreted in feces. Considering the systemic availability (25.6%), it can be calculated that absorbed olmesartan is eliminated both renally (approximately 40%) and via the liver and biliary tract (approximately 60%). All excreted radioactivity was identified as olmesartan. No other significant metabolites were detected. Enterohepatic recirculation of olmesartan is minimal. Since a significant portion of olmesartan is excreted via the biliary tract, the use of the drug is contraindicated in patients with biliary obstruction (see section "Contraindications").

After multiple oral doses, the terminal elimination half-life of olmesartan ranged from 10 to 15 hours. Steady-state concentrations were achieved after the first few doses, and no evidence of further accumulation was observed after 14 days of repeated dosing. Renal clearance was approximately 0.5–0.7 L/h and was independent of dose.

Pharmacokinetics in special patient populations

Pediatric population

The pharmacokinetics of olmesartan were studied in patients with arterial hypertension aged 1 to 16 years. The clearance of olmesartan in these patients was similar to that in adults when adjusted for body weight.

Pharmacokinetic data in pediatric patients with impaired renal function are lacking.

Elderly patients (aged 65 years and older)

In patients with arterial hypertension, the steady-state area under the concentration-time curve (AUC) increased by approximately 35% in elderly patients (aged 65–75 years) and by approximately 44% in patients aged 75 years and older, compared to younger patients. This may be at least partially related to the average reduction in renal function in this patient group.

Renal impairment

In patients with mild, moderate, or severe renal impairment, the steady-state AUC increased by 62%, 82%, and 179%, respectively, compared to healthy control volunteers (see sections "Special precautions" and "Dosage and administration").

Hepatic impairment

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

Interaction with other medicinal products

Bile acid sequestrant colesevelam

Concomitant administration of 40 mg olmesartan medoxomil and 3,750 mg colesevelam hydrochloride in healthy volunteers resulted in a 28% reduction in Cmax and a 39% reduction in AUC of olmesartan. A weaker effect (4% and 15% reduction 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 it was administered simultaneously with or 4 hours before colesevelam hydrochloride.

Preclinical safety data

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 concentrations (due to functional renal changes caused by AT1 receptor blockade), reduced heart weight, decreased erythrocyte parameters (erythrocyte count, hemoglobin, hematocrit), and histological signs of kidney injury (foci of renal epithelial regeneration, thickening of the basement membrane, dilatation of renal tubules). 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 mitigated by concomitant 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, appear to have no clinical significance.

Like other AT1 receptor antagonists, olmesartan medoxomil increases the frequency of chromosomal breaks in in vitro cell cultures. However, similar effects were not 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 during clinical use.

No carcinogenic effects of olmesartan were observed in a two-year study in rats and two six-month studies in transgenic mice.

In reproductive 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 dilatation of renal pelvis was observed in females treated during late pregnancy and lactation. As with other antihypertensive drugs, olmesartan medoxomil was more toxic to pregnant rabbits than to pregnant rats, but did not exhibit fetotoxic effects.

Clinical characteristics.

Indications.

Treatment of essential arterial hypertension.

Treatment of arterial hypertension in children and adolescents aged 6 to 18 years.

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients of the medicinal product.
• Pregnancy or women who are planning to become pregnant (see sections "Special precautions" and "Use during pregnancy or breastfeeding").
• Biliary obstruction.
• Concomitant use of olmesartan medoxomil with medicinal products containing aliskiren is contraindicated in patients with diabetes mellitus and renal impairment (glomerular filtration rate (GFR) < 60 mL/min/1.73 m²) (see sections "Pharmacodynamics" and "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Effect of other medicinal products on olmesartan medoxomil

Other antihypertensive agents

The antihypertensive effect of olmesartan medoxomil may be enhanced when used concomitantly with other antihypertensive medicinal products.

ACE inhibitors, angiotensin II receptor blockers, or aliskiren

Dual blockade of the renin-angiotensin-aldosterone system (RAAS) by combining ACE inhibitors, angiotensin II receptor blockers, or aliskiren is associated with a higher incidence of adverse effects such as arterial hypotension, hyperkalemia, and impaired renal function (including acute renal failure), compared to using a single agent acting on the RAAS.

Potassium-containing preparations and potassium-sparing diuretics

Concomitant use of agents acting on the RAAS with potassium supplements, potassium-based salt substitutes, or other medicinal products that may increase serum potassium levels (e.g., heparin) may lead to elevated serum potassium concentrations. Therefore, such concomitant use is not recommended.

Nonsteroidal anti-inflammatory drugs (NSAIDs)

NSAIDs, including acetylsalicylic acid at doses exceeding 3 g per day, as well as COX-2 inhibitors, used concomitantly with angiotensin II receptor antagonists, may act synergistically to reduce glomerular filtration. Concomitant use of these medicinal products is associated with a risk of acute renal failure. In such cases, renal function should be monitored at the beginning of treatment, and adequate fluid intake should be ensured. Additionally, NSAIDs may reduce the antihypertensive effect of angiotensin II receptor antagonists when used concomitantly, potentially leading to decreased efficacy.

The bile acid sequestrant colesevelam

Concomitant use of the bile acid sequestrant colesevelam hydrochloride reduces systemic exposure and peak plasma concentration of olmesartan and shortens its elimination half-life. Administration of olmesartan medoxomil at least 4 hours before taking colesevelam hydrochloride minimizes their interaction. Therefore, olmesartan medoxomil should be administered at least 4 hours before colesevelam hydrochloride.

Other medicinal products:

A moderate reduction in the bioavailability of olmesartan medoxomil has been observed after treatment with antacids (aluminum-magnesium hydroxide). Concomitant use with warfarin and digoxin did not affect the pharmacokinetics of olmesartan.

Effect of olmesartan medoxomil on other medicinal products

Lithium preparations

When lithium is used concomitantly with ACE inhibitors or angiotensin II receptor antagonists, reversible increases in serum lithium concentrations and increased lithium toxicity have been observed. Therefore, combined use of olmesartan medoxomil with lithium is not recommended. If such concomitant use is necessary, careful monitoring of serum lithium concentrations during treatment is advised.

Other medicinal products

Compounds studied in specific clinical trials in healthy volunteers include warfarin, digoxin, antacids (aluminum and magnesium hydroxide), hydrochlorothiazide, and pravastatin. No clinically relevant interactions were observed. In particular, olmesartan medoxomil had no significant effect on the pharmacokinetics or pharmacodynamics of warfarin or on the pharmacokinetics of digoxin.

Furthermore, no clinically significant inhibitory effect of olmesartan medoxomil on the activity of cytochrome P450 isoenzymes 1A1/2, 2A6, 2C8/9, 2C19, 2D6, 2E1, and 3A4 was observed in vitro; minimal or no induced effect on cytochrome P450 was noted in rats. Therefore, in vivo interaction studies with known inhibitors and inducers of cytochrome P450 enzymes were not conducted, and clinically significant interactions between olmesartan and medicinal products metabolized by the aforementioned cytochrome P450 isoenzymes are not expected.

Special precautions for use.

Reduced circulating blood volume

In patients with reduced circulating blood volume and/or low serum sodium levels due to intensive diuretic therapy, restricted salt intake, diarrhea, or vomiting, symptomatic arterial hypotension may develop, particularly after administration of the first dose of the medicinal product. These conditions should be corrected prior to initiating treatment with olmesartan medoxomil.

Other conditions associated with activation of the RAAS

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

Renovascular hypertension

Administration of medicinal products affecting the RAAS in patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney is associated with a risk of severe arterial hypotension and renal failure.

Renal impairment and kidney transplantation

In patients with renal impairment receiving olmesartan medoxomil, periodic monitoring of serum potassium and creatinine concentrations is recommended. Olmesartan medoxomil is not recommended for patients with severe renal impairment (creatinine clearance less than 20 mL/min). Experience with olmesartan medoxomil in patients who have recently undergone kidney transplantation or in patients with end-stage renal disease (creatinine clearance less than 12 mL/min) is lacking.

Hepatic impairment

Olmesartan medoxomil is not recommended for use in patients with severe hepatic impairment due to lack of experience with its use (see section "Dosage and administration" regarding dosing in mild to moderate hepatic impairment).

Hyperkalemia

Medicinal products affecting the RAAS may provoke hyperkalemia. The risk of its development is increased in elderly patients and may be life-threatening in patients with renal impairment and diabetes mellitus, particularly when other drugs that increase potassium levels are co-administered and/or in the presence of intercurrent illnesses.

Before prescribing concomitant medicinal products affecting the RAAS, the benefit-risk ratio of such treatment should be carefully assessed, and alternative therapeutic options considered (see also section "Dual blockade of the renin-angiotensin-aldosterone system (RAAS)"). Major risk factors for hyperkalemia include:

• diabetes mellitus, renal impairment, age over 70 years;
• combination with one or more medicinal products affecting the RAAS and/or potassium supplements; certain medicinal products, even classes of drugs, may cause hyperkalemia: salt substitutes, potassium-containing preparations, potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists, NSAIDs including selective COX-2 inhibitors, heparin, immunosuppressants such as cyclosporine or tacrolimus, trimethoprim;
• intercurrent diseases and conditions, including dehydration, acute decompensated heart failure, metabolic acidosis, worsening of renal impairment, acute deterioration of renal function (e.g., due to infections), cell lysis such as in acute limb ischemia, rhabdomyolysis, polytrauma.

In patients with such risk factors, regular monitoring of serum potassium concentration is recommended (see section "Interaction with other medicinal products and other forms of interaction").

Dual blockade of the renin-angiotensin-aldosterone system (RAAS)

Evidence indicates that concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren increases the risk of arterial hypotension, hyperkalemia, and reduced renal function (including acute renal failure). Therefore, dual blockade of the RAAS by concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren is not recommended.

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

ACE inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

Lithium preparations

As with other angiotensin II receptor antagonists, concomitant use of lithium with olmesartan medoxomil is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Aortic and mitral valve stenosis, hypertrophic obstructive cardiomyopathy

Olmesartan medoxomil should be used with caution in patients with aortic or mitral valve stenosis or hypertrophic obstructive cardiomyopathy.

Primary hyperaldosteronism

Patients with primary hyperaldosteronism may not respond to antihypertensive drugs acting via inhibition of the RAAS. Therefore, use of olmesartan medoxomil is not recommended in such patients.

Sprue-like enteropathy

In very rare cases, severe chronic diarrhea with substantial weight loss, occurring in patients treated with olmesartan for periods ranging from several months to a year after initiation of therapy, may be caused by a localized delayed-type hypersensitivity reaction. Intestinal biopsies in such patients often show villous atrophy. If such symptoms occur during treatment with olmesartan, other etiologies should be ruled out. Discontinuation of olmesartan medoxomil should be considered when no other etiology is identified. In cases where symptoms resolve and sprue-like enteropathy is confirmed by biopsy, reinitiation of olmesartan medoxomil therapy should not be undertaken. If the diarrhea-related condition does not improve within one week after discontinuation of the drug, further specialist consultation (e.g., with a gastroenterologist) should be considered.

Ethnic differences

As with other angiotensin II receptor antagonists, the antihypertensive effect of olmesartan medoxomil is somewhat lower in black patients compared to other patients, possibly due to a higher prevalence of low renin levels in this patient group.

Pregnancy

Use of angiotensin II receptor antagonists is contraindicated throughout pregnancy and in women planning to become pregnant.

Angiotensin II receptor antagonists should not be initiated during pregnancy. Unless continued therapy with angiotensin II receptor antagonists is considered absolutely necessary, women planning pregnancy should be switched to alternative antihypertensive therapy with an established safety profile during pregnancy. If pregnancy is diagnosed, treatment with angiotensin II receptor antagonists must be discontinued immediately, and, if necessary, alternative therapy approved for use in pregnant women should be initiated.

Additional information

Significant reduction in blood pressure with any antihypertensive agent in patients with ischemic heart disease or cerebrovascular disease may lead to myocardial infarction and stroke.

The medicinal product contains lactose and therefore should not be used in patients with congenital galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.

Use during pregnancy or breastfeeding.

Pregnancy

The use of angiotensin II receptor antagonists is contraindicated throughout the entire pregnancy period and in women planning pregnancy.

Epidemiological data on the teratogenic risk of ACE inhibitors in the first trimester of pregnancy are inconclusive, but a slight increase in risk cannot be excluded. Although there are no controlled epidemiological data on the risk of using angiotensin II receptor antagonists, similar risks may exist with the use of this class of drugs. Unless continued therapy with angiotensin II receptor antagonists is considered absolutely necessary, patients planning pregnancy should be switched to alternative antihypertensive therapy with an established safety profile during pregnancy. If pregnancy is diagnosed, treatment with angiotensin II receptor antagonists must be immediately discontinued and, if necessary, alternative therapy approved for use in pregnant women should be initiated. During the second and third trimesters of pregnancy, angiotensin II receptor antagonists have toxic effects on the fetus (impaired kidney function, oligohydramnios, delayed skull ossification) and on the newborn (renal failure, arterial hypotension, hyperkalemia).

If angiotensin II receptor antagonists have been used from the second trimester of pregnancy, ultrasound examination is recommended to assess kidney function and skull bone development. Newborns whose mothers have used angiotensin II receptor antagonists should be monitored for possible arterial hypotension.

Breastfeeding period

Olmesartan is excreted in milk in lactating rats; however, it is not known whether olmesartan is excreted in human milk. Breastfeeding women should not use olmesartan medoxomil due to the lack of experience with its use during this period. Instead of olmesartan medoxomil, other antihypertensive agents with proven safety during breastfeeding should be used, especially when feeding infants or premature babies.

Ability to influence reaction speed when driving vehicles or operating machinery.

Olmesartan has a minor or moderate effect on the ability to drive vehicles or operate machinery. Patients receiving antihypertensive therapy may occasionally experience dizziness or fatigue, which could affect reaction speed.

Dosage and Administration

Adults

The recommended initial dose of olmesartan medoxomil is 10 mg once daily. If blood pressure reduction is inadequate, the dose of olmesartan medoxomil may be increased to 20 mg once daily. If additional blood pressure reduction is required, the dose of olmesartan medoxomil may be increased to 40 mg once daily (maximum daily dose) or hydrochlorothiazide may be added to the treatment regimen. The antihypertensive effect of olmesartan medoxomil is usually apparent within 2 weeks of starting therapy and reaches its maximum effect approximately 8 weeks after initiation of treatment. This should be taken into account when considering dosage adjustments for each individual patient.

Elderly patients

Dose adjustment is generally not required in elderly patients (see recommended doses for patients with renal impairment). When increasing the daily dose to the maximum of 40 mg, blood pressure should be carefully monitored.

Patients with renal impairment

The maximum dose for patients with mild to moderate renal impairment (creatinine clearance 20–60 mL/min) is 20 mg of olmesartan medoxomil once daily, due to limited experience with higher doses in this patient group. The use of olmesartan medoxomil in patients with severe renal impairment (creatinine clearance < 20 mL/min) is not recommended due to limited experience in such patients.

Hepatic impairment

No dose adjustment is required in patients with mild hepatic impairment. In patients with moderate hepatic impairment, the initial dose of olmesartan medoxomil is 10 mg daily, and the maximum dose is 20 mg. When olmesartan medoxomil is co-administered with diuretics and/or other antihypertensive agents to patients with hepatic impairment, careful monitoring of blood pressure and renal function is required. Olmesartan medoxomil is not recommended in patients with severe hepatic impairment due to lack of sufficient experience (see sections "Pharmacokinetics" and "Special warnings and precautions for use"). Olmesartan medoxomil should not be used in patients with biliary obstruction (see section "Contraindications").

Children and adolescents aged 6 to 18 years

The recommended initial dose of olmesartan medoxomil in children aged 6 to 18 years is 10 mg once daily. If blood pressure is not adequately controlled, the dose may be increased to 20 mg once daily. For greater blood pressure reduction, in children with body weight ≥ 35 kg, the dose of olmesartan medoxomil may be increased to 40 mg daily. For children with body weight < 35 kg, the daily dose should not exceed 20 mg.

Other pediatric populations

The safety and efficacy of the medicinal product in children aged 1 to 5 years have not yet been established. Although some data are available in the sections "Pharmacodynamics" and "Adverse reactions", dosage recommendations cannot be provided. The product should not be used in children under 1 year of age due to safety concerns and lack of data.

Administration

To ensure consistent dosing, the medicinal product should be taken approximately at the same time each day, with or without food, for example during breakfast. Tablets should be taken with sufficient fluid (e.g., one glass of water). The tablet should not be chewed.

Overdose

Symptoms. Information on overdose is limited. The most likely effect of overdose is arterial hypotension.

Treatment. In case of overdose, the patient should be closely monitored and symptomatic, supportive therapy should be administered.

There is no information available on the removal of olmesartan medoxomil by dialysis.

Adverse reactions.

Overview of safety profile

The most commonly occurring adverse reactions during treatment with olmesartan are headache (7.7%), influenza-like symptoms (4.0%), and dizziness (3.7%).

In placebo-controlled monotherapy studies, the only adverse reaction definitively associated with treatment was dizziness (incidence 2.5% with olmesartan medoxomil versus 0.9% in the placebo group).

The frequency of laboratory parameter abnormalities was slightly higher with olmesartan medoxomil compared to placebo: hypertriglyceridemia (2.0% vs 1.1%) and increased creatine phosphokinase (1.3% vs 0.7%).

Adverse reactions reported with olmesartan medoxomil based on clinical trials, post-marketing safety studies, and spontaneous reports are listed in the table.

Adverse reactions are categorized by frequency as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); frequency not known (cannot be estimated based on available data).

Organ systems by MedDRA classification	Adverse reactions	Frequency
Blood and lymphatic system disorders	thrombocytopenia	uncommon
Immune system disorders	anaphylactic reaction	uncommon
Metabolism and nutrition disorders	hypertriglyceridemia	common
	hyperuricemia	common
	hyperkalemia	uncommon
Nervous system disorders	dizziness	common
	headache	common
Ear and labyrinth disorders	vertigo	uncommon
Cardiac disorders	angina pectoris	uncommon
Vascular disorders	arterial hypotension	rare
Respiratory, thoracic and mediastinal disorders	bronchitis	common
	pharyngitis	common
	cough	common
	rhinitis	common
Gastrointestinal disorders	gastroenteritis	common
	diarrhea	common
	abdominal pain	common
	nausea	common
	dyspepsia	common
	vomiting	uncommon
	sprue-like enteropathy (see section "Special warnings and precautions for use")	very rare
Hepatobiliary disorders	autoimmune hepatitis*	frequency unknown
Skin and subcutaneous tissue disorders	exanthema	uncommon
	allergic dermatitis	uncommon
	urticaria	uncommon
	rash	uncommon
	pruritus	uncommon
	angioneurotic edema	rare
Musculoskeletal and connective tissue disorders	arthritis	common
	back pain	common
	bone pain	common
	myalgia	uncommon
	muscle spasms	rare
Renal and urinary disorders	hematuria	common
	urinary tract infections	common
	acute renal failure	rare
	renal function disorders	rare
General disorders and administration site conditions	pain	common
	chest pain	common
	peripheral edema	common
	influenza-like symptoms	common
	increased fatigue	common
	facial swelling	uncommon
	asthenia	uncommon
	malaise	uncommon
	lethargic state	rare
Investigations	elevated liver enzymes	common
	elevated blood urea	common
	elevated creatine phosphokinase in blood	common
	elevated blood creatinine	rare

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

Isolated cases of rhabdomyolysis, temporally associated with angiotensin II receptor blockers, have been reported.

Additional information on special patient populations

Paediatric population

The safety of olmesartan medoxomil has been monitored in two clinical studies involving 361 children and adolescents aged 1 to 17 years. While the nature and severity of adverse reactions were similar to those observed in adult patients, the following adverse reactions occurred more frequently in children than in adults:

• Epistaxis is a common adverse reaction (≥ 1/100 to < 1/10) in children, which has not been reported in adult patients;
• During a 3-week double-blind study, the incidence of dizziness and headache requiring treatment was nearly twice as high in children aged 6 to 17 years in the high-dose olmesartan medoxomil group.

Overall, the safety profile of olmesartan medoxomil in paediatric patients did not differ significantly from that in adult patients.

Elderly patients

In elderly patients, arterial hypotension may occur somewhat more frequently (from "rare" to "occasional").

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua

Shelf life. 3 years.

Storage conditions.

No special storage conditions required.

Keep out of reach and sight of children.

Packaging.

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

Prescription status. Prescription only.

Manufacturer.

STADA Arzneimittel AG, Germany (batch release).

"HEMOPHARM" AD, Serbia (batch release).

Manufacturer's address and location of business activity.

Stadashstrasse 2-18, 61118 Bad Vilbel, Germany.

Belgrade Road, n.n., 26300 Vrsac, Serbia.