Olembic-40

INSTRUCTIONS for medical use of the medicinal product OLEMBIK-20 (OLEMVIC-20) OLEMBIK-40 (OLEMVIC-40)

Composition:

Active substance: olmesartan medoxomil;

1 tablet of Olemvik-20 contains 20 mg of olmesartan medoxomil;

1 tablet of Olemvik-40 contains 40 mg of olmesartan medoxomil;

Excipients: lactose monohydrate, microcrystalline cellulose, low-substituted hydroxypropylcellulose, hydroxypropylcellulose, magnesium stearate;

coating Opadry 03F82788: hypromellose (E464), titanium dioxide (E171), macrogol (E1521), yellow iron oxide (E172).

Dosage form. Film-coated tablets.

Main physicochemical characteristics:

Olembik-20 (20 mg): yellow, round, biconvex, film-coated tablets, embossed with '323' on one side and 'L' on the other side.

Olembik-40 (40 mg): yellow, oval, biconvex, film-coated tablets, embossed with 'L324' on one side and plain on the other side.

Pharmacotherapeutic group. Angiotensin II receptor blockers. ATC code C09CA08.

Pharmacological properties.

Pharmacodynamics.

Olembik is an angiotensin II receptor blocker medication containing olmesartan medoxomil.

Olmesartan medoxomil is a potent, orally active, selective antagonist of angiotensin II receptors (AT1 subtype). It is believed to inhibit all actions of angiotensin II mediated by the AT1 receptor, regardless of the source or pathway of angiotensin II synthesis. Selective blockade of AT1 receptors by angiotensin II leads to increased plasma renin levels and increased concentrations of angiotensin I and II, as well as a slight reduction in plasma aldosterone concentration.

Angiotensin II is the primary vasoactive hormone of the renin-angiotensin-aldosterone system and plays a key 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, long-lasting reduction in blood pressure. There is no evidence of first-dose hypotension, tachyphylaxis during prolonged treatment, or rebound hypertension after discontinuation of therapy.

A single daily dose of olmesartan medoxomil provides effective and smooth blood pressure reduction over 24 hours. A single daily dose produces the same blood pressure reduction as splitting the daily dose into two administrations.

With continuous treatment, maximum blood pressure reduction is achieved within 8 weeks of initiating therapy, although significant blood pressure reduction is observed as early as 2 weeks after starting treatment. When used concomitantly with hydrochlorothiazide, additional blood pressure reduction is observed, and this combination is well tolerated.

The effect of olmesartan on mortality and morbidity is currently unknown.

Pharmacokinetics.

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 in portal blood during absorption from the gastrointestinal tract.

Unhydrolyzed olmesartan medoxomil or the unchanged medoxomil side chain have not been detected in plasma or excretory products. The mean absolute bioavailability of olmesartan from the tablet formulation is 25.6%.

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

Food has practically no effect on the bioavailability of olmesartan; therefore, olmesartan medoxomil can be administered regardless of food intake.

No clinically significant differences in olmesartan pharmacokinetics were observed based on gender.

Plasma protein binding of olmesartan medoxomil is high (99.7%), but the potential for clinically significant displacement due to interactions 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 small (16–29 L).

Metabolism and elimination.

Total plasma clearance is typically about 1.3 L/h (CV, 19%) and is 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 excreted in urine (mostly within 24 hours after dosing), with the remainder eliminated in feces. Based on the systemic availability index (25.6%), it can be estimated that absorbed olmesartan is excreted 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 in patients with biliary obstruction is contraindicated.

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

Pharmacokinetics in special patient populations.

Elderly (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 patients aged 65–75 years and by approximately 44% in patients aged 75 years and older, compared to younger individuals. This may be at least partially related to reduced renal function in this patient group.

Renal impairment

In patients with mild, moderate, or severe renal impairment, steady-state AUC values increased by 62%, 82%, and 179%, respectively, compared to healthy control subjects.

Hepatic impairment

After a single oral dose, AUC values of olmesartan in patients with mild or moderate hepatic impairment were 6% and 65% higher, respectively, than in 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 in patients with moderate hepatic impairment was 65% higher than in healthy volunteers. Mean Cmax values of olmesartan were similar in patients with hepatic impairment and healthy volunteers. The use of olmesartan medoxomil in patients with severe hepatic impairment has not been evaluated.

Clinical characteristics.

Indications.

Essential arterial hypertension.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients of the medicinal product. Biliary obstruction. Concomitant use of olmesartan with medicinal products containing aliskiren is contraindicated in patients with diabetes mellitus and renal impairment (eGFR < 60 mL/min/1.73 m²). The medicinal product is contraindicated in pregnant women and women who plan to become pregnant (see "Use during pregnancy or breastfeeding"). The medicinal product is contraindicated in children and adolescents (under 18 years of age).

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 increased when used concomitantly with other antihypertensive agents.

Angiotensin-converting enzyme (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 hypotension, hyperkalaemia, and impaired renal function (including acute renal failure), compared to monotherapy with agents acting on the RAAS.

Potassium-sparing diuretics and potassium supplements

Concomitant use of agents acting on the renin-angiotensin-aldosterone system with potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, or other agents that may increase potassium levels (e.g., heparin) may lead to increased serum potassium concentrations; therefore, such concomitant use is not recommended.

Non-steroidal anti-inflammatory drugs (NSAIDs)

NSAIDs, including acetylsalicylic acid at doses exceeding 3 g per day, as well as COX-2 inhibitors and angiotensin II receptor antagonists, may act synergistically to reduce glomerular filtration. Concomitant use of these agents 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.

In addition, NSAIDs may reduce the antihypertensive effect of angiotensin II receptor antagonists when used concomitantly, potentially leading to decreased efficacy.

Bile acid sequestrant colesevelam

Concomitant use of the bile acid sequestrant colesevelam hydrochloride reduces systemic exposure to peak plasma concentrations of olmesartan and shortens its elimination half-life. Administration of olmesartan medoxomil at least 4 hours prior to colesevelam hydrochloride reduces 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 (magnesium/aluminum hydroxide). Concomitant use with warfarin and digoxin does not affect the pharmacokinetics of olmesartan medoxomil.

Effect of olmesartan medoxomil on other medicinal products.

Lithium

Elevated and reversible serum lithium concentrations and increased lithium toxicity have been observed when lithium is used concomitantly with angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists; therefore, such combination is not recommended. If concomitant use is necessary, careful monitoring of serum lithium concentrations during treatment is recommended.

Other medicinal products

No clinically significant interactions between olmesartan medoxomil and warfarin, digoxin, antacids (aluminum hydroxide/magnesium hydroxide), hydrochlorothiazide, or pravastatin have been observed. Specifically, olmesartan medoxomil did not significantly affect the pharmacodynamics or pharmacokinetics of warfarin or the pharmacokinetics of digoxin.

Furthermore, no clinically significant inhibitory effect of olmesartan medoxomil on the enzymes 1A1/2, 2A6, 2C8/9, 2C19/2D6, 2E1, 3A4, and cytochrome P450 has been observed in vitro in humans, and minimal or no induction effect on cytochrome P450 has been observed in animals. Therefore, in vivo interaction studies with known inhibitors and inducers of cytochrome P450 enzymes were not conducted. Clinically significant interactions between olmesartan and medicinal products whose metabolism is mediated by the aforementioned cytochrome P450 enzymes 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 drug. Such conditions should be corrected prior to initiating treatment with olmesartan medoxomil.

Other conditions associated with activation of the renin-angiotensin-aldosterone system

Patients in whom vascular tone and function depend predominantly on the activity of the renin-angiotensin-aldosterone system—such as patients with severe congestive heart failure or renal pathology, including renal artery stenosis—may develop acute arterial hypotension, azotemia, oliguria, or, in rare cases, acute renal failure when treated with drugs affecting this system. Treatment with angiotensin II receptor antagonists may be associated with similar effects.

Vasorenal hypertension

Administration of drugs affecting the renin-angiotensin-aldosterone system in patients with bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney is associated with a risk of developing 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.

Hyperkalemia

Drugs affecting the renin-angiotensin-aldosterone system may provoke hyperkalemia. The risk of hyperkalemia is increased in elderly patients and may be life-threatening in patients with renal impairment and diabetes mellitus, particularly when other drugs that increase serum potassium levels are used concomitantly and/or in the presence of intercurrent illnesses.

Before prescribing concomitant medications affecting the renin-angiotensin-aldosterone system, the benefit-risk ratio of such treatment should be carefully evaluated, and alternative therapeutic options should be considered. Major risk factors for hyperkalemia include:

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

In patients with such risk factors, regular monitoring of serum potassium concentration is recommended.

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 deterioration of 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 is considered absolutely necessary, it should be performed only under specialist supervision with 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

Concomitant use of lithium with olmesartan medoxomil is not recommended.

Aortic or mitral valve stenosis; obstructive hypertrophic cardiomyopathy

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

Primary hyperaldosteronism

Patients with primary hyperaldosteronism do not respond to antihypertensive drugs acting via inhibition of the renin-angiotensin system. Therefore, the use of olmesartan medoxomil is not recommended in such patients.

Sprue-like enteropathy

Severe, chronic diarrhea with substantial weight loss, occurring very rarely in patients treated with olmesartan, after several months to a year of treatment, may be due to a localized delayed-type hypersensitivity reaction. Intestinal biopsy often reveals villous atrophy. If such symptoms occur during treatment with olmesartan, other etiologies should be excluded. Discontinuation of olmesartan medoxomil should be considered if no other cause is identified. If symptoms resolve and sprue-like enteropathy is confirmed by biopsy, reinitiation of olmesartan medoxomil therapy is not recommended.

Ethnic differences

The antihypertensive effect of olmesartan medoxomil is somewhat less pronounced in patients of Black race compared to other patients, possibly due to a higher prevalence of low renin levels in this population.

Other

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

The 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 medicinal product is contraindicated (see "Contraindications") in pregnant women and in women who are planning to become pregnant. If pregnancy is confirmed during treatment with this product, therapy should be discontinued immediately and replaced with another medicinal product approved for use during pregnancy. Women planning pregnancy should be switched to alternative antihypertensive therapy with an established safety profile during pregnancy.

Breastfeeding period

Use of the drug during breastfeeding is contraindicated.

Ability to affect reaction speed when driving or operating machinery.

No studies on the effect on the ability to drive vehicles or operate machinery have been conducted. However, it should be considered that during antihypertensive treatment, patients may experience dizziness or fatigue, which may affect their ability to drive vehicles or operate machinery.

Dosage and Administration

The initial daily dose of olmesartan medoxomil is 10 mg once daily. If blood pressure reduction is inadequate, the dose should be increased to 20 mg once daily. If necessary, the dose may be further 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 generally observed within 2 weeks after starting treatment, and the maximum effect is achieved after 8 weeks of therapy. This should be taken into account when considering dosage adjustments for any patient.

The medication should be taken approximately at the same time each day, with or without food, for example during breakfast. Tablets should be swallowed with sufficient fluid (e.g., one glass of water). Tablets must not be chewed.

Elderly patients (aged 65 years and older)

Dosage 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 daily dose for patients with mild to moderate renal impairment (creatinine clearance 20–60 mL/min) is 20 mg, as there is no experience with higher doses in this patient group. Olmesartan medoxomil is contraindicated in patients with severe renal impairment (creatinine clearance <20 mL/min) due to limited experience with its use in such patients.

Hepatic impairment

Dosage adjustment is not 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 in patients with hepatic impairment, careful monitoring of blood pressure and renal function is required. Olmesartan medoxomil is contraindicated in patients with severe hepatic impairment due to insufficient experience with its use. Olmesartan medoxomil should not be used in patients with biliary obstruction.

Children

The use of this medication in children is contraindicated due to insufficient data on safety and efficacy.

Overdose

Information regarding overdose is limited. The most likely manifestation of overdose is arterial hypotension. In case of overdose, close monitoring of the patient and symptomatic, supportive therapy should be initiated.

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

Adverse reactions.

The most commonly reported adverse reactions associated with the use of the medicinal product are headache, dizziness, and increased fatigue.

Adverse reactions may include:

Blood and lymphatic system disorders: thrombocytopenia.

Immune system disorders: anaphylactic reaction.

Metabolism and nutrition disorders: hypertriglyceridemia, hypercholesterolemia, hyperuricemia, hyperkalemia.

Nervous system disorders: dizziness, headache.

Ear and labyrinth disorders: vertigo.

Cardiac disorders: angina pectoris, tachycardia, arterial hypotension.

Respiratory, thoracic and mediastinal disorders: bronchitis, pharyngitis, cough, rhinitis.

Gastrointestinal disorders: gastroenteritis, diarrhea, abdominal pain, nausea, dyspepsia, vomiting, sprue-like enteropathy.

Skin and subcutaneous tissue disorders: exanthema, allergic dermatitis, urticaria, rash, pruritus, alopecia, angioneurotic edema.

Musculoskeletal and connective tissue disorders: arthritis, back pain, bone pain, myalgia, arthralgia, muscle cramps.

Renal and urinary disorders: hematuria, urinary tract infection, acute renal failure, renal dysfunction.

General disorders and administration site conditions: pain, chest pain, peripheral edema, influenza-like symptoms, increased fatigue, facial swelling, asthenia, malaise, lethargy.

Laboratory test abnormalities: increased liver enzymes, increased blood urea levels, increased blood creatine phosphokinase levels, increased blood creatinine levels.

There have been isolated reports of rhabdomyolysis occurring temporally associated with the use of angiotensin II receptor blockers.

Shelf life. 2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 30°C. Keep out of the reach of children.

Packaging. 10 tablets in a blister pack, 3 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Alembic Pharmaceuticals Limited.

Manufacturer's name and address.

Panelav, P.V. Tadhpura, District Halol, Panchmahal, Gujarat – 389 350, India.