Olembic-n 20

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT OLEMBIC – H 20 (OLEMVIC – H 20) OLEMBIC – H 40 (OLEMVIC – H 40)

Composition:

Active substances: olmesartan medoxomil, hydrochlorothiazide;

One film-coated tablet contains: olmesartan medoxomil 20 mg and hydrochlorothiazide 12.5 mg or olmesartan medoxomil 40 mg and hydrochlorothiazide 12.5 mg;

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

Coating Opadry 03F82788: hypromellose (E464), titanium dioxide (E171), polyethylene glycol (E1521), yellow iron oxide (E172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

Olembic – H 20 (20 mg/12.5 mg): yellow, round, biconvex, film-coated tablets, with '346' engraved on one side and 'L' on the other;

Olembic – H 40 (40 mg/12.5 mg): yellow, oval, biconvex, film-coated tablets, with 'L 347' engraved on one side and smooth on the other.

Pharmacotherapeutic group. Combined angiotensin II inhibitors.

ATC code C09D A08.

Pharmacological Properties.

Pharmacodynamics.

Olembik – H 20 and Olembik – H 40 are combination preparations containing the angiotensin II receptor blocker olmesartan medoxomil and the thiazide diuretic hydrochlorothiazide.

Olmesartan medoxomil.

Olmesartan medoxomil is a selective blocker of angiotensin II receptors (type AT1), intended for oral administration. Angiotensin II is the primary vasoactive hormone of the renin-angiotensin-aldosterone system, playing a key role in the pathophysiology of arterial hypertension. It causes vasoconstriction, induces synthesis and secretion of aldosterone, stimulates cardiac activity, and promotes renal sodium reabsorption. Olmesartan inhibits the effects of angiotensin II on vasoconstriction and aldosterone secretion by blocking AT1 receptors in tissues, including vascular smooth muscle and adrenal glands. The action of olmesartan does not depend on the source or pathway of angiotensin II synthesis. Selective binding of olmesartan to angiotensin II AT1 receptors leads to increased plasma renin levels and concentrations of angiotensin I and angiotensin II, as well as a slight reduction in plasma aldosterone concentration.

In patients with arterial hypertension, olmesartan medoxomil produces a sustained reduction in blood pressure, the extent of which is dose-dependent. No signs of arterial hypotension after the first dose (the so-called "first-dose effect"), tachyphylaxis during prolonged use, or rebound arterial hypertension after abrupt discontinuation have been observed.

Once-daily administration of olmesartan medoxomil provides effective and smooth blood pressure reduction over 24 hours until the next dose. When administered once daily, its antihypertensive effect is approximately equivalent to that achieved with twice-daily administration at the same total daily dose.

With regular use, maximum blood pressure reduction is achieved within 8 weeks of starting treatment; however, a significant antihypertensive effect is observed as early as 2 weeks after initiation of therapy.

The effect of olmesartan medoxomil on mortality and the incidence of complications has not been established.

Hydrochlorothiazide.

Hydrochlorothiazide is a thiazide-type diuretic. The mechanism of antihypertensive action of thiazide diuretics is not fully understood. Thiazides affect electrolyte reabsorption in renal tubules, thereby enhancing the excretion of sodium and chloride (approximately to the same extent). As a diuretic, hydrochlorothiazide reduces plasma volume, leading to increased plasma renin activity and aldosterone secretion, increased urinary excretion of potassium and bicarbonate, and decreased serum concentrations of these electrolytes. Since the relationship between renin levels and aldosterone secretion is mediated by angiotensin II, the potassium loss induced by thiazide diuretics may be reduced when hydrochlorothiazide is used in combination with an angiotensin II receptor blocker. After oral administration, diuresis begins approximately 2 hours after intake, peak effect occurs around 4 hours, and the duration of action lasts 6–12 hours.

According to epidemiological data, long-term use of hydrochlorothiazide as monotherapy reduces the risk of cardiovascular complications and mortality from them.

Combined therapy with olmesartan medoxomil and hydrochlorothiazide.

The effect of the combined preparation of olmesartan medoxomil and hydrochlorothiazide on cardiovascular complications and mortality has not been established.

Pharmacokinetics.

Absorption and Distribution.

Olmesartan medoxomil.

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 from the gastrointestinal tract. Neither olmesartan medoxomil nor the medoxomil side group have been detected unchanged in plasma or excretions. The mean absolute bioavailability of olmesartan in tablet form is 25.6%. The mean maximum plasma concentration (Cmax) of olmesartan is reached approximately 2 hours after oral administration. Following single oral doses up to 80 mg, plasma concentrations of olmesartan increase approximately in proportion to the dose. 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 between genders have been observed. Olmesartan is highly bound to plasma proteins (99.7%), but the risk of clinically significant interactions with other drugs due to competition for plasma protein binding sites is low (evidenced by the absence of clinically significant interaction between olmesartan medoxomil and warfarin). Binding to blood cells is negligible. The mean volume of distribution after intravenous administration is small (16–29 L).

Hydrochlorothiazide.

When administered orally in combination with olmesartan medoxomil, the median time to reach Cmax of hydrochlorothiazide in plasma is 1.5–2 hours. Hydrochlorothiazide is 68% bound to plasma proteins, and its apparent volume of distribution is 0.83–1.14 L/kg.

Biotransformation and Elimination.

Olmesartan medoxomil.

Total plasma clearance of olmesartan is approximately 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 the radioactivity was recovered in urine (mostly within 24 hours after administration); the remainder was excreted in feces. Considering the systemic bioavailability of 25.6%, it can be calculated that absorbed olmesartan is eliminated both renally (approximately 40%) and via the hepatobiliary system (approximately 60%). All radioactivity detected in excretions was accounted for by olmesartan. No other significant metabolites have been identified. Olmesartan does not participate significantly in enterohepatic recirculation. Since a large portion of olmesartan is excreted in bile, the drug is contraindicated in patients with biliary obstruction. The terminal elimination half-life of olmesartan after repeated oral dosing ranges from 10 to 15 hours. Steady-state concentrations are achieved after the first few doses; no further accumulation was observed after 14 days of repeated administration. Renal clearance is approximately 0.5–0.7 L/hour and is independent of dose.

Hydrochlorothiazide.

Hydrochlorothiazide is not metabolized in humans and is excreted almost entirely unchanged in urine. After oral administration, approximately 60% of the dose is excreted unchanged within 48 hours. Renal clearance is approximately 250–300 mL/min. The terminal elimination half-life is about 10–15 hours.

Combination of olmesartan medoxomil with hydrochlorothiazide.

When hydrochlorothiazide is administered in combination with olmesartan medoxomil, the systemic bioavailability of the former is reduced by approximately 20%; however, this reduction is not clinically significant. The pharmacokinetics of olmesartan when administered in combination with hydrochlorothiazide are not altered.

Pharmacokinetics in Specific Patient Populations.

Elderly Patients (aged 65 years and older).

In patients aged 65–75 years with arterial hypertension, the steady-state area under the pharmacokinetic curve (AUC) of olmesartan is approximately 35% higher than in younger patients, and in patients aged ≥75 years, it is approximately 44% higher.

Available data suggest that systemic clearance of hydrochlorothiazide is lower in elderly individuals (both healthy and those with arterial hypertension) compared to younger patients.

Renal Impairment.

In patients with mild, moderate, and severe renal impairment, the steady-state AUC of olmesartan is 62%, 82%, and 179% higher, respectively, than in healthy volunteers. The elimination half-life of hydrochlorothiazide is prolonged in patients with renal impairment.

Hepatic Impairment.

After a single oral dose, the AUC of olmesartan in patients with mild and moderate hepatic impairment was 6% and 65% higher, respectively, than in healthy control volunteers. In healthy volunteers and patients with mild and moderate hepatic impairment, the unbound fraction of olmesartan 2 hours after administration was 0.26, 0.34, and 0.41%, respectively. After repeated dosing, the mean AUC of olmesartan in patients with moderate hepatic impairment was 65% higher than in healthy control volunteers. Cmax values of olmesartan in patients with hepatic impairment and healthy volunteers were similar. The efficacy of olmesartan medoxomil has not been established in patients with severe hepatic impairment. Hepatic impairment does not significantly affect the pharmacokinetics of hydrochlorothiazide.

Clinical characteristics.

Indications.

Treatment of essential hypertension.

These fixed combinations are indicated in adult patients in whom treatment with olmesartan medoxomil alone does not provide adequate blood pressure reduction.

Contraindications.

Hypersensitivity (allergic reaction) to the active substances, to any of the excipients, or to other sulfonamide derivatives (hydrochlorothiazide is also a sulfonamide derivative).

Severe renal impairment (creatinine clearance < 30 mL/min).

Persistent hypokalemia, hypercalcemia, hyponatremia, and clinically significant hyperuricemia.

Severe hepatic impairment, cholestasis, and biliary obstructive disorders. Pregnancy and planned pregnancy (see "Use during pregnancy or breastfeeding").

Pediatric population (under 18 years of age).

Concomitant use with medicinal products containing aliskiren in patients with diabetes mellitus or renal impairment (GFR < 60 mL/min/1.73 m²).

Interaction with other medicinal products and other forms of interaction.

Potentially possible interactions are related to the use of both olmesartan medoxomil and hydrochlorothiazide.

Concomitant use not recommended

Lithium preparations.

Concomitant use of lithium with angiotensin-converting enzyme (ACE) inhibitors and, occasionally, with angiotensin II receptor blockers has been associated with reversible increases in serum lithium concentration and lithium toxicity. Additionally, renal clearance of lithium is reduced in the presence of thiazides; therefore, the risk of lithium toxicity may increase during treatment with hydrochlorothiazide. Hence, concomitant use of this medicinal product with lithium is not recommended. In patients who require simultaneous administration of these agents, serum lithium concentrations should be monitored carefully during treatment.

Concomitant use requiring caution

Baclofen.

May enhance the hypotensive effect.

Non-steroidal anti-inflammatory drugs (NSAIDs).

NSAIDs (e.g., acetylsalicylic acid (> 3 g/day), COX-2 inhibitors, and non-selective NSAIDs) may attenuate the antihypertensive effect of thiazide diuretics and angiotensin II receptor blockers. In some patients with impaired renal function (e.g., dehydrated patients or elderly patients with renal disease), the use of angiotensin II receptor blockers together with drugs that inhibit cyclooxygenase may lead to further deterioration of renal function, including acute renal failure, which, however, is mostly reversible. Therefore, these drugs should be used concomitantly with caution, especially in elderly patients. Patients should maintain adequate fluid intake. Furthermore, renal function should be monitored at the start of combined therapy and periodically thereafter.

Concomitant use requiring special attention

Amifostine.

May enhance the antihypertensive effect.

Other antihypertensive agents.

The antihypertensive effect of the medicinal product may be enhanced when used concomitantly with other medicinal products that lower blood pressure.

Ethanol, barbiturates, narcotic analgesics, and antidepressants.

May enhance manifestations of orthostatic hypotension.

Potentially possible interactions with olmesartan medoxomil.

Concomitant use 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 concomitant use of ACE inhibitors and angiotensin II receptor blockers or aliskiren, leads to an increased incidence of adverse events such as hypotension, hyperkalemia, and impaired renal function (including acute renal failure), compared to treatment with a single agent acting on the RAAS.

MEDICINAL PRODUCTS AFFECTING SERUM POTASSIUM CONCENTRATION.

Based on experience with other medicinal products that inhibit the renin-angiotensin system, serum potassium concentration may increase when potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, and other medicinal products capable of increasing serum potassium concentration (e.g., heparin, ACE inhibitors) are used concomitantly. When prescribing the medicinal product together with medicinal products affecting potassium levels, monitoring of serum potassium concentration is recommended.

Cholestyramine sequestrant bile acids colesevelam.

Concomitant use of the bile acid-binding agent colesevelam hydrochloride reduces systemic exposure and peak plasma concentration of olmesartan, as well as shortens its elimination half-life. Administration of olmesartan medoxomil at least 4 hours before colesevelam hydrochloride reduces the effect of this drug interaction. Administration of olmesartan medoxomil at least 4 hours before colesevelam hydrochloride should be considered.

Additional information.

A moderate reduction in the bioavailability of olmesartan medoxomil has been observed after treatment with antacids (magnesium-aluminum hydroxide). Olmesartan medoxomil has no significant effect on the pharmacokinetics and pharmacodynamics of warfarin or on the pharmacokinetics of digoxin. In healthy volunteers receiving olmesartan medoxomil concomitantly with pravastatin, no clinically significant changes in the pharmacokinetics of either drug were observed. In vitro studies showed no clinically significant inhibition by olmesartan of the activity of human cytochrome P450 isoenzymes IA1/2, IIA6, IIC8/9, IIC19, IID6, IIE1, and IIIA4; in animal studies, olmesartan either had minimal inducing effects or no effect at all on cytochrome P450 isoenzymes. Therefore, clinically significant interactions between olmesartan and medicinal products metabolized by the aforementioned cytochrome P450 isoenzymes are not expected.

Potentially possible interactions of hydrochlorothiazide.

Concomitant use not recommended

MEDICINAL PRODUCTS AFFECTING SERUM POTASSIUM CONCENTRATION.

The hypokalemic effect of hydrochlorothiazide may be enhanced when used concomitantly with other medicinal products that cause potassium loss and hypokalemia (e.g., potassium-wasting diuretics, laxatives, corticosteroids, ACTH, amphotericin, carbenoxolone, sodium penicillin G, and salicylate derivatives). Therefore, concomitant use of hydrochlorothiazide with these agents is not recommended.

Concomitant use requiring caution

Calcium salts.

Due to reduced calcium excretion, thiazide diuretics may increase serum calcium concentration. If calcium supplements are required, serum calcium levels should be monitored and the calcium dose adjusted accordingly.

Cholestyramine and colestipol.

Anion-exchange resins may delay the absorption of hydrochlorothiazide.

Cardiac glycosides.

The use of cardiac glycosides may increase the risk of arrhythmias due to thiazide-induced hypokalemia and hypomagnesemia.

MEDICINAL PRODUCTS whose efficacy depends on serum potassium concentration.

Regular monitoring of serum potassium concentration and ECG is recommended when the medicinal product is used concomitantly with medicinal products whose efficacy depends on serum potassium concentration (e.g., cardiac glycosides and antiarrhythmic agents), as well as with agents that may cause torsades de pointes (ventricular tachycardia), including certain antiarrhythmic agents:

• Class Ia antiarrhythmics (e.g., quinidine, hydroquinidine, disopyramide);
• Class III antiarrhythmics (e.g., amiodarone, sotalol, dofetilide, ibutilide);
• certain antipsychotics (e.g., thioridazine, chlorpromazine, levomepromazine, trifluoperazine, zuclopenthixol, sulpiride, sulpirid, amisulpride, tiapride, pimozide, haloperidol, droperidol);
• others (e.g., bepridil, cisapride, difemanyl, intravenous erythromycin, halofantrine, mizolastine, pentamidine, sparfloxacin, terfenadine, intravenous vinca alkaloids).

Non-depolarizing skeletal muscle relaxants (e.g., tubocurarine).

Hydrochlorothiazide may enhance the effect of non-depolarizing skeletal muscle relaxants.

Anticholinergic agents (e.g., atropine and biperiden).

By reducing gastrointestinal motility and gastric emptying rate, anticholinergic agents may increase the bioavailability of thiazide diuretics.

Antidiabetic medicinal products (oral agents and insulin).

Thiazide therapy may affect glucose tolerance. Dose adjustment of antidiabetic agents may be necessary.

Metformin.

Metformin should be used with caution due to the risk of lactic acidosis associated with functional renal impairment, which may occasionally occur with hydrochlorothiazide use.

Beta-blockers and diazoxide.

The hyperglycemic effect of beta-adrenergic blockers and diazoxide may be enhanced by thiazides.

Pressor amines (e.g., noradrenaline).

The effectiveness of pressor amines may be reduced.

MEDICINAL PRODUCTS used for the treatment of gout (probenecid, sulfinpyrazone, and allopurinol).

Since hydrochlorothiazide may occasionally increase serum uric acid concentration, dose adjustment of uricosuric agents for gout treatment may be necessary. Additionally, the dose of probenecid or sulfinpyrazone may sometimes need to be increased. When allopurinol is used concomitantly with thiazides, the frequency of allergic reactions to allopurinol may increase.

Amantadine.

Thiazides may increase the risk of adverse reactions caused by amantadine.

Cytostatic agents (e.g., cyclophosphamide, methotrexate).

Thiazides may reduce renal excretion of antineoplastic agents and enhance their myelosuppressive effects.

Salicylates.
When salicylates are taken in high doses, hydrochlorothiazide may enhance their toxic effects on the central nervous system.

Methyldopa.

Published data report isolated cases of hemolytic anemia resulting from the use of hydrochlorothiazide in combination with methyldopa.

Cyclosporine.

Concomitant use of thiazides with cyclosporine may increase the risk of hyperuricemia and complications similar to gout.

Tetracycline.

Concomitant use of thiazides with tetracycline increases the risk of tetracycline-induced uremia. This interaction likely does not apply to doxycycline.

Special precautions for use.

Reduced circulating blood volume.

In patients with reduced circulating blood volume and/or low sodium levels caused by intensive diuretic therapy, low-salt diet, diarrhoea or vomiting, clinically significant arterial hypotension may occur, especially after the first dose of the drug. These conditions should be corrected before initiating treatment with this medicinal product.

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

Concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren increases the risk of arterial hypotension, hyperkalaemia, and impaired 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, 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.

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

In patients in whom vascular tone and renal function are highly dependent on RAAS activity (e.g. patients with severe congestive heart failure or renal pathology, including renal artery stenosis), reactions to other drugs affecting this system may include acute arterial hypotension, azotemia, oliguria, or, in rare cases, acute renal failure.

Renovascular hypertension.

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

Renal impairment and kidney transplantation.

The drug is contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/min). Dose adjustment is not required in patients with mild to moderate renal impairment (creatinine clearance ≥ 30 mL/min but < 60 mL/min). However, the drug should be used with caution in such patients, and periodic monitoring of serum potassium, creatinine, and uric acid concentrations is recommended. In patients with renal impairment, thiazide diuretics may cause azotemia. If progressive renal failure becomes evident, careful reassessment of the treatment regimen is required, and diuretics may need to be discontinued. There is no clinical experience with the use of this drug in patients who have recently undergone kidney transplantation.

Hepatic impairment.

Experience with olmesartan medoxomil in patients with severe hepatic impairment is lacking. Furthermore, in patients with hepatic impairment or progressive liver disease, even minor disturbances in fluid and electrolyte balance due to thiazide therapy may precipitate hepatic coma. Therefore, the drug should be used with caution in patients with mild to moderate hepatic impairment. The drug is contraindicated in patients with severe hepatic impairment, cholestasis, or biliary obstruction.

Aortic and mitral valve stenosis, hypertrophic obstructive cardiomyopathy.

Like other vasodilators, olmesartan medoxomil should be used with caution in patients with aortic or mitral valve stenosis, as well as in those with obstructive hypertrophic cardiomyopathy.

Primary hyperaldosteronism.

Patients with primary hyperaldosteronism usually do not respond to antihypertensive agents that suppress the renin-angiotensin system. Therefore, the drug is not recommended for such patients.

Metabolic and endocrine effects.

Thiazide-type drugs may impair glucose tolerance. Insulin or oral antidiabetic agents may require dose adjustment in diabetic patients. Thiazide diuretics may unmask latent diabetes mellitus.

During treatment with thiazide diuretics, adverse effects such as increased serum cholesterol and triglyceride levels may occur. In some cases, thiazide use may lead to hyperuricaemia or precipitate gout attacks. Hydrochlorothiazide may increase serum free bilirubin levels.

Electrolyte disturbances.

As with any diuretic, serum electrolyte concentrations should be monitored at regular intervals during hydrochlorothiazide therapy. Thiazide-type drugs, including hydrochlorothiazide, may cause disturbances in fluid and electrolyte balance (including hypokalaemia, hyponatraemia, and hypochloraemic alkalosis). Signs of fluid and electrolyte imbalance include: dry mouth, thirst, weakness, prolonged sleep, drowsiness, restlessness, muscle pain or cramps, muscle fatigue, arterial hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting. The risk of hypokalaemia is particularly high in patients with liver cirrhosis, during a sudden increase in diuresis, or when corticosteroids or ACTH are co-administered. On the other hand, blockade of angiotensin II (AT1) receptors by olmesartan medoxomil may lead to hyperkalaemia, especially in patients with renal impairment and/or heart failure, as well as in patients with diabetes mellitus. Serum potassium levels should be appropriately monitored in these patients. The drug should be used with caution when administered concomitantly with potassium supplements, potassium-sparing diuretics, potassium-containing salt substitutes, or other drugs that may increase serum potassium levels. There are no data indicating that olmesartan medoxomil can reduce or prevent diuretic-induced hyponatraemia. Chloride deficiency is usually mild and does not require specific treatment. Thiazides may reduce urinary calcium excretion and cause a slight and transient increase in serum calcium concentration in the absence of any calcium metabolism disorders. Hypercalcaemia may indicate occult hyperparathyroidism. Thiazides should be discontinued before parathyroid function testing. Thiazides enhance urinary excretion of magnesium, which may lead to hypomagnesaemia. In patients with oedema, "dilutional hyponatraemia" may occur in hot weather.

Lithium preparations.

As with other medicinal products containing angiotensin II receptor blockers in combination with thiazides, this drug is not recommended for concomitant use with lithium preparations.

Sprue-like enteropathy.

Very rarely, severe chronic diarrhoea with substantial weight loss has been reported, developing several months or years after initiation of treatment in patients taking olmesartan, likely due to a local delayed hypersensitivity reaction. Intestinal mucosal biopsies in such patients often show villous atrophy. If these symptoms occur in a patient during olmesartan treatment, alternative etiologies should be ruled out, olmesartan therapy should be discontinued immediately, and re-administration is not recommended. If diarrhoea persists for more than one week after discontinuation of the drug, a specialist (e.g. a gastroenterologist) should be consulted.

Acute myopia and secondary angle-closure glaucoma.

Hydrochlorothiazide is a sulfonamide and may cause idiosyncratic reactions leading to acute transient myopia and acute attacks of angle-closure glaucoma. Symptoms include acute onset of myopia or eye pain and typically occur within hours to weeks after starting treatment. Untreated acute angle-closure glaucoma may lead to permanent vision loss. Hydrochlorothiazide should be discontinued as soon as possible. If intraocular pressure cannot be controlled, immediate therapeutic or surgical intervention may be required. A history of sulfonamide or penicillin allergy may be a risk factor for developing angle-closure glaucoma.

Ethnic differences.

As with other angiotensin II receptor blockers, the antihypertensive effect of olmesartan medoxomil is somewhat less pronounced in black patients compared to other ethnic groups (possibly due to the higher prevalence of low renin levels in black patients).

Anti-doping test.

Hydrochlorothiazide, included in this medicinal product, may yield false-positive results in anti-doping tests.

Pregnancy.

The drug is contraindicated in pregnant women or women planning to become pregnant. If pregnancy is confirmed during treatment, therapy should be discontinued immediately. If necessary, the drug should be replaced with another medicinal product approved for use during pregnancy.

Other precautions.

Excessive reduction in blood pressure in patients with generalized atherosclerosis, ischaemic heart disease, or cerebrovascular ischaemia may lead to myocardial infarction or stroke.

The risk of allergic reactions to hydrochlorothiazide is higher in patients with a history of allergy or bronchial asthma, although such reactions may also occur in patients without such history.

According to scientific literature, thiazide diuretics may exacerbate or activate systemic lupus erythematosus.

This drug contains lactose. It should not be administered to patients with hereditary galactose intolerance, severe lactase deficiency, or glucose-galactose malabsorption syndrome.

Use during pregnancy or breastfeeding.

Pregnancy

The drug is contraindicated in pregnant women or women planning to become pregnant. If pregnancy is confirmed during treatment with this drug, its use must be discontinued immediately and replaced with another medicinal product approved for use during pregnancy.

It has been established that use of angiotensin II receptor blockers during the second and third trimesters of pregnancy may result in fetotoxic effects (impaired renal function, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, arterial hypotension, hyperkalaemia).

If angiotensin II receptor blockers were used during the second trimester of pregnancy, an ultrasound examination to assess fetal renal function and skull development is recommended.

Neonates whose mothers received angiotensin II receptor antagonists should be closely monitored for arterial hypotension.

Breastfeeding

Use of the drug during breastfeeding is contraindicated.

Ability to influence reaction speed when driving or operating machinery.

No studies have been conducted on the effect of this drug on the ability to drive or operate machinery. However, it should be noted that during antihypertensive therapy, patients may experience dizziness or fatigue, which may impair their ability to drive or operate machinery.

Method of Administration and Dosage.

Olmebik – H 20 and Olmebik – H 40 are not first-line agents.

Olmebik – H 20 is prescribed to patients in whom treatment with olmesartan medoxomil alone at a dose of 20 mg does not achieve the required blood pressure control.

For patients requiring further blood pressure reduction after 2 weeks of therapy, the dose may be increased to 40 mg.

Under appropriate clinical circumstances, direct transition from monotherapy with olmesartan medoxomil 20 mg to the combination drug is permitted; however, it should be noted that the maximum antihypertensive effect of olmesartan medoxomil is achieved 8 weeks after initiation of treatment.

Olmebik – H 40 is prescribed to patients in whom treatment with olmesartan medoxomil alone at a dose of 40 mg does not achieve the required blood pressure control.

The drug is taken once daily, independent of food intake. Tablets should be swallowed whole with a glass of water. Tablets must not be chewed. It is recommended to take the drug at the same time each day.

Elderly patients (aged 65 years and older).

Elderly patients should be prescribed the same dosage as that recommended for general adult patients.

Renal impairment.

For patients with mild to moderate renal impairment (creatinine clearance 30–60 mL/min), periodic monitoring of renal function is recommended. The maximum dose of olmesartan medoxomil should not exceed 20 mg once daily due to limited experience with higher doses in this patient group. Olmesartan medoxomil is contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/min) due to very limited experience in this population. Olmebik – H 40 is contraindicated in patients with renal impairment.

Hepatic impairment.

The drug should be used with caution in patients with mild to moderate hepatic impairment. In patients with moderate hepatic impairment, olmesartan medoxomil should be initiated at a dose of 10 mg once daily (for appropriate dosing, use another dosage form), and the maximum dose should not exceed 20 mg once daily. Patients with moderate hepatic impairment who are already receiving diuretics and/or other antihypertensive agents should be closely monitored for blood pressure and renal function. There is no experience with olmesartan medoxomil in patients with severe hepatic impairment. The drug is contraindicated in patients with severe hepatic impairment, as well as in those with cholestasis or biliary obstruction.

Children.

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

Overdose.

There is no specific information available regarding symptoms or treatment of overdose with this drug.

The most likely manifestations of olmesartan medoxomil overdose are arterial hypotension and tachycardia; bradycardia may also occur. Hydrochlorothiazide overdose is associated with electrolyte disturbances (hypokalemia, hypochloremia) and dehydration due to excessive diuresis. The most common symptoms of overdose are nausea and drowsiness. Hypokalemia may cause muscle spasms and/or exacerbate arrhythmias induced by concomitant medications (cardiac glycosides or certain antiarrhythmic agents).

The patient should be closely observed and receive symptomatic and supportive treatment. Management is symptomatic and depends on the time elapsed since drug ingestion and the severity of symptoms. Emetic agents and/or gastric lavage may be indicated. Activated charcoal may occasionally be recommended in overdose management. Serum electrolytes and creatinine levels should be monitored regularly. In case of arterial hypotension, the patient should be placed in a supine position and promptly administered intravenous infusion of isotonic sodium chloride solution.

It is unknown whether olmesartan or hydrochlorothiazide is removed by hemodialysis.

Adverse Reactions

The most commonly observed adverse reactions during treatment with this medicinal product are headache, dizziness, and increased fatigue.

Hydrochlorothiazide may cause or exacerbate hypovolemia, which may lead to disturbances in electrolyte balance.

Possible adverse reactions:

• Infections and parasitic diseases: sialadenitis.
• Blood and lymphatic system disorders: aplastic anemia, bone marrow suppression, hemolytic anemia, leukopenia, neutropenia/agranulocytosis, thrombocytopenia.
• Immune system disorders: anaphylactic reactions.
• Metabolism and nutrition disorders: anorexia, glucosuria, hypercalcemia, hypercholesterolemia, hyperglycemia, hyperkalemia, hypertriglyceridemia, hyperuricemia, hypochloremia, hypochloremic alkalosis, hypokalemia, hypomagnesemia, hyponatremia, hyperamylasemia.
• Psychiatric disorders: apathy, depression, restlessness, sleep disturbances.
• Nervous system disorders: confusion, convulsions, impaired consciousness (e.g., loss of consciousness), dizziness/vertigo, headache, loss of appetite, paresthesia, postural dizziness, somnolence, syncope.
• Eye disorders: decreased lacrimation, transient blurred vision, worsening of pre-existing myopia, acute myopia, acute angle-closure glaucoma, xanthopsia.
• Ear and labyrinth disorders: vertigo.
• Cardiac disorders: angina pectoris, cardiac arrhythmias, palpitations.
• Vascular disorders: embolism, arterial hypotension, necrotizing angiitis (vasculitis), orthostatic hypotension, thrombosis.
• Respiratory, thoracic and mediastinal disorders: bronchitis, cough, dyspnea, interstitial pneumonia, pharyngitis, pulmonary edema, respiratory failure, rhinitis.
• Gastrointestinal disorders: abdominal pain, constipation, diarrhea, gastric mucosal irritation, dyspepsia, gastroenteritis, flatulence, nausea, pancreatitis, paralytic ileus, vomiting, sprue-like enteropathy.
• Hepatobiliary disorders: acute cholecystitis, jaundice (due to intrahepatic cholestasis).
• Skin and subcutaneous tissue disorders: allergic dermatitis, anaphylactic skin reactions, angioedema, cutaneous manifestations of systemic lupus erythematosus, eczema, erythema, exanthema, photosensitivity reactions, pruritus, hemorrhagic rash (purpura), rash, exacerbation of cutaneous systemic lupus erythematosus, toxic epidermal necrolysis, urticaria.
• Musculoskeletal and connective tissue disorders: arthralgia, arthritis, back pain, muscle cramps, muscle weakness, myalgia, limb pain, paresis, bone pain.
• Renal and urinary disorders: acute renal failure, hematuria, interstitial nephritis, renal failure, renal dysfunction, urinary tract infection.
• Reproductive system and breast disorders: erectile dysfunction.
• General disorders and administration site conditions: asthenia, chest pain, facial swelling, fatigue, hot flushes, influenza-like symptoms, somnolence, malaise, pain, peripheral edema.

Additional test findings: increased blood aspartate aminotransferase activity, increased blood creatine phosphokinase activity, hypercalcemia, hypercreatininemia, hyperglycemia, decreased blood hematocrit, hypohemoglobinemia, hyperlipidemia, hypokalemia, hyperkalemia, increased blood urea nitrogen, increased blood urea, hyperuricemia, increased gamma-glutamyltransferase levels, increased liver enzyme levels.

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

Adverse reactions associated with hydrochlorothiazide use have been reported: dry mouth, thirst, anaphylactic shock, coma, Stevens–Johnson syndrome, disorientation, mood changes, pneumonitis. Thiazide diuretics may reduce glucose tolerance, potentially leading to manifestation of latent diabetes mellitus. Use of hydrochlorothiazide may result in hypochloremic alkalosis, which may trigger gout attacks in patients with asymptomatic hyperuricemia.

Shelf life.

2 years.

Storage conditions.

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

Packaging. 8 tablets per blister, 1 blister per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Alembic Pharmaceuticals Limited

Manufacturer's address and place of business.

Panellav, P.O. Tajpura, District Kheda, Taluka Panchmahal, Gujarat – 389 350, India.