Olme stad h
UkraineTable of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT OLMESTAD H (OLMESTAD H)
Composition:
Active substances: olmesartan medoxomil/hydrochlorothiazide;
One film-coated tablet contains olmesartan medoxomil 20 mg/hydrochlorothiazide 12.5 mg;
or olmesartan medoxomil 20 mg/hydrochlorothiazide 25 mg;
or olmesartan medoxomil 40 mg/hydrochlorothiazide 12.5 mg;
or olmesartan medoxomil 40 mg/hydrochlorothiazide 25 mg;
Excipients: microcrystalline cellulose, crospovidone, colloidal anhydrous silicon dioxide, magnesium stearate, lactose monohydrate;
Tablet coating: Opadry II beige 31F27015 and Opadry II pink 31F34029 consisting of: hypromellose, lactose monohydrate, polyethylene glycol, titanium dioxide (E 171), yellow iron oxide (E 172), red iron oxide (E 172); purified water.
Pharmaceutical form. Film-coated tablets.
Main physicochemical properties:
for dosage 20 mg/12.5 mg: beige, round, biconvex film-coated tablets;
for dosage 20 mg/25 mg: pink, round, biconvex film-coated tablets;
for dosage 40 mg/12.5 mg: beige, round, biconvex film-coated tablets with a score line on one side;
for dosage 40 mg/25 mg: pink, round, biconvex film-coated tablets with a score line on one side.
Pharmacotherapeutic group.
Agents acting on the renin-angiotensin system.
Angiotensin II antagonists and diuretics. ATC code C09D A08.
Pharmacological Properties
Pharmacodynamics
Olmesartan H is a combination product containing the angiotensin II receptor blocker olmesartan medoxomil and the thiazide diuretic hydrochlorothiazide. The combination of these components exerts an additive antihypertensive effect, resulting in a greater reduction in blood pressure than with either component administered alone.
Administration of Olmesartan H once daily provides effective and smooth reduction of arterial pressure over 24 hours until the next dose.
Olmesartan Medoxomil
Olmesartan medoxomil is a selective angiotensin II receptor antagonist (type AT1) intended for oral administration. Angiotensin II is the primary vasoactive hormone of the renin-angiotensin-aldosterone system (RAAS) and plays a key role in the pathophysiology of arterial hypertension. 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 is independent of 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 provides sustained dose-dependent reduction in arterial pressure. No signs of first-dose hypotension, tachyphylaxis during prolonged use, or rebound hypertension after abrupt discontinuation have been observed.
Once-daily administration of olmesartan medoxomil provides effective and smooth reduction in arterial pressure over 24 hours until the next dose. When administered once daily, its antihypertensive effect is approximately equivalent to that observed with twice-daily administration at the same total daily dose.
With continuous treatment, maximum reduction in arterial pressure is achieved within 8 weeks of initiating therapy, although a significant antihypertensive effect is evident as early as 2 weeks after starting treatment.
The effect of olmesartan medoxomil on the incidence of complications and mortality has not been established.
The Randomized Olmesartan and Prevention of Diabetic Microalbuminuria (ROADMAP) trial, involving 4447 patients with type 2 diabetes and normal albuminuria levels and at least one additional cardiovascular risk factor, was conducted to determine whether olmesartan therapy could delay the onset of microalbuminuria. During a mean follow-up period of 3.2 years, patients received either olmesartan or placebo in addition to other antihypertensive agents, excluding angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs).
In the primary endpoint of the study, olmesartan significantly reduced the risk of developing microalbuminuria. However, after adjusting for differences in blood pressure levels, this risk reduction was no longer statistically significant. Microalbuminuria developed in 8.2% (178 out of 2160) of patients in the olmesartan group and in 9.8% (210 out of 2139) in the placebo group.
In the secondary endpoint, cardiovascular events occurred in 96 patients (4.3%) receiving olmesartan and in 94 patients (4.2%) receiving placebo. The rate of cardiovascular mortality was higher in the olmesartan group than in the placebo group (15 patients (0.7%) vs. 3 patients (0.1%)), despite similar rates of non-fatal stroke (14 patients (0.6%) vs. 8 patients (0.4%)), non-fatal myocardial infarction (17 patients (0.8%) vs. 26 patients (1.2%)), and non-cardiovascular mortality (11 patients (0.5%) vs. 12 patients (0.5%)). Overall mortality was numerically higher in the olmesartan group (26 patients (1.2%) vs. 15 patients (0.7%)), primarily due to higher cardiovascular mortality.
The ORIENT (Olmesartan Reducing Incidence of End-stage Renal Disease in Diabetic Nephropathy Trial) study evaluated the effect of olmesartan on renal and cardiovascular outcomes in 577 randomized patients in Japan and China with type 2 diabetes and overt nephropathy. During a mean follow-up period of 3.1 years, patients received either olmesartan or placebo in addition to other antihypertensive agents, including ACE inhibitors.
The primary composite endpoint (time to first occurrence of doubling of serum creatinine, end-stage renal disease, or all-cause mortality) was reached in 16 patients (41.1%) in the olmesartan group and in 129 patients (45.4%) in the placebo group (HR 0.97 (95% CI 0.75–1.24); p = 0.791). The secondary composite cardiovascular endpoint was reached in 40 patients receiving olmesartan (14.2%) and in 53 patients receiving placebo (18.7%). This composite cardiovascular endpoint included cardiovascular mortality in 10 (3.5%) patients receiving olmesartan and in 3 (1.1%) patients receiving placebo; overall mortality was 19 (6.7%) and 20 (7.0%), non-fatal stroke occurred in 8 (2.8%) and 11 (3.9%), and non-fatal myocardial infarction in 3 (1.1%) and 7 (2.5%), respectively.
Hydrochlorothiazide
Hydrochlorothiazide is a thiazide diuretic. The mechanism of antihypertensive action of thiazide diuretics is not fully understood. Thiazides affect electrolyte reabsorption in renal tubules, thereby enhancing excretion of sodium and chloride (approximately to a similar 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 link between renin levels and aldosterone secretion is mediated by angiotensin II, the potassium losses 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, reaches maximum effect around 4 hours, and persists for 6–12 hours.
Epidemiological studies indicate that long-term use of hydrochlorothiazide as monotherapy reduces the risk of cardiovascular complications and associated mortality.
Clinical Efficacy and Safety
Combined Therapy with Olmesartan Medoxomil and Hydrochlorothiazide
Combined therapy with olmesartan medoxomil and hydrochlorothiazide produces additive antihypertensive effects, generally exceeding those of either component alone. Based on pooled data from placebo-controlled trials, treatment with olmesartan medoxomil/hydrochlorothiazide at doses of 20/12.5 mg and 20/25 mg resulted in mean placebo-corrected reductions in systolic/diastolic blood pressure at the end of the dosing interval of -12/-7 mm Hg and -16/-9 mm Hg, respectively. Age and sex did not have a clinically significant impact on the efficacy of combined therapy with olmesartan medoxomil and hydrochlorothiazide.
When hydrochlorothiazide at doses of 12.5 mg and 25 mg was added to patients with inadequate response to olmesartan medoxomil monotherapy at 20 mg, additional reductions in mean 24-hour systolic/diastolic blood pressure measured by ambulatory blood pressure monitoring were observed (-7/-5 mm Hg and -12/-7 mm Hg compared to baseline values achieved with olmesartan medoxomil monotherapy). When blood pressure was measured by conventional methods, additional reductions in mean systolic/diastolic blood pressure at the end of the dosing interval were -11/-10 mm Hg and -16/-11 mm Hg (compared to baseline values).
Combined therapy with olmesartan medoxomil and hydrochlorothiazide remained effective over a prolonged treatment period (1 year). No rebound hypertension was observed upon discontinuation of olmesartan medoxomil (whether used in combination with hydrochlorothiazide or alone).
The effect of the combination of olmesartan medoxomil and hydrochlorothiazide on cardiovascular complications and associated mortality is currently unknown.
Hydrochlorothiazide
Non-melanoma Skin Cancer
Available epidemiological data indicate a cumulative dose-dependent association between hydrochlorothiazide use and the development of non-melanoma skin cancer. In a study involving 1,430,833 and 172,462 individuals, respectively, 71,533 cases of basal cell carcinoma and 8,629 cases of squamous cell carcinoma of the skin were recorded. High cumulative doses of hydrochlorothiazide (≥50,000 mg) were associated with an adjusted risk ratio of 1.29 (95% CI: 1.23–1.35) for basal cell carcinoma and 3.98 (95% CI: 3.68–4.31) for squamous cell carcinoma. A clear cumulative dose effect was observed for both basal cell and squamous cell carcinoma. Another study suggested a possible association between lip cancer (squamous cell carcinoma of the skin) and hydrochlorothiazide exposure: 633 cases of lip cancer were reported in a study involving 63,067 individuals using a risk-set sampling strategy. A cumulative dose effect was demonstrated with an adjusted risk ratio of 2.1 (95% CI: 1.7–2.6), increasing to 3.9 (3.0–4.9) with high-dose exposure (~25,000 mg) and to 7.7 (5.7–10.5) with the highest cumulative dose (~100,000 mg) (see section "Special Warnings and Precautions for Use").
Other Information
Concomitant use of ACE inhibitors and angiotensin II receptor blockers was evaluated in two large-scale, randomized, controlled trials (ONTARGET [Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial] and VA NEPHRON-D [The Veterans Affairs Nephropathy in Diabetes]).
ONTARGET was a trial involving patients with a history of cardiovascular or cerebrovascular disease or type 2 diabetes with evidence of target organ damage. VA NEPHRON-D was a trial involving patients with type 2 diabetes and diabetic nephropathy. These studies did not demonstrate a significant beneficial effect on renal and/or cardiovascular outcomes or mortality, while the risk of hyperkalemia, acute kidney injury, and/or hypotension was increased compared to monotherapy. Given the similarity in pharmacodynamic properties, these findings are also applicable to other ACE inhibitors and angiotensin II receptor blockers.
Concomitant use of ACE inhibitors and angiotensin II receptor blockers is contraindicated in patients with diabetic nephropathy.
ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a study designed to evaluate the potential 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. The study was terminated early due to an increased risk of adverse outcomes. Cardiovascular mortality and incidence of stroke were higher in the aliskiren group than in the placebo group; reports of adverse events, including serious events (hyperkalemia, hypotension, and renal dysfunction), were more frequent in the aliskiren group than in the placebo group.
Pharmacokinetics
Absorption and Distribution
Olmesartan Medoxomil
Olmesartan medoxomil is a prodrug. It is rapidly converted to 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 is detected unchanged in plasma or excreta. The mean absolute bioavailability of olmesartan in tablet form is 25.6%. The mean peak 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 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 is low (supported by the absence of clinically significant interaction between olmesartan medoxomil and warfarin). Binding to blood cells is minimal. The mean volume of distribution after intravenous administration is small (16–29 L).
Hydrochlorothiazide
When olmesartan medoxomil is administered in combination with hydrochlorothiazide, 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
The 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 single oral administration of radiolabeled 14C-olmesartan medoxomil, 10–16% of the radioactive label was recovered in urine (mostly within 24 hours after dosing); the remaining radioactivity was found 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 radioactive label detected in excreta was accounted for by olmesartan. No other significant metabolites have been identified. Olmesartan does not significantly undergo 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 administration ranges from 10 to 15 hours. Steady state is achieved after the first few doses; no further accumulation occurs 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 approximately 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 are not altered when administered in combination with hydrochlorothiazide.
Pharmacokinetics in Specific Patient Populations
Elderly Patients (aged 65 years and older)
In elderly hypertensive patients (65–75 years), the steady-state area under the plasma concentration-time curve (AUC) of olmesartan is approximately 35% higher than in younger patients, and approximately 44% higher in patients aged ≥75 years.
Available data suggest that systemic clearance of hydrochlorothiazide is lower in elderly individuals (both healthy and hypertensive) compared to healthy volunteers.
Renal Impairment
In patients with mild, moderate, and severe renal impairment, the steady-state AUC of olmesartan is approximately 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 single oral administration, the AUC of olmesartan in patients with mild and moderate hepatic impairment was approximately 6% and 65% higher, respectively, than in healthy control subjects with similar demographic characteristics. In healthy volunteers and patients with mild and moderate hepatic impairment, the unbound fraction of olmesartan 2 hours after dosing was 0.26%, 0.34%, and 0.41%, respectively. After repeated administration, the mean AUC of olmesartan in patients with moderate hepatic impairment was 65% higher than in healthy control subjects with similar demographic characteristics. 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.
Interaction with Other Medicinal Products
Bile Acid Sequestrant Colesevelam
Concomitant administration of 40 mg olmesartan medoxomil and 3750 mg colesevelam hydrochloride in healthy volunteers resulted in a 28% reduction in Cmax and a 39% reduction in AUC for olmesartan. A lesser effect, with reductions in Cmax and AUC of 4% and 15%, respectively, was observed when olmesartan medoxomil was administered 4 hours before colesevelam hydrochloride. The elimination half-life of olmesartan was reduced by 50–52%, regardless of whether the drugs were administered together or olmesartan was given 4 hours before colesevelam hydrochloride.
Non-clinical Safety Data
The toxic potential of the combination of olmesartan medoxomil and hydrochlorothiazide was evaluated in repeat-dose oral toxicity studies in rats and dogs (up to 6 months).
As with the individual components and other drugs of the same class, the toxic effects of this combination are primarily directed at the kidneys. Functional renal changes (increased blood urea nitrogen and serum creatinine) were observed during treatment with the combination. In rats and dogs receiving high-dose combinations, degeneration and regeneration of the kidneys were observed, possibly due to impaired renal hemodynamics (reduced renal blood flow due to arterial hypotension combined with hypoxia and tubular cell degeneration). Additionally, administration of the combination of olmesartan medoxomil and hydrochlorothiazide led to decreased erythrocyte parameters (red blood cell count, hemoglobin, and hematocrit) and reduced heart weight in rats. These findings have also been observed with other AT1 receptor blockers and ACE inhibitors. They are likely due to the pharmacological action of olmesartan medoxomil at high doses and are not expected at recommended therapeutic doses.
In genotoxicity studies of the combination of olmesartan medoxomil and hydrochlorothiazide, as well as of each component alone, no evidence of clinically significant genotoxicity was observed.
Carcinogenic potential of the combination of olmesartan medoxomil and hydrochlorothiazide has not been studied, as no signs of carcinogenicity have been observed with the individual components in clinical practice.
No teratogenic effects were observed in mice and rats treated with olmesartan medoxomil in combination with hydrochlorothiazide. As expected for drugs of this class, in rats treated with the combination of olmesartan medoxomil and hydrochlorothiazide during pregnancy, fetal toxicity was observed, manifested as a significant reduction in fetal body weight (see sections "Contraindications" and "Pregnancy and Breast-feeding").
Clinical characteristics.
Indications.
Essential hypertension.
The combination drug Olmestad N is intended for adult patients in whom treatment with olmesartan medoxomil alone does not provide adequate reduction of arterial pressure.
Contraindications.
- Hypersensitivity to the active substances, to any of the excipients of the medicinal product, 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 evident hyperuricemia.
- Severe hepatic impairment, cholestasis, and obstructive biliary disorders.
- Pregnancy or planned pregnancy.
Concomitant use of the medicinal product Olmestad N and medicinal products containing aliskiren is contraindicated in patients with diabetes mellitus or renal impairment (eGFR <60 mL/min/1.73 m²).
Interaction with other medicinal products and other forms of interaction.
Potentially possible interactions related to the use of both olmesartan medoxomil and hydrochlorothiazide
Concomitant use not recommended
Lithium preparations
Concomitant use of lithium with ACE inhibitors and sometimes with angiotensin II receptor blockers has been associated with reversible increases in serum lithium concentrations and lithium toxicity. Additionally, thiazides reduce renal clearance of lithium, thereby increasing the risk of lithium toxicity when used with hydrochlorothiazide. Therefore, the use of Olmestad N in combination with lithium is not recommended. In patients who require concomitant administration of these drugs, serum lithium concentrations should be closely monitored during treatment.
Concomitant use requiring caution
Baclofen
May enhance the hypotensive effect.
Nonsteroidal anti-inflammatory drugs (NSAIDs)
NSAIDs (e.g., acetylsalicylic acid (>3 g/day), COX-2 inhibitors, and nonselective NSAIDs) may attenuate the antihypertensive effects of thiazide diuretics and angiotensin II receptor blockers. In some patients with renal impairment (e.g., dehydrated patients or elderly patients with kidney disease), concomitant use of angiotensin II receptor blockers with drugs that inhibit cyclooxygenase may lead to worsening renal function, including acute renal failure, which is usually reversible. Therefore, these drugs should be used together cautiously, especially in elderly patients. Patients should maintain adequate fluid intake. Furthermore, renal function should be monitored closely after initiation of combined therapy and at regular intervals thereafter.
Concomitant use requiring special attention
Amifostine
May enhance the antihypertensive effect.
Other antihypertensive agents
The antihypertensive effect of Olmestad N may be enhanced when used concomitantly with other antihypertensive drugs.
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 concomitant use of ACE inhibitors and angiotensin II receptor blockers or aliskiren, leads to an increased incidence of adverse reactions such as hypotension, hyperkalemia, and renal dysfunction (including acute renal failure), compared to use of a single RAAS-acting drug.
Medicinal products affecting blood potassium concentration
Based on experience with other drugs that inhibit the renin-angiotensin system, serum potassium concentration may increase when potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, or other drugs capable of increasing serum potassium (e.g., heparin, ACE inhibitors) are used concomitantly. When prescribing Olmestad N together with drugs affecting potassium levels, serum potassium concentration should be monitored.
Cholestyramine and colestipol
Absorption of hydrochlorothiazide is delayed when used concomitantly with anion-exchange resins.
Cardiac glycosides
Hypokalemia and hypomagnesemia induced by thiazides increase the risk of arrhythmias when cardiac glycosides are used.
Medicinal products whose efficacy depends on changes in serum potassium concentration
When Olmestad N is used concomitantly with medicinal products whose efficacy depends on changes in serum potassium concentration (e.g., cardiac glycosides and antiarrhythmic agents), or with agents that may cause torsades de pointes (ventricular tachycardia), including certain antiarrhythmic drugs, regular monitoring of serum potassium concentration and ECG is recommended:
- Class Ia antiarrhythmic agents (e.g., quinidine, hydroquinidine, disopyramide);
- Class III antiarrhythmic agents (e.g., amiodarone, sotalol, dofetilide, ibutilide);
- Some antipsychotics (e.g., thioridazine, chlorpromazine, levomepromazine, trifluoperazine, zuclopenthixol, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol);
- Others (e.g., bepridil, cisapride, difemanil, 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 caused by functional renal impairment, which may occasionally occur with hydrochlorothiazide use.
Beta-blockers and diazoxide
The hyperglycemic effect of beta-blockers and diazoxide may be enhanced by thiazides.
Pressor amines (e.g., noradrenaline)
The effectiveness of pressor amines may be reduced.
Medicinal products used to treat gout (probenecid, sulfinpyrazone, and allopurinol)
Since hydrochlorothiazide may occasionally increase serum uric acid concentration, dose adjustment of uricosuric agents used to treat gout may be necessary. Additionally, the dose of probenecid or sulfinpyrazone may occasionally 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 potentiate their toxic effects on the central nervous system.
Metildopa
Published reports describe isolated cases of hemolytic anemia associated with the use of hydrochlorothiazide in combination with methyldopa.
Cyclosporine
Concomitant use of thiazides with cyclosporine may increase the risk of hyperuricemia and gout-like complications.
Tetracycline
Concomitant use of thiazides with tetracycline increases the risk of tetracycline-induced uremia. This effect likely does not apply to doxycycline.
Carbamazepine. Due to the risk of symptomatic hyponatremia, clinical and biological monitoring is required.
Iodine-containing contrast agents. Diuretics may lead to patient dehydration; therefore, adequate rehydration should be performed before administering high doses of iodine-containing contrast agents to reduce the risk of acute renal failure.
Special precautions for use.
Reduced circulating blood volume
In patients with reduced circulating blood volume and/or low sodium levels due to intensive diuretic therapy, low-salt diet, diarrhea, or vomiting, clinically significant arterial hypotension may occur, especially after the first dose of the drug. Before initiating treatment with Olmestad N, the aforementioned conditions should be corrected.
Other conditions associated with activation of the RAAS
Patients in whom vascular tone and renal function are highly dependent on the activity of the renin-angiotensin-aldosterone system (RAAS) (e.g., patients with severe congestive heart failure or renal pathology, including renal artery stenosis) may experience acute arterial hypotension, azotemia, oliguria, or, in rare cases, acute renal failure when treated with drugs affecting this system.
Renovascular hypertension
Administration of drugs affecting the RAAS to patients with bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney is associated with an increased risk of severe arterial hypotension and renal failure.
Renal impairment and kidney transplantation
Olmestad N is contraindicated in patients with severe renal impairment (creatinine clearance <30 mL/min) (see section "Contraindications"). 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. Azotemia due to thiazide diuretics may occur in patients with renal impairment. If progressive renal failure becomes evident, the treatment regimen should be carefully reviewed and diuretics may need to be discontinued. There is no clinical experience with the use of Olmestad N in patients who have recently undergone kidney transplantation.
Dual blockade of the RAAS
Concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren increases the risk of arterial hypotension, hyperkalemia, and decreased renal function (including acute renal failure). Therefore, dual blockade of the RAAS by combining ACE inhibitors, angiotensin II receptor blockers, or aliskiren is not recommended.
If dual blockade therapy is 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 not recommended in patients with diabetic nephropathy.
Hepatic impairment
There is no experience with the use of olmesartan medoxomil in patients with severe hepatic impairment. In addition, minor disturbances in water and electrolyte balance caused by thiazide therapy may precipitate hepatic coma in patients with hepatic impairment or progressive liver disease. Therefore, Olmestad N should be used with caution in patients with mild to moderate hepatic impairment. Olmestad N is contraindicated in patients with severe hepatic impairment, cholestasis, or biliary obstruction.
Aortic stenosis, mitral stenosis, and hypertrophic obstructive cardiomyopathy
As with other vasodilators, olmesartan medoxomil should be administered with caution in patients with aortic stenosis or mitral stenosis, as well as in patients with obstructive hypertrophic cardiomyopathy.
Primary hyperaldosteronism
Patients with primary hyperaldosteronism generally do not respond to antihypertensive agents that suppress the renin-angiotensin system. Therefore, Olmestad N is not recommended for such patients.
Metabolic and endocrine effects
Thiazide drugs may impair glucose tolerance. Insulin or oral antidiabetic agents may require dose adjustment in diabetic patients. Thiazide use may also unmask latent diabetes mellitus.
Thiazide diuretics may cause adverse effects such as increased cholesterol and triglyceride levels. In some cases, thiazide use may lead to hyperuricemia or gout. Hydrochlorothiazide may increase serum free bilirubin levels.
Electrolyte disturbances
As with any diuretic, serum electrolyte concentrations should be monitored periodically during hydrochlorothiazide therapy. Thiazide drugs, including hydrochlorothiazide, may cause disturbances in water and electrolyte balance (including hypokalemia, hyponatremia, and hypochloremic alkalosis). Signs of 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 hypokalemia is highest in patients with liver cirrhosis, sudden increase in diuresis, inadequate oral electrolyte intake, or concomitant use of corticosteroids and ACTH. On the other hand, olmesartan medoxomil, an angiotensin II receptor (AT1) blocker in Olmestad N, may cause hyperkalemia, particularly 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. Olmestad N 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 is no evidence that olmesartan medoxomil can prevent or reduce diuretic-induced hyponatremia. Chloride deficiency is usually mild and does not require specific treatment. Thiazides may reduce urinary calcium excretion and cause mild, transient increases in serum calcium levels in the absence of calcium metabolism disorders. Hypercalcemia may indicate occult hyperparathyroidism. Thiazides should be discontinued before parathyroid function testing. Thiazides increase urinary magnesium excretion, potentially leading to hypomagnesemia. In patients with edema during hot weather, dilutional hyponatremia may occur.
Lithium preparations
As with other drugs containing angiotensin II receptor blockers in combination with thiazides, Olmestad N is not recommended for concomitant use with lithium preparations.
Sprue-like enteropathy
Very rarely, severe chronic diarrhea with significant weight loss has been reported months or years after initiation of olmesartan therapy; the cause is likely a localized delayed hypersensitivity reaction. Intestinal mucosal biopsies in such patients often show villous atrophy. If these symptoms occur during olmesartan treatment and other possible causes are excluded, olmesartan therapy should be discontinued immediately and not restarted in the future. If diarrhea persists for more than one week after stopping the drug, the patient should consult a specialist (e.g., a gastroenterologist).
Choroidal effusion, acute myopia, and secondary angle-closure glaucoma
Hydrochlorothiazide is a sulfonamide and may cause idiosyncratic reactions leading to choroidal effusion with visual field defects, acute transient myopia, and acute angle-closure glaucoma. Symptoms include sudden onset of myopia or eye pain and typically occur from several hours to several 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 lower renin levels in black patients).
Antidoping test
Hydrochlorothiazide, a component of this drug, may produce false-positive results in antidoping tests.
Pregnancy
Olmestad N is contraindicated in pregnant women or women planning pregnancy. If pregnancy is confirmed during treatment with Olmestad N, treatment should be discontinued immediately and, if necessary, replaced with another antihypertensive agent approved for use during pregnancy.
Other precautions
Excessive reduction in blood pressure in patients with generalized atherosclerosis, ischemic heart disease, or ischemic cerebrovascular disease 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.
Photosensitization reactions may occur during treatment with thiazide diuretics. In such cases, discontinuation of the drug is recommended. If the physician considers it necessary to reinitiate treatment, the patient should be advised to protect skin areas exposed to sunlight or artificial ultraviolet radiation.
Non-melanoma skin cancer
An increased risk of non-melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma) associated with higher cumulative doses of hydrochlorothiazide was observed in two epidemiological studies based on data from the Danish National Cancer Registry. Photosensitizing effects of hydrochlorothiazide may be a mechanism underlying non-melanoma skin cancer development.
Patients taking hydrochlorothiazide should be informed about the potential risk of non-melanoma skin cancer. Regular skin examinations for new lesions are recommended, and any suspicious skin changes should be reported immediately.
Patients should be advised about preventive measures such as limiting exposure to sunlight and UV radiation and using adequate skin protection when exposure is unavoidable to minimize skin cancer risk.
Any suspicious skin reactions should be promptly evaluated, including histological examination of biopsy specimens.
In patients with a history of non-melanoma skin cancer, reconsideration of hydrochlorothiazide use may be appropriate (see section "Adverse reactions").
The drug contains lactose and therefore should not be administered to patients with congenital galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.
Use during pregnancy or breastfeeding.
Pregnancy
Olmesartan medoxomil
Angiotensin II receptor blockers are contraindicated in pregnant women or women planning pregnancy.
Epidemiological data on teratogenic risk associated with angiotensin II receptor blockers during the first trimester of pregnancy are inconclusive, although a slight increase in risk cannot be ruled out. Controlled epidemiological studies have not provided data on teratogenic risk, but an increased risk of similar effects cannot be excluded. Except in life-threatening situations, patients planning pregnancy should be switched to antihypertensive agents with established safety during pregnancy. If pregnancy is diagnosed, angiotensin II receptor blockers should be discontinued immediately and alternative therapy initiated if necessary.
Use of angiotensin II receptor blockers during the second and third trimesters of pregnancy may lead to fetotoxic effects (impaired renal function, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, arterial hypotension, hyperkalemia).
If angiotensin II receptor blockers were used during the second trimester of pregnancy, ultrasound monitoring of fetal renal function and skull development is recommended.
Newborns whose mothers received angiotensin II receptor blockers should be closely monitored for arterial hypotension.
Hydrochlorothiazide
Clinical experience with hydrochlorothiazide use during pregnancy, particularly in the first trimester, is limited. Animal studies are insufficient. Hydrochlorothiazide crosses the placenta. Due to its mechanism of action, hydrochlorothiazide use during the second and third trimesters of pregnancy may impair fetoplacental circulation and adversely affect the fetus and newborn, causing jaundice, electrolyte imbalances, and thrombocytopenia.
Hydrochlorothiazide is not indicated for the treatment of edema in pregnancy, gestational hypertension, or preeclampsia, as it may reduce plasma volume and cause placental hypoperfusion without providing therapeutic benefit.
Hydrochlorothiazide is also not recommended for treating essential hypertension in pregnancy, except in rare cases when no other agents can be used.
Combined olmesartan medoxomil/hydrochlorothiazide is contraindicated in pregnant women or women planning pregnancy.
Breastfeeding period
Olmesartan medoxomil
There is no information available on the use of Olmestad N during breastfeeding; therefore, the drug should not be administered to breastfeeding women. Alternative antihypertensive agents with established safety during breastfeeding, especially when nursing newborns or preterm infants, may be used.
Hydrochlorothiazide
Hydrochlorothiazide passes into breast milk in small amounts. High doses of thiazides causing intense diuresis may suppress lactation. If its use is essential, breastfeeding should be discontinued.
Olmestad N is not recommended during breastfeeding. If Olmestad N must be used during breastfeeding, the dose should be kept as low as possible.
Ability to affect reaction speed when driving or operating machinery.
Olmestad N may have a minor or moderate effect on the ability to drive or operate machinery. Dizziness and increased fatigue may occasionally occur in patients receiving antihypertensive therapy, which may impair reaction time.
Method of Administration and Dosage
Adults
Olmesartad H is not a first-line agent. It is indicated for patients in whom treatment with olmesartan medoxomil alone at a dose of 20 mg does not achieve the required blood pressure control.
Olmesartad H tablets should be taken once daily, independently of food intake.
In the presence of clinical indications, 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.
Dose titration of each component is recommended.
Olmesartan medoxomil/hydrochlorothiazide in a dose of 20/12.5 mg or 40/12.5 mg may be prescribed to patients in whom treatment with olmesartan medoxomil alone at a dose of 20 mg or 40 mg does not achieve the required blood pressure control.
Olmesartan medoxomil/hydrochlorothiazide in a dose of 20/25 mg or 40/25 mg may be prescribed to patients in whom treatment with olmesartan medoxomil/hydrochlorothiazide 20/12.5 mg or 40/12.5 mg does not achieve the required blood pressure control.
Elderly Patients
The combination drug is recommended for elderly patients at the same dosage as for adult patients.
Renal Impairment
When Olmesartad H is administered to patients with mild to moderate renal impairment (creatinine clearance 30–60 mL/min), periodic monitoring of renal function is recommended. Olmesartad H is contraindicated in patients with severe renal impairment (creatinine clearance <30 mL/min) (see sections "Pharmacological Properties", "Contraindications", and "Special Warnings and Precautions for Use").
Hepatic Impairment
Olmesartad H 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, and the maximum dose should not exceed 20 mg once daily. In patients with hepatic impairment who are already receiving diuretics and/or other antihypertensive agents, careful monitoring of blood pressure and renal function is recommended. Experience with olmesartan medoxomil in patients with severe hepatic impairment is lacking. Olmesartad H is contraindicated in patients with severe hepatic impairment, as well as in those with cholestasis or biliary obstruction (see sections "Pharmacological Properties" and "Contraindications").
Method of Administration
Tablets should be swallowed whole with sufficient liquid (e.g., a glass of water). Tablets should not be chewed. The drug should be taken daily at the same time.
Children
The safety and efficacy of Olmesartad H in pediatric patients (under 18 years of age) have not been established. Data are lacking.
Overdose
There is no specific information available regarding symptoms or treatment of overdose with Olmesartad H.
Close observation of the patient and symptomatic supportive therapy are required. Treatment is symptomatic and depends on the time elapsed since drug ingestion and the severity of symptoms. Emetics and/or gastric lavage may be recommended. Activated charcoal may sometimes be recommended in the management of overdose. 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.
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 cramps and/or exacerbate arrhythmias induced by concomitant medications (cardiac glycosides or certain antiarrhythmic agents).
It is unknown whether olmesartan or hydrochlorothiazide is removed by hemodialysis.
Adverse reactions
The most commonly observed adverse reactions during treatment with the medicinal product are headache (2.9%), dizziness (1.9%), and increased fatigue (1.0%).
Hydrochlorothiazide may cause or exacerbate hypovolemia, which can lead to disturbances in electrolyte balance.
In clinical studies involving 1155 patients receiving olmesartan medoxomil/hydrochlorothiazide at doses of 20/12.5 mg or 20/25 mg, and 466 patients receiving placebo (treatment duration up to 21 months), the overall incidence of adverse reactions with combination therapy of olmesartan medoxomil/hydrochlorothiazide was approximately similar to that observed with placebo. The incidence of treatment discontinuation due to adverse reactions was also similar in the olmesartan medoxomil/hydrochlorothiazide 20/12.5 mg – 20/25 mg group (2%) and the placebo group (3%). Overall, the incidence of adverse reactions with combination therapy of olmesartan medoxomil/hydrochlorothiazide (compared to placebo) did not depend on patient age (patients under 65 years compared to those aged 65 years and older), sex, or race, although dizziness occurred somewhat more frequently in patients aged 75 years and older.
Furthermore, the safety of high-dose treatment was evaluated in clinical studies involving 3709 patients receiving olmesartan medoxomil in combination with hydrochlorothiazide at doses of 40 mg/12.5 mg and 40 mg/25 mg. Adverse reactions observed during clinical studies, post-marketing surveillance, or reported spontaneously, as well as adverse reactions reported with the individual components of the medicinal product—olmesartan medoxomil and hydrochlorothiazide—are listed in the table below.
The following terminology was used to classify the frequency of adverse reactions: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10000, <1/1000), very rare (<1/10000), and not known (cannot be estimated based on available data).
| Organs and systems according to MedDRA |
Adverse reactions |
Frequency |
||
| Olmesartan H |
Olmesartan |
Hydrochloro-thiazide |
||
| Infections and parasitic diseases |
Sialadenitis |
Uncommon |
||
| Benign and malignant neoplasms, including cysts and polyps |
Non-melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma) |
Frequency unknown |
||
| Blood and lymphatic system disorders |
Aplastic anemia |
Uncommon |
||
| Bone marrow depression |
Uncommon |
|||
| Hemolytic anemia |
Uncommon |
|||
| Leukopenia |
Uncommon |
|||
| Neutropenia/agranulocytosis |
Uncommon |
|||
| Thrombocytopenia |
Uncommon |
Uncommon |
||
| Immune system disorders |
Anaphylactic reactions |
Uncommon |
Uncommon |
|
| Metabolism and nutrition disorders |
Anorexia |
Uncommon |
||
| Glucosuria |
Common |
|||
| Hypercalcemia |
Common |
|||
| Hypercholesterolemia |
Uncommon |
Very common |
||
| Hyperglycemia |
Common |
|||
| Hyperkalemia |
Uncommon |
|||
| Hypertriglyceridemia |
Uncommon |
Common |
Very common |
|
| Hyperuricemia |
Uncommon |
Common |
Very common |
|
| Hypochloremia |
Common |
|||
| Hypochloremic alkalosis |
Very rare |
|||
| Hypokalemia |
Common |
|||
| Hypomagnesemia |
Common |
|||
| Hypnatremia |
Common |
|||
| Hyperamylasemia |
Common |
|||
| Psychiatric disorders |
Apathy |
Uncommon |
||
| Depression |
Uncommon |
|||
| Anxiety |
Uncommon |
|||
| Sleep disorders |
Uncommon |
|||
| Nervous system disorders |
Confusion |
Common |
||
| Convulsions |
Uncommon |
|||
| Disturbance of consciousness, e.g. loss of consciousness |
Uncommon |
|||
| Dizziness sensation/dizziness |
Common |
Common |
Common |
|
| Headache |
Common |
Common |
Uncommon |
|
| Loss of appetite |
Uncommon |
|||
| Paresthesia |
Uncommon |
|||
| Postural dizziness |
Uncommon |
|||
| Somnolence |
Uncommon |
|||
| Syncope |
Uncommon |
|||
| Eye disorders |
Decreased lacrimation |
Uncommon |
||
| Transient visual blurring |
Uncommon |
|||
| Worsening of existing myopia |
Uncommon |
|||
| Acute myopia, acute angle-closure glaucoma, choroidal effusion |
Frequency unknown |
|||
| Xanthopsia |
Uncommon |
|||
| Ear and labyrinth disorders |
Vertigo |
Uncommon |
Uncommon |
Uncommon |
| Cardiac disorders |
Angina pectoris |
Uncommon |
||
| Cardiac rhythm disorders |
Uncommon |
|||
| Palpitations |
Uncommon |
|||
| Vascular disorders |
Embolism |
Uncommon |
||
| Arterial hypotension |
Uncommon |
Uncommon |
||
| Necrotizing angiitis (vasculitis) |
Uncommon |
|||
| Orthostatic hypotension |
Uncommon |
Uncommon |
||
| Thrombosis |
Uncommon |
|||
| Respiratory, thoracic and mediastinal disorders |
Bronchitis |
Common |
||
| Cough |
Uncommon |
Common |
||
| Dyspnea |
Uncommon |
|||
| Interstitial pneumonia |
Uncommon |
|||
| Pharyngitis |
Common |
|||
| Pulmonary edema |
Uncommon |
|||
| Respiratory failure |
Uncommon |
|||
| Rhinitis |
Common |
|||
| Gastrointestinal disorders |
Abdominal pain |
Uncommon |
Common |
Common |
| Constipation |
Common |
|||
| Diarrhea |
Uncommon |
Common |
Common |
|
| Gastric mucosa irritation |
Common |
|||
| Dyspepsia |
Uncommon |
Common |
||
| Gastroenteritis |
Common |
|||
| Flatulence |
Common |
|||
| Nausea |
Uncommon |
Common |
Common |
|
| Pancreatitis |
Uncommon |
|||
| Paralytic ileus |
Very rare |
|||
| Vomiting |
Uncommon |
Uncommon |
Common |
|
| Sprue-like enteropathy |
Very rare |
|||
| Hepatobiliary disorders |
Acute cholecystitis |
Uncommon |
||
| Jaundice (due to intrahepatic cholestasis) |
Uncommon |
|||
| Autoimmune hepatitis* |
Frequency unknown |
|||
| Skin and subcutaneous tissue disorders |
Allergic dermatitis |
Uncommon |
||
| Anaphylactic skin manifestations |
Uncommon |
|||
| Angioedema |
Uncommon |
Uncommon |
||
| Reactions resembling cutaneous manifestations of systemic lupus erythematosus |
Uncommon |
|||
| Exema |
Uncommon |
|||
| Erythema |
Uncommon |
|||
| Exanthema |
Uncommon |
|||
| Photosensitivity reactions |
Uncommon |
|||
| Pruritus |
Uncommon |
Uncommon |
||
| Hemorrhagic rash (purpura) |
Uncommon |
|||
| Rash |
Uncommon |
Uncommon |
Uncommon |
|
| Exacerbation of cutaneous form of systemic lupus erythematosus |
Uncommon |
|||
| Toxic epidermal necrolysis |
Uncommon |
|||
| Urticaria |
Uncommon |
Uncommon |
Uncommon |
|
| Musculoskeletal and connective tissue disorders |
Arthralgia |
Uncommon |
||
| Arthritis |
Common |
|||
| Back pain |
Uncommon |
Common |
||
| Muscle cramps |
Uncommon |
Uncommon |
||
| Muscle weakness |
Uncommon |
|||
| Myalgia |
Uncommon |
Uncommon |
||
| Limb pain |
Uncommon |
|||
| Paralysis |
Uncommon |
|||
| Bone pain |
Common |
|||
| Renal and urinary disorders |
Acute renal failure |
Uncommon |
Uncommon |
|
| Hematuria |
Uncommon |
Common |
||
| Interstitial nephritis |
Uncommon |
|||
| Renal failure |
Uncommon |
|||
| Renal dysfunction |
Uncommon |
|||
| Urinary tract infections |
Common |
|||
| Reproductive system and breast disorders |
Erectile dysfunction |
Uncommon |
Uncommon |
|
| General disorders and administration site conditions |
Weakness |
Common |
Uncommon |
|
| Chest pain |
Common |
Common |
||
| Facial swelling |
Uncommon |
|||
| Fatigue |
Common |
Common |
||
| Hot flush |
Uncommon |
|||
| Influenza-like symptoms |
Common |
|||
| Somnolence |
Uncommon |
|||
| Malaise |
Uncommon |
Uncommon |
||
| Pain |
Common |
|||
| Peripheral edema |
Common |
Common |
||
| Weakness |
Uncommon |
|||
| Investigations |
Increased alanine aminotransferase activity |
Uncommon |
||
| Increased aspartate aminotransferase activity |
Uncommon |
|||
| Increased blood creatine phosphokinase activity |
Common |
|||
| Hypercalcemia |
Uncommon |
|||
| Hypercreatininemia |
Uncommon |
Uncommon |
Common |
|
| Hyperglycemia |
Uncommon |
|||
| Decreased blood hematocrit level |
Uncommon |
|||
| Hypohemoglobinemia |
Uncommon |
|||
| Hyperlipidemia |
Uncommon |
|||
| Hypokalemia |
Uncommon |
|||
| Hyperkalemia |
Uncommon |
|||
| Increased blood urea level |
Uncommon |
Common |
Common |
|
| Increased blood urea nitrogen level |
Uncommon |
|||
| Hyperuricemia |
Uncommon |
|||
| Increased gamma-glutamyltransferase level |
Uncommon |
|||
| Increased liver enzyme levels |
Common |
* Post-marketing reports have described cases of autoimmune hepatitis with a latent period ranging from several months to years, which were reversible upon discontinuation of olmesartan.
Several cases of rhabdomyolysis temporally associated with the use of angiotensin II receptor blockers have been reported.
The following adverse reactions, which may occur during administration of hydrochlorothiazide, have been reported: dry mouth, thirst, anaphylactic shock, coma, Stevens-Johnson syndrome, disorientation, mood changes, pneumonitis. The use of thiazide diuretics may lead to reduced glucose tolerance, which in turn may result in the manifestation of latent diabetes mellitus. Hypochloremic alkalosis may occur during treatment with hydrochlorothiazide, potentially triggering gout attacks in patients with asymptomatic gout.
Cases of choroidal effusion with visual field defects following the use of thiazide and thiazide-like diuretics have been reported.
Reporting suspected adverse reactions
Reporting suspected adverse reactions after marketing authorization is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, as well as patients or their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System 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 per cardboard box.
Prescription status: Prescription only.
Manufacturer:
STADA Arzneimittel AG, Germany (batch release).
"HEMOFARM" AD, Serbia (batch release).
Manufacturer's address and location of operations:
Stadastrasse 2-18, 61118 Bad Vilbel, Germany.
Beogradski put bb, 26300 Vrsac, Serbia.