Cardosal® plus 20/12.5
UkraineTable of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KARDOSAL® PLUS 20/12.5 / KARDOSAL® PLUS 20/25 (CARDOSAL® PLUS 20/12.5 / CARDOSAL® PLUS 20/25)
Composition:
Active substances: olmesartan medoxomil; hydrochlorothiazide;
One film-coated tablet contains olmesartan medoxomil 20 mg and hydrochlorothiazide 12.5 mg, or olmesartan medoxomil 20 mg and hydrochlorothiazide 25 mg;
Excipients: microcrystalline cellulose, low-substituted hydroxypropylcellulose, lactose monohydrate, hydroxypropylcellulose, magnesium stearate; coating Opadry O2A22352 or O2A24576 (hypromellose, talc, titanium dioxide (E 171), yellow iron oxide (E 172), red iron oxide (E 172)).
Pharmaceutical form. Film-coated tablets.
Main physico-chemical properties.
Kardosal® Plus 20/12.5: round film-coated tablets, reddish-yellow in color, with "C 22" embossed on one side.
Kardosal® Plus 20/25: round film-coated tablets, light pink in color, with "C 24" embossed on one side.
Pharmacotherapeutic group. Angiotensin II antagonists and diuretics. ATC code C09DA08.
Pharmacological properties.
Pharmacodynamics.
Cardosall® plus is a combination preparation 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 when each component is used alone.
Administration of Cardosall® plus once daily provides effective and smooth reduction of arterial blood pressure over 24 hours until the next dose.
Olmesartan medoxomil.
Olmesartan medoxomil is a selective angiotensin II receptor (type AT1) blocker intended for oral administration. Angiotensin II is the primary vasoactive hormone of the renin-angiotensin-aldosterone system 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 in plasma, as well as a slight reduction in plasma aldosterone concentration.
In patients with arterial hypertension, olmesartan medoxomil provides sustained reduction in arterial blood pressure, the degree of which is dose-dependent. No signs of arterial hypotension after the first dose (the "first-dose effect"), tachyphylaxis during prolonged use, or rebound hypertension after abrupt discontinuation of the drug have been observed.
Once-daily administration of olmesartan medoxomil provides effective and smooth reduction of arterial blood pressure 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 continuous treatment, maximum reduction in arterial blood pressure is achieved within 8 weeks after initiation of therapy; however, a significant antihypertensive effect is observed as early as 2 weeks after starting treatment.
The effect of olmesartan medoxomil on mortality and the frequency of complications has not been established.
The Randomized Olmesartan and the 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 olmesartan or placebo in addition to other antihypertensive agents, except ACE inhibitors or ARBs.
The primary endpoint, time to onset of microalbuminuria, increased by 23% with olmesartan (hazard ratio for onset of microalbuminuria 0.77; 95.1% confidence interval [CI], 0.63–0.94; p = 0.01). After adjusting for minor baseline differences in body mass index, blood pressure, and high-density lipoprotein cholesterol levels, the hazard ratio for the primary endpoint was 0.75 (95.1% CI, 0.62–0.92; p = 0.006). Similar results were obtained in a pre-specified per-protocol analysis and a post hoc analysis excluding patients who prematurely discontinued study treatment. The reduction in the primary endpoint with olmesartan remained significant after adjustment for blood pressure differences.
In the secondary endpoint, cardiovascular events occurred in 96 patients (4.3%) receiving olmesartan and in 94 patients (4.2%) receiving placebo. The incidence 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.
In the ORIENT trial (The Olmesartan Reducing Incidence of End-stage Renal Disease in Diabetic Nephropathy Trial), the effects of olmesartan on renal and cardiovascular outcomes were studied 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 olmesartan or placebo in addition to other antihypertensive agents, including ACE inhibitors.
The primary composite endpoint (time to first occurrence of doubling of serum creatinine, end-stage renal disease, or death from any cause) was reached in 116 patients in the olmesartan group (41.1%) and in 129 patients receiving placebo (45.4%) (HR 0.97 (95% CI 0.75–1.24); p = 0.791). The secondary composite cardiovascular endpoint was reached in 40 patients receiving olmesartan (14.2%) and in 53 patients receiving placebo (18.7%). This composite cardiovascular endpoint included cardiovascular mortality in 10 (3.5%) patients receiving olmesartan and in 3 (1.1%) patients receiving placebo; overall mortality was 19 (6.7%) and 20 (7.0%), non-fatal stroke 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-type 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 at similar levels). Acting as a diuretic, hydrochlorothiazide reduces plasma volume, thereby increasing plasma renin activity and aldosterone secretion, increasing urinary excretion of potassium and bicarbonate, and decreasing their serum concentrations. Since the relationship between renin levels and aldosterone secretion is mediated by angiotensin II, the urinary 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, maximum effect is achieved approximately 4 hours later, and the effect lasts for 6–12 hours.
According to epidemiological data, long-term use of hydrochlorothiazide as monotherapy reduces the risk of cardiovascular complications and death from them.
Clinical efficacy and safety
Combined therapy with olmesartan medoxomil and hydrochlorothiazide.
Combined therapy with olmesartan medoxomil and hydrochlorothiazide results in additive enhancement of antihypertensive effect, which generally exceeds the effects of each component alone. According to 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 reductions in systolic/diastolic blood pressure at the end of the dosing interval (placebo-corrected) of up to 12/7 mm Hg and 16/9 mm Hg, respectively. Age and sex did not show clinically significant effects on the efficacy of combined therapy with olmesartan medoxomil and hydrochlorothiazide.
When hydrochlorothiazide at doses of 12.5 mg and 25 mg was administered to patients with insufficient response to monotherapy with olmesartan medoxomil 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 up to 11/10 mm Hg and 16/11 mm Hg (compared to baseline values).
Combined therapy with olmesartan medoxomil and hydrochlorothiazide remained effective during long-term treatment (1 year). No rebound hypertension was observed after discontinuation of olmesartan medoxomil (used either in combination with hydrochlorothiazide or alone).
The effect of the combined preparation of olmesartan medoxomil and hydrochlorothiazide on cardiovascular complications and mortality due to them is currently unknown.
Other information.
Concomitant use of ACE inhibitors and angiotensin II receptor blockers was investigated 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 conducted in 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 conducted in patients with type 2 diabetes and diabetic nephropathy. The trials 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 of pharmacodynamic properties, these results 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 trial conducted to evaluate the positive effect of adding aliskiren to standard therapy with ACE inhibitors or angiotensin II receptor blockers in patients with type 2 diabetes and chronic kidney disease, cardiovascular disease, or both. The trial 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, and reports of adverse events and serious adverse events (hyperkalemia, hypotension, and renal dysfunction) were more frequent in the aliskiren group than in the placebo group.
Non-melanoma skin cancer (NMSC). Available epidemiological data have shown an association between cumulative dose of hydrochlorothiazide and the development of NMSC. One study included a population of 71,533 patients with basal cell carcinoma (BCC) and 8,629 patients with squamous cell carcinoma (SCC), compared with 1,430,833 and 172,462 control group participants, respectively. High-dose hydrochlorothiazide use (cumulative ≥ 50,000 mg) was associated with an adjusted odds ratio (OR) of 1.29 (95% confidence interval [CI]: 1.23–1.35) for BCC and 3.98 (95% CI: 3.68–4.31) for SCC. A clear dose-response relationship was observed for both BCC and SCC. Another study suggested a possible link between lip cancer (SCC) and hydrochlorothiazide: 633 patients with lip cancer were compared with 63,067 participants in the control group using a risk-stratified sampling strategy. A dose-response relationship was demonstrated: adjusted OR was 2.1 (95% CI: 1.7–2.6), increasing to OR 3.9 (3.0–4.9) with high-dose use (~25,000 mg) and OR 7.7 (5.7–10.5) with the highest cumulative dose (~100,000 mg) (see also section "Special precautions for use").
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 are detected unchanged in plasma or excreta. 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. After single oral doses up to 80 mg, olmesartan plasma concentrations increase approximately proportionally with dose. Food has minimal effect on olmesartan bioavailability; 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 (evidenced by the absence of clinically significant interaction between olmesartan medoxomil and warfarin). Olmesartan binds minimally to blood cells. The mean volume of distribution after intravenous administration is small (16–29 L).
Hydrochlorothiazide.
After oral administration of olmesartan medoxomil in combination with hydrochlorothiazide, the median time to reach Cmax of hydrochlorothiazide in plasma was 1.5–2 hours. Hydrochlorothiazide is bound to plasma proteins by 68%, 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 single oral administration of radiolabeled (14C) olmesartan medoxomil, 10–16% of the radioactivity was recovered in urine (mostly within 24 hours after administration); the remaining radioactivity was found in feces. Considering that systemic bioavailability of the drug is 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 excreta was accounted for by olmesartan. No other significant metabolites were 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 multiple oral doses ranges from 10 to 15 hours. Steady state is achieved after the first few doses; no further accumulation was observed after 14 days of multiple dosing. Renal clearance is approximately 0.5–0.7 L/hour and is independent of dose.
Hydrochlorothiazide.
Hydrochlorothiazide is not metabolized in humans and is almost entirely excreted 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. 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%, but 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 elderly patients (65–75 years) with arterial hypertension, the steady-state area under the pharmacokinetic curve (AUC) of olmesartan was approximately 35% higher than in younger patients, and in patients aged ≥ 75 years, it was approximately 44% higher.
Available data suggest that systemic clearance of hydrochlorothiazide is lower in elderly individuals (both healthy and those with arterial hypertension) than in healthy volunteers.
Renal impairment.
In patients with mild, moderate, and severe renal impairment, the steady-state AUC of olmesartan was 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 6% and 65% higher, respectively, than in healthy control volunteers with similar demographic characteristics. In healthy volunteers and patients with mild and moderate hepatic impairment, the unbound fraction of olmesartan 2 hours after administration was up to 0.26%, 0.34%, and 0.41%, respectively. After multiple dosing, the mean AUC of olmesartan in patients with moderate hepatic impairment was 65% higher than in healthy control volunteers 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-binding medicinal product 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 administered 4 hours before colesevelam hydrochloride.
Preclinical safety data
The toxic effect 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 administration of the drugs separately or in combination with other drugs of the same class, the toxic effects of this combination are primarily directed at the kidneys. Functional kidney changes (increased blood urea nitrogen and serum creatinine) were observed with the combination of olmesartan medoxomil and hydrochlorothiazide. 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 resulted in decreased erythrocyte parameters (erythrocyte 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 observed when the drug is used at recommended therapeutic doses.
In genotoxicity studies of the combination of olmesartan medoxomil and hydrochlorothiazide, as well as of each component separately, no signs of clinically significant genotoxicity were observed.
The carcinogenic potential of the combination of olmesartan medoxomil and hydrochlorothiazide has not been studied.
In mice and rats administered olmesartan medoxomil in combination with hydrochlorothiazide, no signs of teratogenic effects were observed. As expected for drugs of this class, in rats administered the combination of olmesartan medoxomil and hydrochlorothiazide during pregnancy, toxic effects on the fetus were observed, manifested as a significant reduction in fetal body weight (see sections "Contraindications" and "Use during pregnancy or breastfeeding").
Clinical characteristics.
Indications.
Treatment of essential hypertension.
The combination drug Cardosal® plus is intended for adult patients in whom treatment with olmesartan medoxomil alone does not provide adequate reduction of arterial pressure.
Contraindications.
Allergic reaction (hypersensitivity) 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 evident hyperuricemia.
Severe hepatic impairment, cholestasis, and obstructive biliary disorders. Pregnancy or planned pregnancy.
Concomitant use of Cardosal® plus 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 are associated with the use of both olmesartan medoxomil and hydrochlorothiazide.
Concomitant use not recommended
Lithium preparations.
When lithium preparations are used concomitantly with angiotensin-converting enzyme inhibitors and sometimes with angiotensin II receptor blockers, reversible increases in serum lithium concentration and its toxic effects have been observed. In addition, renal clearance of lithium is reduced in the presence of thiazides, thus the risk of lithium toxicity may increase during treatment with hydrochlorothiazide. Therefore, use of Cardosal**®** plus in combination with lithium is not recommended. In patients who require concomitant administration of these drugs, serum lithium concentration 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 effect of thiazide diuretics and angiotensin II receptor blockers. In some patients with renal impairment (e.g., dehydrated patients or elderly patients with kidney disease), the use of angiotensin II receptor blockers together with drugs that inhibit cyclooxygenase may exacerbate renal dysfunction, including acute renal failure, which is usually reversible. Therefore, these drugs should be prescribed together with caution, especially in elderly patients. Patients should maintain adequate fluid intake. Furthermore, renal function should be monitored closely after initiation of combination therapy and at regular intervals thereafter.
Concomitant use requiring special attention
Amifostine.
May enhance the antihypertensive effect.
Other antihypertensive agents.
The antihypertensive effect of Cardosal**®** plus may be enhanced when used concomitantly with other drugs that lower blood pressure.
Ethanol, barbiturates, narcotic analgesics, and antidepressants.
May enhance symptoms 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 frequency of adverse events such as hypotension, hyperkalemia, and impaired renal function (including acute renal failure), compared to use of a single agent acting on the RAAS.
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, and other drugs capable of increasing blood potassium levels (such as heparin, ACE inhibitors) are used concomitantly. When prescribing Cardosal**®** plus together with drugs affecting potassium levels, monitoring of serum potassium concentration is recommended.
Medicinal product colesevelam, a bile acid sequestrant.
Concomitant use of the bile acid sequestrant colesevelam hydrochloride reduces systemic exposure and peak plasma concentration of olmesartan, as well as shortens its half-life. Administration of olmesartan medoxomil at least 4 hours before colesevelam hydrochloride reduces the effect of this drug interaction. Consideration should be given to administering olmesartan medoxomil at least 4 hours before colesevelam hydrochloride.
Additional information.
A moderate reduction in the bioavailability of olmesartan medoxomil has been observed after treatment with antacids (magnesium-aluminum hydroxide). Olmesartan medoxomil does not exert a significant effect on the pharmacokinetics and pharmacodynamics of warfarin or the pharmacokinetics of digoxin. In healthy volunteers receiving olmesartan medoxomil concomitantly with pravastatin, no clinically significant changes in the pharmacokinetics of these drugs were observed. In in vitro studies, clinically significant inhibition of human cytochrome P450 isoenzymes IA1/2, IIA6, IIC8/9, IIC19, IID6, IIE1, and IIIA4 by olmesartan was not observed; in animals, 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 with hydrochlorothiazide.
Concomitant use not recommended
Medicinal products affecting blood potassium concentration.
The hypokalemic effect of hydrochlorothiazide may be enhanced when used concomitantly with other medicinal products causing 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 drugs is not recommended.
Concomitant use requiring caution
Calcium salts.
Thiazide diuretics may increase serum calcium concentration due to reduced calcium excretion. If calcium supplements are necessary, serum calcium levels should be monitored and the calcium dose adjusted accordingly.
Cholestyramine and colestipol.
The absorption of hydrochlorothiazide is delayed during treatment with anion-exchange resins.
Cardiac glycosides.
Use of cardiac glycosides increases the risk of arrhythmias due to thiazide-induced hypokalemia and hypomagnesemia.
Medicinal products whose efficacy depends on changes in serum potassium concentration. When Cardosal**®** plus is used concomitantly with medicinal products whose efficacy depends on changes in serum potassium concentration (e.g., cardiac glycosides and antiarrhythmic agents), as well as with agents that may cause torsades de pointes (ventricular tachycardia), including some 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, sulpirid, 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 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 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 high doses of salicylates are taken, hydrochlorothiazide may enhance their toxic effects on the central nervous system.
Methyldopa.
Published reports describe 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 gout-like complications.
Tetracycline.
Concomitant use of thiazides with tetracycline increases the risk of tetracycline-induced uremia. This effect probably does not apply to doxycycline.
Special precautions for use.
Reduction in 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 starting treatment with Cardosal® plus, the above conditions should be corrected.
Other conditions associated with activation of the renin-angiotensin-aldosterone system (RAAS).
Patients in whom vascular tone and renal function significantly depend on the activity of the renin-angiotensin-aldosterone system (e.g., in severe congestive heart failure or renal disease, 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.
The use of drugs affecting the renin-angiotensin-aldosterone system in patients with bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney is associated with an increased risk of severe arterial hypotension and renal failure.
Renal impairment and kidney transplantation.
Cardosal® plus 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 or moderate renal impairment (creatinine clearance ≥ 30 mL/min but < 60 mL/min). However, Cardosal® plus 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, careful reevaluation of the treatment regimen and possible discontinuation of diuretics is necessary. There is no clinical experience with the use of Cardosal® plus in patients who have recently undergone kidney transplantation.
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, hyperkalemia, and reduced renal function (including acute renal failure). Therefore, dual RAAS blockade with concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren is not recommended (see sections "Interaction with other medicinal products and other forms of interaction", "Pharmacodynamics").
If dual blockade therapy is absolutely necessary, it should be performed only under the supervision of a specialist, with careful monitoring of renal function, electrolyte levels, and blood pressure.
Patients with diabetic nephropathy should not receive concomitant treatment with ACE inhibitors and angiotensin II receptor blockers.
Hepatic impairment.
There is no experience with the use of olmesartan medoxomil in patients with severe hepatic impairment. Additionally, in patients with hepatic impairment or progressive liver disease, minor disturbances in fluid and electrolyte balance due to thiazide therapy may precipitate hepatic coma. Therefore, Cardosal® plus should be used with caution in patients with mild to moderate hepatic impairment (see section "Posology and method of administration"). Cardosal® plus is contraindicated in patients with severe hepatic impairment, cholestasis, or biliary obstruction (see sections "Contraindications", "Pharmacokinetics").
Aortic valve stenosis and mitral valve stenosis, hypertrophic obstructive cardiomyopathy.
As with other vasodilators, olmesartan medoxomil should be used with caution in patients with aortic valve stenosis or mitral valve stenosis, as well as in patients with obstructive hypertrophic cardiomyopathy.
Primary hyperaldosteronism.
Patients with primary hyperaldosteronism usually do not respond to antihypertensive agents that suppress the renin-angiotensin system. Therefore, Cardosal® plus is not recommended for such patients.
Metabolic and endocrine effects.
Thiazide-type drugs may impair glucose tolerance. Patients with diabetes may require adjustment of insulin or oral hypoglycemic agent doses (see section "Interaction with other medicinal products and other forms of interaction"). Thiazide diuretics may also unmask latent diabetes mellitus.
During treatment with thiazide diuretics, adverse reactions such as increased cholesterol and triglyceride levels may occur. In some cases, thiazide use may lead to hyperuricemia or gout.
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 hypokalemia, hyponatremia, and hypochloremic alkalosis). Signs of fluid and electrolyte imbalance include dry mouth, thirst, weakness, prolonged fatigue, drowsiness, restlessness, muscle pain or cramps, muscle fatigue, arterial hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting (see section "Adverse reactions"). The risk of hypokalemia is highest in patients with hepatic cirrhosis, with a sudden increase in diuresis, inadequate oral intake of electrolytes, or concomitant use of corticosteroids and ACTH (see section "Interaction with other medicinal products and other forms of interaction"). On the other hand, due to blockade of angiotensin II receptors (AT1) by olmesartan medoxomil contained in Cardosal® plus, hyperkalemia may occur, 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. Cardosal® plus should be used with caution when administered concomitantly with potassium supplements, potassium-sparing diuretics, potassium-containing salt substitutes, and other drugs that may increase serum potassium concentration (see section "Interaction with other medicinal products and other forms of interaction"). There are no data indicating that olmesartan medoxomil may attenuate or prevent diuretic-induced hyponatremia. Chloride deficiency is usually mild and does not require specific treatment. Thiazides may reduce urinary excretion of calcium and cause a slight and transient increase in serum calcium concentration in the absence of any calcium metabolism disorders. Hypercalcemia may indicate occult hyperparathyroidism. Thiazides should be discontinued before parathyroid function testing. Thiazides enhance urinary excretion of magnesium, which may lead to hypomagnesemia. In patients with edema, hyponatremia due to dilution may occur in hot weather.
Lithium preparations.
As with other medicinal products containing angiotensin II receptor blockers in combination with thiazides, Cardosal® plus is not recommended for concomitant use with lithium preparations (see section "Interaction with other medicinal products and other forms of interaction").
Sprue-like enteropathy.
In very rare cases, severe chronic diarrhea with significant weight loss has been reported, developing several months or years after initiation of treatment in patients taking olmesartan; the cause is likely a localized delayed hypersensitivity reaction. Intestinal biopsies in such patients often show villous atrophy. If these symptoms occur in a patient during olmesartan treatment and other probable causes are excluded, olmesartan therapy should be discontinued immediately and not restarted. If diarrhea does not resolve within one week after stopping the drug, the patient should consult a specialist (e.g., a gastroenterologist).
Intestinal angioedema.
Cases of intestinal angioedema have been reported in patients taking angiotensin II receptor blockers, [including olmesartan] (see section "Adverse reactions"). These patients experienced abdominal pain, nausea, vomiting, and diarrhea. Symptoms resolved after discontinuation of angiotensin II receptor blockers. If intestinal angioedema is diagnosed, olmesartan should be discontinued and appropriate monitoring initiated until symptoms completely resolve.
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 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 allergy to sulfonamides or penicillin may be a risk factor for developing angle-closure glaucoma.
Non-melanoma skin cancer (NMSC).
In two epidemiological studies based on data from the Danish National Cancer Registry, increasing cumulative doses of hydrochlorothiazide were associated with an increased risk of NMSC (basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)). The photosensitizing effects of hydrochlorothiazide may be a possible mechanism for NMSC development.
Patients taking hydrochlorothiazide should be informed about the risk of NMSC and advised to regularly check their skin for any new lesions and immediately report any suspicious skin changes. To minimize the risk of skin cancer, patients should be advised to take preventive measures such as limiting exposure to sunlight and UV radiation and using appropriate protection when exposed. Suspicious skin lesions should be promptly evaluated, including histological examination of biopsy samples. Patients with a history of NMSC may also require reassessment of hydrochlorothiazide use (see also section "Adverse reactions").
Acute respiratory toxicity.
Rare cases of acute respiratory toxicity have been reported after hydrochlorothiazide administration, including acute respiratory distress syndrome (ARDS). Pulmonary edema usually develops within minutes or hours after hydrochlorothiazide intake. Initial symptoms include dyspnea, fever, worsening lung condition, and hypotension. If ARDS is suspected, Cardosal® plus should be discontinued and appropriate treatment initiated. Hydrochlorothiazide should not be administered to patients who have previously experienced ARDS after taking hydrochlorothiazide.
Ethnic differences.
As with other angiotensin II receptor blockers, the antihypertensive effect of olmesartan medoxomil is somewhat less pronounced in Black patients compared to patients of other races (possibly due to a higher prevalence of low renin levels in Black patients).
Anti-doping testing.
Hydrochlorothiazide, contained in this medicinal product, may produce false-positive results in anti-doping tests.
Pregnancy.
Cardosal® plus is contraindicated in pregnant women or women planning pregnancy. If pregnancy is confirmed during treatment with Cardosal® plus, treatment should be discontinued immediately and, if necessary, replaced with another medicinal product 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 cause exacerbation or activation of systemic lupus erythematosus.
The medicinal product 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 the teratogenic risk associated with the use of angiotensin II receptor blockers during the first trimester of pregnancy do not allow definitive conclusions, but a slight increase in risk cannot be excluded. Controlled epidemiological studies have not provided data on teratogenic risk with angiotensin II receptor blockers, but an increased risk of similar effects cannot be ruled out. Except in cases where angiotensin II receptor blockers are used for life-saving reasons, women planning pregnancy should be switched to other antihypertensive agents with established safety during pregnancy. If pregnancy is diagnosed, angiotensin II receptor blockers should be discontinued immediately and, if necessary, treatment with alternative agents initiated.
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, hyperkalemia).
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.
Newborns whose mothers received angiotensin II receptor blockers should be closely monitored for the development of arterial hypotension.
Hydrochlorothiazide.
Experience with the use of hydrochlorothiazide during pregnancy, especially 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 disturbances, 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 adequate therapeutic benefit.
Hydrochlorothiazide is also not recommended for the treatment of essential hypertension in pregnant women, except in exceptional cases where other drugs cannot be used.
Combined medicinal product olmesartan medoxomil/hydrochlorothiazide.
Cardosal® plus is contraindicated in pregnant women or women planning pregnancy.
Breastfeeding period.
Olmesartan medoxomil.
There is currently no information on the use of Cardosal® plus during breastfeeding; therefore, the drug should not be administered to breastfeeding women. Alternative drugs with established safety during breastfeeding, especially when nursing newborns or premature infants, may be used instead.
Hydrochlorothiazide.
Hydrochlorothiazide passes into breast milk in small amounts. High doses of thiazides causing intense diuresis may suppress milk production. If its use is absolutely necessary, breastfeeding should be discontinued.
The use of Cardosal® plus during breastfeeding is not recommended. If Cardosal® plus is used during breastfeeding, the dose should be kept as low as possible.
Effects on ability to drive and use machines.
Cardosal® plus may have a minor or moderate influence on the ability to drive and operate machinery. Dizziness and increased fatigue may occasionally occur in patients receiving antihypertensive therapy, which may impair reaction time.
Dosage and Administration
Adults.
Cardosal® plus is not a first-line agent. It is intended for patients in whom treatment with olmesartan medoxomil alone at a dose of 20 mg does not provide adequate blood pressure control.
Cardosal® plus tablets should be taken once daily, independently of food intake.
In the presence of clinical indications, transition from monotherapy with olmesartan medoxomil 20 mg to the combination drug may be performed immediately; 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 20/12.5 mg may be prescribed to patients in whom treatment with olmesartan medoxomil 20 mg alone does not achieve adequate blood pressure control.
Olmesartan medoxomil/hydrochlorothiazide 20/25 mg may be prescribed to patients in whom treatment with olmesartan medoxomil/hydrochlorothiazide 20/12.5 mg does not achieve adequate blood pressure control.
Elderly patients (aged 65 years and older).
The combination drug is recommended for elderly patients at the same dosage as for adult patients.
Renal impairment.
When Cardosal® plus is administered to patients with mild to moderate renal impairment (creatinine clearance 30–60 mL/min), periodic monitoring of renal function is recommended. Cardosal® plus is contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/min).
Hepatic impairment.
Cardosal® plus 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. Cardosal® plus is contraindicated in patients with severe hepatic impairment, as well as in those with cholestasis or biliary obstruction.
Children.
The safety and efficacy of Cardosal® plus in children (under 18 years of age) have not been established. Data are lacking.
Administration method.
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 Cardosal® plus in children (under 18 years of age) have not been established. Data are lacking.
Overdose.
Specific information regarding symptoms or treatment of Cardosal® plus overdose is lacking.
Close monitoring and symptomatic supportive treatment should be implemented. Treatment is symptomatic and depends on the time elapsed since drug ingestion and the severity of symptoms. Emetic agents and/or gastric lavage may be recommended. Activated charcoal may sometimes be recommended in the management of overdose. Serum electrolyte and creatinine levels should be monitored regularly. In case of 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 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 include 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 administration of 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 (see section "Special precautions for use").
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 combined therapy of olmesartan medoxomil/hydrochlorothiazide was approximately similar to that observed with placebo. The incidence of treatment discontinuation due to adverse reactions was also comparable between the olmesartan medoxomil/hydrochlorothiazide 20/12.5 mg–20/25 mg group (2%) and the placebo group (3%). Overall, the incidence of adverse reactions during combined therapy with 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 the medicinal product at high doses 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 trials, 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 (≥ 1/10,000, < 1/1000), very rare (< 1/10,000), and not known (cannot be estimated from available data).
| Organ systems according to MedDRA |
Adverse reactions |
Frequency |
||
| Cardosal® plus |
Olmesartan |
Hydrochlorothiazide |
||
| Infections and parasitic disorders |
Sialadenitis |
Uncommon |
||
| Benign, malignant and unspecified neoplasms (including cysts and polyps) |
Non-melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma) |
Unknown | ||
| Blood and lymphatic system disorders |
Aplastic anaemia |
Uncommon |
||
| Bone marrow depression |
Uncommon |
|||
| Haemolytic anaemia |
Uncommon |
|||
| Leukopenia |
Uncommon |
|||
| Neutropenia/agranulocytosis |
Uncommon |
|||
| Thrombocytopenia |
Uncommon |
Uncommon |
||
| Immune system disorders |
Anaphylactic reactions |
Uncommon |
Uncommon |
|
| Metabolism and nutrition disorders |
Anorexia |
Uncommon |
||
| Glucosuria |
Common |
|||
| Hypercalcaemia |
Common |
|||
| Hypercholesterolaemia |
Uncommon |
Very common |
||
| Hyperglycaemia |
Common |
|||
| Hyperkalaemia |
Rare |
|||
| Hypertriglyceridaemia |
Uncommon |
Common |
Very common |
|
| Hyperuricaemia |
Uncommon |
Common |
Very common |
|
| Hypochloraemia |
Common |
|||
| Hypochloraemic alkalosis |
Very rare |
|||
| Hypokalaemia |
Common |
|||
| Hypomagnesaemia |
Common |
|||
| Hypokalaemia |
Common |
|||
| Hyperamylasaemia |
Common |
|||
| Psychiatric disorders |
Apathy |
Rare |
||
| Depression |
Rare |
|||
| Restlessness |
Rare |
|||
| Sleep disorders |
Rare |
|||
| Nervous system disorders |
Confusion |
Common |
||
| Convulsions |
Rare |
|||
| Disturbance of consciousness, e.g. loss of consciousness |
Rare |
|||
| Dizziness/ dizziness |
Common |
Common |
Common |
|
| Headache |
Common |
Common |
Rare |
|
| Loss of appetite |
Uncommon |
|||
| Paraesthesia |
Rare |
|||
| Postural dizziness |
Uncommon |
|||
| Somnolence |
Uncommon |
|||
| Fainting |
Uncommon |
|||
| Eye disorders |
Decreased lacrimation |
Rare |
||
| Transient blurred vision |
Rare |
|||
| Worsening of pre-existing myopia |
Uncommon |
|||
| Acute myopia, acute angle-closure glaucoma |
Unknown |
|||
| Choroidal effusion |
Unknown |
|||
| Xanthopsia |
Rare |
|||
| Ear and labyrinth disorders |
Vertigo |
Uncommon |
Uncommon |
Rare |
| Cardiac disorders |
Angina pectoris |
Uncommon |
||
| Cardiac arrhythmia |
Rare |
|||
| Palpitations |
Uncommon |
|||
| Vascular disorders |
Embolism |
Rare |
||
| Arterial hypotension |
Uncommon |
Rare |
||
| Necrotising angiitis (vasculitis) |
Rare |
|||
| Orthostatic hypotension |
Uncommon |
Uncommon |
||
| Thrombosis |
Rare |
|||
| Respiratory, thoracic and mediastinal disorders |
Bronchitis |
Common |
||
| Cough |
Uncommon |
Common |
||
| Dyspnoea |
Rare |
|||
| Interstitial pneumonia |
Rare |
|||
| Pharyngitis |
Common |
|||
| Lung oedema |
Rare |
|||
| Respiratory failure |
Uncommon |
|||
| Rhinitis |
Common |
|||
| Acute respiratory distress syndrome (ARDS) (see "Special warnings and precautions for use") |
Very rare |
|||
| Gastrointestinal disorders |
Abdominal pain |
Uncommon |
Common |
Common |
| Constipation |
Common |
|||
| Diarrhoea |
Uncommon |
Common |
Common |
|
| Stomach mucosa irritation |
Common |
|||
| Dyspepsia |
Uncommon |
Common |
||
| Gastroenteritis |
Common |
|||
| Flatulence |
Common |
|||
| Nausea |
Uncommon |
Common |
Common |
|
| Pancreatitis |
Rare |
|||
| Paralytic ileus |
Very rare |
|||
| Vomiting |
Uncommon |
Uncommon |
Common |
|
| Angioneurotic intestinal oedema |
Rare |
|||
| Sprue-like enteropathy |
Very rare |
|||
| Hepatobiliary disorders |
Acute cholecystitis |
Rare |
||
| Jaundice (due to intrahepatic cholestasis) |
Rare |
|||
| Autoimmune hepatitis* |
Unknown |
|||
| Skin and subcutaneous tissue disorders |
Allergic dermatitis |
Uncommon |
||
| Anaphylactic skin manifestations |
Rare |
|||
| Angioedema |
Rare |
Rare |
||
| Skin manifestations resembling systemic lupus erythematosus |
Rare |
|||
| Eczema |
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 |
Rare |
|||
| Toxic epidermal necrolysis |
Rare |
|||
| Urticaria |
Rare |
Uncommon |
Uncommon |
|
| Musculoskeletal and connective tissue disorders |
Arthralgia |
Uncommon |
||
| Arthritis |
Common |
|||
| Back pain |
Uncommon |
Common |
||
| Muscle cramps |
Uncommon |
Rare |
||
| Muscle weakness |
Rare |
|||
| Myalgia |
Uncommon |
Uncommon |
||
| Limb pain |
Uncommon |
|||
| Paralysis |
Rare |
|||
| Bone pain |
Common |
|||
| Renal and urinary disorders |
Acute renal failure |
Rare |
Rare |
|
| Haematuria |
Uncommon |
Common |
||
| Interstitial nephritis |
Rare |
|||
| Renal failure |
Rare |
|||
| Renal dysfunction |
Rare |
|||
| Urinary tract infection |
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 |
||
| Feeling of warmth |
Rare |
|||
| Influenza-like symptoms |
Common |
|||
| Somnolence |
Rare |
|||
| Malaise |
Rare |
Uncommon |
||
| Pain |
Common |
|||
| Peripheral oedema |
Common |
Common |
||
| Weakness |
Uncommon |
|||
| Investigations |
Increased alanine aminotransferase activity |
Uncommon |
||
| Increased aspartate aminotransferase activity |
Uncommon |
|||
| Increased blood creatine phosphokinase activity |
Common |
|||
| Hypercalcaemia |
Uncommon |
|||
| Hypercreatininaemia |
Uncommon |
Rare |
Common |
|
| Hyperglycaemia |
Uncommon |
|||
| Decreased blood haematocrit level |
Rare |
|||
| Hypohaemoglobinaemia |
Rare |
|||
| Hyperlipidaemia |
Uncommon |
|||
| Hypokalaemia |
Uncommon |
|||
| Hyperkalaemia |
Uncommon |
|||
| Increased blood urea level |
Uncommon |
Common |
Common |
|
| Increased blood urea nitrogen level |
Rare |
|||
| Hyperuricaemia |
Rare |
|||
| Increased gamma-glutamyltransferase level |
Uncommon |
|||
| Increased liver enzymes |
Common |
|||
* During the post-marketing period, cases of autoimmune hepatitis with a latency period of several months to years have been reported, which were reversible upon discontinuation of olmesartan.
There have been reports of several cases of rhabdomyolysis occurring in temporal association with the use of angiotensin II receptor blockers.
Non-melanoma skin cancer (NMSC): based on available data from epidemiological studies, an association has been identified between cumulative dose of hydrochlorothiazide and NMSC (see also sections "Special precautions for use" and "Pharmacodynamics").
Reporting of suspected adverse reactions.
It is very important to report suspected adverse reactions after a medicine has been authorized. This allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions.
Shelf life.
5 years. Do not use the medicinal product after the expiry date stated on the packaging.
Storage conditions.
No special storage conditions required. Keep out of reach and sight of children.
Packaging.
14 film-coated tablets in a blister; 1 or 2 blisters in a cardboard box.
Prescription status.
Prescription only.
Manufacturer.
BERLIN-CHEMIE AG.
Menarini-von Heyden GmbH.
Manufacturer's address and place of business.
Glienicker Weg 125, 12489 Berlin, Germany.
Leipziger Strasse 7-13, 01097 Dresden, Germany.
Marketing Authorization Holder.
Menarini International Operations Luxembourg S.A.
Address of the Marketing Authorization Holder.
1, Avenue de la Gare, L-1611 Luxembourg, Luxembourg.