Instructions Cardosal plus 20/12.5 film-coated tablets blister No. 28
Composition
active ingredient: olmesartan medoxomil; hydrochlorothiazide;
1 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 hydroxypropyl cellulose, lactose monohydrate, hydroxypropyl cellulose, magnesium stearate; Opadry O2A22352 or O2A24576 coating (hypromellose, talc, titanium dioxide (E 171), yellow iron oxide (E 172), red iron oxide (E 172).
Dosage form
Film-coated tablets.
Basic physicochemical properties.
Cardosal® plus 20/12.5: round, film-coated tablets, reddish-yellow in color, embossed with “C 22” on one side.
Cardosal® plus 20/25: round, film-coated tablets, pale pink in color, embossed with “C 24” on one side.
Pharmacotherapeutic group
Angiotensin II antagonists and diuretics. ATC code C09D A08.
Pharmacological properties
Pharmacodynamics.
Cardosal® plus is a combination of the angiotensin II receptor blocker olmesartan medoxomil and the thiazide diuretic hydrochlorothiazide. The combination of these components has an additive antihypertensive effect, resulting in a greater reduction in blood pressure than when each component is used separately.
Taking Cardosal® plus once a day provides an effective and gentle reduction in blood pressure for 24 hours until the next dose.
Olmesartan medoxomil.
Olmesartan medoxomil is a selective angiotensin II (type AT1) receptor blocker for oral administration. Angiotensin II is the main vasoactive hormone of the renin-angiotensin-aldosterone system and plays an important role in the pathophysiology of hypertension. It causes vasoconstriction, induces the synthesis and secretion of aldosterone, stimulates cardiac activity and renal sodium reabsorption. Olmesartan inhibits the vasoconstrictor and aldosterone secretion effects of angiotensin II by blocking the AT1 receptor in tissues, including vascular smooth muscle and the adrenal glands. The action of olmesartan is independent of the source or route of synthesis of angiotensin II. Selective binding of olmesartan to the AT1 angiotensin II receptor leads to an increase in renin levels and plasma concentrations of angiotensin I and angiotensin II, as well as to a slight decrease in plasma aldosterone concentrations.
In patients with hypertension, olmesartan medoxomil provides a sustained, dose-dependent reduction in blood pressure. There was no evidence of hypotension after the first dose (first-dose effect), tachyphylaxis with long-term use, or rebound hypertension after abrupt withdrawal.
Once-daily dosing of olmesartan medoxomil provides effective and gentle blood pressure reduction for 24 hours before the next dose. When the drug is administered once daily, its antihypertensive effect was approximately the same as that of twice-daily dosing at the same daily dose.
In the case of continuous treatment, the maximum reduction in blood pressure is achieved 8 weeks after the start of treatment; with a significant antihypertensive effect observed after 2 weeks of treatment.
The effect of olmesartan medoxomil on mortality and complication rates has not been established.
The Randomized Trial of Olmesartan and Prevention of Diabetic Microalbuminuria (ROADMAP) trial, conducted in 4447 patients with type 2 diabetes, normal albuminuria, and at least one additional cardiovascular risk factor, was conducted to determine whether olmesartan therapy could delay the onset of microalbuminuria. During a median follow-up of 3.2 years, patients received olmesartan or placebo in addition to other antihypertensive agents, excluding ACE inhibitors or ARBs.
In the secondary endpoint, cardiovascular events were reported in 96 patients (4.3%) treated with olmesartan and 94 patients (4.2%) treated with placebo. The incidence of cardiovascular mortality was higher in the olmesartan group than in the placebo group (15 patients (0.7%) and 3 patients (0.1%)), despite similar incidences of non-fatal stroke (14 patients (0.6%) and 8 patients (0.4%)), non-fatal myocardial infarction (17 patients (0.8%) and 26 patients (1.2%)) and non-cardiovascular mortality (11 patients (0.5%) and 12 patients (0.5%)). Overall mortality was numerically higher in the olmesartan group (26 patients (1.2%) and 15 patients (0.7%)), mainly due to higher mortality from cardiovascular causes.
The ORIENT trial (The Olmesartan Reducing Incidence of End-stage Renal Disease in Diabetic Nephropathy Trial) examined the effects of olmesartan on renal and cardiovascular outcomes in 577 randomized patients in Japan and China with type 2 diabetes and overt nephropathy. During a median follow-up 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 doubling of serum creatinine, end-stage renal disease, all-cause death) was achieved in 116 patients in the olmesartan group (41.1%) and in 129 patients receiving placebo (45.4%) (HR 0.97 (95% CI 0.75 to 1.24); p = 0.791). The secondary composite cardiovascular endpoint was achieved in 40 patients receiving olmesartan (14.2%) and 53 patients receiving placebo (18.7%). This composite cardiovascular endpoint included cardiovascular mortality in 10 (3.5%) patients receiving olmesartan and 3 (1.1%) patients receiving placebo; the overall mortality rate was 19 (6.7%) and 20 (7.0%), non-fatal stroke – 8 (2.8%) and 11 (3.9%), non-fatal myocardial infarction – 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 the reabsorption of electrolytes in the renal tubules, thereby increasing the excretion of sodium and chloride (approximately at the same level). Acting as a diuretic, hydrochlorothiazide reduces blood plasma volume, resulting in increased plasma renin activity and aldosterone secretion, increased urinary potassium and bicarbonate losses, and decreased serum concentrations. Since the relationship between renin levels and aldosterone secretion is mediated by angiotensin II, the use of hydrochlorothiazide in combination with an angiotensin II receptor blocker may reduce urinary potassium losses under the influence of thiazide diuretics. When using hydrochlorothiazide, diuresis occurs approximately 2 hours after administration, the maximum effect is achieved approximately 4 hours, and the effect persists for 6–12 hours.
According to epidemiological studies, long-term use of hydrochlorothiazide as monotherapy reduces the risk of cardiovascular complications and death from them.
Clinical efficacy and safety
Combination therapy of olmesartan medoxomil and hydrochlorothiazide.
In combination therapy with olmesartan medoxomil and hydrochlorothiazide, the antihypertensive effect is additive and usually greater than that of either component alone. In pooled placebo-controlled trials, the mean reduction in systolic/diastolic blood pressure at the end of the dosing interval (placebo-corrected) with olmesartan medoxomil/hydrochlorothiazide 20/12.5 mg and 20/25 mg was 12/7 mmHg and 16/9 mmHg, respectively. Age and gender had no clinically significant effect on the efficacy of combination therapy with olmesartan medoxomil and hydrochlorothiazide.
When hydrochlorothiazide 12.5 mg and 25 mg was used in patients who were inadequately controlled on olmesartan medoxomil 20 mg monotherapy, additional reductions in mean 24-hour systolic/diastolic blood pressure as measured by ambulatory blood pressure monitoring (7/5 mmHg and 12/7 mmHg compared to baseline values achieved with olmesartan medoxomil monotherapy) were observed. 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 mmHg and 16/11 mmHg, respectively (compared to baseline values).
Combination therapy with olmesartan medoxomil and hydrochlorothiazide remained effective over a long period of treatment (1 year). No rebound hypertension was observed when olmesartan medoxomil (used both in combination with hydrochlorothiazide and alone) was discontinued.
The effect of the combination drug olmesartan medoxomil and hydrochlorothiazide on cardiovascular complications and mortality is currently unknown.
Other information.
ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular disease or type 2 diabetes mellitus with evidence of target organ damage. VA NEPHRON-D was a study conducted in patients with type 2 diabetes mellitus and diabetic nephropathy. The studies did not show a significant beneficial effect on renal and/or cardiovascular outcomes and mortality, while there was an increased risk of hyperkalemia, acute kidney injury and/or hypotension compared with monotherapy. Given the similar pharmacodynamic properties, these results are also applicable to other ACE inhibitors and angiotensin II receptor blockers.
The combined 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 investigate the benefit of adding aliskiren to standard therapy with ACE inhibitors or angiotensin II receptor blockers in patients with type 2 diabetes and chronic kidney disease, cardiovascular disease, or both. The study was stopped early due to an increased risk of adverse events. Cardiovascular mortality and stroke were more common 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 common in the aliskiren group than in the placebo group.
Non-melanoma skin cancer (NMSC). Available epidemiological data have shown an association between cumulative hydrochlorothiazide dose 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 subjects, respectively. High-dose hydrochlorothiazide (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 relationship between cumulative dose and response was observed for both BCC and PCC. Another study suggested a possible association between lip cancer (PCC) and hydrochlorothiazide exposure: 633 patients with lip cancer were compared with 63,067 controls using a risk-adjusted sampling strategy. A cumulative dose-response relationship was demonstrated: the adjusted OR was 2.1 (95% CI: 1.7–2.6), increasing to an OR of 3.9 (3.0–4.9) at high doses (25,000 mg) and an OR of 7.7 (5.7–10.5) at the highest cumulative dose (100,000 mg) (see also section 4.4).
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 in the portal blood during absorption from the gastrointestinal tract. Neither olmesartan medoxomil nor the medoxomil side group was detected in the unchanged form in plasma or in the excretion products. The mean absolute bioavailability of olmesartan in tablet form was 25.6%. The mean maximum plasma concentration (Cmax) of olmesartan is reached approximately 2 hours after oral administration. In the case of a single oral administration of up to 80 mg, the plasma concentration of olmesartan increases approximately proportionally to the dose. Food has a minimal effect on the bioavailability of olmesartan, so olmesartan medoxomil can be used regardless of food intake. Clinically significant differences in the pharmacokinetics of olmesartan between men and women have not 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 (as evidenced by the lack of clinically significant interactions between olmesartan medoxomil and warfarin). Olmesartan binds to blood cells to a negligible extent. The mean volume of distribution after intravenous administration is small (16–29 l).
Hydrochlorothiazide.
When olmesartan medoxomil was administered orally in combination with hydrochlorothiazide, the median time to reach Cmax of hydrochlorothiazide in plasma was 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.
The total plasma clearance of olmesartan is approximately 1.3 l/h (coefficient of variation 19%) and is relatively low compared to hepatic blood flow (approximately 90 l/h). After a single oral dose of 14C-labeled olmesartan medoxomil, 10–16% of the radioactivity was recovered in the urine (mostly within 24 hours of administration); the remaining radioactivity was recovered in the faeces. Given that the systemic bioavailability of the drug is 25.6%, it can be estimated that the absorbed olmesartan is excreted both by the kidneys (approximately 40%) and the hepatobiliary system (approximately 60%). All of the radioactivity recovered in the excretion products was contained in olmesartan. No other significant metabolites were identified. Olmesartan is virtually not involved in enterohepatic circulation. Since a large part of olmesartan is excreted in the bile, its use in patients with bile duct obstruction is contraindicated. The terminal half-life of olmesartan after multiple oral administration varies in the range of 10 to 15 hours. Steady state is reached after the first few doses; after 14 days of multiple administration, no further accumulation of the drug was observed. Renal clearance was approximately 0.5–0.7 l/hour and was independent of the dose of the drug.
Hydrochlorothiazide.
Hydrochlorothiazide is not metabolized in humans and is almost completely excreted unchanged in the 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 half-life is approximately 10–15 hours.
Combination of olmesartan medoxomil with hydrochlorothiazide.
When hydrochlorothiazide is used 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 are not changed when it is used in combination with hydrochlorothiazide.
Pharmacokinetics in certain patient groups.
Elderly patients (aged 65 and over).
In elderly patients (65–75 years) with hypertension, the area under the pharmacokinetic curve (AUC) of olmesartan at steady state was approximately 35% higher than in younger patients, and in patients ≥ 75 years of age it was approximately 44% higher.
Based on available data, it can be assumed that in elderly people (both healthy and hypertensive patients) the systemic clearance of hydrochlorothiazide is lower than in healthy volunteers.
Kidney dysfunction.
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 half-life of hydrochlorothiazide was prolonged in patients with renal impairment.
Liver dysfunction.
After a single oral dose of olmesartan, the AUC in patients with mild and moderate hepatic impairment was 6% and 65% higher, respectively, than in healthy controls with the same demographics. In healthy volunteers and in 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 multiple doses, the mean AUC of olmesartan in patients with moderate hepatic impairment was 65% higher than in healthy controls with the same demographics. The Cmax values of olmesartan in patients with hepatic impairment and healthy volunteers were similar. The efficacy of olmesartan medoxomil in patients with severe hepatic impairment has not been established. The pharmacokinetics of hydrochlorothiazide were not significantly affected by hepatic impairment.
Interaction with other drugs
The bile acid sequestrant colesevelam
Co-administration of 40 mg olmesartan medoxomil and 3750 mg colesevelam hydrochloride in healthy volunteers resulted in a 28% decrease in Cmax and a 39% decrease in AUC for olmesartan. A smaller effect, a 4% and 15% decrease in Cmax and AUC, respectively, was observed when olmesartan medoxomil was administered 4 hours before colesevelam hydrochloride. The elimination half-life of olmesartan was reduced by 50–52% regardless of whether the drugs were administered together or whether olmesartan was administered 4 hours before colesevelam hydrochloride.
Preclinical safety data
As with the use of the drug alone, and in the case of use with other drugs of the same class, the toxic effect of this combination is directed mainly to the kidneys. Against the background of the use of the combination of olmesartan medoxomil and hydrochlorothiazide, functional changes in the kidneys (increase in blood urea nitrogen and serum creatinine) were observed. In rats and dogs, which were used in combination with high doses of the components, degeneration and regeneration of the kidneys were observed, possibly due to impaired renal hemodynamics (decreased renal blood flow due to arterial hypotension in combination with hypoxia and degeneration of tubular cells). In addition, the use of the combination of olmesartan medoxomil and hydrochlorothiazide led to a decrease in erythrocyte parameters (erythrocyte count, hemoglobin and hematocrit) and a decrease in heart weight in rats. These results were also observed with the use of other AT1 receptor blockers and ACE inhibitors. They are probably due to the pharmacological action of olmesartan medoxomil at high doses and are not observed when the drug is used at recommended therapeutic doses.
Genotoxicity studies of the combination of olmesartan medoxomil and hydrochlorothiazide, as well as these components separately, did not reveal any evidence of clinically significant genotoxicity.
The carcinogenic effects of the combination of olmesartan medoxomil and hydrochlorothiazide have not been studied.
No evidence of teratogenic effects was observed in mice and rats treated with olmesartan medoxomil in combination with hydrochlorothiazide. As expected for a drug of this class, fetotoxicity was observed in rats treated with the combination of olmesartan medoxomil and hydrochlorothiazide during pregnancy, as evidenced by a significant reduction in foetal body weight (see sections 4.3 and 4.4).
Indication
Treatment of essential hypertension.
The combined drug Cardosal® plus is intended for adult patients in whom the use of olmesartan medoxomil alone does not provide a reduction in blood pressure to the required level.
Contraindication
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 significant hyperuricemia.
Severe liver dysfunction, cholestasis and obstructive biliary tract diseases. Pregnancy or planning of pregnancy.
The combined use of Cardosal® plus and drugs containing aliskiren is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m2).
Interaction with other medicinal products and other types of interactions
Potential interactions are associated with the use of both olmesartan medoxomil and hydrochlorothiazide.
Concomitant use is not recommended.
Lithium preparations.
With the simultaneous use of lithium preparations with angiotensin-converting enzyme inhibitors and sometimes with angiotensin II receptor blockers, a reversible increase in serum lithium concentration and its toxicity was observed. In addition, in the presence of thiazides, renal clearance of lithium is reduced, so the risk of its toxicity against the background of hydrochlorothiazide may increase. In this regard, the use of the drug Cardosal® plus in combination with lithium is not recommended. In patients who need to be prescribed these drugs simultaneously, it is recommended to carefully monitor the concentration of lithium in the serum during treatment.
Concomitant use requiring caution
Baclofen.
The hypotensive effect may be enhanced.
Nonsteroidal anti-inflammatory drugs (NSAIDs).
NSAIDs (e.g. acetylsalicylic acid (> 3 g/day), COX-2 inhibitors and non-selective NSAIDs) may reduce the antihypertensive effect of thiazide diuretics and angiotensin II receptor blockers. In some patients with impaired renal function (e.g. dehydrated patients or elderly patients with pre-existing renal disease), the concomitant use of angiotensin II receptor blockers with cyclooxygenase inhibitors may lead to an exacerbation of these disorders, in particular acute renal failure, which is usually reversible. Therefore, these drugs should be administered with caution, especially in elderly patients. Patients should be adequately hydrated. In addition, renal function should be monitored after initiation of combination therapy and at regular intervals thereafter.
Concomitant use requiring special attention
Amifostine.
The antihypertensive effect may be enhanced.
Other antihypertensive agents.
The antihypertensive effect of Cardosal® plus may be enhanced when used simultaneously with other drugs that lower blood pressure.
Ethyl alcohol, barbiturates, narcotic analgesics and antidepressants.
Manifestations of orthostatic hypotension may increase.
Potential interactions with olmesartan medoxomil.
ACE inhibitors, angiotensin II receptor blockers, or aliskiren.
Clinical trial data show that dual blockade of the renin-angiotensin-aldosterone system (RAAS), associated with the combined use of ACE inhibitors and angiotensin II receptor blockers or aliskiren, leads to an increased incidence of adverse events such as hypotension, hyperkalemia and decreased renal function (including acute renal failure), compared with the use of a single agent acting on the RAAS.
Medicines that affect the concentration of potassium in the blood.
Given the experience with other drugs that inhibit the renin-angiotensin system, the concentration of potassium in the blood serum may increase with the simultaneous use of potassium-sparing diuretics, potassium preparations, potassium-containing salt substitutes and other drugs that can increase the concentration of potassium in the blood (such as heparin, ACE inhibitors). When prescribing the drug Cardosal® plus simultaneously with drugs that affect potassium levels, it is recommended to monitor the serum potassium concentration.
The drug colesevelam, which binds bile acids.
Co-administration of the bile acid sequestrant colesevelam hydrochloride reduces the systemic exposure and peak plasma concentration of olmesartan, and also reduces the half-life. Taking olmesartan medoxomil at least 4 hours before taking colesevelam hydrochloride reduced the effect of the drug interaction. Taking olmesartan medoxomil at least 4 hours before taking colesevelam hydrochloride should be considered.
Additional information.
A modest decrease in the bioavailability of olmesartan medoxomil was observed after treatment with antacids (magnesium-aluminium hydroxide). Olmesartan medoxomil had no significant effect on the pharmacokinetics and pharmacodynamics of warfarin or the pharmacokinetics of digoxin. In healthy volunteers, olmesartan medoxomil was co-administered with pravastatin, but no clinically significant changes in the pharmacokinetics of these drugs were observed. In in vitro studies, olmesartan did not show clinically significant inhibition of the activity of cytochrome P450 isoenzymes IA1/2, IIA6, IIC8/9, IIC19, IID6, IIE1 and IIIA4 in humans; olmesartan had little or no induction of cytochrome P450 isoenzymes in animals. Therefore, clinically significant interactions between olmesartan and drugs metabolized by these cytochrome P450 isoenzymes are not expected.
Potential interactions with hydrochlorothiazide.
Concomitant use is not recommended.
Medicines that affect the concentration of potassium in the blood.
The hypokalemic effect of hydrochlorothiazide may be enhanced by concomitant use with other drugs that cause potassium loss and hypokalemia (e.g., kaliuretic diuretics, laxatives, corticosteroids, ACTH, amphotericin, carbenoxolone, penicillin G sodium, and salicylic acid derivatives). Therefore, concomitant use of hydrochlorothiazide with these drugs is not recommended.
Concomitant use requiring caution
Calcium salts.
By slowing the excretion of calcium, thiazide diuretics may increase its concentration in the blood serum. If calcium preparations are necessary, the level of its concentration in the serum should be monitored and the calcium dose adjusted accordingly.
Cholestyramine and colestipol.
The absorption of hydrochlorothiazide is slowed down by the use of anion exchange resins.
Cardiac glycosides.
The use of cardiac glycosides leads to hypokalemia and hypomagnesemia, which are caused by thiazides, increasing the risk of arrhythmias.
Drugs whose efficacy depends on changes in serum potassium concentration. When using Cardosal® plus simultaneously with drugs whose efficacy depends on changes in serum potassium concentration (e.g. cardiac glycosides and antiarrhythmics), as well as with drugs that cause torsades de pointes (ventricular tachycardia), including some antiarrhythmics, regular monitoring of serum potassium concentration and ECG is recommended:
Class Ia antiarrhythmics (e.g. quinidine, hydroquinidine, disopyramide);
class III antiarrhythmics (e.g. amiodarone, sotalol, dofetilide, ibutilide);
some antipsychotics (e.g. thioridazine, chlorpromazine, levomepromazine, trifluoperazine, cyamemazine, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol);
others (e.g. bepridil, cisapride, diphemanil, erythromycin intravenously, halofantrine, mizolastine, pentamidine, sparfloxacin, terfenadine, vincamine intravenously).
Non-depolarizing skeletal muscle relaxants (e.g. tubocurarine).
Hydrochlorothiazide may enhance the effectiveness of non-depolarizing skeletal muscle relaxants.
Anticholinergics (e.g. atropine and biperiden).
By reducing gastrointestinal motility and gastric emptying rate, anticholinergics may increase the bioavailability of thiazide diuretics.
Antidiabetic medications (oral agents and insulin).
Thiazide therapy may affect glucose tolerance. Dose adjustment of hypoglycemic agents may be necessary.
Metformin should be used with caution due to the risk of lactic acidosis caused by functional renal failure, which sometimes occurs as a result of the use of hydrochlorothiazide.
Beta-blockers and diazoxide.
The hyperglycemic effect of beta-blockers and diazoxide may be potentiated by thiazides.
Pressor amines (e.g., norepinephrine).
The effectiveness of pressor amines may be reduced.
Medicines used to treat gout (probenecid, sulfinpyrazone and allopurinol).
Since hydrochlorothiazide sometimes causes an increase in serum uric acid concentration, it may be necessary to adjust the dose of uricosuric drugs for the treatment of gout. In addition, it may be necessary to increase the dose of probenecid or sulfinpyrazone. When allopurinol is used concomitantly with a thiazide, the frequency of allergic reactions to allopurinol may increase.
Amantadine.
Thiazides may increase the risk of adverse reactions caused by amantadine.
Cytostatics (e.g. cyclophosphamide, methotrexate).
Thiazides may reduce the renal excretion of anticancer drugs and enhance their bone marrow suppressive effects.
Salicylates.
When taking salicylates in high doses, hydrochlorothiazide may enhance their toxic effect on the central nervous system.
Methyldopa.
Publications 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.
The use of thiazides concomitantly with tetracycline increases the risk of tetracycline-induced uremia. This effect probably does not apply to doxycycline.
Application features
Decreased circulating blood volume.
In patients with reduced circulating blood volume and/or low sodium levels due to intensive diuretic therapy, a low-salt diet, diarrhea, or vomiting, clinically significant hypotension may occur, especially after the first dose of the drug. Before starting the use of Cardosal® plus, the above-mentioned phenomena should be eliminated.
Other events associated with stimulation of the renin-angiotensin-aldosterone system: Patients whose vascular tone and renal function depend to a large extent on the activity of the renin-angiotensin-aldosterone system (e.g., severe congestive heart failure or renal disease, including renal artery stenosis) may react to other drugs that affect this system with acute hypotension, azotemia, oliguria, or, in rare cases, acute renal failure.
Renovascular hypertension.
The use of drugs that affect the renin-angiotensin-aldosterone system in patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney is associated with an increased risk of severe 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"). No dose adjustment is 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 is recommended. Thiazide-induced azotemia may occur in patients with renal impairment. If progressive renal failure becomes evident, a careful review of the treatment regimen and possibly discontinuation of diuretics is required. There is no clinical experience with Cardosal® plus in patients who have recently undergone kidney transplantation.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS).
The simultaneous 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 with the simultaneous use of ACE inhibitors, angiotensin II receptor blockers or aliskiren is not recommended (see sections "Interaction with other medicinal products and other types of interactions", "Pharmacodynamics").
If dual blockade therapy is absolutely necessary, it should only be carried out under specialist supervision and with close monitoring of renal function, electrolyte levels and blood pressure.
Patients with diabetic nephropathy should not use ACE inhibitors and angiotensin II receptor blockers concomitantly.
Liver dysfunction.
Experience of use
