Cardosal^® Plus (Tablets) Instructions for Use

Marketing Authorization Holder

Menarini International Operations Luxembourg, S.A. (Luxembourg)

Manufactured By

Daiichi Sankyo Europe, GmbH (Germany)

Labeled By

BERLIN-CHEMIE, AG (Germany)

ATC Code

C09DA08 (Olmesartan medoxomil and diuretics)

Active Substances

Hydrochlorothiazide (Rec.INN registered by WHO)

Olmesartan medoxomil (Rec.INN registered by WHO)

Dosage Forms

	Cardosal® Plus	Film-coated tablets, 12.5 mg+20 mg: 14, 28, 56 or 98 pcs.
		Film-coated tablets, 25 mg+20 mg: 14, 28, 56 or 98 pcs.

Dosage Form, Packaging, and Composition

14 pcs. – blister packs (1) – cardboard packs.
14 pcs. – blister packs (2) – cardboard packs.
14 pcs. – blister packs (4) – cardboard packs.
14 pcs. – blister packs (7) – cardboard packs.

14 pcs. – blister packs (1) – cardboard packs.
14 pcs. – blister packs (2) – cardboard packs.
14 pcs. – blister packs (4) – cardboard packs.
14 pcs. – blister packs (7) – cardboard packs.

Clinical-Pharmacological Group

Angiotensin II receptor antagonist in combination with a diuretic

Pharmacotherapeutic Group

Agents acting on the renin-angiotensin system; angiotensin II receptor antagonists, combinations; angiotensin II receptor antagonists and diuretics

Pharmacological Action

Cardosal^® Plus is a combined preparation containing an angiotensin II receptor antagonist (Olmesartan medoxomil) and a thiazide diuretic (Hydrochlorothiazide). The combination of two active substances has a combined antihypertensive effect, resulting in a greater reduction in blood pressure than when each is taken separately. When taken once a day, effective and uniform reduction of blood pressure is achieved over 24 hours.

Olmesartan medoxomil is a specific angiotensin II receptor antagonist (type AT₁). Angiotensin II is the primary vasoactive component of the renin-angiotensin-aldosterone system (RAAS) and plays a significant role in the pathophysiology of arterial hypertension through its effect on AT₁ receptors. It is assumed that Olmesartan medoxomil blocks all effects of angiotensin II mediated by AT₁ receptors, regardless of the source and pathway of angiotensin II synthesis.

In arterial hypertension, Olmesartan medoxomil causes a dose-dependent, prolonged reduction in blood pressure. There are no data on the development of arterial hypotension after the first dose of the drug or on the development of a “withdrawal” syndrome (a sharp increase in blood pressure after drug discontinuation).

Taking olmesartan medoxomil once a day provides effective and smooth blood pressure reduction over 24 hours. The antihypertensive effect of olmesartan medoxomil usually begins within 2 weeks, and the maximum effect develops approximately 8 weeks after the start of therapy.

Hydrochlorothiazide – a thiazide diuretic – impairs the reabsorption of sodium, chloride, and water ions in the renal tubules. Increases the excretion of potassium, magnesium, and bicarbonate ions, and retains calcium ions in the body. The diuretic effect occurs 2 hours after oral administration of hydrochlorothiazide, reaches a maximum after 4 hours, and lasts up to 12 hours. Contributes to the reduction of elevated blood pressure. With the combined use of olmesartan medoxomil and hydrochlorothiazide, the loss of potassium ions caused by the diuretic is reduced. The result of combination therapy with olmesartan medoxomil and hydrochlorothiazide is a potentiation of the antihypertensive effect, which depends on the dose of each component of the drug. Combination therapy is well tolerated by patients. During long-term treatment, the effectiveness of combination therapy (Olmesartan medoxomil/Hydrochlorothiazide) is maintained, and no “withdrawal” syndrome is observed.

Pharmacokinetics

Absorption and Distribution

Olmesartan medoxomil is a prodrug. It is rapidly converted into the pharmacologically active metabolite olmesartan by enzymes in the intestinal mucosa and in the peripheral blood during absorption from the gastrointestinal tract and circulates in the blood as a metabolite (olmesartan). The bioavailability of olmesartan averages 25.6%.

C_max of olmesartan in plasma is reached on average 2 hours after oral administration and increases approximately linearly with an increase in a single dose up to 80 mg.

Food intake does not significantly affect the bioavailability of olmesartan medoxomil, so Olmesartan medoxomil can be taken regardless of meals.

No clinically significant differences in the pharmacokinetic parameters of olmesartan medoxomil depending on gender were identified.

Olmesartan has a high degree of binding to plasma proteins (99.7%). When olmesartan medoxomil is used concomitantly with other drugs characterized by a high degree of binding to plasma proteins, no significant changes in this value occur (as evidenced by the absence of clinically significant interaction between olmesartan medoxomil and warfarin). The binding of olmesartan to blood cells is insignificant.

After oral administration of olmesartan medoxomil in combination with hydrochlorothiazide, the average time to reach C_max of hydrochlorothiazide is 1.5-2 hours.

Hydrochlorothiazide binds to plasma proteins by 68%. The systemic bioavailability of hydrochlorothiazide when used concomitantly with olmesartan medoxomil decreases by approximately 20%, but this small decrease is not clinically significant. Concomitant administration of hydrochlorothiazide, in turn, does not significantly affect the kinetics of olmesartan medoxomil. In controlled clinical studies, a pronounced antihypertensive effect of this combination was revealed, which exceeded the effect of each component separately, as well as the effect of placebo.

Metabolism and Excretion

The total plasma clearance of olmesartan is usually 1.3 L/h (coefficient of variation – 19%) and is relatively low compared to hepatic blood flow (approximately 90 L/h). Renal excretion of olmesartan is approximately 40%, biliary excretion through the intestine is about 60%; extrahepatic circulation is minimal. Since most of olmesartan medoxomil is metabolized in the liver, its use in patients with biliary obstruction is contraindicated.

The half-life of olmesartan is 10-15 hours. A steady-state effect of therapy is achieved within the first 14 days of daily administration of olmesartan medoxomil. Renal clearance is approximately 0.5-0.7 L/h and is not dose-dependent.

Hydrochlorothiazide is not metabolized in the body and is almost completely excreted unchanged by the kidneys. After oral administration, about 60% of the administered dose of hydrochlorothiazide is excreted unchanged within 48 hours. The renal clearance of hydrochlorothiazide is about 250-300 ml/min; T_1/2 of the terminal phase is 10-15 hours.

Pharmacokinetics in Different Patient Categories

In patients aged 65-75 years with arterial hypertension, the area under the concentration-time curve (AUC) for olmesartan at steady state increases by approximately 35% compared to the group of patients under 65 years of age, in patients over 75 years – by approximately 44%. Available data suggest that the systemic clearance of hydrochlorothiazide is reduced in both healthy elderly volunteers and elderly patients with arterial hypertension compared to younger volunteers. In patients with impaired renal function (CrCl = 30-60 ml/min), the AUC for olmesartan at steady state increases by approximately 62, 82, and 179% in cases of mild, moderate, and severe renal impairment, respectively, compared to healthy volunteers. For this category of patients, an increase in the T_1/2 of hydrochlorothiazide is possible.

In patients with mild and moderate hepatic impairment after a single oral dose, the AUC values for olmesartan were 6% and 65% higher, respectively, compared to healthy volunteers. The unbound fraction of olmesartan 2 hours after drug administration in healthy volunteers, patients with mild and moderate hepatic impairment was 0.26; 0.34 and 0.41%, respectively. The effect of hepatic impairment on the pharmacokinetics of hydrochlorothiazide is insignificant.

Regarding patients with severe hepatic impairment (more than 9 points on the Child-Pugh scale), there are no pharmacokinetic data for olmesartan medoxomil.

Indications

• Essential arterial hypertension (when monotherapy with olmesartan medoxomil is ineffective).

ICD codes

Dosage Regimen

Cardosal^® Plus tablets are taken orally regardless of meals. Before prescribing the combined drug Cardosal^® Plus, preliminary dose selection of each active substance separately (i.e., olmesartan medoxomil and hydrochlorothiazide) is recommended.

Recommended dose

1 tablet of Cardosal^® Plus containing 20 mg olmesartan medoxomil and 12.5 mg hydrochlorothiazide daily, if there is inadequate blood pressure control during monotherapy with olmesartan medoxomil at a dose of 20 mg;

If there is inadequate blood pressure control while taking Cardosal^® Plus containing 20 mg olmesartan medoxomil and 12.5 mg hydrochlorothiazide, it is possible to use Cardosal^® Plus containing 20 mg olmesartan medoxomil and 25 mg hydrochlorothiazide, 1 tablet daily.

The maximum dose of Cardosal^® Plus is 20 mg olmesartan medoxomil and 25 mg hydrochlorothiazide once daily.

Elderly patients (over 65 years) with normal renal function (CrCl greater than 90 ml/min) and patients with impaired renal function (CrCl = 30-60 ml/min) do not require dose adjustment of the drug.

Adverse Reactions

Possible side effects are listed below in descending order of frequency: common (> 1/100, < 1/10), uncommon (> 1/1000, < 1/100), rare (> 1/10000, < 1/1000), very rare (< 1/10000), including isolated reports.

Combination of olmesartan medoxomil and hydrochlorothiazide

From the central nervous system

Common: dizziness.

Uncommon: syncope.

From the cardiovascular system

Uncommon: palpitations, marked decrease in blood pressure, orthostatic hypotension.

From the skin

Uncommon: skin rash, eczema.

From metabolism

Uncommon: hyper- or hypokalemia, hypercalcemia, hypertriglyceridemia, hyperuricemia, increased blood lipid concentration.

From laboratory parameters

Very rare: slight increase in serum creatinine, uric acid and blood urea nitrogen concentrations, slight decrease in hemoglobin and hematocrit concentrations.

Olmesartan medoxomil (monotherapy)

From the hematopoietic system

Very rare: thrombocytopenia.

From the central nervous system

Very rare: dizziness, headache.

From the cardiovascular system

Rare: marked decrease in blood pressure.

Uncommon: angina pectoris.

From the respiratory system

Common: bronchitis, pharyngitis, rhinitis.

Very rare: cough.

From the digestive tract

Common: diarrhea, dyspepsia, gastroenteritis.

Very rare: abdominal pain, nausea, vomiting.

From the urinary system

Common: hematuria, urinary tract infection.

Very rare: acute renal failure.

From the musculoskeletal system

Common: arthritis, back pain.

Very rare: muscle cramps, myalgia.

From the skin

Very rare: skin itching, exanthema, angioedema, allergic dermatitis, urticaria.

From metabolism

Common: increased creatine phosphokinase activity, hypertriglyceridemia, hyperuricemia.

Rare: hyperkalemia.

From laboratory parameters

Very rare: increased serum creatinine and urea concentrations.

Common: increased activity of “hepatic” transaminases.

Other disorders

Common: chest pain, flu-like symptoms, peripheral edema.

Very rare: weakness, increased fatigue, drowsiness, malaise.

Hydrochlorothiazide (monotherapy)

From the hematopoietic system

Rare: leukopenia, neutropenia, agranulocytosis, thrombocytopenia, aplastic anemia, hemolytic anemia, bone marrow depression.

From the central and peripheral nervous system

Common: dizziness, weakness, headache, increased fatigue.

Rare: anxiety, sleep disturbance, confusion, apathy, depression, clouding of consciousness, paresthesia, convulsions.

From the organ of vision

Rare: xanthopsia, transient accommodation disturbance, decreased tear production.

From the cardiovascular system

Uncommon: orthostatic hypotension.

Rare: arrhythmias, thrombosis, embolism.

From the respiratory system

Rare: dyspnea (including interstitial pneumonia and pulmonary edema).

From the digestive tract

Uncommon: anorexia, abdominal pain, nausea, vomiting, diarrhea, constipation, flatulence, inflammation of the salivary glands.

Rare: pancreatitis, acute cholecystitis, intrahepatic cholestatic jaundice.

Very rare: paralytic ileus.

From the genitourinary system

Rare: renal function impairment, interstitial nephritis, acute renal failure, impotence.

From the musculoskeletal system

Rare: muscle cramp, muscle weakness, paresis.

From the skin

Uncommon: photosensitivity, skin rash, urticaria.

Rare: development of lupus-like syndrome (fever, arthralgia, myalgia, serositis, vasculitis, increased erythrocyte sedimentation rate (ESR), leukocytosis, eosinophilia), activation of the cutaneous form of systemic lupus erythematosus, anaphylactic reactions, toxic epidermal necrolysis.

From laboratory parameters

Common: hyperglycemia, glucosuria, hyperuricemia, increased serum creatinine concentration, water-electrolyte imbalance (including hyponatremia, hypomagnesemia, hypochloremia, hypokalemia and hypercalcemia), increased blood cholesterol and triglyceride concentrations.

Other disorders

Rare: fever.

Contraindications

• Hereditary lactose intolerance, lactase deficiency in the body or glucose and lactose malabsorption syndrome;
• Severe hepatic impairment (more than 9 points on the Child-Pugh scale) (risk of hepatic coma), biliary obstruction and cholestasis;
• Severe renal impairment (CrCl less than 30 ml/min.);
• Refractory hypokalemia, hyponatremia, hypercalcemia and symptomatic hyperuricemia;
• Pregnancy;
• Lactation period;
• Age under 18 years (efficacy and safety of the drug have not been studied);
• Hypersensitivity to olmesartan medoxomil, hydrochlorothiazide or other sulfonamide derivatives or to any of the excipients included in the drug (see section Composition).

With caution

• Bronchial asthma;
• Coronary artery disease (CAD);
• Chronic heart failure in the stage of decompensation;
• Severe cerebrovascular disorders;
• Aortic or mitral valve stenosis;
• Hypertrophic obstructive cardiomyopathy;
• Mild and moderate hepatic impairment (less than 9 points on the Child-Pugh scale);
• Renal impairment (CrCl greater than 30 ml/min but less than 60 ml/min.);
• Bilateral renal artery stenosis or stenosis of the artery of a single kidney;
• Condition after recent kidney transplantation (no experience with the drug);
• Primary aldosteronism;
• Diabetes mellitus, gout;
• Water-electrolyte imbalance, dehydration;
• Connective tissue diseases, including systemic lupus erythematosus;
• Patients on a salt-restricted diet or on hemodialysis;
• With bone marrow depression;
• Conditions accompanied by a decrease in circulating blood volume;
• (CBV) including diarrhea, vomiting or prior diuretic therapy.

Use in Pregnancy and Lactation

There is no experience with the use of olmesartan medoxomil in pregnant women. However, due to reports of severe teratogenic effects of drugs acting on the RAAS, like any drug of this class, Cardosal^® Plus is contraindicated for use during pregnancy. If pregnancy is planned or occurs during therapy with Cardosal^® Plus, the drug should be discontinued as soon as possible. It is not known whether Olmesartan medoxomil is excreted in breast milk, but thiazides are excreted in breast milk and may suppress lactation, so if it is necessary to use Cardosal^® Plus during lactation, breastfeeding should be discontinued during its use.

Use in Hepatic Impairment

Contraindicated in severe hepatic impairment (more than 9 points on the Child-Pugh scale) (risk of hepatic coma), in biliary obstruction and cholestasis.

Use in Renal Impairment

Contraindicated in severe renal impairment (CrCl less than 30 ml/min.).

With caution

• Impaired renal function (CrCl greater than 30 ml/min but less than 60 ml/min);
• Bilateral renal artery stenosis or stenosis of the artery to a solitary kidney;
• Condition after recent kidney transplantation (no experience with the drug).

For patients with impaired renal function (CrCl = 30-60 ml/min), no dose adjustment of the drug is required.

Pediatric Use

Contraindicated in children under 18 years of age.

Geriatric Use

For elderly patients (over 65 years of age) with normal renal function (CrCl greater than 90 ml/min), no dose adjustment of the drug is required.

Special Precautions

Symptomatic arterial hypotension, especially after taking the first dose of the drug, may occur in patients with reduced blood volume and/or reduced sodium concentration due to intensive diuretic therapy, dietary salt restriction, as well as due to diarrhea or vomiting. Relevant factors should be corrected before starting treatment with Cardosal^® plus.

Thiazide diuretics, including Hydrochlorothiazide, may cause disturbances in blood volume or serum water-electrolyte balance (including hypokalemia, hyponatremia, and hypochloremic alkalosis). Warning symptoms are: dry oral mucosa, thirst, weakness, drowsiness, restlessness, myalgia or cramps, muscle weakness, arterial hypotension, oliguria, tachycardia, nausea, and vomiting (see section Adverse Reactions).

The highest risk of developing hypokalemia exists in patients with liver cirrhosis, in patients undergoing forced diuresis, and in those patients who are simultaneously taking glucocorticosteroids or ACTH (see section Drug Interactions). Conversely, due to the antagonism of the olmesartan medoxomil contained in Cardosal^® plus on angiotensin II (AT₁) receptors, hyperkalemia may occur – primarily in patients with impaired renal function and/or chronic heart failure, as well as patients with diabetes mellitus. In patients with risk factors, regular monitoring of serum potassium concentration is recommended. There are no data on whether Olmesartan medoxomil can reduce or prevent diuretic-induced hyponatremia. In hot weather, patients prone to edema may experience dilutional hyponatremia. The decrease in chloride concentration is generally mild and usually does not require treatment.

Thiazides may reduce renal excretion of calcium ions and also lead to a transient slight increase in serum calcium concentration in the absence of a history of calcium metabolism disorders. Hypercalcemia may indicate latent hyperparathyroidism. Thiazides should be discontinued before testing parathyroid function.

Thiazide diuretics have been shown to increase renal excretion of magnesium ions, which can lead to hypomagnesemia.

In patients in whom vascular tone and renal function depend significantly on the activity of the RAAS (e.g., patients with severe chronic heart failure or impaired renal function, including renal artery stenosis), treatment with other agents affecting the RAAS has been associated with the possibility of developing acute arterial hypotension, azotemia, oliguria, or, rarely, acute renal failure. The possibility of a similar effect cannot be excluded when using angiotensin II receptor antagonists.

There is an increased risk of developing severe arterial hypotension and renal failure if a patient with bilateral renal artery stenosis or stenosis of the artery to a solitary functioning kidney receives therapy with drugs affecting the RAAS. When using Cardosal^® plus in patients with impaired renal function, periodic monitoring of serum potassium ions, creatinine, and uric acid is recommended. There is no experience with the use of olmesartan medoxomil in patients with recent kidney transplantation or in patients with end-stage renal impairment.

In patients with limited renal function, the use of thiazide diuretics may be accompanied by azotemia. If renal failure progresses obviously, therapy should be reconsidered and the issue of discontinuing diuretics should be decided.

As with any antihypertensive drug, an excessive decrease in blood pressure in patients with coronary artery disease or cerebrovascular insufficiency may lead to myocardial infarction or stroke.

Thiazide diuretics can cause impaired glucose tolerance, as well as increased serum concentrations of cholesterol, triglycerides, and uric acid. In patients with diabetes mellitus, adjustment of the dose of insulin or oral hypoglycemic agents may be necessary (see section Drug Interactions). During treatment with thiazide diuretics, latent diabetes mellitus may become manifest.

There are reports that thiazide diuretics may contribute to the development of a gout attack and cause exacerbation of systemic lupus erythematosus. Hypersensitivity reactions to hydrochlorothiazide are more likely to occur in patients with a burdened allergic history or a history of bronchial asthma.

Effect on ability to drive vehicles and mechanisms

The effect of Cardosal^® plus on the ability to drive vehicles and operate machinery has not been specifically studied, therefore caution should be exercised when driving vehicles and engaging in potentially hazardous activities that require increased concentration and speed of psychomotor reactions during treatment with Cardosal^® plus.

Overdose

Symptoms of olmesartan medoxomil overdose are most likely a pronounced decrease in blood pressure, as well as tachycardia, bradycardia, nausea, drowsiness; symptoms of hydrochlorothiazide overdose are symptoms of electrolyte deficiency (hypokalemia, hypochloremia, hyponatremia) and dehydration due to excessive diuresis.

Treatment gastric lavage and/or administration of activated charcoal is recommended; therapy aimed at correcting dehydration and disturbances in water-electrolyte balance. In case of a pronounced decrease in blood pressure, it is recommended to place the patient in a horizontal position with legs elevated and carry out therapy aimed at replenishing the circulating blood volume. Hemodialysis is not effective.

Drug Interactions

Olmesartan medoxomil

Concomitant use with potassium-sparing diuretics, potassium preparations, salt substitutes containing potassium, or other drugs that can increase serum potassium concentration (e.g., heparin) is not recommended – an increase in serum potassium concentration is possible.

Nonsteroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid in doses greater than 3 g/day, as well as cyclooxygenase-2 (COX-2) inhibitors, and angiotensin II receptor antagonists may act synergistically, reducing glomerular filtration. When NSAIDs and angiotensin II receptor antagonists are used concomitantly, there may be a risk of developing acute renal failure, therefore monitoring of renal function at the beginning of treatment is recommended, as well as regular intake of sufficient fluids. At the same time, concomitant treatment may reduce the antihypertensive effect of angiotensin II receptor antagonists, leading to a partial loss of their therapeutic efficacy. When used concomitantly with antacids (magnesium and aluminum hydroxides), a moderate decrease in the bioavailability of olmesartan medoxomil is possible. There are reports of reversible increases in serum lithium concentration and manifestation of toxicity during concomitant use of lithium preparations with angiotensin-converting enzyme (ACE) inhibitors and with angiotensin II receptor antagonists, therefore the use of olmesartan medoxomil in combination with lithium preparations is not recommended. If the use of such combination therapy is necessary, regular monitoring of serum lithium concentration is recommended. In rare cases, ACE inhibitors may enhance the hypoglycemic effect of insulin and oral hypoglycemic agents (e.g., sulfonylurea derivatives) in patients with diabetes mellitus. In these cases, when using ACE inhibitors concomitantly, a reduction in the dose of the oral hypoglycemic agent and insulin may be required.

Hydrochlorothiazide

Glucocorticosteroids, adrenocorticotropic hormone (ACTH), amphotericin B (parenterally), carbenoxolone, penicillin G sodium salt, salicylic acid derivatives: their concomitant use with hydrochlorothiazide may lead to increased electrolyte losses, especially the development of hypokalemia.

Concomitant use of ion-exchange resins (cholestyramine, colestipol) reduces the absorption of hydrochlorothiazide.

Concomitant use of hydrochlorothiazide with calcium salts may lead to an increase in serum calcium concentration due to reduced excretion. If calcium preparations are necessary, its serum concentration should be monitored and its dose adjusted accordingly.

Concomitant use of hydrochlorothiazide with cardiac glycosides may lead to arrhythmias.

Drugs that can cause torsades de pointes arrhythmia (a special form of polymorphic ventricular tachycardia with a twisting, spiral, or spindle-shaped configuration of ventricular complexes combined with an increase or decrease in the amplitude of QRS complex waves, which can lead to ventricular fibrillation or asystole): due to the risk of hypokalemia, caution is required when hydrochlorothiazide is used concomitantly with certain antiarrhythmic drugs (quinidine, hydroquinidine, disopyramide, amiodarone, sotalol, dofetilide, ibutilide), antipsychotics (thioridazine, chlorpromazine, levomepromazine, trifluoperazine, cyamemazine, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol) and others (bepridil, cisapride, diphemanil methylsulfate, intravenous erythromycin, halofantrine, mizolastine, pentamidine, sparfloxacin, terfenadine, intravenous vincamine), which are known to be able to cause torsades de pointes arrhythmia.

When hydrochlorothiazide is used concomitantly with non-depolarizing muscle relaxants (including tubocurarine chloride) – enhancement of the effect of muscle relaxants.

Thiazides may increase the risk of adverse effects of amantadine. Treatment with thiazide diuretics may impair glucose tolerance. When M-cholinoblockers (atropine) and thiazides are used concomitantly, due to reduced gastrointestinal motility, the bioavailability of thiazide diuretics may increase.

A reduction in the dose of oral hypoglycemic agents and insulin may be required.

Antigout agents (probenecid, sulfinpyrazone, allopurinol): adjustment of the dose of the hypouricemic agent (increase in the dose of probenecid or sulfinpyrazone) may be necessary, since Hydrochlorothiazide may increase serum uric acid concentration. Concomitant use with thiazide diuretics may increase the frequency of hypersensitivity reactions to allopurinol. The effect of sympathomimetics may be weakened when taken concomitantly with thiazide diuretics.

Thiazide diuretics may reduce the renal excretion of cytotoxic agents and enhance their myelosuppressive effect.

When salicylates are taken in high doses, Hydrochlorothiazide may enhance their toxic effect on the central nervous system.

There are reports of isolated cases of hemolytic anemia with concomitant use of methyldopa with hydrochlorothiazide.

Concomitant use of cyclosporine with hydrochlorothiazide may increase the risk of hyperuricemia and exacerbation of gout.

Concomitant use of tetracyclines with thiazide diuretics increases the risk of increased urea concentration caused by tetracyclines. This interaction does not apply to doxycycline.

Olmesartan medoxomil/ Hydrochlorothiazide in combination

Concomitant use of lithium preparations with thiazide diuretics may increase the already elevated risk of lithium intoxication caused by ACE inhibitors, therefore concomitant use of Cardosal^® plus and lithium preparations is not recommended. If such a combination is nevertheless necessary, careful monitoring of serum lithium concentration is also necessary.

When Cardosal^® plus is used concomitantly with baclofen and amifostine, an enhancement of the antihypertensive effect is possible.

When other antihypertensive agents are used concomitantly, the hypotensive effect of Cardosal^® plus may be enhanced. Ethanol, barbiturates, narcotic analgesics, or antidepressants when used with Cardosal^® plus may lead to aggravated orthostatic hypotension.

Storage Conditions

Store at a temperature not exceeding 30°C (86°F). Keep the medicine out of the reach of children!

Shelf Life

Shelf life – 3 years.

Dispensing Status

By prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.