Cardosal Plus, 12.5mg+20 mg 28 pcs

Pharmacodynamics

Cardosal® Plus is a combination drug containing an angiotensin II receptor antagonist (olmesartan medoxomil) and a thiazide diuretic (hydrochlorothiazide). The combination of the two active substances has a combined antihypertensive effect, due to which BP is reduced to a greater extent than when taking each of them separately. When taking the drug once a day, effective and uniform lowering of BP is achieved within 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. Olmesartan medoxomil is thought to block all angiotensin P effects mediated by AT1 receptors regardless of the source or synthesis pathway of angiotensin II.

In arterial hypertension, olmesartan medoxomil causes a dose-dependent prolonged decrease in BP. There are no data on the development of arterial hypotension after the first dose of the drug and on the development of “withdrawal” syndrome (a sharp increase in BP after drug withdrawal).

The administration of olmesartan medoxomil once daily provides effective and gentle BP lowering for 24 hours. Hypotensive effect of olmesartan medoxomil usually comes after 2 weeks, and the maximum effect develops approximately 8 weeks after the beginning of therapy.

Hydrochlorothiazide, a thiazide diuretic, impairs reabsorption of sodium, chloride and water ions in the renal tubules. It increases excretion of potassium ions, magnesium ions, hydrocarbonates, delays calcium ions in the body. Diuretic effect starts 2 hours after hydrochlorothiazide intake, reaches its maximum after 4 hours and lasts up to 12 hours. It helps to reduce high blood pressure. When combined administration of olmesartan medoxomil and hydrochlorothiazide, the loss of potassium ions caused by the action of the diuretic is reduced. The result of combined therapy with olmesartan medoxomil and hydrochlorothiazide is potentiation of the hypotensive effect, which depends on the dose of each component of the drug. Combination therapy is well tolerated by patients. With long-term treatment the effectiveness of combined therapy (olmesartan medoxomil/hydrochlorothiazide) is maintained, development of “withdrawal” syndrome is not observed.

Pharmacokinetics

Absorption and distribution

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

The Cmax of olmesartan in plasma is reached on average 2 hours after oral administration and increases approximately linearly with increasing single dose up to 80 mg.

Eating has no significant effect on the bioavailability of olmesartan medoxomil, so olmesartan medoxomil can be taken regardless of meals.

There are no clinically significant differences in the pharmacokinetic parameters of olmesartan medoxomil depending on gender.

Olmesargan has a high degree of binding to plasma proteins (99.7%). When concomitant use of olmesartan medoxomil with other medicinal agents characterized by high degree of binding to blood plasma proteins no significant changes of the indicated value occur (this is confirmed by absence of clinically significant interaction between olmesartan medoxomil and warfarin). Binding of olmesartan to blood cells is insignificant.

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

Hydrochlorothiazide binds to plasma proteins by 68%. Systemic bioavailability of hydrochlorothiazide in concomitant use with olmesartan medoxomil decreases by about 20%, but this slight decrease is not clinically significant. Concomitant administration of hydrochlorothiazide, for its part, has no significant effect on the kinetics of olmesartan medoxomil. In controlled clinical trials, a pronounced antihypertensive effect of this combination was detected, which exceeded the effect of each of the components separately, as well as the effect of placebo.

Metabolism and excretion

The total plasma clearance of olmesartan is typically 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%, with bile through the intestine 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 elimination half-life of olmesartan is 10-15 h. Sustained effect of therapy is achieved during 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 excreted almost completely unchanged by the kidneys. After oral administration about 60% of the taken dose of hydrochlorothiazide in unchanged form is excreted within 48 hours. Renal clearance of hydrochlorothiazide is about 250-300 ml/min; T1/2 of the end 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 in the saturation phase is increased by approximately 35% compared to the group of patients younger than 65 years, in patients over 75 years – by approximately 44%. The available data suggest that the systemic clearance of hydrochlorothiazide in both healthy elderly volunteers and elderly patients with arterial hypertension is decreased compared to younger volunteers. In patients with impaired renal function (CK = 30-60 ml/min), the AUC for olmesartan at saturation is increased by approximately 62, 82 and 179% for mild, moderate and severe renal impairment, respectively, compared to healthy volunteers. The T1/2 of hydrochlorothiazide may be increased for this category of patients.

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

There are no data on the pharmacokinetics of olmesartan medoxomil in patients with severe hepatic impairment (greater than 9 points on the Child-Pugh scale).

Indications

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

Active ingredient

Composition

1 tablet contains:

acting substances

hydrochlorothiazide 12.5 mg;

olmesartan medoxomil 20 mg.

How to take, the dosage

Tablets of Cardosal® plus are taken orally regardless of meals. Prior to prescribing the combination drug Cardosal® plus, it is recommended that the dose of each active ingredient separately (i.e., olmesartan medoxomil and hydrochlorothiazide) be preselected.

The recommended dose:

1 tablet of Cardosal® plus containing 20 mg olmesartan medoxomil and 12.5 mg hydrochlorothiazide daily in the absence of adequate BP control on olmesartan medoxomil monotherapy at a dose of 20 mg;

If there is inadequate control of blood pressure during therapy with Cardosal® Plus containing 20 mg olmesartan medoxomil and 12.5 mg hydrochlorothiazide, 1 tablet daily may be used with Cardosal® Plus containing 20 mg olmesartan medoxomil and 25 mg hydrochlorothiazide.

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

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

Interaction

Olmesartan medoxomil

The co-administration with potassium-saving diuretics, potassium preparations, potassium salt substitutes, or other drugs that may increase serum potassium concentration (e.g., heparin) is not recommended – serum potassium concentration may increase.

Non-steroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid at doses greater than 3 g/day, as well as cyclooxygenase-2 (COX-2) inhibitors, and angiotensin II receptor antagonists may act synergistically to reduce glomerular filtration.

Concomitant use of NSAIDs and angiotensin II receptor antagonists may result in a risk of acute renal failure, so monitoring renal function at the beginning of treatment is recommended, as well as regular intake of adequate 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 effectiveness.

In concomitant use with antacids (magnesium and aluminum hydroxides) a moderate decrease in bioavailability of olmesartan medoxomil is possible. There have been reports of reversible increase in serum lithium concentration and toxicity during concomitant use of lithium with angiotensin-converting enzyme inhibitors (ACE) and angiotensin II receptor antagonists, so the use of olmesartan medoxomil in combination with lithium preparations is not recommended.

If appropriate combination therapy is required, regular monitoring of serum lithium concentration is recommended. In rare cases, ACE inhibitors may increase the hypoglycemic effect of insulin and hypoglycemic agents for oral administration (e.g., sulfonylurea derivatives) in patients with diabetes. In these cases, the simultaneous use of ACE inhibitors may require reducing the dose of hypoglycemic agents for oral administration and insulin.

Hydrochlorothiazide

Glucocorticosteroids, adrenocorticotropic hormone (ACTH), amphotericin B (parenterally), carbenoxolone, penicillin G sodium salt, salicylic acid derivatives: When they are taken concomitantly with hydrochlorothiazide, there may be increased electrolyte loss, particularly the development of hypokalemia.

The simultaneous use of ion exchange drugs (colesteramine, colestepol) reduces absorption of hydrochlorothiazide.

In concomitant use of hydrochlorothiazide with calcium salts may increase serum calcium concentration due to reduced excretion. If it is necessary to prescribe calcium preparations, its concentration in serum should be monitored and the dose should be adjusted accordingly.

In concomitant use of hydrochlorothiazide with cardiac glycosides, arrhythmias may occur.

The drugs may cause “torsades des pointes” arrhythmias (a particular form of polymorphic ventricular tachycardia with wave-, spiral-, or spindle-shaped ventricular complexes in combination with increased or decreased amplitude of the QRS teeth, which can lead to ventricular fibrillation or asystole) Because of the risk of hypokalemia, caution is required when using hydrochlorothiazide concomitantly with certain antiarrhythmic agents (quinidine, hydroquinidine, disopyramide, amiodarone, sotalol, dofetilide, ibutilide), neuroleptics (thioridazine, chlorpromazine, levomepromazine, trifluoperazine, ciamemazine, sulpiride sultopride, amisulpride, thiapride, pimozide, haloperidol, droperidol) and others (bepridal, cisapride, difemanil methyl sulfate, IV erythromycin, halofantrine, misolastin, nentamidine, sparfloxacin, terfenadine, IV vincamine) known to cause pirouette arrhythmias.

When hydrochlorothiazide is used together with nondepolarizing muscle relaxants (including tubocurarine chloride), the effects of muscle relaxants are increased.

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

Dose reduction of oral hypoglycemic agents and insulin may be required.

Antipodagric agents (probenecid, sulfinpyrazone, allopurinol): it may be necessary to adjust the dose of hypopyuricemic agents (increase the dose of probenecid or sulfinpyrazone), because hydrochlorothiazide may increase the concentration of uric acid in the blood serum. Concomitant use with thiazide diuretics may increase the frequency of hypersensitivity reactions to allopurinol. The effect of sympathomimetics may be impaired when concomitant use of thiazide diuretics.

Thiazide diuretics may decrease renal excretion of cytotoxic agents and increase their myelosuppressive effect.

Hydrochlorothiazide may increase their toxic effects on the CNS when taking salicylates at high doses.

There have been reports of single cases of hemolytic anemia when concomitant administration of methyldopa with hydrochlorothiazide.

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

The concomitant use of tetracyclines with thiazide diuretics increases the risk of tetracyclines-induced increases in urea concentrations. This interaction does not apply to doxycycline.

Olmesartan medoxomil/hydrochlorothiazide in combination

The concomitant use of lithium preparations with thiazide diuretics may increase the already increased risk of lithium intoxication due to 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 concentrations is also necessary.

The simultaneous use of Cardosal® Plus with baclofen and amifostine may increase the antihypertensive effect.

The simultaneous use of other antihypertensive agents may increase the hypotensive effect of Cardosal® Plus. Ethanol, barbiturates, narcotic analgesics or antidepressants when used with Cardosal® Plus may worsen orthostatic hypotension.

Special Instructions

Symptomatic arterial hypotension, especially after the first dose of the drug, may occur in patients with decreased RBC and/or reduced sodium concentration due to intensive diuretic therapy, dietary salt restriction, or due to diarrhea or vomiting. These factors should be eliminated before initiating the use of Cardosal® Plus.

The thiazide diuretics, including hydrochlorothiazide, may cause abnormal CBC or serum water-electrolyte balance (including hypokalemia, hyponatremia, and hypochloremic alkalosis). Precursor symptoms are: dry mouth, thirst, weakness, sleepiness, restlessness, myalgia or cramps, muscle weakness, arterial hypotension, oliguria, tachycardia, nausea and vomiting (see section Side effects).

The highest risk of hypokalemia exists in patients with cirrhosis, in patients undergoing forced diuresis and in those patients who simultaneously take glucocorticosteroids or ACTT (see section Interaction with other medicinal products). On the contrary, because of antagonism of olmesartan medoxomil contained in Cardosal® plus against angiotensin II receptors (AT1) hyperkalemia may occur – especially in patients with decreased renal function and/or chronic heart failure as well as in patients with diabetes. In patients with risk factors, regular monitoring of serum potassium concentrations is recommended. There is no data on whether olmesartan medoxomil can reduce or prevent diuretic-induced hyponatremia. In hot weather, dilutional hyponatremia may occur in patients prone to edema.

The decrease in chloride concentrations is generally mild and does not usually require treatment. Thiazides may decrease renal excretion of calcium ions and also lead to transient slight increase of calcium concentration in blood serum in the absence of a history of calcium metabolism disorders. Hypercalcemia may indicate occult hyperparathyroidism. Thiazides should be discontinued before parathyroid function study.

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

In patients in whom vascular tone and renal function are highly dependent on RAAS activity (e.g., in patients with severe chronic heart failure or impaired renal function including renal artery stenosis), treatment with other agents affecting RAAS is associated with the possibility of acute arterial hypotension, azotemia, oliguria or, in rare cases, acute renal failure. The possibility of similar action cannot be excluded by the use of angiotensin P receptor antagonists.

There is an increased risk of severe arterial hypotension and renal failure if the patient with bilateral renal artery stenosis or artery stenosis of the only functioning kidney is treated with agents that affect the RAAS. When using Cardosal® Plus in patients with impaired renal function, periodic monitoring of serum concentrations of potassium ions, creatinine and uric acid is recommended. There is no experience with olmesartan medoxomil in patients with recent kidney transplantation or in patents with end-stage renal dysfunction.

In patients with restricted renal function, administration of thiazide diuretics may be accompanied by azotemia. If there is obvious progression of renal failure, the therapy should be reconsidered and the issue of discontinuation of diuretics should be considered.

As with any antihypertensive drug, excessive BP reduction in patients with CHD or with cerebrovascular insufficiency may lead to myocardial infarction or stroke.

Thiazide diuretics may cause impaired glucose tolerance and increased serum cholesterol, triglycerides and uric acid concentrations. In patients with diabetes mellitus it may be necessary to adjust the dose of insulin or hypoglycemic oral agent (see section Interaction with other medicinal products). When treated with thiazide diuretics, latent diabetes mellitus may 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 history of allergy or bronchial asthma (history).

Impact on ability to drive vehicles and other mechanisms requiring increased concentration

Introduction of Cardosal® plus Influence of the drug Cardosal® Plus on driving and operating machinery has not been studied so it is necessary to be careful when driving vehicles and engaging in potentially dangerous activities requiring increased concentration and quick psychomotor reactions during the treatment with the drug Cardosal® Plus.

Contraindications

Side effects

Possible side effects are listed below in descending frequency of occurrence:

Combination of olmesartan medoxomil and hydrochlorothiazide

CNS disorders: frequent – dizziness; infrequent – syncope.

Cardiovascular system: infrequent – palpitations, marked BP decrease, orthostatic hypotension.

Skin: infrequent – skin rash, eczema.

Mechanical system disorders: not rare – hyper- or hypokalemia, hypercalcemia, hypertriglyceridemia, hyperuricemia, increased concentration of lipids in blood.

Laboratory disorders: very rarely – slight increase of creatinine, uric acid and urea nitrogen concentration in blood serum, slight decrease of hemoglobin concentration and hematocrit.

Olmesartan Medoxomil (monotherapy)

Blood system disorders: very rare – thrombocytopenia.

CNS disorders: very rare – dizziness, headache.

Cardiovascular system disorders: rare – significant decrease of BP; infrequent – angina pectoris.

Respiratory system: often – bronchitis, pharyngitis, rhinitis; very rarely – cough.

Gastrointestinal tract: often – diarrhea, dyspepsia, gastroenteritis; very rare – abdominal pain, nausea, vomiting.

The urinary system: often – hematuria, urinary tract infection; very rarely – acute renal failure.

Musculoskeletal system: often – arthritis, back pain; very rarely – muscle cramps, myalgia.

Skin disorders: very rarely – skin itching, exanthema, angioedema, allergic dermatitis, urticaria.

Mechanisms: often – increase of creatine phosphokinase activity, hypertriglyceridemia, hyperuricemia; rarely – hyperkalemia.

Laboratory measures: very rarely – increase of concentration of creatinine and urea in blood serum; often – increase of activity of “hepatic” transaminases.

Other disorders: frequently – pain in the chest, flu-like symptoms, peripheral edema; very rarely – weakness, fatigue, somnolence, malaise.

Hydrochlorothiazide (monotherapy)

Hematopoietic system disorders: rarely – leukopenia, neutropenia, agranulocytosis, thrombocytopenia, and plastic anemia, hemolytic anemia, inhibition of medullar hemopoiesis.

The central and peripheral nervous system: frequently – dizziness, weakness, headache, increased fatigue; rarely – anxiety, sleep disturbance, confusion, apathy, depression, numbness, paresthesia, seizures.

An organ of vision: rarely xanthopsia, transient accommodation disorder, decreased lacrimal fluid formation.

Cardiovascular system: infrequent – orthostatic hypotension; rarely – arrhythmias, thrombosis, embolism.

Respiratory system: rarely – dyspnea (including interstitial pneumonia and pulmonary edema).

Gastrointestinal tract: infrequent – anorexia, abdominal pain, nausea, vomiting, diarrhea, constipation, flatulence, salivary gland inflammation; rare – pancreatitis, acute cholecystitis, intrahepatic cholestatic jaundice; very rare – paralytic ileus.

Urogenital system disorders: rarely – renal dysfunction, interstitial nephritis, acute renal failure, impaired potency.

Musculoskeletal system disorders: rare – muscle cramps, muscle weakness, paresis.

Skin disorders: infrequent photosensitization, skin rash, urticaria; rarely: development of lupus-like syndrome (fever, arthralgia, myalgia, serositis, vasculitis, increased erythrocyte sedimentation rate (ESR), leukocytosis, eosinophilia), activation of cutaneous form of systemic lupus erythematosus, anaphylactic reactions, toxic epidermal necrolysis.

Laboratory disorders: often – hyperglycemia, glucosuria, hyperuricemia, increased concentration of creatinine in serum, electrolyte-water balance disorders (including hyponatremia, hypomagnesemia, hypochloremia, hypocalcaemia, and hypercalcaemia), increased concentration of cholesterol and triglycerides in blood.

Other disorders: rarely – fever.

Overdose

Symptoms: In overdose of olmesartan medoxomil pronounced BP decrease is most likely, as well as tachycardia, bradycardia, nausea, somnolence; in hydrochlorothiazide overdose – 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 correction of dehydration and disorders of water-electrolyte balance. If the BP is significantly decreased, it is recommended to put the patient in a horizontal position with elevated legs, and conduct therapy to replenish the blood pressure. Hemodialysis is not effective.