Cardosal® 40 (Cardosal® 40)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceOlmesartan medoxomilOlmesartan medoxomil
Dosage form: & nbspfilm-coated tablets
Composition:

1 tablet, film-coated, contains:

core: дActive substance: olmesartan medoxomil 40.00 mg;

Excipients: microcrystalline cellulose 40.00 mg, giprolose (with a low degree of substitution) 80.00 mg, lactose monohydrate 264.40 mg, giprolose (viscosity 6-10 mPaXs) 10.00 mg, magnesium stearate 3.60 mg;

shell: titanium dioxide (E 171) 1.680 mg, talc 1.680 mg, hypromellose (viscosity 5 mPaXs) 8.640 mg.

Description:

White, oval, double convex tablets, covered with a film shell, with an impression of "C15" on one side, with a subtle specific smell.

Pharmacotherapeutic group:angiotensin II receptor antagonist
ATX: & nbsp

C.09.C.A.08   Olmesartan medoxomil

Pharmacodynamics:

Olmesartan medoxomil, the active ingredient of Cardosal® 40, is a potent specific antagonist of angiotensin II receptors (such as AT1) for oral administration. Angiotensin II is the primary vasoactive hormone of the renin-angiotensin-aldosterone system and plays a significant role in the pathophysiology of hypertension by affecting the AT1-receptors.It is assumed that olmesartan blocks all the actions of angiotensin II, mediated by AT1-receptors, regardless of the source and route of synthesis of angiotensin II. Specific antagonism of olmesartan for angiotensin II (type AT1) leads to an increase in the activity of renin, angiotensin I and II in blood plasma, and also helps to reduce the plasma concentration of aldosterone. With arterial hypertension, olmesartan causes a dose-dependent prolonged decrease in blood pressure (BP). There is no evidence of the development of arterial hypotension after taking the first dose of the drug, of tachyphylaxis during long-term treatment or of the "withdrawal" syndrome (a sharp increase in BP after drug withdrawal).

Taking olmesartan medoxomil once a day provides an effective and gentle decrease in blood pressure within 24 hours, the effect after a single dose is similar to the effect of taking the drug twice a day in the same daily dose.

The antihypertensive effect of olmesartan develops, usually after 2 weeks, and the maximum effect develops approximately 8 weeks after the initiation of therapy.

Pharmacokinetics:

Absorption and distribution: olmesartan medoxomil is a prodrug. It quickly turns into the pharmacologically active metabolite olmesartan under the action of enzymes in the intestinal mucosa and in portal blood during absorption from the gastrointestinal tract. Olmesartan medoxomil in unmodified form or with an intact fragment of medoxomil is not found in blood plasma and / or feces. The bioavailability of olmesartan is 25.6% on average.

The maximum concentration (Cmax) of olmesartan in blood plasma is attained on average 2 hours after taking olmesartan medoxomil by mouth and increases approximately linearly with a single dose increase to 80 mg.

The ingestion of food does not significantly affect the bioavailability of olmesartan, therefore olmesartan medoxomil can be taken regardless of food intake.

Clinically significant differences in pharmacokinetic parameters of olmesartan, depending on sex, were not revealed.

Olmesartan binds to blood plasma proteins (99.7%), but the potential for a clinically significant shift in the amount of binding to proteins during the interaction of olmesartan with other highly-linked and simultaneouslythe drugs used are low (the absence of a clinically significant interaction between olmesartan and warfarin). The association of olmesartan with blood cells is negligible. The average volume of distribution after intravenous administration is low (16-29 L).

Metabolism and excretion: the total plasma clearance is usually 1.3 l / h (the coefficient of variation is 19%) and is relatively low in comparison with the hepatic blood flow (approximately 90 l / h).

Elimination of olmesartan is carried out in two ways. After a single oral administration of olmesartan medoxomil labeled with 14C isotope, 10-16% of the radioactive substance was excreted by the kidneys (most within 24 hours after taking olmesartan medoxomil), and the remaining radioactive substance was released through the intestine. Given the systemic bioavailability of 25.6%, it can be calculated that approximately 40% of the absorbed olmesartan is excreted through the kidneys, and about 60% through the hepatobiliary system. The released radioactive substance was represented by olmesartan. No other metabolites were detected. The intestinal and hepatic recirculation of olmesartan is minimal.Since most of the olmesartan is excreted through the liver, its use in patients with bile duct obstruction is contraindicated (see Contraindications section).

The half-life of olmesartan is 10-15 hours after repeated ingestion. The equilibrium state is achieved after taking the first few doses of the drug and after 14 days of repeated application no further cumulation is observed. Kidney clearance is approximately 0.5-0.7 l / h and does not depend on the dose of the drug.

Pharmacokinetics in patients with renal insufficiency

In patients with renal insufficiency, the area under the concentration-time curve (AUC) in the equilibrium state was increased by approximately 62%, 82% and 179% in the case of renal failure of mild, moderate and severe severity, respectively, compared to healthy volunteers.

Pharmacokinetics in patients with hepatic impairment

After a single oral dose, the AUC values ​​for olmesartan were 6% and 65% higher in patients with mild and moderate hepatic insufficiency, respectively, compared with healthy volunteers.The unbound fraction of olmesartan 2 hours after oral administration of the dose of the drug in healthy volunteers, in patients with mild to moderate hepatic insufficiency, was 0.26%, 0.34%, and 0.41%, respectively. When administered multiple times, the AUC for olmesartan in patients with moderate hepatic impairment was 65% higher than in healthy volunteers in the control group. Mean values ​​of Cmax Olmesartan in patients with hepatic insufficiency and healthy volunteers were similar. The pharmacokinetics of olmesartan medoxomil in patients with hepatic insufficiency of severe severity has not been studied.

Pharmacokinetics in patients 65 years of age and older

In elderly patients (65-75 years) and senile age (75 years and older) with arterial hypertension, the AUC of olmesartan in equilibrium was greater by 35% and approximately 44%, respectively, compared with younger patients, which may be partially related with an age-related decrease in kidney function.

Indications:

Essential hypertension.

Contraindications:

- Hypersensitivity to the active substance or to any of the auxiliary substances included in the preparation;

- Obstruction of the biliary tract;

- renal failure of severe severity (creatinine clearance less than 20 ml / min), condition after kidney transplantation (no experience of clinical use);

- hepatic insufficiency of severe severity (more than 9 points on the Child-Pugh scale, no experience of clinical use);

- simultaneous use with aliskiren and aliskirenoderzhaschimi drugs in patients with diabetes mellitus and / or renal dysfunction (CC less than 60 ml / min);

- pregnancy, the period of breastfeeding;

- age under 18 years (effectiveness and safety not established);

- Hereditary intolerance to galactose, deficiency of lactase and syndrome of malabsorption of glucose and galactose.

Carefully:

- Stenosis of the aortic or mitral valves;

- hypertrophic obstructive cardiomyopathy;

- primary aldosteronism;

- Hyperkalemia, hyponatremia (risk of dehydration, arterial hypotension, renal failure);

- renal failure of mild and moderate severity (QC more than 20 ml / min);

- Chronic heart failure;

- vasorenal hypertension (bilateral stenosis of the renal arteries or stenosis of the artery

the only kidney);

- cardiac ischemia;

- cerebrovascular diseases;

- Older age (over 65 years);

- hepatic insufficiency of moderate severity (less than 9 on the Child-Pugh scale);

- Conditions accompanied by a decrease in the volume of circulating blood (including diarrhea, vomiting), as well as in patients who follow a diet with restriction of table salt;

- with simultaneous use with diuretics;

- with simultaneous use with lithium preparations.

Pregnancy and lactation:

The experience of using olmesartan medoxomil in pregnant women is absent. However, in view of the available reports of severe teratogenic effects of drugs acting directly on the renin-angiotensin-aldosterone system, Cardosal® 40 is contraindicated during pregnancy. If pregnancy occurs during therapy with Cardosal® 40, the drug should be immediately discontinued and, if necessary, an alternative treatment should be prescribed.

Patients planning pregnancy are recommended to be transferred to antihypertensive drugs of other groups, the safety of which is proven in pregnancy, except for the cases when angiotensin II receptor antagonists are used for life indications.

If angiotensin II receptor antagonists are used in the second and third trimesters of pregnancy, ultrasound should be performed to assess kidney function and ossification of the fetal bones. Newborns whose mothers have received angiotensin II receptor antagonists should be observed for possible development of arterial hypotension and impaired renal function.

It has been shown that olmesartan penetrates into breast milk in rats, but there are no analogous data for humans. If you need Cardosal® 40 during lactation, breastfeeding should be discontinued.

Dosing and Administration:

Inside. Cardosal® 40 is taken at the same time regardless of food intake 1 time per day, without chewing, squeezed with enough liquid.

To select the desired dosage regimen, it is advisable to use the most suitable dosage of the drug - 10 mg, 20 mg or 40 mg (Cardosal® 10, Cardosal® 20 or Cardosal® 40, respectively) can be used.

The recommended initial dose of olmesartan medoxomil is 10 mg once daily.In case of insufficient reduction in blood pressure, the dose can be increased to 20 mg once a day, if necessary, the dose may be increased to 40 mg per day.

The maximum daily dose is 40 mg.

Use in patients 65 years and older

When using the drug in patients older than 65 years, it is necessary to carry out a thorough control of blood pressure.

Use in patients with renal insufficiency

The maximum dose of Cardosal® 40 in patients with mild and moderate renal insufficiency (creatinine clearance 20-60 ml / min) is 20 mg per day. The use of Cardosal® 40 in patients with severe renal insufficiency (creatinine clearance <20 ml / min) is contraindicated (see Contraindications section).

Use in patients with hepatic impairment

With hepatic insufficiency of mild severity, dose adjustment is not required. With a moderate level of liver failure, the initial dose of Cardosal® 40 is 10 mg once daily. The maximum daily dose is 20 mg. With concomitant therapy with diuretics and / or other antihypertensive drugs, patients with hepatic insufficiency are recommended to carefully monitor blood pressure and kidney function.The drug Cardosal® 40 is contraindicated in patients with hepatic insufficiency of severe severity. The use of Cardosal® 40 is also contraindicated in patients with bile duct obstruction (see Contraindications section).

Side effects:

Possible side effects are given below on the descending frequency of occurrence: very often (> 1/10); often (> 1/100 <1/10); sometimes (> 1/1000, <1/100); rarely (> 1/10000, <1/1000); Very rarely (<1/10000), including individual messages, (in accordance with the MedDRA classification).

From the side of the blood and lymphatic system: infrequently, thrombocytopenia.

From the nervous system: hasto - dizziness, headache.

From the side of the hearing organ and labyrinthine disorders: infrequently - vertigo.

On the part of the respiratory system, the organs of the thorax and the mediastinum: often - pharyngitis, rhinitis, bronchitis, cough.

From the side of the digestive tract: often - diarrhea, indigestion, gastroenteritis, abdominal pain, nausea; infrequently - vomiting.

From the skin and subcutaneous tissues: infrequently - exanthema, allergic dermatitis, urticaria, rash, itchy skin; rarely angioedema.

From the side of the musculoskeletal system: often - back pain, bone pain, arthritis; infrequently - myalgia; rarely - muscle cramps.

From the side of the kidneys and urinary tract: often - hematuria, urinary tract infection; rarely acute renal failure, renal insufficiency.

From the side of the cardiovascular system: infrequently - angina pectoris; rarely a marked decrease in blood pressure.

From the side of metabolism and nutrition: often - increasing the concentration of triglycerides in blood plasma, increasing the concentration of uric acid in the blood; rarely - an increase in the concentration of potassium in the blood.

From the immune system: infrequently, anaphylactic reactions.

Common violations: often - chest pain, peripheral edema, flu-like symptoms, weakness; infrequently - edema of the face, asthenia, malaise; rarely - drowsiness.

Other violations: often - increased urea concentration in blood plasma, increased activity of liver enzymes, increased concentration of creatine phosphokinase; rarely - an increase in the concentration of creatinine in the blood plasma.

There have also been reports of single cases of rhabdomyolysis, which was associated with the administration of AT-II receptor antagonists over time.

* In elderly patients, arterial hypotension can be observed somewhat more often (from "rarely" to "infrequently").

Overdose:

There are limited data on cases of overdose of olmesartan medoxomil in humans.

Symptoms: marked decrease in blood pressure.

Treatment: with a pronounced decrease in blood pressure, it is recommended to put the patient on his back, lifting his legs. Recommended gastric lavage and / or reception of activated charcoal, therapy aimed at correcting dehydration and disturbances of water-electrolyte metabolism, replenishment of circulating blood volume.

Elimination of olmesartan by dialysis has not been studied.

Interaction:

Do not use concurrently with potassium-sparing diuretics, potassium preparations, salt substitutes containing potassium, or other drugs that increase potassium levels in the blood plasma (eg, anti-inflammatory drugs (including selective inhibitors of cyclooxygenase-2 (COX-2)), immunosuppressants (eg, ciclosporin or tacrolimus), trimethoprim, angiotensin-converting (ACE) inhibitors, heparin), t. this can lead to an increase in the potassium content in the blood plasma (see section Special instructions).

The antihypertensive effect of olmesartan therapy can be enhanced by simultaneous application of with other antihypertensive agents.

Non-steroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid in doses greater than 3 g / day, as well as COX-2 inhibitors and angiotensin II receptor antagonists can act synergistically, reducing glomerular filtration. With the simultaneous use of NSAIDs and angiotensin II receptor antagonists, there may be a risk of developing acute renal failure, so it is recommended that kidney function be monitored at the beginning of treatment and that a sufficient amount of fluid is taken regularly. However, simultaneous use can reduce the antihypertensive effect of angiotensin II receptor antagonists, leading to a partial loss of their therapeutic efficacy.

With simultaneous application with antacids (magnesium and aluminum hydroxide) a moderate decrease in the bioavailability of olmesartan is possible.

With simultaneous application olmesartan medoxomil does not have a clinically significant effect on pharmacokinetics and pharmacodynamics warfarin, digoxin, hydrochlorothiazide, pravastatin and antacids (magnesium and aluminum hydroxide).

There have been reports of a reversible increase in serum lithium concentration and toxicity during simultaneous use of lithium preparations with ACE inhibitors and with angiotensin II receptor antagonists,therefore, the use of olmesartan medoxomil in combination with lithium preparations not recommended (see section Special instructions). If it is necessary to use the appropriate combination therapy, regular monitoring of the concentration of lithium in the blood serum is recommended.

Clinical studies show that the double blockade of the renin-angiotensin-aldosterone system (RAAS) with simultaneous application ACE inhibitors, angiotensin II receptor antagonists, or aliskiren, is associated with a higher incidence of side effects such as hypotension, hyperkalemia, and decreased kidney function (including acute renal failure) than with only one drug that affects RAAS. Thus, simultaneous use of ACE inhibitors, angiotensin II receptor antagonists or aliskiren is not recommended.

Simultaneous use of olmesartan medoxomil and preparations containing aliskiren, is contraindicated in patients with diabetes mellitus and renal insufficiency (at a glomerular filtration rate <60 ml / min /m2).

Patients with diabetic nephropathy should not simultaneously use ACE inhibitors and angiotensin II receptor antagonists.

In the case when the simultaneous use of two agents affecting the RAAS is necessary, their application should be under the supervision of a physician and with regular monitoring of kidney function, blood pressure and electrolyte concentration in the blood plasma.

The clinically significant inhibitory effect of olmesartan on the isoenzymes 1A1 / 2, 2A6, 2C8 / 9, 2C19, 2D6, 2E1 and ZA4 of human cytochrome P450 was not detected in vitro; a minimum or zero inducing effect was noted for rat cytochrome P450, suggesting the absence of clinically significant interactions with the simultaneous use of olmesartan medoxomil and drugs metabolized with the abovementioned cytochrome P450 isoenzymes.

Special instructions:

Symptomatic arterial hypotension, especially after taking the first dose of the drug, can occur in patients with reduced circulating blood volume and / or reduced sodium levels due to intensive diuretic therapy, restricting consumption of table salt with food during dietary intake, and also due to diarrhea or vomiting.Corresponding factors should be eliminated before starting the use of Cardosal® 40.

In patients who have vascular tone and renal function to a large extent depend on the activity of the renin-angiotensin-aldosterone system (for example, in patients with severe chronic heart failure or renal dysfunction, including renal artery stenosis), treatment with other drugs acting on the this system is associated with the possibility of developing acute arterial hypotension, azotemia, oliguria, or, in rare cases, acute renal failure.

The possibility of a similar effect can not be ruled out with the use of angiotensin II receptor antagonists.

There is an increased risk of severe arterial hypotension and kidney failure if a patient with bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney receives therapy with drugs that affect the renin-angiotensin-aldosterone system.

When using Cardosal® 40 in patients with impaired renal function, periodic monitoring of the potassium and creatinine levels in the blood plasma is recommended.The experience with Cardosal® 40 in patients with recent kidney transplantation or in patients with end-stage renal impairment (eg, KC less than 12 mL / min) is not available.

When angiotensin II receptor antagonists or ACE inhibitors are used, hyperkalaemia may develop, which in some cases can lead to death. The risk of hyperkalemia increases with simultaneous use with drugs that increase the potassium content in the blood plasma (see Interactions with other drugs), in elderly patients, with renal failure (including with the progression of renal failure, acute disruption of function kidneys, for example, in infectious diseases), diabetes mellitus, dehydration, acute cardiac decompensation, metabolic acidosis, conditions accompanied by massive lysis of the cell ok (for example, with acute limb ischemia, rhabdomyolysis, extensive injuries). Patients at this risk group are recommended to monitor the potassium content in the blood plasma.

Before the appointment simultaneously with the drug Cardosal® 40 other drugs that affect the renin-angiotensin-aldosterone system should carefully evaluate the benefit / risk ratio of this combination and consider other options for therapy.

As with other angiotensin II receptor antagonists, a combination of lithium preparations and Cardosal® 40 is not recommended (see Interactions with Other Drugs).

As with other angiotensin II receptor antagonists, in Negroid hypertensive patients, the effectiveness of Cardosal® 40 treatment is slightly lower than in patients of other races, possibly due to the greater prevalence of low renin activity in plasma in this population. As with any antihypertensive drug, excessive reduction in blood pressure in patients with coronary heart disease or with cerebrovascular insufficiency can lead to myocardial infarction or stroke.

The drug contains lactose, so its use in patients with hereditary intolerance to galactose, a deficiency of lactase and a syndrome of malabsorption of glucose and galactose is contraindicated.

Effect on the ability to drive transp. cf. and fur:

Cardosal® 40 has little or moderate influence on the ability to drive vehicles and other mechanisms.

Since during the period of treatment with Cardosal® 40, side effects such as drowsiness and weakness are possible, care should be taken when driving vehicles, other mechanisms and employing potentially dangerous activities requiring increased concentration of attention and speed of psychomotor reactions.

Form release / dosage:

Tablets, film-coated, 40 mg.

Packaging:

For 14 tablets in a planar cell package (blister) made of a laminated film (polyamide / aluminum / PVC) and aluminum foil.

By I, 2,4 or 7 blisters together with instructions for use in a cardboard pack.

Storage conditions:

Store at a temperature not exceeding 30 0 FROM.

Keep out of the reach of children.
Shelf life:

3 years.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription
Registration number:LSR-000629/10
Date of registration:03.02.2010
The owner of the registration certificate:Berlin-Chemie / Menarini Pharma, GmbH Berlin-Chemie / Menarini Pharma, GmbH Germany
Manufacturer: & nbsp
Representation: & nbspBERLIN-CHEMI / MENARINI PHARMA GmbH BERLIN-CHEMI / MENARINI PHARMA GmbH Germany
Information update date: & nbsp17.08.2015
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