МикардисПлюс®

General characteristics. Structure:

Active ingredients: 40 mg or 80 mg of a telmisartan, 12,5 mg of Hydrochlorthiazidum.

Excipients: povidone, меглумин, sodium hydroxide, sorbitol, magnesium stearate, cellulose microcrystallic, ferrous oxide red, starch sodium glycollate, lactoses monohydrate, starch corn.

The combined anti-hypertensive drug with a diuretic component.

Pharmacological properties:

Pharmacodynamics. МикардисПлюс® represents a combination of a telmisartan (the antagonist of receptors of angiotensin II) and Hydrochlorthiazidum - thiazide diuretic. Simultaneous use of these components results in bigger anti-hypertensive effect, than use of each of them separately. Reception of Mikardisplus® once a day, leads to an essential gradual lowering of arterial pressure (ABP).

Telmisartan. Telmisartan is the specific antagonist of receptors of angiotensin II (AT1 type). Has high affinity to the AT1 subtype of receptors of angiotensin II through which effect of angiotensin II is implemented. Telmisartan forces out angiotensin of II of communication with a receptor, without possessing action of an agonist concerning this receptor. Telmisartan forms communication only with the AT1 subtype of receptors of angiotensin II. Binding has long character. Telmisartan has no affinity to other receptors, including to AT2 to a receptor and another, less studied angiotensin receptors. Functional value of these receptors, and also effect of their possible excess stimulation by angiotensin II which concentration increases at purpose of a telmisartan, are not studied. Telmisartan leads to decrease in level of Aldosteronum in blood. Telmisartan does not block a renin in blood and ion channels, does not block an angiotensin-converting enzyme, bradikinin does not inactivate.

At people телмисартан in a dose of 80 mg completely block hypertensive effect of angiotensin II. Effect of drug continues more than 24 hours, including the last 4 hours before reception of the next dose.

The beginning of hypotensive action is noted within 3 hours after the first reception of a telmisartan. The maximum lowering of arterial pressure (ABP) is usually observed in 4 weeks after an initiation of treatment.

At the patients having arterial hypertension телмисартан reduces systolic and diastolic the ABP, without exerting impacts on the heart rate (HR).

In case of sharp cancellation of a telmisartan of the ABP gradually is returned to initial level without development of a syndrome of "cancellation".

Hydrochlorthiazidum. Hydrochlorthiazidum is thiazide diuretic. Thiazide diuretics influence a reabsorption of electrolytes in renal tubules, directly increasing excretion of sodium and chlorides (approximately in equivalent quantities). Diuretic action of Hydrochlorthiazidum leads to reduction of volume of the circulating blood, increase in activity of a renin of plasma, increase in secretion of Aldosteronum and is followed by increase in content in urine of potassium and bicarbonates, and also a hypopotassemia. At a concomitant use of a telmisartan the tendency to the termination of the loss of potassium caused by these diuretics, presumably due to blockade system renin-angiotensin-aldosteronovoy is noted.

After reception of Hydrochlorthiazidum the diuresis amplifies in 2 hours, and the maximum effect is observed approximately in 4 hours. Diuretic effect of drug remains within about 6-12 hours.

Prolonged use of Hydrochlorthiazidum reduces risk of development of complications of cardiovascular diseases and mortality from them.

The maximum anti-hypertensive effect of Mikardisplus® is usually reached in 4 weeks after an initiation of treatment.

Pharmacokinetics. Combined use of a hydrochlorothiazide and telmisartan does not exert impact
on pharmacokinetics of each of drug components.

Telmisartan. At intake the maximum concentration of a telmisartan are reached within 0.5 - 1.5 hours after use. Absolute bioavailability of a telmisartan in doses from 40 to 160 mg was 42% and 58%, respectively. At reception along with food bioavailability of a telmisartan with decrease in the area under a curve of dependence of concentration from time (AUC) for 6% slightly decreases at a dose of 40 mg and about 19% at a dose of 160 mg. 3 hours later after intake concentration in a blood plasma is leveled irrespective of whether drug together with food or on an empty stomach was accepted. Pharmacokinetics of a telmisartan at use inside nonlinear at doses of 20 - 160 mg with more, than proportional increase in plasma concentration (Cmax and AUC) at increase in doses.

Hydrochlorthiazidum: after intake Mikardisplus, the maximum concentration of Hydrochlorthiazidum are reached within 1 - 3 hours. Absolute bioavailability, is estimated on cumulative renal excretion of Hydrochlorthiazidum and makes about 60%.

Telmisartan: communication with proteins of a blood plasma is considerable (> 99.5%), generally albumine and alpha 1 - a glycoprotein. Distribution volume for a telmisartan about 500 liters.

Hydrochlorthiazidum: 64% of Hydrochlorthiazidum communicate proteins of a blood plasma, and the volume of distribution of 0.8+0.3 l/kg.

Telmisartan: The most part of the entered dose (> 97%) is removed with bile, and then with a stake. In insignificant quantities drug is removed by kidneys. Telmisartan is metabolized by a konjyugirovaniye with glucuronic acid. The metabolite (acylglucuronide) pharmacological is inactive. A glucuronide - the main metabolite which is defined only at people.
The general plasma clearance makes more than 1500 ml/min. The elimination half-life (T 1/2) makes more than 20 hours.

The hydrochlorothiazide is not metabolized in a human body and removed by kidneys practically in not changed look. About 60% of the dose accepted inside eliminirutsya within 48 hours. Renal clearance about 250 - 300 ml/min. T of % of a hydrochlorothiazide of 10 - 15 hours.

The difference in plasma concentration at men and women is observed. At women concentration of a telmisartan in plasma is 2-3 times higher, than at men, also at women is tended to increase in plasma of concentration of Hydrochlorthiazidum. Nevertheless, strengthening of hypotensive effect at the same time at women is not observed.

Elderly patients. Pharmacokinetic indicators of a telmisartan do not differ considerably at patients of young and advanced age.

Patients with a renal failure. Renal excretion does not influence clearance of a telmisartan. Based on excretion level at patients with easy to average degree of a renal failure (clearance of creatinine of 30-60 ml/min., an average of 50 ml/min.), any correction of the mode of dosing is not required.

Telmisartan does not leave at dialysis. At patients with an impaired renal function the speed of removal of Hydrochlorthiazidum is reduced. The researches conducted with participation of patients with clearance of creatinine of 90 ml/min. showed that the T of % of Hydrochlorthiazidum increases. Patients with reduced function of kidneys of T have a % about 34 hours.

Patients with a liver failure. Pharmacokinetics researches at patients with a liver failure showed increase in absolute bioavailability practically to 100%. At a liver failure the elimination half-life does not change.

Drug gets through a placental barrier and is defined in umbilical cord blood.

Indications to use:

Arterial hypertension (in case of inefficiency of a telmisartan or Hydrochlorthiazidum in the form of monotherapy).

Route of administration and doses:

Inside, irrespective of meal. МикардисПлюс® it is necessary to accept once a day.

• Î¿¬áÓñ¿ßŽ¯ß® 40/12,5 mg can be appointed to patients who have a use of Mikardisa® in a dose of 40 mg or Hydrochlorthiazidum do not lead to adequate control of the ABP.

• Î¿¬áÓñ¿ßŽ¯ß® 80/12,5 mg can be appointed to patients who have a use of Mikardisa® in a dose of 80 mg or МикардисПлюс® 40/12,5 mg do not lead to adequate control of the ABP.

Renal failures. The available limited experience of use of Mikardisplus® for patients with the small or moderately expressed renal failures does not demand changes of a dose of drug in these cases. At such patients it is necessary to control function of kidneys.

Abnormal liver functions. At patients with small or moderate abnormal liver functions of Mikardisplus® it is not necessary to apply in a dose more than 40/12,5 mg a day.

Elderly people. Changes of the mode of dosing are not required

Features of use:

Abnormal liver functions. At patients with abnormal liver functions or the progressing diseases of a liver of Mikardisplus® it has to be applied with care as even little changes of water and electrolytic balance can promote development of a hepatic coma.

Renovascular hypertensia. Patients with a bilateral stenosis of renal arteries or a stenosis have arteries of the only functioning kidney when using the medicines influencing system renin-angiotensin-Aldosteronum the risk of development of the expressed arterial hypotension and a renal failure increases.

Renal failures and state after renal transplantation of Experience of use of Mikardisplus® for patients with heavy renal failures or after transplantation of a kidney is not available for patients. As experience of use of Mikardisplus® for patients with small and moderate renal failures is small, in such cases periodic determination of levels of potassium, creatinine in blood serum is recommended. Use of thiazide diuretic means for patients with renal failures can lead to an azotemia. Periodic control of function of kidneys is recommended.

Decrease in volume of the circulating blood. At the patients with the reduced volume of the circulating blood and/or a hyponatremia who arose owing to massive diuretic therapy, restriction of reception of table salt, diarrhea or vomiting clinically expressed arterial hypotension, especially after reception of the first dose of drug can develop. Before use of Mikardisplus® correction of these disturbances is necessary.

Other states promoting increase in activity of system renin-angiotensin-Aldosteronum. When the tone of vessels and function of kidneys substantially depend on activity of system renin-angiotensin-Aldosteronum (for example, at patients with the expressed chronic heart failure or associated diseases of kidneys, including a renal artery stenosis), Use of medicines which influence a condition of this system can be followed by development of acute arterial hypotension, a hyperazotemia, oligouriya or, in rare instances, of an acute renal failure.

Primary aldosteronism. Patients with primary aldosteronism have anti-hypertensive drugs which mechanism of action consists in inhibition of activity of system renin-angiotensin-Aldosteronum, are usually inefficient. In such cases purpose of Mikardisplus® is not recommended.

Stenosis of aortal and mitral valves, subaortic hypertrophic stenosis. With an aortal or mitral stenosis or a subaortic hypertrophic stenosis use of Mikardisplus® (as well as other vazodilatator) demands extra care from patients.

Influence on metabolism and function of closed glands. At patients with a diabetes mellitus changes of dosing of insulin or peroral hypoglycemic means can be required. During performing therapy of a tiazidama the latent form of a diabetes mellitus can demonstrate.

In certain cases at use of thiazide diuretic means development of a hyperuricemia and gout is possible.

Disturbances of electrolytic balance. When using Mikardisplus®, as well as in each case of use of diuretic therapy, periodic determination of level of electrolytes in blood serum is necessary.

Thiazide diuretics, including Hydrochlorthiazidum, can cause disturbances of electrolytic balance and the ksilotno-main state (a hypopotassemia, a hyponatremia and a gipokhloremichesky alkalosis). The signs guarding concerning these disturbances are dryness in a mouth, thirst, the general weakness, slackness, drowsiness, feeling of concern, a mialgiya or convulsive twitchings of gastrocnemius muscles (krampa), muscular weakness, arterial hypotension, an oliguria, tachycardia and such gastrointestinal frustration as nausea or vomiting.

When using thiazide diuretic the hypopotassemia, but at the same time applied телмисартан can develop, it is capable to reduce this disturbance. The risk of a hypopotassemia is most high at patients with cirrhosis, at a profound diuresis, at inadequate peroral compensation of electrolytes, and also in case of simultaneous use of corticosteroids or AKTG. Telmisartan who is a part of Mikardisplus®, on the contrary, can lead to a hyperpotassemia owing to antagonism to angiotensin II receptors (AT1 subtype). Though when using Mikardisplus®, clinically significant hyperpotassemia was not registered, it is necessary to take into account that renal and/or heart failure and a diabetes mellitus belong to risk factors of its development.

Data that Mikardisplus® can reduce or prevent the hyponatremia caused by diuretic drugs are not available. Deficit of chlorides is usually small and does not demand treatment.

Thiazide diuretics can reduce excretion of calcium and cause (in the absence of the known disturbances of metabolism of this ion) passing and small increase in level of calcium in blood serum. More considerable hypercalcemia can be a sign of the hidden hyperparathyreosis. Before definition of function of epithelial bodies thiazide diuretics have to be cancelled.

It is shown that thiazide diuretics increase magnesium excretion with urine that can lead to a hypomagnesiemia.

Other cautions. At patients with an ischemic cardiopathy or coronary heart disease any anti-hypertensive drug in case of excessive decrease in the ABP can lead to a myocardial infarction or a stroke.

The recommended daily dose Mikardisplus 40/12.5 or 80/12.5 contains 169 or 338 mg of sorbitol respectively. Therefore drug is contraindicated to patients with hereditary intolerance of fructose (see the section "Contraindications").

Cautions of the general character. There can be reactions of hypersensitivity to Hydrochlorthiazidum, especially at patients with an allergy or bronchial asthma in the anamnesis.

There are messages on development of a system lupus erythematosus when using thiazide diuretics.

МикардисПлюс® it can be applied, if necessary, together with other anti-hypertensive drug.

At combined use with Mikardisplus® of kaliysoderzhashchy diuretics, purgatives, corticosteroids, AKTG, Amphotericinum, a karbenoksolon, penicillin G (sodium salt), salicylic acid and its derivatives, regular control of content of potassium in a blood plasma is recommended.

At combined use of Mikardisplus® and kaliysberegayushchy diuretics, drugs of potassium, other means capable to increase the content of potassium in blood serum (for example, heparin sodium), or when replacing table salt with salts of potassium, regular control of level of potassium in a blood plasma is recommended.

If it is required to use calcium drugs, it is regularly necessary to control concentration of calcium in blood and if it is necessary, to change a dose of these drugs.

Influence on ability to drive the car and the machine equipment. The special research of influence of drug on ability to drive the car and the machine equipment was not conducted. However when driving and the machine equipment it is necessary to remember a possibility of development of dizziness and drowsiness at use of the drugs used for treatment of arterial hypertension.

Pregnancy and period of a lactation. Telmisartan does not possess teratogenic action, but has fetotoksichesky effect. Therefore as a precautionary measure, Mikardisplus® should not be applied during the I trimester of pregnancy. In case of the planned pregnancy it is necessary to replace Mikardisplus® with the drugs allowed for use during pregnancy. If pregnancy is established, it is necessary to stop administration of drug immediately.

In II and the III trimester use of drug can cause electrolytic disturbances in a fruit, and also, perhaps, and other disturbances which are known at adults. It was reported about development of neonatal thrombocytopenia, jaundice (at a fruit or at the newborn) in case of reception by mother of thiazide diuretic means. Therefore drug is contraindicated in II and the III trimester of pregnancy.

It is not known yet whether gets телмисартан into breast milk, thiazide diuretics get into breast milk and can inhibit a lactation. Therefore Mikardisplus is contraindicated during feeding by a breast.

Side effects:

1. The uses of a telmisartan which are expected on the basis of experience
2. The uses of Hydrochlorthiazidum which are expected on the basis of experience

From respiratory system. Upper respiratory tract infections (including bronchitis, pharyngitis, sinusitis), odyshka1, диспноэ, a respiratory distress syndrome (including pneumonia and a fluid lungs) 2

From cardiovascular system. Bradikardiya1, takhikardiya1, aritmii2, the expressed decrease in AD1, orthostatic gipotenziya2, a necrotic angiitis (vasculitis) 2, pain in grudi1

From the central nervous system. Excitability, sensation of fear, depressiya1,2, feeling bespokoystva2, dizziness, obmorok1, bessonnitsa1, a poshatyvaniye at hodbe2, parestezii2,

From the alimentary system. Abdominal pains, diarrhea, dyspepsia, gastritis, anoreksiya2, decrease appetita2), sialoadenit2), dryness in rtu1, meteorizm1, rvota1, zapor2, pankreatit2, jaundice (hepatocellular or cholestatic) 2

From endocrine system. Loss of control of level of a hypoglycemia at a diabetes mellitus

Metabolic disturbances. A hypercholesterolemia, a hyperuricemia, a hypopotassemia, giponatriyemiya2, reduction of volume of the circulating blood 2, disturbance electrolytic obmena2, giperglikemiya2, a hypercalcemia 1

From system of a hemopoiesis. Eozinofiliya1, aplastic anemiya2, hemolitic anemiya2, oppression marrowy krovetvoreniya2, leykopeniya2, neutropenia / агранулоцитоз2, trombotsitopeniya1,2

From an urinary system. Infections of an urinary system, intersticial nefrit2, dysfunction pochek2, glyukozuriya2

From a musculoskeletal system. Arthralgia, arthrosis, dorsodynia, shin pain, mialgiya, convulsive twitchings of gastrocnemius muscles (krampa) 1, symptoms similar tendinitu1, slabost1,2, muscular spazm2

Allergic reactions. Anaphylactic reaktsii2, eczema, eritema1, zud1, skin volchanochnopodobny reaktsii2, skin vaskulit2, reactions fotochuvstvitelnosti2, syp2, reactivation skin red volchanki2, toxic epidermal nekroliz2. A Quincke's disease, a small tortoiseshell and other similar reactions (as well as in case of use of other antagonists of angiotensin II).

From sense bodys. Sharpness disturbances zreniya1, tranzitorny illegibility zreniya2, ksantopsiya2, вертиго.

Disturbances from reproductive system. Decrease in a potentiality.

Laboratory indicators. Decrease gemoglobina1, increase in level uric kisloty1, kreatinina1, enzymes pecheni1, triglitseridov2

Others. Grippopodobny symptoms, likhoradka2, strengthening potootdeleniya1

Use of thiazide diuretic means can break tolerance to glucose.

Interaction with other medicines:

At simultaneous use of lithium and antagonists of receptors of angiotensin II increase in concentration of lithium in blood serum and strengthening of the toxic phenomena was in rare instances noted. Besides, use of tiazid reduces clearance of lithium. Therefore simultaneous use of drugs of lithium and Mikardisplus® is allowed only on condition of careful medical observation; control of level of lithium in blood serum is recommended.

The Gipokaliyemichesky effect of Hydrochlorthiazidum is compensated to a kaliysberegayushchiya by effect of a telmisartan. However, the gipokaliyemichesky effect of Hydrochlorthiazidum can amplify other medicines which lead to removal of potassium and to a hypopotassemia (for example, other diuretics removing potassium; purgatives; corticosteroids; AKTG; Amphotericinum; karbenoksolony; penicillin G (sodium salt), salicylic acid and its derivatives).

Simultaneous use of kaliysberegayushchy diuretics, drugs of potassium, other means capable to increase the content of potassium in blood serum (for example, heparin sodium), or replacement of table salt with salts of potassium, can lead to a hyperpotassemia, on the contrary.

When Mikardisplus® is applied together with drugs which effect changes at decrease in content of potassium in blood (for example, the cardiac glycosides, antiarrhytmic drugs and drugs capable to cause disturbances of a heart rhythm like "pirouette"), periodic control of level of potassium in a blood plasma is recommended.

Telmisartan can strengthen hypotensive effect of other anti-hypertensive drugs.

In pharmacokinetic researches such drugs as digoxin, warfarin, Hydrochlorthiazidum, Glibenclamidum, an ibuprofen, paracetamol, симвастатин and амлодипин were studied. As 20% increase in a median of basal concentration of digoxin (in one case increase in concentration reached 39%) is revealed, it is necessary to consider that control of concentration of digoxin in a blood plasma can be required.

The following drugs can interact with thiazide diuretics (in case of simultaneous use):
• alcohol, barbiturates or drugs (risk of orthostatic hypotension);
• hypoglycemic means (both peroral hypoglycemic, and insulin): change of doses of antidiabetic drugs can be required;
• Metforminum: at simultaneous use of Hydrochlorthiazidum there is a risk of development of lactoacidosis;
• холестирамин and холестипол: in the presence of anion exchange pitches absorption of Hydrochlorthiazidum is broken;
• cardiac glycosides: the hypopotassemia or a hypomagnesiemia caused by thiazide diuretics promotes development of "digitalis" arrhythmias;
• non-steroidal anti-inflammatory drugs: reduce diuretic, natriuretic and anti-hypertensive effect of thiazide diuretics at some patients;
• pressor amines (for example, noradrenaline): easing of effect of pressor amines is possible;
• not depolarizing muscular relaxants (for example, tubocurarine): Hydrochlorthiazidum can strengthen effect of the muscular not depolarizing muscular relaxants;
• the drugs which are applied to treatment of gout: changes of dosing of uricosuric drugs as Hydrochlorthiazidum is capable to increase the level of uric acid in blood serum can be required. Use of thiazide diuretics can increase the frequency of reactions of hypersensitivity to Allopyrinolum;
• calcium salts: thiazide diuretics can increase calcium level in blood serum owing to reduction of its excretion.

Thiazide diuretics can strengthen the hyperglycemia caused by beta adrenoblockers and diazoxide. Antikholi nergichesky drugs (for example, atropine, Biperidinum) can, reducing a peristaltics of a stomach and intestines, to increase bioavailability of thiazide diuretics.

Drug can increase risk of the undesirable effects caused amantadiny, reduce renal excretion of cytotoxic drugs (for example, cyclophosphamide, a methotrexate) and to strengthen their myelosuppressive action.

Use together with Mikardisplus® of kaliysberegayushchy diuretics, drugs of potassium or replacement of table salt with salts of potassium have to be carried out with care.

Contraindications:

• Hypersensitivity to drug or other derivatives of sulfonamides;
• Pregnancy (II and III trimester) and lactation period;
• Cholestasia and obstructive diseases of biliary tract;
• The expressed abnormal liver functions;
• The expressed renal failures (clearance of creatinine less than 30 ml/min.);
• Hypopotassemia, hyponatremia, hypercalcemia;
• Hereditary intolerance of fructose (contains sorbitol);
• Age up to 18 years (efficiency and safety are not established)

With care: an abnormal liver function or the progressing liver diseases; bilateral stenosis of renal arteries or stenosis of an artery of the only kidney; renal failure; a state after transplantation of kidneys; reduction of volume circulating blood owing to the previous diuretic therapy, restriction of reception of table salt, diarrhea or vomiting; chronic cordial nedotatochnost; stenosis of the aortal and mitral valve; subaortic hypertrophic stenosis; diabetes mellitus; coronary heart disease; system lupus erythematosus; gout.

Overdose:

The expressed decrease in the ABP, tachycardia and/or bradycardia can be the most probable symptoms of overdose of a telmisartan.

The overdose of Hydrochlorthiazidum is followed by loss of electrolytes (a hypopotassemia, a hypochloraemia) and the dehydration arising owing to a massive diuresis. The most frequent signs and symptoms of overdose of Hydrochlorthiazidum are nausea and drowsiness. The hypopotassemia can lead to spasms of muscles and/or strengthen the heart arrhythmias caused by simultaneous use of cardiac glycosides or some antiarrhytmic drugs.

Treatment: a symptomatic and maintenance therapy which character depend on time which passed from the moment of administration of drug and on severity of symptoms. It is recommended to cause vomiting and/or to carry out a gastric lavage, to appoint absorbent carbon. Frequent control of electrolytes and creatinine in blood serum is necessary. In case of development of arterial hypotension, the patient it is necessary to lay on a back and to quickly carry out the therapy directed to substitution of electrolytes and volume of the circulating blood.

Telmisartan does not leave by means of a hemodialysis. Extent of removal of Hydrochlorthiazidum when carrying out a hemodialysis is not established.

Storage conditions:

List B. At a temperature not above 25 °C, in the place protected from moisture. To store in the place, unavailable to children. Period of validity of 36 months. Not to use after the expiry date specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Tablets 40/12,5 of mg and 80/12,5 mg. Packagings on 14, 28, 56 or 98 tablets. On 7 tablets in the blister from polyamide/aluminium/PVC; on 2, 4, 8 or 14 blisters with the application instruction in a cardboard pack.