Expiration date: 03/2025

The composition and form of issue:

Tablets. 1 tablet contains active substances:

hydrochlorothiazide 12.5 mg

telmisartan 40 mg

auxiliary substances: sodium hydroxide to 3.36 mg povidone 12 mg meglumin 12 mg sorbitol — 168,64 mg magnesium stearate 5 mg lactose monohydrate — MCC 112,17 mg — 64 mg dye iron oxide red (E172) — 0.33 mg sodium carboximetilkrahmal 4 mg corn starch 6 mg 

Tablets. 1 tablet contains active substances: 

hydrochlorothiazide 12.5 mg

telmisartan 80 mg

auxiliary substances: sodium hydroxide of 6.72 mg povidone 24 mg meglumin — 24 mg of sorbitol — 337,28 mg of magnesium stearate and 9 mg of lactose monohydrate — MCC 112,17 mg — 64 mg dye iron oxide red (E172) — 0.33 mg sodium carboximetilkrahmal 4 mg corn starch 6 mg 

blister polyamide/aluminium foil/PVC 7 PCs the paper cartons 2, 4 or 8 blisters.

Description pharmaceutical form:

Tablets of two-layer biconvex oval shaped, one layer of pinkish-beige color, the other layer is white with possible patches of a pinkish beige color on the white side engraved "H4" (tablets of 40 mg) or "N8" (tablets of 80 mg), and the company logo.

Pharmacokinetics:

The combined use of telmisartan and hydrochlorothiazide has no effect on the pharmacokinetics of each component of the drug.

Telmisartan

If ingestion is rapidly absorbed from the gastrointestinal tract. Bioavailability is approximately 50%. The peak concentration occurs approximately 0.5–1.5 h When taken in conjunction with food reduction AUC ranged from 6% (at the dose of 40 mg) to 19% (at the dose of 160 mg). After 3 h after ingestion, the concentration in plasma aligned regardless of the meal. There is a difference in concentration of telmisartan in plasma in men and women. Cmax and AUC about 3 and 2 times, respectively, higher in women compared with men without significant effect on the efficiency. However, the antihypertensive effect in women is not observed.

Relationship with blood plasma proteins significant (> 99,5%), mainly albumin and alpha1-acid glycoprotein. Vd is approximately 500 l.

Telmisartan is metabolized by conjugation with glucuronic acid. Metabolites pharmacologically inactive. T1/2 — more than 20 hours Excreted through the intestines in unchanged renal excretion — less than 2%. The total plasma clearance is high (about 900 ml/min).

Elderly patients. Pharmacokinetics of telmisartan in elderly patients is not different from younger patients. Correction doses is not required.

Patients with renal insufficiency. Changing doses of telmisartan in patients with renal insufficiency not required, including patients, on hemodialysis. Telmisartan is not removed by hemodialysis.

Patients with hepatic insufficiency. Study of pharmacokinetics in patients with hepatic impairment showed an increase in absolute bioavailability of telmisartan almost 100%. When liver failure T1/2 not changed (see "Method of application and dosage").

Hydrochlorothiazide

After ingestion of the drug Mikardisplus hydrochlorothiazide Cmax in plasma achieved within 1-3 h. the Absolute bioavailability based on total excretion by the kidney is about 60%. Binds to blood plasma proteins 64% hydrochlorothiazide, and Vd is (0,8±0,3) l/kg.

Hydrochlorothiazide not metabolized in the body and excreted by the kidneys almost unchanged. About 60% of the dose of inside is eliminated within 48 h. the Renal clearance of about 250-300 ml/min. T1/2 of hydrochlorothiazide 10-15 hours Observed difference in plasma concentrations in men and women. In women, the concentration of telmisartan in plasma is 2-3 times higher than that of men, also women have a tendency to increase in plasma concentration of hydrochlorothiazide (clinically insignificant).

Patients with renal insufficiency. In patients with impaired renal function the rate of hydrochlorothiazide elimination is reduced. Studies conducted involving patients with Cl creatinine 90 ml/min showed that T1/2 hydrochlorothiazide increases. In patients with reduced renal function T1/2 is approximately 34 h.

Description pharmacological action:

Mikardisplus is a combination of telmisartan (angiotensin II receptor antagonist) and hydrochlorothiazide — thiazide diuretic. The simultaneous use of these components leads to a more pronounced antihypertensive action than the application of each of them separately.

The drug Mikardisplus 1 time per day leads to a significant gradual decrease in blood pressure.

Telmisartan

Telmisartan is a specific antagonist of the angiotensin II receptor (AT1 subtype), effective when administered. Has a high affinity to a subtype of AT1-angiotensin II receptor, through which is realized the action of angiotensin II. Displaces angiotensin II from the receptor, showing the properties of the agonist against this receptor. Telmisartan binds only to a subtype of AT1-angiotensin II receptor. The relationship is a long. Has no affinity for other receptors, including AT2-receptor and other less studied receptors of angiotensin. The functional significance of these receptors, as well as the effect of possible excessive stimulation of angiotensin II, whose concentration increases with the appointment of telmisartan, has not been studied. Telmisartan reduces the concentration of aldosterone in the blood, does not inhibit the renin in the blood plasma and does not block ion channels. Telmisartan does not inhibit ACE (kininase II, an enzyme that also breaks down bradykinin). Therefore, the enhancement of bradykinin-induced side effects are not expected.

In patients with arterial hypertension telmisartan dose of 80 mg completely blocks the hypertensive effect of angiotensin II. Start antihypertensive effect observed within 3 h after the 1-St reception of telmisartan inside. The effect of the drug lasts for 24 hours and remains significant up to 48 h. significant antihypertensive effect usually develops within 4 weeks after the regular drug administration.

In patients with hypertension telmisartan reduces both SBP and DBP, not affecting heart rate.

In the case of abrupt cancellation of telmisartan AD slowly returns to the source without the development of withdrawal syndrome.

Hydrochlorothiazide

Hydrochlorothiazide is a thiazide diuretic. Thiazide diuretics affect the reabsorption of electrolytes in renal reabsorption, directly increasing excretion of sodium and chloride (approximately equivalent quantities). The diuretic action of hydrochlorothiazide reduces BCC, the increase in renin activity of blood plasma, increase of aldosterone secretion with subsequent increase in urine potassium and bicarbonates and, as a consequence, reducing the concentration of potassium in the blood plasma. While concurrent use with telmisartan, there is a tendency to the cessation of potassium loss caused by this diuretic, presumably due to blockade of the RAAS.

After ingestion, diuresis is increased after 2 h and the maximum effect is observed after about 4 h. the Diuretic effect of the drug persists for approximately 6-12 hours.

Prolonged use of hydrochlorothiazide reduces the risk of complications of cardiovascular disease and mortality.

The maximum antihypertensive effect of the drug Mikardisplus usually achieved after 4-8 weeks after initiation of treatment.

Indications:

Hypertension, in case of failure of telmisartan or hydrochlorothiazide monotherapy.

Contraindications:

• hypersensitivity to the active substance or auxiliary components of the drug or other sulfonamides derived
  
• pregnancy
  
• the breast-feeding period
  
• obstructive diseases of the biliary tract
  
• marked disorders of liver function (class C child-Pugh)
  
• expressed by the human kidney (Cl creatinine <30 ml/min)
  
• refractory hypokalemia, hypercalcemia
  
• hereditary fructose intolerance (contains sorbitol)
  
• galactose intolerance, and lactase deficiency, lactose intolerance, syndrome of glucose-galactose malabsorption
  
• the age of 18 years (efficacy and safety not established).
  

Precautions: bilateral renal artery stenosis or stenosis of the artery to a solitary kidney, severe violations of kidney function (see "precautions") disturbances of liver function or progressive liver disease (class A and b on a scale child-Pugh) (see "Precautions") the decrease in BCC as a result of prior diuretic therapy, limit salt intake, diarrhea or vomiting hyperkalemia condition after kidney transplantation (experience of the missing) congestive heart failure III–IV functional class NYHA classification aortic stenosis and mitral valve idiomatic hypertrophic subaortic stenosis hypertrophic obstructive cardiomyopathy diabetes mellitus primary aldosteronism gout.

Experience of use in patients with renal insufficiency (Cl creatinine >30 ml/min) is limited, but does not confirm the development of side effects in the kidneys and dose adjustment is not required.

Drug interactions:

Telmisartan

Other antihypertensives. May increase antihypertensive effect. In one study, the combined use of telmisartan and ramipril was an increase in AUC0–24 and Cmax of ramipril and ramiprilat in 2.5 times. The clinical significance of this interaction is not established.

Drugs lithium. It was observed a reversible increase in the concentration of lithium in the blood, accompanied by toxic effects when taking ACE inhibitors. In rare cases, such change was in the appointment of antagonists of a receptor of angiotensin II, in particular of telmisartan. While the appointment of lithium drugs and antagonists of the receptor of angiotensin II is recommended that the definition of lithium content in the blood.

NSAIDs, including acetylsalicylic acid. In doses used as anti-inflammatory agents (not exceeding 3 g/day), COX inhibitors and nonselective NSAIDs may cause the development of acute renal failure in patients with reduced BCC. Drugs affecting the RAAS, may have a synergistic effect. Patients receiving NSAIDs and telmisartan, in the beginning of treatment should be compensated BCC and monitoring of renal function. The decrease in the effect of antihypertensive drugs like telmisartan through inhibition of vasodilatory effect of PG was noted in a joint treatment with NSAIDs. The simultaneous administration of telmisartan with ibuprofen or paracetamol have not identified a clinically significant effect.

Digoxin, warfarin, hydrochlorothiazide, glibenclamide, simvastatin and amlodipine. No clinically significant interaction. The marked increase in the average concentration of digoxin in plasma in average by 20% (in one case by 39%). While the appointment of telmisartan and digoxin it is advisable to periodically determine the concentration of digoxin in the blood.

Hydrochlorothiazide

Ethanol, barbiturates, or narcotic analgesics. There is a risk of orthostatic hypotension.

Hypoglycemic means for ingestion and insulin. May require correction doses of hypoglycemic agents for oral administration and insulin.

Metformin. There is a risk of lactic acidosis.

Cholestyramine and colestipol. In the presence of anionic exchange resins absorption of hydrochlorothiazide is broken.

Cardiac glycosides. There is a risk of hypokalemia and/or hypomagnesemia caused by thiazide diuretics, development of arrhythmias, caused by taking cardiac glycosides.

Pressor amines (e.g. norepinephrine ). May weaken the effect of Pressor amines.

Miorelaksanty non-depolarizing (e.g. tubocurarine chloride). Hydrochlorothiazide may increase the effect of non-depolarizing myorelaxants.

Protivopodagricakih funds. May increase the concentration of uric acid in the blood serum and can therefore require changing the doses of uricosuric of funds.

The use of a thiazide diuretic increases the incidence of hypersensitivity reactions to allopurinol.

Calcium pills. Thiazide diuretics can raise calcium levels in serum by reducing its excretion by the kidneys. If you want to apply calcium Supplement, should regularly monitor the content of calcium in the blood and, if necessary, to change the dose of calcium.

&beta-blockers and diazoxide. Thiazide diuretics can potentiate hyperglycemia caused by &beta-blockers and diazoxide.

M-anticholinergics (e.g. atropine, biperidin ). The decrease in the motility of the gastrointestinal tract, increasing the bioavailability of thiazide diuretics.

Amantadine. Thiazide diuretics can increase the risk of adverse effects caused by amantadine.

Cytotoxic agents (eg cyclophosphamide, methotrexate). A decrease in renal excretion of cytotoxic agents and enhance their myelosuppressive action.

NSAIDs. Concomitant use with thiazide diuretics may reduce diuretic and antihypertensive effects.

The means which lead to the excretion of potassium and hypokalemia (e.g. diuretics, deducing potassium, laxatives, corticosteroids and mineralokortikosteroidy, corticotropin, amphotericin b, carbenoxolone, benzylpenicillin, derivatives of acetylsalicylic acid). Strengthening the hypokalemic effect. Hypokalemia caused by hydrochlorothiazide, kompensiruet kaliysberegayuschimi effect of telmisartan.

Potassium-sparing diuretics, potassium supplements, other means to increase the content of potassium in the blood serum (for example heparin), or replacement of sodium salt with potassium salts may cause hyperkalemia.

Recommended periodic monitoring of potassium content in the blood plasma in cases where the drug Mikardisplus appointed jointly with drugs that can cause hypokalemia, and drugs that can increase potassium levels in the blood serum.

Method of application and dose:

Inside.

To take regardless of the meal.

The drug Mikardisplus should take 1 times a day.

Mikardisplus 40/12. 5 mg may be administered to patients in whom the use of the drug, Micardis at a dose of 40 mg and hydrochlorothiazide does not lead to adequate control of AD.

Mikardisplus 80/12,5 mg may be administered to patients in whom the use of the drug, Micardis at a dose of 80 mg or drug Mikardisplus 40/12. 5 mg does not lead to adequate control of AD.

In patients with severe arterial hypertension maximum daily dose of telmisartan 160 mg/day. This dose was well tolerated and effective.

Violations of kidney function. Existing limited experience of Mikardisplus in patients with mild or moderately severe disorders of renal function does not require modification of the dose in these cases. These patients should monitor kidney function (Cl creatinine <30 ml/min, see "Contraindications").

Violations liver function. In patients with mild and moderate impaired liver function (classes a and b on a scale child-Pugh) daily dose of the drug Mikardisplus should not exceed 40/12. 5 mg per day.

Elderly patients. The dosage regimen requires no changes.

Overdose:

Cases of overdose have not been identified. Possible overdose symptoms consist of symptoms of the individual components of the drug.

Telmisartan

Symptoms: expressed lower AD, tachycardia, aetiology.

Hydrochlorothiazide

Symptoms of violations vodno-elektrolitnogo balance (gipokaliemia, gipohloremia), reduction of BCC, which can lead to muscle spasms and/or exacerbate violations of the SSS — arrhythmia, caused by simultaneous application of cardiac glycosides or certain antiarrhythmics.

Treatment: symptomatic therapy, hemodialysis is effective, the removal of hydrochlorothiazide for kidney dialysis is not installed. Requires regular monitoring of electrolytes and creatinine in serum.

Precautions:

State, contributing to the increased activity of the RAAS. Some patients, due to the suppression of the activity of the RAAS, especially at simultaneous appointment of drugs acting on this system, impaired kidney function, including acute renal failure. Therefore, therapy involving this kind of dual blockade of the RAAS, should be carried out strictly individually and with regular monitoring of renal function (including periodic monitoring of potassium and creatinine in the serum).

The use of a thiazide diuretic in patients with impaired renal function may lead to azotemia. Recommended periodic monitoring of renal function.

Renovascular hypertension. In patients with bilateral renal artery stenosis or stenosis of the artery only functioning kidney use of medicines affecting the RAAS, increases the risk of arterial expressed hypotension and renal failure.

Violations liver function. In patients with impaired hepatic function or progressive liver disease drug Mikardisplus should be used with caution, as even small changes in fluid and electrolyte balance may contribute to the development of hepatic coma.

Effect on the metabolism and function of endocrine glands. Patients with diabetes may require dosage adjustment of insulin or hypoglycemic agents for oral administration. During therapy thiazide diuretics may manifest latent flowing diabetes. In some cases, the use of thiazide diuretics may develop hyperuricemia and exacerbation of gout.

Violations of water-electrolyte balance. In applying the drug Mikardisplus, as in the case of the diuretic therapy requires periodic monitoring of electrolytes in blood serum.

Thiazide diuretics, including hydrochlorothiazide, can cause violations of water-electrolyte balance and acid-base balance (hypokalemia, hyponatremia and alkalosis gipohloremichesky). Signs, alarming in respect of these violations are dryness of the mucous membrane of the mouth, thirst, weakness, drowsiness, anxiety, myalgia or convulsive twitching calf muscles (crampy), muscle weakness, expressed lower AD, oliguria, tachycardia, and such gastrointestinal symptoms as nausea or vomiting.

In the application of thiazide diuretics may develop hypokalemia, but at the same time that telmisartan can increase the content of potassium in the blood. The risk of hypokalemia is increased most in patients with liver cirrhosis, with increased urine output, subject to a salt-free diet, and in the case of simultaneous use of corticosteroids and mineralokortikosteroidov or corticotropin. Telmisartan, a part of the drug Mikardisplus, on the contrary can cause hyperkalemia due to antagonism of angiotensin II receptors (subtype AT1). Although the use of the drug Mikardisplus clinically significant hyperkalemia has not been registered, should be taken into account that the risk factors for its development include kidney and/or heart failure and diabetes.

Evidence that the drug Mikardisplus can reduce or prevent giponatriemia, caused by administration of diuretics, no. Gipohloremia usually mild and does not require treatment. Thiazide diuretics may decrease the excretion of calcium by the kidneys and cause in the absence of obvious metabolic disorders of calcium transient and a slight increase of calcium content in blood serum. More severe hypercalcemia can be a sign of hidden hyperparathyroidism. Before assessment of function of the parathyroid glands thiazide diuretics should be abolished. It is shown that thiazide diuretics increase the excretion of magnesium by the kidneys that can lead to gipomagniemii.

In patients with coronary artery disease the use of any antihypertensive medications, in case of excessive loss AD can lead to myocardial infarction or stroke.

There are reports of the development of systemic lupus erythematosus in the application of thiazide diuretics.

Mikardisplûs may optionally be used in conjunction with other antihypertensive agents.

Mikardisplûs less effective in patients of Negroid race.

Effects on ability to drive or to perform work requiring high speed physical and mental reactions. Special clinical studies to assess the impact of the drug Mikardisplûs on the ability to drive vehicles and operate machinery that require attention, were not carried out. However, when driving vehicles and occupation potentially hazardous activities should take into account the possibility of dizziness and sleepiness, which requires caution.