Pharmacological properties

Pharmacodynamics. telmisartan — the specific and effective antagonist of receptors of ii angiotensin (type at1). telmisartan with very high degree of affinity substitutes ii angiotensin in places of its linking with receptors like at1, responsible for physiological effects of ii angiotensin. telmisartan does not show partial agonistic activity concerning receptors at1. telmisartan selectively contacts a receptor at1. binding is long. telmisartan has no affinity to other receptors, including at2 — and another, less studied at-receptors. the functional role of these receptors is unknown as the effect of their possible "superstimulation" is not revealed by ii angiotensin which level increases under the influence of a telmisartan. telmisartan reduces Aldosteronum level in blood plasma. telmisartan does not inhibit renin in blood plasma of the person, does not block ion channels. telmisartan angiotensin-converting enzyme (kininaza of ii), enzyme which also destroys bradykinin is not inhibited. therefore it is not necessary to expect potentiation of bradikininsoprovozhdayushchy side effects.

At the person telmisartan in a dose of 80 mg is almost completely inhibited by increase in the ABP which is caused by angiotensin II. The blocking effect remains during 24 h and there is notable up to 48 h

a Pharmacokinetics. Absorption. Absorption of a telmisartan fast though the absorbed quantities are various. Average absolute bioavailability — about 50%. If Mikardis accept at meal time, decrease in AUC value varies from 6% (at reception in a dose of 40 mg) up to 19% (at reception in a dose of 160 mg). In 3 h after administration of medicament the concentration in blood plasma is identical and does not depend on that, accepted telmisartan on an empty stomach or with food.

Linearity/nonlinearity. Consider that small decrease in AUC does not cause decrease in therapeutic effectiveness. There is no linear dependence between a dose and level in blood plasma. The C _max and to a lesser extent AUC increase disproportionally at doses higher than 40 mg.

Distribution. Telmisartan substantially contacts proteins of blood plasma (99.5%), generally albumine and an alpha 1-acid glycoprotein. Distribution volume in an equilibrium state is about 500 l.

Metabolism. Telmisartan is metabolized by conjugation with a glucuronide. The pharmacological activity of a conjugate is not established.

Removal. Telmisartan is characterized by a biexponentsialny pharmacokinetic profile with T _½ in a terminal phase more than 20 h. With _max in blood plasma and AUC raise disproportionately a dose. There are no data on clinically significant cumulation in an organism at use in the recommended doses. Concentration in blood plasma at women is higher, than at men, without change of efficiency.

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After oral administration telmisartan it is almost completely removed with a stake, as a rule, in not changed look. Cumulative renal excretion is 1% of a dose. The general plasma clearance (Cl _tot ) high (about 1000 ml/min.) in comparison with a hepatic blood-groove (about 1500 ml/min.).

Special categories of patients

Floor. Concentration in plasma With _max and AUC at women approximately in 3 and 2 times are respectively higher, than at men.

Patients of advanced age. The pharmacokinetics of a telmisartan at elderly people and aged up to 65 years does not differ.

Patients with a renal failure. At patients with the moderated to average and heavy degree of a renal failure noted increase in concentration in blood plasma twice. However at the patients with a renal failure who are subject to dialysis the low concentration in blood plasma is revealed. Telmisartan has high affinity to proteins of blood plasma at patients with a renal failure and cannot be brought by means of dialysis. At patients with a renal failure of T _½ does not change.

Patients with an abnormal liver function. Pharmacokinetic researches at patients with disturbances of a liver showed increase in bioavailability approximately to 100%. At patients with a liver failure of T _½ does not change.

Indication

Hypertensia.

Lecheniye of essential hypertensia at adults.

Prevention of cardiovascular diseases

Decrease in incidence of cardiovascular diseases at patients:

• with a manifest aterotrombotichesky cardiovascular disease (ischemic heart disease, a stroke or damage of peripheral arteries in the anamnesis);
• diabetes of the II type with the documented damage of target organs.

Use

Lecheniye ag. the usual effective dose makes 40 mg/days some patients can have sufficient a dose of 20 mg/days in cases when desirable level hell is not reached, the dose of a telmisartan can be raised to 80 mg/days alternatively telmisartan it is possible to apply in a combination with thiazide diuretics (hydrochlorothiazide) which showed additional decrease hell at use along with telmisartany. at the solution of a question of increase in a dose it is necessary to consider that the maximum antihypertensive effect develops in 4–8 weeks after an initiation of treatment.

Prevention of cardiovascular diseases. The recommended dose makes 80 mg of 1 times a day. The efficiency of a telmisartan in doses of 80 mg at prevention of cardiovascular diseases is unknown.

Beginning with

treatment telmisartany for the purpose of prevention of cardiovascular diseases, it is recommended to carry out monitoring of the ABP and if necessary to adjust administration of drugs, the lowering arterial blood pressures.

Drug is taken irrespective of food.

Special groups of patients

Renal failure. Experience of treatment of patients with a renal failure or the patients who are on a hemodialysis is limited. At such patients it is recommended to begin treatment with a low dose — 20 mg (see. Special INSTRUCTIONS). For patients with a renal failure of easy and average degree there is no need for dose adjustment.

Abnormal liver function. Mikardis is contraindicated to patients with heavy abnormal liver functions.

At patients with a slight or moderate abnormal liver function the daily dose should not exceed 40 mg of 1 times a day (see. Special INSTRUCTIONS).

Patients of advanced age. Dose adjustment is not required from elderly people.

Contraindication

Hypersensitivity to medicament components; ii and iii pregnancy trimester; obstructive biliary disturbances; heavy abnormal liver functions.

Side effects

Serious side effects which include anaphylactic reactions and a Quincke's disease are possible

in isolated cases (≥1/10,000, 1/1000), also noted opn.

General frequency of manifestations of by-effects at patients with AG during controlled clinical trials at reception of a telmisartan was usually comparable

to intake of placebo (41.4% in comparison with 43.9%). Frequency of manifestations of by-effects does not depend on a dose and has no interrelation with a sex, age or race of patients. Data on safety of the medicament Mikardis at prevention of cardiovascular diseases corresponded to AG given at treatment.

side Below-mentioned reactions on medicament are noted by

in controlled clinical trials with the assistance of patients with AG and also according to post-marketing reports. This list also included serious side reactions and side reactions which led to the termination of treatment and were revealed during 3 clinical long trials with the assistance of 21,642 patients receiving telmisartan for prevention of cardiovascular diseases and mortality for 6 years.

Side effects are stated to

with the indication of frequency with use of the following designations: very often (≥1/10); often (from 1/100 to 1/10); infrequently (from 1/1000 to 1/100); seldom (from 1/10 000 to 1/1000); very seldom (1/10,000).

side effects are provided to

In each group as reduction of severity.

Infection and invasion: infrequently — upper respiratory tract infections, including pharyngitis and sinusitis, infections of urinary tract, including cystitis; seldom — sepsis, including with a lethal outcome ¹ .

from the system of blood and lymphatic system: infrequently — anemia; seldom — thrombocytopenia, an eosinophilia.

from the immune system: seldom — hypersensitivity, anaphylactic reaction.

Disbolism: infrequently — a hyperpotassemia; seldom — a hypoglycemia (at patients with diabetes).

Mental disorders: infrequently — insomnia, a depression; seldom — concern.

from central nervous system: infrequently — a syncope; seldom — drowsiness.

from an organ of sight: seldom — a disorder of vision.

from a vestibular mechanism: infrequently — vertigo.

from heart: infrequently — bradycardia; seldom — tachycardia.

from vessels: infrequently — arterial hypotension ² , orthostatic hypotension.

from the respiratory system, bodies of a thorax and mediastinum: infrequently — dispnoe, cough; very seldom — an interstitial pulmonary disease ⁴ .

from a GIT: infrequently — abdominal pain, diarrhea, dyspepsia, a meteorism, vomiting; seldom — discomfort in a stomach, dryness in a mouth.

from a gepatobiliarny system: seldom — dysfunction of a liver / hepatic disturbances ³ .

from skin and hypodermic cellulose: infrequently — the strengthened sweating, an itching, rash; seldom — an erythema, a Quincke's disease (including with a lethal outcome), medicamentous dermatitis, toxic dermatitis, eczema, a small tortoiseshell.

from the musculoskeletal system and connective tissue: infrequently — myalgia, a dorsodynia (for example a sciatica), myotonia; seldom — an arthralgia, extremity pain, sinew pain (the symptoms similar to a tendinitis).

from an urinary system: infrequently — a renal failure, including OPN.

General disturbances: infrequently — a stethalgia, an asthenia (weakness); seldom — grippopodobny symptoms.

Datas of laboratory: infrequently — increase in creatinine in blood; seldom — increase in uric acid in blood, increase in hepatic enzymes, increase in the KFK level in blood, decrease in hemoglobin.

¹ Sepsis. In the research PRoFESS among the patients accepting telmisartan noted the high frequency of cases of sepsis in comparison with the receiving placebos. It can be both accident, and sign of process which essence is still unknown.

² Hypotension. This side reaction came to light often at the patients with the controlled ABP accepting telmisartan for reduction of severity of cardiovascular diseases in addition to standard therapy.

³ Dysfunction of a liver / hepatic disorders. According to postmarkegingovy data, the majority of cases of dysfunctions of a liver / hepatic disorders noted at patients of the Japanese nationality. Patients of the Japanese nationality are more subject to these side reactions.

⁴ Interstitial pulmonary disease. Cases of an interstitial disease of lungs noted temporarily at use of a telmisartan during post-marketing observations. However the causal interrelation is not established.

Special instructions

Pregnancy. during pregnancy it is impossible to begin treatment by antagonists of receptors of ii angiotensin. if continuation of therapy by antagonists of receptors of ii angiotensin is not considered necessary extremely for the patient planning pregnancy, it has to pass to alternative antihypertensive therapy which has the established safety profile for use during pregnancy. at pregnancy establishment the treatment by antagonists of receptors of an angiogenzin of ii needs to be stopped urgently and in case of need to begin alternative treatment (see contraindications and use during pregnancy and feeding with a breast).

Liver failure. Mikardis it is impossible to appoint the patient with a cholestasia, obstructive diseases of bile ducts and a liver failure of heavy degree (see CONTRAINDICATIONS) as telmisartan it is removed mainly with bile. At such patients it is possible to expect reduction of hepatic clearance of a telmisartan. Mikardis it is necessary to appoint with care the patient with a liver failure from moderated to average degree.

Renovascular hypertensia. There is an increased risk of serious arterial hypotension and renal failure if patients with a bilateral renal artery stenosis or a stenosis of an artery of the only kidney are treated medicaments which influence renin-angiotensin-aldosteronovuyu a system.

Renal failure and transplantation of a kidney. When Mikardis appoint to patients with impaired renal function, periodic monitoring of level of potassium and creatinine in blood serum is recommended. There is no experience of use Mikardis to patients with recent transplantation of a kidney.

Decrease in OCK. Symptomatic hypotension, especially after the first dose Mikardis, can arise at patients with reduced OCK and/or level of sodium which arises owing to therapy by diuretics, restrictions of the use of the salt arriving with food, diarrheas or vomiting. Before reception Mikardis it is necessary to adjust such states, especially decrease in intravascular volume and/or level of sodium.

Double blockade system renin-angiotensin-aldosteronovoy. As a result of braking system renin-angiotensin-aldosteronovoy at more sensitive patients was noted arterial hypotension, a syncope, the hyperpotassemia and changes of function of kidneys (including OPN), especially if entered combination therapy the medicines influencing this system. Therefore double blockade system renin-angiotensin-aldosteronovoy (for example use of a telmisartan with other blockers system renin-angiotensin-aldosteronovoy) is not recommended. In need of simultaneous use the careful monitoring of function of kidneys is recommended.

Other states demanding stimulation system renin-angiotensin-aldosteronovoy

At patients who have a vascular tone and function of kidneys depend mainly on activity system renin-angiotensin-aldosteronovoy (for example patients with heavy stagnant heart failure or the profound disease of kidneys, including a renal artery stenosis), administration of medicament Mikardis with other medications influencing renin-angiotensin-aldosteronovuyu a system was connected with acute arterial hypotension, a hyperazotemia, an oliguria, occasionally — with OPN (see. Side EFFECTS).

Primary hyper aldosteronism. Patients with primary hyper aldosteronism in general do not react to the antihypertensive medicaments operating by blockade system renin-angiotenzinovoy. Therefore purpose of a telmisartan is not recommended to them.

Stenosis of an aorta and mitral valve, subaortic hypertrophic stenosis. As well as concerning other vazodilatator, Mikardis with extra care appoint to patients for whom the stenosis of an aorta, the mitral valve or a subaortic hypertrophic stenosis is diagnosed.

Patients with diabetes who are treated by insulin or anti-diabetic medicines

during treatment telmisartany at such patients the hypoglycemia can develop. It is necessary to consider need of the corresponding control of level of glucose for blood at such patients. According to indications the dose adjustment of insulin or antidiabetic medicines can be required.

At patients with diabetes, with cardiovascular risks (patients with diabetes and associated diseases of coronary arteries) risk of developing a myocardial infarction with a lethal outcome and a sudden cardiovascular lethal outcome can be higher at treatment by antihypertensive drugs, such as antagonists of receptors of angiotensin II and APF inhibitors. Patients with diabetes, can have an asymptomatic course of associated diseases of coronary arteries and therefore they can be not diagnosed. The patients sick with diabetes, it is necessary to survey carefully, for example, stressful testing to reveal and treat associated diseases of coronary arteries before appointing drug.

Hyperpotassemia. During all intake of the medicines influencing renin-angiotensin-aldosteronovuyu a system there can be a hyperpotassemia.

, at patients with a renal failure, diabetes, at the patients in parallel accepting other medicines which can cause increase in level of potassium, and/or with associated diseases a hyperpotassemia can lead

At elderly people to a lethal outcome.

Before consideration of a question of simultaneous use of the medicines oppressing renin-angiotenzinovuyu a system needs to estimate a ratio of advantage and risk.

Major factors of risk of development of a hyperpotassemia to which it is necessary to pay attention:

• diabetes, a renal failure, age (70 years are more senior);
• combination therapy with one or several medicaments influencing renin-angiotenzinovuyu a system and/or potassium additives. The salt substitutes containing potassium, kaliysberegayushchy diuretics, APF inhibitors, antagonists of receptors of angiotensin II, NPVP including selection TsOG-2 inhibitors, heparin, immunodepressants (cyclosporine or takrolimus) and Trimethoprimum belong to medicaments or therapeutic groups of medicines which can provoke a hyperpotassemia;
• associated diseases, especially dehydration, sharp warm decompensation, metabolic acidosis, renal failure, sharp aggravation of symptoms of kidneys (infectious diseases), cellular lysis (for example acute ischemia of extremities, acute necrosis of skeletal muscles, extensive injury).

Sick risk groups needs to undergo careful control of serumal potassium concentration (see INTERACTIONS).

Sorbite. Medicine contains sorbite (E420). Patients with rare hereditary diseases of intolerance of fructose should not take this drug.

Ethnic distinctions. As well as all other antagonists of receptors of angiotensin II, telmisartan is obviously less effective for decrease in the ABP at patients of negroid race, than at representatives of other races. Perhaps, it has a talk big distribution of low reninovy states at patients of negroid race with AG.

Others. As well as at use of any other antihypertensive drugs, considerable decrease in the ABP at patients with an ischemic cardiopathy or an ischemic cardiovascular disease can lead to a myocardial infarction or a stroke.

Use during pregnancy and feeding by a breast. Use of antagonists of receptors of angiotensin II is not recommended in the I trimester of pregnancy (see. Special INSTRUCTIONS). Use of antagonists of receptors of angiotensin II is contraindicated in II and III trimester of pregnancy (see CONTRAINDICATIONS and SPECIAL INSTRUCTIONS).

pregnant women have

no sufficient data on use Mikardis.

Epidemiological justification of risk of teratogenecity owing to use APF inhibitors in the I trimester of pregnancy were not convincing, however it is impossible to exclude small increase in risk. Despite the absence of controlled epidemiological data on risk of teratogenecity at use of antagonists of receptors of angiotensin II, similar risks can exist for this class of medicines. If continuation of therapy by antagonists of receptors of angiotensin II is not considered necessary extremely, the patients planning pregnancy have to pass to antihypertensive medicines which have the established safety profile for use during pregnancy. At pregnancy establishment the treatment by antagonists of receptors of angiotensin II needs to be stopped urgently and if necessary to begin alternative treatment. In II and III trimester of pregnancy the antagonists of receptors of angiotensin II, as we know, cause a fetotoksichnost (depression of function of kidneys, oligogidramnion, a delay of forming of bones of a skull) and neonatal toxicity (renal failure, hypotonia, a hyperpotassemia). If use of antagonists of receptors of angiotensin II was begun in the II trimester of pregnancy, it is recommended to carry out ultrasonography of function of kidneys and bones of a skull. Children whose mothers antagonists of receptors of angiotensin II accepted need to be examined carefully on presence of arterial hypotension (see CONTRAINDICATIONS and SPECIAL INSTRUCTIONS).

use of the medicament Mikardis during feeding by a breast is not recommended to

due to the lack of information. Preference is given to alternative treatment with better the studied safety profile, especially when feeding by a breast of the newborn or premature child.

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during preclinical trials did not reveal influence Mikardis on fertility of men and women.

Children. Safety and efficiency of the medicament Mikardis was not investigated at children (aged up to 18 years). Data are absent.

Influence on speed of response at control of vehicles or work with other mechanisms. When driving and mechanisms it is necessary to consider possibility of dizziness or a hypersomnia at antihypertensive therapy, including the medicament Mikardis.

Interaction

As well as other medicaments which oppress renin-angiotenzinovuyu a system telmisartan can provoke a hyperpotassemia (see special instructions). the risk can increase at treatment in a combination with other means which can also provoke a hyperpotassemia (the salt substitutes containing potassium, kaliysberegayushchy diuretics, inhibitors apf, antagonists of receptors of ii angiotensin, npvp (including selection inhibitors tsog tsog-2 heparin, immunosuppressants (cyclosporine or takrolimus) and Trimethoprimum).

Cases of a hyperpotassemia depend on the related risk factors. The risk increases in case of the therapeutic combinations given above. Especially high risk at a combination with kaliysberegayushchy diuretics and in combination with the salt substitutes containing potassium. The combination with APF or NPVP inhibitors causes smaller risk on condition of accurate observance of preventive measures at use.

Accompanying use is not recommended to

Kaliysberegayushchy diuretics or potassium additives. Such antagonists of receptors of angiotensin II, as telmisartan, soften the potassium loss caused by diuretics. Kaliysberegayushchy diuretics, for example, Spironolactonum, eplerenon, Triamterenum or amiloride, potassium additives or substitutes of salt containing potassium can be the cause of substantial increase of potassium concentration in blood serum. If the accompanying use is shown in view of documentary confirmed hypopotassemia, it is necessary to take with caution, often controlling potassium level in blood serum.

Lities. Cases of reversible increase in concentration of lithium in blood serum and increase in toxicity are known during the accompanying intake of lithium with APF inhibitors and antagonists of receptors of angiotensin II, including telmisartan. If purpose of this combination is necessary, during the accompanying use it is necessary to control attentively lithium level in blood serum.

Accompanying use demanding care

NPVP (acetylsalicylic acid in anti-inflammatory schemes of therapy, TsOG-2 inhibitors and non-selective NPVP) can reduce expressiveness of antihypertensive action of antagonists of receptors of angiotensin II.

combined reception of antagonists of receptors of angiotensin II and the means braking COG can lead

At some patients with deterioration in function of kidneys (for example patients with dehydration or patients of advanced age with deterioration in function of kidneys) to further deterioration in function of kidneys, including possible OPN which is usually reversible. Therefore it is necessary to appoint such combination with care, especially to elderly people. Patients should provide appropriate hydration; besides, after the beginning of combination therapy and also periodically further it is necessary to control function of kidneys.

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In one research it is reported that the combined reception of a telmisartan and ramipril led to increase by 2.5 times of AUC _0-24 and the C _max a rampiril and the ramiprilat. The clinical importance of this observation is unknown.

Diuretics (thiazide or loopback). The previous treatment by high doses of such diuretics as furosemide (loopback diuretic) and a hydrochlorothiazide (thiazide diuretic), can lead to loss of volume and risk of hypotension if to begin treatment telmisartany.

Should pay attention at the accompanying use

Other antihypertensive drugs. The ability of a telmisartan lower the arterial blood pressure can be increased by the accompanying use of other antihypertensive medicines.

can expect

On the basis of pharmacological properties of Baclofenum and an amifostin that these medicines can strengthen hypotensive effect of all antihypertensive drugs, including telmisartan. Besides, orthostatic hypotension can be worsened by alcohol, barbiturates, medicaments and antidepressants.

Corticosteroids (system use). Decrease in antihypertensive action.

Overdose

Information concerning overdose at people is limited to

.

Symptoms. Arterial hypotension and tachycardia were the most considerable manifestations at overdose of a telmisartan and also it was reported about bradycardia, dizziness, increase in concentration of creatinine in blood serum and OPN.

Therapy. Telmisartan is not brought by a hemodialysis.

Patients have to be under careful control and receive symptomatic and maintenance therapy. Therapy depends on time when took the drug, and weights of symptoms. The recommended measures include calling of vomiting and/or gastric lavage. At therapy of overdose it is possible to apply activated carbon. It is necessary to control often the level of electrolytes and creatinine in blood serum. When developing arterial hypotension the patient should give horizontal position and to help, directed to fast completion of volume of liquid and salt in an organism.

Storage conditions

In the dry place in original packing at a temperature not above 30 °C.