Telmisartan

Pharmacological properties

mechanism of action. telmisartan is a specific and effective angiotensin ii receptor antagonist (type at1). Telmisartan, with a very high affinity, replaces angiotensin ii at its binding sites on the at1 subtype receptors, which are responsible for the activity of angiotensin ii. telmisartan does not show any partial agonistic effect on the at1 receptor. telmisartan selectively binds the at1 receptor. binding is long-term.

Telmisartan does not show affinity for other receptors, including AT₂ and other, less studied, AT receptors. The functional role of these receptors is unknown, as is the unknown effect of their possible “hyperstimulation” of angiotensin II, the level of which increases under the influence of telmisartan. Telmisartan reduces plasma aldosterone levels. Telmisartan does not inhibit renin in human blood plasma and does not block the ion channel. Telmisartan does not inhibit the angiotensin converting enzyme (kininase II), and also destroys bradykinin. Therefore, one should not expect potentiation of bradykinin-accompanying side effects.

In humans, telmisartan at a dose of 80 mg almost completely inhibits the increase in blood pressure caused by angiotensin II. The blocking effect persists for 24 hours and remains noticeable up to 48 hours.

Pharmacokinetics

Suction. Telmisartan absorption is rapid, although the adsorbed amount is different. The average absolute bioavailability of telmisartan is about 50%.

When telmisartan is taken with meals, the decrease in AUC for telmisartan varies from about 6% (40 mg) to 19% (160 mg). 3 hours after administration, the plasma concentration is the same, regardless of whether telmisartan is taken on an empty stomach or with food.

Linearity / nonlinearity. It is believed that a slight decrease in AUC does not cause a decrease in therapeutic efficacy. There is no linear relationship between dose and plasma level. WITH_max and to a lesser extent, AUC increase disproportionately at doses above 40 mg.

Distribution. Telmisartan is actively associated with plasma proteins (99.5%), mainly with albumin and alpha-1 acid glycoprotein. Distribution volume (Vss) is approximately 500 liters.

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

Telmisartan is characterized by biexponential pharmacokinetics with terminal T_½ 20 h. C_max and AUC increase disproportionately to the dose. There is no evidence of clinically significant cumulation of telmisartan when used in recommended doses. Plasma concentrations were higher in women than in men, without a corresponding effect on efficacy.

After oral administration, telmisartan is almost completely excreted in the feces mainly in an unchanged form. Cumulative renal excretion is 1% of the dose. Total clearance in blood plasma (Cl_tot) high (about 1000 ml / min), when compared with hepatic circulation (about 1500 ml / min).

Special categories of patients

Children. The results of studies of pharmacokinetics in children are generally consistent with data obtained for adults and confirm the nonlinearity of telmisartan, in particular for C_max.

Floor. C_max and AUC in women is approximately 3 and 2 times higher than in men, respectively.

Elderly patients. The pharmacokinetics of telmisartan does not differ in the elderly and those under the age of 65.

Patients with impaired renal function. In patients with moderate, moderate and severe renal failure, a 2-fold increase in plasma concentration was observed. However, in patients with renal failure subject to dialysis, a low plasma concentration was observed. Telmisartan has a high affinity for blood plasma proteins in individuals with renal failure and cannot be eliminated by dialysis.In patients with renal failure T_½ does not change.

Patients with impaired liver function. In pharmacokinetic studies in patients with hepatic impairment, an increase in bioavailability of up to about 100% was detected. In patients with liver failure T_½ does not change.

Indications

Ag: treatment of essential hypertension in adults.

Prevention of cardiovascular disease in patients with:

• manifest atherothrombotic cardiovascular disease (IHD, stroke or history of peripheral arterial damage);
• type II diabetes mellitus with documented target organ damage.

Application

Treatment ag. the usual effective dose is 40 mg / day. a daily dose of 20 mg may be sufficient for some patients. in cases where the desired effect is not achieved, the dose of telmisartan can be increased to 80 mg once a day. alternatively, telmisartan can be prescribed in combination with thiazide diuretics, such as hydrochlorothiazide, which has shown an additional decrease in hell when used with telmisartan. when the question of increasing the dose is considered, it must be taken into account that the maximum antihypertensive effect is generally achieved after 4-8 weeks from the start of treatment.

Prevention of cardiovascular disease. The recommended dose is 80 mg 1 time per day. The effectiveness of telmisartan in doses of less than 80 mg in the prevention of cardiovascular disease is unknown.

At the beginning of treatment with telmisartan, in order to prevent cardiovascular diseases, it is recommended to monitor blood pressure and, if necessary, adjust the dose of drugs that reduce blood pressure.

Special patient groups

Impaired renal function. Experience in treating patients with renal failure or patients on hemodialysis is limited. Such patients are recommended to start treatment with a low dose of 20 mg (see SPECIAL INSTRUCTIONS). For patients with mild to moderate renal failure, dose adjustment is not required.

The simultaneous use of telmisartan and aliskiren in patients with diabetes mellitus or with impaired renal function (glomerular filtration rate (GFR) 60 ml / min / 1.73 m²) is contraindicated (see CONTRAINDICATIONS).

Impaired liver function. Hypotel is contraindicated in patients with severely impaired liver function. For patients with mild or moderate impaired liver function, the daily dose should not exceed 40 mg once a day (see SPECIAL INSTRUCTIONS).

Elderly patients. Dose adjustment for elderly patients is not required.

Mode of application. Hypotel take 1 time per day with a sufficient amount of liquid, regardless of food intake.

Store tablets in an airtight blister to protect against moisture. Tablets should be removed from the blister just before use.

Contraindications

• Hypersensitivity to the components of the drug; period of pregnancy and women of reproductive age who may be pregnant (see use during pregnancy and lactation); obstructive biliary disorders; severe dysfunction of the liver.

The simultaneous use of telmisartan and aliskiren in patients with diabetes mellitus or with impaired renal function (GFR 60 ml / min / 1.73 m²) is contraindicated (see APPLICATION, SPECIAL INSTRUCTIONS, INTERACTIONS).

Side effects

Infections and infestations: upper respiratory tract infections, including pharyngitis and sinusitis, urinary tract infections, including cystitis; sepsis, including fatal.

On the part of the blood system and lymphatic system: anemia, thrombocytopenia, eosinophilia.

From the immune system: hypersensitivity, anaphylactic reactions.

From the side of metabolism: hyperkalemia, hypoglycemia (in patients with diabetes).

Mental disorders: depression, insomnia, anxiety.

From the nervous system: syncope, drowsiness.

From the side of the organ of vision: visual impairment.

On the part of the organ of hearing, the vestibular apparatus: vertigo.

From the side of the heart: bradycardia, tachycardia.

From the vessels: arterial hypotension, orthostatic hypotension.

From the respiratory system, chest and mediastinal organs: dyspnea, cough, interstitial lung disease.

From the digestive system: abdominal pain, diarrhea, dyspepsia, flatulence, vomiting, discomfort in the stomach, dry mouth.

From the hepatobiliary system: impaired liver function / liver disorders.

On the part of the skin and subcutaneous tissue: increased sweating, itching, rashes, erythema, angioedema (including fatal outcome), drug dermatitis, toxic dermatitis, eczema, urticaria.

From the musculoskeletal system and connective tissue: myalgia, back pain (e.g. sciatica), muscle cramps, arthralgia, pain in the limbs, pain in the tendon (symptoms similar to tendonitis).

From the urinary system: impaired renal function, including acute renal failure.

Common disorders: chest pain, asthenia (weakness), flu-like symptoms.

Laboratory data: increased creatinine in the blood, increased uric acid in the blood, increased liver enzymes, increased levels of CPK in the blood, decreased hemoglobin.

special instructions

Pregnancy. during pregnancy, treatment with angiotensin II receptor antagonists cannot be initiated. if the continuation of angiotensin ii receptor antagonist therapy is not absolutely necessary for a patient planning a pregnancy, she should switch to alternative antihypertensive therapy, which has an established safety profile for use during pregnancy. when pregnancy is established, treatment with angiotensin ii receptor antagonists should be stopped immediately and, if necessary, alternative treatment should be started (see contraindications and use during pregnancy and lactation).

Liver failure. Hypothel should not be prescribed to patients with cholestasis, obstructive diseases of the bile ducts and severe liver failure (see CONTRAINDICATIONS), since telmisartan is excreted mainly with bile. In such patients, a decrease in hepatic clearance of telmisartan can be expected.

Hypotel should be used with caution in patients with moderate to moderate liver failure.

Renovascular hypertension. There is an increased risk of severe arterial hypotension and renal failure if patients with bilateral renal artery stenosis or single kidney artery stenosis are treated with drugs that affect the renin-angiotensin-aldosterone system (RAAS).

Renal failure and kidney transplantation. When Hypotel is prescribed to patients with impaired renal function, periodic monitoring of the level of potassium and creatinine in blood plasma is recommended. There is no experience with telmisartan in patients with recent kidney transplantation.

Decreased intravascular fluid volume. Symptomatic hypotension, especially after the first dose of Hypotel, may occur in patients with reduced BCC and / or sodium levels that result from diuretic therapy, restriction of dietary salt, diarrhea, or vomiting. Before taking Hypotel, it is necessary to correct such conditions, especially a decrease in intravascular volume and / or sodium level.

Double blockade of RAAS. The use of telmisartan in combination with aliskiren in patients with diabetes mellitus or with impaired renal function (GFR 60 ml / min / 1.73 m²) is contraindicated (see CONTRAINDICATIONS).

As a result of inhibition of RAAS in more sensitive patients, arterial hypotension, syncope, hyperkalemia, and changes in kidney function (including acute renal failure) were noted, especially if the combination of drugs included drugs that affect this system. Therefore, a double blockade of RAAS (for example, the use of telmisartan with other RAAS blockers) is not recommended. If simultaneous use is necessary, careful monitoring of renal function is recommended.

Other conditions requiring stimulation of RAAS. In patients whose vascular tone and renal function mainly depend on RAAS activity (for example, patients with severe congestive heart failure or severe kidney disease, including renal artery stenosis), taking telmisartan with other drugs that affect RAAS can lead to acute arterial hypotension, hyperazotemia, oliguria, rarely with acute renal failure (see ADVERSE EFFECTS).

Primary hyperaldosteronism. Patients with primary hyperaldosteronism generally do not respond to antihypertensive drugs that act by blocking the renin-angiotensin system. Therefore, the appointment of telmisartan is not recommended.

Stenosis of the aorta and mitral valve, obstructive hypertrophic cardiomyopathy. Like other vasodilators, the drug is prescribed with extreme caution to patients who are diagnosed with aortic stenosis, mitral valve or obstructive hypertrophic cardiomyopathy.

Patients with diabetes who are treated with insulin or antidiabetic drugs. During treatment with telmisartan, such patients may develop hypoglycemia. Consideration should be given to the need for appropriate monitoring of blood glucose levels in such patients. According to indications, dose adjustment of insulin or antidiabetic drugs may be required.

In patients with diabetes mellitus, with cardiovascular risks (patients with diabetes mellitus, with concomitant diseases of the coronary arteries), the risk of developing myocardial infarction with a fatal outcome and sudden cardiovascular lethal outcome may be higher when treated with antihypertensive drugs, such as angiotensin II receptor antagonists and A inhibitors. In patients with diabetes mellitus, the course of concomitant coronary artery disease may be asymptomatic, and therefore they may be undiagnosed. Diabetic patients should be carefully examined, for example, by stress testing, to identify and treat concomitant coronary artery diseases before prescribing the drug.

Hyperkalemia Hyperkalemia may occur during the entire period of use of drugs that affect RAAS.

In elderly patients, patients with renal failure, diabetes, in patients taking other drugs in parallel, which can cause an increase in potassium levels, and / or patients with concomitant diseases, hyperkalemia can be fatal.

Before the concomitant use of drugs that inhibit RAAS, it is necessary to assess the ratio of benefits and risks.

The main risk factors for the development of hyperkalemia, which need attention:

• diabetes mellitus, renal failure, age over 70 years;
• combination therapy with one or more other drugs that affect RAAS and / or potassium supplements. Preparations or therapeutic groups of drugs that can cause hyperkalemia include salt substitutes containing potassium, potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists, NSAIDs (including selective COX-2 inhibitors), heparin, immunosuppressants (cyclosporin or tacrol trimethoprim;
• concomitant diseases, especially dehydration, acute cardiac decompensation, metabolic acidosis, impaired renal function, a sharp deterioration in the condition of the kidneys (e.g. due to infectious diseases), cell lysis (e.g. due to acute limb ischemia, acute skeletal muscle necrosis, extensive injury).

Patients at risk need to undergo careful monitoring of the plasma concentration of potassium (see INTERACTIONS).

Ethnic differences. Like all other angiotensin II receptor antagonists, telmisartan is less effective in lowering blood pressure in patients of the Negroid race than in representatives of other races. Perhaps this is due to the high prevalence of low renin states in patients of the Negroid race with hypertension.

Others. As with any other antihypertensive drug, a significant decrease in blood pressure in patients with ischemic cardiopathy or ischemic cardiovascular disease can lead to myocardial infarction or stroke.

Use during pregnancy or lactation. Pregnancy. Angiotensin II receptor antagonists should not be prescribed to pregnant women or women who may be pregnant (see CONTRAINDICATIONS). If pregnancy is confirmed during treatment with this drug, its use should be stopped immediately and, if necessary, alternative treatment should be started.

Fatal outcomes in the fetus and newborn, oligohydramnios, hypotension in the fetus and newborn, renal failure, hyperkalemia, skull hypoplasia, limb contracture / cerebral, craniofacial deformity / pulmonary dysplasia, possibly caused by oligohydramnios in pregnant patients treated with angiotensin receptor antagonists, have been reported. II in the II or III trimester of pregnancy.

Patients receiving angiotensin II receptor antagonists and planning a pregnancy should switch to antihypertensive drugs that have an established safety profile for use during pregnancy.

Lactation. Due to the lack of information on the use of telmisartan during lactation, Hypotel is not recommended for use. Preference should be given to alternative treatment with a better-studied safety profile, especially when breastfeeding a newborn or premature baby.

Fertility. In the course of preclinical studies, no effect of telmisartan on the fertility of men and women was revealed.

Children. Hypotel is contraindicated in children due to limited information on the safety and effectiveness of the drug in this category of patients.

The ability to influence the reaction rate when driving vehicles or working with other mechanisms. When driving a car and mechanisms, it is necessary to take into account the possibility of dizziness or hypersomnia with antihypertensive therapy, including the Hypotel drug.

Interactions

Double blockade of raas. the combination of telmisartan and aliskiren is contraindicated for patients with diabetes mellitus and impaired renal function (SCF 60 ml / min / 1.73 m2) and is not recommended for patients of other groups (see contraindications, special instructions).

Digoxin. With the simultaneous use of telmisartan and digoxin, an average increase in peak concentrations of digoxin in plasma (by 49%) and minimum concentrations (by 20%) was noted. At the beginning of administration, in the event of dose adjustment and discontinuation of telmisartan, digoxin levels should be monitored to maintain them within the therapeutic range.

Like other drugs that suppress RAAS, telmisartan can cause hyperkalemia (see SPECIAL INSTRUCTIONS). The risk may be increased in the case of treatment in combination with other agents that can also lead to hyperkalemia (salt substitutes containing potassium, potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists, NSAIDs, including selective COX-2 inhibitors), heparin, immunosuppressants ( cyclosporine or tacrolimus) and trimethoprim.

Cases of hyperkalemia depend on associated risk factors. The risk increases with the above therapeutic combinations.Especially high risk when combined with potassium-sparing diuretics and in combination with salt substitutes containing potassium. The combination with ACE inhibitors or NSAIDs, for example, is less risky, provided that the precautions for use are clearly observed.

Concomitant use is not recommended.

Potassium-sparing diuretics or potassium supplements. Angiotensin II receptor antagonists such as telmisartan alleviate diuretic-induced potassium loss. Potassium-sparing diuretics such as spironolactone, eplerenone, triamteren or amiloride, potassium supplements or salt substitutes containing potassium can cause a significant increase in the concentration of potassium in the blood plasma. If simultaneous use is indicated due to documented hypokalemia, it is necessary to take drugs with caution, often monitoring the level of potassium in the blood plasma.

Lithium. There are known cases of reversible increase in plasma lithium concentration and toxicity with concomitant use of lithium with ACE inhibitors and angiotensin II receptor antagonists, including telmisartan. If the appointment of this combination is considered necessary, during simultaneous use should carefully monitor the level of lithium in blood plasma.

Concomitant use requires caution.

NSAIDs. NSAIDs (i.e., anti-inflammatory doses of acetylsalicylic acid, COX-2 inhibitors and non-selective NSAIDs) can reduce the antihypertensive effect of angiotensin II receptor antagonists.

In some patients with impaired renal function (for example, in patients with dehydration or in elderly people with impaired renal function), the combined use of angiotensin II receptor antagonists and agents that inhibit COX can lead to further impairment of renal function, including possible acute renal failure, which is usually is reversible. Therefore, this combination should be prescribed with caution, especially for the elderly. Patients should ensure proper hydration; in addition, after the start of combination therapy, as well as periodically in the future, it is necessary to monitor renal function.

There is evidence that the combined use of telmisartan and ramipril leads to a 2.5-fold increase in AUC_0–24 and C_max ramipril and ramiprilat. The clinical significance of this observation is unknown.

Diuretics (thiazide or loop diuretics). Previous treatment with high doses of diuretics such as furosemide (loop diuretic) and hydrochlorothiazide (thiazide diuretic) can lead to a loss of bcc and the risk of arterial hypotension if treatment with telmisartan is started.

Should be taken into account while applying

Other antihypertensive agents. The ability of telmisartan to lower blood pressure can be increased by the concomitant use of other antihypertensive drugs.

Based on the pharmacological properties of baclofen and amifostine, it can be expected that these drugs can enhance the hypotensive effect of all antihypertensive drugs, including telmisartan. In addition, orthostatic hypotension can be exacerbated by alcohol, barbiturates, drugs, and antidepressants.

Corticosteroids (systemic use). Reducing the severity of antihypertensive action.

Overdose

Information on overdose in humans is insufficient.

Symptoms Significant manifestations of an overdose of telmisartan were arterial hypotension and tachycardia; bradycardia, dizziness, increased plasma creatinine and acute renal failure have also been reported.

Therapy. Telmisartan is not excreted by hemodialysis.

Patients should be under strict control and receive symptomatic and supportive therapy. Therapy depends on the time elapsed after taking the drug, and the severity of the symptoms.Recommended measures include inducing vomiting and / or gastric lavage. In the treatment of overdose, activated charcoal can be used. It is often necessary to check the level of electrolytes and creatinine in blood plasma. If arterial hypotension occurs, the patient should be laid on his back and assisted in quickly filling up the volume of fluid and salt in the body.

Storage conditions

At a temperature not exceeding 25 ° c in the original packaging.