Micardis^® (Tablets) Instructions for Use

Marketing Authorization Holder

Boehringer Ingelheim International, GmbH (Germany)

Manufactured By

Boehringer Ingelheim Pharma, GmbH & Co. KG (Germany)

Or

Boehringer Ingelheim Ellas, A.E. (Greece)

ATC Code

C09CA07 (Telmisartan)

Active Substance

Telmisartan (Rec.INN registered by WHO)

Dosage Forms

	Micardis®	Tablets 40 mg: 14 or 28 pcs.
		Tablets 80 mg: 14, 28, or 56 pcs.

Dosage Form, Packaging, and Composition

Tablets white or almost white, oblong, engraved with “51H” on one side and the company symbol on the other side.

Excipients: sodium hydroxide – 3.36 mg, povidone (Kollidon 25) – 12 mg, meglumine – 12 mg, sorbitol – 168.64 mg, magnesium stearate – 4 mg.

7 pcs. – blisters (2) – cardboard packs.
7 pcs. – blisters (4) – cardboard packs.

Tablets white or almost white, oblong, engraved with “52H” on one side and the company symbol on the other side.

Excipients: sodium hydroxide – 6.72 mg, povidone (Kollidon 25) – 24 mg, meglumine – 24 mg, sorbitol – 337.28 mg, magnesium stearate – 8 mg.

7 pcs. – blisters (2) – cardboard packs.
7 pcs. – blisters (4) – cardboard packs.
7 pcs. – blisters (8) – cardboard packs.

Clinical-Pharmacological Group

Angiotensin II receptor antagonist

Pharmacotherapeutic Group

Angiotensin II receptor antagonist

Pharmacological Action

Antihypertensive drug.

Pharmacodynamics

Telmisartan is a specific angiotensin II receptor antagonist. It has high affinity for the angiotensin II receptor subtype AT₁, through which the action of angiotensin II is mediated. Telmisartan displaces angiotensin II from binding to the receptor, having no agonist action on this receptor. It binds only to the angiotensin II receptor subtype AT₁. The binding is long-lasting. Telmisartan has no affinity for other receptors (including AT₂ receptors) and other, less studied angiotensin receptors. The functional significance of these receptors, as well as the effect of their possible overstimulation by angiotensin II, the concentration of which increases with the administration of telmisartan, has not been studied. It reduces the concentration of aldosterone in the blood, does not inhibit plasma renin and does not block ion channels. It does not inhibit ACE (kininase II), an enzyme that also breaks down bradykinin, so an increase in bradykinin-mediated side effects is not expected.

Telmisartan at a dose of 80 mg completely blocks the hypertensive effect of angiotensin II. The onset of the antihypertensive effect is noted within 3 hours after the first dose of telmisartan. The effect of the drug persists for 24 hours and remains significant for up to 48 hours. A pronounced antihypertensive effect usually develops after 4-8 weeks of regular use.

In patients with arterial hypertension, Telmisartan reduces systolic and diastolic blood pressure without affecting heart rate.

In case of abrupt withdrawal of telmisartan, blood pressure gradually returns to the initial level without the development of withdrawal syndrome.

Pharmacokinetics

Absorption

When taken orally, Telmisartan is rapidly absorbed from the gastrointestinal tract. Bioavailability is 50%.

When taken simultaneously with food, the decrease in AUC values ranges from 6% (when used at a dose of 40 mg) to 19% (when used at a dose of 160 mg). After 3 hours of administration, the plasma concentration levels off regardless of the time of food intake.

Distribution

Plasma protein binding is more than 99.5%, mainly with albumin and α₁-glycoprotein. The mean apparent V_d at steady state is 500 L.

Metabolism

It is metabolized by conjugation with glucuronic acid. The metabolites are pharmacologically inactive.

Excretion

T_1/2 is more than 20 hours. It is excreted through the intestine unchanged, renal excretion is less than 2% of the administered dose. Total plasma clearance is high (900 ml/min) compared to hepatic blood flow (about 1500 ml/min).

Pharmacokinetics in special clinical cases

A difference in concentrations is observed between men and women. In women, C_max and AUC were approximately 3 and 2 times higher, respectively, than in men (without significant effect on efficacy).

The pharmacokinetics of telmisartan in elderly patients does not differ from the pharmacokinetics in young patients. Dose adjustment is not required.

Dose adjustment in patients with renal impairment is not required, including patients on hemodialysis. Telmisartan is not removed by hemodialysis.

In patients with mild to moderate hepatic impairment (Child-Pugh class A and B), the daily dose of the drug should not exceed 40 mg.

The main pharmacokinetic parameters of telmisartan in children and adolescents aged 6 to 18 years after taking telmisartan at a dose of 1 mg/kg or 2 mg/kg for 4 weeks are generally comparable with data obtained in the treatment of adults and confirm the non-linearity of telmisartan pharmacokinetics, especially with respect to C_max.

Indications

• Arterial hypertension;
• Reduction of cardiovascular morbidity and mortality in patients aged 55 years and older at high risk of cardiovascular diseases.

ICD codes

Dosage Regimen

The drug is administered orally, regardless of meals.

For arterial hypertension, the recommended initial dose of Micardis^® is 1 tab. (40 mg) once a day. In cases where the therapeutic effect is not achieved, the dose of the drug can be increased to 80 mg once a day. When deciding to increase the dose, it should be taken into account that the maximum antihypertensive effect is usually achieved within 4-8 weeks after the start of treatment.

For reduction of cardiovascular morbidity and mortality, the recommended dose is 1 tab. (80 mg) once a day. In the initial period of treatment, additional blood pressure correction may be required.

Patients with renal impairment (including those on hemodialysis) do not require dose adjustment of the drug.

In patients with mild to moderate hepatic impairment (Child-Pugh class A and B), the daily dose of the drug should not exceed 40 mg.

The dosage regimen in elderly patients does not require changes.

Adverse Reactions

Observed cases of side effects did not correlate with the gender, age or race of the patients.

Infections sepsis, including fatal sepsis, urinary tract infections (including cystitis), upper respiratory tract infections.

From the hematopoietic system anemia, eosinophilia, thrombocytopenia.

From the central nervous system insomnia, anxiety, depression, syncope, vertigo.

From the organ of vision visual disturbances.

From the cardiovascular system marked decrease in blood pressure, orthostatic hypotension, bradycardia, tachycardia.

From the respiratory system dyspnea.

From the digestive system abdominal pain, diarrhea, dry mouth, dyspepsia, flatulence, stomach discomfort, vomiting, impaired liver function/liver disease* (*according to post-marketing surveillance data, in most cases impaired liver function/liver disease was detected in Japanese patients).

Allergic reactions anaphylactic reactions, hypersensitivity (erythema, urticaria, angioedema), eczema, pruritus, rash (including drug rash), angioedema (with fatal outcome), toxic rash, hyperhidrosis.

From the musculoskeletal system arthralgia, back pain, muscle cramps (calf cramps), lower limb pain, myalgia, tendon pain (symptoms similar to tendinitis).

From the urinary system impaired renal function (including acute renal failure).

From laboratory parameters decreased hemoglobin, increased blood uric acid and creatinine concentrations, increased activity of liver enzymes, increased CPK activity, hyperkalemia, hypoglycemia (in patients with diabetes mellitus).

Other chest pain, flu-like syndrome, general weakness.

Contraindications

• Obstructive biliary tract diseases;
• Severe hepatic impairment (Child-Pugh class C);
• Concomitant use with aliskiren in patients with diabetes mellitus or renal impairment (GFR <60 ml/min/1.73 m²);
• Fructose intolerance, glucose/galactose malabsorption syndrome or sucrase/isomaltase deficiency;
• Age under 18 years (efficacy and safety not established);
• Pregnancy;
• Breastfeeding period;
• Hypersensitivity to the active substance or auxiliary components of the drug.

With caution

• Bilateral renal artery stenosis or stenosis of the artery of a single kidney;
• Impaired liver and/or kidney function;
• Reduced blood volume due to previous diuretic therapy, salt restriction, diarrhea or vomiting;
• Hyponatremia;
• Hyperkalemia;
• Conditions after kidney transplantation (no experience of use);
• Chronic heart failure;
• Aortic and mitral valve stenosis;
• Idiopathic hypertrophic subaortic stenosis;
• Primary aldosteronism (efficacy and safety not established).

Use in Pregnancy and Lactation

The use of Micardis^® is contraindicated during pregnancy.

The use of angiotensin II receptor antagonists in the first trimester of pregnancy is not recommended; these drugs should not be prescribed during pregnancy. When pregnancy is diagnosed, the use of the drug should be discontinued immediately. If necessary, alternative therapy should be prescribed (other classes of antihypertensive drugs approved for use during pregnancy).

The use of angiotensin II receptor antagonists in the second and third trimesters of pregnancy is contraindicated. In preclinical studies of telmisartan, no teratogenic effects were identified, but fetotoxicity was established. It is known that exposure to angiotensin II receptor antagonists in the second and third trimesters of pregnancy causes fetotoxicity in humans (decreased renal function, oligohydramnios, delayed skull ossification), as well as neonatal toxicity (renal failure, arterial hypotension, hyperkalemia).

Patients planning pregnancy should be prescribed alternative therapy. If treatment with angiotensin II receptor antagonists was carried out in the second trimester of pregnancy, it is recommended to perform ultrasound of the kidneys and skull bones of the fetus.

Newborns whose mothers received angiotensin II receptor antagonists should be carefully monitored for arterial hypotension.

Therapy with Micardis^® is contraindicated during breastfeeding.

Studies on the effect on human fertility have not been conducted.

Use in Hepatic Impairment

The use of the drug is contraindicated in case of impaired biliary tract patency, severe hepatic impairment (Child-Pugh class C).

In patients with mild to moderate hepatic impairment (Child-Pugh class A and B), the daily dose of the drug should not exceed 40 mg.

Use in Renal Impairment

Patients with renal impairment (including those on hemodialysis) do not require dose adjustment of the drug.

With caution, the drug should be used in case of bilateral renal artery stenosis or stenosis of the artery of a single kidney, impaired renal function, condition after kidney transplantation.

Pediatric Use

The drug is contraindicated for use in children and adolescents under 18 years of age, because data on efficacy and safety in this category of patients are lacking.

Geriatric Use

The dosage regimen in elderly patients does not require changes.

Special Precautions

In some patients, due to suppression of the RAAS, especially when using a combination of agents acting on this system, renal function is impaired (including acute renal failure). Therefore, therapy accompanied by such dual blockade of the RAAS (for example, when adding ACE inhibitors or a direct renin inhibitor – aliskiren to angiotensin II receptor antagonists) should be carried out strictly individually and with careful monitoring of renal function (including periodic monitoring of serum potassium and creatinine concentrations).

In cases where vascular tone and renal function depend predominantly on the activity of the RAAS (for example, in patients with chronic heart failure or kidney disease, including renal artery stenosis or stenosis of the artery of a single kidney), the administration of drugs affecting this system may be accompanied by the development of acute arterial hypotension, hyperazotemia, oliguria and, in rare cases, acute renal failure.

Based on the experience of using other drugs affecting the RAAS, when prescribing Micardis^® simultaneously with potassium-sparing diuretics, potassium-containing supplements, potassium-containing food salt, and other agents that increase blood potassium concentration (for example, heparin), this indicator should be monitored in patients.

In patients with diabetes mellitus and additional cardiovascular risk, for example, in patients with diabetes mellitus and coronary artery disease, when using blood pressure-lowering drugs, such as angiotensin II receptor antagonists or ACE inhibitors, the risk of fatal myocardial infarction and sudden cardiovascular death may increase. In patients with diabetes mellitus, coronary artery disease may be asymptomatic and therefore may be undiagnosed. Before starting the use of Micardis^®, appropriate diagnostic studies, including an exercise test, should be performed to detect and treat coronary artery disease.

As an alternative, Micardis^® can be used in combination with thiazide diuretics, such as hydrochlorothiazide, which additionally have an antihypertensive effect (for example, the drug Micardis^® Plus 40 mg/12.5 mg, 80 mg/12.5 mg).

In patients with primary aldosteronism, antihypertensive drugs whose mechanism of action is to inhibit the RAAS are generally not effective.

Caution should be exercised when using Micardis^® (as well as other vasodilators) in patients with aortic or mitral stenosis and with hypertrophic obstructive cardiomyopathy.

Telmisartan is excreted mainly in the bile. In patients with obstructive biliary tract diseases or hepatic insufficiency, a decrease in drug clearance can be expected.

In patients with severe arterial hypertension, a dose of telmisartan 160 mg/day in combination with hydrochlorothiazide 12.5-25 mg was effective and well tolerated.

Impaired liver function when prescribing telmisartan was observed in most cases in Japanese residents.

Micardis^® is less effective in patients of the Black race.

Effect on the ability to drive vehicles and mechanisms

No special clinical studies have been conducted on the effect of the drug on the ability to drive a car and operate machinery. However, when driving a car and working with machinery, the possibility of developing dizziness and drowsiness should be taken into account, which requires caution.

Overdose

No cases of overdose have been identified.

Symptoms marked decrease in blood pressure, tachycardia, bradycardia.

Treatment symptomatic therapy. Hemodialysis is ineffective.

Drug Interactions

Telmisartan may increase the hypotensive effect of other antihypertensive agents. Other types of interactions of clinical significance have not been identified.

Concomitant use with digoxin, warfarin, hydrochlorothiazide, glibenclamide, ibuprofen, paracetamol, simvastatin and amlodipine does not lead to clinically significant interaction. An increase in the average plasma concentration of digoxin by an average of 20% (in one case by 39%) was noted. When prescribing telmisartan and digoxin simultaneously, it is advisable to periodically determine the concentration of digoxin in the blood.

With simultaneous use of telmisartan and ramipril, an increase in AUC_0-24 and C_max of ramipril and ramiprilat by 2.5 times was observed. The clinical significance of this phenomenon has not been established.

With simultaneous use of ACE inhibitors and lithium preparations, a reversible increase in blood lithium concentration was noted, accompanied by a toxic effect. In rare cases, similar changes were registered when prescribing angiotensin II receptor antagonists. When prescribing lithium preparations and angiotensin II receptor antagonists simultaneously, it is recommended to determine the concentration of lithium in the blood.

Treatment with NSAIDs, including acetylsalicylic acid, COX-2 inhibitors and non-selective NSAIDs, can cause the development of acute renal failure in patients with dehydration. Drugs acting on the RAAS may have a synergistic effect. In patients receiving NSAIDs and Telmisartan, blood volume should be compensated and renal function should be examined at the beginning of treatment.

A decrease in the effect of antihypertensive agents, such as Telmisartan, by inhibiting the vasodilating effect of prostaglandins was noted with simultaneous therapy with NSAIDs.

Storage Conditions

The drug should be stored out of the reach of children, in a dry place at a temperature not exceeding 30°C (86°F).

Shelf Life

The shelf life is 4 years. Do not use after the expiration date.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.