Instructions for use Micardis tablets 80 mg blister No. 28
Composition
active ingredient: telmisartan;
1 tablet contains telmisartan 80 mg;
excipients: sodium hydroxide, povidone (E 1201), meglumine, sorbitol (E 420), magnesium stearate (E 470b).
Dosage form
Pills.
Main physicochemical properties: oval tablets of white or almost white color with embossing “52H” on one side and the company symbol on the other side.
Pharmacotherapeutic group
Simple angiotensin II antagonist drugs.
ATX code C09C A07.
Pharmacological properties
Pharmacodynamics.
Mechanism of action.
Telmisartan is a specific and potent angiotensin II receptor (type AT1) antagonist for oral administration. Telmisartan displaces angiotensin II with very high affinity at the binding sites of the AT1 receptor subtype responsible for the activity of angiotensin II. Telmisartan does not exhibit any partial agonist activity at the AT1 receptor.
Telmisartan binds selectively to the AT1 receptor. Binding is long-lasting. Telmisartan has no affinity for other receptors, including AT2 and other, less well-studied AT receptors.
The functional role of these receptors is not clear, as is the effect of their possible stimulation by angiotensin II, the levels of which are increased by telmisartan. Telmisartan reduces plasma aldosterone levels. Telmisartan does not reduce plasma renin levels and does not block ion channels. Telmisartan does not inhibit angiotensin-converting enzyme (kininase II), an enzyme that also degrades bradykinin. Therefore, potentiation of bradykinin-related side effects should not be expected.
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 significant for up to 48 hours.
Pharmacokinetics.
Absorption. Telmisartan is rapidly absorbed, but the amount of drug absorbed is variable. The mean absolute bioavailability of telmisartan is approximately 50%. When MICARDIS is administered with food, the area under the concentration-time curve (AUC) for telmisartan decreases from approximately 6% (40 mg) to 19% (160 mg). Three hours after dosing, plasma concentrations are similar to those observed when telmisartan is administered without food.
Linearity/non-linearity. A slight decrease in AUC is not expected to reduce therapeutic efficacy. There is no linear relationship between dose and plasma levels. Cmax and, to a lesser extent, AUC increase disproportionately at doses above 40 mg.
Distribution: Telmisartan is extensively bound to plasma proteins (>99.5%), mainly to albumin and alpha-1 acid glycoprotein. The mean volume of distribution (Vss) at steady state is approximately 500 l.
Metabolism: Telmisartan is metabolized by conjugation to the glucuronide of the parent compound. The pharmacological activity of the conjugate has not been established.
Elimination. Telmisartan is characterized by a biexponential pharmacokinetic curve with a terminal half-life of > 20 hours. Maximum plasma concentration (Cmax) and, to a lesser extent, AUC increase disproportionately with dose. There is no evidence of clinically significant accumulation of telmisartan at recommended doses. Plasma concentrations were higher in women than in men, without a corresponding effect on efficacy.
After oral (and intravenous) administration, telmisartan is almost completely excreted in the feces, mainly as unchanged compound. Cumulative renal excretion is < 1% of the dose.
Total plasma clearance (Cltot) is high (approximately 1000 ml/min) compared to hepatic blood flow (approximately 1500 ml/min).
Special categories of patients.
Children. The pharmacokinetics of two doses of telmisartan were evaluated as a secondary objective in hypertensive patients (n = 57) aged 6 to < 18 years after telmisartan was administered at a dose of 1 mg/kg or 2 mg/kg for 4 weeks of treatment. The pharmacokinetic objectives included determining steady-state telmisartan levels in children and adolescents and investigating age-related differences. Although the study was underpowered to reliably assess pharmacokinetics in children < 12 years of age, the results are generally consistent with those obtained in adults and confirm the non-linearity of telmisartan, particularly for Cmax.
Gender: Plasma Cmax and AUC are approximately 3- and 2-fold higher in women than in men, respectively.
Elderly patients: The pharmacokinetics of telmisartan do not differ between elderly patients and those under 65 years of age.
Patients with renal impairment. In patients with mild to moderate and severe renal impairment, a 2-fold increase in plasma concentrations was observed. However, in patients with renal impairment undergoing dialysis, low plasma concentrations were observed. Telmisartan is highly bound to plasma proteins in patients with renal impairment and cannot be removed by dialysis. The elimination half-life is not altered in patients with renal impairment.
Patients with hepatic impairment: Pharmacokinetic studies in patients with hepatic impairment have shown an increase in absolute bioavailability to approximately 100%. The elimination half-life is not altered in patients with hepatic insufficiency.
Indication
Hypertension.
Prevention of cardiovascular diseases.
Reducing the incidence of cardiovascular disease in patients with:
- severe manifestations of atherothrombotic cardiovascular disease (history of ischemic heart disease, stroke or peripheral arterial disease);
- type II diabetes mellitus with diagnosed target organ damage.
Contraindication
- Hypersensitivity to the active substance or to any excipient of the drug;
- pregnant women or women planning to become pregnant (see sections "Special instructions for use", "Use during pregnancy or breastfeeding");
- obstructive diseases of the bile ducts;
- severe liver dysfunction;
- childhood (up to 18 years old).
The concomitant use of telmisartan and aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m2) (see sections “Interaction with other medicinal products and other forms of interaction” and “Pharmacological properties”).
Interaction with other medicinal products and other types of interactions
Digoxin
When telmisartan and digoxin were co-administered, mean increases in peak plasma digoxin concentrations (by 49%) and trough concentrations (by 20%) were observed. Digoxin levels should be monitored at the start of treatment, when the dose is adjusted, and when telmisartan is discontinued to maintain them within the therapeutic range.
As with other drugs that inhibit the renin-angiotensin-aldosterone system, telmisartan may induce hyperkalemia (see section 4.4). The risk may be increased by concomitant treatment with other drugs that may also induce hyperkalemia (salt substitutes containing potassium, potassium-sparing diuretics, angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists, non-steroidal anti-inflammatory drugs (NSAIDs, including selective COX-2 inhibitors), heparin, immunosuppressants (ciclosporin or tacrolimus) and trimethoprim).
The incidence of hyperkalemia depends on the associated risk factors. The risk increases with the above therapeutic combinations. The risk is particularly high in combination with potassium-sparing diuretics and in combination with potassium-containing salt substitutes. The combination with ACE inhibitors or NSAIDs, for example, is less risky if the precautions for use are strictly observed.
Concomitant use is not recommended.
Potassium-sparing diuretics or potassium supplements. Angiotensin II receptor antagonists such as telmisartan reduce potassium loss caused by diuretics. Potassium-sparing diuretics such as spironolactone, eplerenone, triamterene or amiloride, potassium supplements or potassium-containing salt substitutes may lead to significant increases in serum potassium. If concomitant use is indicated because of documented hypokalaemia, they should be used with caution, with frequent monitoring of serum potassium.
Lithium: Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant use of lithium with ACE inhibitors and angiotensin II receptor antagonists, including telmisartan. If the combination proves necessary, careful monitoring of serum lithium levels is recommended.
Concomitant use requires caution.
Nonsteroidal anti-inflammatory drugs: NSAIDs (i.e. acetylsalicylic acid at anti-inflammatory doses, COX-2 inhibitors and non-selective NSAIDs) may reduce the antihypertensive effect of angiotensin II receptor antagonists.
In some patients with impaired renal function (e.g. dehydrated patients or elderly patients with impaired renal function), the combined use of angiotensin II receptor antagonists and cyclooxygenase inhibitors may lead to further deterioration of renal function, including possible acute renal failure, which is usually reversible. Therefore, such a combination should be used with caution, especially in elderly patients. Patients should be adequately hydrated and consideration should be given to monitoring renal function after initiation of concomitant treatment and periodically thereafter.
In one study, concomitant administration of telmisartan and ramipril resulted in a 2.5-fold increase in AUC0-24 and Cmax for ramipril and ramiprilat. The clinical significance of this finding is unknown.
Diuretics (thiazide or loop diuretics): Pre-treatment with high doses of diuretics such as furosemide (loop diuretic) and hydrochlorothiazide (thiazide diuretic) may lead to dehydration and a risk of hypotension at the start of treatment with telmisartan.
This should be taken into account when used concomitantly.
Clinical data have shown that dual blockade of the renin-angiotensin-aldosterone system (RAAS) through the combined use of ACE inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher incidence of adverse events such as hypotension, hyperkalemia and decreased renal function (including acute renal failure) compared with the use of a single RAAS-acting agent (see sections 4.4, 4.3 and 5.1).
Given the pharmacological properties of baclofen and amifostine, it can be expected that these drugs may potentiate the hypotensive effect of all antihypertensive drugs, including telmisartan. In addition, orthostatic hypotension may be aggravated by alcohol, barbiturates, narcotics and antidepressants.
Corticosteroids (systemic use). Decreased antihypertensive effect.
Application features
Pregnancy.
Angiotensin II receptor antagonists should not be initiated during pregnancy. Unless continued angiotensin II receptor antagonist therapy is considered essential for the patient planning pregnancy, she should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with angiotensin II receptor antagonists should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.8).
Liver failure.
MICARDIS should not be administered to patients with cholestasis, obstructive bile duct disease and severe hepatic impairment (see section 4.3) as telmisartan is mainly excreted in the bile. In patients with these conditions, hepatic clearance of telmisartan is reduced.
MICARDIS should be used with caution in patients with mild to moderate hepatic impairment.
Renovascular hypertension: There is an increased risk of severe hypotension and renal failure in patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney when treated with drugs that affect the renin-angiotensin-aldosterone system.
Renal impairment and kidney transplantation: When using MICARDIS in patients with impaired renal function, periodic monitoring of serum potassium and creatinine is recommended. There is no experience with the use of MICARDIS in patients with a recent kidney transplantation.
Intravascular volume depletion. Symptomatic hypotension, especially after the first dose of MICARDIS, may occur in patients who are volume and/or sodium depleted by vigorous diuretic therapy, dietary salt restriction, or diarrhea and vomiting. These conditions should be corrected before MICARDIS is administered. Sodium and/or volume depletion should be corrected before initiating therapy with MICARDIS.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS).
There is evidence that concomitant use of angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalemia and decreased renal function (including acute renal failure).
Therefore, dual blockade through the combined use of ACE inhibitors, angiotensin II receptor blockers or aliskiren is not recommended (see sections 4.5 and 5.1).
If dual blockade is considered absolutely necessary, it should only be performed under specialist supervision and with continuous close monitoring of renal function, electrolytes and blood pressure.
ACE inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.
Other conditions requiring stimulation of the renin-angiotensin-aldosterone system.
In patients whose vascular tone and renal function depend predominantly on the activity of the renin-angiotensin-aldosterone system (such as patients with severe congestive heart failure or severe renal disease, including renal artery stenosis), the use of MICARDIS with other medicinal products that affect the renin-angiotensin-aldosterone system may result in acute hypotension, hyperazotemia, oliguria, and rarely acute renal failure (see section 4.8).
Primary aldosteronism: Patients with primary aldosteronism usually do not respond to antihypertensive drugs that act by blocking the renin-angiotensin system. Therefore, the use of telmisartan in these patients is not recommended.
Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy. As with other vasodilators, caution should be exercised when prescribing the drug to patients with known aortic or mitral stenosis or obstructive hypertrophic cardiomyopathy.
During treatment with telmisartan, hypoglycemia may develop in such patients. In such patients, blood glucose levels should be monitored and this should be taken into account when adjusting the dose of insulin or antidiabetic drugs.
In patients with diabetes mellitus at cardiovascular risk (diabetic patients with concomitant coronary artery disease), the risk of fatal myocardial infarction and sudden cardiovascular death may be increased when treated with antihypertensive drugs such as angiotensin II receptor antagonists and ACE inhibitors. In patients with diabetes mellitus, concomitant coronary artery disease may be asymptomatic and therefore undiagnosed. Patients with diabetes mellitus should be carefully evaluated, e.g. by stress testing, to identify and treat concomitant coronary artery disease before prescribing the drug.
Hyperkalemia. The use of drugs that affect the renin-angiotensin-aldosterone system may cause hyperkalemia.
In elderly patients, patients with renal insufficiency, patients with diabetes, in patients who are concomitantly receiving other drugs that may increase potassium levels, and/or in patients with concomitant diseases, hyperkalemia can be fatal.
Before considering the concomitant use of medicinal products that inhibit the renin-angiotensin system, the benefit-risk ratio should be weighed.
The main risk factors for developing hyperkalemia that should be taken into account are:
- diabetes, renal failure, age over 70 years;
- combination therapy with one or more other medicinal products that affect the renin-angiotensin-aldosterone system and/or dietary supplements containing potassium. Medicinal products or therapeutic classes of medicinal products that may induce hyperkalaemia include salt substitutes containing potassium, potassium-sparing diuretics, angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists, non-steroidal anti-inflammatory drugs (NSAIDs, including selective COX-2 inhibitors), heparin, immunosuppressants (ciclosporin or tacrolimus) and trimethoprim;
- intercurrent manifestations, especially dehydration, acute cardiac decompensation, metabolic acidosis, deterioration of renal function, acute deterioration of renal status (e.g. infectious diseases), cellular lysis (e.g. acute limb ischemia, acute skeletal muscle necrosis, extensive trauma).
Patients at risk should undergo careful monitoring of serum potassium concentrations (see section “Interaction with other medicinal products and other types of interactions”).
Sorbitol. This medicinal product contains sorbitol (E 420). Patients with rare hereditary problems of fructose intolerance should not take this medicinal product.
Ethnic differences: As with all angiotensin II receptor antagonists, telmisartan is apparently less effective in lowering blood pressure in black patients than in non-blacks. This may be due to a higher prevalence of low-renin states in black hypertensive patients.
Others: As with any other antihypertensive agent, excessive blood pressure reduction in patients with coronary artery disease or ischemic cardiopathy may result in myocardial infarction or stroke.
Use during pregnancy or breastfeeding.
Pregnancy.
The drug is contraindicated for use in pregnant women or women planning to become pregnant. If pregnancy is confirmed during treatment with this drug, its use should be discontinued immediately and, if necessary, replaced with another drug approved for use in pregnant women (see sections "Contraindications" and "Special Instructions").
There are no adequate data from the use of MICARDIS in pregnant women.
The use of angiotensin II receptor antagonists during the second and third trimesters of pregnancy is known to induce human fetotoxicity (renal impairment, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalemia). If exposure to angiotensin II receptor antagonists has been initiated from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended. Infants whose mothers have taken angiotensin II receptor antagonists should be closely monitored for hypotension (see sections 4.3 and 4.4).
Breast-feeding.
Because no information is available regarding the use of MICARDIS during breast-feeding, this medicine is not recommended for use in women who are breast-feeding. Alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.
Fertility.
In nonclinical studies, no effect of MICARDIS on male or female fertility was observed.
Ability to influence reaction speed when driving vehicles or other mechanisms
When driving a car or operating machinery, it is necessary to take into account the possibility of dizziness or hypersomnia during antihypertensive therapy, including MICARDIS.
Method of administration and doses
Treatment of arterial hypertension.
The usual effective dose of telmisartan is 40 mg per day. Some patients may be satisfied with a daily dose of 20 mg telmisartan. If blood pressure is not controlled to the desired level, the dose of telmisartan may be increased to 80 mg once daily. Alternatively, telmisartan may be given in combination with thiazide diuretics, such as hydrochlorothiazide, which have an additive blood pressure-lowering effect when used with telmisartan. When deciding whether to increase the dose, it should be borne in mind that the maximum antihypertensive effect is achieved 4–8 weeks after the start of treatment.
Prevention of cardiovascular diseases.
The recommended dose is 80 mg once daily. The efficacy of telmisartan at doses below 80 mg in the prevention of cardiovascular disease is unknown.
When initiating treatment with telmisartan to reduce cardiovascular disease, it is recommended to carefully monitor blood pressure and, if necessary, adjust the dose of blood pressure-lowering drugs.
Special patient groups
Kidney dysfunction.
Experience in patients with renal insufficiency or patients undergoing hemodialysis is limited. In such patients, it is recommended to start treatment with the lowest initial dose of telmisartan 20 mg (see section "Special instructions"). There is no need for dose adjustment in patients with mild to moderate renal insufficiency.
Hepatic impairment: MICARDIS is contraindicated in patients with severe hepatic impairment.
For patients with mild or moderate hepatic impairment, the daily dose of telmisartan should not exceed 40 mg once daily (see section 4.4).
Elderly patients: No dose adjustment is required.
Method of application.
MICARDIS is taken orally once a day with sufficient fluid, regardless of food intake.
The tablets should be stored in a sealed blister to protect from moisture. The tablets should be removed from the blister immediately before use.
Children.
The safety and efficacy of MICARDIS in children (under 18 years of age) have not been studied.
Overdose
Information on drug overdose is limited.
Symptoms: The most common symptoms of telmisartan overdose were hypotension and tachycardia; bradycardia, dizziness, increased serum creatinine and acute renal failure have also been reported.
Therapy. Telmisartan is not removed from the body by hemodialysis. Patients should be closely monitored and receive symptomatic and supportive therapy. Treatment depends on the time since overdose and the severity of symptoms. It is recommended to induce vomiting and/or perform gastric lavage. Activated charcoal can be used in the treatment of overdose. Frequent monitoring of serum electrolytes and creatinine is necessary. If hypotension occurs, the patient should be placed on his back and assistance should be provided aimed at rapid replenishment of fluid and salt volume in the body.
Adverse reactions
The overall incidence of adverse reactions in patients with hypertension in controlled clinical trials with telmisartan was generally comparable to that with placebo (41.4% versus 43.9%). The incidence of adverse reactions was independent of dose and was not related to gender, age, or race. The safety profile of telmisartan in patients treated for the prevention of cardiovascular disease was consistent with that observed in patients with hypertension.
The following adverse drug reactions are based on results from controlled clinical trials in hypertensive patients and post-marketing reports. This list also includes serious adverse reactions and adverse reactions leading to discontinuation of the drug in three long-term clinical trials involving 21,642 patients treated with telmisartan for the prevention of cardiovascular disease for six years.
Adverse reactions are listed according to their frequency: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000).
Within each group, adverse reactions are presented in order of decreasing severity.
Infectious diseases and invasions:
uncommon – urinary tract infections (including cystitis), upper respiratory tract infections (including pharyngitis and sinusitis);
rarely – sepsis, including fatal outcome1.
From the blood and lymphatic system:
infrequently - anemia;
rarely - eosinophilia, thrombocytopenia.
On the part of the immune system:
rarely - anaphylactic reaction, hypersensitivity.
Metabolic disorders:
infrequently - hyperkalemia;
rarely - hypoglycemia (in patients with diabetes).
Mental disorders:
infrequently - insomnia, depression;
rarely - anxiety.
From the nervous system:
infrequently – syncope;
rarely - drowsiness.
On the part of the organs of vision:
rarely - visual impairment.
From the side of the organs of hearing, vestibular apparatus:
infrequently - vertigo.
From the heart:
infrequently – bradycardia;
rarely - tachycardia.
From the vascular side:
uncommon – arterial hypotension2, orthostatic hypotension.
From the respiratory system, chest organs and mediastinum:
infrequently – dyspnoea, cough;
very rarely – interstitial lung disease4.
From the digestive tract:
infrequently - abdominal pain, diarrhea, dyspepsia, flatulence, vomiting;
rarely - dry mouth, stomach discomfort, dysgeusia.
Hepatobiliary disorders:
Rare: liver dysfunction/hepatic disorders3.
From the skin and subcutaneous tissue:
infrequently - itching, increased sweating, rash;
rarely - angioedema (including fatal), eczema, erythema, urticaria, drug dermatitis, toxic dermatitis.
Musculoskeletal and connective tissue disorders:
uncommon – back pain (e.g. sciatica), muscle cramps, myalgia;
rarely - arthralgia, pain in the extremities, tendon pain (symptoms similar to tendinitis).
From the urinary system:
uncommon - renal dysfunction, including acute renal failure.
General violations:
infrequently - chest pain, asthenia (weakness);
rarely - flu-like symptoms.
Laboratory data:
infrequently - increased creatinine in the blood;
rarely - decreased hemoglobin levels, increased uric acid in the blood, increased liver enzymes, increased creatine phosphokinase levels in the blood.
1, 2, 3, 4 - See section "Adverse reactions".
Description of selected adverse reactions
Sepsis: In the PRoFESS trial, a higher rate of sepsis was observed in patients taking telmisartan than in those taking placebo. This may be a coincidence or a sign of a process whose nature is currently unknown.
Hypotension: This adverse reaction was observed commonly in patients with controlled blood pressure who were treated with telmisartan to reduce cardiovascular disease in addition to standard therapy.
Hepatic impairment/hepatic disorders: In post-marketing experience, the majority of cases of hepatic impairment/hepatic disorders have been reported in patients of Japanese ethnicity. Japanese patients appear to be more susceptible to these adverse reactions.
Interstitial lung disease: Cases of interstitial lung disease have been observed transiently with the use of telmisartan during post-marketing surveillance. However, a causal relationship has not been established.
Expiration date
4 years.
Storage conditions
Store in the original packaging at a temperature not exceeding 30 ºC. Keep out of the reach of children.
Packaging
7 tablets in a blister; 2 or 4 blisters in a box.
Vacation category
According to the recipe.
Producer
Boehringer Ingelheim Pharma GmbH & Co. KG.
or
Boehringer Ingelheim Ellas AE, Greece.
Location of the manufacturer and address of its place of business.
Binger Straße 173, D-55216 Ingelheim, Germany/Binger Straße 173, D-55216 Ingelheim, Germany
or
5th km Paiania-Markopoulo, Koropi Attiki 19400, Greece/5th km Paiania-Markopoulo, Koropi Attiki 19400, Greece.
