for medical use
active substances: telmisartan;
1 tablet contains telmisartan 20 mg, 40 mg or 80 mg;
excipients: sodium hydroxide, meglumine, mannitol (E 421), crospovidone, magnesium stearate.
Pharmaceutical form. Tablets.
Main physicochemical properties: white or almost white, round biconvex tablets.
Simple preparations of angiotensin II antagonists.
АТС code С09С А07.
Mechanism of action.
Telmisartan is a specific and effective angiotensin II receptor antagonist (type AT1). Telmisartan with very high affinity replaces angiotensin II in the places of its binding with AT1-type receptors which are responsible for the activity of angiotensin II. Telmisartan does not exhibit any partial agonist effect on the AT1 receptor. Telmisartan selectively binds the AT1 receptor. The binding is long-lasting. Telmisartan does not show affinity for other receptors, including AT2 and other less studied AT receptors. The functional role of these receptors is not known, nor is the effect of their possible «overstimulation» by angiotensin II, whose levels are increased by telmisartan. Plasma aldosterone levels are decreased by telmisartan. Telmisartan does not inhibit human plasma renin or block ion channels. Telmisartan does not inhibit angiotensin-converting enzyme (kininase II), the enzyme which also degrades bradykinin. Therefore it is not expected to potentiate bradykinin-mediated adverse effects.
In human, 80 mg dose of telmisartan almost completely inhibits the angiotensin II evoked blood pressure increase. The blocking effect is maintained over 24 hours and still measurable up to 48 hours.
Absorption. Absorption of telmisartan is rapid although the amount absorbed varies. The mean absolute bioavailability for telmisartan is about 50%. When telmisartan is taken with food, the reduction in the area under the plasma «concentration-time curve» (AUC) of telmisartan varies from approximately 6% (40 mg) to approximately 19% (160 mg). By 3 hours after administration plasma concentrations are similar whether telmisartan is taken fasting or with food.
Linearity/non-linearity. The small reduction in AUC is not expected to cause a reduction in the therapeutic efficacy. There is no linear relationship between doses and plasma levels. Cmax and to a lesser extent AUC increase disproportionately at doses above 40 mg.
Distribution. Telmisartan is largely bound to plasma protein (> 99.5%), mainly albumin and alpha-1 acid glycoprotein. The mean volume of distribution (Vss) is approximately 500 L.
Metabolism. Telmisartan is metabolised by conjugation to the glucuronide of the parent compound. No pharmacological activity has been shown for the conjugate.
Elimination. Telmisartan is characterised by biexponential pharmacokinetics with a terminal elimination half-life of >20 hours. The maximum plasma concentration (Cmax) and, to a smaller extent, AUC increase disproportionately with dose. There is no evidence of clinically relevant accumulation of telmisartan taken at the recommended dose. Plasma concentrations were higher in females than in males, without relevant influence on efficacy.
After oral administration, telmisartan is nearly exclusively excreted with the faeces, mainly as unchanged compound. Cumulative urinary excretion is tot) is high (approximately 1.000 ml/min) compared with hepatic blood flow (about 1.500 ml/min).
Children. The results of pharmacokinetic studies in children generally correspond to data obtained for adults, and confirm the nonlinearity of telmisartan in particular for Cmax.
Gender. Plasma concentrations were observed, with Cmax and AUC being approximately 3- and 2-fold higher, respectively, in females compared to males.
Elderly patients. The pharmacokinetics of telmisartan do not differ between the elderly and those younger than 65 years.
Patients with renal impairment. In patients with mild to moderate and severe renal impairment, doubling of plasma concentrations was observed. However, lower plasma concentrations were observed in patients with renal insufficiency undergoing dialysis. Telmisartan is highly bound to plasma protein in renal-insufficient patients and cannot be removed by dialysis. The elimination half-life is not changed in patients with renal impairment.
Patients with hepatic impairment. Pharmacokinetic studies in patients with hepatic impairment showed an increase in absolute bioavailability up to nearly 100 %. The elimination half-life is not changed in patients with hepatic impairment.
Treatment of essential hypertension in adults.
Prevention of cardiovascular diseases.
Reduction of the incidence of cardiovascular disease in patients with:
- manifest atherothrombotic cardiovascular disease (ischemic heart disease, stroke or history of peripheral arterial disease);
- type II diabetes mellitus with documented damage of target organs.
- Hypersensitivity to drug components;
- pregnant women and woman of childbearing age who might be pregnant (see. Section «Use during pregnancy or breast-feeding»);
- biliary obstructive disorders;
- severely impaired liver function.
Concomitant use of telmisartan and aliskirenum in patients with diabetes mellitus or renal impairment (GFR 2) is contraindicated (see. Sections «Dosage and Administration», «Peculiarities of use », « Interaction with other medicinal products and other forms of interaction »).
Interaction with other medicinal products and other forms of interaction.
Dual renin-angiotensin-aldosterone system blockade (RAAS).
The combination of telmisartan and aliskiren is contraindicated for patients with diabetes mellitus and renal impairment (GFR < 60 ml/min/1.73 m2) and is not recommended for other patients (see. Section «Contraindications», «Peculiarities of use»).
Concomitant administration of telmisartan and digoxin increases average peak plasma concentrations of digoxin (by 49%) and minimal concentrations (by 20%). Monitoring of digoxin levels is useful on the early stages of treatment in case of dose adjustment and discontinuation of telmisartan, for maintaining them within therapeutic range.
As other drugs inhibiting renin-angiotensin system, telmisartan may provoke hyperkalemia (see Section «Peculiarities of use»). The risk may increase in case of treatment in combination with other agents which may cause hyperkalemia (potassium-containing salt substitutes, potassium-sparing diuretics, angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists, nonsteroidal anti-inflammatory drugs (NSAIDs, including COX-2 selective inhibitors), heparin, immunosuppressors (cyclosporine or tacrolimus) and trimethoprim).
The occurrence of hyperkalemia depends on the corresponding risk factors. The risk increases in case of using the above mentioned therapeutic combinations. Especially high is the risk when using a combination with potassium-sparing diuretics and potassium-containing salt substitutes. Combination with ACE or nonsteroidal anti-inflammatory drugs is less risky on condition of strict compliance with the precautions in use.
Concomitant administration is not recommended.
Potassium-sparing diuretics or potassium supplements. Such angiotensin II receptor antagonists as telmisartan lessen the loss of potassium caused by diuretics. Potassium-sparing diuretics, such as spironolactone, eplerenone, triamterene, or amiloride, potassium-containing additives and potassium-containing salt substitutes, may significantly increase serum potassium concentration. If the concomitant use is indicated because of documented hypokalemia, the drugs should be taken with caution frequently controlling serum potassium level.
Lithium. Cases of reversible increase in serum lithium concentration and increased toxicity during concomitant intake of lithium with angiotensin converting enzyme inhibitors and angiotensin receptor antagonists II, including telmisartan, are known. If it is necessary to prescribe this combination, serum lithium level should be thoroughly controlled during concomitant use.
Concomitant administration requires caution.
Nonsteroidal anti-inflammatory drugs. NSAIDs (i.e. acetylsalicylic acid in anti-inflammatory treatment doses, COX-2 inhibitors and non-selective NSAIDs) may reduce antihypertensive effect of angiotensin II receptor antagonists.
In some patients with deterioration of renal function (for instance, in patients with dehydration or elderly patients with deterioration of renal function) combined use of angiotensin II receptor antagonists and cyclooxygenase-inhibiting agents may lead to further deterioration of renal function, including possible acute renal failure, which is reversible as a rule. Therefore, this combination should be prescribed with caution, especially in elderly patients. Patients should be provided with adequate hydration; besides, after starting the combined therapy, as well as from time to time in future, renal function should be controlled. There aredata that a combined treatment with telmisartan and ramipril increases AUC0-24 and Cmax of ramipril and ramiprilat by 2.5-fold. The clinical significance of this observation is unknown.
Diuretics (thiazide or loop diuretics). Prior treatment with high doses of diuretics such as furosemide (loop diuretic) and hydrochlorothiazide (a thiazide diuretic) may result in loss of volume and the risk of arterial hypotension if treatment with telmisartan is initiated.
Should be kept in mind when concomitant treatment.
Other antihypertensive agents. The ability of telmisartan to reduce blood pressure may be increased by concomitant use of other antihypertensive agents.
Keeping in mind pharmacological properties of baclofen and amifostine, it may be expected that these medicinal products may increase the antihypertensive effect of all antihypertensive agents, including telmisartan. Furthermore, orthostatic hypotension may be induced by alcohol, barbiturates, narcotics and antidepressants.
Corticosteroids (systemic use). Reduction of antihypertensive effect.
Peculiarities of use.
Hepatic failure. Hypotel should not be prescribed for patients with cholestasis, obstructive diseases of bile ducts and severe hepatic failure (see Section “Contraindications”) as telmisartan is excreted mainly with bile. A decrease of hepatic clearance of telmisartan may be anticipated in such patients.
Caution should be exercised when prescribing Hypotel for patients with mild to moderate hepatic failure.
Renovascular hypertension. There is an increased risk of severe arterial hypotension and renal failure, if patients with bilateral renal artery stenosis or stenosis in a solitary functioning kidney are treated with drugs affecting angiotensin-aldosterone system.
Renal failure and kidney transplantation. When Hypotel is prescribed for patients with impaired renal function, it is recommended to monitor the serum levels of potassium and creatinine from time to time. There is no experience of using telmisartan in patients with resent kidney transplantation.
Decreased interavascular fluid volume. Symptomatic hypotension, especially after the first dose of Hypotel, may occur in patients with decreased intravascular volume and/or sodium level, which occurs as a result of treatment with diuretics, limiting the amount of salt coming with food, diarrhoea or vomiting. Such conditions especially decreased intravascular volume and/or sodium level, should be corrected before using Hypotel.
Dual blockade of the renin-angiotensin-aldosterone system.
Concomitant use of telmisartan and aliskirenum in patients with diabetes mellitus or renal impairment (GFR 2) is contraindicated (see. Section «Contraindications»).
As a consequence of inhibiting the renin-angiotensin-aldosterone system arterial hypotension, syncope, hyperkalemia and changes in renal function (including acute renal failure) have been observed in more susceptible patients, especially if the combined therapy included drugs affecting this system. Therefore, dual blockade of the renin-angiotensin-aldosterone system (for instance, using telmisartan with other renin-angiotensin-aldosterone system blockers) is not recommended. In case if concomitant use is necessary, thorough monitoring of renal function is recommended.
Other conditions requiring stimulation of the renin-angiotensin-aldosterone system.
In patients whose vascular tone and renal function depend mainly on renin-angiotensin-aldosterone system activity (for instance, in patients with severe congestive heart failure or apparent kidney disease, including renal artery stenosis) using telmisartan with other medical preparations affecting the renin-angiotensin-aldosterone system may cause acute arterial hypotension, hyperazotemia, oliguria, occasionally – acute renal failure (see Section «Adverse effects»).
Primary hyperaldosteronism. Patients with primary hyperaldosteronism in general do not react to antihypertensive preparations which act by blocking the renin-angiotensin system.
Therefore, it is not recommended to administer telmisartan to such patients.
Stenosis of aorta and mitral valve, obstructive hypertrophic cardiomyopathy. As with other vasodilators, special caution should be exercised when prescribing the drug for patients diagnosed with stenosis of aorta, mitral valve or obstructive hypertrophic cardiomyopathy.
Diabetic patients taking insulin or antidiabetic drugs. During treatment with telmisartan such patients may develop hypokalemia. The necessity of appropriate blood glucose level control should be regarded in such patients. If indicated, insulin or antidiabetic drug dose adjustment may be required.
In diabetic patients with cardiovascular risks (diabetic patients with concomitant coronary artery disease) the risk of lethal myocardial infarction and sudden cardiovascular death may be higher in case of treatment with antihypertensive drugs such as angiotensin II receptor antagonists and ACE inhibitors. In diabetic patients the course of concomitant coronary artery diseases may be asymptomatic, and therefore they may be undiagnosed. Diabetic patients should be thoroughly examined, for instance, by stress test to detect and treat concomitant coronary artery diseases before prescribing the drug.
Hyperkalemia. During the whole period of using medical preparations which affect renin-angiotensin-aldosterone system, hyperkalemia may occur.
In elderly patients, patients with renal failure, diabetes, in patients concomitantly using other medical preparations which may increase potassium levels, and/or patients with concomitant diseases, hyperkalemia may cause lethal outcome.
Before concomitant prescription of medical preparations which suppress renin-angiotensin system, it is necessary to evaluate the risks and benefits ratio.
The main risk factors of hyperkalemia which require attention:
- Diabetes mellitus, renal failure, age (over 70 years).
- Combined therapy with one or several drugs, which affect renin-angiotensin system, and/or potassium additives. Preparations or therapeutic groups which may provoke hyperkalemia, include potassium-containing salt substitutes, potassium-sparing diuretics, angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists, nonsteroidal anti-inflammatory drugs (NSAIDs, including COX-2 selective inhibitors), heparin, immunosuppressors (cyclosporine or tracolimus) and trimethoprim;
- concomitant conditions, especially dehydration, acute cardiac decompensation, metabolic acidosis, impairment of renal function, rapid deterioration of kidney condition (for instance, infectious diseases), cell lysis (for instance, acute limb ischemia, acute necrosis of skeletal muscles, major trauma).
Patients at risk should be carefully monitored for serum potassium concentrations (see Section «Interaction with other medicinal products and other forms of interaction»).
Ethnic differences. As all other angiotensin II receptor antagonists, telmisartan is apparently less effective in lowering blood pressure in black race patients than in representatives of other races. This might be explained by high prevalence of low renin conditions in black race patients with arterial hypertension.
Others. As with any other antihypertensive drug, a significant blood pressure decrease in patients with ischemic cardiopathy or ischemic cardiovascular disease may lead to myocardial infarction or stroke.
Use during pregnancy or lactation.
The use of angiotensin II receptor antagonists is not recommended for pregnant women or women who may become pregnant (see Section «Contraindications»). When pregnancy is established during the treatment with this drug, its usage should be stopped immediately and if necessary, alternative treatment should be started.
Deaths of fetus and newborns, oligoamnios, hypotension in fetus and newborns, renal failure, hyperkalemia, hypocalvaria, limb contracture/cerebral, cranial-facial deformation/pulmonary dysplasia possibly caused by oligoamnios, have been reported in pregnant women who used angiotensin II receptor antagonists in ІІ or ІІІ trimester of pregnancy.
Patients receiving angiotensin II receptor antagonists and planning pregnancy should initiate antihypertensive drugs, which have established safety profile of use during pregnancy.
Because no information is available regarding the use of telmisartan during breast-feeding, Hypotel is not recommended for use. Alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.
Preclinical studies have not shown any impact of telmisartan on male and female fertility.
Influence on velocity reactions in driving motor transport and operating other mechanisms.
When driving vehicles or operating machinery it should be taken into account that dizziness or hypersomnia may occur when taking antihypertensive therapy, including Hypotel.
Posology and method of administration.
Treatment of arterial hypertension.
The usually effective dose is 40 mg once daily. Some patients may already benefit at a daily dose of 20 mg. In cases where the target blood pressure is not achieved, the dose of telmisartan can be increased to a maximum of 80 mg once daily. Alternatively, telmisartan may be used in combination with thiazide-type diuretics such as hydrochlorothiazide, which has been shown to have an additive blood pressure lowering effect with telmisartan. When considering raising the dose, it must be borne in mind that the maximum antihypertensive effect is generally attained 4-8 weeks after the start of treatment.
Prevention of cardiovascular diseases.
The recommended dose is 80 mg one time per day. The efficacy of telmisartan in doses less than 80 mg for prevention of cardiovascular diseases is unknown.
At the beginning of treatment with telmisartan to prevent cardiovascular diseases, it is recommended to monitor blood pressure, and if necessary, adjust the doses of the drugs which decrease the blood pressure.
Special groups of patients.
Kidney dysfunction. Experience of treatment of patients with kidney failure or patients on hemodialysis is limited. Such patients are recommended to start treatment with the low dose of 20 mg (see Section «Peculiarities of use»). For patients with mild to moderate renal insufficiency dose adjustment is not required.
Concomitant use of telmisartan and aliskirenum in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m2) is contraindicated (see Section «Contraindications»).
Liver dysfunction. Hypotel is contraindicated for patients with severe liver dysfunction.
For patients with mild to moderate liver disorders the daily dose should not be more than 40 mg 1 time per day (see Section “Peculiarities of use”).
Elderly. No dose adjustment is required for elderly patients.
Route of administration.
Hypotel should be taken orally once daily with plenty of liquid, with/or without food.
Tablets should be stored in the sealed blister to protect from moisture. Tablets should be removed from the blister immediately before use.
Hypotel is contraindicated for children due to limited information on safety and efficiency of the drug in this population.
There is limited information available with regard to overdose in humans.
Symptoms. The most prominent manifestations of telmisartan overdose were hypotension and tachycardia; bradycardia, dizziness, increase in serum creatinine, and acute renal failure have also been reported.
Treatment. Telmisartan is not removed by haemodialysis. The patient should be closely monitored, and the treatment should be symptomatic and supportive. Treatment depends on the time since drug use and the severity of the symptoms. Recommended measures include induction of emesis and/or gastric lavage. Activated charcoal may be useful in the treatment of overdose. Serum electrolytes and creatinine should be monitored frequently. If hypotension occurs, the patient should be placed in a supine position, with salt and volume replacement given quickly.
Infections and invasions: upper respiratory tract infections, including pharyngitis and sinusitis; urinary tract infections, including cystitis; sepsis, including with lethal outcome.
Blood and lymphatic system: anaemia, thrombocytopenia, eosinophilia.
Immune system: hypersensitivity, anaphylactic reaction.
Metabolism disorders: hyperkalemia, hypoglycemia (in diabetic patients).
Mental disorders: depression, insomnia, anxiety.
Nervous system: syncope, drowsiness.
Visual organs: visual impairment.
Organs of hearing and vestibular system: vertigo.
Cardiac disorders: bradycardia, tachycardia.
Vascular disorders: arterial hypotension, orthostatic hypotension.
Respiratory, thoracic and mediastinal disorders: dyspnea, cough, interstitial lung disease.
Gastrointestinal disorders: abdominal pain, diarrhoea, dyspepsia, meteorism, vomiting, stomach discomfort, dry mouth.
Hepatobiliary system disorders: abnormal liver function/liver disorder.
Skin and subcutaneous covering: increased sweating, itching, rash, erythema, angioneurotic edema (including lethal outcome), drug-induced dermatitis, toxic dermatitis, eczema, urticaria.
Musculoskeletal system and connective tissue: myalgia, back pain (for instance, ischias), muscle spasms, arthralgia, pain in extremities, tendon pain (tendinitis-like symptoms).
Urinary system: impaired renal function, including acute renal failure.
General disorders: chest pain, asthenia (weakness), flu-like symptoms.
Laboratory data: blood creatinine increase, blood urea increase, liver enzymes increase, increase in creatine phosphokinase (CPK) levels, hemoglobin decrease.
Store at temperatures not more than 25ºC in the original package.
Keep out of reach of children.
There are 10 tablets in a blister; there are 3 blisters in a carton pack.
There are 14 tablets in a blister; there are 2 or 4, or 6 blisters in a carton pack.
Conditions of supply.
Ukraine, 40020, Sumy, Skryabina St., 54.
Last revision date.