40 mg: White or off-white, oblong tablets; one face marked with "51 H", the other with the Boehringer Company symbol.
80 mg: White or off-white, oblong tablets; one face impressed with "52 H"; the other face impressed with the Company symbol.
1 tablet contains 40 or 80 mg [1,1'-biphenyl]-2-carboxylic acid, 4'-[(1,4'-dimethyl-2'-propyl[2,6-bi-1H-benzimidazole]-1'-yl)methyl] (= telmisartan).
Pharmacotherapeutic group: Angiotensin II receptor blocker. ATC code: C09CA07.
Pharmacology: Pharmacodynamics: Mode of action: Telmisartan is an orally effective and specific angiotensin II receptor (type AT1) antagonist. Telmisartan displaces angiotensin II with very high affinity from its binding site at the AT1 receptor subtype, which is responsible for the known actions of angiotensin II. Telmisartan does not exhibit any partial agonist activity at 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 characterised 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 man, an 80 mg dose of telmisartan almost completely inhibits the angiotensin II evoked blood pressure increase. The inhibitory effect is maintained over 24 hours and still measurable up to 48 hours.
Treatment of essential hypertension: After the first dose of telmisartan, the antihypertensive activity gradually becomes evident within 3 hours. The maximum reduction in blood pressure is generally attained 4 weeks after the start of treatment and is sustained during long-term therapy.
The antihypertensive effect persists constantly over 24 hours after dosing and includes the last 4 hours before the next dose as shown by ambulatory blood pressure measurements. This is confirmed by trough to peak ratios consistently above 80% seen after doses of 40 and 80 mg of telmisartan in placebo-controlled clinical studies.
There is an apparent trend to a dose relationship to a time to recovery of baseline SBP. In this respect data concerning DBP are inconsistent.
In patients with hypertension, telmisartan reduces both systolic and diastolic blood pressure without affecting pulse rate. The antihypertensive efficacy of telmisartan has been compared to antihypertensive drugs (in clinical trials comparing telmisartan to agents such as amlodipine, atenolol, enalapril, hydrochlorothiazide, losartan, lisinopril, ramipril and valsartan).
Upon abrupt cessation of treatment with telmisartan, blood pressure gradually returns to pre-treatment values over a period of several days without evidence of rebound hypertension.
Telmisartan treatment has been shown in clinical trials to be associated with statistically significant reductions in Left Ventricular Mass and Left Ventricular Mass Index in patients with hypertension and Left Ventricular Hypertrophy.
Telmisartan treatment has been shown in clinical trials (including comparators like losartan, ramipril and valsartan) to be associated with statistically significant reductions in proteinuria (including microalbuminuria and macroalbuminuria) in patients with hypertension and diabetic nephropathy.
The incidence of dry cough was significantly lower in patients treated with telmisartan than in those given angiotensin converting enzyme inhibitors in clinical trials directly comparing the two antihypertensive treatments.
Clinical trials: Cardiovascular risk reduction: ONTARGET (ONgoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial) compared the effects of telmisartan, ramipril and the combination of telmisartan and ramipril on cardiovascular outcomes in 25620 patients aged 55 years or older with a history of coronary artery disease, stroke, peripheral vascular disease, or diabetes mellitus accompanied by evidence of end-organ damage (e.g. retinopathy, left ventricular hypertrophy, macro- or microalbuminuria), which represents a broad cross-section of cardiovascular high-risk patients.
Patients were randomized to one of the three following treatment groups: telmisartan 80 mg (n=8542), ramipril 10 mg (n=8576), or the combination of telmisartan 80 mg plus ramipril 10 mg (n=8502), and followed for a mean observation time of 4.5 years. The population studied was 73% male, 74% Caucasian, 14% Asian and 43% were 65 years of age or older. Hypertension was present in nearly 83% of randomized patients: 69% of patients had a history of hypertension at randomization and an additional 14% had actual blood pressure readings above 140/90 mm Hg. At baseline, the total percentage of patients with a medical history of diabetes was 38% and an additional 3% presented with elevated fasting plasma glucose levels. Baseline therapy included acetylsalicylic acid (76%), statins (62%), beta-blockers (57%), calcium channel blockers (34%), nitrates (29%) and diuretics (28%).
The primary endpoint was a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for congestive heart failure.
Adherence to treatment was better for telmisartan than for ramipril or the combination of telmisartan and ramipril, although the study population had been pre-screened for tolerance to treatment with an ACE-inhibitor. The analysis of adverse events leading to permanent treatment discontinuation and of serious adverse events showed that cough and angioedema were less frequently reported in patients treated with telmisartan than in patients treated with ramipril, whereas hypotension was more frequently reported with telmisartan.
Telmisartan had similar efficacy to ramipril in reducing the primary endpoint. The incidence of the primary endpoint was similar in the telmisartan (16.7%), ramipril (16.5%) and telmisartan plus ramipril combination (16.3%) arms. The hazard ratio for telmisartan vs. ramipril was 1.01 (97.5% CI 0.93 - 1.10, p (non-inferiority) = 0.0019). The treatment effect was found to persist following corrections for differences in systolic blood pressure at baseline and over time. There was no difference in the primary endpoint based on age, gender, race, baseline therapies or underlying disease.
Telmisartan was also found to be similarly effective to ramipril in several pre-specified secondary endpoints, including a composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke, the primary endpoint in the reference study HOPE (The Heart Outcomes Prevention Evaluation Study), which had investigated the effect of ramipril vs. placebo. The hazard ratio of telmisartan vs. ramipril for this endpoint in ONTARGET was 0.99 (97.5% CI 0.90-1.08, p (non-inferiority) = 0.0004).
Combining telmisartan with ramipril did not add further benefit over ramipril or telmisartan alone. In addition, there was a significantly higher incidence of hyperkalaemia, renal failure, hypotension and syncope in the combination arm. Therefore the use of a combination of telmisartan and ramipril is not recommended in this population.
Pharmacokinetics: 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 dose) to approximately 19% (160 mg dose). By 3 hours after administration plasma concentrations are similar whether telmisartan is taken fasting or with food. The small reduction in AUC is not expected to cause a reduction in the therapeutic efficacy.
Distribution: Telmisartan is largely bound to plasma protein (>99.5%), mainly albumin and alpha-1 acid glycoprotein. The mean steady state apparent volume of distribution (Vss) is approximately 500 L.
Biotransformation: 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 decay pharmacokinetics with a terminal elimination half-life of >20 hours.
After oral (and intravenous) administration telmisartan is nearly exclusively excreted with the faeces, exclusively as unchanged compound. Cumulative urinary excretion is <2% of dose.
Total plasma clearance (CLtot) is high (approximately 900 ml/min compared with hepatic blood flow (about 1500 ml/min).
Linearity: The maximum plasma concentration (Cmax) and, to a smaller extent, area under the plasma concentration-time curve (AUC) increase disproportionately with dose. There is no evidence of clinically relevant accumulation of telmisartan.
PK in specific populations: Gender differences: Gender differences in plasma concentrations were observed, Cmax and AUC being approximately 3- and 2-fold higher, respectively, in females compared to males without relevant influence on efficacy.
Geriatric patients: The pharmacokinetics of telmisartan do not differ between younger and geriatric patients.
Renal impairment: Lower plasma concentrations were observed in patients with renal insufficiency undergoing dialysis. Telmisartan is highly bound to plasma protein in renal-insufficient subjects and cannot be removed by dialysis. The elimination half-life is not changed in patients with renal impairment.
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.
Hypertension: Treatment of essential hypertension.
Cardiovascular risk reduction: MICARDIS is indicated for reduction of the risk of myocardial infarction, stroke, or death from cardiovascular causes in patients 55 years of age or older at high risk of developing major cardiovascular events who are unable to take ACE inhibitors.
High risk of cardiovascular events can be evidenced by history of coronary artery disease, peripheral arterial disease, stroke, transient ischemic attack, or high-risk diabetes (insulin-dependent or non-insulin dependent) with evidence of end-organ damage. MICARDIS can be used in additional to other needed treatment (such as antihypertensive, antiplatelet or lipid-lowering therapy).
Studies of Telmisartan in this setting do not exclude that it may not preserve a meaningful fraction of the effect of the ACE inhibitor to which it was compared. Consider using the ACE inhibitor first, and, if it is stopped for cough only, consider re-trying the ACE inhibitor after the cough resolves.
Use of telmisartan with an ACE inhibitor is not recommended.
Dosage: Treatment of essential hypertension: The recommended dose is 40 mg once daily. In cases where the target blood pressure is not achieved, telmisartan dose can be increased to a maximum of 80 mg once daily. When considering raising the dose, it must be borne in mind that the maximum antihypertensive effect is generally attained four to eight weeks after the start of treatment. Alternatively, telmisartan may be used in combination with thiazide-type diuretics such as hydrochlorothiazide or calcium-channel blockers such as amlodipine, which have been shown to have an additive blood pressure lowering effect with telmisartan.
In patients with severe hypertension treatment with telmisartan at doses up to 160 mg alone and in combination with hydrochlorothiazide 12.5 - 25 mg daily was well tolerated and effective.
Cardiovascular risk reduction: The recommended dose of MICARDIS Tablets is 80 mg once a day and can be administered with or without food. It is not known whether doses lower than 80 mg of telmisartan are effective in reducing the risk of cardiovascular morbidity and mortality.
When initiating MICARDIS therapy for cardiovascular risk reduction, monitoring of blood pressure is recommended, and if appropriate adjustment of medications that lower blood pressure may be necessary.
Special Populations: Renal impairment: No posology adjustment is required for patients with renal impairment, including those on haemodialysis. Telmisartan is not removed from blood by hemofiltration and is not dialyzable.
Hepatic impairment: In patients with mild to moderate hepatic impairment MICARDIS should be administered with caution. For telmisartan, the posology should not exceed 40 mg once daily (see Contraindications).
Geriatric patients: No dose adjustment is necessary for geriatric patients.
Paediatric patients: The safety and efficacy of MICARDIS for use in patients aged below 18 years have not been established.
Method of Administration: Micardis tablets are for once-daily administration and should be swallowed whole with liquid. MICARDIS can be taken with or without food.
Handling Instructions: Due to the hygroscopic property of the tablets, they should be taken out of the sealed blister shortly before administration.
Limited information is available with regard to overdose in humans.
Symptoms: The most prominent manifestations of telmisartan overdose were hypotension, tachycardia; bradycardia also occurred.
Therapy: If symptomatic hypotension should occur, supportive treatment should be instituted. Telmisartan is not removed by y hemofiltration and is not dialyzable.
Hypersensitivity to the active substance or to any of the excipients.
Second and third trimesters of pregnancy.
Lactation.
Biliary obstructive disorders.
Severe hepatic impairment.
The concomitant use of telmisartan with aliskiren is contraindicated in patients with diabetes mellitus or renal impairment (GFR <60 ml/min/1.73 m2).
In case of rare hereditary conditions that may be incompatible with an excipient of the product (refer to "Precautions") the use of the product is contraindicated.
Hyperkalaemia: During treatment with medicinal products that affect the renin-angiotensin-aldosterone system hyperkalaemia may occur, especially in the presence of renal impairment and/or heart failure. Monitoring of serum potassium in patients at risk is recommended.
Based on experience with the use of medicinal products that affect the renin-angiotensin system, concomitant use with potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium or other medicinal products that may increase the potassium level (heparin, etc.) may lead to an increase in serum potassium and should therefore be co-administered cautiously with telmisartan.
Volume and/or sodium depleted patients: Symptomatic hypotension, especially after the first dose, may occur in patients who are volume and/or sodium depleted by e.g. vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting. Such conditions, especially volume and/or sodium depletion, should be corrected before the administration of telmisartan.
Renovascular hypertension: There is an increased risk of severe hypotension and renal insufficiency when patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney are treated with medicinal products that affect the renin-angiotensin-aldosterone system.
Dual blockade of the renin-angiotensin-aldosterone system: As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function (including acute renal failure) have been reported in susceptible individuals, especially if combining medicinal products that affect this system. Dual blockade of the renin-angiotensin-aldosterone system (e.g. by adding an ACE-inhibitor or the direct renin-inhibitor aliskiren to an angiotensin II receptor blocker) is not recommended and should therefore be limited to individually defined cases with close monitoring of renal function (see Contraindications).
Other conditions with 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 (e.g. patients with severe congestive heart failure or underlying renal disease, including renal artery stenosis), treatment with medicinal products that affect this system has been associated with acute hypotension, hyperazotaemia, oliguria, or rarely acute renal failure.
Primary aldosteronism: Patients with primary aldosteronism generally will not respond to antihypertensive medicinal products acting through inhibition of the renin-angiotensin system. Therefore, the use of telmisartan is not recommended.
Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy: As with other vasodilators, special caution is indicated in patients suffering from aortic or mitral stenosis, or obstructive hypertrophic cardiomyopathy.
Sorbitol: MICARDIS tablets 40 mg contains 168.64 mg sorbitol in each tablet. MICARDIS tablets 80 mg contains 337.28 mg sorbitol in each tablet. Sorbitol is a source of fructose. MICARDIS tablets 80 mg is not recommended for use in patients with hereditary fructose intolerance (HFI).
Diabetes mellitus: In diabetic patients with an additional cardiovascular risk, i.e. patients with diabetes mellitus and coexistent coronary artery disease (CAD), the risk of fatal myocardial infarction and unexpected cardiovascular death may be increased when treated with blood pressure lowering agents such as ARBs or ACE-inhibitors. In patients with diabetes mellitus CAD may be asymptomatic and therefore undiagnosed. Patients with diabetes mellitus should undergo appropriate diagnostic evaluation, e.g. exercise stress testing, to detect and to treat CAD accordingly before initiating treatment with MICARDIS.
Ethnic differences: As observed for angiotensin-converting enzyme inhibitors, angiotensin receptor blockers including telmisartan are apparently less effective in lowering blood pressure in black people than in non-blacks, possibly because of higher prevalence of low-renin states in the black hypertensive population.
Ischaemic heart disease: As with any antihypertensive agent, excessive reduction of blood pressure in patients with ischaemic cardiopathy or ischaemic cardiovascular disease could result in a myocardial infarction or stroke.
Effects on ability to drive and use machines: No studies on the effect on the ability to drive and use machines have been performed. However, when driving vehicles or operating machinery it should be taken into account that syncope or vertigo may occasionally occur when taking antihypertensive therapy.
Hepatic impairment: Telmisartan is mostly eliminated in the bile. Patients with biliary obstructive disorders or hepatic insufficiency can be expected to have reduced clearance. MICARDIS should be used with caution in these patients.
Renal impairment and kidney transplant: When telmisartan is used in patients with impaired renal function, periodic monitoring of potassium and creatinine serum levels is recommended. There is no experience regarding the administration of telmisartan in patients with a recent kidney transplant.
Telmisartan is not removed from blood by hemofiltration and is not dialyzable.
Use in Pregnancy: Angiotensin II receptor antagonists should not be initiated during pregnancy.
Unless continued angiotensin II receptor antagonist therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive 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.
Pregnancy: The use of angiotensin II receptor blockers is not recommended during the first trimester of pregnancy and should not be initiated during pregnancy. When pregnancy is diagnosed, treatment with angiotensin II receptor blocker should be stopped immediately, and, if appropriate, alternative therapy should be started.
Unless continued angiotensin II receptor antagonist therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy.
Non-clinical studies with telmisartan do not indicate teratogenic effect but have shown fetotoxicity.
The use of angiotensin II receptor blockers is contraindicated during the second and third trimester of pregnancy.
Angiotensin II receptor blocker exposure during the second and third trimesters is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia).
Should exposure to angiotensin II receptor blocker have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended.
Infants whose mothers have taken angiotensin II receptor blocker should be closely observed for hypotension.
Lactation: Telmisartan is contraindicated during lactation since it is not known whether it is excreted in human milk. Animal studies have shown excretion of telmisartan in breast milk.
Fertility: No studies on fertility in humans have been performed.
In non-clinical studies, no effects of telmisartan on male and female fertility were observed.
Summary of the safety profile: In patients treated for hypertension, the overall incidence of adverse events reported with telmisartan (41.4%) was usually comparable to those reported with placebo (43.9%) in controlled clinical trials in patients treated for hypertension. The incidence of adverse events was not dose-related and showed no correlation with gender, age or race of the patients.
The safety profile of MICARDIS in patients treated for cardiovascular risk reduction was consistent with that obtained in hypertensive patients.
Tabulated summary of adverse reactions: The following adverse drug reactions derived from the use of telmisartan as monotherapy in clinical trials in patients treated for hypertension or from post-marketing experience are shown in the table as follows classified by MedDRA System organ class and MedDRA Preferred terms. The listing also takes into account serious adverse events and adverse events leading to discontinuation reported in three clinical long-term studies including 21642 patients treated with telmisartan for cardiovascular risk reduction for up to six years. (See table.)
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Telmisartan may increase the hypotensive effect of other antihypertensive agents.
Co-administration of telmisartan did not result in a clinically significant interaction with digoxin, warfarin, hydrochlorothiazide, glibenclamide, ibuprofen, paracetamol, simvastatin and amlodipine. For digoxin a 20% increase in median plasma digoxin trough concentration has been observed (39% in a single case), monitoring of plasma digoxin levels should be considered.
In one study the co-administration of telmisartan and ramipril led to an increase of up to 2.5 fold in the AUC0-24 and Cmax of ramipril and ramiprilat. The clinical relevance of this observation is not known.
Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with angiotensin converting enzyme inhibitors. Cases have also been reported with angiotensin II receptor blocker including telmisartan. Therefore, serum lithium level monitoring is advisable during concomitant use.
Treatment with NSAIDs (i.e. ASA at anti-inflammatory dosage regimens, COX-2 inhibitors and non-selective NSAIDs) is associated with the potential for acute renal insufficiency in patients who are dehydrated. Compounds acting on the Renin-Angiotensin-System like telmisartan may have synergistic effects. Patients receiving NSAIDs and telmisartan should be adequately hydrated and their renal function should be monitored at the beginning of combined treatment.
A reduced effect of antihypertensive drugs like telmisartan by inhibition of vasodilating prostaglandins has been reported during combined treatment with NSAIDs.
Store below 30°C.
Store in original package in order to protect from moisture.
C09CA07 - telmisartan ; Belongs to the class of angiotensin II receptor blockers (ARBs). Used in the treatment of cardiovascular disease.
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