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Pharmacotherapeutic group: Angiotensin II Antagonists, plain. ATC Code: C09CA07.
Pharmacology: Pharmacodynamics: Mechanism of action: Telmisartan is an orally active 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 human, 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.
Clinical efficacy and safety: 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 to 8 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 systolic blood pressure (SBP). In this respect data concerning diastolic blood pressure (DBP) are inconsistent.
In patients with hypertension telmisartan reduces both systolic and diastolic blood pressure without affecting pulse rate. The contribution of the medicinal product's diuretic and natriuretic effect to its hypotensive activity has still to be defined. The antihypertensive efficacy of telmisartan is comparable to that of agents representative of other classes of antihypertensive medicinal products (demonstrated in clinical trials comparing telmisartan to amlodipine, atenolol, enalapril, hydrochlorothiazide, and lisinopril).
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.
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.
Cardiovascular prevention: ONTARGET (ON going 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, TIA, peripheral arterial disease, or type 2 diabetes mellitus accompanied by evidence of end-organ damage (e.g. retinopathy, left ventricular hypertrophy, macro- or microalbuminuria), which is a population at risk for cardiovascular events.
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.
Telmisartan showed a similar effect to ramipril in reducing the primary composite endpoint of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for congestive heart failure. The incidence of the primary endpoint was similar in the telmisartan (16.7 %) and ramipril (16.5 %) groups. The hazard ratio for telmisartan vs. ramipril was 1.01 (97.5 % CI 0.93 - 1.10, p (non-inferiority) = 0.0019 at a margin of 1.13). The all-cause mortality rate was 11.6 % and 11.8 % among telmisartan and ramipril treated patients, respectively.
Telmisartan was found to be similarly effective to ramipril in the pre-specified secondary endpoint of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke [0.99 (97.5 % CI 0.90 - 1.08), p (non-inferiority) = 0.0004], the primary endpoint in the reference s t u d y HOPE (The Heart Outcomes Prevention Evaluation Study), which had investigated the effect of ramipril vs. placebo.
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.
Combining telmisartan with ramipril did not add further benefit over ramipril or telmisartan alone. CV mortality and all cause mortality were numerically higher with the combination. In addition, there was a significantly higher incidence of hyperkalemia, 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.
In the "Prevention Regimen For Effectively avoiding Second Strokes" (PRoFESS) trial in patients 50 years and older, who recently experienced stroke, an increased incidence of sepsis was noted for telmisartan compared with placebo, 0.70 % vs. 0.49 % [RR 1.43 (95 % confidence interval 1.00 - 2.06)]; the incidence of fatal sepsis cases was increased for patients taking telmisartan (0.33 %) vs. patients taking placebo (0.16 %) [RR 2.07 (95 % confidence interval 1.14 - 3.76)]. The observed increased occurrence rate of sepsis associated with the use of telmisartan may be either a chance finding or related to a mechanism not currently known.
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 (AUC0-24 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.
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 steady state apparent volume of distribution (Vdss) is approximately 500 l.
Biotransformation: Telmisartan is metabolized 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. The maximum plasma concentration (Cmax) and, to a smaller extent, the area under the plasma concentration-time curve (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 (and intravenous) administration, telmisartan is nearly exclusively excreted with the faeces, mainly as unchanged compound. Cumulative urinary excretion is <1 % of dose. Total plasma clearance (Cltot) is high (approximately 1,000 ml/min) compared with hepatic blood flow (about 1,500 ml/min).
Special Populations: Gender: Differences in plasma concentrations were observed, with Cmax and AUC being approximately 3- and 2-fold higher, respectively, in females compared to males.
Elderly: The pharmacokinetics of telmisartan do not differ between the elderly and those younger than 65 years.
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.
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.
