Source: Pharmaceutical Benefits Scheme (AU) Revision Year: 2023 Publisher: Arrotex Pharmaceuticals Pty Ltd, 15 – 17 Chapel Street, Cremorne, Victoria 3121
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 binds selectively with the AT1 receptor and does not reveal relevant affinity for other receptors nor does it inhibit human plasma renin or block ion channels. The clinically relevant effect of AT1 receptor blockade is to lower blood pressure by inhibition of angiotensin II mediated vasoconstriction leading to reduction of systemic vascular resistance. During administration with telmisartan, removal of angiotensin II negative feedback on renin secretion results in increased plasma renin activity, which in turn leads to increases in angiotensin II in plasma. Despite these increases, antihypertensive activity and suppressed aldosterone levels indicate effective angiotensin II receptor blockade. 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 or cause oedema.
In humans, an 80 mg dose of telmisartan almost completely inhibits the angiotensin II evoked increase in blood pressure. The inhibitory effect is maintained over 24 hours and still measurable up to 48 hours.
After administration of the first dose of telmisartan, onset of antihypertensive activity occurs gradually within 3 hours. The maximal reduction in blood pressure is generally attained 4-8 weeks after the start of treatment.
With ambulatory blood pressure monitoring and conventional blood pressure measurements, the 24 hour trough to peak ratio for 40-80 mg doses of telmisartan was >70% for both systolic and diastolic blood pressure.
In patients with hypertension, telmisartan reduces both systolic and diastolic blood pressure without affecting pulse rate. The antihypertensive efficacy of telmisartan is independent of gender or age, and has been compared to antihypertensive drugs including amlodipine, atenolol, enalapril, ramipril, hydrochlorothiazide, lisinopril and valsartan. Telmisartan (40-120 mg once daily) is at least as effective as amlodipine (5-10 mg) and atenolol (50-100 mg once daily). Telmisartan (20-80 mg once daily) is equivalent to enalapril (5-20 mg once daily), and telmisartan (40-160 mg once daily) is comparable to lisinopril (10-40 mg once daily) (see also Section 5.1 PHARMACODYNAMIC PROPERTIES, CLINICAL TRIALS).
After the first dose of telmisartan, the incidence of symptomatic orthostatic hypotension with symptoms severe enough to be reported as an adverse event in 3445 patients was 0.4% (14/3445).
Upon abrupt cessation of treatment, blood pressure gradually returns to pre-treatment values over a period of several days without evidence of rebound hypertension.
The antihypertensive effects of telmisartan were examined in three pivotal short-term (8-12 weeks) placebo-controlled clinical trials, studying a range of 40-160 mg daily. The studies involved a total of 908 patients with hypertension (diastolic blood pressure of 95-114 mmHg), 483 of whom were randomised to receive telmisartan. One of the studies was a 12 week, fixed-dose study comparing telmisartan (40-160 mg), enalapril 20 mg, and placebo. The other two were dose titration studies; one comparing telmisartan (40 to 80 mg and 80 to 120 mg), atenolol (50 to 100 mg), and placebo over an 8 week period, the other comparing telmisartan (40 to 80 to 120 mg), amlodipine (5 to 10 mg), and placebo over a 12 week period. Once daily doses of 40- 160 mg provided statistically and clinically significant decreases in both systolic and diastolic blood pressure.
Last trough readings of mean decreases in placebo-subtracted systolic/diastolic blood pressure in the fixed-dose study were 12.4 ± 2.2 / 7.5 ± 1.3 mmHg (40 mg dose) and 12.6 ± 2.2 / 7.9 ± 1.3 mmHg (80 mg dose). Dose titration regimens attained mean decreases in placebo- subtracted systolic/diastolic blood pressure of 9.2 ± 3.0 / 5.7 ± 1.5 mmHg (40 to 80 mg titrated regimen), 13.1 ± 3.1 / 6.4 ± 1.5 mmHg (80 to 120 mg titrated regimen), and 13.2 ± 2.3 / 7.1 ± 1.4 mmHg (40 to 80 to 120 mg optional titration regimen).
In long term open-label dose-titration studies of telmisartan (with optional hydrochlorothiazide add-on and addition of calcium channel blocker or beta-blocker), 1425 patients were analysed after 46-58 weeks treatment for hypertension. Mean reductions from baseline in last trough systolic/diastolic blood pressure ranged from 17.9 to 25.8 / 14.1 to 16.1 mmHg.
By combining all clinical trials involving angiotensin converting enzyme inhibitors, the incidence of cough was significantly less in patients treated with telmisartan than in those treated with angiotensin converting enzyme (ACE) inhibitors. Additionally, the incidence of cough occurring with telmisartan in six placebo-controlled trials was identical to that noted for placebo-treated patients(1.6%).
In a study in 378 patients with stable congestive heart failure (NYHA class II to III), telmisartan (10 to 80 mg) replaced former enalapril treatment. No difference was observed between telmisartan and enalapril with respect to ejection fraction, functional capacity, signs of heart failure or body weight.
Another study of 533 patients found no significant differences after treatment between both the telmisartan and atenolol treatment groups in a subgroup of hypertensive patients (78 of 533 patients) with respect to left atrium and ventricular or aortic diameters, or in left ventricular wall thickness or muscle mass, when compared to baseline results. In a small substudy involving 33 patients (21 on telmisartan, 11 on atenolol) with left ventricular hypertrophy (defined as LVM index ≥125 g/m² at baseline), telmisartan and atenolol reduced left ventricular mass index to a similar degree (14-19 g/m²) after 4 months of treatment.
In a study in 30 patients receiving telmisartan with or without hydrochlorothiazide, no significant effects were found on renal plasma flow, glomerular filtration rate or creatinine clearance after 8 weeks treatment, when both systolic and diastolic blood pressure were lowered significantly. In another study in 71 patients with moderate renal failure (creatinine clearance 30-80 mL/min), blood pressure was lowered significantly without changes in creatinine clearance or other renal function parameters. In both trials urinary albumin and protein secretion was reduced, while no changes in sodium or potassium elimination were detected. Plasma electrolytes remained unaffected. Treatment with telmisartan showed no uricosuric effect.
No effect on plasma glucose, C-peptide or insulin levels was found after telmisartan administration. There is no evidence that telmisartan adversely affects patients who have stabilised diabetes.
The ONTARGET study evaluated prevention of cardiovascular morbidity and mortality in patients with known high risk for its occurrence either due to prior documented disease or the presence of risk factors, such as diabetes with documented end organ damage. The TRANSCEND and PRoFESS studies included different populations, ACE-I intolerant patients and those with a recent stroke (<120 days), respectively; and evaluated prevention of cardiovascular morbidity and mortality and secondary stroke prevention,respectively as the primary endpoint.
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, transient ischaemic attack, 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 patients at high risk of cardiovascular events.
The co-primary objectives of the ONTARGET trial were to determine if (a) the combination of telmisartan 80 mg and ramipril 10 mg is superior to ramipril 10 mg alone and if (b) telmisartan 80 mg is not inferior to ramipril 10 mg alone in reducing the primary composite endpoint of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or hospitalisation for congestive heart failure. Hypothesis tests were performed using hazard ratios and time-to-event analyses(Kaplan-Meier).
The principal patient exclusion criteria included: symptomatic heart failure or other specific cardiac diseases, syncopal episodes of unknown aetiology or planned cardiac surgery within 3 months of the start of study, uncontrolled hypertension or haemorrhagic stroke.
Patients were randomised 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 randomised patients: 69% of patients had a history of hypertension at randomisation and an additional 14% had actual blood pressure readings ≥140/90 mmHg. 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%).
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. During the study, significantly less telmisartan patients (22.0%) discontinued treatment, compared to ramipril patients (24.4%) and telmisartan/ramipril patients (25.3%). 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.
Comparison of telmisartan versus ramipril: The choice of the non-inferiority margin of 1.13 was solely based on the results of the HOPE (Heart Outcomes Prevention Evaluation) study. Telmisartan showed a similar effect to ramipril in reducing the primary composite endpoint of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or hospitalisation for congestive heart failure. The incidence of the primary endpoint was similar in the telmisartan (16.7%) and ramipril (16.5%) groups. In the intention-to-treat (ITT) analysis, the hazard ratio for telmisartan versus ramipril was 1.01 (97.5% CI 0.93-1.10, p(non-inferiority)=0.0019). The non-inferiority result was confirmed in the per-protocol (PP) analysis, where the hazard ratio was 1.02 (97.5% CI 0.93- 1.12, p(non-inferiority)=0.0078). Since the upper limit of the 97.5% CI was below the pre-defined non-inferiority margin of 1.13 and the p-value for non-inferiority was below 0.0125 in both the ITT and PP analyses, the trial succeeded in demonstrating the non-inferiority of telmisartan versus ramipril in the prevention of the composite primary endpoint. The non-inferiority conclusion 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 in subgroups based on age, gender, race, baseline concomitanttherapies or underlying diseases.
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, which had investigated the effect of ramipril versus placebo. The ITT hazard ratio of telmisartan versus ramipril for this endpoint in ONTARGET was 0.99 (97.5% CI 0.90-1.08, p(non-inferiority)=0.0004), and confirmed by the PP hazard ratio of 1.00 (97.5% CI 0.91-1.11, p(non-inferiority)=0.0041.
Comparison of telmisartan plus ramipril combination versus ramipril monotherapy alone: Combining telmisartan with ramipril did not add further benefit over ramipril or telmisartan alone, thus superiority of the combination could not be demonstrated. The incidence of the primary endpoint was 16.3% in the telmisartan plus ramipril combination group, compared to the telmisartan (16.7%) and ramipril (16.5%) groups. In addition, there was a significantly higher incidence of hyperkalaemia, renal failure, hypotension and syncope in the combination group. Therefore the use of a combination of telmisartan and ramipril is not recommended in this population.
TRANSCEND (Telmisartan Randomised AssessmeNt Study in aCE iNtolerant subjects with cardiovascular Disease) randomised a total of 5926 ACE-I intolerant patients with otherwise similar inclusion criteria as ONTARGET to telmisartan 80 mg (n=2954) or placebo (n=2972), both given on top of standard care. The exclusion criteria of TRANSCEND were similar to those of ONTARGET, with the additional exclusion of patients with proteinuria.
The primary objective of the TRANSCEND trial was to determine if telmisartan 80 mg is superior to placebo given on top of standard care in reducing the composite endpoint of cardiovascular death, myocardial infarction, stroke and hospitalisation for congestive heart failure in patients who are intolerant to ACE-inhibitors. Hypothesis test was performed using hazard ratios and time-toevent analyses (Kaplan-Meier).
The mean duration of follow-up was 4 years and 8 months. The population studied was 57% male, 62% Caucasian, 21% Asian, and 60% were 65 years of age or older. Baseline therapy included acetylsalicylic acid (75%), lipid lowering agents (58%), beta-blockers (58%), calcium channel blockers (41%), nitrates (34%) and diuretics (33%). Mean baseline blood pressure at baseline was 140/82 mmHg. During the study, 17.7% of telmisartan patients discontinued treatment, compared to 19.4% of placebo patients.
No statistically significant difference in the incidence of the primary composite endpoint (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or hospitalisation for congestive heart failure) was found [15.7% in the telmisartan and 17.0% in the placebo groups; the event rates per 100 patient years were 3.58 and 3.87, respectively, with a hazard ratio of 0.92 (95% CI 0.81-1.05, p=0.22)]. Thus the trial was not able to demonstrate superiority of telmisartan over placebo given on top of standard care. Analysis of the secondary and other endpoints are therefore considered exploratory in nature. For the pre-specified secondary composite endpoint of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke (the primary endpoint in HOPE), a lower incidence was found in the telmisartan group (13.0%) compared to the placebo group (14.8%); the event rates per 100 patient years were 2.90 and 3.33, respectively.
The observed yearly event rates observed in TRANSCEND were lower than expected, most likely due to improved medical care, including more frequent use of cardioprotective medications (e.g. statins and beta blockers). This caused the study to be underpowered to detect between group differences. Additionally, in more patients in the placebo group, cardioprotective medications (e.g. blood pressure-lowering drugs such as beta blockers and diuretics) were added during the course of the trial than in the telmisartan group, which could have further confounded the detection of a treatment difference.
The PRoFESS (PRevention Regimen For Effectively avoiding Second Strokes) study was a randomised, parallel group, international, double-blind, double-dummy, active and placebo controlled, 2x2 factorial study to compare aspirin plus extended-release dipyridamole with clopidogrel, and simultaneously telmisartan with placebo in the prevention of stroke in patients who had previously experienced an ischaemic stroke, mainly of non-cardioembolic origin. The study specifically enrolled only patients soon after their stroke (<120 days) and there were no blood pressure related inclusion criteria.
Of the 20332 patients randomised, 10146 received telmisartan 80 mg and 10186 received placebo, both given on a background of standard treatment. The mean blood pressure at baseline was 144.1/83.8 mmHg.
The primary efficacy outcome measure was the time to first recurrent stroke of any type. For the telmisartan versus placebo comparison, hypothesistest of the primary efficacy outcome measure was performed as a test of superiority using hazard ratios and time-to-event analyses (KaplanMeier).
The mean duration of follow-up in PRoFESS was short (2.5 years) and more patients in the placebo group received concomitant blood-pressure lowering medications, which may have confounded the results. Additionally, the adherence to the telmisartan regimen was much lower than in ONTARGET, due in part to the factorial nature of the trial and patient population studied (early post stroke).
The incidence of the primary endpoint of recurrent stroke were 8.7% for telmisartan and 9.2% for placebo (hazard ratio 0.95; 95% CI 0.86-1.04, p=0.23). Thus the trial was not able to demonstrate superiority of telmisartan over placebo given on top of standard care. Analysis of the secondary, tertiary and other endpoints are therefore considered exploratory in nature. The incidence of the pre-defined secondary composite endpoint of recurrent stroke, myocardial infarction, death due to vascular causes, and new or worsening congestive heart failure were 13.5% for telmisartan and 14.4% for placebo.
Following oral administration of telmisartan, absorption is rapid (tmax ranges from 0.5 to 2 hours) although the amount absorbed varies. Absolute bioavailability of telmisartan was shown to be dose dependent. The mean absolute bioavailability of 40 mg telmisartan was 40%, whereas the mean absolute bioavailability of the 160 mg dose amounted to about 60%.
The maximum plasma concentration (Cmax) and, to a smaller extent, area under the plasma concentration-time curve (AUC) increase disproportionately with dose. In a Phase II clinical trial, 40, 80 and 120 mg of telmisartan were administered (in capsules) for 28 days to hypertensive subjects. Maximum plasma concentrations at steady state, Cmax,ss, and AUCss were determined in 37–39 subjects per dose group.
In this trial, the mean Cmax showed a more-than-proportional increase with dose, increasing 4.4 fold for a two-fold increase in dose from 40 to 80 mg, and increasing 2.4 fold with a 1.5 fold increase in dose from 80 to 120 mg. The mean AUCss were nearly proportional with increasing dose, increasing 2.3 fold for a two-fold increase in dose from 40 to 80 mg, and increasing 1.5 fold with a 1.5 fold increase in dose from 80 to 120 mg.
There is no evidence of clinically relevant accumulation of telmisartan taken at the recommended dose.
When telmisartan is taken with food, the reduction in the area under the plasma concentrationtime curve (AUC0-∞) of telmisartan varies from approximately 6% (40 mg dose) to approximately 19% (160 mg dose). The small reduction in AUC should not cause a reduction in the therapeutic efficacy. Therefore, telmisartanmay be taken with or without food.
Telmisartan is highly bound to plasma protein (>99.5%), mainly albumin and alpha-1-acid glycoprotein. The mean steady state apparent volume of distribution (Vdss) is approximately 6.6 L/kg.
Telmisartan undergoes substantial first-pass metabolism by conjugation to the acylglucuronide. No pharmacological activity has been shown for the conjugate. Telmisartan is not metabolised by the cytochrome P450 system.
Telmisartan is characterised by bi-exponential decay pharmacokinetics with a terminal elimination half-life of 18.3-23.0 hours.
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 1000 mL/min) when compared with hepatic blood flow (about 1500 mL/min).
The pharmacokinetics of telmisartan do not differ between younger and elderly patients(i.e., patients older than 65 years of age).
Lower plasma concentrations were observed in patients with renal insufficiency (creatinine clearance 30-80 mL/min) undergoing dialysis, however, this has proved not to be of clinical significance. Telmisartan is highly bound to plasma proteins in renal-insufficientsubjects and cannot be removed by dialysis.
Pharmacokinetic studies in patients with hepatic impairment showed an increase in absolute bioavailability up to nearly 100%.
Plasma concentrations are generally 2-3 times higher in females than in males. In clinical trials, however, no clinically significant increases in blood pressure response or incidences of orthostatic hypotension were found in females. No dosage adjustment is necessary.
There are limited data on the pharmacokinetics of telmisartan in patients less than 18 years of age.
Telmisartan was not genotoxic in a battery of tests for gene mutations and clastogenicity.
Two-year studies in mice and rats did not show any increases in tumour incidences when telmisartan was administered in the diet at doses up to 1000 and 100 mg/kg/day, respectively.
Plasma AUC values at the highest dose levels were approximately 60 and 15 times greater, respectively, than those anticipated in humans at the maximum recommended dose.
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