USE IN PREGNANCY
When used in pregnancy during the second and third trimesters, drugs that
act directly on the renin-angiotensin system can cause injury and even death
to the developing fetus. When pregnancy is detected, MICARDIS tablets should
be discontinued as soon as possible. See WARNINGS: Fetal/Neonatal morbidity
1 tablet contains ...........20, 40 or 80 mg
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
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 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
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
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 risk reduction
ONTARGET (ONgoin 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°k 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
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 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.
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.
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.
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.
Telmisartan is metabolised by conjugation to the glucuronide of the parent
compound. No pharmacological activity has been shown for the conjugate.
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, area under the
plasma concentration-time curve (AUC) increase disproportionately with dose.
There is no evidence of clinically relevant accumulation of telmisartan.
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
The pharmacokinetics of telmisartan do not differ between younger and
Patients with 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.
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.