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Micardis Plus
Composition
1 tablet contains:
[1,1'-biphenyl]-2-carboxylic acid, 4'-[(1,4'dimethyl-2'-propyl[2,6-bi-1H-benzimidazole]-1'-yl)methyl](= telmisartan) 40 or 80 mg and hydrochlorothiazide 12.5 mg
Description
40 mg : Oval, white-red, Biconvex two-layer tablets. The white face
is marked with "H4" and the Boehringer Ingelheim company symbol 80 mg :
Oval, white-red, Biconvex two-layer tablets. The white face is marked with
"H8" and the Boehringer Ingelheim company symbol
Properties
Micardis Plus is a combination of an angiotensin II receptor antagonist,
telmisartan, and a thiazide diuretic, hydrochlorothiazide. The combination
of these ingredients has an additive antihypertensive effect, reducing blood
pressure to a greater degree than either component alone. Micardis Plus once
daily produces effective and smooth reductions in blood pressure across the
therapeutic dose range.
Telmisartan:
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. 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 through to peak ratios
consistently above 80% seen after doses of 40 and 80 mg of telmisartan in
placebo controlled clinical studies.
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.
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.
Hydrochlorothiazide:
Hydrochlorothiazide is a thiazide diuretic. The mechanism of the
antihypertensive effect of thiazide diuretics is not fully known. Thiazides
effect the renal tubular mechanisms of electrolyte re-absorption, directly
increasing excretion of sodium and chloride in approximately equivalent
amounts. The diuretic action of hydrochlorothiazide reduces plasma volume,
increases plasma renin activity, increases aldosterone secretion, with
consequent increases in urinary potassium and bicarbonate loss, and
decreases in serum potassium. Presumably through blockade of the
renin-angiotensin-aldosterone system, co-admmistrdttan of telmisartan tends
to reverse the potassium loss associated with these diuretics.
With hydrochlorothiazides, onset of diuresis occurs in 2 hours, and peak
effect occurs at about 4 hours, while the action persists for approximately
6-12 hours.
Epidemiological studies have shown that long-term treatment with
hydrochlorothiazide reduces the risk of cardiovascular mortality and
morbidity.
Pharmacokinetics
Concomitant administration of hydrochlorothiazide and telmisartan has no
effect on the pharmacokinetics of either drug.
Absorption:
Telmisartan: Following oral administration peak concentrations of
telmisartan are reached in 0.5-1.5 h after dosing. The absolute
bioavailability of telmisartan at 40 mg and 160 mg was 42% and 58%,
respectively. Food slightly reduces the bioavailability of telmisartan with
a reduction in the area under the plasma concentration time curve (AUC) of
about 6% with the 40 mg tablet and about 19% after a 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. The pharmacokinetics of orally administered
telmisartan are non-linear over doses from 20-160 mg with greater than
proportional increases of plasma concentrations (Cmax and AUC) with
increasing doses. Telmisartan does not accumulate significantly in plasma on
repeated administration. Hydrochlorothiazide: Following oral administration
of MICARDIS PLUS peak concentrations of hydrochlorothiazide are reached in
approximately 1.0-3.0 hours after dosing. Based on cumulative renal
excretion of hydrochlorothiazide the absolute bioavailability was about 60%.
Distribution:
Telmisartan:Telmisartan is highly bound to plasma proteins (> 99.5%) mainly
albumin and alpha1-acid glycoprotein. The apparent volume of distribution
for telmisartan is approximately 500 litres indicating additional tissue
binding.
Hydrochlorothiazide: Hydrochlorothiazide is 64% protein bound in the plasma
and its apparent volume of distribution is 0.8 ± 0.3 l/kg.
Biotransformation and elimination:
Telmisartan: Following either intravenous or oral administration of
14C-labelled telmisartan most of the administered dose (>97%) was eliminated
in faeces via biliary excretion. Only minute amounts were found in urine.
Telmisartan is metabolised by conjugation to form a pharmacologically
inactive acylglucuronide. The glucuronide of the parent compound is the only
metabolite that has been identified in humans. After a single dose of
14C-labelled telmisartan the glucuronide represents approximately 11% of the
measured radioactivity in plasma. The cytochrome P450 isoenzymes are not
involved in the metabolism of telmisartan. Total plasma clearance of
telmisartan after oral administration is > 1500 ml/min. Terminal elimination
half-life was >20 hours.
Hydrochlorothiazide: Hydrochlorothiazide is not metabolised in man and is
excreted almost entirely as unchanged drug in urine. About 60% of the oral
dose are eliminated as unchanged drug within 48 hours. Renal clearance is
about 250-300 ml/min. The terminal elimination half-life of
hydrochlorothiazide is 10-15 hours.
Elderly patients:
Pharmacokinetics of telmisartan do not differ between the elderly and those
younger than 65 years.
Gender:
Plasma concentrations of telmisartan are generally 2- 3 times higher in
females than in males. In clinical trials however, no significant increases
in blood pressure response or in the incidence of orthostatic hypotension
were found in women. No dosage adjustment is necessary. There was a trend
towards higher plasma concentrations of hydrochlorothiazide in female than
in male subjects. This is not considered to be of clinical relevance.
Patients with renal impairment:
Renal excretion does not contribute to the clearance of telmisartan. Based
on modest experience in patients with mild to moderate renal impairment (creatinine
clearance of 30-60 ml/min, mean about 50 ml/min) no dosage adjustment is
necessary in patients with decreased renal function. Telmisartan is not
removed from blood by haemodialysis. In patients with impaired renal
function the rate of hydrochlorothiazide elimination is reduced.
In a typical study in patients with a mean creatinine clearance of 90 ml/min
the elimination half-life of hydrochlorothiazide was increased. In
functionally anephric patients the elimination half-life is about 34 hours.
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.
Indications
Treatment of essential hypertension.
As fixed dose combination MICARDIS PLUS is indicated in patients whose blood
pressure is not adequately controlled on telmisartan alone.
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