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Pharmacology: 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 pretreatment 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 reabsorption, 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 reninangiotensin- aldosterone system, co-administration 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.
Clinical Trial: 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.
Toxicology: In non-clinical safety studies performed with co-administration of telmisartan and hydrochlorothiazide in normotensive rats and dogs, doses producing exposure comparable to that in the clinical therapeutic range caused no additional findings not already observed with administration of either substance alone. There were no toxicological findings observed of relevance to human therapeutic use.
Toxicological findings also well known from non-clinical studies with angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists were: a reduction of red cell parameters (erythrocytes, haemoglobin, haematocrit), changes of renal haemodynamics (increased blood urea nitrogen and creatinine), increased plasma renin activity, hypertrophy/hyperplasia of the juxtaglomerular cells and gastric mucosal injury.
Gastric lesions could be prevented/ameliorated by oral saline supplementation and group housing of animals. In dogs renal tubular dilation and atrophy were observed. These findings are considered to be due to the pharmacological activity of telmisartan.
Telmisartan showed no evidence of mutagenicity and relevant clastogenic activity in in vitro studies and no evidence of carcinogenicity in rats and mice. Studies with hydrochlorothiazide have shown equivocal evidence for a genotoxic or carcinogenic effect in some experimental models. However, the extensive human experience with hydrochlorothiazide has failed to show an association between its use and an increase in neoplasms.
There is no clear evidence of a teratogenic or embryotoxic potential for either telmisartan or hydrochlorothiazide administered as single entities or in combination. At toxic doses levels, however, non-clinical studies indicated some hazardous potential of telmisartan to fetal development (increased number of late resorptions in rabbits) and to the postnatal development of the offspring: lower body weight, delayed eye opening, and higher mortality.
