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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.
Micardis/Micardis Plus: 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. It 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 hrs and is still measurable up to 48 hrs.
Treatment of Essential Hypertension: After the 1st dose of telmisartan, the antihypertensive activity gradually becomes evident within 3 hrs. 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 hrs after dosing and includes the last 4 hrs before the next dose as shown by ambulatory blood pressure measurements. This is confirmed by trough to peak ratios consistently >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 eg, 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 hypertrophy.
Telmisartan treatment has been shown in clinical trials (including comparators eg, losartan, ramipril and valsartan) to be associated with statistically significant reductions in proteinuria (including microalbuminuria and macroalbuminuria) in patients with hypertension and diabetic nephropathy.
The incidence of dry cough was significantly lower in patients treated with telmisartan than in those who were given angiotensin-converting enzyme inhibitors in clinical trials directly comparing the 2 antihypertensive treatments.
Prevention of Cardiovascular Morbidity and Mortality: Ongoing telmisartan alone and in combination with ramipril global endpoint trial (ONTARGET) compared the effects of telmisartan, ramipril and the combination of telmisartan and ramipril on cardiovascular outcomes in 25,620 patients ≥55 years with a history of coronary artery disease, stroke, peripheral vascular disease or diabetes mellitus accompanied by evidence of end-organ damage (eg, 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 3 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 male 73%, Caucasian 74%, Asian 14% and 43% were ≥65 years. 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 reading >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 level. Baseline therapy included acetylsalicylic acid (76%), statins (62%), β-blockers (57%), calcium channel blockers (34%), nitrates (29%) and diuretics (28%).
The primary endpoint was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke or hospitalization for congestive heart failure.
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 angiotensin-converting enzyme (ACE) inhibitor. The analysis of adverse events leading to permanent treatment discontinuation 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.
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 versus ramipril was 1.01 [97.5% CI 0.93-1.1, 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 prespecified secondary endpoints, including a composite of cardiovascular death, nonfatal myocardial infarction and nonfatal stroke, the primary endpoint in the reference study The Heart Outcomes Prevention Evaluation Study (HOPE), which had investigated the effect of ramipril versus placebo. The hazard ratio of telmisartan versus ramipril for this endpoint in ONTARGET was 0.99 [97.5% CI 0.9-1.08, 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 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.
Paediatric Population: The blood pressure lowering effects of 2 doses of telmisartan were assessed in hypertensive patients 6 to <18 years (n=76) after taking telmisartan 1 mg/kg (n=30 treated) or 2 mg/kg (n=31 treated) over a 4-week treatment period. After adjustment for age group effects and baseline SBP values an average placebo-corrected SBP change from baseline (primary objective) of -8.5 mmHg was observed in the telmisartan 2 mg/kg group and a -3.6 mmHg SBP change was found in the telmisartan 1 mg/kg group. The adjusted and placebo-controlled DBP changes from baseline were -4.5 mmHg and -4.8 mmHg in the telmisartan 1 mg/kg and 2 mg/kg groups, respectively. The change was dose dependent. The safety profile appeared generally comparable to that observed in adults.
Micardis Plus: Hydrochlorothiazide: Hydrochlorothiazide is a thiazide diuretic. The mechanism of the antihypertensive effect of thiazide diuretics is not fully known. Thiazides affect 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 renin-angiotensin-aldosterone system, co-administration of telmisartan tends to reverse the potassium loss associated with these diuretics.
With hydrochlorothiazides, onset of diuresis occurs in 2 hrs, and peak effect occurs at about 4 hrs, while the action persists for approximately 6-12 hrs.
Epidemiological studies have shown that long-term treatment with hydrochlorothiazide reduces the risk of cardiovascular mortality and morbidity.
Pharmacokinetics: Concomitant administration of hydrochlorothiazide and Micardis has no effect on the pharmacokinetics of either drug.
Absorption: Following oral administration, peak concentrations of telmisartan are reached in 0.5-1.5 hrs 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 hrs 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 nonlinear 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.
Micardis Plus: Hydrochlorothiazide: Following oral administration of Micardis Plus, peak concentrations of hydrochlorothiazide are reached in approximately 1-3 hrs 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 α1-acid glycoprotein. The apparent volume of distribution for telmisartan is approximately 500 L 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: Following either IV or oral administration of 14C-labelled telmisartan, most of the administered dose (>97%) was eliminated in feces via biliary excretion. Only minute amounts were found in urine.
Telmisartan is metabolized by conjugation to form a pharmacologically inactive acylglucuronide. No pharmacological activity has been shown for the conjugate. 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 P-450 isoenzymes are not involved in the metabolism of telmisartan. Total plasma clearance of telmisartan after oral administration is >1500 mL/min. Telmisartan is characterized by biexponential decay pharmacokinetics with a terminal elimination half-life (t½) of >20 hrs. The Cmax and, to a smaller extent, AUC increase disproportionately with dose. There is no evidence of clinically relevant accumulation of telmisartan.
After oral (and IV) 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 1500 mL/min).
Hydrochlorothiazide: Hydrochlorothiazide is not metabolised in man and is excreted almost entirely as unchanged drug in urine. About 60% of the oral dose is eliminated as unchanged drug within 48 hrs. Renal clearance is about 250-300 mL/min. The terminal elimination half-life of hydrochlorothiazide is 10-15 hrs.
Elderly Patients: Pharmacokinetics of telmisartan do not differ between the elderly and those <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: Micardis: 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 t½ is not changed in patients with renal impairment.
Micardis Plus: Renal excretion does not contribute to the clearance of telmisartan. Based on modest experience in patients with mild to moderate renal impairment [creatinine clearance (CrCl) 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 CrCl of 90 mL/min, the elimination t½ of hydrochlorothiazide was increased. In functionally anephric patients, the elimination t½ is about 34 hrs.
Patients with Hepatic Impairment: Pharmacokinetic studies in patients with hepatic impairment showed an increase in absolute bioavailability up to nearly 100%. The elimination t½ is not changed in patients with hepatic impairment.
Paediatric Population: Micardis: The pharmacokinetics of 2 doses of telmisartan were assessed as a secondary objective in hypertensive patients (n=57) aged 6 to <18 years after taking telmisartan 1 mg/kg or 2 mg/kg over a 4-week treatment period. Pharmacokinetic objectives included the determination of the steady state of telmisartan in children and adolescents, and investigation of age-related differences. Although the study was too small for a meaningful assessment of the pharmacokinetics of children <12 years, the results are generally consistent with the findings in adults and confirm the nonlinearity of telmisartan, particularly for Cmax.
Toxicology: In nonclinical 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 nonclinical studies with angiotensin-converting enzyme (ACE) 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 dose levels, however, nonclinical 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, andhigher mortality).
