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Pharmacotherapeutic group: Angiotensin II receptor blocker, plain (telmisartan), combination with Diuretics (hydrochlorothiazide). ATC code: C09DA07.
Pharmacology: Mode of Action: MICARDIS PLUS is a combination of an angiotensin II receptor blocker, 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) blocker.
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.
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-administration of telmisartan tends to reverse the potassium loss associated with these diuretics.
With hydrochlorothiazide, onset of diuresis occurs in 2 hours, and peak effect occurs at about 4 hours, while the action persists for approximately 6 - 12 hours; the antihypertensive effect lasts for up to 24 hours.
Pharmacodynamics: Telmisartan: 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.
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 agents representative of other classes of antihypertensive drugs (in clinical trials comparing telmisartan to agents 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 Hypertrophy.
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 diabetic nephropathy.
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 inhibits sodium reabsorption primarily in the distal tubule, whereby a maximum of about 15% of sodium filtered by the glomerulus may be excreted. The extent of chloride excretion is roughly equivalent to that of sodium excretion. Potassium excretion is also increased by hydrochlorothiazide and is essentially determined by potassium secretion in the distal tubule and collecting duct (increased sodium and potassium ion exchange). Bicarbonate excretion may be increased by high hydrochlorothiazide doses as a result of carbonic anhydrase inhibition, resulting in urine alkalisation.
The saluretic/diuretic effect of hydrochlorothiazide is not significantly affected by acidosis or alkalosis.
Initially, the glomerular filtration rate is slightly reduced.
During long-term therapy with hydrochlorothiazide, calcium excretion via the kidneys is reduced, which may result in hypercalcaemia.
In hypertensive patients, hydrochlorothiazide has an antihypertensive effect. However, the mechanism has yet to be sufficiently clarified. It has been argued, for instance, that the effect of thiazide diuretics in terms of reducing vascular tone is due to a decrease in sodium concentration in the vascular wall and, hence, due to reduced responsiveness to norepinephrine.
In patients with chronic renal impairment (creatinine clearance less than 30 mL/min and/or serum creatinine above 1.8 mg/100 mL), hydrochlorothiazide has virtually no effect.
In patients with renal and ADH-sensitive diabetes insipidus, hydrochlorothiazide has an antidiuretic effect.
Clinical Trials: Prevention of cardiovascular morbidity and mortality: 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, 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% 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 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 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.
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.
Epidemiological studies have shown that long-term treatment with hydrochlorothiazide reduces the risk of cardiovascular mortality and morbidity.
The effects of fixed dose combination of telmisartan/HCTZ on mortality and cardiovascular morbidity are currently unknown.
Non-melanoma skin cancer: Based on available data from epidemiological studies, cumulative dose-dependent association between HCTZ and NMSC has been observed. One study included a population comprised of 71,533 cases of BCC and of 8,629 cases of SCC matched to 1,430,833 and 172,462 population controls, respectively. High HCTZ use (≥50,000 mg cumulative) was associated with an adjusted OR of 1.29 (95% CI: 1.23-1.35) for BCC and 3.98 (95% CI: 3.68-4.31) for SCC. A clear cumulative dose response relationship was observed for both BCC and SCC. Another study showed a possible association between lip cancer (SCC) and exposure to HCTZ: 633 cases of lip-cancer were matched with 63,067 population controls, using a risk-set sampling strategy. A cumulative dose-response relationship was demonstrated with an adjusted OR 2.1 (95% CI: 1.7-2.6) increasing to OR 3.9 (3.0-4.9) for high use (~25,000 mg) and OR 7.7 (5.7-10.5) for the highest cumulative dose (~100,000 mg) (see also Use in Pregnancy & Lactation).
Pharmacokinetics: Concomitant administration of hydrochlorothiazide and telmisartan has no effect on the pharmacokinetics of either drug.
Absorption: 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.
Distribution: 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.
Biotransformation: 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.
Elimination: Total plasma clearance (CLtot) is high (approximately 900 mL/min compared with hepatic blood flow (about 1500 mL/min). Terminal elimination half-life was > 20 hours.
Linearity: The pharmacokinetics of orally administered telmisartan are non-linear overdoses 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: Absorption: 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: Hydrochlorothiazide is 64% protein bound in the plasma and its apparent volume of distribution is 0.8 ;± 0.3 l/kg.
Biotransformation: Hydrochlorothiazide is not metabolised in man and is excreted almost entirely as unchanged drug in urine.
Elimination: 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.
PK in specific populations: Gender differences: Gender differences in plasma concentrations of telmisartan were observed, Cmax and AUC being approximately 3- and 2-fold higher in females compared to males without relevant influence on efficacy. 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.
Geriatric patients: Pharmacokinetics of telmisartan do not differ between the younger and geriatric patients.
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. 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.
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.
