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Pharmacotherapeutic group: Angiotensin II antagonists, plain (telmisartan), combinations with dihydropyridine derivatives (amlodipine).
Pharmacology: Mode of action: Telmisartan + Amlodipine besilate combines two antihypertensive compounds with complementary mechanisms to control blood pressure in patients with essential hypertension: an angiotensin II receptor antagonist, telmisartan, and a dihydropyridinic calcium channel blocker, amlodipine.
The combination of these substances has an additive antihypertensive effect, reducing blood pressure to a greater degree than either component alone.
Telmisartan + Amlodipine besilate once daily produces effective and consistent reductions in blood pressure across the 24-hour 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.
Amlodipine: Amlodipine is a calcium ion influx inhibitor of the dihydropyridine group (slow channel blocker or calcium ion antagonist) and inhibits the transmembrane influx of calcium ions into cardiac and vascular smooth muscle.
The mechanism of the antihypertensive action of amlodipine is due to a direct relaxant effect on vascular smooth muscle, leading to reductions in peripheral vascular resistance and in blood pressure. Experimental data indicate that amlodipine binds to both dihydropyridine and non-dihydropyridine binding sites. Amlodipine is relatively vessel-selective, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells.
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 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 is comparable to that of agents representative of other classes of antihypertensive drugs (demonstrated in clinical trials comparing telmisartan to 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.
Amlodipine: In patients with hypertension, once daily dosing provides clinically significant reductions of blood pressure in both the supine and standing positions throughout the 24 hour interval. Due to the slow onset of action, acute hypotension is not a feature of amlodipine administration.
In hypertensive patients with normal renal function, therapeutic doses of amlodipine resulted in a decrease in renal vascular resistance and an increase in glomerular filtration rate and effective renal plasma flow, without change in filtration fraction or proteinuria.
Pharmacokinetics: Pharmacokinetics of the Fixed Dose Combination: The rate and extent of absorption of Telmisartan + Amlodipine besilate are equivalent to the bioavailability of telmisartan and amlodipine when administered as individual tablets.
Pharmacokinetic of the single components: Absorption: 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.
After oral administration of therapeutic doses of amlodipine alone, peak plasma concentrations of amlodipine are reached in 6-12 hours. Absolute bioavailability has been calculated as between 64% and 80%. Amlodipine bioavailability is unaffected by food ingestion.
Distribution: 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.
The volume of distribution of amlodipine is approximately 21 L/kg. In vitro studies with amlodipine have shown that approximately 97.5% of circulating drug is bound to plasma proteins in hypertensive patients.
Metabolism: Telmisartan is metabolised by conjugation to the glucuronide of the parent compound. No pharmacological activity has been shown for the conjugate.
Amlodipine is extensively (approximately 90%) metabolised by the liver to inactive metabolites.
Elimination: 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 1500 mL/min). Amlodipine elimination from plasma is biphasic, with a terminal elimination half-life of approximately 30 to 50 hours. Steady-state plasma levels are reached after continuous administration for 7-8 days. Ten percent (10%) of original amlodipine and 60% of amlodipine metabolites are excreted in urine.
Paediatric population (age below 18 years): No pharmacokinetic data for Telmisartan + Amlodipine besilate are available in the paediatric population.
Gender effects: Gender differences in plasma concentrations of telmisartan were observed, Cmax and AUC being approximately 3 and 2-fold higher, respectively, in females compared to males without relevant influence on efficacy.
Elderly Patients: The pharmacokinetics of telmisartan do not differ between younger and elderly patients. Time to peak plasma amlodipine concentrations is similar in young and elderly patients. In elderly patients, amlodipine clearance tends to decline, causing increases in the area under the curve (AUC) and elimination half-life.
Renal impairment: Lower plasma concentrations of telmisartan 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. The pharmacokinetics of amlodipine are not significantly influenced by renal impairment.
Hepatic impairment: Pharmacokinetic studies in patients with hepatic impairment showed an increase in absolute bioavailability of telmisartan up to nearly 100%. The elimination half-life is not changed in patients with hepatic impairment.
Patients with hepatic insufficiency have decreased clearance of amlodipine with resulting increase of approximately 40-60% in AUC.
Toxicology: Since the non-clinical toxicity profiles of telmisartan and amlodipine besilate are not overlapping, no exacerbation of toxicity was expected for the combination.
This has been shown in a subchronic (13-week) toxicology study in rats, in which dose levels of 3.2/0.8, 10/2.5 and 40/10 mg/kg of telmisartan and amlodipine besilate were tested. In this study no additive or greater than additive adverse effects of amlodipine and telmisartan in combination as well as no change of the toxicity with regard to target organs were observed.
With respect to Telmisartan + Amlodipine besilate separate reproduction toxicity studies assessing the potential effects of telmisartan and amlodipine on male and female fertility when both compounds are given in combination, have not been conducted.
Telmisartan: In non-clinical safety studies doses producing exposure comparable to that in the clinical therapeutic range caused reduced red cell parameters (erythrocytes, haemoglobin, haematocrit) and changes in renal haemodynamics (increased blood urea nitrogen and creatinine), as well as increased serum potassium in normotensive animals. In dogs, renal tubular dilation and atrophy were observed. Gastric mucosal injury (erosion, ulcers or inflammation) also was noted in rats and dogs. These pharmacologically mediated side effects, known from non-clinical studies with both angiotensin converting enzyme inhibitors and angiotensin II antagonists, were prevented by oral saline supplementation.
In both species increased plasma renin activity and hypertrophy/hyperplasia of the renal juxtaglomerular cells were observed. These changes, also a class effect of ACE-inhibitors and other angiotensin II antagonists, do not appear to have clinical significance.
No clear evidence of a teratogenic effect was observed; 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.
No effects of telmisartan on male and female fertility were observed.
There was no evidence of mutagenicity and relevant clastogenic activity in in vitro studies and no evidence of carcinogenicity in rats and mice.
Amlodipine: Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential.
In reproductive toxicity studies in rats, delayed parturition, difficult labour and impaired fetal and pup survival were seen at high doses. There was no effect on the fertility of rats treated orally with amlodipine maleate (males for 64 days and females for 14 days prior to mating) at doses of up to 10 mg amlodipine/kg/day (about 10 times the MRHD of 10 mg/day on a mg/m2 basis).
No effects of amlodipine on male and female fertility were observed.
