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Pharmacology: TELSAT AM combines two antihypertensive compounds with complementary mechanisms to control blood pressure in patients with essential hypertension: an angiotensin II receptor antagonist, telmisartan, and a dihydropyridine 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.
TELSAT AM once daily produces effective and consistent reductions in blood pressure across the 24-hours 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 characterized 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 patients with hypertension, telmisartan reduces both systolic and diastolic blood pressures without affecting pulse rate. The contribution of the medicinal product's diuretic and natriuretic effect to its hypotensive activity has still to be defined.
The antihypertensive efficacy of telmisartan is comparable to that of agent representative of other classes of 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.
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. 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.
In patients with hypertension, once daily dosing provides clinically significant reductions of blood pressure in both the supine and standing positions throughout the 24 hours 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.
Amlodipine has not been associated with any adverse metabolic effects or changes in plasma lipids and is suitable for use in patients with asthma, diabetes, and gout.
Use in patients with heart failure: Amlodipine did not lead to clinical deterioration as measured by exercise tolerance, left ventricular ejection fraction, and clinical symptomatology in NYHA class II-IV heart failure patients.
Amlodipine did not lead to an increase in risk of mortality or combined mortality and morbidity with heart failure in patients with NYHA class III-IV heart failure that receiving digoxin, diuretics, and ACE inhibitors.
In patients with NYHA class III and IV heart failure without clinical symptoms or objective findings suggestive or underlying ischemic disease, on stable doses of ACE inhibitors, digitalis, and diuretics, amlodipine had no effect on total cardiovascular mortality. In this same population amlodipine was associated with increased reports of pulmonary edema.
Pharmacokinetics: Telmisartan/amlodipine 80/10 mg fixed-dose combination (TELSAT AM) tablet has been studied in an open-label, randomized, single-dose, three-period, three-sequence, partial replicated study under fasting conditions which included 31 healthy adult male subjects (18-55 years). The pharmacokinetic parameters assessed in this study were AUC0-72h, Cmax, tmax and t½. These parameters were determined from plasma concentrations of telmisartan and amlodipine.
After oral administration of TELSAT AM, the mean (SD) AUC0-72h of telmisartan and amlodipine were 3110.65 (1845.67) ng·hour/ml and 385.04 (130.99) ng·hour/ml, respectively. The mean (SD) maximum plasma concentration (Cmax) of telmisartan and amlodipine were 546.06 (334.49) ng/ml and 11.46 (3.41) ng/ml, respectively. Cmax of telmisartan and amlodipine reached within 0.75 (0.50-2.00) hours and 8.00 (6.00-12.00) hours, respectively. The mean (SD) elimination half-lives (t½) of telmisartan and amlodipine were 24.89 (8.26) hours and 33.64 (8.18) hours, respectively.
The geometric mean ratios (90% confidence intervals) of telmisartan were 99.10% (92.02-106.73%) for AUC0-72h and 91.99% (78.64-107.61%) for Cmax. The geometric mean ratios (90% confidence intervals) of amlodipine were 100.60% (95.03-106.49%) for AUC0-72h and 104.21% (99.41-109.24%) for Cmax. The result of this study showed that the pharmacokinetic parameters of TELSAT AM tablet were within the acceptance range for bioequivalence, therefore, TELSAT AM tablet was similar or bioequivalent to the reference drug.
Pediatric patients (age below 18 years): No pharmacokinetic data are available in the pediatric 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.
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.
Patients with renal impairment: In patients with mild to moderate and severe renal impairment, doubling of plasma concentrations of telmisartan was observed. Lower plasma concentrations of telmisartan were observed in patients with renal insufficiency undergoing dialysis. Telmisartan is highly bound to plasma protein in renal-insufficient patients and cannot be removed by dialysis. The elimination half-life is not changed in patients with renal impairment.
The pharmacokinetics of amlodipine is not significantly influenced by renal impairment.
Patients with hepatic impairment: Absolute bioavailability of telmisartan increases up to nearly 100% in patients with hepatic impairment. 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.
