Hydrochlorothiazide 12.5 mg, Telmisartan 40 mg Uncoated Tablets

TELMISARTAN AND HYDROCHLOROTHIAZIDE TABLETS — Telmisartan and hydrochlorothiazide tablets are combination of two drugs with antihypertensive properties: a thiazide diuretic, hydrochlorothiazide, and an angiotensin II receptor blocker (ARB), telmisartan.

Telmisartan — Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE, kininase II). Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium. Telmisartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT 1receptor in many tissues, such as vascular smooth muscle and the adrenal gland. Its action is therefore independent of the pathways for angiotensin II synthesis.

There is also an AT 2receptor found in many tissues, but AT 2is not known to be associated with cardiovascular homeostasis. Telmisartan has much greater affinity (>3,000-fold) for the AT 1receptor than for the AT 2receptor.

Telmisartan does not inhibit ACE (kininase II) nor does it bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.

Blockade of the angiotensin II receptor inhibits the negative regulatory feedback of angiotensin II on renin secretion, but the resulting increased plasma renin activity and angiotensin II circulating levels do not overcome the effect of telmisartan on blood pressure.

Absorption: — Following oral administration, peak concentrations (C max) of telmisartan are reached in 0.5 to 1 hour after dosing. Food slightly reduces the bioavailability of telmisartan, with a reduction in the area under the plasma concentration-time curve (AUC) of approximately 6% with 40 mg and approximately 20% after a 160 mg dose. Telmisartan and hydrochlorothiazide tablets can be administered with or without food. The absolute bioavailability of telmisartan is dose dependent. At 40 and 160 mg the bioavailability was 42% and 58%, respectively. The pharmacokinetics of telmisartan with orally administered telmisartan tablets are nonlinear over the dose range 20 mg to 160 mg, with greater than proportional increases of plasma concentrations (C maxand AUC) with increasing doses. Telmisartan shows bi-exponential decay kinetics with a terminal elimination half-life of approximately 24 hours. Trough plasma concentrations of telmisartan with once-daily dosing are approximately 10% to 25% of peak plasma concentrations. Telmisartan has an accumulation index in plasma of 1.5 to 2 upon repeated once-daily dosing.

Distribution: — Telmisartan is highly bound to plasma proteins (>99.5%), mainly albumin and α 1-acid glycoprotein. Plasma protein binding is constant over the concentration range achieved with recommended doses. The volume of distribution for telmisartan is approximately 500 liters, indicating additional tissue binding.

Metabolism: — Telmisartan is metabolized by conjugation to form a pharmacologically inactive acyl glucuronide; the glucuronide of the parent compound is the only metabolite that has been identified in human plasma and urine. After a single dose, the glucuronide represents approximately 11% of the measured radioactivity in plasma. The cytochrome P450 isoenzymes are not involved in the metabolism of telmisartan.

Elimination: — Following either intravenous or oral administration of 14C-labeled telmisartan, most of the administered dose (>97%) was eliminated unchanged in feces via biliary excretion; only minute amounts were found in the urine (0.91% and 0.49% of total radioactivity, respectively).

Total plasma clearance of telmisartan is >800 mL/min. Terminal half-life and total clearance appear to be independent of dose.

Hydrochlorothiazide — Hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidney. When plasma levels have been followed for at least 24 hours, the plasma half-life has been observed to vary between 5.6 and 14.8 hours. At least 61% of the oral dose is eliminated unchanged within 24 hours. Hydrochlorothiazide crosses the placental but not the blood-brain barrier and is excreted in breast milk.

Telmisartan — Renal Insufficiency:Telmisartan is not removed from blood by hemofiltration and is not dialyzable [see Warnings and Precautions ( 5.3) and Use in Specific Populations ( 8.7)].

Hepatic Insufficiency:In patients with hepatic insufficiency, plasma concentrations of telmisartan are increased, and absolute bioavailability approaches 100% [see Use in Specific Populations ( 8.6)].

Gender:Plasma concentrations of telmisartan are generally 2 to 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.

Geriatric Patients:The pharmacokinetics of telmisartan do not differ between the elderly and those younger than 65 years of age.

Telmisartan — Ramipril:Co-administration of telmisartan 80 mg once daily and ramipril 10 mg once daily to healthy subjects increases steady-state C maxand AUC of ramipril 2.3- and 2.1-fold, respectively, and C maxand AUC of ramiprilat 2.4- and 1.5-fold, respectively. In contrast, C maxand AUC of telmisartan decrease by 31% and 16%, respectively. When co-administering telmisartan and ramipril, the response may be greater because of the possibly additive pharmacodynamic effects of the combined drugs, and also because of the increased exposure to ramipril and ramiprilat in the presence of telmisartan.