Bisoprolol Fumarate 2.5 mg, Telmisartan 40 mg Tablets

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 AT1 receptor 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 AT2 receptor found in many tissues, but AT2 is not known to be associated with cardiovascular homeostasis. Telmisartan has much greater affinity (>3,000 fold) for the AT1 receptor than for the AT2 receptor.

Blockade of the renin-angiotensin system with ACE inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin I, is widely used in the treatment of hypertension. ACE inhibitors also inhibit the degradation of bradykinin, a reaction also catalyzed by ACE. Because telmisartan does not inhibit ACE (kininase II), it does not affect the response to bradykinin. Whether this difference has clinical relevance is not yet known. Telmisartan does not 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 (Cmax) of telmisartan are reached in 0.5 to1 hour after dosing. 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 20% after a 160 mg dose. The absolute bioavailability of telmisartan is dose dependent. At 40 and 160 mg the bioavailability was 42% and 58%, respectively. The pharmacokinetics of orally administered telmisartan are nonlinear over the dose range 20 to160 mg, with greater than proportional increases of plasma concentrations (Cmax and 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 about 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 α1-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 and 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).

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.

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

Renal Insufficiency — No dosage adjustment is necessary in patients with decreased renal function. Telmisartan is not removed from blood by hemofiltration [see Warnings and Precautions (5.5) and Dosage and Administration (2.1)].

Hepatic Insufficiency — In patients with hepatic insufficiency, plasma concentrations of telmisartan are increased, and absolute bioavailability approaches 100% [see Warnings and Precautions (5.4) and 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 [see Dosage and Administration (2.1)].

Pediatric Patients — Telmisartan pharmacokinetics have not been investigated in patients <18 years of age.

Telmisartan — Ramipril and Ramiprilat: Co-administration of telmisartan 80 mg once daily and ramipril 10 mg once daily to healthy subjects increases steady-state Cmax and AUC of ramipril 2.3- and 2.1-fold, respectively, and Cmax and AUC of ramiprilat 2.4- and 1.5-fold, respectively. In contrast, Cmax and 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.

Other Drugs: Co-administration of telmisartan did not result in a clinically significant interaction with acetaminophen, amlodipine, glyburide, simvastatin, hydrochlorothiazide, warfarin, or ibuprofen. Telmisartan is not metabolized by the cytochrome P450 system and had no effects in vitro on cytochrome P450 enzymes, except for some inhibition of CYP2C19. Telmisartan is not expected to interact with drugs that inhibit cytochrome P450 enzymes; it is also not expected to interact with drugs metabolized by cytochrome P450 enzymes, except for possible inhibition of the metabolism of drugs metabolized by CYP2C19.

Bisoprolol fumarate is a beta 1-selective (cardioselective) adrenoceptor blocking agent without significant membrane stabilizing activity or intrinsic sympathomimetic activity in its therapeutic dosage range. Cardioselectivity is not absolute, however, and at higher doses (≥ 20 mg) bisoprolol fumarate also inhibits beta 2-adrenoceptors, chiefly located in the bronchial and vascular musculature; to retain selectivity it is therefore important to use the lowest effective dose.

The absolute bioavailability after a 10 mg oral dose of bisoprolol fumarate is about 80%. Absorption is not affected by the presence of food. The first pass metabolism of bisoprolol fumarate is about 20%.

Binding to serum proteins is approximately 30%. Peak plasma concentrations occur within 2 to 4 hours of dosing with 5 to 20 mg, and mean peak values range from 16 ng/mL at 5 mg to 70 ng/mL at 20 mg. Once daily dosing with bisoprolol fumarate results in less than two-fold intersubject variation in peak plasma levels. The plasma elimination half-life is 9 to 12 hours and is slightly longer in elderly patients, in part because of decreased renal function in that population. Steady state is attained within 5 days of once daily dosing. In both young and elderly populations, plasma accumulation is low; the accumulation factor ranges from 1.1 to 1.3, and is what would be expected from the first order kinetics and once daily dosing. Plasma concentrations are proportional to the administered dose in the range of 5 to 20 mg. Pharmacokinetic characteristics of the two enantiomers are similar.

Bisoprolol fumarate is eliminated equally by renal and non-renal pathways with about 50% of the dose appearing unchanged in the urine and the remainder appearing in the form of inactive metabolites. In humans, the known metabolites are labile or have no known pharmacologic activity. Less than 2% of the dose is excreted in the feces. Bisoprolol fumarate is not metabolized by cytochrome P450 II D6 (debrisoquin hydroxylase).

In subjects with creatinine clearance less than 40 mL/min, the plasma half-life is increased approximately three-fold compared to healthy subjects.

In patients with cirrhosis of the liver, the elimination of bisoprolol fumarate is more variable in rate and significantly slower than that in healthy subjects, with plasma half-life ranging from 8.3 to 21.7 hours.

The most prominent effect of bisoprolol fumarate is the negative chronotropic effect, resulting in a reduction in resting and exercise heart rate. There is a fall in resting and exercise cardiac output with little observed change in stroke volume, and only a small increase in right atrial pressure, or pulmonary capillary wedge pressure at rest or during exercise.

Findings in short-term clinical hemodynamics studies with bisoprolol fumarate are similar to those observed with other beta-blocking agents.

The mechanism of action of its antihypertensive effects has not been completely established. Factors which may be involved include:

2) Inhibition of renin release by the kidneys, — 3) Diminution of tonic sympathetic outflow from the vasomotor centers in the brain.

In normal volunteers, bisoprolol fumarate therapy resulted in a reduction of exercise- and isoproterenol-induced tachycardia. The maximal effect occurred within 1 to 4 hours post-dosing. Effects persisted for 24 hours at doses equal to or greater than 5 mg.

Electrophysiology studies in man have demonstrated that bisoprolol fumarate significantly decreases heart rate, increases sinus node recovery time, prolongs AV node refractory periods, and, with rapid atrial stimulation, prolongs AV nodal conduction.

Beta 1-selectivity of bisoprolol fumarate has been demonstrated in both animal and human studies. No effects at therapeutic doses on beta 2-adrenoceptor density have been observed. Pulmonary function studies have been conducted in healthy volunteers, asthmatics, and patients with chronic obstructive pulmonary disease (COPD). Doses of bisoprolol fumarate ranged from 5 to 60 mg, atenolol from 50 to 200 mg, metoprolol from 100 to 200 mg, and propranolol from 40 to 80 mg. In some studies, slight, asymptomatic increases in airways resistance (AWR) and decreases in forced expiratory volume (FEV 1) were observed with doses of bisoprolol fumarate 20 mg and higher, similar to the small increases in AWR also noted with the other cardioselective beta-blockers. The changes induced by beta-blockade with all agents were reversed by bronchodilator therapy.

Bisoprolol fumarate had minimal effect on serum lipids during antihypertensive studies. In U.S. placebo-controlled trials, changes in total cholesterol averaged +0.8% for bisoprolol fumarate-treated patients, and +0.7% for placebo. Changes in triglycerides averaged +19% for bisoprolol fumarate-treated patients, and +17% for placebo.

Bisoprolol fumarate has also been given concomitantly with thiazide diuretics. Even very low doses of hydrochlorothiazide (6.25 mg) were found to be additive with bisoprolol fumarate in lowering blood pressure in patients with mild-to-moderate hypertension.