Telmisartan and Hydrochlorothiazide

TELMISARTAN AND HYDROCHLOROTHIAZIDE- telmisartan and hydrochlorothiazide tablet
Roxane Laboratories, Inc.

Prescribing Information

WARNING: FETAL TOXICITY

When pregnancy is detected, discontinue Telmisartan and Hydrochlorothiazide Tablets USP as soon as possible.
Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus (see WARNINGS, Fetal Toxicity).

DESCRIPTION

Telmisartan and Hydrochlorothiazide Tablets USP are a combination of telmisartan, an orally active angiotensin II antagonist acting on the AT1 receptor subtype, and hydrochlorothiazide, a diuretic.

Telmisartan, a non-peptide molecule, is chemically described as 4′-[(1,4'-dimethyl-2'-propyl[2,6'-bi-1H-benzimidazol]-1′-yl)methyl]-[1,1'-biphenyl]-2-carboxylic acid. Its empirical formula is C33 H30 N4 O2 , its molecular weight is 514.63, and its structural formula is:

Telmisartan structure
(click image for full-size original)

Telmisartan is a white to slightly yellowish solid. It is practically insoluble in water and in the pH range of 3 to 9, sparingly soluble in strong acid (except insoluble in hydrochloric acid), and soluble in strong base.

Hydrochlorothiazide is a white, or practically white, practically odorless, crystalline powder with a molecular weight of 297.74. It is slightly soluble in water, and freely soluble in sodium hydroxide solution. Hydrochlorothiazide is chemically described as 6-chloro-3,4-dihydro-2H -1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. Its empirical formula is C7 H8 ClN3 O4 S2 , and its structural formula is:

Telmisartan structure

Telmisartan and Hydrochlorothiazide Tablets USP are formulated for oral administration in three combinations of 40 mg/12.5 mg, 80 mg/12.5 mg, and 80 mg/25 mg telmisartan and hydrochlorothiazide, respectively. The tablets contain the following inactive ingredients: sodium hydroxide, meglumine, povidone, sorbitol, magnesium stearate, lactose monohydrate, microcrystalline cellulose, maize starch, sodium starch glycolate. As coloring agents, the 40 mg/12.5 mg and 80 mg/12.5 mg tablets contain ferric oxide red, and the 80 mg/25 mg tablets contain ferric oxide yellow. Telmisartan and Hydrochlorothiazide Tablets USP are hygroscopic and require protection from moisture.

CLINICAL PHARMACOLOGY

Mechanism of Action

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.

Hydrochlorothiazide is a thiazide diuretic. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of sodium salt and chloride in approximately equivalent amounts. Indirectly, the diuretic action of hydrochlorothiazide reduces plasma volume, with consequent increases in plasma renin activity, increases in aldosterone secretion, increases in urinary potassium loss, and decreases in serum potassium. The renin-aldosterone link is mediated by angiotensin II, so coadministration of an angiotensin II receptor antagonist tends to reverse the potassium loss associated with these diuretics.

The mechanism of the antihypertensive effect of thiazides is not fully understood.

Pharmacokinetics

General

Telmisartan

Following oral administration, peak concentrations (Cmax ) of telmisartan are reached in 0.5-1 hour after dosing. Food slightly reduces the bioavailability of telmisartan, with a reduction in the area under the plasma concentration-time curve (AUC) of 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 20-160 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 10-25% of peak plasma concentrations. Telmisartan has an accumulation index in plasma of 1.5 to 2.0 upon repeated once daily dosing.

Hydrochlorothiazide

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.

Metabolism and Elimination

Telmisartan

Following either intravenous or oral administration of 14 C-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 acylglucuronide; 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.

Hydrochlorothiazide

Hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidney. At least 61% of the oral dose is eliminated as unchanged drug within 24 hours.

Distribution

Telmisartan

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.

Hydrochlorothiazide

Hydrochlorothiazide crosses the placental but not the blood-brain barrier and is excreted in breast milk.

Special Populations

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

Geriatric : The pharmacokinetics of telmisartan do not differ between the elderly and those younger than 65 years (see DOSAGE AND ADMINISTRATION).

Gender : Plasma concentrations of telmisartan are generally 2-3 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.

Renal Insufficiency : Renal excretion does not contribute to the clearance of telmisartan. Based on modest experience in patients with mild-to-moderate renal impairment (creatinine clearance of 30-80 mL/min, mean clearance approximately 50 mL/min), no dosage adjustment is necessary in patients with decreased renal function. Telmisartan is not removed from blood by hemofiltration (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).

Hepatic Insufficiency : In patients with hepatic insufficiency, plasma concentrations of telmisartan are increased, and absolute bioavailability approaches 100% (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).

Drug Interactions: See PRECAUTIONS, Drug Interactions.

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