Telmisartan and Hydrochlorthiazide (Page 4 of 7)

8.2 Lactation

Risk Summary

There is no information regarding the presence of telmisartan and hydrochlorothiazide or telmisartan in human milk, the effects on the breastfed infant or the effects on milk production. Limited published studies report that hydrochlorothiazide is present in human milk. However, there is insufficient information to determine the effects of hydrochlorothiazide on the breastfed infant or the effects of hydrochlorothiazide on milk production. Telmisartan is present in the milk of lactating rats. (see Data). Because of the potential for serious adverse reactions in the breastfed infant including hypotension, hyperkalemia and renal impairment, advise a nursing woman not to breastfeed during treatment with telmisartan and hydrochlorothiazide tablets.

Data

Telmisartan was present in the milk of lactating rats at concentrations 1.5 to 2 times those found in plasma from 4 to 8 hours after administration.

8.4 Pediatric Use

Safety and effectiveness of telmisartan and hydrochlorothiazide tablets in pediatric patients have not been established.

Neonates with a history of in utero exposure to Telmisartan and Hydrochlorothiazide tablets:

If oliguria or hypotension occurs, support blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as means of reversing hypotension and/or substituting for disordered renal function.

8.5 Geriatric Use

In the controlled clinical trials (n=1017), approximately 20% of patients treated with telmisartan/hydrochlorothiazide were 65 years of age or older, and 5% were 75 years of age or older. No overall differences in effectiveness and safety of telmisartan/hydrochlorothiazide were observed in these patients compared to younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function and of concomitant diseases or other drug therapy.

8.6 Use in Patients with Hepatic Impairment

Patients with biliary obstructive disorders or hepatic insufficiency should initiate treatment under close medical supervision using the 40 mg/12.5 mg combination .

Telmisartan

As the majority of telmisartan is eliminated by biliary excretion, patients with biliary obstructive disorders or hepatic insufficiency can be expected to have reduced clearance and higher blood levels .

Hydrochlorothiazide

Minor alterations of fluid and electrolyte balance may precipitate hepatic coma in patients with impaired hepatic function or progressive liver disease.

8.7 Use in Patients with Renal Impairment

Safety and effectiveness of telmisartan and hydrochlorothiazide tablets in patients with severe renal impairment (CrCl ≤30 mL/min) have not been established. In patients with severe renal impairment, telmisartan and hydrochlorothiazide tablets are not recommended. No dose adjustment is required in patients with mild (CrCl 60 to 90 mL/min) or moderate (CrCl 30 to 60 mL/min) renal impairment.

10 OVERDOSAGE

Telmisartan

Limited data are available with regard to overdosage of telmisartan in humans. The most likely manifestations of overdosage with telmisartan are hypotension, dizziness, and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. If symptomatic hypotension should occur, supportive treatment should be instituted. Telmisartan is not removed by hemodialysis.

Hydrochlorothiazide

The most common signs and symptoms observed in patients with a hydrochlorothiazide overdose are those caused by electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. If digitalis has also been administered, hypokalemia may accentuate cardiac arrhythmias. The degree to which hydrochlorothiazide is removed by hemodialysis has not been established. The oral LD 50 of hydrochlorothiazide is greater than 10 g/kg in both mice and rats.

11 DESCRIPTION

Telmisartan and hydrochlorothiazide tablets, USP are a combination of telmisartan, an orally active angiotensin II antagonist acting on the AT 1 receptor subtype, and hydrochlorothiazide, a thiazide 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 C 33 H 30 N 4 O 2 , its molecular weight is 514.63, and its structural formula is:

telmisartan-structure
(click image for full-size original)

Telmisartan, USP 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, USP 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-2 H -1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. Its empirical formula is C 7 H 8 ClN 3 O 4 S 2 , and its structural formula is:

hctz-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: hypromellose, lactose monohydrate, mannitol, meglumine, povidone, sodium hydroxide, sodium stearyl fumarate. As coloring agents, the 40 mg/12.5 mg and 80 mg/25 mg tablets contain ferric oxide yellow, and the 80 mg/12.5 mg tablets contain ferric oxide red. Telmisartan and hydrochlorothiazide tablets, USP are hygroscopic and require protection from moisture.

Meets USP Dissolution Test 2.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Telmisartan and Hydrochlorothiazide Tablets

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

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.

Hydrochlorothiazide

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 co-administration of an ARB tends to reverse the potassium loss associated with these diuretics. The mechanism of the antihypertensive effect of thiazides is not fully understood.

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