Olmesartan Medoxomil and Hydrochlorothiazide

Name: Olmesartan Medoxomil and Hydrochlorothiazide

Dosage Forms and Strengths

Olmesartan Medoxomil and Hydrochlorothiazide Tablets are available containing 20 mg of olmesartan medoxomil, USP and 12.5 mg of hydrochlorothiazide, USP; 40 mg of olmesartan medoxomil, USP and 12.5 mg of hydrochlorothiazide, USP or 40 mg of olmesartan medoxomil, USP and 25 mg of hydrochlorothiazide, USP.

• The 20 mg/12.5 mg tablets are pink, film-coated, round, unscored tablets debossed with M on one side of the tablet and 413 on the other side. • The 40 mg/12.5 mg tablets are pink, film-coated, modified capsule shaped, unscored tablets debossed with M on one side of the tablet and 422 on the other side. • The 40 mg/25 mg tablets are pink, film-coated, round, unscored tablets debossed with M on one side of the tablet and 425 on the other side.

Contraindications

Olmesartan Medoxomil and Hydrochlorothiazide tablets are contraindicated:

• In patients with hypersensitivity to any component of Olmesartan Medoxomil and Hydrochlorothiazide tablets [see Adverse Reactions (6.1, 6.2)] • In patients with anuria [see Warnings and Precautions (5.3) and Adverse Reactions (6.1)] • For co-administration with aliskiren in patients with diabetes [see Drug Interactions (7.4)].

Use in specific populations

Pregnancy

Pregnancy Category D

Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity, and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Olmesartan Medoxomil and Hydrochlorothiazide tablets as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus.

In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intraamniotic environment. If oligohydramnios is observed, discontinue Olmesartan Medoxomil and Hydrochlorothiazide tablets, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to Olmesartan Medoxomil and Hydrochlorothiazide tablets for hypotension, oliguria, and hyperkalemia [see Use in Specific Populations (8.4)].

Nursing Mothers

It is not known whether olmesartan is excreted in human milk, but olmesartan is secreted at low concentration in the milk of lactating rats. Thiazides appear in human milk. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue Olmesartan Medoxomil and Hydrochlorothiazide tablets, taking into account the importance of the drug to the mother.

Pediatric Use

Neonates with a History of in utero Exposure to Olmesartan Medoxomil and Hydrochlorothiazide Tablets

If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and substituting for disordered renal function.

Safety and effectiveness of Olmesartan Medoxomil and Hydrochlorothiazide tablets in pediatric patients have not been established.

Geriatric Use

Clinical studies of Olmesartan Medoxomil and Hydrochlorothiazide tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. 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.

Olmesartan and hydrochlorothiazide are substantially excreted by the kidney, and the risk of toxic reactions to Olmesartan Medoxomil and Hydrochlorothiazide tablets may be greater in patients with impaired renal function.

Renal Impairment

Safety and effectiveness of Olmesartan Medoxomil and Hydrochlorothiazide tablets in patients with severe renal impairment (CrCl ≤ 30 mL/min) have not been established. No dose adjustment is required in patients with mild (CrCl 60-90 mL/min) or moderate (CrCl 30-60 mL/min) renal impairment.

Hepatic Impairment

Olmesartan Medoxomil

No dose adjustment is necessary for patients with mild-to-severe liver disease.

Hydrochlorothiazide

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

Olmesartan Medoxomil and Hydrochlorothiazide Description

Olmesartan Medoxomil and Hydrochlorothiazide tablets are a combination of an angiotensin II receptor antagonist (AT1 subtype), olmesartan medoxomil, and a thiazide diuretic, hydrochlorothiazide (HCTZ).

Olmesartan medoxomil is 1H-Imidazole-5-carboxylic acid, 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]methyl]-, (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl ester.

Its molecular formula is C29H30N6O6 and its structural formula is:

Olmesartan medoxomil, USP is a white to off-white powder with a molecular weight of 558.6. It is practically insoluble in water and sparingly soluble in methanol.

Hydrochlorothiazide is 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. Its molecular formula is C7H8ClN3O4S2 and its structural formula is:

Hydrochlorothiazide, USP is a white, or practically white, crystalline powder with a molecular weight of 297.7. Hydrochlorothiazide is slightly soluble in water but freely soluble in sodium hydroxide solution.

Olmesartan Medoxomil and Hydrochlorothiazide tablets are available for oral administration in tablets containing 20 mg or 40 mg of olmesartan medoxomil combined with 12.5 mg of hydrochlorothiazide, or 40 mg of olmesartan medoxomil combined with 25 mg of hydrochlorothiazide. Inactive ingredients include: colloidal silicon dioxide, D&C Red No. 30 Aluminum Lake, hypromellose, lactose monohydrate, low substituted hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol and sodium lauryl sulfate.

Clinical Studies

Olmesartan Medoxomil and Hydrochlorothiazide

In clinical trials 1230 patients were exposed to the combination of olmesartan medoxomil (2.5 mg to 40 mg) and hydrochlorothiazide (12.5 mg to 25 mg). These trials included one placebo-controlled factorial trial in mild-moderate hypertensive patients (n = 502) with combinations of olmesartan medoxomil (10 mg, 20 mg, 40 mg, or placebo) and hydrochlorothiazide (12.5 mg, 25 mg, or placebo). The antihypertensive effect of the combination on trough blood pressure was related to the dose of each component (see Table 2).

Once-daily dosing with 20 mg olmesartan medoxomil and 12.5 mg hydrochlorothiazide, 40 mg olmesartan medoxomil and 12.5 mg hydrochlorothiazide or 40 mg olmesartan medoxomil and 25 mg hydrochlorothiazide produced mean placebo-adjusted blood pressure reductions at trough (24 hours post-dosing) ranging from 17/8 to 24/14 mm Hg.

Table 2: Placebo-Adjusted Reductions in Sitting Systolic/Diastolic Blood Pressure (mmHg)

HCTZ

Olmesartan Medoxomil

0 mg

10 mg

20 mg

40 mg

0 mg

-

7/5

12/5

13/7

12.5 mg

5/1

17/8

17/8

16/10

25 mg

14/5

19/11

22/11

24/14

The antihypertensive effect had onset within 1 week and was near maximal at 4 weeks. The antihypertensive effect was independent of gender, but there were too few subjects to identify response differences based on race or age greater than or less than 65 years. No appreciable changes in trough heart rate were observed with combination therapy.

There are no trials of Olmesartan Medoxomil and Hydrochlorothiazide tablets demonstrating reductions in cardiovascular risk in patients with hypertension, but at least one drug pharmacologically similar to olmesartan medoxomil has demonstrated such benefits, and hydrochlorothiazide demonstrated reduction of cardiovascular risk in patients with hypertension.

Olmesartan Medoxomil

The antihypertensive effects of olmesartan medoxomil have been demonstrated in seven placebo-controlled studies at doses ranging from 2.5 mg to 80 mg for 6 to 12 weeks, each showing statistically significant reductions in peak and trough blood pressure. A total of 2693 patients (2145 olmesartan medoxomil; 548 placebo) with essential hypertension were studied. Olmesartan medoxomil once daily (QD) lowered diastolic and systolic blood pressure. The response was dose-related. An olmesartan medoxomil dose of 20 mg daily produced a trough sitting BP reduction over placebo of about 10/6 mm Hg and a dose of 40 mg daily produced a trough sitting BP reduction over placebo of about 12/7 mm Hg. Olmesartan medoxomil doses greater than 40 mg had little additional effect. The onset of the antihypertensive effect occurred within 1 week and was largely manifest after 2 weeks.

The blood pressure lowering effect was maintained throughout the 24-hour period with olmesartan medoxomil once daily, with trough-to-peak ratios for systolic and diastolic response between 60% and 80%.

The blood pressure lowering effect of olmesartan medoxomil, with and without hydrochlorothiazide, was maintained in patients treated for up to 1 year. There was no evidence of tachyphylaxis during long-term treatment with olmesartan medoxomil or rebound effect following abrupt withdrawal of olmesartan medoxomil after 1 year of treatment.

The antihypertensive effect of olmesartan medoxomil was similar in men and women and in patients older and younger than 65 years. The effect was smaller in black patients (usually a low-renin population), as has been seen with other ACE inhibitors, angiotensin receptor blockers, and beta-blockers. Olmesartan medoxomil had an additional blood pressure lowering effect when added to hydrochlorothiazide.

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