Tribenzor (Page 5 of 9)

8. 6 Hepatic Impairment

There are no studies of Tribenzor in patients with hepatic insufficiency, but both amlodipine and olmesartan medoxomil show moderate increases in exposure in patients with severe hepatic impairment. The recommended initial dose of amlodipine in patients with severe hepatic impairment is 2.5 mg, a dose not available with Tribenzor [see Warnings and Precautions ( 5.5)] .

Amlodipine. Amlodipine is extensively metabolized by the liver and the plasma elimination half-life (t ½ ) is 56 hours in patients with severely impaired hepatic function.

Olmesartan medoxomil. Increases in AUC 0- and peak plasma concentration (C max ) for olmesartan were observed with moderate hepatic impairment compared to those in matched controls with an increase in AUC of about 60%.

Hydrochlorothiazide. In patients with impaired hepatic function or progressive liver disease, minor alterations of fluid and electrolyte balance may precipitate hepatic coma.

8. 7 Renal Impairment

There are no studies of Tribenzor in patients with renal impairment. Avoid use in patients with severe renal impairment (creatinine clearance <30 mL/min).

Olmesartan medoxomil. Patients with renal insufficiency have elevated serum concentrations of olmesartan compared with patients with normal renal function. After repeated dosing, AUC was approximately tripled in patients with severe renal impairment (creatinine clearance <20 mL/min). No initial dosage adjustment is recommended for patients with moderate to marked renal impairment (creatinine clearance <40 mL/min). The pharmacokinetics of olmesartan in patients undergoing hemodialysis has not been studied.

Amlodipine. The pharmacokinetics of amlodipine are not significantly influenced by renal impairment.

Hydrochlorothiazide. Thiazide should be used with caution in patients with severe renal disease. In patients with renal disease, thiazides may precipitate azotemia. Cumulative effects of the drug may develop in patients with impaired renal function.

8.8 Black Patients

Of the total number of patients who received Tribenzor in a randomized trial, 29% (184/627) were black. Tribenzor was effective in lowering both systolic and diastolic blood pressure in black patients (usually a low-renin population) to the same extent as in non-black patients.

10 OVERDOSAGE

There is no information on overdosage with Tribenzor in humans.

Olmesartan medoxomil. Limited data are available related to overdosage in humans. The most likely manifestations of overdosage would be hypotension and tachycardia; bradycardia could be encountered if parasympathetic (vagal) stimulation occurs. If symptomatic hypotension should occur, supportive treatment should be initiated. The dialyzability of olmesartan is unknown.

Amlodipine. Single oral doses of amlodipine maleate equivalent to 40 mg amlodipine/kg and 100 mg amlodipine/kg in mice and rats, respectively, caused deaths. Single oral amlodipine maleate doses equivalent to 4 or more mg amlodipine/kg or higher in dogs (11 or more times the maximum recommended human dose on a mg/m 2 basis) caused a marked peripheral vasodilation and hypotension.

Overdosage might be expected to cause excessive peripheral vasodilation with marked hypotension and possibly a reflex tachycardia. In humans, experience with intentional overdosage of amlodipine is limited.

If massive overdose should occur, active cardiac and respiratory monitoring should be instituted. Frequent blood pressure measurements are essential. Should hypotension occur, cardiovascular support including elevation of the extremities and the judicious administration of fluids should be initiated. If hypotension remains unresponsive to these conservative measures, administration of vasopressors (such as phenylephrine) should be considered with attention to circulating volume and urine output. Intravenous calcium gluconate may help to reverse the effects of calcium entry blockade. As amlodipine is highly protein bound, hemodialysis is not likely to be of benefit.

Hydrochlorothiazide. The most common signs and symptoms of overdose observed in humans 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, more than 1000-fold the highest recommended human dose.

11 DESCRIPTION

Tribenzor provided as a tablet for oral administration, is a fixed combination of olmesartan medoxomil (ARB), amlodipine (CCB), and hydrochlorothiazide (thiazide diuretic).

Olmesartan medoxomil, a prodrug, is hydrolyzed to olmesartan during absorption from the gastrointestinal tract.

The olmesartan medoxomil component of Tribenzor is chemically described as 2,3-dihydroxy-2-butenyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[ p-(o- 1 H -tetrazol-5-ylphenyl)benzyl]imidazole-5-carboxylate, cyclic 2,3-carbonate. Its empirical formula is C 29 H 30 N 6 O 6 .

The amlodipine besylate component of Tribenzor is chemically described as 3-ethyl-5-methyl (±)-2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate, monobenzenesulphonate. Its empirical formula is C 20 H 25 ClN 2 O 5 •C 6 H 6 O 3 S.

The hydrochlorothiazide component of Tribenzor is chemically described as 6-chloro-3,4-dihydro-2 H -1,2,4-benzo-thiazidiazine-7-sulfonamide 1,1-dioxide. Its empirical formula is C 7 H 8 ClN 3 O 4 S 2 .

The structural formula for olmesartan medoxomil is:

The structural formula for olmesartan medoxomil is hydrolyzed to olmesartan during absorption from the gastrointestinal tract.
(click image for full-size original)

The structural formula for amlodipine besylate is:

The structural formula for amlodipine besylate is chemically described as 3 ethyl 5-methyl (±)-2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate, monobenzene
(click image for full-size original)

The structural formula for hydrochlorothiazide is:

The structural formula for hydrochlorothiazide is chemically described as 6 chloro 3,4-dihydro-2H-1,2,4-benzo-thiazidiazine-7-sulfonamide 1,1-dioxide.  Its empirical formula is C7H8CIN3O4S2.

Tribenzor contains olmesartan medoxomil, a white to light yellowish-white powder or crystalline powder, amlodipine besylate, a white to off-white crystalline powder, and hydrochlorothiazide, a white or practically white, crystalline powder. The molecular weights of olmesartan medoxomil, amlodipine besylate, and hydrochlorothiazide are 558.6, 567.1, and 297.7, respectively. Olmesartan medoxomil is practically insoluble in water and sparingly soluble in methanol. Amlodipine besylate is slightly soluble in water and sparingly soluble in ethanol. Hydrochlorothiazide is slightly soluble in water but freely soluble in sodium hydroxide solution.

Each tablet of Tribenzor also contains the following inactive ingredients: silicified microcrystalline cellulose, pregelatinized starch, croscarmellose sodium, and magnesium stearate. The color coating contains polyvinyl alcohol, macrogol/polyethylene glycol 3350, titanium dioxide, talc, iron oxide yellow (20 /5 /12.5 mg, 40 /5 /12.5 mg, 40 /5 /25 mg, 40 /10 /12.5 mg, and 40 /10 /25 mg tablets), iron oxide red (20 /5 /12.5 mg, 40 /10 /12.5 mg, and 40 /10 /25 mg tablets), and iron oxide black (20 /5 /12.5 mg tablets).

12 CLINICAL PHARMACOLOGY

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