Amlodipine and Olmesartan Medoxomil (Page 4 of 7)

8.2 Lactation

Risk Summary

There is limited information regarding the presence of amlodipine and olmesartan medoxomil tablets in human milk, the effects on the breastfed infant, or the effects on milk production. Amlodipine is present in human milk. Olmesartan is present in rat milk [see Data]. Because of the potential for adverse effects on the nursing infant, advise a nursing woman that breastfeeding is not recommended during treatment with amlodipine and olmesartan medoxomil tablets.

Data

Presence of olmesartan in milk was observed after a single oral administration of 5 mg/kg [ 14 C] olmesartan medoxomil to lactating rats.

8.4 Pediatric Use

The safety and effectiveness of amlodipine and olmesartan medoxomil tablets in pediatric patients have not been established.

8.5 Geriatric Use

Of the total number of subjects in the double-blind clinical study of amlodipine and olmesartan medoxomil tablets, 20% (384/1,940) were 65 years of age or older and 3% (62/1,940) were 75 years or older. No overall differences in safety or effectiveness were observed between subjects 65 years of age or older and younger subjects.

Elderly patients have decreased clearance of amlodipine. Starting amlodipine or adding amlodipine at 2.5 mg in patients ≥75 years old is recommended. The lowest dose of amlodipine and olmesartan medoxomil tablets is 5/20 mg; therefore, initial therapy with amlodipine and olmesartan medoxomil tablets is not recommended in patients ≥75 years old.

Amlodipine. 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 disease or other drug therapy. Elderly patients have decreased clearance of amlodipine with a resulting increase of AUC of approximately 40% to 60%, and a lower initial dose may be required.

Olmesartan medoxomil. Of the total number of hypertensive patients receiving olmesartan medoxomil in clinical studies, more than 20% were 65 years of age and over, while more than 5% were 75 years of age and older. No overall differences in effectiveness or safety were observed between elderly patients and 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.

8.6 Hepatic Impairment

There are no studies of amlodipine and olmesartan medoxomil tablets in patients with hepatic insufficiency, but both amlodipine and olmesartan medoxomil show moderate increases in exposure in patients with hepatic impairment.

The recommended initial dose of amlodipine in patients with severe hepatic impairment is 2.5 mg, a dose not available with amlodipine and olmesartan medoxomil tablets.

Amlodipine. Amlodipine is extensively metabolized by the liver and the plasma elimination half-life (t½) is 56 hours in patients with severely impaired hepatic function [see Warnings and Precautions ( 5.5)] .

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

8.7 Renal Impairment

There are no studies of amlodipine and olmesartan medoxomil tablets in patients with renal impairment.

Amlodipine. The pharmacokinetics of amlodipine are not significantly influenced by renal impairment. Patients with renal failure may therefore receive the usual initial dose.

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).

8.8 Black Patients

Of the total number of subjects in the double-blind clinical study of amlodipine and olmesartan medoxomil tablets, 25% (481/1,940) were black patients. Amlodipine and olmesartan medoxomil tablets were effective in treating black patients (usually a low-renin population), and the magnitude of blood pressure reduction in black patients approached that observed for non-black patients.

10 OVERDOSAGE

There is no information on overdosage with amlodipine and olmesartan medoxomil tablets in humans.

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.

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.

11 DESCRIPTION

Amlodipine and olmesartan medoxomil tablets provided as a tablet for oral administration is a combination of the calcium channel blocker (CCB) amlodipine besylate, USP and the angiotensin II receptor blocker (ARB) olmesartan medoxomil, USP.

The amlodipine besylate, USP component of amlodipine and olmesartan medoxomil tablets 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.

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

The olmesartan medoxomil, USP component of amlodipine and olmesartan medoxomil tablets 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 structural formula for amlodipine besylate, USP is:

amlo structure
(click image for full-size original)

The structural formula for olmesartan medoxomil, USP is:

Olme Medo
(click image for full-size original)

Amlodipine and olmesartan medoxomil tablets contain amlodipine besylate, USP, a white to off-white crystalline powder, and olmesartan medoxomil, USP a white to light yellowish-white powder or crystalline powder. The molecular weights of amlodipine besylate, USP and olmesartan medoxomil, USP are 567.1 and 558.59, respectively. Amlodipine besylate, USP is slightly soluble in water and sparingly soluble in ethanol. Olmesartan medoxomil, USP is practically insoluble in water and sparingly soluble in methanol.

Each tablet of amlodipine and olmesartan medoxomil tablets also contains the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, lactose monohydrate, magnesium stearate, maize starch, pregelatinized maize starch, silicified microcrystalline cellulose, and talc.

The color coating material contains the following ingredients.

Strength Ingredients
10/20 mg and 10/40 mg Polyvinyl alcohol, titanium dioxide, macrogol/polyethylene glycol, talc, iron oxide yellow, iron oxide red
5/40mgPolyvinyl alcohol, titanium dioxide, macrogol/polyethylene glycol, talc, iron oxide yellow
5/20mgPolyvinyl alcohol, titanium dioxide, macrogol/polyethylene glycol, talc

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