Amlodipine and Olmesartan Medoxomil (Page 4 of 7)

8.3 Nursing Mothers

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

8.4 Pediatric Use

Neonates with a history of in utero exposure to amlodipine and olmesartan medoxomil 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/or substituting for disordered renal function.
The safety and effectiveness of amlodipine and olmesartan medoxomil tablets in pediatric patients have not been established.

Amlodipine. The effect of amlodipine on blood pressure in patients less than 6 years of age is not known.

Olmesartan medoxomil. Safety and effectiveness of olmesartan medoxomil 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% (384/1940) were 65 years of age or older and 3% (62/1940) 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 (t^½) 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 (C_max ) 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% (481/1940) 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/m² 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 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.
The amlodipine besylate, USP component of amlodipine and olmesartan medoxomil tablets is chemically described as 3-ethyl-5methyl (±)-2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5pyridinedicarboxylate,monobenzenesulphonate. Its empirical formula is C₂₀ H₂₅ ClN₂ O₅ •C₆ H₆ O₃ 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-1H -tetrazol-5-ylphenyl)benzyl]imidazole-5-carboxylate, cyclic 2,3-carbonate. Its empirical formula is C₂₉ H₃₀ N₆ O₆ . The structural formula for amlodipine besylate, USP is:

The structural formula for olmesartan medoxomil, USP is:

Amlodipine and olmesartan medoxomil tablets contains amlodipine besylate, USP a white or almost white powder, and olmesartan medoxomil, USP a white to off-white 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 2-propanol, water, freely soluble in methanol 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 also contains the following inactive ingredients: microcrystalline cellulose, pregelatinized starch, croscarmellose sodium, colloidal silicon dioxide and magnesium stearate. The color coatings contain polyvinyl alcohol, macrogol/ polyethylene glycol 3350, macrogol/ polyethylene glycol 8000, titanium dioxide, talc, iron oxide yellow (5/40 mg, 10/20 mg, 10/40 mg tablets), iron oxide red (10/20 mg and 10/40 mg tablets), and iron oxide black (10/40 mg tablets).