Amlodipine and Olmesartan Medoxomil (Page 6 of 7)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Amlodipine. Rats and mice treated with amlodipine maleate in the diet for up to two years, at concentrations calculated to provide daily dosage levels of amlodipine 0.5, 1.25, and 2.5 mg/kg/day showed no evidence of a carcinogenic effect of the drug. For the mouse, the highest dose was, on a mg/m 2 basis, similar to the maximum recommended human dose (MRHD) of amlodipine 10 mg/day. For the rat, the highest dose was, on a mg/m 2 basis, about two and a half times the MRHD. (Calculations based on a 60 kg patient.)

Mutagenicity studies conducted with amlodipine maleate revealed no drug related effects at either the gene or chromosome level.

There was no effect on the fertility of rats treated orally with amlodipine maleate (males for 64 days and females for 14 days prior to mating) at doses of amlodipine up to 10 mg/kg/day (about 10 times the MRHD of 10 mg/day on a mg/m 2 basis).

Olmesartan medoxomil. Olmesartan was not carcinogenic when administered by dietary administration to rats for up to 2 years. The highest dose tested (2000 mg/kg/day) was, on a mg/m 2 basis, about 480 times the maximum recommended human dose (MRHD) of 40 mg/day. Two carcinogenicity studies conducted in mice, a 6-month gavage study in the p53 knockout mouse and a 6-month dietary administration study in the Hras2 transgenic mouse, at doses of up to 1,000 mg/kg/day (about 120 times the MRHD), revealed no evidence of a carcinogenic effect of olmesartan. Both olmesartan medoxomil and olmesartan tested negative in the in vitro Syrian hamster embryo cell transformation assay and showed no evidence of genetic toxicity in the Ames (bacterial mutagenicity) test. However, both were shown to induce chromosomal aberrations in cultured cells in vitro (Chinese hamster lung) and tested positive for thymidine kinase mutations in the in vitro mouse lymphoma assay. Olmesartan medoxomil tested negative in vivo for mutations in the MutaMouse intestine and kidney and for clastogenicity in mouse bone marrow (micronucleus test) at oral doses of up to 2,000 mg/kg (olmesartan not tested).

Fertility of rats was unaffected by administration of olmesartan at dose levels as high as 1,000 mg/kg/day (240 times the MRHD) in a study in which dosing was begun 2 (female) or 9 (male) weeks prior to mating.

14 CLINICAL STUDIES

14.1 Amlodipine and Olmesartan Medoxomil Tablets

An 8-week multicenter, randomized, double-blind, placebo controlled, parallel group factorial study in patients with mild to severe hypertension was conducted to determine if treatment with amlodipine and olmesartan medoxomil tablets was associated with clinically significant reduction in blood pressure compared to the respective monotherapies. The study randomized 1940 patients equally to one of the following 12 treatment arms: placebo, monotherapy treatment with amlodipine 5 mg or 10 mg, monotherapy treatment with olmesartan medoxomil 10 mg, 20 mg, or 40 mg, or combination therapy with amlodipine/olmesartan medoxomil at doses of 5/10 mg, 5/20 mg, 5/40 mg, 10/10 mg, 10/20 mg, and 10/40 mg. Patients discontinued their prior antihypertensive treatment. The mean baseline blood pressure of the study population was 164/102 mmHg. Of the total cohort, 970 patients were treated with the combination as initial therapy.

Treatment with amlodipine and olmesartan medoxomil tablets resulted in statistically significant greater reductions in diastolic and systolic blood pressure compared to the respective monotherapy components. Maximum antihypertensive effects were attained within 2 weeks after a change in dose.

The following table presents the results for mean reduction in seated systolic and diastolic blood pressure following 8 weeks of treatment with amlodipine and olmesartan medoxomil tablets. Placebo-adjusted reductions from baseline in blood pressure were progressively greater with increases in dose of both amlodipine and olmesartan medoxomil components of amlodipine and olmesartan medoxomil tablets.

Reduction in Seated Systolic/Diastolic Blood Pressure (mmHg): Combination Therapy vs. Monotherapy Components (Double-Blind Treatment Period)

Olmesartan medoxomil
(mmHg) Placebo 10 mg 20 mg 40 mg
Amlodipine Placebo Mean Change Placebo-Adjusted Mean Change -5/-3 — -12/-8 -8/-5 -14/-9 -10/-6 -16/-10 -13/-7
Amlodipine 5 mg Mean Change Placebo-Adjusted Mean Change -15/-9 -12/-7 -24/-14 -20/-11 -24/-14 -20/-11 -25/-16 -22/-13
Amlodipine 10 mg Mean Change Placebo-Adjusted Mean Change -20/-13 -16/-10 -25/-16 -22/-13 -29/-17 -25/-14 -30/-19 -26/-16

The antihypertensive effect of amlodipine and olmesartan medoxomil tablets was similar in patients with and without prior antihypertensive medication use, in patients with and without diabetes, in patients ≥65 years of age and <65 years of age, and in women and men. Limited data exist in patients ≥75 years of age.

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. This effect in black patients has been seen with ACE inhibitors, angiotensin receptor blockers, and beta-blockers.

The blood pressure lowering effect was maintained throughout the 24-hour period with amlodipine and olmesartan medoxomil tablets once daily, with trough-to-peak ratios for systolic and diastolic response between 71% and 82%.

Upon completing the 8-week, double-blind, placebo-controlled study, 1,684 patients entered a 44-week open-label extension and received combination therapy with amlodipine 5 mg plus olmesartan medoxomil 40 mg. During the open-label extension, patients whose blood pressure was not adequately controlled (i.e., did not achieve a blood pressure goal of <140/90 mmHg, or <130/80 mmHg for those patients with diabetes) on amlodipine/olmesartan medoxomil 5/40 mg were titrated to amlodipine/olmesartan medoxomil 10/40 mg. Patients whose blood pressure was still not adequately controlled were offered additional hydrochlorothiazide 12.5 mg and subsequently 25 mg as required to achieve adequate blood pressure goal.

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

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