13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Olmesartan medoxomil and hydrochlorothiazide
No carcinogenicity studies with olmesartan medoxomil and hydrochlorothiazide have been conducted.
Olmesartan medoxomil and hydrochlorothiazide in a ratio of 20:12.5 were negative in the Salmonella-Escherichia coli /mammalian microsome reverse mutation test up to the maximum recommended plate concentration for the standard assays. Olmesartan medoxomil and hydrochlorothiazide were tested individually and in combination ratios of 40:12.5, 20:12.5 and 10:12.5, for clastogenic activity in the in vitro Chinese hamster lung (CHL) chromosomal aberration assay. A positive response was seen for each component and combination ratio. However, no synergism in clastogenic activity was detected between olmesartan medoxomil and hydrochlorothiazide at any combination ratio. Olmesartan medoxomil and hydrochlorothiazide in a ratio of 20:12.5, administered orally, tested negative in the in vivo mouse bone marrow erythrocyte micronucleus assay at administered doses of up to 3144 mg/kg.
No studies of impairment of fertility with olmesartan medoxomil and hydrochlorothiazide have been conducted.
Olmesartan medoxomil
Olmesartan medoxomil 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/m2 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 1000 mg/kg/day (about 120 times the MRHD), revealed no evidence of a carcinogenic effect of olmesartan medoxomil.
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 both 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 2000 mg/kg (olmesartan not tested).
Fertility of rats was unaffected by administration of olmesartan medoxomil at dose levels as high as 1000 mg/kg/day (240 times the MRHD) in a study in which dosing was begun 2 (female) or 9 (male) weeks prior to mating.
Hydrochlorothiazide
Two-year feeding studies in mice and rats conducted under the auspices of the National Toxicology Program (NTP) uncovered no evidence of a carcinogenic potential of hydrochlorothiazide in female mice (at doses of up to approximately 600 mg/kg/day) or in male and female rats (at doses of up to approximately 100 mg/kg/day). The NTP, however, found equivocal evidence for hepatocarcinogenicity in male mice.
Hydrochlorothiazide was not genotoxic in vitro in the Ames mutagenicity assay of Salmonella typhimurium strains TA 98, TA 100, TA 1535, TA 1537 and TA 1538, or in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations. It was also not genotoxic in vivo in assays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, or the Drosophila sex-linked recessive lethal trait gene. Positive test results were obtained in the in vitro CHO Sister Chromatid Exchange (clastogenicity) assay, the Mouse Lymphoma Cell (mutagenicity) assay and the Aspergillus nidulans non-disjunction assay.
Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of either sex in studies wherein these species were exposed, via their diet, to doses of up to 100 and 4 mg/kg, respectively, prior to mating and throughout gestation.
13.3 Developmental Toxicity
Olmesartan medoxomil and hydrochlorothiazide
No teratogenic effects were observed when 1.6:1 combinations of olmesartan medoxomil and hydrochlorothiazide were administered to pregnant mice at oral doses up to 1625 mg/kg/day (122 times the maximum recommended human dose [MRHD] on a mg/m2 basis) or pregnant rats at oral doses up to 1625 mg/kg/day (280 times the MRHD on a mg/m2 basis). In rats, however, fetal body weights at 1625 mg/kg/day (a toxic, sometimes lethal dose in the dams) were significantly lower than control. The no observed effect dose for developmental toxicity in rats, 162.5 mg/kg/day, is about 28 times, on a mg/m2 basis, the MRHD of olmesartan medoxomil and hydrochlorothiazide (40 mg olmesartan medoxomil /25 mg hydrochlorothiazide/day).
14 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)
| Hydrochlorothiazide | 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 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 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.
16 HOW SUPPLIED/STORAGE AND HANDLING
Olmesartan medoxomil and hydrochlorothiazide tablets 20 mg/12.5 mg are reddish-yellow, round shaped, biconvex film-coated tablets, debossed with ‘K’ on one side and ‘23’ on the other side.
Bottles of 30 NDC 65862-779-30
Bottles of 90 NDC 65862-779-90
Bottles of 1,000 NDC 65862-779-99
10 x 10 Unit-dose Tablets NDC 65862-779-78
Olmesartan medoxomil and hydrochlorothiazide tablets 40 mg/12.5 mg are reddish-yellow, oval shaped, biconvex film-coated tablets, debossed with ‘K’ on one side and ‘53’ on the other side.
Bottles of 30 NDC 65862-780-30
Bottles of 90 NDC 65862-780-90
Bottles of 1,000 NDC 65862-780-99
10 x 10 Unit-dose Tablets NDC 65862-780-78
Olmesartan medoxomil and hydrochlorothiazide tablets 40 mg/25 mg are pink, oval shaped, biconvex film-coated tablets, debossed with ‘K’ on one side and ‘54’ on the other side.
Bottles of 30 NDC 65862-781-30
Bottles of 90 NDC 65862-781-90
Bottles of 1,000 NDC 65862-781-99
10 x 10 Unit-dose Tablets NDC 65862-781-78
Storage
Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].
17 PATIENT COUNSELING INFORMATION
Pregnancy: Advise female patients of childbearing age about the consequences of exposure to olmesartan medoxomil and hydrochlorothiazide during pregnancy. Discuss treatment options with women planning to become pregnant. Tell patients to report pregnancies to their physicians as soon as possible [see Use in Specific Populations (8.1)].
Symptomatic hypotension and syncope: Advise patients that lightheadedness can occur, especially during the first days of therapy, and to report this symptom to a healthcare provider. Inform patients that dehydration from inadequate fluid intake, excessive perspiration, vomiting, or diarrhea may lead to an excessive fall in blood pressure. If syncope occurs advise patients, to contact their healthcare provider.
Potassium Supplements: Advise patients not to use potassium supplements or salt substitutes containing potassium without consulting their healthcare provider.
Acute myopia and secondary angle-closure glaucoma : Advise patients to discontinue olmesartan medoxomil and hydrochlorothiazide and seek immediate medical attention if they experience symptoms of acute myopia or secondary angle-closure glaucoma [see Warnings and Precautions (5.6)].
Non-melanoma Skin Cancer: Instruct patients taking hydrochlorothiazide to protect skin from the sun and undergo regular skin cancer screening.
Distributed by:
Aurobindo Pharma USA, Inc.
279 Princeton-Hightstown Road
East Windsor, NJ 08520
Manufactured by:
Aurobindo Pharma Limited
Hyderabad-500 038, India
Revised: 09/2020
PACKAGE LABEL-PRINCIPAL DISPLAY PANEL — 20 mg/12.5 mg (30 Tablets Bottle)
NDC 65862-779-30
Rx only
Olmesartan Medoxomil
and Hydrochlorothiazide
Tablets
20 mg/12.5 mg
AUROBINDO 30 Tablets
PACKAGE LABEL-PRINCIPAL DISPLAY PANEL — 20 mg/12.5 mg (30 Tablets Bottle)
PACKAGE LABEL-PRINCIPAL DISPLAY PANEL — 20 mg/12.5 mg Blister Carton (10 x 10 Unit-dose)
NDC 65862-779-78
Rx only
Olmesartan Medoxomil and
Hydrochlorothiazide Tablets
20 mg/12.5 mg
AUROBINDO 100 (10 x 10) Unit-dose Tablets
PACKAGE LABEL-PRINCIPAL DISPLAY PANEL — 40 mg/12.5 mg (30 Tablets Bottle)
NDC 65862-780-30
Rx only
Olmesartan Medoxomil
and Hydrochlorothiazide
Tablets
40 mg/12.5 mg
AUROBINDO 30 Tablets
PACKAGE LABEL-PRINCIPAL DISPLAY PANEL — 40 mg/12.5 mg Blister Carton (10 x 10 Unit-dose)
NDC 65862-780-78
Rx only
Olmesartan Medoxomil and
Hydrochlorothiazide Tablets
40 mg/12.5 mg
AUROBINDO 100 (10 x 10) Unit-dose Tablets
PACKAGE LABEL-PRINCIPAL DISPLAY PANEL — 40 mg/25 mg (30 Tablets Bottle)
NDC 65862-781-30
Rx only
Olmesartan Medoxomil
and Hydrochlorothiazide
Tablets
40 mg/25 mg
AUROBINDO 30 Tablets
PACKAGE LABEL-PRINCIPAL DISPLAY PANEL — 40 mg/25 mg Blister Carton (10 x 10 Unit-dose)
NDC 65862-781-78
Rx only
Olmesartan Medoxomil and
Hydrochlorothiazide Tablets
40 mg/25 mg
AUROBINDO 100 (10 x 10) Unit-dose Tablets
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Revised: 09/2020 Aurobindo Pharma Limited
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