Olmesartan Medoxomil, Amlodipine and Hydrochlorothiazide

Name: Olmesartan Medoxomil, Amlodipine and Hydrochlorothiazide

Olmesartan Medoxomil, Amlodipine and Hydrochlorothiazide Dosage and Administration

Dose once daily. Dosage may be increased in 2 week intervals, as needed. The maximum recommended dose of olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets is 40/10/25 mg.

Dose selection should be individualized based on previous therapy.

Contraindications

Because of the hydrochlorothiazide component, olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets are contraindicated in patients with anuria, hypersensitivity to any component or hypersensitivity to other sulfonamide-derived drugs.

Do not coadminister aliskiren with olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets in patients with diabetes [see Drug Interactions (7.2)].

Warnings and Precautions

Fetal Toxicity

Pregnancy Category D

Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets as soon as possible [see Use in Specific Populations (8.1)].

Hypotension in Volume- or Salt-Depleted Patients

Olmesartan medoxomil. In patients with an activated renin-angiotensin system, such as volume- and/or salt-depleted patients (e.g., those being treated with high doses of diuretics) symptomatic hypotension may be anticipated after initiation of treatment with olmesartan medoxomil. Initiate treatment with amlodipine besylate and olmesartan medoxomil under close medical supervision. If hypotension does occur, place the patient in the supine position and, if necessary, give an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized.

Amlodipine. Symptomatic hypotension is possible, particularly in patients with severe aortic stenosis. Because of the gradual onset of action, acute hypotension is unlikely.

Increased Angina and/or Myocardial Infarction

Amlodipine. Patients, particularly those with severe obstructive coronary artery disease, may develop increased frequency, duration, or severity of angina or acute myocardial infarction upon starting calcium channel blocker therapy or at the time of dosage increase. The mechanism of this effect has not been elucidated.

Impaired Renal Function

Olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets.

Impaired renal function was reported in 2.1% of subjects receiving olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets compared to 0.2% to 1.3% of subjects receiving dual combination therapy of olmesartan medoxomil and amlodipine, olmesartan medoxomil and hydrochlorothiazide or amlodipine and hydrochlorothiazide.

If progressive renal impairment becomes evident consider withholding or discontinuing olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets.

Olmesartan medoxomil. Changes in renal function occur in some individuals treated with olmesartan medoxomil as a consequence of inhibiting the renin-angiotensin-aldosterone system. In patients whose renal function may depend upon the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe congestive heart failure), treatment with ACE inhibitors and angiotensin receptor antagonists has been associated with oliguria or progressive azotemia and (rarely) with acute renal failure and/or death. Similar effects may occur in patients treated with olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets due to the olmesartan medoxomil component [see Drug Interactions (7.2) and Clinical Pharmacology (12.3)].

In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen (BUN) have been reported. There has been no long-term use of olmesartan medoxomil in patients with unilateral or bilateral renal artery stenosis, but similar effects would be expected with olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets because of the olmesartan medoxomil component.

Hydrochlorothiazide. Thiazides may precipitate azotemia in patients with renal disease. Cumulative effects of the drug may develop in patients with impaired renal function.

Patients With Hepatic Impairment

Amlodipine. Since amlodipine is extensively metabolized by the liver and the plasma elimination half-life (t1/2) is 56 hours in patients with severely impaired hepatic function, titrate slowly when administering to patients with severe hepatic impairment.

Electrolyte and Metabolic Imbalances

Olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets contain hydrochlorothiazide which can cause hypokalemia, hyponatremia and hypomagnesmia. Hypomagnesmia can result in hypokalemia which may be difficult to treat despite potassium repletion. Olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets also contain olmesartan, a drug that affects the RAS. Drugs that inhibit the RAS can also cause hyperkalemia.

Hydrochlorothiazide may alter glucose tolerance and raise serum levels of cholesterol and triglycerides.

Hyperuricemia may occur or frank gout may be precipitated in patients receiving thiazide therapy.

Hydrochlorothiazide decreases urinary calcium excretion and may cause elevations of serum calcium. Monitor calcium levels.

Postsympathectomy Patients

The antihypertensive effects of the drug may be enhanced in the post-sympathectomy patient.

Systemic Lupus Erythematosus

Hydrochlorothiazide. Thiazide diuretics have been reported to cause exacerbation or activation of systemic lupus erythematosus.

Acute Myopia and Secondary Angle-Closure Glaucoma

Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in acute transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

Sprue-like Enteropathy

Olmesartan medoxomil. Severe, chronic diarrhea with substantial weight loss has been reported in patients taking olmesartan months to years after drug initiation. Intestinal biopsies of patients often demonstrated villous atrophy. If a patient develops these symptoms during treatment with olmesartan, exclude other etiologies. Consider discontinuation of olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets in cases where no other etiology is identified.

Nonclinical Toxicology

The rationale for no or limited new toxicity from the triple combination of olmesartan medoxomil, amlodipine, and hydrochlorothiazide has already been established on the basis of the safety profile of the individual compounds or the dual combinations. To clarify the toxicological profile for olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets, a 3 month repeated dose toxicity study was conducted in rats, and the results demonstrated that the combined administration of olmesartan medoxomil, amlodipine, and hydrochlorothiazide neither augment any existing toxicities of the individual agents nor induce any new toxicities and there were no toxicologically synergistic effects observed in the study.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity, mutagenicity or fertility studies have been conducted with the combination of Olmesartan Medoxomil, Amlodipine and Hydrochlorothiazide. However, these studies have been conducted for Olmesartan Medoxomil, Amlodipine and Hydrochlorothiazide alone.

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/m2 basis, about 480 times the 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 (on a mg/m2 basis, about 120 times the MRHD of 40 mg/day), 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 2000 mg/kg (olmesartan not tested).

Fertility of rats was unaffected by administration of olmesartan at dose levels as high as 1000 mg/kg/day (240 times the MRHD of 40 mg/day on a mg/m2 basis) in a study in which dosing was begun 2 (female) or 9 (male) weeks prior to mating. (Calculations based on a 60 kg patient.)

Amlodipine.Rats and mice treated with amlodipine maleate in the diet for up to 2 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/m2 basis, similar to the MRHD of amlodipine 10 mg/day. For the rat, the highest dose was, on a mg/m2 basis, about two 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/m2 basis).

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). These doses in mice and rats are about 117 and 39 times, respectively, the MRHD of 25 mg/day on a mg/m2 basis. (Calculations based on a 60 kg patient.) 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 in Drosophilla 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 nondisjunction 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. These doses in mice and rats are about 19 and 1.5 times, respectively, the MRHD of 25 mg/day on a mg/m2 basis. (Calculations based on a 60 kg patient.)

Developmental Toxicity

No reproductive studies have been conducted with the combination of Olmesartan Medoxomil, Amlodipine and Hydrochlorothiazide. However, these studies have been conducted for Olmesartan Medoxomil, Amlodipine and Hydrochlorothiazide alone, and olmesartan medoxomil and hydrochlorothiazide together.

Olmesartan medoxomil. No teratogenic effects were observed when olmesartan medoxomil was administered to pregnant rats at oral doses up to 1000 mg/kg/day (240 times the maximum recommended human dose [MRHD] on a mg/m2 basis) or pregnant rabbits at oral doses up to 1 mg/kg/day (half the MRHD on a mg/m2 basis; higher doses could not be evaluated for effects on fetal development as they were lethal to the does). In rats, significant decreases in pup birth weight and weight gain were observed at doses ≥ 1.6 mg/kg/day, and delays in developmental milestones (delayed separation of ear auricular, eruption of lower incisors, appearance of abdominal hair, descent of testes, and separation of eyelids) and dose-dependent increases in the incidence of dilation of the renal pelvis were observed at doses ≥ 8 mg/kg/day. The no observed effect dose for developmental toxicity in rats is 0.3 mg/kg/day, about one-tenth the MRHD of 40 mg/day.

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 MRHD on a mg/m2 basis) or pregnant rats up to 1625 mg/kg/day (243 times the MRHD on a mg/m2 basis) or pregnant rabbits at oral doses up to 1 mg/kg/day (0.3 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 is 162.5 mg/kg/day, about 24 times, on a mg/m2 basis, the MRHD of 40 mg olmesartan medoxomil/25 mg hydrochlorothiazide/day. (Calculations based on a 60 kg patient.)

Amlodipine. No evidence of teratogenicity or other embryo/fetal toxicity was found when pregnant rats and rabbits were treated orally with amlodipine maleate at doses of up to 10 mg amlodipine/kg/day (respectively about 10 and 20 times the maximum recommended human dose of 10 mg amlodipine on a mg/m2 basis) during their respective periods of major organogenesis (calculations based on a patient weight of 60 kg). However, litter size was significantly decreased (by about 50%) and the number of intrauterine deaths was significantly increased (about 5 fold) in rats receiving amlodipine maleate at a dose equivalent to 10 mg amlodipine/kg/day for 14 days before mating and throughout mating and gestation. Amlodipine maleate has been shown to prolong both the gestational period and the duration of labor in rats at this dose. There are no adequate and well-controlled studies in pregnant women. Amlodipine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Hydrochlorothiazide. Thiazides cross the placental barrier and appear in cord blood. There is a risk of fetal or neonatal jaundice, thrombocytopenia and possibly other adverse reactions that have occurred in adults.

Clinical Studies

Olmesartan Medoxomil, Amlodipine, and Hydrochlorothiazide Tablets

The antihypertensive efficacy of olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets was studied in a double-blind, active-controlled study in hypertensive patients. A total of 2492 patients with hypertension (mean baseline blood pressure 169/101 mmHg) received olmesartan medoxomil/amlodipine/hydrochlorothiazide 40 mg/10 mg/25 mg (627 patients), olmesartan medoxomil/amlodipine 40 mg/10 mg (628 patients), olmesartan medoxomil/hydrochlorothiazide 40 mg/25 mg (637 patients), or amlodipine/hydrochlorothiazide 10 mg/25 mg (600 patients). Each subject was randomized to one of the three dual therapy combinations for two to four weeks. Patients were then randomized to continue on the dual therapy they were receiving or to receive triple therapy. A total of 53% of patients were male, 19% were 65 years or older, 67% were white, 30% were black, and 15% were diabetic.

After 8 weeks of treatment, the triple combination therapy produced greater reductions in both systolic and diastolic blood pressures (p < 0.0001) compared to each of the 3 dual combination therapies. The full blood pressure lowering effects were attained within 2 weeks after a change in dose.

The seated blood pressure reductions attributable to the addition of a single high-dose drug to each high-dose dual drug combination are shown in Table 2.

Table 2: Additional Blood Pressure Reductions on High-Dose Olmesartan Medoxomil, Amlodipine, and Hydrochlorothiazide Tablets Compared to High Doses of Dual Combination Drugs
* all highly statistically significant.

Start on

Adding

BP reduction*

Olmesartan medoxomil 40 mg/

amlodipine 10 mg

HCTZ 25 mg

8.4/4.5 mmHg

Olmesartan medoxomil 40 mg/

HCTZ 25 mg

Amlodipine 10 mg

7.6/5.4 mmHg

Amlodipine 10 mg/

HCTZ 25 mg

Olmesartan medoxomil 40 mg

8.1/5.4 mmHg

There were no apparent differences in terms of seated diastolic blood pressure (SeDBP) or seated systolic blood pressure (SeSBP) reductions in black and non-black patients treated with olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets [see Use in Specific Populations (8.8)].

There were no apparent differences in terms of SeDBP or SeSBP reductions in diabetic and non-diabetic patients treated with olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets.

A total of 440 patients participated in the ambulatory blood pressure monitoring portion of the study. Over the 24 hour period, there was a greater reduction in diastolic and systolic ambulatory blood pressure for olmesartan medoxomil/amlodipine/hydrochlorothiazide 40 mg/10 mg/25 mg compared to each of the dual combination therapies (see Figure 1 and Figure 2).

Figure 1: Mean Ambulatory Diastolic Blood Pressure at Endpoint by Treatment and Hour

Figure 2: Mean Ambulatory Systolic Blood Pressure at Endpoint by Treatment and Hour

The blood pressure lowering effects of lower dose strengths of olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets, 20 mg/5 mg/12.5 mg, 40 mg/5 mg/12.5 mg, 40 mg/10 mg/12.5 mg, and 40 mg/5 mg/25 mg have not been studied.

All of the dose strengths of the triple combination are expected to provide superior blood pressure lowering effects compared to their respective mono and dual combination components. The order of the blood pressure lowering effects among the different dose strengths of olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets is expected to be 20 mg/5 mg/12.5 mg < 40 mg/5 mg/12.5 mg < (40 mg/10 mg/12.5 mg ≈ 40 mg/5 mg/25 mg) < 40 mg/10 mg/25 mg.

There are no trials of olmesartan medoxomil, amlodipine, hydrochlorothiazide 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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