Consumer medicine information

1 Name of Medicine

Olmesartan medoxomil, amlodipine (as besilate) and hydrochlorothiazide.

2 Qualitative and Quantitative Composition

APO-Olmesartan/Amlodipine/HCTZ 20/5/12.5 mg contains 20 mg olmesartan medoxomil, 5 mg amlodipine as besilate and 12.5 mg hydrochlorothiazide.
APO-Olmesartan/Amlodipine/HCTZ 40/5/12.5 mg contains 40 mg of olmesartan medoxomil, 5 mg amlodipine as besilate and 12.5 mg hydrochlorothiazide.
APO-Olmesartan/Amlodipine/HCTZ 40/5/25 mg contains 40 mg of olmesartan medoxomil, 5 mg amlodipine as besilate and 25 mg hydrochlorothiazide.
APO-Olmesartan/Amlodipine/HCTZ 40/10/12.5 mg contains 40 mg of olmesartan medoxomil, 10 mg amlodipine as besilate and 12.5 mg hydrochlorothiazide.
APO-Olmesartan/Amlodipine/HCTZ 40/10/25 mg contains 40 mg of olmesartan medoxomil, 10 mg amlodipine as besilate and 25 mg hydrochlorothiazide.
Excipients with known effect. Contains lactose. For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Film-coated tablet.
APO-Olmesartan/Amlodipine/HCTZ 20/5/12.5 mg is an off white to peach, round, bevel-edged, film-coated tablets debossed with "OC1" on one side and plain on other side.
APO-Olmesartan/Amlodipine/HCTZ 40/5/12.5 mg is a light yellow, round, bevel-edged, film-coated tablets debossed with "OC2" on one side and plain on other side.
APO-Olmesartan/Amlodipine/HCTZ 40/5/25 mg is a light yellow, oval, bevel-edged, film-coated tablets debossed with "OC3" on one side and plain on other side.
APO-Olmesartan/Amlodipine/HCTZ 40/10/12.5 mg is a brick red, round, bevel-edged, film-coated tablets debossed with "OC4" on one side and plain on other side.
APO-Olmesartan/Amlodipine/HCTZ 40/10/25 mg is a brick red, oval, bevel-edged, film-coated tablets debossed with "OC5" on one side and plain on other side.

4 Clinical Particulars

4.9 Overdose

For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).
Symptoms. There is no experience of overdose with APO-Olmesartan/Amlodipine/HCTZ. The most likely effects of olmesartan medoxomil overdosage are hypotension and tachycardia; bradycardia could be encountered if parasympathetic (vagal) stimulation occurred. Amlodipine overdosage can be expected to lead to excessive peripheral vasodilatation with marked hypotension and possibly a reflex tachycardia. Marked and potentially prolonged systemic hypotension up to and including shock with fatal outcome has been reported. Non-cardiogenic pulmonary oedema has rarely been reported as a consequence of amlodipine overdose that may manifest with a delayed onset (24-48 hours post-ingestion) and require ventilatory support. Early resuscitative measures (including fluid overload) to maintain perfusion and cardiac output may be precipitating factors (see following section).
Overdosage with hydrochlorothiazide is associated with electrolyte depletion (hypokalaemia, hypochloraemia) and dehydration resulting from excessive diuresis. The most common signs and symptoms of overdosage are nausea and somnolence. Hypokalaemia may result in muscle spasm and/or accentuate cardiac arrhythmias associated with the concomitant use of digitalis glycosides or certain anti-arrhythmic drugs.
Treatment. In healthy subjects, the administration of activated charcoal immediately or up to 2 hours after ingestion of amlodipine has been shown to reduce substantially the absorption of amlodipine.
Clinically significant hypotension due to an overdose of APO-Olmesartan/Amlodipine/HCTZ requires active support of the cardiovascular system, including close monitoring of heart and lung function, elevation of the extremities, and attention to circulating fluid volume and urine output. A vasoconstrictor may be helpful in restoring vascular tone and blood pressure, provided that there is no contraindication to its use. Intravenous calcium gluconate may be beneficial in reversing the effects of calcium channel blockade.
Since amlodipine is highly protein-bound, dialysis is not likely to be of benefit.
No information is available regarding the dialysability of olmesartan or hydrochlorothiazide.
For further advice on the management of an overdose contact the Poisons Information Centre.

5 Pharmacological Properties

5.3 Preclinical Safety Data

Genotoxicity. No genotoxicity studies have been conducted with the olmesartan medoxomil/amlodipine/hydrochlorothiazide combination.
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 tested positive for thymidine kinase mutations in the in vitro mouse lymphoma assay. Olmesartan medoxomil tested negative in vivo for mutations in intestinal and kidney cells from the transgenic mouse strain MutaMouse and for clastogenicity in mouse bone marrow (micronucleus test) at oral doses of up to 2000 mg/kg (olmesartan not tested). On balance, the weight-of-evidence indicates that olmesartan medoxomil does not pose a genotoxic risk at clinically relevant doses.
Amlodipine. Amlodipine did not induce gene mutation in bacteria and mouse lymphoma cells; nor did it induce chromosome aberrations in human lymphocytes or Chinese hamster V79 fibroblast (in vitro) and in mouse bone marrow cells (in vivo).
Hydrochlorothiazide. Hydrochlorothiazide was negative in several different assays of gene mutation and chromosomal aberration. However, positive test results were obtained in the in vitro CHO sister chromatid exchange (clastogenicity) assay and the mouse lymphoma (mutagenicity) assay at hydrochlorothiazide concentrations of 43-1,200 microgram/mL.
Carcinogenicity. There are no carcinogenicity studies with the olmesartan medoxomil/amlodipine/hydrochlorothiazide combination.
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 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.
Amlodipine. The carcinogenic potential of amlodipine has not been fully elucidated. Amlodipine did not induce any tumours when tested in rats at oral doses up to 2.5 mg/kg. This dose gave rise to plasma levels that are similar to those achieved clinically.
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 mg/m² basis, similar to the maximum recommended human dose [MRHD] of 10 mg amlodipine/day. For the rat, the highest dose was, on a mg/m² basis, about two and a half times the MRHD (calculations based on a 60 kg patient).
Hydrochlorothiazide. Two-year feeding studies in mice and rats 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). There was equivocal evidence for hepatocarcinogenicity in male mice treated with hydrochlorothiazide alone at approximately 600 mg/kg/day.

6 Pharmaceutical Particulars

6.7 Physicochemical Properties

Olmesartan medoxomil is chemically described as (5-Methyl-2-oxo-1,3-dioxol-4-yl) methyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[ [2'-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] -1H-imidazole-5-carboxylate. The empirical formula is C₂₉H₃₀N₆O₆ and its molecular weight is 558.6.
Olmesartan medoxomil is a white or almost white crystalline powder. It is practically insoluble in water and slightly soluble in ethanol (96 per cent), practically insoluble in heptane.
Amlodipine besilate is a racemic mixture and is chemically described as 3-Ethyl 5-methyl (4RS)-2-[(2-aminoethoxy) methyl]-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate benzenesulfonate. The empirical formula is C₂₀H₂₅ClN₂O₅.C₆H₆O₃S and its molecular weight is 567.1.
Amlodipine besilate is a white or almost white powder, slightly soluble in water and freely soluble in methanol, sparingly soluble in anhydrous ethanol, slightly soluble in 2-propanol.
Hydrochlorothiazide is described chemically as 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. The empirical formula is C₇H₈ClN₃O₄S₂ and its molecular weight is 297.7.
Hydrochlorothiazide is a white, or almost white, crystalline powder. Hydrochlorothiazide is very slightly soluble in water, soluble in acetone, sparingly soluble in alcohol. It dissolves in dilute solutions of alkali hydroxides.
Chemical structure. Olmesartan medoxomil has the following structural formula:
https://stagingapi.mims.com/au/public/v2/images/fullchemgif/CSOLMMED.gif Amlodipine besilate has the following structural formula:
https://stagingapi.mims.com/au/public/v2/images/fullchemgif/CSAMLBSI.gif Hydrochlorothiazide has the following structural formula:
https://stagingapi.mims.com/au/public/v2/images/fullchemgif/CSHYDROC.gif CAS number. Olmesartan medoxomil. Its CAS number is 144689-63-4.
Amlodipine besilate. The CAS number is 111470-99-6.
Hydrochlorothiazide. Its CAS no. is 58-93-5.

7 Medicine Schedule (Poisons Standard)

Prescription only medicine (Schedule 4).

Summary Table of Changes

https://stagingapi.mims.com/au/public/v2/images/fulltablegif/APOAHCST.gif