APPROVED PRODUCT INFORMATION

OLMETEC PLUS(r)

(olmesartan medoxomil/hydrochlorothiazide) OLMETEC PLUS 20/12.5 mg OLMETEC PLUS 20/25 mg OLMETEC PLUS 40/12.5 mg OLMETEC PLUS 40/25 mg

NAME OF THE MEDICINE

OLMETEC PLUS consists of olmesartan medoxomil and hydrochlorothiazide (HCTZ). Olmesartan medoxomil is a prodrug, hydrolyzed to olmesartan during absorption from the gastrointestinal tract. Olmesartan is a selective AT1 subtype angiotensin II receptor antagonist. HCTZ is a thiazide diuretic. Olmesartan medoxomil (CAS no. 144689-63-4) is described chemically 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 C29H30N6O6 and its structural formula is: HCTZ (CAS no. 58-93-5) 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 the structural formula is:

DESCRIPTION

Olmesartan medoxomil is a white to light yellowish-white powder or crystalline powder with a molecular weight of 558.59. It is practically insoluble in water and sparingly soluble in methanol. HCTZ is a white, or almost white, crystalline powder, with a molecular weight of 297.7. HCTZ is very slightly soluble in water, soluble in acetone, sparingly soluble in alcohol. It dissolves in dilute solutions of alkali hydroxides. OLMETEC PLUS is available for oral use as film-coated tablets containing 20/12.5 mg, 20/25 mg, 40/12.5 mg, or 40/25 mg olmesartan medoxomil/HCTZ. OLMETEC PLUS tablets also contain the following inactive ingredients: microcrystalline cellulose, lactose, hydroxypropylcellulose, magnesium stearate, and Opadry O2A22352 or Opadry O2A24576. These contain titanium dioxide, purified talc, hypromellose, and iron oxides.

PHARMACOLOGY

Pharmacodynamics

OLMETEC PLUS is a combination of an angiotensin II receptor antagonist, olmesartan medoxomil, and a thiazide diuretic, HCTZ. The combination of these ingredients has an additive antihypertensive effect, reducing blood pressure to a greater degree than either component alone. Once daily dosing with OLMETEC PLUS provides an effective and smooth reduction in blood pressure over the 24-hour dose interval. Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin converting enzyme (ACE, kininase II). Angiotensin II is the principal pressor agent of the renin- angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation and renal reabsorption of sodium. Olmesartan medoxomil is an orally active angiotensin II receptor (type AT1) antagonist. It has more than a 12,500-fold greater affinity for the AT1 receptor than for the AT2 receptor. It is expected to block all actions of angiotensin II mediated by the AT1 receptor, regardless of the source or route of synthesis of angiotensin II. The selective antagonism of the angiotensin II (AT1) receptors results in increases in plasma renin levels and angiotensin I and II concentrations, and some decrease in plasma aldosterone concentrations. Angiotensin II plays a significant role in the pathophysiology of hypertension via the type 1 (AT1) receptor. In hypertension, olmesartan medoxomil causes a dose-dependent, long-lasting reduction in arterial blood pressure. There has been no evidence of first-dose hypotension, of tachyphylaxis during long-term treatment, or of rebound hypertension after cessation of therapy. With continuous treatment, maximum reductions in blood pressure are achieved by 8 weeks after the initiation of therapy, although a substantial proportion of the blood pressure lowering effect is already observed after 2 weeks of treatment. When used together with HCTZ, the reduction in blood pressure is additive and co-administration is well tolerated. The effect of olmesartan on mortality and morbidity is not yet known. HCTZ is a thiazide diuretic. The mechanism of the antihypertensive effect of thiazide diuretics is not fully known. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of sodium and chloride in approximately equivalent amounts. The diuretic action of HCTZ reduces plasma volume, increases plasma renin activity and increases aldosterone secretion, with consequent increases in urinary potassium and bicarbonate loss, and decreases in serum potassium. The renin-aldosterone link is mediated by angiotensin II and therefore co-administration of an angiotensin II receptor antagonist tends to reverse the potassium loss associated with thiazide diuretics. With HCTZ, onset of diuresis occurs at about 2 hours and peak effect occurs at about 4 hours post-dose, whilst the action persists for approximately 6-12 hours. The combination of olmesartan medoxomil and HCTZ produces additive reductions in blood pressure, which generally increase with the dose of each component. In pooled placebo- controlled studies, administration of the 20/12.5 mg, 20/25 mg, 40/12.5 mg, and 40/25 mg combinations of olmesartan medoxomil/HCTZ resulted in mean placebo-subtracted systolic/diastolic blood pressure reductions at trough ranging from 12/7 to 16/9 mmHg. Age and gender had no clinically relevant effect on response to treatment with olmesartan medoxomil/HCTZ combination therapy. Administration of 12.5 mg and 25 mg HCTZ in patients insufficiently controlled by olmesartan medoxomil 20 mg monotherapy gave additional reductions in 24-hour systolic/diastolic blood pressures measured by ambulatory blood pressure monitoring of 7/5 mmHg and 12/7 mmHg, respectively, compared with olmesartan medoxomil monotherapy baseline. The additional mean systolic/diastolic blood pressure reductions at trough compared with baseline, measured conventionally, were 11/10 mmHg and 16/11 mmHg, respectively. The addition of 12.5 mg HCTZ in patients not achieving target blood pressure (130/85 mmHg) on olmesartan medoxomil 40 mg decreased systolic/diastolic blood pressure by an additional 13/6 mmHg, and titration of the HCTZ dose to 25 mg in non-achievers at the lower add-on dose resulted in a further blood pressure decrease of 9/5 mmHg. Conversely, addition of olmesartan medoxomil 10-20 mg in patients with moderate to severe hypertension insufficiently controlled by HCTZ 25 mg monotherapy provided mean systolic/diastolic blood pressure reductions at trough of 21/18 mmHg compared with HCTZ monotherapy baseline. The effectiveness of olmesartan medoxomil/HCTZ combination therapy was maintained over long-term (1-year) treatment. Withdrawal of olmesartan medoxomil therapy, with or without concomitant HCTZ therapy, did not result in rebound hypertension. The effects of fixed dose combination of olmesartan medoxomil/HCTZ on mortality and cardiovascular morbidity are currently unknown.

Pharmacokinetics Absorption and distribution Olmesartan medoxomil

Olmesartan medoxomil is a prodrug. It is rapidly converted to the pharmacologically active metabolite, olmesartan, by esterases in the gut mucosa and in portal blood during absorption from the gastrointestinal tract. No intact olmesartan medoxomil or intact side chain medoxomil moiety have been detected in plasma or excreta. The mean absolute bioavailability of olmesartan from a tablet formulation was 25.6%. The mean peak plasma concentration (Cmax) of olmesartan is reached within about 2 hours after oral dosing with olmesartan medoxomil, and olmesartan plasma concentrations increase approximately linearly with increasing single oral doses up to about 80 mg. Food had minimal effect on the bioavailability of olmesartan and therefore olmesartan medoxomil may be administered with or without food. The mean volume of distribution after intravenous dosing is in the range of 16-29 litres. Olmesartan is highly bound to plasma proteins (99.7%), but the potential for clinically significant protein binding displacement interactions between olmesartan and other highly bound co-administered drugs is low (as confirmed by the lack of a clinically significant interaction between olmesartan medoxomil and warfarin). The binding of olmesartan to blood cells is negligible. In rats, olmesartan crossed the blood-brain barrier poorly, if at all. Olmesartan crossed the placental barrier in rats and was distributed to the foetus. Olmesartan was distributed to milk at low levels in rats.

HCTZ

Following oral administration of olmesartan medoxomil and HCTZ in combination, the median time to peak concentrations of HCTZ was 1.5 to 2 hours after dosing. HCTZ is 68% protein bound in the plasma and its apparent volume of distribution is 0.83-1.14 L/kg.

Metabolism and elimination Olmesartan medoxomil

Following the rapid and complete conversion of olmesartan medoxomil to olmesartan during absorption, there is virtually no further metabolism of olmesartan. Total plasma clearance was typically 1.3 L/h (CV, 19%) and was relatively slow compared with hepatic blood flow (approximately 90 L/h). Approximately 30% to 50% of the systemically absorbed drug is excreted in the urine whilst the remainder is excreted in faeces (via the bile). The terminal elimination half-life of olmesartan varied between 10 and 15 hours after multiple oral dosing. Steady state was reached after the first few doses and no further accumulation was evident after 14 days of repeated dosing. Renal clearance was approximately 0.5- 0.7 L/h and was independent of dose.

HCTZ

HCTZ is not metabolised in man and is excreted almost entirely as unchanged drug in urine. About 60% of the oral dose is eliminated as unchanged drug within 48 hours. Renal clearance is about 250-300 mL/min. The terminal elimination half-life of HCTZ is 10- 15 hours.

Pharmacokinetics in special populations

Elderly

In hypertensive patients, the AUC at steady state was increased by approximately 33% in elderly patients (65-75 years old) and by approximately 31% (adjusted for gender and body mass index) in very elderly patients (75 years old) compared with the younger age group (See DOSAGE AND ADMINISTRATION).

Paediatric

The pharmacokinetics of olmesartan have not been investigated in patients <18 years of age.

Gender

Minor differences were observed in the pharmacokinetics of olmesartan in women compared with men. AUC and Cmax were 10-15% higher in women than in men.

Renal impairment

In patients with renal insufficiency, serum concentrations of olmesartan were elevated compared to subjects with normal renal function. After repeated dosing, the AUC was approximately tripled in patients with severe renal impairment (creatinine clearance <30 mL/min)) * * (See DOSAGE AND ADMINISTRATION and PRECAUTIONS, Renal insufficiency). The pharmacokinetics of olmesartan in patients undergoing haemodialysis has not been studied.

Hepatic impairment * *

Mean olmesartan AUC after single oral administration to patients with moderate hepatic impairment (Child-Pugh score 7 - 9) was increased by about 48% compared with healthy controls (total group), or by about 60% when compared with matched controls only. Following repeated dosing, a similar increase in olmesartan mean AUC was observed in patients with moderate hepatic impairment (Child-Pugh score 7 - 9) when compared with matched healthy controls. Olmesartan mean Cmax values were similar in hepatically-impaired and healthy subjects. Olmesartan medoxomil has not been evaluated in patients with severe hepatic impairment (Child-Pugh score 10 - 15) (See DOSAGE AND ADMINISTRATION and PRECAUTIONS).

CLINICAL TRIALS

Olmesartan medoxomil

The antihypertensive effects of OLMETEC have been demonstrated in seven placebo- controlled studies at doses ranging from 2.5 to 80 mg for 6 to 12 weeks. Approximately 2,800 patients with essential hypertension were studied. The blood pressure lowering effect of OLMETEC tended to increase with time and to increase with dose up to the 40 mg dose. OLMETEC 10 mg (n=521), 20 mg (n=513), and 40 mg (n=195) once daily produced statistically significant reductions in peak and trough blood pressure compared with placebo (n=543) at every time point from Week 2 to Week 12 (sSBP p<0.001 and sDBP p<0.001). The blood pressure lowering effect was maintained throughout the 24-hour period with OLMETEC once daily, with trough-to-peak ratios for systolic and diastolic response between 60 and 80%. The blood pressure lowering effect of OLMETEC, with and without HCTZ, was maintained in patients treated for up to 1-year. There was no evidence of tachyphylaxis during long-term treatment with OLMETEC or rebound effect following abrupt withdrawal of olmesartan medoxomil after 1-year of treatment. The antihypertensive effect of OLMETEC 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. OLMETEC had an additional blood pressure lowering effect when added to HCTZ.

Olmesartan medoxomil and HCTZ

In clinical trials, 1,230 patients were exposed to the combination of olmesartan medoxomil (2.5 mg to 40 mg) and HCTZ (12.5 mg to 25 mg). These trials included one placebo- controlled factorial trial (n=502) in mild-moderate hypertensives with combinations of olmesartan medoxomil (10 mg, 20 mg, 40 mg or placebo) and HCTZ (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 below).

Table 1. Placebo-adjusted changes in sitting systolic and diastolic blood pressure (mmHg)

Once daily dosing with 20 mg olmesartan medoxomil and 12.5 mg HCTZ, 40 mg olmesartan medoxomil and 12.5 mg HCTZ or 40 mg olmesartan medoxomil and 25 mg HCTZ produce mean placebo-adjusted blood pressure reductions at trough (24 hours post-dosing) ranging from 17/8 to 24/14 mmHg. The onset of the antihypertensive effect occurred 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 in the placebo-controlled trial.

Use in the elderly

The antihypertensive effects of OLMETEC PLUS were investigated in a randomised, double- blind, parallel group with losartan in elderly patients (65 years or older; olmesartan n=251 whom 69 were >75 years; losartan n=130 whom 48 were >75 years) with essential hypertension for 52 weeks. Patients were initiated on a starting dose of 20mg OLMETEC. At 4 week intervals, the treatment was titrated to achieve target BP. The results obtained for those on OLMETEC PLUS were similar to those in the losartan group.

CONTRAINDICATIONS

OLMETEC PLUS is contraindicated in: Patients who are hypersensitive to olmesartan medoxomil, sulfonamide derived drugs (e.g. thiazides), or any other component of this medication Pregnancy (see PRECAUTIONS, Use in pregnancy) Patients with severe renal impairment (creatinine clearance <30 mL/min) (see PRECAUTIONS, Renal impairment) Patients with severe hepatic impairment (Child-Pugh score 10 - 15), cholestasis or biliary obstruction (see PRECAUTIONS, Hepatic impairment) Patients who are breastfeeding Patients with refractory hypokalaemia, hypercalcaemia, hyponatraemia, and symptomatic hyperuricaemia (see PRECAUTIONS, Electrolyte imbalance)

PRECAUTIONS

Intravascular volume depletion

Symptomatic hypotension, especially after the first dose, may occur in patients who are volume and/or sodium depleted by vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting. Such conditions should be corrected before the administration of OLMETEC PLUS.

Other conditions with stimulation of the renin-angiotensin-aldosterone system

In patients whose vascular tone and renal function depend predominantly on the activity of the renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure or underlying renal disease, including renal artery stenosis), treatment with ACE inhibitors and angiotensin receptor antagonists has been associated with acute hypotension, azotaemia, oliguria or, rarely with acute renal failure and/or death * *. The possibility of similar effects cannot be excluded with olmesartan medoxomil.

Renovascular hypertension

There is an increased risk of severe hypotension and renal insufficiency when patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney are treated with medicinal products that affect the renin-angiotensin-aldosterone system.

Renal impairment and kidney transplantation

OLMETEC PLUS should not be used in patients with severe renal impairment (creatinine clearance <30 mL/min) (see DOSAGE AND ADMINISTRATION). No dosage adjustment is necessary in patients with mild (creatinine clearance 50 - 80 mL/min)to moderate (creatinine clearance 30 - <50 mL/min) renal impairment. * * In such patients OLMETEC PLUS should be administered with caution and periodic monitoring of serum potassium, creatinine and uric acid levels is recommended. Thiazide diuretic-associated azotaemia may occur in patients with impaired renal function. There is no experience of the administration of OLMETEC PLUS in patients with recent kidney transplantation. The pharmacokinetics of OLMETEC PLUS or coadministered olmesartan medoxomil and HCTZ have not been studied in patients with renal impairment.

Hepatic impairment * *

OLMETEC PLUS should be used with caution in patients with impaired hepatic function or progressive liver disease since minor alterations of fluid and electrolyte balance during thiazide therapy may precipitate hepatic coma. Use of olmesartan medoxomil in patients with severe hepatic impairment (Child-Pugh score 10 - 15), cholestasis and biliary obstruction is contraindicated (see CONTRAINDICATIONS). The pharmacokinetics of OLMETEC PLUS or coadministered olmesartan medoxomil and HCTZ have not been studied in patients with hepatic impairment.

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy

As with other vasodilators, special caution is indicated in patients suffering from aortic or mitral stenosis, or obstructive hypertrophic cardiomyopathy.

Primary aldosteronism

Patients with primary aldosteronism generally will not respond to anti-hypertensive drugs acting through inhibition of the renin-angiotensin system. Therefore, the use of OLMETEC PLUS is not recommended in such patients.

Metabolic and endocrine effects

Thiazide therapy may impair glucose tolerance. In diabetic patients dosage adjustments of insulin or oral hypoglycaemic agents may be required (see Interactions with other medicines). Latent diabetes mellitus may become manifest during thiazide therapy. Increases in cholesterol and triglyceride levels have been associated with thiazide diuretic therapy. Hyperuricaemia may occur or frank gout may be precipitated in some patients receiving thiazide therapy.

Electrolyte imbalance

As for any patient receiving diuretic therapy, periodic determination of serum electrolytes should be performed at appropriate intervals. Thiazides, including HCTZ, can cause fluid or electrolyte imbalance (including hypokalaemia, hyponatraemia and hypochloraemic alkalosis). Warning signs of fluid or electrolyte imbalance are dryness of the mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pain or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea or vomiting (see ADVERSE EFFECTS). Although hypokalaemia may develop with the use of thiazide diuretics, concurrent therapy with olmesartan medoxomil may reduce diuretic-induced hypokalaemia. The risk of hypokalaemia is greatest in patients with cirrhosis of the liver, in patients experiencing brisk diuresis, in patients who are receiving inadequate oral intake of electrolytes and in patients receiving concomitant therapy with corticosteroids or ACTH. Conversely, due to antagonism at the angiotensin-II receptors (AT1) through the olmesartan medoxomil component of OLMETEC PLUS hyperkalaemia may occur, especially in the presence of renal impairment and/or heart failure, and diabetes mellitus. Adequate monitoring of serum potassium in patients at risk is recommended. Potassium-sparing diuretics, potassium supplements or potassium-containing salt substitutes should be co-administered cautiously with OLMETEC PLUS (see Interactions with other medicines). There is no evidence that olmesartan medoxomil would reduce or prevent diuretic-induced hyponatraemia. Chloride deficit is generally mild and usually does not require treatment. Thiazides may decrease urinary calcium excretion and cause an intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcaemia may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function. Thiazides have been shown to increase the urinary excretion of magnesium, which may result in hypomagnesaemia.

Lithium

The co-administration of OLMETEC PLUS and lithium is not recommended (see Interactions with other medicines).

Concomitant use of ACE inhibitors or angiotensin receptor antagonists and anti- inflammatory drugs and thiazide diuretics

The use of ACE-inhibitors or angiotensin receptor antagonists, and an anti-inflammatory drug (NSAID or COX-2 inhibitor), and a thiazide diuretic at the same time increases the risk of renal impairment. This includes use with fixed-combination products containing more than one class of drug. Concomitant use of all three classes of these medications should be accompanied by increased monitoring of serum creatinine, particularly at the institution of the treatment. The concomitant use of drugs from these three classes should be used with caution particularly in elderly patients or those with pre-existing renal impairment.

Other

As with any anti-hypertensive agent, excessive blood pressure decrease in patients with ischaemic heart disease or ischaemic cerebrovascular disease could result in a myocardial infarction or stroke. Hypersensitivity reactions to HCTZ may occur in patients with or without a history of allergy or bronchial asthma, but are more likely in patients with such a history. Exacerbation or activation of systemic lupus erythematosus has been reported with the use of thiazide diuretics.

Carcinogenicity

The carcinogenic potential of olmesartan and HCTZ in combination has not been investigated. Olmesartan medoxomil was not carcinogenic when administered by dietary administration to rats for up to 2 years. The highest dose tested (2,000 mg/kg/day) corresponded to a relative systemic exposure to olmesartan that was about 30 times that anticipated at the maximum recommended human dose (MRHD) of 40 mg/day (based on AUC). 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 11 times anticipated clinical exposure to olmesartan at the MRHD, based on AUC in Hras2), revealed no evidence of a carcinogenic effect of olmesartan medoxomil. Two-year feeding studies in mice and rats showed no evidence of carcinogenic potential for HCTZ in female mice at doses up to approximately 600 mg/kg/day, or in male and female rats at doses up to approximately 100 mg/kg/day. There was equivocal evidence for hepatocarcinogenicity in male mice treated with HCTZ at approximately 600 mg/kg/day.

Genotoxicity

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 the intestine and kidney of a mutagenic susceptible mouse (MutaMouse) and for clastogenicity in mouse bone marrow (micronucleus test) at oral doses of up to 2,000 mg/kg/day. Olmesartan not tested in this mouse model. On balance,

the weight-of-evidence indicates that olmesartan medoxomil does not pose a genotoxic risk at clinically relevant doses.

HCTZ

HCTZ 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 HCTZ concentrations of 43-1,200 g/mL.

Olmesartan medoxomil and HCTZ

Olmesartan medoxomil/HCTZ in a ratio of 20:12.5 was negative in the bacterial reverse mutation test up to the maximum recommended plate concentration for the standard assays. As expected, positive clastogenicity responses were observed with either drug or the combination (40:12.5, 20:12.5, 10:12.5) in Chinese hamster lung cells but no synergistic clastogenicity was observed. However, the combination (20:12.5) was negative in the in vivo mouse micronucleus test at oral doses (1,935/1,209 mg/kg) that were likely to achieve high relative systemic exposure (>33-700-fold based on AUC) to both components.

Effects on fertility

The effects of olmesartan and HCTZ in combination on fertility have not been investigated. Fertility of rats was unaffected by administration of olmesartan medoxomil at dose levels as high as 1,000 mg/kg/day (relative plasma exposure of 7-8 times that anticipated at the MRHD based on AUC) in a study in which dosing was begun 2 (female) or 9 (male) weeks prior to mating. No animal fertility studies are available for HCTZ.

Use in pregnancy (Category D)

Olmesartan medoxomil

Drugs that act directly on the renin-angiotensin system can cause foetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature of patients who were taking ACE inhibitors. When pregnancy is detected, OLMETEC PLUS should be discontinued as soon as possible. The use of drugs that act directly on the renin-angiotensin system during the second and third trimesters of pregnancy has been associated with foetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure and death. Oligohydramnios has also been reported, presumably resulting from decreased foetal function; oligohydramnios in this setting has been associated with foetal limb contractures, craniofacial deformation and hypoplastic lung development. Prematurity, intrauterine growth retardation and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to exposure to the drug. These adverse effects do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester. Mothers whose embryos and foetuses are exposed to an angiotensin II receptor antagonist only during the first trimester should be so informed. If pregnancy occurs during therapy, OLMETEC PLUS must be discontinued as soon as possible. Rarely (probably less often than once in every thousand pregnancies), no alternative to a drug acting on the renin-angiotensin system will be found. In these rare cases, the mothers should be apprised of the potential hazards to their foetuses and serial ultrasound examinations should be performed to assess the intra-amniotic environment. If oligohydramnios is observed, OLMETEC PLUS should be discontinued unless it is considered life-saving for the mother. Contraction stress testing (CST), a nonstress test (NST) or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the foetus has sustained irreversible injury. Infants with histories of in utero exposure to an angiotensin II receptor antagonist should be closely observed for hypotension, oliguria and hyperkalaemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as means of reversing hypotension and/or substituting for disordered renal function. There is no clinical experience with the use of OLMETEC in pregnant women. No teratogenic effects were observed when olmesartan medoxomil was administered to pregnant rats at oral doses up to 1,000 mg/kg/day (7 times clinical exposure to olmesartan at MRHD based on AUC) 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 foetal 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 auricula, 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 adverse effect dose for developmental toxicity in rats is 0.3 mg/kg/day, about one-tenth the MRHD of 40 mg/day.

Thiazide diuretics

Thiazides cross the placental barrier and appear in cord blood. They may cause foetal electrolyte disturbances and possible other reactions that have occurred in adults. Cases of neonatal thrombocytopenia, or foetal or neonatal jaundice have been reported with maternal thiazide therapy.

Use in lactation

It is not known whether olmesartan is excreted in human milk, but olmesartan is secreted at low concentration in the milk of lactating rats. Thiazides appear in human milk. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug.

Paediatric use

The safety and effectiveness of OLMETEC PLUS in children have not been established.

Use in the elderly

Clinical Studies of OLMETEC PLUS of 415 subjects aged 65 and over determined that the elderly do not respond differently from younger subjects. 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 diseases or other drug therapy.

Effects on ability to drive and use machines

The effect of OLMETEC PLUS on the ability to drive and use machines has not been specifically studied. However, it should be borne in mind that dizziness or fatigue may occasionally occur in patients taking antihypertensive therapy.

Interactions with other medicines

Effects of other medicinal products on OLMETEC PLUS

Medicinal products affecting potassium levels

The potassium-depleting effect of HCTZ may be potentiated by the co-administration of other medicinal products associated with potassium loss and hypokalaemia (e.g. other kaliuretic diuretics, laxatives, corticosteroids, ACTH, amphotericin, benzyl penicillin sodium or salicylic acid derivatives). Conversely, based on experience with the use of other drugs that affect the renin-angiotensin system, concomitant use of potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium or other drugs that may increase serum potassium levels (e.g. heparin) may lead to increases in serum potassium (see PRECAUTIONS). If drugs which affect potassium levels are to be prescribed in combination with OLMETEC PLUS, monitoring of potassium plasma levels is advised.

Other antihypertensive medications

The blood pressure lowering effect of OLMETEC PLUS can be increased by concomitant use of other antihypertensive medications.

Non-steroidal anti-inflammatory drugs (NSAIDs)

NSAIDs (including acetylsalicylic acid at doses >3 g/day and also COX-2 inhibitors) and angiotensin-II receptor antagonists may act synergistically by decreasing glomerular filtration. The risk of the concomitant use of NSAIDs and angiotensin II antagonists is the occurrence of acute renal failure. Monitoring of renal function at the beginning of treatment should be recommended as well as regular hydration of the patient. Additionally, concomitant treatment can reduce the antihypertensive effect of angiotensin II receptor antagonists, leading to their partial loss of efficacy. In some patients the administration of NSAIDs reduces the diuretic, natriuretic and antihypertensive effects of loop, potassium-sparing and thiazide diuretics. Therefore, when OLMETEC PLUS tablets and NSAIDs are used concomitantly, the patient should be observed closely to determine if the desired effect of the diuretic is obtained.

Other drugs

After treatment with antacid (aluminium magnesium hydroxide), a modest reduction in bioavailability of olmesartan was observed. Co-administration of warfarin and digoxin had no effect on the pharmacokinetics of olmesartan.

Alcohol, barbiturates, narcotics or antidepressants Potentiation of orthostatic hypotension may occur. Baclofen, amifostine Potentiation of antihypertensive effect may occur.

Cholestyramine and colestipol resins

Absorption of HCTZ is impaired in the presence of anionic exchange resins.

Anticholinergic agents (e.g. atropine, biperiden)

Increase of the bioavailability of thiazide-type diuretics by decreasing gastrointestinal motility and stomach emptying rate.

Effects of OLMETEC PLUS on other medicinal products

Lithium

Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors and angiotensin II antagonists. Therefore, use of olmesartan and lithium in combination is not recommended (see PRECAUTIONS, Lithium). If use of the combination proves necessary, careful monitoring of serum lithium levels is recommended.

Medicinal products affected by serum potassium disturbances

Periodic monitoring of serum potassium and ECG is recommended when OLMETEC PLUS is administered with drugs affected by serum potassium disturbances (e.g. digitalis glycosides and antiarrhythmics) and with the following torsades de pointes-inducing medicinal products (including some antiarrhythmics), hypokalaemia being a predisposing factor to torsades de pointes: Class Ia antiarrythmics (e.g. quinidine, hydroquinidine, disopyramide) Class III antiarrythmics (e.g. amiodarone, sotalol, dofetilide, ibutilide) Some antipsychotics (e.g. thioridazine, chlorpromazine, levomepromazine, trifluoperazine, cyamemazine, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol) Others (e.g. bepridil, cisapride, diphemanil, erythromycin IV, halofantrin, mizolastin, pentamidine, sparfloxacin, terfenadine, vincamine IV).

Digitalis glycosides

Thiazide-induced hypokalaemia or hypomagnesaemia may favour the onset of digitalis- induced cardiac arrhythmias.

Antidiabetic drugs (oral agents and insulin)

The treatment with a thiazide may influence the glucose tolerance. Dosage adjustment of the antidiabetic drug may be required.

Metformin

Metformin should be used with caution because of the risk of lactic acidosis induced by possible functional renal failure linked to HCTZ.

Beta-blockers and diazoxide

The hyperglycaemic effect of beta-blockers and diazoxide may be enhanced by thiazides.

Pressor amines (e.g. noradrenaline)

The effect of pressor amines may be decreased.

Non-depolarizing skeletal muscle relaxants (e.g. tubocurarine)

The effect of non-depolarizing skeletal muscle relaxants may be potentiated by HCTZ.

Medicinal products used in the treatment of gout (probenecid, sulfinpyrazone and allopurinol)

Dosage adjustment of uricosuric medications may be necessary since HCTZ may raise the level of serum uric acid. Increase in dosage of probenecid or sulfinpyrazone may be necessary. Co-administration of a thiazide may increase the incidence of hypersensitivity reactions to allopurinol.

Calcium salts

Thiazide diuretics may increase serum calcium levels due to decreased excretion. If calcium supplements must be prescribed, serum calcium levels should be monitored and calcium dosage adjusted accordingly.

Amantadine

Thiazides may increase the risk of adverse effects caused by amantadine.

Cytotoxic agents (e.g. cyclophosphamide, methotrexate)

Thiazides may reduce the renal excretion of cytotoxic drugs and potentiate their myelosuppressive effects.

Additional information

Concomitant administration of olmesartan medoxomil and HCTZ had no clinically relevant effects on the pharmacokinetics of either component in healthy subjects. Olmesartan medoxomil had no significant effect on the pharmacokinetics or pharmacodynamics of warfarin or the pharmacokinetics of digoxin. Co-administration of olmesartan medoxomil with pravastatin had no clinically relevant effects on the pharmacokinetics of either component in healthy subjects. Olmesartan had no clinically relevant inhibitory effects on human cytochrome P450 enzymes 1A1/2, 2A6, 2C8/9, 2C19, 2D6, 2E1 and 3A4 in vitro, and had no or minimal inducing effects on rat cytochrome P450 activities. No clinically relevant interactions between olmesartan and drugs metabolised by the above cytochrome P450 enzymes are expected.

DOSAGE AND ADMINISTRATION

Adults

OLMETEC PLUS is administered once daily, with or without food, in patients whose blood pressure is not adequately controlled by olmesartan medoxomil or HCTZ alone. OLMETEC PLUS is registered in combinations of 20/12.5 mg, 20/25 mg, 40/12.5 mg and 40/25 mg (See Presentation and Storage Conditions for marketed strengths). Dosing should be individualised and dependent on the patient's condition. Depending on the blood pressure response, the dose may be titrated after 4 weeks. If blood pressure is not adequately controlled on OLMETEC alone, HCTZ may be added with a starting dose of 12.5 mg. Should blood pressure still remain inadequately controlled either up-titration of HCTZ to 25 mg or OLMETEC to 40 mg dose may be advisable. If blood pressure is not adequately controlled on HCTZ alone, olmesartan may be added with a starting dose of 20 mg with up-titration to 40 mg should blood pressure still remain inadequately controlled. Doses of OLMETEC PLUS above 40/25 mg are not recommended.

Special populations

Elderly

No dosage adjustment is necessary. If up-titration to the maximum dose of 40mg daily is required, blood pressure should be closely monitored.

Renal insufficiency * *

No adjustment of dosage is necessary for patients with mild (creatinine clearance of 50 - 80 mL/min) to moderate (creatinine clearance of 30-<50 mL/min) renal impairment . When OLMETEC PLUS is used in such patients, periodic monitoring of renal function is advised (see PRECAUTIONS). OLMETEC PLUS is contraindicated in patients with severe renal impairment (creatinine clearance <30 mL/min) (see CONTRAINDICATIONS).

Intravascular volume depletion * *

For patients with possible depletion of intravascular volume, particularly those with impaired renal function, OLMETEC PLUS should be administered under close medical supervision. If a patient becomes volume depleted whilst taking OLMETEC PLUS, blood pressure and renal function should be closely monitored until the situation resolves.

Hepatic insufficiency * *

No adjustment of dosage is necessary for patients with mild (Child-Pugh score 5 - 6) to moderate (Child-Pugh score 7 - 9) hepatic impairment. Close monitoring of blood pressure and renal function is advised in hepatically-impaired patients who are already receiving diuretics and/or other antihypertensive agents. There is no experience of olmesartan medoxomil in patients with severe (Child-Pugh score 10 - 15) hepatic impairment (see PRECAUTIONS, hepatic impairment). OLMETEC PLUS should not be used in patients with severe hepatic impairment, cholestasis and biliary obstruction (see CONTRAINDICATIONS). If up-titration of the olmesartan medoxomil component to the maximum dose of 40 mg daily is required, blood pressure should be closely monitored.

Children and adolescents

The safety and efficiency of OLMETEC PLUS in children have not been established.

OVERDOSAGE

No specific information is available on the effects or treatment of OLMETEC PLUS overdosage. The patient should be closely monitored, and the treatment should be symptomatic and supportive. Management depends upon the time since ingestion and the severity of the symptoms. Activated charcoal may be useful in the treatment of overdosage. Serum electrolytes and creatinine should be monitored frequently. If hypotension occurs, the patient should be placed in a supine position, with salt and volume replacements given quickly. The most likely manifestations of olmesartan overdosage are expected to be hypotension and tachycardia; bradycardia might also occur. Overdosage with HCTZ 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. No information is available regarding the dialysability of olmesartan or HCTZ. For further advice on the management of an overdose contact the Poisons Information Centre.

PRESENTATION AND STORAGE CONDITIONS

OLMETEC PLUS 20/12.5 mg

contains 20 mg of olmesartan medoxomil and 12.5 mg of hydrochlorothiazide. It is a round tablet, approximately 8.5 mm in diameter, reddish yellow in colour with C22 debossed on one side.

OLMETEC PLUS 20/25 mg

contains 20 mg of olmesartan medoxomil and 25 mg of hydrochlorothiazide. It is a round tablet, approximately 8.5 mm in diameter, pinkish in colour with C24 debossed on one side. Not currently available in Australia

OLMETEC PLUS 40/12.5 mg

contains 40 mg of olmesartan medoxomil and 12.5 mg of hydrochlorothiazide. It is an oval tablet, approximately 15 mm x 7 mm, reddish yellow in colour with C23 debossed on one side.

OLMETEC PLUS 40/25 mg

contains 40 mg of olmesartan medoxomil and 25 mg of hydrochlorothiazide. It is an oval tablet, approximately 15 mm x 7 mm in diameter, pinkish in colour with C25 debossed on one side.

OLMETEC PLUS is available in blister packs of 10 and 30 film-coated tablets. Not all pack sizes may be available. Store below 25C.

NAME AND ADDRESS OF THE SPONSOR

Merck Sharp & Dohme (Australia) Pty Limited 54-68 Ferndell Street South Granville NSW 2142

POISON SCHEDULE OF THE MEDICINE

Prescription only medicine (S4)

DATE OF APPROVAL

Approved by the Therapeutic Goods Administration on 13 May 2011 Date of most recent amendment: 21st December 2011 Changes notified on 11 April 2011 indicated by an asterisk * Changes approved on 13 May 2011 indicated by a double asterisk * *

(r) Registered Trademark of Daiichi Sankyo Company Ltd. Version 7