OLMESARTAN

Main information

  • Trade name:
  • OLMESARTAN SANDOZ olmesartan medoxomil 10 mg film coated tablets blister pack
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • OLMESARTAN SANDOZ olmesartan medoxomil 10 mg film coated tablets blister pack
    Australia
  • Language:
  • English

Other information

Status

  • Source:
  • Dept. of Health,Therapeutic Goods Administration - Australia
  • Authorization number:
  • 221060
  • Last update:
  • 08-10-2017

Public Assessment Report

Public Summary

Summary for ARTG Entry:

221060

OLMESARTAN SANDOZ olmesartan medoxomil 10 mg film coated tablets blister pack

ARTG entry for

Medicine Registered

Sponsor

Sandoz Pty Ltd

Postal Address

54 Waterloo Road,Macquarie Park, NSW, 2113

Australia

ARTG Start Date

5/02/2015

Product category

Medicine

Status

Active

Approval area

Drug Safety Evaluation Branch

Conditions

Conditions applicable to all therapeutic goods as specified in the document "Standard Conditions Applying to Registered or Listed Therapeutic Goods

Under Section 28 of the Therapeutic Goods Act 1989" effective 1 July 1995.

Conditions applicable to the relevant category and class of therapeutic goods as specified in the document "Standard Conditions Applying to Registered

or Listed Therapeutic Goods Under Section 28 of the Therapeutic Goods Act 1989" effective 1 July 1995.

Products

1. OLMESARTAN SANDOZ olmesartan medoxomil 10 mg film coated tablets blister pack

Product Type

Single Medicine Product

Effective date

26/07/2017

Warnings

See Product Information and Consumer Medicine Information for this product

Standard Indications

Specific Indications

OLMESARTAN SANDOZ is indicated for the treatment of hypertension.

Additional Product information

Container information

Type

Material

Life Time

Temperature

Closure

Conditions

Blister Pack

Al/Al

2 Years

Store below 25

degrees Celsius

Not recorded

Store in a Dry Place

Pack Size/Poison information

Pack Size

Poison Schedule

(S4) Prescription Only Medicine

Components

1. OLMESARTAN SANDOZ olmesartan medoxomil 10 mg film coated tablets blister pack

Dosage Form

Tablet, film coated

Route of Administration

Oral

Visual Identification

10 mg tablet: Yellow film-coated, round, biconvex tablets debossed with

392 one one side, and L on the other side. Blister pack of 30.

Active Ingredients

Olmesartan medoxomil

10 mg

© Commonwealth of Australia.This work is copyright.You are not permitted to re-transmit, distribute or commercialise the material without obtaining prior

written approval from the Commonwealth.Further details can be found at http://www.tga.gov.au/about/website-copyright.htm.

Public Summary

Page 1 of

Produced at 26.11.2017 at 01:38:02 AEDT

This is not an ARTG Certificate document.

The onus is on the reader to verify the current accuracy of the information on the document subsequent to the date shown.

Visit www.tga.gov.au for contact information

Summary of Product characteristics

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PRODUCT INFORMATION

OLMESARTAN SANDOZ 10MG, 20MG, 40 MG TABLETS

NAME OF THE MEDICINE

Olmesartan Sandoz contains the active ingredient olmesartan medoxomil. Olmesartan

medoxomil, a prodrug, is hydrolysed to olmesartan during absorption from the

gastrointestinal tract. Olmesartan is a selective AT

subtype angiotensin II receptor

antagonist.

Olmesartan medoxomil (CAS no. 144689-63-4) is described chemically as

2,3-dihydroxy-2-butenyl 4-(1-hydroxy-1-methylethyl)-2-propyl-

p

o

-1H-tetrazol-5-ylphenyl)benzyl] imidazole-5-carboxylate, cyclic 2,3-carbonate.

Its empirical formula is C29H30N6O6 and its 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.

Olmesartan Sandoz is available for oral use as film-coated tablets containing

10 mg, 20 mg, or 40 mg olmesartan medoxomil. The tablets also contain the following

inactive ingredients: lactose monohydrate, microcrystalline cellulose, hyprolose,

hypromellose, magnesium stearate, and OPADRY complete film coating system

03F82788 Yellow.

PHARMACOLOGY

Pharmacodynamics

Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin

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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 AT

antagonist. It has more than a 12,500-fold greater affinity for the AT

receptor than for

the AT

receptor. It is expected to block all actions of angiotensin II mediated by the

receptor, regardless of the source or route of synthesis of angiotensin II. The

selective antagonism of the angiotensin II (AT

) 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 (AT

) 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.

Once daily dosing with olmesartan medoxomil provides an effective and smooth

reduction in blood pressure over the 24-hour dose interval. Once daily dosing

produced similar decreases in blood pressure as twice daily dosing at the same total

daily dose.

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 hydrochlorothiazide, the reduction in blood pressure is additive and

coadministration is well tolerated.

The effect of olmesartan on mortality and morbidity is not yet known.

Pharmacokinetics

Absorption

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 (C

) 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.

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Food has minimal effect on the bioavailability of olmesartan and therefore olmesartan

medoxomil may be administered with or without food.

Distribution

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 coadministered 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.

Metabolism

Following the rapid and complete conversion of olmesartan medoxomil to olmesartan

during absorption, there is virtually no further metabolism of olmesartan.

Elimination

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.

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.

Paediatric

The single-dose pharmacokinetics of olmesartan was investigated in an open-label

study in paediatric hypertensive patients aged 1 to 16 years. Refer to Table 1 for a

summary of PK parameters. The clearance of olmesartan in paediatric patients was

similar to that in adult patients when adjusted by body weight. There are, however, very

limited data on the pharmacokinetics of olmesartan in children less than 6 years (see

PRECAUTIONS, Paediatric Use).

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Table 1.

Mean plasma pharmacokinetic parameters of olmesartan in paediatric

hypertension patients

1

Parameter; mean (SD)

6-12 Year Age Group (n=10)

13-16 Year Age Group (n=10)

(ng/mL)

1227 (451)

895 (262)

(ng/mL*hr)

7874 (2913)

5851 (2083)

0-∞

(ng/mL*hr)

7988 (2913)

5982 (2130)

(hr)

2.8 (1.3)

2.5 (1.1)

(hr)

8.4 (2.4)

9.1 (1.9)

CL/F (L/hr)

4.3 (1.9)

6.1 (2.6)

Sample size insufficient to support calculation of summary statistics in 2-5 year age group (n=4)

Gender

Minor differences were observed in the pharmacokinetics of olmesartan in women

compared with men. AUC and C

were 10-15% higher in women than in men.

Renal impairment

In patients with renal insufficiency, serum concentrations of olmesartan were elevated

compared with subjects with normal renal function. After repeated dosing, the AUC

was approximately tripled in patients with severe renal impairment (creatinine

clearance <30 mL/min).

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 C

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).

CLINICAL TRIALS

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.

Approximately 2,800 patients with essential hypertension were studied. The blood

pressure lowering effect of olmesartan medoxomil tended to increase with time and to

increase with dose up to the 40 mg dose (refer Table 2). Olmesartan medoxomil 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).

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Table 2.

Absolute reduction in mean systolic and diastolic BP

1

(mmHg)

(placebo-controlled studies)

Data above from seven placebo-controlled studies also confirm that 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%.

In a 4-month, open-label, extension study, all patients received 20 mg olmesartan

medoxomil, which was titrated to 40 mg as required. If sitting diastolic blood pressure

(sDBP) remained uncontrolled, hydrochlorothiazide 12.5–25 mg was then added. By

Week 16, the majority of patients remained on 20 mg olmesartan medoxomil therapy

(56.8%). Mean blood pressures generally continued to decrease in each treatment

group from Week 4 to Week 16, as expected from the study design, which allowed

treatment to be individually tailored to achieve blood pressure control (refer Table 3).

Table 3.

Mean systolic and diastolic BP

1

(mmHg) values (open-label study)

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

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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.

Use in elderly

The antihypertensive effects of olmesartan medoxomil 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 20 mg olmesartan medoxomil and if required, titrated to 40 mg after 4 weeks.

If after 4 weeks on 40 mg olmesartan medoxomil target blood pressure was not

achieved then hydrochlorothiazide was added. The results obtained for those on

olmesartan medoxomil were similar to those in the losartan group.

Paediatric use

The antihypertensive effect of olmesartan medoxomil once daily was evaluated in a

randomised, double-blind study involving 361 hypertensive paediatric patients (1-5

years n=59, 6-16 years n=302). Renal and urinary disorders with / without obesity

were the most common underlying causes of hypertension in these patients enrolled in

this study. Refer to Table 4 for a summary of the baseline demographic characteristics

of study participants.

Table 4.

Summary demographic and baseline characteristics

The study included three periods: a 3 week double-blind, randomised, dose-response

period for patients aged 6-16 years or, for patients aged 1-5 years, an open-label dose

period; up to 2 week double-blind, randomised, placebo-controlled withdrawal period;

and a 46 week open-label safety and efficacy period. The primary endpoints were the

dose response in systolic blood pressure or in diastolic blood pressure for subjects 6 to

16 years of age at the end of this period. This study was not a clinical outcome study.

In the dose-response period, patients aged 6-16 years were randomised to receive either

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low or high dose of olmesartan medoxomil based on their weight. Patients weighing

20 to <35 kg received 2.5 mg (low) or 20 mg (high); those weighing ≥ 35 kg, received 5

mg (low) or 40 mg (high). Patients aged 1-5 years who weighed ≥ 5 kg received a dose

of 0.3 mg/kg.

At the end of this period, olmesartan medoxomil reduced both systolic and diastolic

blood pressure in a dose-dependent manner. In patients aged 6-16 years the low and

high doses of olmesartan medoxomil significantly reduced systolic blood pressure by

6.63 and 11.87 mmHg from the baseline, respectively. Patients aged 1-5 years of age

had a clinically, and a statistically significant change from baseline reduction in systolic

blood pressure of 13.31

mmHg.

In the placebo-controlled withdrawal period, patients who continued on olmesartan

medoxomil had smaller increases in their systolic and diastolic blood pressure

compared to patients switched to placebo. The difference between placebo and

olmesartan medoxomil was statistically significant in patients aged 6-16 years, but was

not statistically significant in patients aged 1-5 years. Refer to Table 5 for a summary of

the mean change in SeSBP and SeDBP for both groups during the open-label (1-5 year

age group)/double-blind (6-16 year age group) and placebo-controlled withdrawal

periods of the study.

Table 5.

Summary of mean change in SeSBP and SeDBP (mm Hg) during open-label (1-5

year age group)/double-blind (6-16 year age group) period and

placebo-controlled withdrawal period

1-5 Year Age Group

SeSBP

SeDBP

Baseline BP

Mean (SD)

Change from

baseline

Mean (SD)

Baseline BP

Mean (SD)

Change from

baseline

Mean (SD)

Open-label period

olmesartan medoxomil

(n=59)

115.4 (8.62)

-13.31 (10.94)

72.6 (8.80)

-10.42 (9.78)

Placebo-controlled withdrawal period

olmesartan medoxomil

(n=29)

101.8 (11.87)

1.36 (8.99)

60.9 (9.16)

0.31 (8.56)

Placebo (n=28)

101.4 (10.09)

4.95 (8.57)

61.9 (8.56)

3.77 (7.20)

6-16 Year Age Group

SeSBP

SeDBP

Baseline BP

Mean (SD)

Change from

baseline

Mean (SD)

Baseline BP

Mean (SD)

Change from

baseline

Mean (SD)

Double-blind period

Low dose olmesartan

medoxomil (n=150)

130.4 (9.09)

-6.63 (10.17)

78.6 (8.53)

-4.76 (8.39)

High dose olmesartan

medoxomil (n=150)

129.8 (8.98)

-11.87 (9.84)

77.4 (7.78)

-8.78 (9.22)

Placebo-controlled withdrawal period

olmesartan medoxomil

(n=145)

121.5 (12.66)

0.77 (9.45)

71.3 (9.70)

0.85 (7.79)

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Placebo (n=141)

120.2 (13.00)

4.50 (9.75)

70.8 (10.42)

3.99 (9.63)

Baseline at start of study period

At the end of the open-label efficacy and safety period, compared to baseline, the mean

systolic and diastolic blood pressure were reduced at all visits for all patient age groups.

However data in children 1-5 years are limited due to small numbers of patients

enrolled in the clinical studies. Overall the clinical trials were unable to demonstrate

that olmesartan medoxomil was significantly better than placebo in reducing blood

pressure in children 1-5 years of age.

INDICATIONS

Olmesartan Sandoz is indicated for the treatment of hypertension.

CONTRAINDICATIONS

Olmesartan medoxomil is contraindicated in:

Patients who are hypersensitive to either olmesartan medoxomil or any 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) or biliary

obstruction (see PRECAUTIONS, Hepatic impairment)

Patients with diabetes who are taking aliskiren (see INTERACTIONS WITH

OTHER MEDICINES)

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 olmesartan medoxomil.

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.

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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 drugs that affect the renin-angiotensin-aldosterone system.

Renal impairment and kidney transplantation

When olmesartan medoxomil is used in patients with impaired renal function, periodic

monitoring of serum potassium and creatinine levels is recommended. Use of

olmesartan medoxomil is not recommended in patients with severe renal impairment

(creatinine clearance <30 mL/min, eGFR <30 mL/min/1.73 m

) (see DOSAGE AND

ADMINISTRATION). There is no experience of the administration of olmesartan

medoxomil in patients with a recent kidney transplant or in patients with end-stage

renal impairment (i.e. creatinine clearance <12 mL/min, eGFR <15 mL/min/1.73 m

There are no data on the use of olmesartan in children with eGFR less than 25

mL/min/1.73 m

Hepatic impairment

There is no experience in patients with severe hepatic impairment (Child-Pugh score 10

- 15) and therefore use of olmesartan medoxomil in this patient group is not

recommended (see DOSAGE AND ADMINISTRATION).

Hyperkalaemia

As with other angiotensin receptor antagonists and ACE inhibitors, hyperkalaemia may

occur during treatment with olmesartan medoxomil, especially in the presence of renal

impairment and/or heart failure. This is because OLMESARTAN SANDOZ contains

olmesartan medoxomil, a drug which inhibits the renin-angiotensin system (RAS) and

drugs that inhibit the RAS can cause hyperkalaemia.

Close monitoring of serum

potassium levels in at risk patients is recommended.

Lithium

As with other angiotensin receptor antagonists, the combination of lithium and

olmesartan medoxomil is not recommended (see INTERACTIONS WITH OTHER

MEDICINES).

Aortic or mitral valve stenosis; obstructive hypertrophic cardiomyopathy

As with other vasodilators, special caution is indicated in patients suffering from aortic

or mitral valve stenosis, or obstructive hypertrophic cardiomyopathy.

Primary aldosteronism

Patients with primary aldosteronism generally will not respond to antihypertensive

drugs acting through inhibition of the renin-angiotensin system. Therefore, the use of

olmesartan medoxomil is not recommended in such patients.

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Ethnic differences

As with all other angiotensin receptor antagonists, the blood pressure lowering effect of

olmesartan medoxomil is somewhat less in black patients than in non-black patients,

possibly because of a higher prevalence of low-renin status in the black hypertensive

population.

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.

Sprue-like Enteropathy

Severe, chronic diarrhoea with substantial weight loss has been reported in patients

taking olmesartan medoxomil months to years after drug initiation. Intestinal biopsies

of patients often demonstrated villous atrophy. If a patient develops these symptoms

during treatment with olmesartan medoxomil, exclude other etiologies. Consider

discontinuation of olmesartan medoxomil in cases where no other etiology is identified.

Angioedema

Angioedema, including swelling of the larynx and glottis, causing airway obstruction

and/or swelling of the face, lips, pharynx, and/or tongue has been reported in patients

treated with olmesartan medoxomil; some of these patients previously experienced

angioedema with other drugs including ACE inhibitors. Olmesartan medoxomil should

be immediately discontinued in patients who develop angioedema, and olmesartan

medoxomil should not be re-administered.

General

Caution should be exercised in patients who have shown prior hypersensitivity to other

angiotensin II receptor antagonists.

Other

As with any antihypertensive agent, excessive blood pressure decrease in patients with

ischaemic heart disease or ischaemic cerebrovascular disease could result in a

myocardial infarction or stroke.

Effects on fertility

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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.

Use in pregnancy (Category D)

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, olmesartan medoxomil 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 receptor antagonist only during the first trimester should be

so informed. Nonetheless, when patients become pregnant, physicians should have

the patient discontinue the use of olmesartan medoxomil 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, olmesartan medoxomil 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 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 olmesartan medoxomil in pregnant

women. No teratogenic effects were observed when olmesartan medoxomil was

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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 effect dose for developmental

toxicity in rats is 0.3 mg/kg/day, about one-tenth the MRHD of 40 mg/day.

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. 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

Not to be used for children aged below 1 year of age. Pharmacokinetic information is

limited in patients less than 6 years.

Use in the elderly

Of the total number of hypertensive patients receiving olmesartan medoxomil in

clinical studies, including two studies investigating safety and efficacy in the elderly,

more than 40% were 65 years of age and over, while more than 10% were 75 years of

age and older. No overall differences in effectiveness or safety were observed

between elderly patients and younger patients. Other reported clinical experience has

not identified differences in responses between the elderly and younger patients, but

greater sensitivity of some older individuals cannot be ruled out.

Genotoxicity

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. 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.

Carcinogenicity

Olmesartan medoxomil was not carcinogenic when administered by dietary

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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.

Effects on laboratory tests

olmesartan medoxomil

In post-marketing experience, increased blood creatinine levels and hyperkalaemia

have been reported.

Effects on ability to drive and use machines

The effect of olmesartan medoxomil on the ability to drive has not been specifically

studied. With respect to driving vehicles or operating machines, it should be taken

into account that occasionally dizziness or fatigue may occur in patients taking

antihypertensive therapy.

INTERACTIONS WITH OTHER MEDICINES

Drugs that affect olmesartan medoxomil

Colesevelam hydrochloride

Concomitant administration of 40 mg olmesartan medoxomil and 3750 mg

colesevelam hydrochloride in healthy subjects resulted in 28% reduction in C

39% reduction in AUC of olmesartan. Lesser effects, 4% and 15% reduction in C

and AUC respectively, were observed when olmesartan medoxomil was administered 4

hours prior to colesevelam hydrochloride. Consider administering olmesartan

medoxomil 4 hours before the colesevelam hydrochloride dose.

Potassium supplements and potassium sparing diuretics

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. Such concomitant use

is therefore not recommended.

Other antihypertensive medications

The blood pressure lowering effect of olmesartan medoxomil can be increased by

concomitant use of other antihypertensive medications.

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Non-steroidal anti-inflammatory drugs (NSAIDs)

NSAIDs (including acetylsalicylic acid at doses >3 g/day and also COX-2 inhibitors)

and angiotensin receptor antagonists may act synergistically by decreasing glomerular

filtration. The risk of the concomitant use of NSAIDs and angiotensin receptor

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 receptor antagonists, leading to their partial loss of efficacy.

Dual Blockade of the Renin-Angiotensin System (RAS)

Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or

aliskiren is associated with increased risks of hypotension, hyperkalaemia, and changes

in renal function (including acute renal failure) compared to monotherapy. Closely

monitor blood pressure, renal function and electrolytes in patients on olmesartan

medoxomil and other agents that affect the RAS.

Do not co-administer aliskiren with olmesartan medoxomil in patients with diabetes

(see CONTRAINDICATIONS). Avoid use of aliskiren with olmesartan medoxomil in

patients with renal impairment (GFR <60 ml/min).

Other drugs

After treatment with antacid (aluminium magnesium hydroxide), a modest reduction in

bioavailability of olmesartan was observed. Coadministration of warfarin and digoxin

had no effect on the pharmacokinetics of olmesartan medoxomil.

Drugs that are affected by olmesartan medoxomil

Lithium

Reversible increases in serum lithium concentrations and toxicity have been reported

during concomitant administration of lithium with ACE inhibitors and angiotensin

receptor antagonists. Therefore use of olmesartan medoxomil 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.

Other drugs

Drugs, which have been investigated in specific clinical studies in healthy volunteers,

include warfarin, digoxin, an antacid (magnesium aluminium hydroxide),

hydrochlorothiazide and pravastatin. No clinically relevant interactions were

observed and in particular olmesartan medoxomil had no significant effect on the

pharmacokinetics or pharmacodynamics of warfarin or the pharmacokinetics of

digoxin.

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Olmesartan had no clinically relevant inhibitory effects on in vitro human cytochrome

P450 enzymes 1A1/2, 2A6, 2C8/9, 2C19, 2D6, 2E1 and 3A4, and had no or minimal

inducing effects on rat cytochrome P450 activities. Therefore

in vivo

interaction

studies with known cytochrome P450 enzyme inhibitors and inducers were not

conducted, and no clinically relevant interactions between olmesartan and drugs

metabolised by the above cytochrome P450 enzymes are expected.

ADVERSE EFFECTS

Olmesartan medoxomil has been evaluated for safety in more than 3,825

patients/subjects, including more than 3,275 patients treated for hypertension in

controlled trials. This experience included about 900 patients treated for at least 6

months and more than 525 for at least 1 year.

Treatment with olmesartan medoxomil was well tolerated, with an incidence of adverse

events similar to placebo. Events generally were mild, transient and had no

relationship to the dose of olmesartan medoxomil.

The overall frequency of adverse events was not dose-related. Analysis of gender, age

and race groups demonstrated no differences between olmesartan medoxomil and

placebo-treated patients. The rate of withdrawals due to adverse events in all trials of

hypertensive patients was 2.4% (i.e. 79/3,278) of patients treated with olmesartan

medoxomil and 2.7% (i.e. 32/1,179) of control patients. In placebo-controlled trials,

the only adverse event that occurred in more than 1% of patients treated with

olmesartan medoxomil and at a higher incidence versus placebo was dizziness (2.5%

versus 0.9%).

Adverse events reported in placebo-controlled monotherapy studies with a greater than

1% incidence are shown in Table 6:

Table 6. Clinical adverse effects (all causalities) occurring in ≥1% of patients

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Other adverse events of potential clinical relevance reported in the clinical trials are

listed below. Adverse events reported across all clinical trials with olmesartan

medoxomil (including trials with active as well as placebo control), irrespective of

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causality or incidence relative to placebo, included those events listed below.

Frequencies are defined as: common (≥1/100, <1/10); uncommon (≥1/1,000, <1/100);

rare (≥1/10,000, <1/1,000), very rare (<1/10,000).

Cardiovascular:

Uncommon: Tachycardia; Rare: Hypotension

Central nervous system:

Uncommon: Vertigo

Gastro-intestinal:

Common: Abdominal pain

Myo/endo/pericardial and valve disorders:

Uncommon: Angina pectoris

Musculoskeletal:

Uncommon: Myalgia

Skin and appendages:

Uncommon: Rash

Laboratory parameters

In placebo-controlled monotherapy studies the incidence was somewhat higher on

olmesartan medoxomil compared with placebo for hypertriglyceridaemia (2.0% versus

1.1%) and for raised creatine phosphokinase (1.3% versus 0.7%).

Laboratory adverse events reported across all clinical trials with olmesartan medoxomil

(including trials without a placebo control), irrespective of causality or incidence

relative to placebo, included:

Metabolic and nutritional:

Common: Blood urea increased;

Uncommon: Hypercholesterolaemia, hyperlipaemia;

Rare: Hyperkalaemia

Investigations:

Decrease in haemoglobin and haematocrit

Post-marketing experience

The following adverse reactions have been reported in post-marketing experience:

Blood and lymphataic system disorders:

Thrombocytopenia

General disorders and administration site conditions:

Peripheral oedema, asthenic

conditions, such as asthenia, fatigue, lethargy, malaise

Gastrointestinal disorders:

Abdominal pain, nausea, vomiting, diarrhoea, sprue-like

enteropathy

Immune system disorders:

Anaphylactic reactions

Investigations:

Hepatic enzymes increased, increased blood creatinine levels

Metabolic and nutritional disorders:

Hyperkalaemia

Musculoskeletal and connective tissue disorders:

Rhabdomyolysis, myalgia, muscle

spasm

Nervous systems disorders:

Headache

Respiratory, thoracic and mediastinal disorders:

Cough

Skin and subcutaneous tissue disorders:

Alopecia, angioedema, rash, pruritus,

urticaria, exanthema, allergic dermatitis.

Renal and urinary disorders:

Acute renal failure,

Vascular disorders:

Flushing

Use in elderly patients

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Olmesartan medoxomil has been evaluated for safety in 1646 patients aged 65 years or

older of whom, 454 were aged 75 years or older. Overall the incidence of adverse

events in the elderly is comparable to that of the adult population. The number of

withdrawals due to olmesartan medoxomil-related adverse effects was very low

(6/1206; 0.5%) compared to the placebo (1/85; 1.2%) or losartan (0/184; 0.0%).

Adverse events reported with olmesartan medoxomil monotherapy in the elderly with a

greater than 1% incidence are shown in table 7:

Table 7. Clinical adverse effects (all causalities) occurring in ≥1% of elderly patients.

The most common adverse events considered to be treatment related in elderly patients

were headache (1.5%) and dizziness (1.1%) on 40 mg olmesartan medoxomil.

Paediatric Use

No clinically relevant differences were identified between the adverse experience

profile for paediatric patients aged 1 to 18 years and that previously reported for adult

patients.

In placebo-controlled period, the only adverse event that occurred in more than 2% of

patients treated with olmesartan medoxomil and at a higher incidence versus placebo

was pseudohyperkalaemia (Cohort A: 1.1% versus 2.3%; Cohort C: 0% versus 7.1%).

Clinical adverse effects (all causalities) occurring in ≥ 2% of patients aged 6-16 years (Cohorts A

and B) and aged 1-5 years (Cohort C) versus placebo.

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DOSAGE AND ADMINISTRATION

Adults

Dosage must be individualised. The optimal recommended starting dose is 20 mg

once daily when used as monotherapy in patients who are not volume-contracted. If

additional blood pressure reduction is required, the dose may be increased to a

maximum of 40 mg daily.

Olmesartan medoxomil may be administered with or without food. In order to assist

compliance, it is recommended that olmesartan medoxomil tablets be taken at about the

same time each day. Twice-daily dosing offers no advantage over the same total dose

given once daily.

The antihypertensive effect of olmesartan medoxomil is substantially present within 2

weeks of initiating therapy and is maximal by about 8 weeks after initiating therapy.

This should be borne in mind when considering changing the dose regimen for any

patient.

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Hydrochlorothiazde therapy should be considered in those patients requiring additional

blood pressure control beyond 40 mg daily. Olmesartan medoxomil may be

administered with other antihypertensive agents.

Special populations

Elderly

No dosage adjustment is necessary.

If up-titration to the maximum dose of 40 mg daily is required, blood pressure should

be closely monitored.

Renal insufficiency

No adjustment of dosage is required for patients with mild (creatinine clearance of 50 –

80 mL/min, eGFR 60-89 mL/min/1.73 m

) to moderate (creatinine clearance of 30 –

<50 mL/min, eGFR 30-59 mL/min/1.73 m

) renal impairment. The use of olmesartan

medoxomil in patients with severe renal impairment (creatinine clearance <30 mL/min,

eGFR <30 mL/min/1.73 m

) is not recommended, since there is only limited experience

in this patient group (see PRECAUTIONS, Renal impairment and kidney

transplantation). There are no data on the use of olmesartan in children with eGFR less

than 25 mL/min/1.73 m

Intravascular volume depletion

For patients with possible depletion of intravascular volume, particularly those with

impaired renal function, olmesartan medoxomil should be administered under close

medical supervision. In these patients a lower starting dose of 10 mg once daily is

recommended (see PRECAUTIONS, Intravascular volume depletion) (see

PRESENTATIONS AND STORAGE CONDITIONS for marketed strengths).

If a patient becomes volume depleted whilst taking olmesartan medoxomil, blood

pressure and renal function should be closely monitored until the situation resolves.

Hepatic insufficiency

No adjustment of dosage is required 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).

If up-titration of olmesartan medoxomil to the maximum dose of 40 mg daily is

required, blood pressure should be closely monitored.

Paediatric Use

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Dosing must be individualised. The recommended starting dose is based on age

and/or weight (see Dosing recommendation table). If after 2 weeks of therapy further

reduction in blood pressure is required, the dose of olmesartan medoxomil may be

increased to a maximum of either 20 mg or 40 mg (see Dosing recommendation table).

There are limited data available for the pharmacokinetics of olmesartan in children

aged less than 6 years (see PHARMACOLOGY, Pharmacokinetics in special

populations,

Paediatric

) and there are no pharmacokinetic data available in children

with renal impairment (see DOSAGE AND ADMINISTRATION, Renal

insufficiency).

For children who cannot swallow tablets, the equivalent dose may be given as an

extemporaneous suspension. This brand of product has not been approved for use as

an extemporaneous suspension. An alternative brand approved for use to compound an

extemporaneous suspension is to be used if treatment is required in the suspension

form.

OVERDOSAGE

Only limited information is available regarding overdosage in humans. The most

likely effect of overdosage is hypotension and tachycardia; bradycardia could be

encountered if parasympathetic (vagal) stimulation occurs. In the event of

overdosage, the patient should be carefully monitored and treatment should be

symptomatic and supportive.

No information is available regarding the dialysability of olmesartan.

For further advice on the management of an overdose contact the Poisons Information

Centre (on 131126 in Australia).

PRESENTATION AND STORAGE CONDITIONS

10 mg tablet:

Yellow film-coated, round, biconvex tablets debossed with 392 one one

side, and L on the other side. Aluminium/Aluminium blister pack of 30 tablets.

20 mg tablet:

Yellow film coated, round, biconvex tablets debossed with 323 on one

side and L on the other side. Aluminium/Aluminium blister pack of 30 tablets.

40 mg tablet:

Yellow film coated, oval shape, bioconvex tablets debossed with L324

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on one side and plain on the other side. Aluminium/Aluminium blister pack of 30

tablets.

Not all pack sizes and strengths may be marketed in Australia.

Store below 25°C.

NAME AND ADDRESS OF THE SPONSOR

Sandoz Pty Ltd

ABN 60 075 449 553

54 Waterloo Road

Macquarie Park

NSW 2113 Australia

POISON SCHEDULE OF THE MEDICINE

Prescription only medicine (S4)

DATE OF FIRST INCLUSION IN THE AUSTRALIAN REGISTER OF

THERAPEUTIC GOODS (ON ARTG)

05 February 2015

DATE OR MOST RECENT AMENDMENT: 3 March 2017

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