ABISART

Main information

  • Trade name:
  • ABISART irbesartan 150 mg tablet bottle
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • ABISART irbesartan 150 mg tablet bottle
    Australia
  • Language:
  • English

Other information

Status

  • Source:
  • Dept. of Health,Therapeutic Goods Administration - Australia
  • Authorization number:
  • 214580
  • Last update:
  • 09-10-2017

Public Assessment Report

Public Summary

Summary for ARTG Entry:

214580

ABISART irbesartan 150 mg tablet bottle

ARTG entry for

Medicine Registered

Sponsor

Alphapharm Pty Ltd

Postal Address

PO Box R1462,ROYAL EXCHANGE, NSW, 1225

Australia

ARTG Start Date

6/11/2013

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. ABISART irbesartan 150 mg tablet bottle

Product Type

Single Medicine Product

Effective date

16/06/2017

Warnings

See Product Information and Consumer Medicine Information for this product

Standard Indications

Specific Indications

ABISART is indicated for the treatment of hypertension.,ABISART is indicated for delaying the progression of renal disease in hypertensive type II

diabetics with persistent micro-albuminuria (> 30 mg per 24 hours) or urinary protein in excess of 900 mg per 24 hours.

Additional Product information

Container information

Type

Material

Life Time

Temperature

Closure

Conditions

Bottle

HDPE

2 Years

Store below 25

degrees Celsius

Child resistant closure

Not recorded

Pack Size/Poison information

Pack Size

Poison Schedule

(S4) Prescription Only Medicine

(S4) Prescription Only Medicine

(S4) Prescription Only Medicine

(S4) Prescription Only Medicine

Components

1.

Dosage Form

Tablet

Route of Administration

Oral

Visual Identification

A white to off-white, film-coated, round, biconvex, bevelled edge tablet

debossed with "M" on one side of the tablet and "IN2" on the other side.

Active Ingredients

Irbesartan

150 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 09:26:01 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

ABISART

Irbesartan

PRODUCT INFORMATION

NAME OF THE MEDICINE

Active ingredient

Irbesartan

Chemical name

2-butyl-3-[p-(o-1H-tetrazol-5-ylphenyl)benzyl]-1,3-diazaspiro [4,4] non-1-en-4-one

Structural formula

Molecular formula

Molecular weight

428.53

CAS Registry no.

138402-11-6

DESCRIPTION

Irbesartan is a white, to practically white, powder that is less than 0.1mg/mL soluble in water and slightly soluble

in alcohol and methylene chloride.

Abisart (irbesartan) is a nonpeptide angiotensin II receptor (AT

subtype) antagonist. It is available as 75 mg, 150

mg or 300 mg tablets for oral administration. The inactive ingredients are: povidone, lactose, microcrystalline

cellulose, croscarmellose sodium, magnesium stearate, colloidal anhydrous silica and OPADRY II Complete

Film Coating System OY-LS-28908 White (ARTG no. 12435).

PHARMACOLOGY

Pharmacodynamics

Irbesartan is a specific antagonist of angiotensin II receptors (AT1 subtype). Angiotensin II is an important

component of the renin-angiotensin system and is involved in the pathophysiology of hypertension and in sodium

homeostasis. Irbesartan does not require metabolic activation for its activity.

Irbesartan blocks the potent vasoconstrictor and aldosterone-secreting effects of angiotensin II by selective

antagonism of the angiotensin II (AT

subtype) receptors localized on vascular smooth muscle cells and in the

adrenal cortex. It has no agonist activity at the AT

receptor and a much greater affinity (more than 8500-fold)

for the AT

receptor than for the AT

receptor (a receptor that has not been shown to be associated with

cardiovascular homeostasis).

Irbesartan does not inhibit enzymes involved in the renin-angiotensin system (i.e., renin, angiotensin converting

enzyme [ACE]) or affect other hormone receptors or ion channels involved in the cardiovascular regulation of

blood pressure and sodium homeostasis.

Abisart – PRODUCT INFORMATION

In healthy subjects, single oral irbesartan doses of up to 300 mg produced dose-dependent inhibition of the pressor

effect of angiotensin II infusions. Inhibition was complete (>90%) at the time of peak irbesartan concentrations

and sustained for 24 hours (60% and 40% at 300 mg and 150 mg, respectively).

In hypertensive patients, angiotensin II receptor inhibition following chronic administration of irbesartan causes

a 1.5-2 fold rise in angiotensin II plasma concentration and a 2-3 fold increase in plasma renin levels. Aldosterone

plasma concentrations generally decline following irbesartan administration, however serum potassium levels are

not significantly affected at recommended doses.

In hypertensive patients, chronic oral doses of irbesartan (up to 300 mg) had no effect on glomerular filtration

rate, renal plasma/blood flow or filtration fraction. In multiple dose studies in hypertensive patients, there were

no notable effects on fasting triglycerides, total cholesterol or HDL-cholesterol or fasting glucose concentrations.

There was no effect on serum uric acid during chronic oral administration. Following repeated doses of irbesartan,

there was no uricosuric effect.

Pharmacokinetics

Irbesartan is an orally active agent and does not require biotransformation for its activity.

Absorption

Following oral administration, irbesartan is rapidly and well absorbed. In studies employing an injection and an

oral solution containing radio-labelled irbesartan the average absolute oral bioavailability of irbesartan was

60-80%. Median peak plasma concentrations generally occurred 1.5-2 hours after oral administration of

irbesartan tablets. Food did not affect the bioavailability.

Distribution

Irbesartan is 90% protein-bound in the plasma, and has negligible binding to cellular components of blood. The

volume of distribution (V

) is 53-93 Litres.

Metabolism

Following oral or intravenous administration of

C irbesartan more than 80% of the circulating plasma

radioactivity was attributable to unchanged irbesartan. Irbesartan is metabolised by the liver via glucuronide

conjugation and oxidation. The major circulating metabolite is irbesartan glucuronide (~6%). Irbesartan

undergoes oxidation primarily by the cytochrome P450 isoenzyme

CYP

2C9; isoenzyme

CYP

3A4 has negligible

effect. It is not metabolised by, nor does it substantially induce or inhibit most isoenzymes commonly associated

with drug metabolism (i.e.,

CYP

1A1,

CYP

1A2,

CYP

2A6,

CYP

2B6,

CYP

2D6, or

CYP

2E1). Irbesartan does not

induce nor inhibit isoenzyme

CYP

3A4.

Excretion

Irbesartan and its metabolites are excreted by both biliary and renal routes. About 20% of the administered

radioactivity after an oral or intravenous dose of

C irbesartan was recovered in urine with the remainder in the

faeces. Less than 2% of the dose was excreted in urine as unchanged irbesartan.

The terminal elimination half-life (t

) of irbesartan averaged 11 - 15 hours over a range of doses following

multiple oral dosing. The total body clearance of intravenously administered irbesartan was 157 - 176 mL/min,

of which 3.0-3.5 mL/min was renal clearance. Irbesartan exhibits linear pharmacokinetics over the therapeutic

dose range. Steady-state plasma concentrations are attained within 3 days after initiation of a once-daily dosing

regimen. Limited accumulation (<20%) is observed in plasma upon repeated once-daily dosing.

A bioequivalent study on 27 subjects has been conducted comparing the generic irbesartan 300 mg tablet with

the originator irbesartan 300 mg tablet. The generic and originator mean C

for irbesartan was 3.694 and 3.598

μg/mL respectively. The C

print estimate for irbesartan was 1.02 with the 90% confidence interval between

97.27% - 107.62%. The mean AUC

point estimate for irbesartan was 0.99 with the 90% confidence interval

between 92.49% - 105.41%. The T

for generic and originator was 1.426 and 1.389 hr respectively.

Abisart – PRODUCT INFORMATION

Special Populations

In male and female hypertensive subjects,

higher (11-44%) plasma concentrations of irbesartan were observed in

females than in males, although, following multiple dosing, males and females did not show differences in either

accumulation or elimination half-life. No gender-specific differences in clinical effect have been observed.

In elderly (male and female)

normotensive subjects (65-80 years) with clinically normal renal and hepatic

function, the plasma AUC and peak plasma concentrations (C

) of irbesartan are approximately 20%-50%

greater than those observed in younger subjects (18-40 years). Regardless of age, the elimination half-life is

comparable. No significant age-related differences in clinical effect have been observed.

In black and white normotensive subjects

, the plasma AUC and t

of irbesartan are approximately 20-25% greater

in blacks than in whites; the peak plasma concentrations (C

) of irbesartan are essentially equivalent.

In patients with renal impairment

(regardless of degree) and in haemodialysis patients, the pharmacokinetics of

irbesartan are not significantly altered. Irbesartan is not removed by hemodialysis.

In patients with hepatic insufficiency due to mild to moderate cirrhosis

, the pharmacokinetics of irbesartan are

not significantly altered.

CLINICAL TRIALS

The antihypertensive effects of irbesartan were examined in seven (7) major placebo-controlled 8-12 week trials

in patients with baseline diastolic blood pressures of 95-110 mmHg.

The seven (7) studies of irbesartan monotherapy included a total of 1915 patients randomized to irbesartan

(1-900 mg) and 611 patients randomised to placebo. Once daily doses of 150 to 900 mg provided statistically and

clinically significant decreases in systolic and diastolic blood pressure with a plateau in effect at doses above 300

Systolic/diastolic mean decreases in blood pressure at trough (24 hours post-dosing), compared to placebo,

following 6 to 12 weeks of treatment were in the range of 7.5-9.9/4.6- 6.2 mmHg with a 150 mg dose, and

7.9-12.6/5.2-7.9 mmHg with a 300mg dose.

Once-daily dosing with 150 mg gave trough and mean 24 hour responses corresponding to those observed in

patients receiving twice-daily dosing at the same total daily dose. Peak (3-6 hour) effects were uniformly, but

moderately, larger than trough effects, with the trough-to peak ratio for systolic and diastolic response generally

between 60-70%.

seven

placebo-controlled

trials

identified

above

additional

studies

examined

antihypertensive effects of irbesartan and hydrochlorothiazide in combination.

Addition of a low dose of hydrochlorothiazide (12.5 mg) to irbesartan (75 to 300 mg) once daily resulted in

further diastolic blood pressure reductions at trough (24 hours post-dosing) of 2.3-4.8 mmHg and an overall

systolic/diastolic placebo-subtracted reduction of up to 13.6/11.5 mmHg at a dose of 300 mg irbesartan and 12.5

mg hydrochlorothiazide. Once daily dosing with 150mg irbesartan and 12.5 mg hydrochlorothiazide gave

systolic/diastolic

mean

placebo-adjusted

blood

pressure

reductions

trough

hours

post-dosing)

12.9/6.9 mmHg.

In patients not adequately controlled (SeDBP>90 mmHg) on irbesartan (up to 300 mg) alone, the addition of

12.5mg hydrochlorothiazide gave an added reduction of up to 6.1 mmHg in trough (24 hours) diastolic blood

pressure.

In patients not adequately controlled (SeDBP 93-120 mmHg) on 25 mg hydrochlorothiazide alone, the addition

of irbesartan (75-150 mg) gave an added systolic/diastolic mean reduction of 11.1/7.2 mmHg.

Analysis of age, gender and race subgroups of patients showed that men and women, and patients over and under

65 years of age, had generally similar responses.

Abisart – PRODUCT INFORMATION

The effect of irbesartan is apparent after the first dose, substantially present within 1-2 weeks, and reaches a

maximal effect within 4-6 weeks. In long-term studies the effect of irbesartan appeared to be maintained for more

than one year. After withdrawal of irbesartan, blood pressure gradually returned towards baseline; no rebound

was observed. There was essentially no change in average heart rate in irbesartan-treated patients in controlled

trials.

Hypertension and type II diabetic renal disease

The Irbesartan Diabetic Nephropathy Trial (IDNT) was a multicentre, randomised, controlled, double-blind,

morbidity and mortality trial comparing irbesartan, amlodipine and placebo. In 1715 hypertensive patients with

type II diabetes (proteinuria > 900mg/day and serum creatinine 110-265 μmol/L in men and 90-265 μmol/L in

women) the long-term effects (mean 2.6 years) of irbesartan on the progression of renal disease and all-cause

mortality were examined. In addition, a secondary end-point, the effect of irbesartan on the risk of fatal or

non-fatal cardiovascular events were assessed. Patients were randomised to receive irbesartan 75 mg, amlodipine

matching

placebo

once-daily.

Patients

were

then

titrated

maintenance

dose

300 mg irbesartan, 10 mg amlodipine, or placebo as tolerated. Additional antihypertensive agents (excluding

ACE inhibitors, angiotensin II receptor antagonists and calcium channel blockers) were added as needed to help

achieve blood pressure goal (≤135/85 or 10 mmHg reduction in systolic blood pressure if higher than

160 mmHg) for patients in all groups. Irbesartan demonstrated a 20% relative risk reduction in the composite

primary endpoint (first occurrence of any of the following: doubling of serum creatinine, end-stage renal disease

or all-cause mortality) compared to placebo (95% CI (3%, 34%), p =0.023) and a 23% relative risk reduction

compared to amlodipine (95% CI (7%, 37%), p = 0.006). When the individual components of the primary

endpoint were analysed, no effect in all cause mortality was observed, while a positive trend in the reduction in

ESRD and a significant reduction in doubling of serum creatinine were observed. Similar blood pressure was

achieved in the irbesartan and amlodipine groups. There was no significant difference in the assessment of fatal

or non-fatal cardiovascular events (cardiovascular death, non-fatal myocardial infarction, hospitalization for heart

failure, permanent neurologic deficit attributed to stroke, or above-the-ankle amputation) among the three

treatment groups.

The study of the Effects of Irbesartan on MicroAlbuminuria in Hypertensive Patients with Type 2 Diabetes

Mellitus (IRMA 2) was a multicentre, randomised, placebo-controlled, double-blind morbidity study, conducted

hypertensive

patients

with

type

diabetes,

microalbuminuria

(20-200mcg/min;

30-300 mg/day) and normal renal function (serum creatinine ≤130 µmol/L in males and ≤100 µmol/L in females).

The study examined as a primary endpoint the long-term effects (2 years) of irbesartan on the progression to

(overt)

proteinuria

(urinary

albumin

excretion

rate

[AER]

>200

µg/min

[>

approximately

300 mg/day] and an increase in AER of at least 30% from baseline). In addition, after one and two years of

treatment, the effect of irbesartan on the change in overnight AER and the change in 24-hour creatinine clearance

was assessed. Patients were randomised to receive irbesartan 150 mg, irbesartan 300 mg, or matching placebo

once daily. Additional antihypertensive agents (excluding ACE inhibitors, angiotensin II receptor antagonists and

dihydropyridine calcium blockers) were added as needed to help achieve blood pressure goal (≤135/85 mmHg)

for patients in all groups. Irbesartan 300 mg demonstrated a 70% relative risk reduction in the development of

clinical

(overt)

proteinuria

compared

placebo

(95%

(39%,

86%),

p=0.0004).

Irbesartan

150mg

demonstrated

relative

risk

reduction

development

proteinuria

compared

placebo

(95% CI (-8%, 66%), p=0.085). In the intent to treat analysis, when the primary endpoint is adjusted for urinary

albumin excretion rate and mean arterial pressure, irbesartan 300 mg demonstrated a 68% relative risk reduction,

(95% CI (35%, 85%), p=0.002). The slowing of progression to clinical (overt) proteinuria was evident as early

as three months and continued over the 2 year period. The decline in 24-hour creatinine clearance did not differ

significantly among the 3 groups. Regression to normoalbuminuria (<20µg/min; <30mg/day) was more frequent

in the irbesartan 300 mg group (34%) than in the placebo group (21%).

The adverse experiences reported in these two studies are summarised under

ADVERSE EFFECTS -

Hypertension

and

Type

II

Diabetic

Renal

Disease

ADVERSE

EFFECTS

-

Laboratory

Test

Abnormalities

INDICATIONS

ABISART is indicated for the treatment of hypertension.

Abisart – PRODUCT INFORMATION

ABISART is indicated for delaying the progression of renal disease in hypertensive type II diabetics with

persistent micro-albuminuria (>30 mg per 24 hours) or urinary protein in excess of 900 mg per 24 hours.

CONTRAINDICATIONS

Irbesartan is contraindicated in patients who are hypersensitive to irbesartan or to any other component of the

irbesartan formulation.

Do not co-administer ABISART with aliskiren-containing medicines in patients with diabetes or with moderate

to severe renal impairment.

Do not co-administer ABISART with ACE inhibitors in patients with diabetic nephropathy.

Pregnancy (see

PRECAUTIONS - Use in Pregnancy

PRECAUTIONS

Hypotension - Volume-Depleted Patients

Irbesartan has been rarely associated with hypotension in hypertensive patients without other co-morbid

conditions. Symptomatic hypotension, as with ACE inhibitors, may be expected to occur in sodium/volume-

depleted patients such as those treated vigorously with diuretics and/or salt restriction, or on haemodialysis.

Volume and/or sodium-depletion should be corrected before initiating therapy with irbesartan or a lower starting

dose (e.g. 75 mg) should be considered. Patients undergoing haemodialysis should receive a starting dose of 75

mg and the dose should be adjusted according to B.P. response.

Renal Function

As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be

anticipated in susceptible individuals. In patients whose renal function depends on the activity of the renin-

angiotensin-aldosterone system (e.g. hypertensive patients with renal artery stenosis in one or both kidneys, or

patients with severe congestive heart failure), treatment with drugs that affect this system has been associated

with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death. The possibility of a

similar effect occurring with the use of an angiotensin II receptor antagonist, including irbesartan cannot be

excluded.

In hypertensive type II diabetic patients with proteinuria (≥ 900mg/day), a population which has a high risk of

renal artery stenosis, no patient treated with irbesartan in IDNT had an early acute rise in serum creatinine

attributable to renal artery disease (see

CLINICAL TRIALS

Experience is limited with irbesartan in patients with moderate to severe renal impairment; careful monitoring of

renal function and potassium in such patients is advised.

Hyperkalaemia

While hyperkalaemia in uncomplicated patients with hypertension has not been reported with irbesartan,

hyperkalaemia may occur during treatment with other drugs that affect the renin-angiotensin-aldosterone system,

especially in the presence of renal impairment and/or heart failure. Adequate monitoring of serum potassium in

patients at risk is recommended.

Dual blockade of the Renin-Angiotensin-Aldosterone System (RAAS)

Dual blockade of the RAAS by combining ABISART with an ACE inhibitor or with aliskiren is not recommended

since there are increased risks of hypotension, hyperkalemia, and changes in renal function compared to

Abisart – PRODUCT INFORMATION

monotherapy. The use of ABISART in combination with aliskiren is contraindicated in patients with diabetes

mellitus or with moderate to severe renal impairment (see

CONTRAINDICATIONS

The use of ABISART in combination with an ACE inhibitor is contraindicated in patients with diabetic

nephropathy (see

CONTRAINDICATIONS

INTERACTIONS WITH OTHER MEDICINES

Cardiac Disorders

The safety of irbesartan in the presence of heart failure has not been fully defined. Sudden death has occurred in

some studies of patients with heart failure, and although such deaths may have reflected the natural history of the

underlying heart failure, caution is recommended when treating such patients with irbesartan.

At this time, experience is limited with irbesartan in the treatment of patients with ventricular dysfunction or

cardiac arrhythmias; caution is advised.

Effects on Fertility

Fertility and reproductive performance were not affected in studies of male and female rats at oral doses of up to

650 mg/kg/day (approximately 3 (male) and 8 (female) fold higher exposure, based on AUC, than that of humans

at the maximum recommended clinical dose of 300 mg/day).

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 in patients who

were taking angiotensin-converting enzyme inhibitors. When pregnancy is detected, irbesartan 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 have 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 renal 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.

Nonetheless, when patients become pregnant, physicians should have the patient discontinue the use of irbesartan

as soon as possible.

Infants with histories of in utero exposure to an angiotensin II receptor antagonist should be closely observed for

hypotension, oliguria and hyperkalemia.

When pregnant rats were treated with irbesartan from day 0 to day 20 of gestation, at doses of 50mg/kg/day and

higher, transient effects (increased renal pelvic cavitation, hypoureter or subcutaneous oedema) were noted in

full term rat foetuses but not in the young animals necropsied after 6 weeks of age. In pregnant rabbits, at doses

of 30mg/kg/day, maternal mortality, abortion and early foetal resorptions were noted. No teratogenic effects were

observed in the rat or rabbit.

Use in Lactation

Irbesartan is excreted in the milk of lactating rats. It is not known whether irbesartan or its metabolites are excreted

in human milk. A decision should be made whether to discontinue breast feeding or to discontinue the drug,

taking into account the importance of irbesartan to the therapy of the mother and the potential risk to the infant.

Abisart – PRODUCT INFORMATION

Paediatric Use

Safety and effectiveness in paediatric patients have not been established.

Use in the Elderly

Among patients who received irbesartan in clinical studies, no overall differences in efficacy or safety were

observed between older patients (65 years or older) and younger patients.

Genotoxicity

Irbesartan was not genotoxic in a series of assays for mutagenic and clastogenic effects.

Carcinogenicity

The carcinogenic potential of irbesartan was assessed in two 104 week studies in mice and rats. No carcinogenic

potential

observed

either

species

doses

mg/kg/day

(males

rats)

1000 mg/kg/day (mice and female rats). The AUC based exposure levels were 3-6 fold higher in mice, 3 fold

higher in male rats and 25 fold higher in female rats than that of humans at the maximum recommended clinical

dose of 300 mg/day.

Effect on Laboratory Tests

No clinically significant changes in laboratory test parameters occurred in controlled clinical studies of

hypertension. No special monitoring of laboratory parameters is necessary for patients with uncomplicated

essential hypertension. Monitoring of potassium levels and renal function is recommended for patients with heart

failure and those with moderate to severe renal impairment (see

PRECAUTIONS

In two clinical studies of patients with hypertension and type II diabetic renal disease (IDNT and IRMA2) the

following was reported.

Hyperkalaemia:

In IDNT the percent of subjects with hyperkalaemia (>6 mmol/L) was 18.6% in the irbesartan

group compared to 6.0% in the placebo group. In IRMA 2 the percent of subjects with hyperkalaemia

(>6 mmol/L) was 1.0% in the irbesartan groups and none in the placebo group. In IDNT discontinuations due to

hyperkalaemia in the irbesartan group were 2.1% vs 0.36% in the placebo group. In IRMA 2 discontinuations

due to hyperkalaemia in the irbesartan groups were 0.5% vs none in the placebo group.

Effects on Ability to Drive or Use Machines

The effect of irbesartan on ability to drive and use machines has not been studied. When driving vehicles or

operating machines, it should be taken into account that occasionally dizziness or weariness may occur during

treatment of hypertension.

INTERACTIONS WITH OTHER MEDICINES

Based on

in vitro

data, no interactions would be expected to occur with drugs whose metabolism is dependent

upon cytochrome P450 isoenzymes

CYP

1A1,

CYP

1A2,

CYP

2A6,

CYP

2B6,

CYP

2D6,

CYP

2E1 or

CYP

3A4.

Irbesartan is primarily metabolised by

CYP

2C9, however, during clinical interaction studies, no significant

pharmacodynamic interactions were observed when irbesartan was co-administered with warfarin (a drug

metabolised by

CYP

2C9).

Irbesartan does not affect the pharmacokinetics of digoxin. The pharmacokinetics of irbesartan is not affected by

coadministration with nifedipine or hydrochlorothiazide.

Potassium-sparing diuretics, potassium supplements, potassium containing salt substitutes

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 medicinal

Abisart – PRODUCT INFORMATION

products that may increase kalaemia with irbesartan may lead to increases in serum potassium, sometimes severe,

and requires close monitoring of serum potassium.

Lithium

Increases in serum lithium concentrations and lithium toxicity have been reported with concomitant use of

irbesartan. Monitor lithium levels in patients receiving irbesartan and lithium.

Combination use of ACE inhibitors or angiotensin receptor antagonists, anti-inflammatory

drugs and thiazide diuretics

Concomitant use of a renin-angiotensin system inhibiting drug (ACE-inhibitor or angiotensin receptor antagonist),

an anti-inflammatory drug (NSAID, including COX-2 inhibitor) alone or with a thiazide diuretic may increase

the risk of renal impairment, including possible acute renal failure. These effects are usually reversible. This

includes use in fixed-combination products containing more than one class of drug. The combination of these

agents should be administered with caution, especially in the elderly, volume-depleted and in patients with pre-

existing renal impairment. Renal function (serum creatinine) should be monitored after initiation of concomitant

therapy, and periodically thereafter. The antihypertensive effect of angiotensin II receptor antagonists, including

irbesartan, may be attenuated by NSAIDs including selective COX-2 inhibitors.

The use of ABISART in combination with an ACE inhibitor is contraindicated in patients with diabetic

nephropathy and is not recommended in other patients (see

CONTRAINDICATIONS

PRECAUTIONS

Renin inhibitor

The combination of ABISART with aliskiren-containing medicinal products is contraindicated in patients with

diabetes mellitus or moderate to severe renal impairment and is not recommended in other patients (see

CONTRAINDICATIONS

Angiotensin-Converting Enzyme inhibitors (ACE inhibitors)

The combination of ABISART with ACE inhibitors is not recommended.

ADVERSE EFFECTS

Hypertension

Irbesartan has been evaluated for safety in approximately 5000 subjects in clinical studies, including 1300

hypertensive patients treated for over 6 months and over 400 patients treated for one year or more. Adverse events

in patients receiving irbesartan were generally mild and transient with no relationship to dose. The incidence of

adverse events was not related to age, gender, or race.

In placebo-controlled clinical studies, including 1965 irbesartan-treated patients (usual duration of treatment

1 to 3 months), discontinuations due to any clinical or laboratory adverse event were 3.3 percent for irbesartan-

treated patients and 4.5 percent for placebo-treated patients (p=0.029).

Clinical adverse events, occurring in at least 1% of patients treated with irbesartan in placebo controlled trials are

shown in the table below. The incidence of the same adverse events in the placebo control group is also shown.

Clinical Adverse Events* in Placebo-Controlled Hypertension Trials

Incidence Percentage (%) of Patients*

BODY SYSTEMEVENT

Irbesartan

n = 1965

Placebo

n = 641

General

Fatigue

Influenza

Chest pain

Cardiovascular

Abisart – PRODUCT INFORMATION

Oedema

Tachycardia

Gastrointestinal

Diarrhoea

Nausea/Vomiting

Dyspepsia/Heartburn

Abdominal Pain

Nervous System

Dizziness

Headache

Anxiety/Nervousness

12.3

16.7

Dermatological

Rash

Musculoskeletal/Connective

Musc/Skel Pain

Musc/Skel Trauma

Renal/Genitourinary

Respiratory

Upper Resp. Infection

Sinus Abnormality

Cough

Pharyngitis

Rhinitis

Statistically significant difference between irbesartan and placebo treatment groups.

Adverse reactions that occurred in 2 or more hypertensive patients in clinical trials involving 3396 patients have

been classified using standard terminology and in the following listing are categorised by body system and listed

in order of decreasing frequency according to the following definitions: common adverse reactions are those

occurring on one or more occasions in at least 1/100 but less than 1/10 patients; uncommon adverse reactions are

those occurring in at least 1/1000 but less than 1/100 patients; rare adverse reactions are those occurring in less

than 1/1000 patients.

Cardiovascular

Uncommon

: subjective rhythm disturbance, flushing, ECG abnormality, cardiac murmur,

cardiac rhythm disturbance, orthostatic hypotension, atrial rhythm disturbance, bradycardia, hypotension;

Rare:

syncope, conduction disorder, myocardial infarction.

Dermatologic

Uncommon

: pruritus, facial erythema;

Rare:

dermatitis, acne, scalp-hair abnormality.

Endocrine/Metabolic/Electrolyte Imbalance

Uncommon:

sexual dysfunction, libido change;

Rare:

breast

disorder, gout, hot flashes

.

Gastrointestinal

Uncommon:

constipation, flatulence, dry mouth, abdomen distention;

Rare:

abnormal stool,

decreased appetite, increased appetite, oral lesion, dysphagia, oesophagitis.

General

Uncommon:

weakness, hyperhidrosis, malaise, weight gain;

Rare:

cold sensation, warmth sensation,

pain.

Hematopoietic

Rare:

anaemia.

Immunology/Sensitivity Disorder

Uncommon:

upper extremity oedema;

Rare:

head/neck oedema.

Musculoskeletal/Connective Tissue

Uncommon:

muscle cramp, swelling extremity;

Rare:

arthritis, muscle

ache, myalgia, extremity weakness, stiffness lower extremity.

Nervous

System

Uncommon:

orthostatic

dizziness,

numbness,

sleep

disturbance,

depression,

emotion

labile/disturbance,

somnolence,

vertigo,

paresthesia;

Rare:

stress

related

disorder,

tremor,

coordination

disturbance, disturbing dreams.

Abisart – PRODUCT INFORMATION

Renal/Genitourinary

Uncommon:

urination abnormality.

Respiratory

Uncommon:

epistaxis, dyspnea.

Special Senses

Uncommon:

vision disturbance, hearing abnormality;

Rare:

eye disturbance - other, eyelid

abnormality, visual field abnormality, medication bad taste, taste disturbance.

Hypertension and Type II Diabetic Renal Disease

In clinical studies (see

CLINICAL TRIALS - Hypertension and type II diabetic renal disease

), the adverse

experiences were similar to those in clinical trials of hypertensive patients with the exception of orthostatic

symptoms

(dizziness,

orthostatic

dizziness

orthostatic

hypotension)

observed

IDNT

(proteinuria

≥900mg/day, and serum creatinine from 90-265 µmol/L). In IDNT orthostatic symptoms occurred more

frequently in the irbesartan group (dizziness 10.2%, orthostatic dizziness 5.4%, orthostatic hypotension 5.4%)

than in the placebo group (dizziness 6.0%, orthostatic dizziness 2.7%, orthostatic hypotension 3.2%). The rates

(percents) of discontinuations due to orthostatic symptoms for irbesartan versus placebo were: dizziness 0.3 vs

0.5; orthostatic dizziness 0.2 vs 0.0; and orthostatic hypotension, 0.0 vs 0.0.

Post-marketing Experience

As with other angiotensin-II receptor antagonists, rare cases of hypersensitivity reactions (urticaria, angioedema)

have been reported since the marketing of irbesartan. The following have been reported during post-marketing

surveillance: vertigo, asthenia, hyperkalaemia, thrombocytopenia, myalgia, jaundice, elevated liver function tests,

hepatitis, arthralgia, tinnitus and impaired renal function including isolated cases of renal failure in patients at

risk (see

PRECAUTIONS - General

Rare cases of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers.

DOSAGE AND ADMINISTRATION

Irbesartan may be used either alone or in combination with other antihypertensive agents (e.g., thiazide diuretic,

beta-adrenergic blocking agent, long-acting calcium-channel blocking agent).

The usual initial and maintenance dose of irbesartan is 150 mg once daily. Irbesartan may be administered with

or without food. Therapy should be adjusted according to blood pressure response. Patients requiring further

reduction in blood pressure should have the dose increased to 300 mg once daily.

In patients with hypertension and type II diabetic renal disease, 300 mg of irbesartan once daily is the preferred

maintenance dose. Although irbesartan slowed the progression of renal disease in hypertensive patients separately

to its effect on blood pressure, this does not remove the clinical requirement for a patient’s blood pressure to be

adequately controlled. If irbesartan alone is insufficient, then other agents should be added in order to gain blood

pressure control.

Irbesartan increases the risk of significant hyperkalaemia in hypertensive patients with type II diabetes and

moderate to severe renal insufficiency (see

PRECAUTIONS - Effect on Laboratory Test, Hyperkalaemia).

Serum potassium should be monitored regularly in such patients.

If blood pressure is not adequately controlled with irbesartan alone, a diuretic (e.g. hydrochlorothiazide 12.5 mg

daily) or another antihypertensive drug (e.g., beta-adrenergic blocking agent, long-acting calcium channel

blocking agent) may be added.

Patients with Intravascular Volume Depletion

: Volume and/or sodium- depletion should be corrected before

initiating therapy with irbesartan or a lower starting dose (e.g. 75 mg) should be considered. Patients undergoing

haemodialysis should receive a starting dose of 75 mg and the dose should be adjusted according to B.P. response.

If the blood pressure is not adequately controlled, the dose can be increased.

Elderly and Patients with Renal or Hepatic Impairment:

No dosage reduction is generally necessary in the

elderly or in patients with impaired hepatic function (mild to moderate degree) or impaired renal function

Abisart – PRODUCT INFORMATION

(regardless

degree),

unless

accompanied

uncorrected

volume

depletion

(see

DOSAGE

AND

ADMINISTRATION - Patients with Intravascular Volume Depletion

OVERDOSAGE

Experience in adults exposed to doses of up to 900 mg/day for 8 weeks revealed no toxicity. No specific

information is available on the treatment of overdosage with irbesartan. The patient should be closely monitored,

and the treatment should be symptomatic and supportive. If simple supine positioning is found insufficient to

correct hypotension, then judicious I.V. volume replacement/ augmentation may be indicated. Irbesartan is not

removed from the body by hemodialysis.

For information on the management of overdosage, contact the Poison Information Centre on 13 11 26 (Australia).

PRESENTATION AND STORAGE CONDITIONS

ABISART

75 mg

White to off white, film-coated, round, biconvex, bevelled edge tablet debossed

with “M” on one side and “IN1” on the other side.

PCTFE (Aclar)/Al blisters or PVC/PVDC blisters of 3, 5, 7, 14, 28, 30, 56, 98

tablets and HDPE bottles of 7, 14, 30, 90 tablets.

ABISART 150 mg

White to off white, film-coated, round, biconvex, bevelled edge tablet debossed

with “M” on one side and “IN2” on the other side.

PCTFE (Aclar)/Al blisters or PVC/PVDC blisters of 3, 5, 7, 14, 28, 30, 56, 98

tablets and HDPE bottles of 7, 14, 30, 90 tablets.

ABISART 300 mg

White to off white, film-coated, oval, biconvex, bevelled edge tablet debossed with

“M” on one side and “IN3” on the other side.

PCTFE (Aclar)/Al blisters or PVC/PVDC blisters of 3, 5, 7, 14, 28, 30, 56, 98

tablets and HDPE bottles 7, 14, 30, 90 tablets

Some strengths, pack sizes and/or pack types may not be marketed.

Storage

ABISART tablets should be stored below 25°C.

NAME AND ADDRESS OF THE SPONSOR

Alphapharm Pty Limited

Level 1, 30 The Bond

30-34 Hickson Road

Millers Point NSW 2000

ABN 93 002 359 739

www.mylan.com.au

Abisart – PRODUCT INFORMATION

POISON SCHEULE OF MEDICINE

S4 – Prescription Only Medicine

DATE OF FIRST INCLUSION IN THE AUSTRALIAN REGISTER OF

THERAPEUTIC GOODS (THE ARTG)

14/08/2012

DATE OF MOST RECENT AMENDMENT

13/06/2017

Abisart_pi\APR17/00

30-10-2018

Sciegen Pharmaceuticals, Inc. Issues Voluntary Nationwide Recall of Irbesartan Tablets, USP  75 Mg, 150 Mg, and 300 Mg Due to The Detection of Trace Amounts of NDEA (N-Nitrosodiethylamine) Impurity Found in The Active Pharmaceutical Ingredient (API)

Sciegen Pharmaceuticals, Inc. Issues Voluntary Nationwide Recall of Irbesartan Tablets, USP 75 Mg, 150 Mg, and 300 Mg Due to The Detection of Trace Amounts of NDEA (N-Nitrosodiethylamine) Impurity Found in The Active Pharmaceutical Ingredient (API)

ScieGen Pharmaceuticals, Inc. is voluntarily recalling listed lots, within expiry, of Irbesartan Tablets, USP 75 mg, 150 mg, and 300 mg dosage forms to the consumer level. These products are being recalled due to the presence of an impurity, N-nitrosodiethylamine (NDEA) contained in the API Irbesartan, USP manufactured by Aurobindo Pharma Limited. This impurity, which is a substance that occurs naturally in certain foods, drinking water, air pollution, and industrial processes, has been classified as a...

FDA - U.S. Food and Drug Administration

29-10-2018

Aurobindo Pharma Limited Issues Voluntary Recall of Irbesartan Drug Substance due to the Detection of Trace Amounts of NDEA (NNitrosodiethylamine) Impurity Found in the Active Pharmaceutical Ingredient (API)

Aurobindo Pharma Limited Issues Voluntary Recall of Irbesartan Drug Substance due to the Detection of Trace Amounts of NDEA (NNitrosodiethylamine) Impurity Found in the Active Pharmaceutical Ingredient (API)

Aurobindo Pharma Limited is voluntarily recalling 22 Batches of the drug substance Irbesartan due to the presence of an impurity, N-nitrosodiethylamine (NDEA). The impurity, which is a substance that occurs naturally in certain foods, drinking water, air pollution, and industrial processes, has been classified as a probable human carcinogen as per International Agency for Research on Cancer (IARC).

FDA - U.S. Food and Drug Administration

22-10-2018

Irbesartan / Hydrochlorothiazide Teva (Teva B.V.)

Irbesartan / Hydrochlorothiazide Teva (Teva B.V.)

Irbesartan / Hydrochlorothiazide Teva (Active substance: irbesartan / hydrochlorothiazide) - Centralised - Yearly update - Commission Decision (2018) 6974 of Mon, 22 Oct 2018

Europe -DG Health and Food Safety

12-10-2018

Irbesartan Zentiva (Zentiva k.s.)

Irbesartan Zentiva (Zentiva k.s.)

Irbesartan Zentiva (Active substance: Irbesartan) - Centralised - Transfer Marketing Authorisation Holder - Commission Decision (2018)6772 of Fri, 12 Oct 2018 European Medicines Agency (EMA) procedure number: EMEA/H/C/785T/79

Europe -DG Health and Food Safety

2-10-2018

CoAprovel (Sanofi Clir SNC)

CoAprovel (Sanofi Clir SNC)

CoAprovel (Active substance: Irbesartan / hydrochlorothiazide) - Centralised - Yearly update - Commission Decision (2018)6465 of Tue, 02 Oct 2018

Europe -DG Health and Food Safety

24-9-2018

Karvezide (Sanofi-Aventis groupe)

Karvezide (Sanofi-Aventis groupe)

Karvezide (Active substance: Irbesartan / hydrochlorothiazide) - Centralised - Yearly update - Commission Decision (2018)6222 of Mon, 24 Sep 2018

Europe -DG Health and Food Safety

1-8-2018

Aprovel (Sanofi Clir SNC)

Aprovel (Sanofi Clir SNC)

Aprovel (Active substance: Irbesartan) - Centralised - Yearly update - Commission Decision (2018)5198 of Wed, 01 Aug 2018

Europe -DG Health and Food Safety

23-7-2018

Irbesartan Zentiva (Sanofi-Aventis groupe)

Irbesartan Zentiva (Sanofi-Aventis groupe)

Irbesartan Zentiva (Active substance: Irbesartan) - Centralised - Yearly update - Commission Decision (2018)4892 of Mon, 23 Jul 2018

Europe -DG Health and Food Safety

17-7-2018

Karvea (Sanofi-Aventis groupe)

Karvea (Sanofi-Aventis groupe)

Karvea (Active substance: Irbesartan) - Centralised - Yearly update - Commission Decision (2018)4781 of Tue, 17 Jul 2018

Europe -DG Health and Food Safety

4-7-2018

Ifirmacombi (Krka d. d., Novo mesto)

Ifirmacombi (Krka d. d., Novo mesto)

Ifirmacombi (Active substance: Irbesartan / hydrochlorothiazide) - Centralised - Yearly update - Commission Decision (2018)4340 of Wed, 04 Jul 2018

Europe -DG Health and Food Safety