Consumer medicine information

Avapro Tablets

Irbesartan

BRAND INFORMATION

Brand name

Avapro

Active ingredient

Irbesartan

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Avapro Tablets.

What is in this leaflet

Read this leaflet carefully before taking AVAPRO. This leaflet answers some common questions about AVAPRO. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist. Do not throw this leaflet away. You may need to refer to it again later.

Always follow the instructions that your doctor and pharmacist give you about AVAPRO. If you have any concerns about taking AVAPRO, ask your doctor or pharmacist.

What is AVAPRO

AVAPRO is a trade name (manufacturer's name) for the medicine, irbesartan. This medicine is in the tablets your doctor has prescribed for you.

What AVAPRO is used for

AVAPRO lowers high blood pressure, which doctors call hypertension

Your doctor measured your blood pressure and found it to be too high. Everyone has blood pressure. This pressure helps get your blood all around your body. Your blood pressure may be different at different times of the day, depending on how busy or worried you are. You have hypertension (high blood pressure) which means your blood pressure stays high, even when you are calm and relaxed.

There are usually no symptoms of high blood pressure. The only way of knowing that you have hypertension is to have your blood pressure checked on a regular basis. High blood pressure, if not treated, can damage blood vessels in several organs such as the heart, the kidneys, the brain and the eyes. This may lead to heart attacks, heart or kidney failure, strokes, or blindness. There are usually no symptoms of high blood pressure before damage occurs, so your doctor needs to measure your blood pressure to see if it is too high.

High blood pressure can be treated and controlled with medicines such as AVAPRO. Your doctor may also have recommended that you adjust your lifestyle to help to lower your high blood pressure (losing weight, avoiding smoking, reducing alcohol consumption and restricting the amount of salt in the diet). Your doctor may also have encouraged the practice of regular, mild (not strenuous) exercise such as walking, swimming, etc.

AVAPRO is also used in the treatment of kidney disease in patients with high blood pressure and type 2 diabetes.

What AVAPRO does and how it works

AVAPRO belongs to a group of medicines known as angiotensin-II receptor antagonists. Angiotensin II is a substance produced in the body which causes blood vessels to tighten. AVAPRO blocks angiotensin-II and therefore relaxes your blood vessels. This helps to lower your blood pressure.

AVAPRO slows the decrease of kidney function in patients with high blood pressure and type 2 diabetes.

Your doctor may have prescribed AVAPRO for another use. If you want more information, ask your doctor.

When you must not take AVAPRO

Do not take AVAPRO if:

  • you are pregnant (or think you may be pregnant) or are planning to become pregnant
    Your baby may absorb this medicine in the womb and there is a possibility of harm to the baby.
  • you are breast-feeding
    It is not known if AVAPRO passes into breast milk, therefore it is not recommended to be taken while you are breast-feeding.
  • you are allergic to irbesartan or to any of the ingredients listed under Product Description at the end of this leaflet.
  • you are diabetic or have kidney problems and are being treated with an ACE inhibitor, any aliskiren-containing medicines or a group of medicines known as AIIRAs (medicines also used to treat high blood pressure);
  • the packaging is torn or shows signs of tampering
  • the expiry date on the pack has passed

If you take this medicine after the expiry date has passed, it may not work.

If you are not sure if you should start taking AVAPRO, talk to your doctor.

AVAPRO should not be given to children.

Before you start to take AVAPRO

Tell your doctor if:

  • you are or intend to become pregnant or plan to breast-feed
    AVAPRO should not be used during pregnancy or while breast-feeding
  • you have recently had excessive vomiting or diarrhoea
  • you suffer from any medical conditions especially:
    - kidney problems, or you have had a kidney transplant or dialysis
    - heart problems
    - liver problems, or have had liver problems in the past
    - diabetes
    - high levels of potassium in your blood
  • you are strictly restricting your salt intake
  • you are lactose intolerant or have had any allergies to any other medicine or any other substances, such as foods, preservatives or dyes.

Be sure you tell your doctor about any of these things before you take any AVAPRO.

Taking AVAPRO with other medicines

Tell your doctor if you are taking or intend to take any other medicines, including medicines that you buy without a prescription from your pharmacy, supermarket or health food shop.

It is especially important that you tell your doctor if you are taking, or plan to take any of the following:

  • other tablets for high blood pressure
  • fluid tablets or diuretics
  • lithium or lithium containing medicines (for example Lithicarb)
  • potassium tablets (for example Span-K, Slow-K, Mag-K)
  • potassium containing salt substitutes (for example Pressor-K)
  • anti-inflammatory medicines (these are used to relieve pain, swelling and other symptoms of inflammation, including arthritis) and include nonsteroidal anti-inflammatory agents - NSAIDs (for example Voltaren, Indocid, ibuprofen) and COX-2 inhibitors (for example Celebrex).
    Taking a combination of Avapro and an anti-inflammatory medicine, alone or with a thiazide diuretic (fluid tablet) may damage your kidneys. It may also reduce the effect AVAPRO has on reducing blood pressure.
  • a medicine containing aliskiren. Taking Avapro with aliskiren may affect your blood pressure, electrolyte balance and your kidney function

Your doctor will decide whether your treatment needs to be altered or whether you should have check ups or blood tests more frequently

How to take AVAPRO

The tablets should be taken regularly as directed by your doctor. The tablets should be swallowed with a glass of water.

How much to take:

Your doctor will tell you how many tablets to take each day.

Usually patients start with one 150 mg tablet once a day, however some patients may need a lower starting dose. Your doctor will tell you if this is necessary. The full blood pressure lowering effect of AVAPRO should be reached about 4-6 weeks after starting treatment.

Depending on how your blood pressure responds, your daily dose of AVAPRO may need to be increased. Most patients take either 150mg or 300mg each day.

In patients with high blood pressure and type 2 diabetes, 300mg once daily is the preferred maintenance dose for the treatment of associated kidney disease.

Follow all directions given to you by your doctor carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions on the box, ask your doctor or pharmacist for help.

When to take it:

You should try to take your daily dose of AVAPRO at about the same time each day. Taking your AVAPRO tablets at the same time each day will have the best effect.

It does not matter whether you take AVAPRO tablets before or after food.

How long to take it:

AVAPRO helps to control your high blood pressure, but it does not cure it. Therefore AVAPRO must be taken every day. Continue taking AVAPRO until your doctor tells you to stop.

If you miss a dose:

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to. Otherwise, take it as soon as you remember, and go back to taking your tablets as you would normally.

If you are not sure whether to skip the dose, talk to your doctor or pharmacist.

Do not take a double dose to make up for the missed dose.

If you have trouble remembering to take your tablets, ask your pharmacist for some hints.

If you take too much AVAPRO (overdose)

Immediately telephone your doctor or Poisons Information Centre (telephone 131126) or go to the Accident and Emergency Department at your nearest hospital, if you or anyone else may have taken too much AVAPRO. Do this even if there are no signs of discomfort or poisoning.

If you take too many AVAPRO tablets you will probably feel lightheaded or dizzy.

While you are using AVAPRO

Things you must do:

  • If you become pregnant while taking AVAPRO tell your doctor immediately.
  • Have your blood pressure checked when your doctor tells you to, to make sure AVAPRO is working.
  • If you are about to start on any new medicine, tell your doctor and pharmacist that you are taking AVAPRO.
  • Get up slowly when getting out of bed or standing up.
    You may feel light-headed or dizzy while taking AVAPRO, especially if you are also taking a diuretic (fluid tablet). This may become worse if you stand up quickly as your blood pressure may fall. Standing up slowly, especially when you get up from bed or chairs, will help your body get used to the change in position and blood pressure. This problem is not common. If it occurs talk to your doctor.
  • If you plan to have surgery or other treatment (even at the dentist) that needs a general anaesthetic, tell your doctor or dentist that you are taking AVAPRO.
  • Make sure you drink enough water during exercise and hot weather when you are taking AVAPRO, especially if you sweat a lot.
    If you do not drink enough water while taking AVAPRO, you may faint or feel light-headed or sick. This is because your body does not have enough fluid and your blood pressure is low. If you continue to feel unwell, tell your doctor.
  • If you have excessive vomiting and/or diarrhoea while taking AVAPRO, tell your doctor.
    This can also mean that you are losing too much water and your blood pressure may become too low.

Things you must not do:

  • Do not give AVAPRO tablets to anyone else, even if they have the same condition as you.

Things to be careful of:

  • Be careful driving or operating machinery until you know how AVAPRO affects you.
    As with many other medicines used to treat high blood pressure, AVAPRO may cause dizziness or light-headedness in some people. Make sure you know how you react to AVAPRO before you drive a car, operate machinery or do anything else that could be dangerous if you are dizzy or light-headed.
    If you drink alcohol, dizziness or light-headedness may be worse.

Side effects

AVAPRO helps most people with high blood pressure, but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not.

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking AVAPRO.

Tell your doctor if you notice any of the following and they worry you -

  • headache
  • dizziness or light-headedness (vertigo)
  • unusual tiredness or weakness, fatigue
  • nausea/vomiting
  • These are common side effects. They are generally mild and do not normally require treatment to be interrupted.

Tell your doctor immediately if you notice any of the following-

  • skin rash or itchiness
  • aching muscles or aching joints, not caused by exercise
  • muscle pain
  • buzzing, ringing or other persistent noise in the ears
  • yellowing of the skin and/or eyes, also called jaundice
  • symptoms that may indicate kidney disease, such as passing little or no urine, drowsiness, nausea, vomiting, breathlessness, loss of appetite and weakness
  • symptoms that may indicate high potassium levels in the blood such as nausea, diarrhoea, muscle weakness and change in heart rhythm
  • symptoms that may indicate low platelet count such as easy or excessive bruising, bleeding from gums or nose, prolonged bleeding from cuts and blood in urine or stools.

These are serious side effects. Skin rash and itchiness may be symptoms of an allergic reaction. You may need medical attention.

These side effects are not common.

If any of the following happen, stop taking AVAPRO and tell your doctor immediately or go to Accident and Emergency Department at your nearest hospital -

  • swelling to the face, lips, tongue or throat which may cause difficulty in swallowing or breathing.
  • severe and sudden onset of pinkish, itchy swellings on the skin, also called hives.

These are serious side effects. If you have them you may have had a serious allergic reaction to AVAPRO. You may need urgent medical attention or hospitalisation.

These side effects are very rare.

Other side effects not listed above may occur in some patients. If you notice any other unwanted effects, you should tell your doctor or pharmacist and ask for their advice.

After using AVAPRO

Storage:

Keep your AVAPRO tablets in the blister pack until it is time to take them. If you take the tablets out of the blister pack they may not keep well.

Keep AVAPRO tablets in a cool dry place where the temperature stays below 25°C. Do not store AVAPRO or any other medicine in the bathroom or near a sink. Do not leave them near a radiator, in a car on hot days or on a window sill.

Heat and dampness can destroy some medicines.

Keep all medicines out of the reach of children.

A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal:

If your doctor tells you to stop taking AVAPRO or the tablets have passed their expiry date, ask your pharmacist what to do with any tablets that are left over.

Product description

What it looks like

AVAPRO 75 mg tablets - white to off-white, oval, film-coated tablet with a heart shape on one side and "2871" on the other. Pack size: 30 tablets.
AUST R 101730

AVAPRO 150 mg tablets - white to off-white, oval, film-coated tablet with a heart shape on one side and "2872" on the other. Pack size: 30 tablets.
AUST R 101734

AVAPRO 300 mg tablets - white to off-white, oval, film-coated tablet with a heart shape on one side and "2873" on the other. Pack size: 30 tablets.
AUST R 101736

Active ingredients

AVAPRO 75 mg tablets - 75 mg irbesartan per tablet.

AVAPRO 150 mg tablets - 150 mg irbesartan per tablet.

AVAPRO 300 mg tablets - 300 mg irbesartan per tablet.

Other Ingredients

AVAPRO tablets also contain carnauba wax, croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, silicon dioxide, and OPADRY II complete film coating system 32F38977 WHITE.

Sponsored by

sanofi-aventis australia pty ltd
12-24 Talavera Road
Macquarie Park, NSW 2113.

Date of Preparation: April 2020.

This information in no way replaces the advice of your doctor or pharmacist.

AVAPRO® is a registered sanofi-aventis Trademark.

avapro-ccdsv14-cmiv18-29apr20

Published by MIMS June 2020

BRAND INFORMATION

Brand name

Avapro

Active ingredient

Irbesartan

Schedule

S4

 

1 Name of Medicine

Irbesartan.

2 Qualitative and Quantitative Composition

Avapro 75 mg tablets contain 75 mg of irbesartan.
Avapro 150 mg tablets contain 150 mg of irbesartan.
Avapro 300 mg tablets contain 300 mg of irbesartan.

Excipients with known effect.

Contains sugars (as lactose monohydrate).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Avapro 75 mg tablets are white, biconvex, oval-shaped tablets are marked with a heart on one side and on the other side 2871.
Avapro 150 mg tablets are white, biconvex, oval-shaped tablets are marked with a heart on one side and on the other side 2872.
Avapro 300 mg tablets are white, biconvex, oval-shaped tablets are marked with a heart on one side and on the other side 2873.

4 Clinical Particulars

4.1 Therapeutic Indications

Avapro is indicated for the treatment of hypertension.
Avapro is indicated for delaying the progression of renal disease in hypertensive type II diabetics with persistent microalbuminuria (≥ 30 mg per 24 hours) or urinary protein in excess of 900 mg per 24 hours.

4.2 Dose and Method of 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 Avapro is 150 mg once daily. Avapro 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 Avapro 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 Section 4.8 Adverse Effects (Undesirable Effects); Section 4.4 Special Warnings and Precautions for Use, Effects on laboratory tests, Hyperkalaemia). Serum potassium should be monitored regularly in such patients.
If blood pressure is not adequately controlled with Avapro 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 BP 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 (regardless of degree), unless accompanied by uncorrected volume depletion (see Patients with intravascular volume depletion).

4.3 Contraindications

Avapro is contraindicated in patients who are hypersensitive to irbesartan or to any other component of the Avapro formulation.
Do not coadminister Avapro with aliskiren containing medicines in patients with diabetes or with moderate to severe renal impairment.
Do not coadminister Avapro with ACE inhibitors in patients with diabetic nephropathy.
Pregnancy (see Section 4.6 Fertility, Pregnancy and Lactation).

4.4 Special Warnings and Precautions for Use

Hypotension, volume depleted patients.

Irbesartan has been rarely associated with hypotension in hypertensive patients without other comorbid 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 on salt restriction, or 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 BP 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 (≥ 900 mg/day), a population which has a high risk of renal artery stenosis, no patient treated with Avapro in IDNT had an early acute rise in serum creatinine attributable to renal artery disease. (See Section 5.1 Pharmacodynamic Properties.)
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 Avapro with an ACE inhibitor or with aliskiren is not recommended since there are increased risks of hypotension, hyperkalaemia, and changes in renal function compared to monotherapy. The use of Avapro in combination with aliskiren is contraindicated in patient with diabetes mellitus or renal impairment (see Section 4.3 Contraindications).
The use of Avapro in combination with an ACE inhibitor is contraindicated in patients with diabetic nephropathy (see Section 4.3 Contraindications; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Hypoglycemia.

Avapro may induce hypoglycaemia, particularly in patients treated for diabetes. Therefore, dose adjustment of antidiabetic treatment such as repaglinide or insulin may be required (see Section 4.8 Adverse Effects (Undesirable Effects)).

Psoriasis.

The use of Avapro in patients with psoriasis or a history of psoriasis should be carefully weighed as it may exacerbate psoriasis.

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.

Use in renal impairment.

See comments under Renal function, above.

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.

Paediatric use.

Safety and effectiveness in paediatric patients have not been established.

Effects 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 Section 4.4 Special Warnings and Precautions for Use).
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 Avapro 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 Avapro groups and none in the placebo group. In IDNT discontinuations due to hyperkalaemia in the Avapro group were 2.1% vs 0.36% in the placebo group. In IRMA 2 discontinuations due to hyperkalaemia in the Avapro groups were 0.5% vs none in the placebo group.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Based on in vitro data, no interactions would be expected to occur with drugs whose metabolism is dependent upon cytochrome P450 isoenzymes CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2D6, CYP2E1 or CYP3A4. Irbesartan is primarily metabolised by CYP2C9, however, during clinical interaction studies, no significant pharmacodynamic interactions were observed when irbesartan was coadministered with warfarin (a drug metabolised by CYP2C9).
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 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), and 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 Avapro in combination with an ACE inhibitor is contraindicated in patients with diabetic nephropathy and is not recommended in other patients (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).

Renin inhibitor.

The combination of Avapro 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 Section 4.3 Contraindications).

Angiotensin converting enzyme inhibitors (ACE inhibitors).

The combination of Avapro with ACE inhibitors is not recommended.

Repaglinide.

Irbesartan has the potential to inhibit OATP1B1. In a clinical study, it was reported that irbesartan increased the Cmax and AUC of repaglinide (substrate of OATP1B1) by 1.8-fold and 1.3-fold, respectively, when administered 1 hour before repaglinide. In another study, no relevant pharmacokinetic interaction was reported when the two drugs were co-administered. Therefore, dose adjustment of antidiabetic treatment such as repaglinide may be required (see Section 4.4 Special Warnings and Precautions for Use).

4.6 Fertility, Pregnancy and Lactation

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).
(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, Avapro 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 Avapro 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 hyperkalaemia.
When pregnant rats were treated with irbesartan from day 0 to day 20 of gestation, at doses of 50 mg/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 30 mg/kg/day, maternal mortality, abortion and early foetal resorptions were noted. No teratogenic effects were observed in the rat or rabbit.
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 breastfeeding 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.

4.7 Effects on Ability to Drive and 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.

4.8 Adverse Effects (Undesirable 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 Table 1. The incidence of the same adverse events in the placebo control group is also shown.
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.

Haematopoietic.

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, paraesthesia. Rare: stress related disorder, tremor, coordination disturbance, disturbing dreams.

Renal/ genitourinary.

Uncommon: urination abnormality.

Respiratory.

Uncommon: epistaxis, dyspnoea.

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 Section 5.1 Pharmacodynamic Properties, 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 and orthostatic hypotension) observed in IDNT (proteinuria ≥ 900 mg/day, and serum creatinine from 90-265 micromol/L). In IDNT orthostatic symptoms occurred more frequently in the Avapro 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 Avapro versus placebo were: dizziness 0.3 vs 0.5; orthostatic dizziness 0.2 vs 0.0; and orthostatic hypotension, 0.0 vs 0.0.

Postmarketing experience.

As with other angiotensin-II receptor antagonists, hypersensitivity reactions (urticaria, angioedema, anaphylactic reactions including anaphylactic shock) have been reported since the marketing of irbesartan. The following have been reported during post-marketing surveillance: vertigo, asthenia, hyperkalaemia, thrombocytopenia (including thrombocytopenic purpura), myalgia, jaundice, elevated liver function tests, hepatitis, arthralgia, tinnitus, anaemia, psoriasis (and psoriasis exacerbation) (see Section 4.4 Special Warnings and Precautions for Use), photosensitivity, impaired renal function including cases of renal failure in patients at risk, and hypoglycaemia (see Section 4.4 Special Warnings and Precautions for Use).
Rare cases of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers.

Reporting suspected adverse reactions.

Reporting of suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at http://www.tga.gov.au/reporting-problems.

4.9 Overdose

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

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: angiotensin II antagonist, plain, ATC code: C09CA04.

Mechanism of action.

Avapro (irbesartan) is a nonpeptide angiotensin II receptor (AT1 subtype) antagonist.
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 (AT1 subtype) receptors localized on vascular smooth muscle cells and in the adrenal cortex. It has no agonist activity at the AT1 receptor and a much greater affinity (more than 8500-fold) for the AT1 receptor than for the AT2 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.
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, or total cholesterol or HDL cholesterol. There was no effect on serum uric acid during chronic oral administration. Following repeated doses of irbesartan, there was no uricosuric effect.

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 randomised 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 mg.
Systolic/diastolic mean decreases in blood pressure at trough (24 hours postdosing), 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 300 mg 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%.
Two of the seven placebo controlled trials identified above and two additional studies examined the 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 postdosing) 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 150 mg irbesartan and 12.5 mg hydrochlorothiazide gave systolic/diastolic mean placebo adjusted blood pressure reductions at trough (24 hours postdosing) of 12.9/6.9 mmHg.
In patients not adequately controlled (SeDBP ≥ 90 mmHg) on irbesartan (up to 300 mg) alone, the addition of 12.5 mg 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.
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 Avapro, amlodipine and placebo. In 1715 hypertensive patients with type II diabetes (proteinuria ≥ 900 mg/day and serum creatinine 110-265 micromol/L in men and 90-265 micromol/L in women) the long-term effects (mean 2.6 years) of Avapro on the progression of renal disease and all cause mortality were examined. In addition, a secondary endpoint, the effect of Avapro on the risk of fatal or nonfatal cardiovascular events was assessed. Patients were randomised to receive Avapro 75 mg, amlodipine 2.5 mg, or matching placebo once daily. Patients were then titrated to a maintenance dose of 300 mg Avapro, 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. Avapro demonstrated a 20% relative risk reduction in the composite primary endpoint (first occurrence of any of the following: doubling of serum creatinine, endstage 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 Avapro and amlodipine groups. There was no significant difference in the assessment of fatal or nonfatal cardiovascular events (cardiovascular death, nonfatal 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 in 590 hypertensive patients with type II diabetes, microalbuminuria (20-200 microgram/min; 30-300 mg/day) and normal renal function (serum creatinine ≤ 130 micromol/L in males and ≤ 100 micromol/L in females). The study examined as a primary endpoint the long-term effects (2 years) of Avapro on the progression to (overt) proteinuria (urinary albumin excretion rate [AER] > 200 microgram/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 Avapro on the change in overnight AER and the change in 24 hour creatinine clearance was assessed. Patients were randomised to receive Avapro 150 mg, Avapro 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. Avapro 300 mg demonstrated a 70% relative risk reduction in the development of clinical (overt) proteinuria compared to placebo (95% CI (39%, 86%), p = 0.0004). Avapro 150 mg demonstrated a 39% relative risk reduction in the development of proteinuria compared to 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, Avapro 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 (< 20 microgram/min; < 30 mg/day) was more frequent in the Avapro 300 mg group (34%) than in the placebo group (21%).
The adverse experiences reported in these two studies are summarised (see Section 4.8 Adverse Effects (Undesirable Effects), Hypertension and type II diabetic renal disease; Section 4.4 Special Warnings and Precautions for Use, Effects on laboratory tests).

5.2 Pharmacokinetic Properties

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 radiolabelled 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 capsules and 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 (Vss) is 53-93 L.

Metabolism.

Following oral or intravenous administration of 14C-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 CYP2C9; isoenzyme CYP3A4 has negligible effect. It is not metabolised by, nor does it substantially induce or inhibit, most isoenzymes commonly associated with drug metabolism (i.e. CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2D6, or CYP2E1). Irbesartan does not induce nor inhibit isoenzyme CYP3A4.

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 14C-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 (t1/2) 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.

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 (Cmax) 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 t1/2 of irbesartan are approximately 20-25% greater in blacks than in whites; the peak plasma concentrations (Cmax) 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 haemodialysis.
In patients with hepatic insufficiency due to mild to moderate cirrhosis, the pharmacokinetics of irbesartan are not significantly altered.

5.3 Preclinical Safety Data

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 was observed in either species at doses of up to 500 mg/kg/day (male rats) and 1000 mg/kg/day (mice and female rats). The AUC based exposure levels were 3 to 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.

6 Pharmaceutical Particulars

6.1 List of Excipients

The inactive ingredients are: carnauba wax, croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, silicon dioxide, and Opadry II complete film coating system 32F38977 White.

6.2 Incompatibilities

Incompatibilities were either not accessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

Pack sizes include: 3, 5, 7*, 14, 28, 30*, 56 and 98 tablets in polyvinyl chloride/polyvinylidene chloride/aluminium (PVC/PVDC/Al) blisters.
* Indicates the packs marketed in Australia.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Irbesartan is a white, to practically white, powder that is less than 0.1 mg/mL soluble in water and slightly soluble in alcohol and methylene chloride.
Irbesartan is 2-butyl-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-1,3-diazaspiro [4,4] non-1-en-4-one.

Chemical structure.

The chemical structure of irbesartan is:
Irbesartan: C25H28N6O.
MW = 428.5.

CAS number.

138402-11-6.

7 Medicine Schedule (Poisons Standard)

Schedule 4.

Summary Table of Changes