Consumer medicine information

Karbesat

Irbesartan

BRAND INFORMATION

Brand name

Karbesat Tablets

Active ingredient

Irbesartan

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Karbesat.

What is in this leaflet

This leaflet answers some common questions about KARBESAT.

It does not contain all of the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have benefits and risks. Your doctor has weighed the risks of you taking KARBESAT against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, talk to your doctor or pharmacist.

Keep this leaflet with your medicine. You may need to read it again.

What KARBESAT is used for

KARBESAT lowers high blood pressure, also called hypertension.

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 KARBESAT. 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.

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

KARBESAT 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. KARBESAT blocks angiotensin-II and therefore relaxes your blood vessels. This helps to lower your blood pressure.

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

Your doctor may have prescribed KARBESAT for another reason.

Ask your doctor if you have any questions about why KARBESAT has been prescribed for you.

KARBESAT is not recommended for use in children.

KARBESAT is available only with a doctor's prescription.

Before you take KARBESAT

When you must not take it

Do not take KARBESAT if you are allergic to medicines containing irbesartan or any of the ingredients listed at the end of this leaflet.

Do not take KARBESAT if you are pregnant.

KARBESAT may harm your developing baby if you take it during pregnancy.

Do not take KARBESAT if the expiry date (Exp.) printed on the pack has passed.

Do not take KARBESAT if the packaging is torn or shows signs of tampering.

Before you start to take it

Tell your doctor if you are allergic to any other medicines, foods, dyes or preservatives.

Tell your doctor if you are breastfeeding or wish to breastfeed.

Your doctor will discuss the risks and benefits of taking KARBESAT when breastfeeding.

Tell your doctor if you plan to become pregnant.

Tell your doctor if you have, or have had, any medical conditions, especially the following:

  • kidney problems
  • heart problems
  • liver problems
  • recent excessive vomiting or diarrhoea.

Tell your doctor if you are restricting salt intake in your diet.

If you have not told your doctor about any of the above, tell them before you start taking KARBESAT.

Taking other medicines

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

Some medicines may be affected by KARBESAT, or may affect how well it works. These include:

  • other medicines 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, used to relieve pain, swelling and other symptoms of inflammation, including arthritis. These include nonsteroidal anti-inflammatory agents - NSAIDs (for example Voltaren, Indocid) and COX-2 inhibitors (for example Celebrex).

Taking a combination of KARBESAT with a thiazide diuretic (fluid tablet) and an anti-inflamatory medicine may damage your kidneys.

Your doctor can tell you what to do if you are taking any of these medicines.

If you are not sure whether you are taking any of these medicines, check with your doctor or pharmacist.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking KARBESAT.

How to take KARBESAT

How much to take

The dose varies from patient to patient.

The usual starting dose is one 150 mg tablet once a day, although a lower dose may be needed in some patients.

Depending on how your blood pressure responds, your daily dose of KARBESAT may need to be increased. The full blood pressure lowering effect of KARBESAT should be reached about 4-6 weeks after starting treatment.

Most patients take either 150 mg or 300 mg each day.

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

Follow all directions given to you by your doctor and pharmacist carefully.

How to take KARBESAT

Swallow the tablets with a glass of water.

Take your daily dose of Karbesat at about the same time each day.

Taking your KARBESAT tablets at the same time each day will have the best effect.

To help you remember to take your tablets each day, KARBESAT tablets are supplied in a calendar pack with the foil backing marked with the days of the week. This is just a way to help you remember to take your tablets. All of the tablets in the pack are the same.

When you start a new strip of tablets take the tablet marked “START”. On the next day, take the tablet marked with the relevant day of the week. Continue taking your tablets each day until all of the tablets are taken. Commence the next strip at “START” and continue as before.

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

If you forget to take KARBESAT

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 the missed dose as soon as you remember, and then go back to taking your tablets as you would normally.

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

If you are not sure what to do, ask your doctor or pharmacist.

How long to take KARBESAT for

KARBESAT helps control your high blood pressure but does not cure it. To properly control your condition, KARBESAT must be taken every day.

Keep taking KARBESAT for as long as your doctor recommends.

If you take too much KARBESAT (overdose)

Immediately telephone your doctor, or the Poisons Information Centre (telephone 13 11 26), or go to Accident and Emergency at the nearest hospital, if you think you or anyone else may have taken too much KARBESAT. Do this even if there are no signs of discomfort or poisoning.

You may need urgent medical attention.

If you take too much KARBESAT, you may feel dizzy or lightheaded.

While you are taking KARBESAT

Things you must do

Before starting any new medicine, tell your doctor or pharmacist that you are taking KARBESAT.

Tell all the doctors, dentists and pharmacists who are treating you that you are taking KARBESAT.

If you become pregnant while taking KARBESAT, tell your doctor immediately.

If you plan to have surgery, including dental surgery, that needs a general anaesthetic, tell your doctor or dentist that you are taking KARBESAT.

Visit your doctor regularly so they can monitor your blood pressure and ensure that KARBESAT is working for you.

Things you must not do

Do not use KARBESAT to treat any other conditions unless your doctor tells you to.

Do not give KARBESAT 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 KARBESAT affects you.

KARBESAT may cause drowsiness, dizziness or light-headedness in some people. If any of these occur, do not drive, operate machinery or do anything else that could be dangerous.

If you drink alcohol, dizziness or light-headedness may be worse.

Be careful getting up from a sitting or lying position.

Dizziness, light-headedness or fainting may occur, especially when you get up quickly. Getting up slowly may help. This problem can be more common if you are also taking a diuretic (fluid tablets). 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.

Make sure you drink enough water during exercise and hot weather when you are taking KARBESAT, especially if you sweat a lot.

If you do not drink enough water while taking KARBESAT, 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 KARBESAT, tell your doctor.

This can also mean that you are losing too much water and your blood pressure may become too low.

Side effects

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

Like all other medicines, KARBESAT may have unwanted side effects in some people. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Do not be alarmed by this list of possible side effects.

You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

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

  • headache
  • dizziness or light-headedness
  • 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.

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

If any of the following happen, stop taking KARBESAT and tell your doctor immediately, or go to Accident and Emergency at the 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 or nettlerash.

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

Other side effects not listed above may also occur in some patients. Tell your doctor if you notice anything that is making you feel unwell.

After using KARBESAT

Storage

Keep KARBESAT where children cannot reach it.

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

Keep your tablets in a cool dry place where the temperature stays below 25°C.

Do not store KARBESAT or any other medicine in the bathroom or near a sink.

Do not leave KARBESAT in the car or on window sills.

Heat and dampness can destroy some medicines.

Disposal

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

Product description

What it looks like

KARBESAT comes in 3 strengths of tablets:

  • KARBESAT 75 - White, oval shaped coated tablet with ‘IS’ on one side and “>” on the other side
  • KARBESAT 150 - White, oval shaped coated tablet with “IS 150’ on one side and “>” on the other side
  • KARBESAT 300 - White, oval shaped coated tablet with ‘IS 300’ on one side and “>” on the other side.

Each pack contains 30 tablets.

Ingredients

The active ingredient in KARBESAT is irbesartan.

  • each KARBESAT 75 tablet contains 75 mg of irbesartan
  • each KARBESAT 150 tablet contains 150 mg of irbesartan
  • each KARBESAT 300 tablet contains 300 mg of irbesartan.

The tablets also contain:

  • microcrystalline cellulose
  • lactose
  • crospovidone
  • hyydroxypropylcellulose
  • purified talc
  • sodium stearylfumarate
  • Opadry II 8F18378 White.

The tablets do not contain gluten, sucrose, tartrazine or any other azo dyes.

Supplier

Aspen Pharma Pty Ltd
34-36 Chandos Street
St. Leonards NSW 2065
Australia

Australian registration numbers:
KARBESAT 75 - AUST R 171460
KARBESAT 150 - AUST R 171462
KARBESAT 300 - AUST R 171458

Date of preparation: July 2011

BRAND INFORMATION

Brand name

Karbesat Tablets

Active ingredient

Irbesartan

Schedule

S4

 

Name of the medicine

Irbesartan.

Excipients.

Microcrystalline cellulose, lactose, crospovidone, hydroxypropylcellulose, purified talc, sodium stearylfumarate and Opadry II complete film coating system 8F18378 White (ARTG 12135). The tablets are gluten free.

Description

Chemical name: 2-butyl-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-1,3-diazaspiro [4,4] non-1-en-4-one. Molecular formula: C25H28N6O. MW: 428.53. CAS: 138402-11-6. Irbesartan is a white or almost white crystalline powder that is practically insoluble in water, sparingly soluble in methanol and slightly soluble in methylene chloride.
Karbesat (irbesartan) is a nonpeptide angiotensin II receptor (AT1 subtype) antagonist. It is available as 75, 150 or 300 mg film coated tablets for oral administration.

Pharmacology

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 to 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 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.
In a comparative bioavailability study, healthy volunteers were administered a single dose of irbesartan 300 mg Karbesat 300 tablet or the Australian reference tablet of the corresponding dose. Results demonstrated bioequivalence of Karbesat 300 with the Australian reference tablet (Table 1).

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 litres.

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 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 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 irbesartan, 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 irbesartan on the progression of renal disease and all cause mortality were examined. In addition, a secondary endpoint, the effect of irbesartan on the risk of fatal or nonfatal cardiovascular events was assessed. Patients were randomised to receive irbesartan 75 mg, amlodipine 2.5 mg, or matching placebo once daily. Patients were then titrated to a maintenance dose of 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, 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 irbesartan 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 irbesartan 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 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 to placebo (95% CI (39%, 86%), p = 0.0004). Irbesartan 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, 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 (< 20 microgram/min; < 30 mg/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 and Adverse Effects, Laboratory test abnormalities.

Indications

Karbesat is indicated for the treatment of hypertension.
Karbesat 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.

Contraindications

Karbesat is contraindicated in patients who are hypersensitive to irbesartan or to any other component of the Karbesat formulation.
Pregnancy (see Precautions, Use in pregnancy).

Precautions

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 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 (≥ 900 mg/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.

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 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, Karbesat 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 Karbesat 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 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.

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 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.

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 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.

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 (males 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.

Genotoxicity.

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

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).

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, or salt substitutes containing potassium may lead to increases in serum potassium.

Lithium.

Reversible increases in lithium concentrations have been very rarely reported with irbesartan. Therefore if coadministration of Karbesat and lithium proves necessary, careful monitoring of serum lithium levels is necessary.

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) and a thiazide diuretic may increase the risk of renal impairment. 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 and in patients with pre-existing renal impairment. Renal function (serum creatinine) should be monitored after initiation of concomitant therapy, and periodically thereafter.

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 2. 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.

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.

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 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 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.

Laboratory test abnormalities.

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.

Postmarketing 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 very rarely during postmarketing surveillance: asthenia, hyperkalaemia, 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).
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 Karbesat is 150 mg once daily. Karbesat 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 Karbesat 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 Adverse Effects, Laboratory test abnormalities, Hyperkalaemia). Serum potassium should be monitored regularly in such patients.
If blood pressure is not adequately controlled with Karbesat 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 (regardless of degree), unless accompanied by uncorrected volume depletion (see Precautions, Hypotension, volume depleted patient patients).

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.
The Poisons Information Centre, telephone number 131 126, should be contacted for advice on management.

Presentation

Tablets (white, oval, film coated, marked > on reverse), 75 mg (marked IS, AUST R 171460), 150 mg (marked IS 150, AUST R 171462), 300 mg (marked IS 300, AUST R 171458).

Storage

Store below 25°C.

Poison Schedule

S4.