Consumer medicine information

Avapro HCT Tablets

Irbesartan; Hydrochlorothiazide

BRAND INFORMATION

Brand name

Avapro HCT

Active ingredient

Irbesartan; Hydrochlorothiazide

Schedule

S4

 

Consumer medicine information (CMI) leaflet

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

What is in this leaflet

Read this leaflet carefully before taking AVAPRO HCT. This leaflet answers some common questions about AVAPRO HCT. 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 HCT. If you have any concerns about taking AVAPRO HCT, ask your doctor or pharmacist.

What is AVAPRO HCT

AVAPRO HCT is a trade name (manufacturer's name). AVAPRO HCT tablets contain two medicines, irbesartan and hydrochlorothiazide. Both these medicines are in the tablets your doctor has prescribed for you.

What AVAPRO HCT is used for

AVAPRO HCT 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 HCT. 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.

What AVAPRO HCT does and how it works

AVAPRO HCT contains irbesartan and hydrochlorothiazide. Both medicines reduce blood pressure in different ways. Irbesartan 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. Irbesartan blocks angiotensin-II and therefore relaxes your blood vessels. This helps to lower your blood pressure.

Hydrochlorothiazide belongs to the class of medicines known as diuretics. Diuretics cause an increase in the volume of urine. They also help with lowering blood pressure particularly when combined with other blood pressure reducing medicines.

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

When you must not take AVAPRO HCT

Do not take AVAPRO HCT 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.
  • you are allergic to irbesartan or hydrochlorothiazide or to sulfonamide derived medicines, 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).
  • you are not producing urine.
  • 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 HCT, talk to your doctor.

AVAPRO HCT should not be given to children.

Before you start to take AVAPRO HCT

Tell your doctor if:

  • you are or intend to become pregnant or plan to breast-feed
    AVAPRO HCT should not be used during pregnancy or while breast-feeding
  • you have recently had excessive vomiting or diarrhoea or think you are dehydrated
  • you suffer from any medical conditions especially:
    - kidney problems, or have had a kidney transplant or dialysis
    - heart problems
    - liver problems, or have had liver problems in the past
    - diabetes
    - gout or have had gout in the past
    - lupus erythematosus
    - high or low levels of potassium or sodium or other electrolytes in your blood
    - primary aldosteronism
  • 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.
  • have had a sympathectomy
  • you have been taking diuretics
  • you have a history of allergy or asthma
  • you have had skin cancer or you develop an unexpected skin lesion during the treatment. Treatment with hydrochlorothiazide, particularly long term use with high doses, may increase the risk of some types of skin and lip cancer (non-melanoma skin cancer). Protect your skin from sun exposure and UV rays while taking Avapro HCT.

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

Taking AVAPRO HCT with other medicines

Tell your doctor if you are taking 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.
  • other water 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 HCT and an anti-inflammatory medicine, alone or with a thiazide diuretic (fluid tablet) may damage your kidneys. It may also reduce the effect AVAPRO HCT has on reducing blood pressure.
  • a medicine containing aliskiren. Taking Avapro HCT with aliskiren may affect your blood pressure, electrolyte balance and your kidney function
  • alcoholic drinks
  • sleeping tablets
  • strong pain killing medicines such as codeine or morphine
  • medicines for diabetes (oral tablets or capsules or insulins)
  • calcium supplements, medicines containing calcium or calcium sparing drugs (for example Vitamin D therapy).
  • medicines for gout.
  • powder or granules used to help reduce cholesterol (Questran Lite or Colestid Granules).
  • heart medicines such as digoxin or antiarrhythmic medicines (for example Sotacor®).
  • corticosteroid medicines such as prednisone, cortisone or ACTH.
  • medicines used to treat cancer (cytotoxic medicines).
  • amantadine (Symmetrel), a medicine used to treat Parkinson's disease or to prevent influenza.
  • anticholinergic medicines, these can be used to treat Parkinson's disease, to relieve stomach cramps or spasms or used to prevent travel sickness.
  • carbamazepine anticonvulsant medication (such as Tegretol)
  • medicines used during surgery.
  • medicines used in an emergency situation such as adrenaline.

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

How to take AVAPRO HCT

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

How much to take:

AVAPRO HCT will usually be prescribed by your doctor if previous treatment does not produce a sufficient drop in your blood pressure. Your doctor will tell you how to switch from your previous treatment to AVAPRO HCT.

The usual dose of AVAPRO HCT is one tablet a day. The full blood pressure lowering effect should be reached 6-8 weeks after beginning treatment. If your blood pressure is not satisfactorily reduced with AVAPRO HCT, your doctor may prescribe another medicine to be taken with AVAPRO HCT.

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 always take your daily dose of AVAPRO HCT at about the same time each day. Taking your AVAPRO HCT tablets at the same time each day will have the best effect.

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

How long to take it:

AVAPRO HCT helps to control your high blood pressure, but does not cure it. Therefore AVAPRO HCT must be taken every day. Continue taking AVAPRO HCT 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 HCT (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 HCT. Do this even if there are no signs of discomfort or poisoning.

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

While you are using AVAPRO HCT

Things you must do:

  • If you become pregnant while taking AVAPRO HCT tell your doctor immediately.
  • Have your blood pressure checked when your doctor tells you to, to make sure AVAPRO HCT is working.
  • If you are about to start on any new medicine, tell your doctor and pharmacist that you are taking AVAPRO HCT.
  • Get up slowly when getting out of bed or standing up.
    You may feel light-headed or dizzy while taking AVAPRO HCT. 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. If you get dizzy or light-headed talk to your doctor.
  • If you plan to have surgery or other treatment (even at the dentist) that needs an anaesthetic, make sure that you tell your doctor or dentist that you are taking AVAPRO HCT
  • Make sure you drink enough water during exercise and hot weather when you are taking AVAPRO HCT, especially if you sweat a lot.
    If you do not drink enough water while taking AVAPRO HCT, 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 HCT, tell your doctor. This can also mean that you are losing too much water and your blood pressure may become too low.
  • Tell your doctor if you experience an increased sensitivity of the skin to the sun with symptoms of sunburn (such as redness, itching, swelling, blistering) occurring more quickly than normal

Things you must not do:

  • Do not give AVAPRO HCT 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 HCT affects you. As with many other medicines used to treat high blood pressure, AVAPRO HCT may cause dizziness or light-headedness in some people. Make sure you know how you react to AVAPRO HCT 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.
  • The hydrochlorothiazide contained in this medicine could produce a positive analytical result in an antidoping test.

Side effects

AVAPRO HCT 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 HCT.

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
  • pain in the stomach or gut; nausea and/or vomiting
  • sexual problems

These 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, weakness or paralysis of muscles
  • buzzing, ringing or other persistent noise in the ears
  • changes in heart rhythm
  • you are not urinating (passing water) as much as normal
  • numbness or tingling in fingers or toes
  • painful, swollen joints which may be symptoms of gout
  • fainting
  • yellowing of the skin and/or eyes, also known as jaundice
  • symptoms that may occur if you have developed diabetes, such as excessive thirst, passing greatly increased amounts of urine, increased appetite with weight loss, feeling tired, drowsy, weak, depressed, irritable and generally unwell
  • 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 changes 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
  • disturbances in your vision (such as blurred vision and seeing haloes around lights) and eye pain

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 HCT and tell your doctor immediately or go to casualty at your nearest hospital -

  • swelling to the face, lips, tongue or throat, which may cause difficulty in swallowing or breathing. If you have them, you may have a serious allergic reaction to AVAPRO HCT
  • severe and sudden onset of pinkish, itchy swellings on the skin, also called hives or nettle rash. If you have them, you may have a serious allergic reaction to AVAPRO HCT
  • symptoms that may indicate liver disease with nausea, vomiting, loss of appetite, feeling generally unwell, fever, itching, yellowing of the skin and eyes and dark coloured urine.

These are serious side effects. 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 HCT

Storage:

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

Keep AVAPRO HCT tablets in a cool dry place where the temperature stays below 25°C. Do not store AVAPRO HCT or any other medicine in the bathroom near a sink. Do not leave them near a radiator, in a car on a hot day 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 HCT 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 HCT 150/12.5 tablets - peach, oval, film-coated tablet with a heart shape on one side and "2875" on the other. Pack size: 30 tablets. AUST R 102017

AVAPRO HCT 300/12.5 tablets - peach, oval, film-coated tablet with a heart shape on one side and "2876" on the other. Pack size: 30 tablets. AUST R 102086

AVAPRO HCT 300/25 tablets - pink, oval, film-coated tablet with a heart shape on one side and "2788" on the other. Pack size: 30 tablets. AUST R 129436.

Active Ingredients

AVAPRO HCT 150/12.5 tablets - 150 mg Irbesartan and 12.5 mg Hydrochlorothiazide per tablet.

AVAPRO HCT 300/12.5 tablets - 300 mg Irbesartan and 12.5 mg Hydrochlorothiazide per tablet.

AVAPRO HCT 300/25 tablets - 300 mg Irbesartan and 25 mg Hydrochlorothiazide per tablet.

Other Ingredients

AVAPRO HCT 150/12.5 tablets and 300/12.5 tablets also contain carnauba wax, croscarmellose sodium, hypromellose, lactose monohydrate, OPADRY II complete film coating system 32F24503 PINK, magnesium stearate, microcrystalline cellulose, and silicon dioxide.

AVAPRO HCT 300/25 tablets also contain carnauba wax, microcrystalline cellulose, croscarmellose sodium, lactose monohydrate, magnesium stearate, silicon dioxide, pregelatinised maize starch, OPADRY II Complete film coating system 32F24304 PINK, iron oxide yellow, and iron oxide red.

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® HCT is a registered sanofi-aventis Trademark.

avapro-hct-ccdsv15-cmiv10-29apr20

Published by MIMS June 2020

BRAND INFORMATION

Brand name

Avapro HCT

Active ingredient

Irbesartan; Hydrochlorothiazide

Schedule

S4

 

1 Name of Medicine

Irbesartan/hydrochlorothiazide.

2 Qualitative and Quantitative Composition

Avapro HCT 150/12.5 tablets contain 150 mg of irbesartan and 12.5 mg of hydrochlorothiazide.
Avapro HCT 300/12.5 tablets contain 300 mg of irbesartan and 12.5 mg of hydrochlorothiazide.
Avapro HCT 300/25 tablets contain 300 mg of irbesartan and 25 mg of hydrochlorothiazide.

Excipients with known effect.

Lactose monohydrate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Avapro HCT 150/12.5 tablets are peach to mottled peach coloured, biconvex, oval-shaped, film-coated tablets debossed with a heart on one side and the number "2875" on the other side.
Avapro HCT 300/12.5 tablets are peach to mottled peach coloured, biconvex, oval-shaped, film-coated tablets debossed with a heart on one side and the number "2876" on the other side.
Avapro HCT 300/25 tablets are pink, biconvex, oval-shaped, film-coated tablets debossed with a heart on one side and the number "2788" on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Avapro HCT is indicated for the treatment of hypertension. Treatment should not be initiated with this fixed-dose combination.

4.2 Dose and Method of Administration

Avapro HCT should not be initiated as first-line therapy. The daily dose can be administered with or without food.

Replacement therapy.

The combination may be substituted for the titrated components at the same dose level.

Dose titration by clinical effect.

When clinically appropriate, direct change from monotherapy to the fixed combinations may be considered:
Avapro HCT 150/12.5 mg may be administered to patients whose blood pressure is not adequately controlled with hydrochlorothiazide or irbesartan 150 mg alone;
Avapro HCT 300/12.5 mg may be administered to patients insufficiently controlled by irbesartan 300 mg or by Avapro HCT 150/12.5 mg;
Avapro HCT 300/25 mg may be administered to patients insufficiently controlled by Avapro HCT 300/12.5 mg.
Doses higher than 300 mg irbesartan/25 mg hydrochlorothiazide once daily are not recommended. When necessary, Avapro HCT may be administered with another antihypertensive drug.

Patients with intravascular volume depletion.

In severely volume-depleted and/or sodium-depleted patients, such as those treated vigorously with diuretics, the condition should be corrected prior to administration of Avapro HCT.

Elderly patients.

No dosage reduction is generally necessary for daily dosage of irbesartan 150 mg/ hydrochlorothiazide 12.5 mg in the elderly.

Patients with renal impairment.

No dosage reduction is generally necessary for daily dosage of irbesartan 150 mg/ hydrochlorothiazide 12.5 mg in patients with mild to moderate renal impairment (creatinine clearance > 30 mL/min).

Patients with hepatic impairment.

No dosage reduction is thought to be necessary in patients with mild to moderate hepatic impairment as the pharmacokinetics of neither irbesartan nor hydrochlorothiazide are affected by hepatic impairment. Due to the hydrochlorothiazide component, Avapro HCT should be used with caution in patients with severe hepatic impairment (see Section 4.4 Special Warnings and Precautions for Use).

4.3 Contraindications

Avapro HCT is contraindicated in patients who are hypersensitive to irbesartan, sulfonamide derived drugs (e.g. thiazides), or to any other component of the Avapro HCT formulation. In general, hypersensitivity reactions are more likely to occur in patients with a history of allergy or bronchial asthma.
Avapro HCT is contraindicated in patients who are anuric.
Do not co-administer Avapro HCT with aliskiren containing medicines in patients with diabetes or with moderate to severe renal impairment.
Do not co-administer Avapro HCT 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

Non-melanoma skin cancer.

An increased risk of non-melanoma skin cancer (NMSC) [basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)] with increasing cumulative dose of hydrochlorothiazide (HCTZ) exposure has been observed in two epidemiological studies based on Danish National Cancer Registry (see Section 5.1 Pharmacodynamic Properties). Photosensitizing actions of HCTZ could act as a possible mechanism for NMSC.
Patients taking HCTZ should be informed of the risk of NMSC and advised to regularly check their skin for any new lesions and promptly report any suspicious skin lesions.
Possible preventive measures such as limited exposure to sunlight and ultraviolet (UV) rays and, in case of exposure, adequate protection should be advised to the patients in order to minimise the risk of skin cancer. Suspicious skin lesions should be promptly examined potentially including histological examinations of biopsies. The use of HCTZ may also need to be reconsidered in patients who have experienced previous non-melanoma skin cancer (see Section 4.8 Adverse Effects (Undesirable Effects)).

Hypotension, volume-depleted patients.

Avapro HCT has been rarely associated with hypotension in hypertensive patients without other risk factors for hypotension. Symptomatic hypotension may be expected to occur in patients who have been sodium and/or volume depleted by vigorous diuretic therapy and/or dietary salt restriction, or vomiting and/or diarrhoea or haemodialysis. Volume and/or sodium depletion should be corrected before initiating therapy with Avapro HCT. Thiazides may potentiate the action of other antihypertensive drugs (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Renal impairment.

As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function during therapy with Avapro HCT 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 Avapro HCT cannot be excluded.
There is no experience with Avapro HCT in patients with a recent renal transplant.
Avapro HCT is not recommended for patients with severe renal disease (creatinine clearance ≤ 30 mL/min) (see Section 4.3 Contraindications). Hydrochlorothiazide-associated precipitation of azotemia may occur in patients with impaired renal function. As experience is limited in patients with a creatinine clearance > 30 and < 60 mL/min, Avapro HCT should be administered with caution to such patients.

Hyperkalaemia.

Concomitant use of irbesartan with potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium or other medicinal products which may increase the potassium level (e.g. trimethoprim containing medicines) may lead to an increase in serum potassium and should therefore be co-administered cautiously with irbesartan.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS).

Dual blockade of the RAAS by combining Avapro HCT with an ACE inhibitor or with aliskiren is not recommended since there are increased risk of hypotension, hyperkalaemia, and changes in renal function. The use of Avapro HCT in combination with aliskiren is contraindicated in patient with diabetes mellitus or renal impairment (see Section 4.3 Contraindications).
The use of Avapro HCT in combination with aliskiren is contraindicated in patients with diabetes mellitus or with moderate to severe renal impairment.
The use of Avapro HCT 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).

Psoriasis.

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

Renal artery stenosis.

See comments under Renal impairment, above.

Primary aldosteronism.

Patients with primary aldosteronism generally will not respond to antihypertensive medicines acting through inhibition of the renin angiotensin system. Therefore the use of Avapro HCT is not recommended.

Postsympathectomy.

The antihypertensive effects of thiazide diuretics may be increased in the postsympathectomy patient.

Fluid and electrolyte imbalance.

Thiazides, including HCTZ, can cause fluid or electrolyte imbalance (hypokalaemia, hyponatremia and hypochloraemic alkalosis). Although hypokalaemia may develop when thiazide diuretics are used alone, especially with higher doses, concurrent therapy with irbesartan reduces the frequency of diuretic induced hypokalaemia. Chloride deficit is generally mild and usually does not require treatment. Calcium excretion is decreased by thiazides which may cause intermittent and slight elevation of serum calcium. Marked hypercalcaemia suggests the possibility of hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function. Thiazides have been shown to increase the urinary excretion of magnesium, which may result in hypomagnesaemia.
Monitoring of laboratory parameters may be necessary in patients at risk of electrolyte imbalance.

Metabolic and endocrine effects.

Hyperuricemia may occur, and an acute attack of gout may be precipitated in certain patients receiving thiazide therapy. Insulin requirements in diabetic patients may be increased and latent diabetes mellitus may become manifest during thiazide administration. Increases in cholesterol and triglyceride levels have been associated with thiazide diuretic therapy, however, minimal or no effects were reported at the 12.5 mg hydrochlorothiazide dose contained in Avapro HCT.
Monitoring of laboratory parameters may be necessary in patients at risk of metabolic disturbances.

Hypoglycemia.

Irbesartan may induce hypoglycemia, 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)).

Systemic lupus erythematosus.

Exacerbation or activation of systemic lupus erythematosus has been reported with the use of thiazide diuretics.

Secondary acute angle-closure glaucoma and/or acute myopia.

Hydrochlorothiazide is a sulfonamide. Sulfonamide, or sulfonamide derivative, drugs can cause an idiosyncratic reaction, which may result in secondary acute angle-closure glaucoma and/or acute myopia. Isolated cases of acute angle-closure glaucoma without definite causal association have been reported with hydrochlorothiazide. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue drug intake as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy (see Section 4.8 Adverse Effects (Undesirable Effects)).

Photosensitivity.

Photosensitivity reactions have been reported with the use of thiazide diuretics.
If the photosensitivity reactions occur during treatment with hydrochlorothiazide drugs, treatment should be stopped.

Heart failure.

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.

Cardiac arrhythmia.

At this time, experience is limited with irbesartan in the treatment of patients with ventricular dysfunction or cardiac arrhythmias; caution is advised.

Use in hepatic impairment.

Avapro HCT should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations in fluid and electrolyte balance may precipitate hepatic coma.

Use in renal impairment.

See comments under Renal impairment, above.

Use in the elderly.

Among patients who received Avapro HCT 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.

In premarketing controlled clinical trials, clinically important changes in standard laboratory parameters were rarely associated with administration of Avapro HCT tablets.

Creatinine, blood urea nitrogen.

Minor increases in blood urea nitrogen (BUN) or serum creatinine were observed in 2.3 and 1.1 percent respectively, of patients with essential hypertension treated with Avapro HCT alone. No patient discontinued taking Avapro HCT due to increased BUN. One patient discontinued taking Avapro HCT due to a minor increase in creatinine.

Haemoglobin.

Mean decreases of approximately 0.2 g/dL occurred in patients treated with Avapro HCT alone, but were rarely of clinical importance. This compared to a mean of 0.4 g/dL in patients receiving placebo. No patients were discontinued due to anaemia.

Liver function tests.

Occasional elevations of liver enzymes and/or serum bilirubin have occurred. In patients with essential hypertension treated with Avapro HCT alone, one patient was discontinued due to elevated liver enzymes.

Serum electrolytes.

In double blind clinical trials of various doses of irbesartan and hydrochlorothiazide, the incidence of hypertensive patients who developed hypokalaemia (serum potassium < 3.5 mmol/L) was 7.5% versus 6.0% for placebo; the incidence of hyperkalaemia (serum potassium > 5.7 mmol/L) was < 1.0% versus 1.7% for placebo. No patient discontinued due to increases or decreases in serum potassium. Overall, the combination of irbesartan and hydrochlorothiazide had no effect on serum potassium. Higher doses of irbesartan ameliorated the hypokalaemic response to hydrochlorothiazide (see Section 4.4 Special Warnings and Precautions for Use).

4.5 Interactions with Other Medicines and Other Forms of Interactions

Based on in vitro data, no interactions with irbesartan 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 metabolized by CYP2C9, however, during clinical interaction studies, no significant pharmacokinetic and pharmacodynamic interactions were observed when irbesartan was coadministered with warfarin (a drug metabolized by CYP2C9).
Irbesartan does not affect the pharmacokinetics of digoxin or simvastatin. The pharmacokinetics of irbesartan are not affected by co-administration with nifedipine or hydrochlorothiazide.
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 potassium (e.g. trimethoprim containing medicines) with irbesartan may lead to increases in serum potassium, sometimes severe, and requires close monitoring of serum potassium. Concurrent therapy with hydrochlorothiazide may reduce the frequency of this effect.

Alcohol, barbiturates or narcotics.

Potentiation of thiazide diuretic-induced orthostatic hypotension may occur.

Antidiabetic drugs (oral agents and insulin).

Thiazides may elevate blood glucose levels thus, dosage adjustments of antidiabetic agents may be necessary.

Antigout medication.

Dosage adjustments of antigout medication may be needed since HCTZ may raise the blood level of uric acid.

Cardiac glycosides (e.g. digoxin) and other antiarrhythmic drugs (e.g. sotalol).

Diuretic induced hypokalaemia may accentuate cardiac arrhythmias.

Calcium salts.

Thiazide diuretics may increase serum calcium levels due to decreased excretion. If calcium or a calcium sparing drug (e.g. vitamin D therapy) is prescribed, serum calcium levels should be monitored and calcium dosage adjusted accordingly.

Colestyramine resin and colestipol HCl.

May delay or decrease absorption of HCTZ. Avapro HCT should be taken at least one hour before or four hours after these medications.

Lithium.

Diuretic agents reduce the renal clearance of lithium and increase the risk of lithium toxicity. Increases in serum lithium concentrations and lithium toxicity have been reported with concomitant use of irbesartan. Co-administration with Avapro HCT should be approached with caution and frequent monitoring of serum lithium levels is recommended.

Inhibitors of endogenous prostaglandin synthesis (i.e. NSAIDs).

In some patients, these agents can reduce the effects of thiazide diuretics.

Other diuretics and antihypertensive medications.

The thiazide component of Avapro HCT may potentiate the actions of other antihypertensive drugs, especially ganglionic or peripheral adrenergic-blocking drugs. HCTZ may interact with diazoxide; blood glucose, serum uric acid levels and blood pressure should be monitored.

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 HCT 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).

Renin inhibitor.

The combination of Avapro HCT 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 use of Avapro HCT in combination with an ACE inhibitor is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.

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).

Drugs used during surgery.

The effects of nondepolarising muscle relaxants (e.g. tubocurarine), preanaesthetics and anaesthetics used in surgery may be potentiated by HCTZ; dosage adjustments may be required. Preanaesthetic and anaesthetic agents should be given in reduced dosage, and if possible, HCTZ therapy discontinued one week prior to surgery.

Carbamazepine.

Concomitant use of carbamazepine and hydrochlorothiazide has been associated with the risk of symptomatic hyponatraemia. Electrolytes should be monitored during concomitant use. If possible, another class of diuretics should be used.

Pressor amines (e.g. noradrenaline).

Due to the thiazide component there is a possible decreased response to pressor amines but not sufficient to preclude their use.

Corticosteroids, ACTH.

Intensified electrolyte depletion, particularly hypokalaemia, can occur with thiazide use.

Other interactions.

The hypoglycaemic effect of beta-blockers and diazoxide may be enhanced by thiazides. Anticholinergic agents (e.g. atropine) may increase the bioavailability of thiazide-type diuretics by decreasing gastrointestinal motility and stomach emptying rate. Thiazides may increase the risk of adverse effects caused by amantadine. Thiazides may reduce the renal excretion of cytotoxic drugs (e.g. cyclophosphamide monohydrate, methotrexate) and potentiate their myelosuppressive effects.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

The effects of hydrochlorothiazide and the irbesartan/ hydrochlorothiazide combination on fertility have not been evaluated in animal studies. However, with irbesartan alone, fertility and reproductive performance were not affected in studies of male and female rats at oral doses 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 HCT 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 HCT 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.
Thiazides cross the placental barrier and appear in cord blood. The routine use of diuretics in otherwise healthy pregnant women is not recommended and exposes mother and foetus to unnecessary hazard, including foetal or neonatal jaundice, thrombocytopenia and possibly other adverse reactions which have occurred in the adult.
No teratogenic effects were seen in rats given irbesartan and hydrochlorothiazide in combination at doses as high as 150/150 mg/kg/day. When pregnant rats were treated with irbesartan alone from day 0 to day 20 of gestation, at doses of 50 mg/kg/day and higher, transient effects (increased renal pelvic cavitation, hydroureter or subcutaneous oedema) were noted in full term rat foetuses but not in young animals necropsied after six 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 the rabbit.
Irbesartan is excreted in the milk of lactating rats. It is not known whether irbesartan or its metabolites are excreted in human milk. Hydrochlorothiazide is excreted in human breast milk. Thiazides in high doses causing intense diuresis can inhibit the milk production. The use of Avapro HCT during breastfeeding is not recommended.
Because of the potential risk to the infant, a decision should be made whether to discontinue breastfeeding or to discontinue the drug, taking into account the importance of Avapro HCT to the therapy of the mother.

4.7 Effects on Ability to Drive and Use Machines

The effects of Avapro HCT on the ability to drive motor vehicles or operate machinery have not been specifically studied, but based on its pharmacodynamic properties. Avapro HCT is unlikely to affect this ability. When driving vehicles or operating machinery, it should be taken into account that occasionally dizziness may occur during treatment of hypertension.

4.8 Adverse Effects (Undesirable Effects)

The combination of irbesartan and hydrochlorothiazide has been evaluated for safety in approximately 2750 subjects in clinical studies, including 1540 hypertensive patients treated for over 6 months and over 960 patients treated for one year or more. Adverse events in patients receiving Avapro HCT 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 898 irbesartan/ HCTZ-treated patients (usual duration of treatment 2 to 3 months), discontinuations due to any clinical or laboratory adverse event were 3.6 percent for irbesartan/ HCTZ-treated patients and 6.8 percent for placebo treated patients (p = 0.023).
Adverse events occurring in at least 1% of patients treated with irbesartan/ HCTZ, in placebo controlled trials are shown in Table 1.
The incidences of the same adverse events in the placebo, irbesartan and hydrochlorothiazide control groups are also shown.
Adverse reactions (clinical events probably or possibly related to therapy as determined by the clinical investigator) that occurred in more than 2 hypertensive patients when they were taking irbesartan/ HCTZ and no additional study medications in premarketing clinical trials involving 2700 subjects, and that were not reported in the tabulation of adverse events, are listed in the following section.
These adverse reactions have been classified using standard terminology and are categorized by body system. They are listed in order of decreasing frequency according to the following definitions: common: those adverse reactions occurring on one or more occasions in at least 1/100 but less than 1/10 patients; uncommon: adverse reactions occurring in at least 1/1000 but less than 1/100 patients; rare: those adverse reactions occurring in less than 1/1000 patients.

Cardiovascular.

Uncommon: bradycardia; disturbance of cardiac rhythm; subjective disturbance of cardiac rhythm; disturbance of ventricular rhythm; ECG abnormality; flushing; hypotension; orthostatic hypotension; syncope.

Dermatologic.

Uncommon: pruritus; skin discomfort.

Endocrine/ metabolic.

Common: sexual dysfunction.
Uncommon: diabetes; gout; hot flashes; libido changes.

Gastrointestinal.

Uncommon: constipation; decreased appetite; abdominal distention; dry mouth; epigastric pain; flatulence; gastroesophageal reflux.

General.

Uncommon: cold sensation; hyperhidrosis; malaise; weakness; weight gain.

Musculoskeletal/ connective tissue.

Uncommon: abnormal reflexes; muscle ache; myalgia; extremity swelling; extremity weakness.

Nervous system.

Uncommon: coordination disturbance; depression; emotional lability/ disturbance; numbness; paraesthesia; sleep disturbance; somnolence; vertigo.

Respiratory.

Uncommon: dry nasopharynx; dyspnoea; wheezing.

Special senses.

Uncommon: abnormal hearing; taste disturbance; vision disturbance.
Other clinical adverse reactions reported with the use of irbesartan or hydrochlorothiazide alone include:

Cardiovascular.

Subjective rhythm disturbance, flushing, ECG abnormality, cardiac murmur, cardiac rhythm disturbance, orthostatic hypotension, atrial rhythm disturbance, conduction disorder, myocardial infarction.

Dermatologic.

Facial erythema, dermatitis, acne, scalp hair abnormality.

Endocrine/ metabolic/ electrolyte imbalance.

Breast disorder, hyperglycaemia, glycosuria, hyperuricaemia, electrolyte imbalance (including hyponatraemia and hypokalaemia).

Gastrointestinal.

Abnormal stool, increased appetite, oral lesion, dysphagia, oesophagitis, anorexia, gastric irritation, jaundice (intrahepatic cholestatic jaundice), pancreatitis, sialadenitis, xanthopsia.

General.

Weakness, weight gain, warmth sensation, pain.

Haematopoietic.

Leucopenia, neutropenia/ agranulocytosis, thrombocytopenia, anaemia, aplastic anaemia, haemolytic anaemia.

Immunology/ sensitivity disorder.

Upper extremity oedema, head/ neck oedema, photosensitivity reactions, fever, urticaria, necrotizing angiitis, (vasculitis, cutaneous vasculitis), respiratory distress (including pneumonitis and pulmonary oedema), anaphylactic reactions, toxic epidermal necrolysis.

Musculoskeletal/ connective tissue.

Arthritis, stiffness lower extremity, muscle spasm, weakness.

Nervous system.

Stress related disorder, tremor, disturbing dreams, restlessness.

Renal/ genitourinary.

Urination abnormality, renal dysfunction, interstitial nephritis.

Respiratory.

Epistaxis.

Special senses.

Eye disturbance-other, eyelid abnormality, visual field abnormality, medication bad taste, eye disorders (transient blurred vision, secondary acute angle-closure glaucoma and/or acute myopia) (see Section 4.4 Special Warnings and Precautions for Use).

Postmarketing experience.

As with other angiotensin-II receptor antagonists, hypersensitivity reactions (urticaria, angioedema, anaphylactic reactions including anaphylactic shock) have been reported. The following have also been reported during post-marketing surveillance: vertigo, asthenia, hyperkalaemia, thrombocytopenia (including thrombocytopenic purpura), myalgia, jaundice, elevated liver function tests, hepatitis, arthralgia, tinnitus, 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.
Frequency 'not known': non-melanoma skin cancer* (basal cell carcinoma and squamous cell carcinoma).
*Non-melanoma skin cancer: Based on available data from epidemiological studies, cumulative dose-dependent association between HCTZ and NMSC has been observed (see Section 4.4 Special Warnings and Precautions for Use; Section 5.1 Pharmacodynamic Properties, Clinical trials).

Reporting suspected adverse effects.

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 irbesartan doses of up to 900 mg/day for 8 weeks revealed no toxicity. No specific information is available on the treatment of overdosage with Avapro HCT. The patient should be closely monitored, and the treatment should be symptomatic and supportive, including fluid and electrolyte replacement. Irbesartan is not removed from the body by haemodialysis.
The most common signs and symptoms observed in adults exposed to hydrochlorothiazide are those caused by electrolyte depletion (hypokalaemia, hypochloraemia, hyponatraemia) and dehydration resulting from excessive diuresis. If a cardiac glycoside (e.g. digoxin) or other antiarrhythmic drugs (e.g. sotalol) has also been administered, hypokalaemia may accentuate cardiac arrhythmias. The degree to which hydrochlorothiazide is removed by haemodialysis has not been established.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: angiotensin II antagonists and diuretics, ATC code: C09DA04.

Mechanism of action.

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.
Hydrochlorothiazide is a benzothiadiazine (thiazide) diuretic with diuretic, natriuretic and antihypertensive effects. The mechanism of antihypertensive effect of thiazide diuretics, such as hydrochlorothiazide is not fully known. Thiazides affect the renal tubular mechanism of electrolyte reabsorption, increasing excretion of sodium and chloride in approximately equivalent amounts. Natriuresis causes a secondary loss of potassium and bicarbonate. Hydrochlorothiazide increases plasma renin activity, increases aldosterone secretion and decreases serum potassium. Co-administration of an angiotensin II receptor antagonist tends to reverse the potassium loss associated with thiazide diuretics.

Clinical trials.

Based on data from placebo-controlled clinical trials, the following effects were noted. The blood pressure lowering effect of irbesartan in combination with hydrochlorothiazide was apparent after the first dose and substantially present within 1-2 weeks, with the maximal effect occurring by 6-8 weeks. In long-term follow-up studies, the blood pressure lowering effect of irbesartan/ hydrochlorothiazide with dose-to-response addition of adjunctive therapy was maintained for over one year.
The combination of hydrochlorothiazide and irbesartan produced dose related additive reductions in blood pressure across their therapeutic dose ranges. The addition of 12.5 mg hydrochlorothiazide to 300 mg irbesartan once daily in patients not adequately controlled on 300 mg irbesartan alone resulted in further placebo-corrected diastolic blood pressure reductions at trough (24 hours postdosing) of 6.1 mmHg. The combination of 300 mg irbesartan and 12.5 mg hydrochlorothiazide resulted in an overall placebo-subtracted systolic/ diastolic reduction of up to 13.6/11.5 mmHg.
Limited clinical data (7 out of 22 patients) suggest that patients not controlled with 300/12.5 mg combination may respond when uptitrated to 300/25 mg. In these patients, an incremental blood pressure lowering effect was observed for both SBP and DBP (13.3 and 8.3 mmHg, respectively).
Once daily dosing with 150 mg irbesartan and 12.5 mg hydrochlorothiazide showed systolic/ diastolic mean placebo-adjusted blood pressure reductions at trough (24 hours postdosing) of 12.9/6.9 mmHg. Peak effects occurred at 3-6 hours.
When assessed by ambulatory blood pressure monitoring, Irbesartan HCT Sanofi 150/12.5 once daily produced consistent reduction in blood pressure over the 24 hours period with a mean 24 hour placebo subtracted systolic/ diastolic reductions of 15.8/10.0 mmHg. The observed trough-to-peak effects were at least 68% of the corresponding placebo-subtracted peak diastolic and peak systolic responses.
In a clinical trial with patients not adequately controlled on 25 mg hydrochlorothiazide alone after 4 weeks' treatment, the addition of irbesartan (with dose-to-response uptitration from 75 mg to 150 mg at 6 weeks) produced mean systolic/ diastolic reductions at 12 weeks which were 11.1/7.2 mmHg greater than hydrochlorothiazide alone.
Blood pressure was lowered to about the same extent in both standing and supine positions. Orthostatic effects were infrequent, but may be expected to occur in patients who develop intercurrent sodium and/or volume-depletion.
The effect of the combination of irbesartan and hydrochlorothiazide on morbidity and mortality has not been studied. Epidemiological studies have shown that long-term treatment with hydrochlorothiazide reduces the risk of cardiovascular mortality and morbidity.
The effectiveness of irbesartan/ hydrochlorothiazide was not influenced by age, race, or gender. The overall antihypertensive response to the combination was similar for black and non-black patients.
After withdrawal of irbesartan, blood pressure gradually returned toward baseline. Rebound hypertension was not observed with irbesartan or hydrochlorothiazide.
With hydrochlorothiazide, onset of diuresis occurred in 2 hours, and peak effect occurred at about 4 hours, while the action persisted for approximately 6-12 hours.

Non-melanoma skin cancer.

Based on available data from epidemiological studies, cumulative dose-dependent association between HCTZ and non-melanoma skin cancer has been observed. One study included a population comprised of 71,553 cases of BCC and of 8,629 cases of SCC matched to 1,430,883 and 172,462 population controls, respectively. High HCTZ use (≥ 50,000 mg cumulative) was associated with an adjusted OR of 1.29 (95% CI: 1.23-1.35) for BCC and 3.98 (95% CI: 3.68-4.31) for SCC. A clear cumulative dose-response relationship was observed for both BCC and SCC. Another study showed a possible association between risk of lip cancer (SCC) and exposure to HCTZ: 633 cases of lip cancer were matched with 63,067 population controls, using a risk-set sampling strategy. A clear cumulative dose response relationship was demonstrated with an adjusted OR 2.1 (95% CI: 1.7-2.6) for ever-use, OR 3.9 (3.0-4.9) for high use (at least 25,000 mg) and OR 7.7 (5.7-10.5) for the highest cumulative dose (at least 100,000 mg) (see Section 4.4 Special Warnings and Precautions for Use).

5.2 Pharmacokinetic Properties

Concomitant administration of hydrochlorothiazide and irbesartan has no effect on the pharmacokinetics of either drug.

Absorption.

The oral bioavailabilities of irbesartan and hydrochlorothiazide measured after administration of Avapro HCT are similar to the bioavailabilities of irbesartan and hydrochlorothiazide administered as separate entities. The absolute oral bioavailability for irbesartan has previously been shown to be 60-80% whilst the absolute oral bioavailability for hydrochlorothiazide is documented as 50-80%.
Food does not affect the bioavailability of Avapro HCT. Peak plasma concentrations occur 1.5-2 hours after oral administration for irbesartan and 1-2.5 hours for hydrochlorothiazide.

Distribution.

Irbesartan is 90% protein-bound in the plasma, and has negligible binding to cellular components of blood. The volume of distribution is 53-93 litres (0.72-1.24 L/kg). Hydrochlorothiazide is 68% protein-bound in the plasma, and its apparent volume of distribution is 0.83-1.141 L/kg.

Metabolism.

In plasma, unchanged irbesartan accounts for more than 80% of the circulating radioactivity following oral or intravenous administration of 14C-irbesartan. Irbesartan is metabolized 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 metabolized 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.
Hydrochlorothiazide is not metabolized.

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 is recovered in urine with the remainder in the faeces. Less than 2% of the dose is excreted in urine as unchanged irbesartan.
The terminal elimination half-life (t1/2) of irbesartan from plasma is 11-15 hours. The total body clearance of intravenously administered irbesartan is 157-176 mL/min, of which 3.0-3.5 mL/min is 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.
Hydrochlorothiazide is eliminated by the kidneys. The mean plasma half-life (t1/2) of hydrochlorothiazide from plasma reportedly ranges from 5-15 hours.

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 concentration (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. The area under the plasma concentration time curve (AUC) for hydrochlorothiazide was elevated in the elderly group following multiple dosing consistent with previously published data.
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 severe renal impairment (creatinine clearance < 20 mL/min), the elimination half-life of hydrochlorothiazide was reported to increase to 21 hours.
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 and the irbesartan/ hydrochlorothiazide combination were not genotoxic in a series of assays for gene-mutagenic activity in bacterial and mammalian cells, and for clastogenic effects in vitro and in vivo. Hydrochlorothiazide alone was not genotoxic in a gene mutation assay in bacterial cells, or in tests for clastogenic activity in vitro and in vivo. However, positive results were obtained in a mammalian cell assay for gene mutation (mouse lymphoma cell assay), and in two other tests (sister chromatid exchange assay in Chinese hamster ovary cells and non-disjunction assay in Aspergillus nidulans).

Carcinogenicity.

The carcinogenic potential of irbesartan and hydrochlorothiazide in combination has not been evaluated in animal studies. However, 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. With hydrochlorothiazide two-year feeding studies in mice and rats uncovered no evidence of carcinogenic potential in female mice at doses up to approximately 600 mg/kg/day, or in male and female rats at doses up to approximately 100 mg/kg/day. The studies, however, uncovered equivocal evidence for hepatocarcinogenicity in male mice treated with hydrochlorothiazide at approximately 600 mg/kg/day.

6 Pharmaceutical Particulars

6.1 List of Excipients

The inactive ingredients in Avapro HCT 150/12.5 and 300/12.5 tablets include: carnauba wax, croscarmellose sodium, hypromellose, Opadry II complete film coating system 32F24503 Pink, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and silicon dioxide.
The inactive ingredients in Avapro HCT 300/25 tablets include: carnauba wax, croscarmellose sodium, iron oxide red, iron oxide yellow, lactose monohydrate, magnesium stearate, microcrystalline cellulose, Opadry II complete film coating system 32F24304 Pink, pregelatinised maize starch, and silicon dioxide.

6.2 Incompatibilities

Incompatibilities were either not assessed 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.

2-butyl-3-[(2'-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl]-1,3-diazaspiro [4,4] non-1-en-4-one.
Irbesartan is a white to off-white crystalline powder. It is a relatively non-polar compound with a partition coefficient (octanol-water) of 10.1 at a pH of 7.4. Irbesartan is slightly soluble in alcohol and methylene chloride, and practically insoluble in water.

Hydrochlorothiazide.

6-chloro-3,4-dihydro- 2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide.
Hydrochlorothiazide is a white crystalline powder. It is slightly soluble in water but freely soluble in sodium hydroxide solution.

Chemical structure.

The chemical structure of irbesartan is:
C25H28N6O.
MW = 428.5.
The chemical structure of hydrochlorothiazide is:
C7H8ClN3O4S2.
MW = 297.7.

CAS number.

Irbesartan CAS number: 138402-11-6.
Hydrochlorothiazide CAS number: 58-93-5.

7 Medicine Schedule (Poisons Standard)

Schedule 4.

Summary Table of Changes