Consumer medicine information

Irbesartan/HCT Sandoz

Irbesartan; Hydrochlorothiazide

BRAND INFORMATION

Brand name

Irbesartan/HCT Sandoz

Active ingredient

Irbesartan; Hydrochlorothiazide

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Irbesartan/HCT Sandoz.

WHAT IS IN THIS LEAFLET

This leaflet answers some common questions about Irbesartan/HCT Sandoz.

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

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

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

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

WHAT IRBESARTAN/HCT SANDOZ IS USED FOR

This medicine is used to lower 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) when your blood pressure stays higher than is needed, even when you are calm and relaxed.

There are often no symptoms of high blood pressure. The only way of knowing that you have high blood pressure is to have your blood pressure checked on a regular basis.

If high blood pressure is not treated, it can damage blood vessels in several organs such as the heart, kidneys, brain and eyes. This may lead to serious health problems, such as blindness, stroke, heart disease and kidney failure. 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 Irbesartan/HCT Sandoz. 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.

This medicine contains the active ingredients 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 that causes blood vessels to narrow. 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.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

This medicine is available only with a doctor's prescription.

There is no evidence that this medicine is addictive.

BEFORE YOU TAKE IRBESARTAN/HCT SANDOZ

When you must not take it

Do not take this medicine if you have an allergy to:

  • irbesartan or hydrochlorothiazide, the active ingredients, or to any of the other ingredients listed at the end of this leaflet under Product Description
  • sulfonamide derived medicines (commonly known as sulfur drugs)
  • any other similar medicines.

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin.

Do not take this medicine if you are pregnant or are planning to become pregnant. It may affect your developing baby if you take it during pregnancy.

Do not breastfeed if you are taking this medicine. It is not known if the active ingredient in Irbesartan/HCT Sandoz passes into breast milk, therefore it is recommended that you do not take it while you are breastfeeding.

Do not give this medicine to children. Safety and effectiveness in children have not been established.

Do not take this medicine if you are not producing urine.

Do not take this medicine if 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).

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

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

  • 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.

Tell your doctor if you:

  • are strictly restricting your salt intake
  • plan to have surgery (even at the dentist) that needs a general anaesthetic
  • have recently had excessive vomiting or diarrhoea or think you are dehydrated
  • are lactose intolerant
  • have had a sympathectomy
  • have been taking diuretics
  • 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 (nonmelanoma skin cancer). Protect your skin from sun exposure and UV rays while taking Irbesartan/HCT Sandoz.

Tell your doctor if you are pregnant or plan to become pregnant or are breastfeeding. Your doctor can discuss with you the risks and benefits involved.

If you have not told your doctor about any of the above, tell him/her before you start taking Irbesartan/HCT Sandoz.

Taking other medicines

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

Some medicines and Irbesartan/HCT Sandoz may interfere with each other. These include:

  • other medicines for high blood pressure
  • other fluid tablets or diuretics
  • lithium or lithium-containing medicines (for example lithium carbonate)
  • potassium tablets
  • potassium containing salt substitutes
  • anti-inflammatory medicines, used to relieve pain, swelling and other symptoms of inflammation, including arthritis and nonsteroidal anti-inflammatory agents - NSAIDS (for example diclofenac, ibuprofen) and COX-2 inhibitors (for example celecoxib). Taking a combination of Irbesartan/HCT Sandoz and an anti-inflammatory medicine, alone or with a thiazide diuretic (fluid tablet) may damage your kidneys. It may also reduce the effect Irbesartan/HCT Sandoz has on reducing blood pressure.
  • a medicine containing aliskiren. Taking Irbesartan/HCT Sandoz with aliskiren may affect your blood pressure, electrolyte balance and your kidney function
  • alcoholic drinks
  • sleeping tablets
  • codeine or morphine, strong pain killing medicines
  • medicines for diabetes (oral tablets or capsules or insulins)
  • calcium supplements, medicines containing calcium
  • Vitamin D
  • medicines for gout
  • powder or granule medicines, used to help reduce cholesterol (cholestyramine or colestipol hydrochloride)
  • heart medicines such as digoxin or antiarrhythmic medicines (for example sotalol hydrochloride)
  • corticosteroid medicines such as prednisone, cortisone or ACTH
  • medicines used to treat cancer (cytotoxic medicines)
  • amantadine, a medicine used to treat Parkinson's disease or to prevent influenza
  • anticholinergic medicines, used to treat Parkinson's disease, to relieve stomach cramps or spasms or used to prevent travel sickness
  • carbamazepine, anticonvulsant medication
  • medicines used during surgery
  • medicines used in an emergency situation such as adrenaline.

These medicines may be affected by Irbesartan/HCT Sandoz or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

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

HOW TO TAKE IRBESARTAN/HCT SANDOZ

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

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

How much to take

Irbesartan/HCT Sandoz 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 Irbesartan/HCT Sandoz.

The usual dose of Irbesartan/HCT Sandoz 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 Irbesartan/HCT Sandoz, your doctor may prescribe another medicine to be taken with Irbesartan/HCT Sandoz.

Ask your doctor or pharmacist if you are unsure of the correct dose for you. They will tell you exactly how much to take.

Follow the instructions they give you.

If you take the wrong dose, Irbesartan/HCT Sandoz may not work as well and your problem may not improve.

How to take it

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

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

When to take Irbesartan/HCT Sandoz

Take your medicine at about the same time each day. Taking it at the same time each day will have the best effect. It will also help you remember when to take it.

How long to take Irbesartan/HCT Sandoz

Continue taking your medicine for as long as your doctor tells you.

This medicine helps to control your high blood pressure, but it does not cure it. Therefore Irbesartan/HCT Sandoz must be taken every day. Continue taking Irbesartan/HCT Sandoz until your doctor tells you to stop.

If you forget to take it

Take your dose as soon as you remember, and continue to take it as you would normally.

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

Do not take a double dose to make up for the dose that you missed. This may increase the chance of you getting an unwanted side effect.

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

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

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone Australia 13 11 26 or New Zealand 0800 POISON or 0800 764766) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much Irbesartan/HCT Sandoz. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

Symptoms of an overdose may include light-headedness or dizziness.

WHILE YOU ARE TAKING IRBESARTAN/HCT SANDOZ

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking Irbesartan/HCT Sandoz.

Tell any other doctors, dentists and pharmacists who treat you that you are taking this medicine.

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

Have your blood pressure checked when your doctor tells you to, to make sure this medicine is working.

If you plan to have surgery or other treatment (even at the dentist) that needs a general anaesthetic, tell your doctor or dentist that you are taking this medicine. Your blood pressure may drop suddenly.

Make sure you drink enough water during exercise and hot weather when you are taking this medicine, especially if you sweat a lot. If you do not drink enough water while taking this medicine, 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 this medicine, tell your doctor. You may lose too much water and salt and your blood pressure may drop too much.

Get up slowly when getting out of bed or standing up. You may feel light-headed or dizzy while taking Irbesartan/HCT Sandoz. 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 lightheaded talk to your doctor.

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 take Irbesartan/HCT Sandoz to treat any other complaints unless your doctor tells you to.

Do not give your medicine to anyone else, even if they have the same condition as you.

Do not stop taking your medicine or lower the dosage without checking with your doctor.

Things to be careful of

Be careful driving or operating machinery until you know how Irbesartan/HCT Sandoz affects you. This medicine may cause dizziness or light-headedness in some people. If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous.

Be careful when drinking alcohol while you are taking this medicine. 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

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Irbesartan/HCT Sandoz.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

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

Tell your doctor or pharmacist 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 gout; nausea and/or vomiting
  • sexual problems.

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 (symptoms of an allergic reaction)
  • aching muscles or aching joints (not caused by exercise)
  • muscle pain, weakness or paralysis of muscles
  • buzzing, ringing or other persistent noise in the ear
  • changes in heart rhythm
  • 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, change in heart rhythm
  • symptoms that may indicate liver disease such as nausea, vomiting, loss of appetite, feeling generally unwell, fever, itching, yellowing of the skin and eyes and dark coloured urine
  • 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.

The above list includes serious side effects that may require medical attention. Serious side effects are not common.

If any of the following happen, stop taking this medicine and tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

  • swelling of 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 nettle rash.

The above list includes serious side effects. You may need urgent medical attention or hospitalisation. These side effects are very rare.

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

AFTER TAKING IRBESARTAN/HCT SANDOZ

Storage

Keep your medicine in the original container.

If you take it out of its original container it may not keep well.

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

Keep your medicine where it is protected from moisture.

Do not store Irbesartan/HCT Sandoz or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car.

Heat and dampness can destroy some medicines.

Keep it 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.

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

PRODUCT DESCRIPTION

What it looks like

Irbesartan/HCT Sandoz 150 mg/12.5 mg - apricot, oval biconvex film-coated tablet, debossed with 150H on one side.

Irbesartan/HCT Sandoz 300 mg/12.5 mg - apricot, oval biconvex film-coated tablet, debossed with 300H on one side.

Irbesartan/HCT Sandoz 300 mg/25 mg - dark pink, oval biconvex film-coated tablet, debossed with 300 on one side and 25H on the other side.

Available in bottles and blister packs of 30 tablets.

Not all strengths or presentations may be marketed.

Ingredients

Active ingredients:

  • Irbesartan/HCT Sandoz 300 mg/25 mg - 300 mg irbesartan and 25 mg hydrochlorothiazide
  • Irbesartan/HCT Sandoz 150 mg/12.5 mg - 150 mg irbesartan and 12.5 mg hydrochlorothiazide
  • Irbesartan/HCT Sandoz 300 mg/12.5 mg - 300 mg irbesartan and 12.5 mg hydrochlorothiazide.

Inactive ingredients:

  • microcrystalline cellulose
  • lactose monohydrate
  • croscarmellose sodium
  • colloidal anhydrous silica
  • hypromellose
  • magnesium stearate
  • hyprolose
  • macrogol 6000
  • titanium dioxide
  • talc
  • iron oxide red (CI77491)
  • iron oxide yellow (CI77492) - Irbesartan/HCT Sandoz 150 mg/12.5 mg and 300 mg/12.5 mg only
  • iron oxide black (CI77499) - Irbesartan/HCT Sandoz 300 mg/25 mg only.

This medicine does not contain sucrose or gluten.

Supplier

Sandoz Pty Ltd
ABN 60 075 449 553
54 Waterloo Road
Macquarie Park NSW 2113
Tel: 1800 726 369

Novartis New Zealand Ltd
PO Box 99102
Newmarket, Auckland 1149
New Zealand
Tel: 0800 354 335

This leaflet was prepared in November 2019.

Australian Register Number(s)

150 mg/12.5 mg tablets: AUST R 174729 (blister)

300 mg/12.5 mg tablets: AUST R 174724 (blister)

300 mg/25 mg tablets: AUST R 174731 (blister)

Published by MIMS January 2020

BRAND INFORMATION

Brand name

Irbesartan/HCT Sandoz

Active ingredient

Irbesartan; Hydrochlorothiazide

Schedule

S4

 

1 Name of Medicine

Irbesartan/hydrochlorothiazide.

6.7 Physicochemical Properties

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 is a white crystalline powder. It is slightly soluble in water but freely soluble in sodium hydroxide solution.

Irbesartan.

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.
Molecular weight: 428.5.

Hydrochlorothiazide.

Chemical name: 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1- dioxide.
Molecular formula: C7H8ClN3O4S2.
Molecular weight: 297.73.

Chemical structure.


CAS number.

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

2 Qualitative and Quantitative Composition

Irbesartan/HCT Sandoz 150 mg/12.5 mg film-coated tablets contain 150 mg irbesartan and 12.5 mg hydrochlorothiazide.
Irbesartan/HCT Sandoz 300 mg/12.5 mg film-coated tablets contain 300 mg irbesartan and 12.5 mg hydrochlorothiazide.
Irbesartan/HCT Sandoz 300 mg/25 mg film-coated tablets contain 300 mg irbesartan and 25 mg hydrochlorothiazide.
Not all strengths may be marketed in Australia.

Excipient with known effect.

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

3 Pharmaceutical Form

Irbesartan/HCT Sandoz 150 mg/12.5 mg film-coated tablets are apricot, oval biconvex film-coated tablets, debossed with 150 H on one side.
Irbesartan/HCT Sandoz 300 mg/12.5 mg film-coated tablets are apricot, oval biconvex film-coated tablets, debossed with 300 H on one side.
Irbesartan/HCT Sandoz 300 mg/25 mg film-coated tablets are dark pink, oval biconvex film-coated tablets, debossed with 300 on one side and 25 H on the other side.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

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

Mechanism of action.

Irbesartan/HCT Sandoz (irbesartan/hydrochlorothiazide) is an oral antihypertensive agent combining a nonpeptide angiotensin II receptor (AT1 subtype) antagonist, irbesartan and a thiazide diuretic, hydrochlorothiazide.
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. Coadministration 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 reductions of up to 13.6/11.5 mmHg.
Limited clinical data (7 out of 22 patients) suggest that patients not controlled with the 300 mg/12.5 mg combination may respond when uptitrated to 300 mg/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/ hydrochlorothiazide 150 mg/12.5 mg 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 nonblack 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 hydrochlorothiazide 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 hydrochlorothiazide 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 hydrochlorothiazide: 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; Section 4.8 Adverse Effects (Undesirable Effects)).

5.2 Pharmacokinetic Properties

In a bioequivalence study comparing 300 mg/ 25 mg Irbesartan/Hydrochlorothiazide Sandoz tablets with the innovator's tablets, following an oral administration of single dose of Irbesartan/ Hydrochlorothiazide Sandoz to healthy male subjects under fasting condition, a mean peak plasma concentration (Cmax) of irbesartan of approximately 3784.9 nanogram/mL was achieved within approximately 1.25 hours (Tmax) and a mean peak plasma concentration (Cmax) of hydrochlorothiazide of approximately 190.55 nanogram/mL was achieved within approximately 1.75 hours (Tmax).
Concomitant administration of hydrochlorothiazide and irbesartan has no effect on the pharmacokinetics of either medicine.

Absorption.

The oral bioavailabilities of irbesartan and hydrochlorothiazide measured after administration of irbesartan/ hydrochlorothiazide 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 irbesartan/ hydrochlorothiazide. 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 L (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 medicine 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 is 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 nondisjunction 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 - 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.

4 Clinical Particulars

4.1 Therapeutic Indications

Irbesartan/HCT Sandoz is indicated for the treatment of hypertension. Treatment should not be initiated with this fixed dose combination.

4.3 Contraindications

Irbesartan/HCT Sandoz is contraindicated in patients who are hypersensitive to irbesartan, sulfonamide derived medicines (e.g. thiazides), or to any other component of the irbesartan/ hydrochlorothiazide formulation. In general, hypersensitivity reactions are more likely to occur in patients with a history of allergy or bronchial asthma.
Irbesartan/ hydrochlorothiazide is contraindicated in patients who are anuric.
Refractory hypokalaemia, hypercalcaemia.
Severe hepatic impairment, biliary cirrhosis and cholestasis.
Do not coadminister irbesartan/ hydrochlorothiazide with aliskiren containing medicines in patients with diabetes or with moderate to severe renal impairment.
Do not coadminister irbesartan/ hydrochlorothiazide with ACE inhibitors in patients with diabetic nephropathy.
Pregnancy (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy).

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 exposure has been observed in two epidemiological studies based on Danish National Cancel Registry (see Section 5.1 Pharmacodynamic Properties). Photosensitizing actions of hydrochlorothiazide could act as a possible mechanism for NMSC.
Patients taking hydrochlorothiazide 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 hydrochlorothiazide 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.

Irbesartan/ hydrochlorothiazide 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 irbesartan/ hydrochlorothiazide. Thiazides may potentiate the action of other antihypertensive medicines (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

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 irbesartan/ hydrochlorothiazide with an ACE inhibitor or with aliskiren is not recommended since there are increased risk of hypotension, hyperkalemia, and changes in renal function. The use of irbesartan/ hydrochlorothiazide in combination with aliskiren is contraindicated in patient with diabetes mellitus or renal impairment (see Section 4.3 Contraindications).
The use of irbesartan/ hydrochlorothiazide in combination with aliskiren is contraindicated in patients with diabetes mellitus or with moderate to severe renal impairment.
The use of irbesartan/ hydrochlorothiazide 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 irbesartan/hydrochlorothiazide in patients with psoriasis or a history of psoriasis should be carefully weighed as it may exacerbate psoriasis.

Renal artery stenosis.

See comments under Use in renal impairment below.

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy.

As with other vasodilators, special caution is indicated in patients suffering from aortic or mitral stenosis, or obstructive hypertrophic cardiomyopathy.

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 irbesartan/ hydrochlorothiazide is not recommended.

Postsympathectomy.

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

Fluid and electrolyte imbalance.

Thiazides, including hydrochlorothiazide, can cause fluid or electrolyte imbalance (hypokalaemia, hyponatremia and hypochloremic 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. The risk of hypokalaemia is greatest in patients with cirrhosis of the liver, in patients experiencing brisk diuresis, in patients who are receiving inadequate oral intake of electrolytes and in patients receiving concomitant therapy with corticosteroids or ACTH. Conversely, due to the irbesartan component of irbesartan/ hydrochlorothiazide hyperkalaemia might occur, especially in the presence of renal impairment and/or heart failure, and diabetes mellitus. Adequate monitoring of serum potassium in patients at risk is recommended. Potassium-sparing diuretics, potassium supplements or potassium-containing salts substitutes should be co-administered cautiously with irbesartan/ hydrochlorothiazide. There is no evidence that irbesartan would reduce or prevent diuretic-induced hyponatraemia.
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 hypercalcemia 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.
Warning signs of fluid or electrolyte imbalance are dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pain or cramps, muscular fatigue, hypotension, oliguria, tachycardia and gastrointestinal disturbances such as nausea or vomiting.
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 irbesartan/ hydrochlorothiazide.
Monitoring of laboratory parameters may be necessary in patients at risk of metabolic disturbances.

Hypersensitivity reactions.

Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergy or bronchial asthma, but are more likely in patients with such a history.

Systemic lupus erythematosus.

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

Photosensitivity.

Cases of photosensitivity reactions have been reported with thiazide diuretics. If photosensitivity reaction occurs during treatment, it is recommended to stop the treatment. If readministration of the diuretic is deemed necessary, it is recommended to protect exposed areas to the sun or to artificial UVA.

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 so far 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)).

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.

Irbesartan/hydrochlorothiazide 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.

As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function during therapy with irbesartan/hydrochlorothiazide 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 medicines that affect this system has been associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death. As with any antihypertensive agent, excessive blood pressure decrease in patients with ischaemic cardiopathy or ischaemic cardiovascular disease could result in a myocardial infarction or stroke. The possibility of a similar effect occurring with the use of an angiotensin II receptor antagonist, including irbesartan/hydrochlorothiazide cannot be excluded.
There is no experience with irbesartan/hydrochlorothiazide in patients with a recent renal transplant.
Irbesartan/hydrochlorothiazide 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, irbesartan/hydrochlorothiazide should be administered with caution to such patients.
When irbesartan/hydrochlorothiazide is used in patients with impaired renal function, a periodic monitoring of potassium, creatinine and uric acid serum levels is recommended.

Use in the elderly.

Among patients who received irbesartan/ hydrochlorothiazide 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 irbesartan/ hydrochlorothiazide 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 irbesartan/ hydrochlorothiazide alone. No patient discontinued taking irbesartan/ hydrochlorothiazide due to increased BUN. One patient discontinued taking irbesartan/ hydrochlorothiazide due to a minor increase in creatinine.

Haemoglobin.

Mean decreases of approximately 0.2 g/dL occurred in patients treated with irbesartan/ hydrochlorothiazide 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 irbesartan/ hydrochlorothiazide 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 hyperkalemia (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 medicines 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 medicine metabolized by CYP2C9).
Irbesartan does not affect the pharmacokinetics of digoxin or simvastatin. The pharmacokinetics of irbesartan is not affected by coadministration with nifedipine or hydrochlorothiazide.
Based on experience with the use of other medicines 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 medicines (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 hydrochlorothiazide may raise the blood level of uric acid. Coadministration of thiazide diuretics may increase the incidence of hypersensitivity reactions to allopurinol.

Cardiac glycosides (e.g. digoxin) and other antiarrhythmic medicines (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 medicine (e.g. vitamin D therapy) is prescribed, serum calcium levels should be monitored and calcium dosage adjusted accordingly.

Cholestyramine resin and colestipol HCl.

May delay or decrease absorption of hydrochlorothiazide. Irbesartan/ hydrochlorothiazide 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 irbesartan/ hydrochlorothiazide 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 irbesartan/ hydrochlorothiazide may potentiate the actions of other antihypertensive medicines, especially ganglionic or peripheral adrenergic blocking medicines. Hydrochlorothiazide 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 medicines and thiazide diuretics.

Concomitant use of a renin angiotensin system inhibiting medicine (ACE inhibitor or angiotensin receptor antagonist), an anti-inflammatory medicine (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 medicine. 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 irbesartan/ hydrochlorothiazide 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 irbesartan/ hydrochlorothiazide 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 irbesartan/ hydrochlorothiazide in combination with an ACE inhibitor is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.

Medicines used during surgery.

The effects of nondepolarizing muscle relaxants (e.g. tubocurarine), preanaesthetics and anaesthetics used in surgery may be potentiated by hydrochlorothiazide; dosage adjustments may be required. Preanesthetic and anaesthetic agents should be given in reduced dosage, and if possible, hydrochlorothiazide 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.

Digitalis glycosides.

Thiazide induced hypokalaemia or hypomagnaesemia favour the onset of digitalis induced cardiac arrhythmias.

Other interactions.

The hyperglycaemic 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 medicines (e.g. cyclophosphamide, 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)
Medicines that act directly on the renin angiotensin system can cause foetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature in patients who were taking angiotensin converting enzyme inhibitors. When pregnancy is detected, irbesartan/ hydrochlorothiazide should be discontinued as soon as possible.
The use of medicines 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 medicine.
These adverse effects do not appear to have resulted from intrauterine medicine exposure that has been limited to the first trimester. Mothers whose embryos and foetuses are exposed to an angiotensin II receptor antagonist only during the first trimester should be so informed. Nonetheless, when patients become pregnant, physicians should have the patient discontinue the use of irbesartan/ hydrochlorothiazide as soon as possible.
As for any medicine that also acts directly on the RAAS, irbesartan/ hydrochlorothiazide should not be used during pregnancy (see Section 4.3 Contraindications) or in women planning to become pregnant. Physicians prescribing any agents acting on the RAAS should warn women of childbearing potential about the potential risk of these agents during pregnancy.
Infants with histories of in utero exposure to an angiotensin II receptor antagonist should be closely observed for hypotension, oliguria and hyperkalemia.
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 effects which have occurred in the adult.
Hydrochlorothiazide should not be used for gestational oedema, gestational hypertension or pre-eclampsia due to the risk of decreased plasma volume and placental hypoperfusion, without a beneficial effect on the course of the disease.
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 irbesartan/ hydrochlorothiazide 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 medicine, taking into account the importance of irbesartan/ hydrochlorothiazide to the therapy of the mother.

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 irbesartan/ hydrochlorothiazide 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/ hydrochlorothiazide 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/ hydrochlorothiazide 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/ hydrochlorothiazide, 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 effects (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/ hydrochlorothiazide and no additional study medications in premarketing clinical trials involving 2700 subjects, and that were not reported in the above tabulation of adverse events, are listed in the following section.
These adverse effects 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 effects 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.

General.

Weakness, weight gain, warmth sensation, pain.

Haematopoietic.

Leucopenia, bone marrow depression, 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), cutaneous lupus erythematosus-like reactions, reactivation of cutaneous lupus erythematosus, 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, xanthopsia, 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, rare cases of hypersensitivity reactions (urticaria, angioedema, anaphylactic reactions including anaphylactic shock) have been reported. The following have also been reported during post-marketing surveillance: vertigo, arthralgia, asthenia, hyperkalaemia, thrombocytopenia (including thrombocytopenic purpura), myalgia, tinnitus, jaundice, elevated liver function tests, psoriasis (and psoriasis exacerbation) (see Section 4.4 Special Warnings and Precautions for Use), photosensitivity, increases in blood urea nitrogen (BUN), increases in creatinine and creatine kinase, hepatitis and impaired renal function including cases of renal failure in patients at risk.
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 hydrochlorothiazide 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 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 www.tga.gov.au/reporting-problems.

4.2 Dose and Method of Administration

Irbesartan/HCT Sandoz 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.
Irbesartan/HCT Sandoz 150 mg/12.5 mg may be administered to patients whose blood pressure is not adequately controlled with hydrochlorothiazide or irbesartan 150 mg alone.
Irbesartan/HCT Sandoz 300 mg/12.5 mg may be administered to patients insufficiently controlled by irbesartan 300 mg or by Irbesartan/HCT Sandoz 150 mg/12.5 mg.
Irbesartan/HCT Sandoz 300 mg/25 mg may be administered to patients insufficiently controlled by Irbesartan/HCT Sandoz 300 mg/12.5 mg.
Doses higher than Irbesartan/HCT Sandoz 300 mg/25 mg once daily are not recommended. When necessary, Irbesartan/HCT Sandoz may be administered with another antihypertensive medicine.

Dosage adjustment.

Renal impairment.

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

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, irbesartan/hydrochlorothiazide should be used with caution in patients with severe hepatic impairment (see Section 4.4 Special Warnings and Precautions for Use, Use in hepatic impairment).

Elderly.

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

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 irbesartan/hydrochlorothiazide.

4.7 Effects on Ability to Drive and Use Machines

The effects of irbesartan/ hydrochlorothiazide on the ability to drive motor vehicles or operate machinery have not been specifically studied, but based on its pharmacodynamic properties. Irbesartan/ hydrochlorothiazide 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.

4.9 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 irbesartan/ hydrochlorothiazide. 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 medicines (e.g. sotalol) have 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 Poisons Information Centre on 131126 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Irbesartan/HCT Sandoz 300 mg/12.5 mg and 150 mg/12.5 mg tablets contain the inactive ingredients: microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, colloidal anhydrous silica, hypromellose, magnesium stearate, hyprolose, macrogol 6000, titanium dioxide, talc, iron oxide red CI77491 and iron oxide yellow CI77492.
Irbesartan/HCT Sandoz 300 mg/25 mg tablets contain the inactive ingredients: microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, colloidal anhydrous silica, hypromellose, magnesium stearate, hyprolose, macrogol 6000, titanium dioxide, talc, iron oxide red CI77491 and iron oxide black CI77499.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.
For information on interactions with other medicines and other forms of interactions, see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

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.
Protect from moisture.

6.5 Nature and Contents of Container

Available in HDPE bottles and PVC/PVDC/AL or Al/Al blister packs of 30 tablets.
Not all presentations may be marketed in Australia.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

Summary Table of Changes