Consumer medicine information

Candesan Combi

Candesartan cilexetil; Hydrochlorothiazide

BRAND INFORMATION

Brand name

Candesan Combi

Active ingredient

Candesartan cilexetil; Hydrochlorothiazide

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Candesan Combi.

SUMMARY CMI

CANDESAN COMBI

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I taking CANDESAN COMBI?

CANDESAN COMBI contains the active ingredient candesartan cilexetil and hydrochlorothiazide.

CANDESAN COMBI is used to treat high blood pressure.

For more information, see Section 1. Why am I taking CANDESAN COMBI? in the full CMI.

2. What should I know before I take CANDESAN COMBI?

Do not take if you have ever had an allergic reaction to any medicine containing candesartan cilexetil or hydrochlorothiazide or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I take CANDESAN COMBI? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with CANDESAN COMBI and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I take CANDESAN COMBI?

  • CANDESAN COMBI should be taken once daily with a glass of water, at about the same time each day.
  • It does not matter whether you take CANDESAN COMBI tablets with food or on an empty stomach.

More instructions can be found in Section 4. How do I take CANDESAN COMBI? in the full CMI.

5. What should I know while taking CANDESAN COMBI?

Things you should do
  • Call your doctor straight away if you become pregnant or plan to become pregnant while you are taking CANDESAN COMBI.
  • If you develop any severe shortness of breath or difficulty breathing after taking CANDESAN COMBI, seek medical attention immediately.
Things you should not do
  • Do not stop taking CANDESAN COMBI unless you have discussed it with your doctor.
Driving or using machines
  • Be careful before you drive or use any machines or tools until you know how CANDESAN COMBI affects you.
Drinking alcohol
  • Alcohol may interfere with CANDESAN COMBI.
Looking after your medicine
  • Keep it in a cool, dry place where the temperature stays below 25°C.
  • Keep your tablets in the blister pack until it is time to take them.

For more information, see Section 5. What should I know while taking CANDESAN COMBI? in the full CMI.

6. Are there any side effects?

Less serious side effects are headache or dizziness, flu-like symptoms or infections, chest, throat or sinus infections, feeling sick (nausea) or vomiting, back pain, urinary tract infection, feeling tired, stomach ache, symptoms of sunburn which happens more quickly than normal.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

CANDESAN COMBI

Active ingredient(s): Candesartan cilexetil and Hydrochlorothiazide

Consumer Medicine Information (CMI)

This leaflet provides important information about taking CANDESAN COMBI. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about taking CANDESAN COMBI.

Where to find information in this leaflet:

1. Why am I taking CANDESAN COMBI?
2. What should I know before I take CANDESAN COMBI?
3. What if I am taking other medicines?
4. How do I take CANDESAN COMBI?
5. What should I know while taking CANDESAN COMBI?
6. Are there any side effects?
7. Product details

1. Why am I taking CANDESAN COMBI?

CANDESAN COMBI contains the active ingredients candesartan cilexetil and hydrochlorothiazide.

CANDESAN COMBI is used to treat high blood pressure.

Candesartan cilexetil is a type of medicine called an angiotensin-II receptor antagonist (or blocker). It mainly works by causing relaxation of blood vessels.

Hydrochlorothiazide is a type of medicine called a diuretic. It works by reducing the amount of excess fluid in the body.

Taking these two medicines together will lower your blood pressure more than using either one on its own.

2. What should I know before I take CANDESAN COMBI?

Warnings

Do not take CANDESAN COMBI if:

  • you are allergic to any medicine containing candesartan cilexetil or hydrochlorothiazide, or any of the ingredients listed at the end of this leaflet or any medicine containing an angiotensin II receptor antagonist (or blocker), or any sulphur drugs (sulphonamides) such as some antibiotics or some medicines to treat diabetes. Always check the ingredients to make sure you can use this medicine.
  • you have gout.
  • you have severe kidney or liver disease and/or conditions associated with impaired bile flow (cholestasis).
  • you are taking blood pressure medicine containing aliskiren, especially if you have diabetes mellitus or have kidney problems.
  • the packaging is torn or shows signs of tampering.
  • the expiry date on the pack has passed.

Check with your doctor if you:

  • have allergies to any other medicines or foods.
  • have any of the following medical conditions:
    - Kidney problems.
    - Liver problems.
    - Heart problems.
    - Diabetes.
    - Recent excessive vomiting or diarrhoea.
    - Systemic Lupus Erythematosus (SLE), a disease affecting the skin, joints and kidneys.
    - A salt restricted diet.
    - A condition called primary hyperaldosteronism.
    - A past operation known as sympathectomy.
    - A decrease in vision or eye pain. These could be symptoms of fluid accumulation in the vascular layer of the eye (choroidal effusion) or an increase of pressure in your eye and can happen within hours to weeks of taking CANDESAN COMBI. This can lead to permanent vision loss, if not treated. If you earlier have had a penicillin or sulphonamide allergy, you can be at higher risk of developing this.
  • experienced breathing or lung problems (including inflammation or fluid in the lungs) following hydrochlorothiazide intake in the past.
  • have any questions about how you should be taking CANDESAN COMBI.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Do not take CANDESAN COMBI if you are pregnant or are planning to become pregnant.

It may affect your baby if you take it during pregnancy.

Do take CANDESAN COMBI if you are breastfeeding.

Your baby can take in components of CANDESAN COMBI from breast milk if you are breastfeeding.

Use in children

Do not give CANDESAN COMBI to children. There is no information about its use in children.

3. What if I am taking other medicines?

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

Some medicines and CANDESAN COMBI may interfere with each other. These include:

  • Other blood pressure lowering medicines, particularly diuretics (fluid tablets) and ACE inhibitors, especially if you have diabetes-related kidney problems.
  • Medicines containing potassium, including salt substitutes.
  • Digoxin, a medicine used to treat heart failure.
  • Non-steroidal anti-inflammatory drugs (NSAIDs), medicines used to relieve pain, swelling and other symptoms of inflammation, including arthritis.
  • Colestipol and cholestyramine, medicines used to treat high blood cholesterol levels.
  • Lithium, a medicine used to treat mood swings and some types of depression.
  • Alcohol.
  • Strong pain killers such as codeine, morphine, dextropropoxyphene.
  • Barbiturates, such as phenobarbitone.
  • Medicines like insulin that are used to treat diabetes.
  • Calcium supplements, or medicines containing calcium.
  • Vitamin D supplements.
  • Medicines to treat irregular heart beats.
  • Corticosteroids such as prednisone, cortisone, dexamethasone.
  • Laxatives.
  • Medicines used to treat cancer such as cyclophosphamide.
  • Methotrexate, a medicine used to treat arthritis and some cancers.
  • Amantadine, a medicine used to treat Parkinson's disease.
  • Ciclosporin.

These medicines may be affected by CANDESAN COMBI or may affect how it works. You may need different amounts of your medicines, or may need to take different medicines.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect CANDESAN COMBI.

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

4. How do I take CANDESAN COMBI?

How much to take

  • The usual dose is one tablet once daily, taken whole with a glass of water.

When to take

CANDESAN COMBI should be taken once daily, at about the same time each day.

Keeping a regular time for taking CANDESAN COMBI will help to remind you to take it.

It does not matter whether you take CANDESAN COMBI tablets with food or on an empty stomach.

How long to take

CANDESAN COMBI helps control your condition, but does not cure it. Therefore you must take CANDESAN COMBI every day.

Continue taking CANDESAN COMBI for as long as your doctor tells you to.

If you forget to take CANDESAN COMBI

If you forget to take a dose, take it as soon as you remember, as long as it is at least 12 hours before your next dose is due.

Then go back to taking it as you would normally.

If it is less than 12 hours to 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 you missed.

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

If you take too much CANDESAN COMBI

If you think that you have taken too many CANDESAN COMBI tablets, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

If you take too many CANDESAN COMBI tablets, you may get a headache, feel sick (nausea), dizzy, thirsty and very tired.

5. What should I know while taking CANDESAN COMBI?

Things you should do

  • Take CANDESAN COMBI exactly as your doctor has told you to.
    Your blood pressure will not be well controlled if you do not.
  • If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking CANDESAN COMBI.
  • Tell your doctor if you have excessive vomiting or diarrhoea while taking CANDESAN COMBI.
    You may lose too much water and your blood pressure may become too low.
  • If you plan to have surgery (even at the dentist) that needs a general anaesthetic; tell your doctor or dentist that you are taking CANDESAN COMBI.
  • Tell your doctor if you plan to have an examination such as an X-ray or a scan requiring an injection of iodinated contrast (dye) that you are taking CANDESAN COMBI.
  • If you have had skin cancer or if you develop a suspicious skin lesion during treatment with CANDESAN COMBI, tell your doctor or pharmacist.
    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). Limit exposure to sunlight and protect your skin when exposed to sun while taking CANDESAN COMBI.
  • If you develop any severe shortness of breath or difficulty breathing after taking CANDESAN COMBI, seek medical attention immediately.
  • Remind any doctor, dentist or pharmacist you visit that you are taking CANDESAN COMBI.
  • Be sure to keep all of your doctor's appointments so that your progress can be checked.
    Your doctor will check your progress and may want to take some tests (e.g. blood tests, blood pressure) from time to time. These tests may help to prevent side effects.

Call your doctor straight away if you:

  • become pregnant or plan to become pregnant while taking CANDESAN COMBI. You should not use CANDESAN COMBI if you are pregnant or thinking about becoming pregnant. Your doctor can discuss different treatment options with you.

Things you should not do

  • Do not take CANDESAN COMBI to treat any other conditions unless your doctor says to.
  • Do not give CANDESAN COMBI to anyone else, even if they have symptoms that seem similar to yours.
  • Do not stop taking CANDESAN COMBI unless you have discussed it with your doctor.

Things you should be careful of

  • Move slowly when getting out of bed or standing up if you feel faint, dizzy or light-headed.
  • Drink plenty of water while you are taking CANDESAN COMBI, especially if you sweat a lot.

Talk to your doctor or pharmacist about these possibilities if you think they may bother you.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how CANDESAN COMBI affects you.

CANDESAN COMBI may cause dizziness when you start taking it due to the drop in your blood pressure.

Drinking alcohol

Tell your doctor if you drink alcohol.

Alcohol may interfere with CANDESAN COMBI.

Looking after your medicine

  • Keep your tablets in the blister pack until it is time to take them.
  • If you take CANDESAN COMBI out of the blister pack it will not keep well.
  • Keep it in a cool, dry place where the temperature stays below 25°C.

Follow the instructions on the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

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

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
  • Headache or dizziness.
  • Chest, throat or sinus infection.
  • Flu-like symptoms or infections.
  • Feeling sick (nausea) or vomiting.
  • Back pain.
  • Urinary tract infection.
  • Feeling tired.
  • Stomach ache.
  • Symptoms of sunburn which happens more quickly than normal.
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
Allergic reaction:
  • Swelling of the face, lips, tongue or throat.
  • Swelling of the hands, feet or ankles.
  • Rash, itching or hives.
Others:
  • Rapid heartbeats.
  • Aching muscles, tenderness or weakness in the muscles.
  • Suspicious skin lesions.
  • Harsh sounds when breathing.
  • Easy bruising or bleeding more easily than normal.
  • Feel extremely tired.
  • Yellowing of the skin and/or eyes.
  • Signs of frequent infections such as fever, severe chills, sore throat or mouth ulcers.
  • Worsening of kidney function including passing little or no urine, drowsiness, nausea, vomiting, breathlessness, loss of appetite and weakness (especially in patients with existing kidney problems or heart failure).
  • Changes in your potassium, sodium and red or white blood cell levels may occur. Such changes are usually detected by a blood test.
  • Decrease in vision or pain in your eyes due to high pressure (possible signs of fluid accumulation in the vascular layer of the eye (choroidal effusion) or acute angle-closure glaucoma).
  • Symptoms that may indicate high potassium levels in the blood include nausea, diarrhoea, muscle weakness and changes in heart rhythm.
  • Acute respiratory distress (very rare): signs include severe shortness of breath, fever, weakness and confusion.
Stop taking CANDESAN COMBI and call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.
You may need urgent medical attention. Serious side effects are rare.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

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

What CANDESAN COMBI contains

Active ingredient
(main ingredient)
  • Candesartan cilexetil 16 mg or 32 mg.
  • Hydrochlorothiazide 12.5 mg or 25 mg.
Other ingredients
(inactive ingredients)
  • Lactose monohydrate.
  • Carmellose calcium.
  • Maize starch.
  • Macrogol 8000.
  • Hyprolose.
  • Magnesium stearate.
  • Pigment Blend PB‐24880 Pink (PI 108327) (16 mg/12.5 mg and 32 mg/25 mg tablets).
  • Pigment Blend PB-52290 Yellow (PI 108950)
    (32 mg/12.5 mg tablet).
Potential allergensCANDESAN COMBI contains sugars as lactose.

Do not take this medicine if you are allergic to any of these ingredients.

What CANDESAN COMBI looks like

CANDESAN COMBI 16/12.5

Each tablet is light pink, oval biconvex uncoated tablet with ‘L3’ & ‘02’ on either side of break line on one side and a break line on the other side.

AUST R 204577.

CANDESAN COMBI 32/12.5

Each tablet is light yellow, oval biconvex uncoated tablet with ‘L3’ & ‘04’ on either side of break line on one side and a break line on the other side.

AUST R 204578.

CANDESAN COMBI 32/25

Each tablet is light pink, oval biconvex uncoated tablet with ‘L3’ & ‘04’ on either side of break line on one side and a break line on the other side.

AUST R 204579.

Each pack contains 30 tablets.

Who distributes CANDESAN COMBI

Arrotex Pharmaceuticals Pty Ltd
15-17 Chapel St
Cremorne VIC 3121
Australia
www.arrotex.com.au

This leaflet was prepared in August 2024.

Published by MIMS September 2024

BRAND INFORMATION

Brand name

Candesan Combi

Active ingredient

Candesartan cilexetil; Hydrochlorothiazide

Schedule

S4

 

1 Name of Medicine

Candesartan cilexetil and hydrochlorothiazide.

2 Qualitative and Quantitative Composition

Candesan Combi tablets come in three strengths and contain 16 mg of candesartan cilexetil and 12.5 mg of hydrochlorothiazide, 32 mg of candesartan cilexetil and 12.5 mg of hydrochlorothiazide or 32 mg of candesartan cilexetil and 25 mg of hydrochlorothiazide.

Excipients with known effect.

Sugars as lactose monohydrate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Candesan Combi 16/12.5.

Candesartan cilexetil 16 mg and hydrochlorothiazide 12.5 mg uncoated tablet; Light pink, oval biconvex uncoated tablet with 'L3' and '02' on either side of break line on one side and a break line on the other side.

Candesan Combi 32/12.5.

Candesartan cilexetil 32 mg and hydrochlorothiazide 12.5 mg uncoated tablet; Light yellow, oval biconvex uncoated tablet with 'L3' and '04' on either side of break line on one side and a break line on the other side.

Candesan Combi 32/25.

Candesartan cilexetil 32 mg and hydrochlorothiazide 25 mg uncoated tablet; Light pink, oval biconvex uncoated tablet with 'L3' and '04' on either side of break line on one side and a break line on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Treatment of hypertension. Treatment should not be initiated with this fixed dose combination.

4.2 Dose and Method of Administration

The dose of candesartan with hydrochlorothiazide combination tablets must be determined by careful titration of the dose of each of the individual components.
The recommended dose is 1 tablet once daily. The tablets may be taken with or without food. The tablets should not be divided.
Candesan Combi 16/12.5 may be administered in patients whose blood pressure is not optimally controlled with hydrochlorothiazide alone or candesartan cilexetil 16 mg monotherapy.
Candesan Combi 32/12.5 or 32/25 may be administered in patients whose blood pressure is not optimally controlled with hydrochlorothiazide alone or candesartan 32 mg monotherapy, or at a lower dose of Candesan Combi. Dose titration of candesartan cilexetil is recommended when adding on to hydrochlorothiazide monotherapy.
Most of the antihypertensive effect is usually attained within 4 weeks of initiation of treatment.
Candesan Combi should not be used to initiate treatment.

Special patient populations.

Paediatrics.

The safety and efficacy of candesartan cilexetil with hydrochlorothiazide tablets has not been established in children.

Use in elderly.

Dose titration of candesartan cilexetil is recommended before treatment with candesartan cilexetil with hydrochlorothiazide tablets.

Hepatic impairment.

Dose titration of candesartan cilexetil is recommended before treatment with candesartan cilexetil with hydrochlorothiazide tablets in patients with mild to moderate chronic liver disease.
Candesan Combi should not be used in patients with severe hepatic impairment and/or cholestasis (see Section 4.3 Contraindications).

Renal impairment.

In patients with mild to moderate renal impairment (i.e. creatinine clearance 30-80 mL/min/1.73 m2 BSA) a dose titration is recommended.
Loop diuretics are preferred to thiazides in this population.
Candesan Combi should not be used in patients with severe renal impairment (creatinine clearance < 30 mL/min/1.73 m2 BSA).

Intravascular volume depletion.

Patients who are severely volume and/or sodium depleted should have this corrected before being treated with Candesan Combi.

4.3 Contraindications

Hypersensitivity to any component of Candesan Combi tablets or to sulfonamide derived drugs.
Pregnancy and lactation.
Severe renal impairment (creatinine clearance < 30 mL/min/1.73 m2 BSA).
Severe hepatic impairment and/or cholestasis.
Gout.
The use of Candesan Combi in combination with aliskiren-containing medicines in patients with diabetes mellitus (type I or II) or with moderate to severe renal impairment (GFR < 60 mL/min/1.73 m2).

4.4 Special Warnings and Precautions for Use

General.

In patients whose vascular tone and renal function depend predominantly on the activity of the renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure or underlying renal disease, including renal artery stenosis), treatment with drugs that affect this system has been associated with acute hypotension, azotaemia, oliguria or, rarely, acute renal failure. As with any antihypertensive agent, excessive blood pressure decrease in patients with ischaemic heart disease or atherosclerotic cerebrovascular disease could result in a myocardial infarction or stroke.

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

There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of candesartan/hydrochlorothiazide with ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
If dual blockade therapy is considered necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure.
ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy. The use of candesartan/hydrochlorothiazide with aliskiren is contraindicated in patients with diabetes mellitus (type I or II) or moderate to severe renal impairment (GFR < 60 mL/min/1.73 m2) (see Section 4.3 Contraindications).

Renal artery stenosis.

Other drugs that affect the renin-angiotensin-aldosterone system, i.e. angiotensin converting enzyme (ACE) inhibitors, may increase blood urea and serum creatinine in patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney. A similar effect may be anticipated with angiotensin II receptor antagonists.

Aortic and mitral valve stenosis or obstructive hypertrophic cardiomyopathy.

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

Primary hyperaldosteronism.

Patients with primary hyperaldosteronism will not generally respond to antihypertensive drugs acting through inhibition of the renin-angiotensin-aldosterone system. Therefore, the use of candesartan in these patients is not recommended.

Fluid and electrolyte imbalance.

As for any patient receiving diuretic therapy, periodic determination of serum electrolytes should be performed at appropriate intervals.
Thiazides, including hydrochlorothiazide, can cause fluid or electrolyte imbalance (hypercalcaemia, hypokalaemia, hyponatraemia, hypomagnesaemia and hypochloraemic alkalosis).
Hydrochlorothiazide dose-dependently increases urinary potassium excretion which may result in hypokalaemia. This effect of hydrochlorothiazide seems to be less evident when combined with candesartan cilexetil. The risk of hypokalaemia may be increased in patients with cirrhosis of the liver, in patients experiencing brisk diuresis, in patients with an inadequate oral intake of electrolytes and in patients receiving concomitant therapy with corticosteroids or adrenocorticotropic hormone (ACTH).
Based on experience with the use of other drugs that affect the renin-angiotensin-aldosterone system, concomitant use of candesartan with hydrochlorothiazide tablets and ACE inhibitors, aliskiren, potassium sparing diuretics, potassium supplements or salt substitutes or other drugs that may increase serum potassium levels may lead to increases in serum potassium.

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 Cancer Registry (see Section 5.1 Pharmacodynamic Properties, Clinical trials). 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 UV rays and, in case of exposure, adequate protection should be advised to the patients in order to minimize 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 NMSC (see Section 4.8 Adverse Effects (Undesirable Effects)).

Acute respiratory toxicity.

Very rare severe cases of acute respiratory toxicity, including acute respiratory distress syndrome (ARDS) have been reported after taking hydrochlorothiazide. Pulmonary oedema typically develops within minutes to hours after hydrochlorothiazide intake. At the onset, symptoms include dyspnoea, fever, pulmonary deterioration, and hypotension. If diagnosis of ARDS is suspected, Candesartan HCTZ should be withdrawn, and appropriate treatment given. Hydrochlorothiazide should not be administered to patients who previously experienced ARDS following hydrochlorothiazide intake.

Kidney transplantation.

There is limited clinical experience regarding the administration of candesartan with hydrochlorothiazide tablets in patients who have undergone renal transplantation.

Combination use of ACE inhibitors or angiotensin receptor antagonists, anti-inflammatory drugs and thiazide diuretics.

The use of an ACE inhibiting drug (ACE-inhibitor or angiotensin receptor antagonist), an anti-inflammatory drug (NSAID or COX-2 inhibitor) and a thiazide diuretic at the same time increases the risk of renal impairment. This includes use in fixed-combination products containing more than one class of drug. Combined use of these medications should be accompanied by increased monitoring of serum creatinine, particularly at the institution of the combination. The combination of drugs from these three classes should be used with caution particularly in elderly patients or those with pre-existing renal impairment.

Metabolic and endocrine effects.

Treatment with a thiazide diuretic may impair glucose tolerance. Dosage adjustment of antidiabetic drugs, including insulin, may be required. Latent diabetes mellitus may become manifest during thiazide therapy. Increases in cholesterol and triglyceride levels have been associated with thiazide diuretic therapy. At the doses contained in Candesan Combi only minimal effects were observed. Thiazide diuretics increase serum uric acid concentration and may precipitate gout in susceptible patients.

Hypotension, volume depleted patients.

Candesartan with hydrochlorothiazide tablets, like all anti-hypertensive agents may cause symptomatic hypotension in some patients. Symptomatic hypotension may be expected to occur more frequently in patients who have been sodium and/or volume depleted by vigorous diuretic therapy and/or dietary salt restrictions, or vomiting and/or diarrhoea or haemodialysis. Sodium and/or volume depletion should be corrected prior to administration of candesartan with hydrochlorothiazide tablets.

Postsympathectomy.

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

Systemic lupus erythematosus.

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

Anaesthesia and surgery.

Hypotension may occur during anaesthesia and surgery in patients treated with angiotensin II antagonists due to blockade of the renin-angiotensin-aldosterone system. Very rarely, hypotension may be severe such that it may warrant the use of intravenous fluids and/or vasopressors.

Choroidal effusion, acute myopia and angle-closure glaucoma.

Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction resulting in choroidal effusion with visual field defect, transient myopia and acute angle-closure glaucoma. 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.

Use in hepatic impairment.

Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma. There is no clinical experience with candesartan with hydrochlorothiazide tablets in patients with hepatic impairment.
Use in patients with severe hepatic impairment is contraindicated. Caution is advised in patients with mild to moderate hepatic impairment.

Use in renal impairment.

As with other agents inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible patients treated with candesartan with hydrochlorothiazide tablets (see Section 4.3 Contraindications). When candesartan with hydrochlorothiazide tablets is used in patients with renal impairment, periodic monitoring of serum potassium, creatinine and uric acid levels is recommended. Loop diuretics are preferred to thiazides in this population.
There is no experience regarding the administration of candesartan with hydrochlorothiazide tablets in patients with a kidney transplantation.

Use in the elderly.

For dosage recommendations for use of candesartan with hydrochlorothiazide tablets in elderly patients, see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use, Combination use of ACE inhibitors or angiotensin receptor antagonists, anti-inflammatory drugs and thiazide diuretics; Section 5.2 Pharmacokinetic Properties, Pharmacokinetics in special populations.

Paediatric use.

Safety and efficacy have not been established in children.

Effects on laboratory tests.

In general, there were no clinically important influences of candesartan cilexetil/hydrochlorothiazide on routine laboratory variables. Increases in creatinine, urea, potassium, uric acid, glucose and ALAT (SGPT) and decreases in sodium have been observed. Minor decreases in haemoglobin and increases in ASAT (SGOT) have been observed in single patients.

4.5 Interactions with Other Medicines and Other Forms of Interactions

The antihypertensive effect of candesartan with hydrochlorothiazide tablets may be enhanced by other antihypertensives.

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

Clinical trial data has shown that dual blockade of the RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting agent (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).

Candesartan cilexetil.

Compounds which have been investigated include hydrochlorothiazide, warfarin, digoxin (see Hydrochlorothiazide below), oral contraceptives (i.e. ethinyloestradiol/levonorgestrel), glibenclamide and nifedipine. No pharmacokinetic interactions of clinical significance were identified in these studies.
The antihypertensive effect of angiotensin II receptor antagonists, including candesartan, may be attenuated by NSAIDs, including COX-2 inhibitors and acetylsalicylic acid.
As with ACE inhibitors, concomitant use of AIIRAs and NSAIDs may lead to an increased risk of worsening of renal function, including possible acute renal failure, and an increase in serum potassium, especially in patients with poor pre-existing renal function. The combination should be administered with caution, especially in older patients and in volume depleted patients. Patients should be adequately hydrated and consideration should be given to monitoring renal function after initiation of concomitant therapy and periodically thereafter.
Candesartan is eliminated only to a minor extent by hepatic metabolism (CYP2C9).
Interaction studies performed to date show no effect of candesartan on the metabolising capacity of CYP2C9 and CYP3A4. Based on in vitro data, no interaction would be expected to occur in vivo with drugs whose metabolism is dependent upon cytochrome P450 isoenzymes CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4.

Hydrochlorothiazide.

Alcohol, barbiturates, opioids and anaesthetics.

Potentiation of thiazide diuretic induced orthostatic hypotension may occur.

Anti-diabetic agents (oral and insulin).

Thiazides may increase blood glucose concentration and adjustment of anti-diabetic medication may be required.

Cardiac glycosides and other anti-arrhythmics.

Thiazide induced hypokalaemia and hypomagnesaemia predisposes to the potential cardiotoxic effects of digitalis glycosides and antiarrhythmics. Periodic monitoring of serum potassium is recommended when candesartan with hydrochlorothiazide tablets is administered with such drugs.

Calcium salts and vitamin D.

Thiazide diuretics may increase the serum calcium concentration due to decreased excretion. If calcium or vitamin D is prescribed, serum calcium levels should be monitored and calcium dosage adjusted accordingly.

Cholestyramine resin and colestipol hydrochloride.

The absorption of thiazide may be delayed or decreased in the presence of bile acids sequestrants. Candesartan with hydrochlorothiazide tablets should be taken at least one hour before or after such drugs.

Lithium.

Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors or hydrochlorothiazide. A similar effect may occur with angiotensin II receptor antagonists (AIIRAs) and careful monitoring of serum lithium levels is recommended during concomitant use.

Non-steroidal anti-inflammatory drugs (NSAIDs).

The diuretic, natriuretic and antihypertensive effect of hydrochlorothiazide is blunted by NSAIDs.

Hypokalaemic agents.

The potassium depleting effect of hydrochlorothiazide could be expected to be potentiated by other drugs associated with potassium loss and hypokalaemia (e.g. other kaliuretic diuretics, laxatives, amphotericin, carbenoxolone, salicylic acid derivatives).

Potassium sparing agents.

Based on experience with the use of other drugs that affect the renin-angiotensin-aldosterone system, concomitant use of candesartan and hydrochlorothiazide tablets and potassium sparing diuretics, potassium supplements or salt substitutes or other drugs that may increase serum potassium levels (e.g. heparin sodium, trimethoprim/sulfamethoxazole) may lead to increases in serum potassium.

Nondepolarizing muscle relaxants (e.g. tubocurarine).

The effect of nondepolarising skeletal muscle relaxants (e.g. tubocurarine) may be potentiated by hydrochlorothiazide.

Pressor amines.

Hydrochlorothiazide may cause the arterial response to pressor amines to decrease but not enough to exclude a pressor effect.

Iodinated contrast media.

Hydrochlorothiazide may increase the risk of acute renal insufficiency especially with high doses of iodinated contrast media.

Corticosteroids, ACTH.

The risk for hypokalaemia may be increased during concomitant use of steroids or adrenocorticotropic hormone (ACTH).

Amantadine.

Thiazide may increase the risk of adverse effects caused by amantadine.

Beta-blockers and diazoxide.

The hyperglycaemic effect of beta-blockers and diazoxide may be enhanced by thiazides.

Anticholinergic agents (e.g. atropine).

Anticholinergic agents (e.g. atropine, biperiden) may increase the bioavailability of thiazide diuretics by decreasing gastrointestinal motility and stomach emptying rate.

Cytotoxic drugs (e.g. cyclophosphamide, methotrexate).

Thiazides may reduce the renal excretion of cytotoxic drugs (e.g. cyclophosphamide, methotrexate) and potentiate their myelosuppressive effects.

Ciclosporin.

Concomitant treatment with ciclosporin may increase the risk of hyperuricaemia and gout-type complications.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

The effects of hydrochlorothiazide alone or in combination with candesartan cilexetil on fertility have not been evaluated in animal studies. However, candesartan cilexetil alone had no adverse effects on the reproductive performance of male or female rats at oral doses up to 300 mg/kg/day.
(Category D)
The use of candesartan with hydrochlorothiazide tablets is contraindicated during pregnancy (see Section 4.3 Contraindications). Patients receiving candesartan with hydrochlorothiazide tablets should be made aware of that before contemplating a possibility of becoming pregnant so that they can discuss appropriate options with their treating physician. When pregnancy is diagnosed, treatment with candesartan with hydrochlorothiazide tablets must be stopped immediately and if appropriate, alternative therapy should be started.
The use of drugs that act directly on the renin-angiotensin system has been associated with foetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Exposure to angiotensin II receptor antagonist therapy is known to induce human foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia).
There is limited experience with hydrochlorothiazide during pregnancy, especially during the first trimester. Animal studies are insufficient. Hydrochlorothiazide crosses the placenta. Based on the pharmacological mechanism of action of hydrochlorothiazide, its use during pregnancy may compromise foeto-placental perfusion and may cause foetal and neonatal effects like icterus, disturbance of electrolyte balance and thrombocytopenia.
 It is not known whether candesartan is excreted in human milk. However, candesartan is excreted in the milk of lactating rats. Hydrochlorothiazide passes into human milk. Because of the potential for adverse effects on the nursing infant, breast feeding should be discontinued if the use of candesartan with hydrochlorothiazide tablets is considered essential.

4.7 Effects on Ability to Drive and Use Machines

When driving vehicles or operating machines, it should be taken into account that dizziness or weariness may occur during treatment of hypertension.

4.8 Adverse Effects (Undesirable Effects)

Adverse events were mild and transient in controlled clinical studies with various doses of candesartan cilexetil/hydrochlorothiazide (candesartan cilexetil up to 32 mg and hydrochlorothiazide up to 25 mg). The overall incidence of adverse events showed no association with age or gender. Withdrawals from treatment due to adverse events were similar with candesartan cilexetil/hydrochlorothiazide (2.3-3.3%) and placebo (2.7-4.3%).
Clinical adverse events, regardless of causal relationship, with a cumulative 8-week incidence rate of ≥ 1% during treatment with candesartan cilexetil/hydrochlorothiazide up to 16/12.5 mg in double-blind placebo-controlled trials are presented in Table 1.
The following clinical adverse events occurred with a frequency of 0.5% to < 1% with no occurrence in the placebo group: AV-block, vomiting.
Clinical adverse events, regardless of causal relationship, occurring in ≥ 1% of the patients during 8-week randomised treatment with candesartan cilexetil/hydrochlorothiazide 32/12.5 mg and 32/25 mg in double-blind clinical trials are presented in Table 2.

Adverse events on individual components.

Candesartan cilexetil.

The following clinical adverse events, regardless of whether attributed to therapy, have been reported to occur with a cumulative 8-week incidence rate of ≥ 1% in placebo-controlled clinical trials with candesartan cilexetil monotherapy: cough, diarrhoea, peripheral oedema and rhinitis. Angioedema, urticaria, pruritus and rash have been reported very rarely in patients treated with candesartan cilexetil. Very rare cases of increased liver enzymes, abnormal hepatic function or hepatitis have also been reported. Very rare adverse reactions include hyponatraemia, hyperkalaemia and renal impairment, including renal failure in susceptible patients (see Section 4.4 Special Warnings and Precautions for Use). Other adverse events reported for candesartan cilexetil where a causal relationship could not be established include very rare cases of leukopenia, neutropenia and agranulocytosis.

Hydrochlorothiazide.

The following clinical adverse events have been reported to occur with hydrochlorothiazide monotherapy: anorexia, loss of appetite, gastric irritation, diarrhoea, constipation, jaundice (intrahepatic cholestatic jaundice), pancreatitis, leucopenia, neutropenia/agranulocytosis, thrombocytopenia, aplastic anaemia, hemolytic anaemia, bone marrow depression, photosensitivity reactions, fever, rash, cutaneous lupus erythematosus-like reactions, reactivation of cutaneous lupus erythematosus, urticaria, necrotising angiitis (vasculitis, cutaneous vasculitis), anaphylactic reactions, toxic epidermal necrolysis, respiratory distress (including pneumonitis and pulmonary oedema and acute respiratory distress syndrome (very rare) - see Section 4.4 Special Warnings and Precautions for Use), hyperglycaemia, glycosuria, hyperuricaemia, electrolyte imbalance (including hyponatraemia and hypokalaemia), increases in cholesterol and triglycerides, increases in BUN and serum creatinine, renal dysfunction, interstitial nephritis, muscle spasm, weakness, restlessness, transient blurred vision, light-headedness, postural hypotension, vertigo, paraesthesia, cardiac arrhythmias, sleep disturbances, depression, choroidal effusion, acute myopia, acute angle-closure glaucoma.

Postmarketing.

The following adverse reactions have been reported very rarely (< 0.01%) in postmarketing experience:

Musculoskeletal, connective tissue and bone disorders.

Myalgia.
Rare reports of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers.
Although causality to candesartan has not been established, the following neuropsychiatric cardiovascular adverse reactions have been very rarely reported during post-marketing surveillance. These were: agitation, anxiety, depression, insomnia, somnolence, nervousness, nightmare, sleep disorder and palpitations.
The following adverse reactions have been reported post-marketing with hydrochlorothiazide, regardless of causality:

Neoplasms benign, malignant and unspecified (incl cysts and polyps).

Frequency "not known": Non-melanoma skin cancer (Basal cell carcinoma and squamous cell carcinoma) (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.

4.9 Overdose

Symptoms.

Based on pharmacological considerations, the main manifestation of an overdose of candesartan cilexetil is likely to be symptomatic hypotension and dizziness. In two case reports of overdose (160 mg and 432 mg candesartan cilexetil) patient recovery was uneventful.
The main manifestation of an overdose of hydrochlorothiazide is acute loss of fluid and electrolytes. Symptoms such as dizziness, hypotension, thirst, tachycardia, ventricular arrhythmias, sedation/impairment of consciousness and muscle cramps can also be observed.

Management.

No specific information is available on the treatment of overdosage with candesartan cilexetil with hydrochlorothiazide tablets. The following measures are, however, suggested in case of overdosage.
Administration of activated charcoal with or without gastric lavage. If symptomatic hypotension should occur, symptomatic treatment should be instituted and vital signs monitored. The patient should be placed supine with the legs elevated. If this is not sufficient, plasma volume should be increased by infusion of isotonic saline solution. Serum electrolyte and acid balance should be checked and corrected, if needed. Sympathomimetic drugs may be administered if the abovementioned measures are not sufficient.
Candesartan cannot be removed by haemodialysis. It is not known to what extent hydrochlorothiazide is removed by haemodialysis. Contact the Poisons Information Centre for advice on management.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Angiotensin II is the primary vasoactive hormone of the renin-angiotensin-aldosterone system and plays a significant role in the pathophysiology of hypertension and other cardiovascular disorders. It also has an important role in the pathogenesis of end organ hypertrophy and damage. The major physiological effects of angiotensin II, such as vasoconstriction, aldosterone stimulation, regulation of salt and water homeostasis and stimulation of cell growth, are mediated via the type 1 (AT1) receptor.
Candesartan cilexetil is a prodrug suitable for oral use. It is rapidly converted to the active drug, candesartan, by ester hydrolysis during absorption from the gastrointestinal tract. Candesartan is an angiotensin II receptor antagonist, selective for AT1 receptors, with tight binding to and slow dissociation from the receptor. It has no agonist activity.
Candesartan does not inhibit angiotensin converting enzyme (ACE), which converts angiotensin I to angiotensin II and degrades bradykinin. Since there is no effect on ACE and no potentiation of bradykinin or substance P, angiotensin II receptor antagonists are unlikely to be associated with cough. This has been confirmed in controlled clinical studies with candesartan. Candesartan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.
Hydrochlorothiazide inhibits the active reabsorption of sodium, mainly in the distal kidney tubules, and promotes the excretion of sodium, chloride and water. The renal excretion of potassium and magnesium increases dose-dependently, while calcium is reabsorbed to a greater extent. Hydrochlorothiazide decreases plasma volume and extracellular fluid and reduces cardiac output and blood pressure. During long-term therapy, reduced peripheral resistance contributes to the blood pressure reduction.
Candesartan and hydrochlorothiazide have additive antihypertensive effects. In hypertensive patients, it results in dose-dependent and long lasting reduction in arterial blood pressure without a reflex increase in heart rate. There is no indication of serious or exaggerated first dose hypotension or rebound effect after cessation of treatment.
After administration of a single dose of candesartan with hydrochlorothiazide, onset of the antihypertensive effect generally occurs within 2 hours. With continuous treatment, most of the reduction in blood pressure is attained within four weeks and is sustained during long-term treatment.
Candesartan with hydrochlorothiazide once daily provides effective and smooth blood pressure reduction over 24 hours, with little difference between maximum and trough effects during the dosing interval. In double-blind, randomised studies, the incidence of cough was lower during treatment with candesartan cilexetil/hydrochlorothiazide than during treatment with combinations of ACE inhibitors and hydrochlorothiazide.
Age and gender have no influence on the efficacy of candesartan with hydrochlorothiazide tablets.
In a variety of preclinical safety studies conducted in several species, expected exaggerated pharmacological effects (e.g. renal changes leading to juxtaglomerular cell hypertrophy, adrenal gland zona glomerulosa atrophy and reduced heart weight related to reduced afterload), due to modification of the renin-angiotensin-aldosterone system homeostasis, have been observed. The incidence and severity of the effects induced were dose and time related and have been shown to be reversible in adult animals. Addition of hydrochlorothiazide caused a potentiation of the nephrotoxicity seen with candesartan alone, however, without any qualitatively new findings.

Clinical trials.

In a randomised, double-blind, parallel group, 8 week clinical study, including 1975 randomised patients not adequately controlled on 32 mg candesartan cilexetil once daily, the addition of 12.5 mg or 25 mg hydrochlorothiazide resulted in additional blood pressure reductions of 7/3 mmHg and 9/4 mmHg respectively over 32 mg monotherapy. The candesartan cilexetil/hydrochlorothiazide 32/12.5 mg and 32/25 mg combinations produced overall mean blood pressure reductions of 13/9 mmHg and 16/10 mmHg, respectively. This study also demonstrated that the 32/25 mg combination was significantly more effective than the 32/12.5 mg combination.
In two 8 week clinical studies (randomised, double-blind, placebo controlled, parallel group) including 275 and 1524 randomised patients respectively, the candesartan cilexetil/hydrochlorothiazide combinations 32/12.5 mg and 32/25 mg resulted in blood pressure reductions of 21/14 mmHg for the highest dose, and were significantly more effective than the respective monotherapy components.
Epidemiological studies have shown that long term treatment with hydrochlorothiazide reduces the risk for cardiovascular morbidity and mortality. There are no data regarding the effects of candesartan cilexetil and candesartan cilexetil/hydrochlorothiazide on morbidity and mortality in hypertensive patients.

Non-melanoma skin cancer (NMSC).

Based on available data from epidemiological studies, cumulative dose-dependent association between hydrochlorothiazide (HCTZ) and NMSC has been observed. One study included a population comprised of 71,553 cases of basal cell carcinoma (BCC) and of 8,629 cases of squamous cell carcinoma (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 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 cumulative dose-response relationship was demonstrated with an adjusted OR 2.1 (95% CI: 1.7-2.6) increasing to OR 3.9 (3.0-4.9) for high use (~25,000 mg) and OR 7.7 (5.7-10.5) for the highest cumulative dose (~100,000 mg) (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)).

5.2 Pharmacokinetic Properties

The individual pharmacokinetic profiles of candesartan and hydrochlorothiazide were not clinically significantly affected when given in combination.

Absorption and distribution.

Candesartan cilexetil.

Following oral administration, candesartan cilexetil is converted to the active drug candesartan. The absolute bioavailability of candesartan is approximately 40% after an oral solution of candesartan cilexetil. The relative bioavailability of the tablet formulation compared with the same oral solution is approximately 34%, with little variability. The absolute bioavailability of candesartan following administration of the tablet is approximately 14%. The mean peak plasma concentration (Cmax) is reached 3-4 hours after taking a tablet. The candesartan plasma concentrations increase linearly with increasing doses in the therapeutic dose range.
The area under the plasma concentration versus time curve (AUC) of candesartan is not significantly affected by food. The peak concentration (Cmax) is increased by 26% and the rate of absorption is increased when taken with food. These changes are unlikely to result in clinically significant effects.
Candesartan is highly bound to plasma protein (more than 99%). The apparent volume of distribution (Vss) of candesartan is 0.1 L/kg.

Hydrochlorothiazide.

Hydrochlorothiazide is rapidly absorbed from the gastrointestinal tract with an absolute bioavailability of approximately 70%. Concomitant intake of food increases the absorption by approximately 15%. The bioavailability may decrease in patients with cardiac failure and pronounced oedema.
The plasma protein binding of hydrochlorothiazide is approximately 60%. The apparent volume of distribution is approximately 0.8 L/kg.

Metabolism and excretion.

Candesartan cilexetil.

Candesartan cilexetil is mainly eliminated unchanged via urine and bile and is eliminated by hepatic metabolism only to a minor extent (CYP2C9). The terminal half-life of candesartan is approximately 9 hours. There is no accumulation following multiple doses.
The half-life of candesartan remains unchanged (approximately 9 h) after administration of candesartan cilexetil in combination with hydrochlorothiazide. No accumulation of candesartan occurs after repeated doses of the combination compared to monotherapy.
Total plasma clearance of candesartan is about 0.37 mL/min/kg, with a renal clearance of about 0.19 mL/min/kg. The renal elimination of candesartan is both by glomerular filtration and active tubular secretion. Following an oral dose of 14C-labelled candesartan cilexetil about 30% and 70% of the total radioactivity is recovered in the urine and faeces, respectively.

Hydrochlorothiazide.

Hydrochlorothiazide is not metabolised and is excreted almost entirely as unchanged drug by glomerular filtration and active tubular secretion. The terminal t1/2 of hydrochlorothiazide is approximately 8 hours. Approximately 70% of an oral dose is eliminated in the urine within 48 hours. The half-life of hydrochlorothiazide remains unchanged (approximately 8 h) after administration of hydrochlorothiazide in combination with candesartan cilexetil. No accumulation of hydrochlorothiazide occurs after repeated doses of the combination compared to monotherapy.

Pharmacokinetics in special populations.

Candesartan cilexetil.

In the elderly (over 65 years) both Cmax and AUC of candesartan are increased by approximately 50% and 80%, respectively in comparison to young subjects.
However, the blood pressure response and the incidence of adverse events are similar after a given dose of candesartan with hydrochlorothiazide in young and elderly patients.
In patients with mild to moderate renal impairment Cmax and AUC of candesartan increased during repeated dosing by approximately 50% and 70% respectively, but t½ was not altered, compared to patients with normal renal function. The corresponding changes in patients with severe renal impairment were approximately 50% and 110% respectively. The terminal t½ of candesartan was approximately doubled in patients with severe renal impairment. The pharmacokinetics in patients undergoing haemodialysis were similar to those in patients with severe renal impairment.
In patients with mild to moderate hepatic impairment, there was a 23% increase in the AUC of candesartan. No initial dosage adjustment is necessary in these patients.

Hydrochlorothiazide.

The terminal t½ of hydrochlorothiazide is prolonged in patients with renal impairment.

5.3 Preclinical Safety Data

Genotoxicity.

Candesartan cilexetil alone or in combination with hydrochlorothiazide showed no evidence of genotoxic potential in a series of assays for gene mutations (Salmonella typhimurium and Escherichia coli), chromosomal aberrations (mouse micronucleus assay) and DNA damage (unscheduled DNA synthesis in rat liver). In addition, candesartan cilexetil alone showed no evidence of genotoxic potential in further assays for gene mutations (mouse L5178Y cells and Chinese hamster ovary cells). The active metabolite, candesartan, caused an increase in chromosomal aberrations in vitro (Chinese hamster lung cells) but not in vivo (mouse micronucleus test and chromosomal aberrations in rat bone marrow). However, hydrochlorothiazide had mutagenic activity in a mammalian cell assay (mouse L5178Y cells) and caused an increase in chromosomal aberrations in vitro (Chinese hamster lung cells). Candesartan at subclastogenic concentration did not modify these effects of hydrochlorothiazide. Hydrochlorothiazide also had a genotoxic activity in the sister chromatid exchange assay in Chinese hamster ovary cells and a non-disjunction assay in Aspergillus nidulans.

Carcinogenicity.

The carcinogenic potential of candesartan cilexetil in combination with hydrochlorothiazide has not been evaluated in animal studies.
Candesartan cilexetil alone was not carcinogenic when administered orally to mice and rats for 2 years at doses of up to 100 and 1000 mg/kg/day, corresponding to ca. 7 times and 260 times the clinical exposure at the maximum recommended daily human dose of 32 mg (based on AUC, respectively).
Hydrochlorothiazide alone was not carcinogenic in female mice in doses ca. 600 mg/kg/day, or in male and female rats at doses up to ca. 100 mg/kg/day in two-year feeding studies. These doses correspond to ca. 110 times (female mice) or 40 times (male and female rats) the clinical exposure at the maximum recommended daily human dose of 25 mg (based on BSA). However, there was equivocal evidence for hepatocarcinogenicity in male mice that received ca. 600 mg/kg/day.

6 Pharmaceutical Particulars

6.1 List of Excipients

The tablets also contain lactose monohydrate, carmellose calcium, maize starch, macrogol 8000, hyprolose, magnesium stearate, Pigment Blend PB-24880 Pink (ARTG 108327; 16/12.5 mg and 32/25 mg tablets only) and yellow colouring (iron oxide yellow and lactose monohydrate) in the 32/12.5 mg tablets only. The tablets are gluten free.

6.2 Incompatibilities

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

6.5 Nature and Contents of Container

Aluminium/Aluminium foil blister packs and HDPE bottles with child-resistant PP closures*.
Packs of 30 tablets.
* Not marketed.

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

Candesartan cilexetil is a white or almost white powder and is practically insoluble in water, freely soluble in methylene chloride and slightly soluble in anhydrous ethanol. Three polymorphic forms have been identified; crystal form I, crystal form II and an amorphous form. Crystalline form I is used in Candesan Combi.
Hydrochlorothiazide is a sulfonamide derived drug. It is white, crystalline powder. It is very slightly soluble in water, soluble in acetone, sparingly soluble in ethanol (96 per cent). It dissolves in dilute solutions of alkali hydroxides.

Chemical structure.

Candesartan cilexetil.

The chemical name for candesartan cilexetil is (1RS)-1-[[(Cyclohexyloxy)carbonyl]oxy] ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]- 1H-benzimidazole-7-carboxylate. Its structural formula is:
The molecular weight is 610.67.
The molecular formula is C33H34N6O6.

Hydrochlorothiazide.

The chemical name is 6-chloro-3,4-dihydro-2H- 1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. Its structural formula is:
The molecular weight is 297.7.
The molecular formula is C7H8ClN3O4S2.

CAS number.

Candesartan cilexetil.

145040-37-5.

Hydrochlorothiazide.

58-93-5.

7 Medicine Schedule (Poisons Standard)

Prescription only medicines (Schedule 4).

Summary Table of Changes