Consumer medicine information

APO-Candesartan

Candesartan cilexetil

BRAND INFORMATION

Brand name

APO-Candesartan

Active ingredient

Candesartan cilexetil

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using APO-Candesartan.

SUMMARY CMI

APO-CANDESARTAN

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 APO-CANDESARTAN?

APO-CANDESARTAN contains the active ingredient candesartan cilexetil. APO-CANDESARTAN is used to treat high blood pressure, also called hypertension.

APO-CANDESARTAN is also used to treat heart failure. It is used in combination with other medicines to treat your condition.

For more information, see Section 1. Why am I taking APO-CANDESARTAN? in the full CMI.

2. What should I know before I take APO-CANDESARTAN?

Do not use if you have ever had an allergic reaction to APO-CANDESARTAN 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 APO-CANDESARTAN? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with APO-CANDESARTAN 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 APO-CANDESARTAN?

  • Your doctor will tell you how many tablets to take each day. The usual dose is 8 mg or 16 mg once daily. This dose may be increased to 32 mg once daily.
  • Swallow the tablets whole with a glass of water at about the same time each day.

More instructions can be found in Section 4. How do I take APO-CANDESARTAN? in the full CMI.

5. What should I know while taking APO-CANDESARTAN?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are taking APO-CANDESARTAN.
  • If you are taking APO-CANDESARTAN for high blood pressure, drink plenty of water during exercise and hot weather, especially if you sweat a lot. If you do not drink plenty of water while taking APO-CANDESARTAN, 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 are taking APO-CANDESARTAN for heart failure, restricted fluid intake is generally recommended. Speak with your doctor about how much water you should drink.
  • Move slowly when getting out of bed or standing up if you feel faint, dizzy or light-headed.
Things you should not do
  • Do not stop taking APO-CANDESARTAN or lower the dosage without checking with your doctor.
Driving or using machines
  • Be careful driving or operating machinery until you know how APO-CANDESARTAN affects you. APO-CANDESARTAN may cause dizziness and tiredness in some people.
Drinking alcohol
  • Tell your doctor if you drink alcohol. Alcohol may interfere with APO-CANDESARTAN.
Looking after your medicine
  • Keep your tablets in the blister pack until it is time to take them.
  • Keep it in a cool dry place where the temperature stays below 25°C.

For more information, see Section 5. What should I know while taking APO-CANDESARTAN? in the full CMI.

6. Are there any side effects?

Less serious side effects are chest or throat infection, flu-like symptoms, feeling sick (nausea/vomiting), back pain, headache and dizziness.

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

APO-CANDESARTAN

Active ingredient: candesartan cilexetil

Consumer Medicine Information (CMI)

This leaflet provides important information about taking APO-CANDESARTAN. 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 APO-CANDESARTAN.

Where to find information in this leaflet:

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

1. Why am I taking APO-CANDESARTAN?

APO-CANDESARTAN contains the active ingredient candesartan cilexetil.

Candesartan cilexetil is a type of medicine called an angiotensin II receptor antagonist (or blocker). Candesartan cilexetil lowers blood pressure by dilating (expanding) small blood vessels from the heart, letting the blood be pumped around the body more easily.

APO-CANDESARTAN is used to treat:

  • high blood pressure, also called hypertension.
  • heart failure, in combination with other medicines to treat your condition.

2. What should I know before I take APO-CANDESARTAN?

Warnings

Do not take APO-CANDESARTAN if:

  • you are allergic to any medicine containing candesartan cilexetil, any medicine containing an angiotensin II receptor antagonist (blocker) or any of the ingredients listed at the end of this leaflet. Always check the ingredients to make sure you can take this medicine.
    Symptoms of an allergic reaction may include:
    - shortness of breath
    - wheezing or difficulty breathing
    - swelling of the lips, tongue or other parts of the body
    - rash, itching or hives on the skin.
  • you have severe 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.

Check with your doctor if you:

  • have any other medical conditions:
    - kidney problems
    - liver problems
    - heart problems
    - recent excessive vomiting or diarrhoea
    - a condition called primary hyperaldosteronism.

You may have to take a lower dose of APO-CANDESARTAN if you have these conditions.

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?

Use in children

APO-CANDESARTAN is not recommended for children. There is no information about its use in children.

Pregnancy and breastfeeding

Do not take APO-CANDESARTAN if you are pregnant or planning to become pregnant.

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

Do not take APO-CANDESARTAN if you are breastfeeding.

It is not known if APO-CANDESARTAN passes into breast milk.

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 APO-CANDESARTAN may interfere with each other. These include:

  • Any medicines containing potassium, including salt substitutes.
  • Diuretics (fluid tablets).
  • Lithium, a medicine used to treat mood swings and some types of depression.
  • Non-steroidal anti-inflammatory drugs (NSAIDs), medicines used to relieve pain, swelling and other symptoms of inflammation, including arthritis.
  • Angiotensin-converting-enzyme (ACE) inhibitors, medicines used to help lower blood pressure, especially if you have diabetes related kidney problems.
  • Mineralocorticoid receptor antagonists (MRAs), such as spironolactone and eplerenone, medicines used to treat heart failure.

These medicines may be affected by APO-CANDESARTAN or may affect the way APO-CANDESARTAN works. You may need different amounts of your medicines or you may need to take different medicines.

It may be necessary to have regular blood tests done if you take any of these medicines.

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

4. How do I take APO-CANDESARTAN?

How much to take

The usual dose is one 8 mg tablet or one 16 mg tablet taken daily. Sometimes an increase in dose to 32 mg tablet once daily is needed. Your doctor will tell you the dose of APO-CANDESARTAN you should take.

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

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

When to take APO-CANDESARTAN

APO-CANDESARTAN should be taken once a day, at about the same time each day. Keeping a regular time for taking APO-CANDESARTAN will help to remind you to take it.

How to take APO-CANDESARTAN

Swallow the tablets whole with a full glass of water. It does not matter whether you take APO-CANDESARTAN with food or on an empty stomach.

How long to take APO-CANDESARTAN

Continue taking APO-CANDESARTAN for as long as your doctor tells you. APO-CANDESARTAN helps to control your condition but does not cure it. It is important to keep taking APO-CANDESARTAN even if you feel well.

If you forget to take APO-CANDESARTAN

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 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 you missed.

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

If you take too much APO-CANDESARTAN

If you think that you have taken too many APO-CANDESARTAN 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 APO-CANDESARTAN tablets you may get a headache, feel sick (nausea), dizzy and very tired.

5. What should I know while taking APO-CANDESARTAN?

Things you should do

  • Take APO-CANDESARTAN 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, dentist or pharmacist that you are taking APO-CANDESARTAN.
  • If you plan to have surgery (even at the dentist) that needs a general anaesthetic, tell your doctor or dentist that you are taking APO-CANDESARTAN.
  • 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.
  • Remind any doctor, dentist or pharmacist you visit that you are taking APO-CANDESARTAN.

Call your doctor straight away if you:

  • become pregnant or plan to become pregnant while you are taking APO-CANDESARTAN. You should not take APO-CANDESARTAN 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 APO-CANDESARTAN to treat any other complaints unless your doctor tells you to.
  • Do not give APO-CANDESARTAN to anyone else, even if they have the same condition as you.
  • Do not stop taking APO-CANDESARTAN unless you have discussed it with your doctor.

Things to be careful of

  • Move slowly when getting out of bed or standing up if you feel faint, dizzy or light-headed.
  • If you are taking APO-CANDESARTAN for high blood pressure, drink plenty of water during exercise and hot weather, especially if you sweat a lot.
  • If you do not drink enough water while taking APO-CANDESARTAN, 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 are taking APO-CANDESARTAN for heart failure, restricted fluid intake is generally recommended. Speak with your doctor about how much water you should drink.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how APO-CANDESARTAN affects you.

APO-CANDESARTAN may cause dizziness and tiredness 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 APO-CANDESARTAN.

Looking after your medicine

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

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 or if the packaging is torn or shows signs of tampering.

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.

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
  • Chest or throat infection.
  • Flu-like symptoms.
  • Feeling sick (nausea/vomiting).
  • Back pain.
  • Headache.
  • Dizziness.
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
  • Aching muscles, tenderness or weakness in the muscle.
  • Swelling of the face, lips, tongue or throat.
  • Swelling of hands, feet or ankles.
  • Harsh sounds when breathing.
  • Unusual skin reactions (severe and sudden onset of rash, itchiness, hives (itchy swelling on the skin).
  • Jaundice (yellowing of the skin and/or eyes).
  • Easy bruising or bleeding more easily than normal.
  • Extreme fatigue, tiredness, weakness.
  • Signs of frequent infections such as fever, severe chills, sore throat or mouth ulcers.
  • Worsening of the 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.
  • Symptoms that may indicate high potassium levels in the blood include nausea, diarrhoea, muscle weakness and change in heart rhythm.
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.

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 APO-CANDESARTAN contains

Active ingredient
(main ingredient)
  • Candesartan cilexetil.
Other ingredients
(inactive ingredients)
  • Lactose monohydrate.
  • Carmellose calcium.
  • Maize starch.
  • Macrogol 8000.
  • Hyprolose.
  • Magnesium stearate.
  • Pigment Blend PB-24880 Pink (iron oxide red and lactose monohydrate).
Potential allergensContains sugars as lactose.

This medicine does not contain gluten, sucrose, tartrazine or any other azo dyes.

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

What APO-CANDESARTAN looks like

APO-CANDESARTAN 4 mg Tablet

Light pink, mottled, round biconvex uncoated tablet with ‘291’ on one side and a scoreline on the other side.

AUST R 210529.

APO-CANDESARTAN 8 mg Tablet

Light pink, mottled, round biconvex uncoated tablet with ‘292’ on one side and a scoreline on the other side.

AUST R 210530.

APO-CANDESARTAN 16 mg Tablet

Light pink, mottled, round biconvex uncoated tablet with ‘L293’ on one side and a scoreline on the other side.

AUST R 210531.

APO-CANDESARTAN 32 mg Tablet

Light pink, mottled, round biconvex uncoated tablet with ‘L294’ on one side and a scoreline on the other side.

AUST R 210532.

Available in blister pack of 30 tablets.

*Not all strengths may be available.

Who distributes APO-CANDESARTAN

Arrotex Pharmaceutical Pty Ltd
15-17 Chapel Street
Cremorne VIC 3121
Australia

This leaflet was prepared in August 2024.

Published by MIMS September 2024

BRAND INFORMATION

Brand name

APO-Candesartan

Active ingredient

Candesartan cilexetil

Schedule

S4

 

1 Name of Medicine

Candesartan cilexetil.

2 Qualitative and Quantitative Composition

APO-Candesartan tablets come in four strengths and contain 4 mg, 8 mg, 16 mg or 32 mg of candesartan cilexetil.

Excipients with known effect.

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

3 Pharmaceutical Form

APO-Candesartan candesartan cilexetil 4 mg tablets.

Light pink, mottled, round biconvex uncoated tablet with '291' on one side and a scoreline on the other side.

APO-Candesartan candesartan cilexetil 8 mg tablets.

Light pink, mottled, round biconvex uncoated tablet with '292' on one side and a scoreline on the other side.

APO-Candesartan candesartan cilexetil 16 mg tablets.

Light pink, mottled, round biconvex uncoated tablet with 'L293' on one side and a scoreline on the other side.

APO-Candesartan candesartan cilexetil 32 mg tablets.

Light pink, mottled, round biconvex uncoated tablet with 'L294' on one side and a scoreline on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

APO-Candesartan is indicated for the treatment of:
hypertension;
patients with heart failure and impaired left ventricular systolic function (left ventricular ejection fraction ≤ 40%) as add-on therapy to ACE inhibitors or when ACE inhibitors are not tolerated.

4.2 Dose and Method of Administration

APO-Candesartan should be taken once daily with or without food.

Hypertension.

The recommended maintenance dose of candesartan is 8 mg or 16 mg once daily. The maximal antihypertensive effect is attained within 4 weeks following initiation of treatment. For those patients who start on 8 mg and require further blood pressure reduction, a dose increase to 16 mg is recommended. An initial dose of 16 mg is also well tolerated. Some patients may receive an additional benefit by increasing the dose to 32 mg once daily.
In patients with less than optimal blood pressure reduction on candesartan, combination with a thiazide diuretic is recommended.

Geriatrics.

An initial dose of 8 mg is recommended.

Hepatic insufficiency.

Dose titration is recommended in patients with mild to moderate chronic liver disease, and a lower initial dose of 4 mg should be considered.
Candesartan should not be used in patients with severe hepatic impairment and/or cholestasis (see Section 4.3 Contraindications).

Renal insufficiency.

No initial dosage adjustment is necessary in patients with mild to moderate impaired renal function (i.e. creatinine clearance 30-80 mL/min/1.73 m2 BSA). In patients with severely impaired renal function (i.e. creatinine clearance < 30 mL/min/1.73 m2 BSA) including patients on haemodialysis a lower initial dose of 4 mg should be considered.

Heart failure.

The usual recommended initial dose of candesartan is 4 mg once daily. Up titration to the target dose of 32 mg once daily or the highest tolerated dose is performed by doubling the dose at intervals of at least 2 weeks (see Section 4.4 Special Warnings and Precautions for Use).

Special patient populations.

No initial dose adjustment is necessary for elderly patients or in patients with renal or hepatic impairment.

Concomitant therapy.

Candesartan can be administered with other heart failure treatment, including ACE inhibitors, beta-blockers, diuretics and digitalis or a combination of these medicines (see Section 5.1 Pharmacodynamic Properties).

4.3 Contraindications

Patients with known hypersensitivity to candesartan cilexetil or any of the excipients.
Pregnancy and lactation (see Section 4.6 Fertility, Pregnancy and Lactation).
Severe hepatic impairment and/or cholestasis.
The use of candesartan cilexetil 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.

Kidney transplantation.

There is limited clinical experience regarding candesartan use in patients who have undergone renal transplant.

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 (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.

Hypotension.

Hypotension may occur during treatment with candesartan in heart failure patients. As described for other agents acting on the renin angiotensin aldosterone system, it may also occur in hypertensive patients with intravascular volume depletion. Caution should be observed when initiating therapy and correction of hypovolemia should be attempted.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS) with aliskiren-containing medicines.

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 cilexetil with an ACE-inhibitor 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 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).

Use in heart failure.

Triple combination of candesartan cilexetil with an ACE-inhibitor and a mineralocorticoid receptor antagonist used in heart failure is also not recommended. Use of these combinations should be under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure.

Hyperkalaemia.

Based on experience with the use of other drugs that affect the renin angiotensin aldosterone system, concomitant use of candesartan with potassium sparing diuretics, potassium supplements, salt substitutes containing potassium, or other drugs that may increase potassium levels (e.g. heparin) may lead to increases in serum potassium in hypertensive patients. In heart failure patients treated with candesartan, hyperkalaemia may occur. During treatment with candesartan in patients with heart failure, periodic monitoring of serum potassium is recommended, especially when taken concomitantly with ACE inhibitors and potassium sparing diuretics such as spironolactone.

Anaesthesia and surgery.

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

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.

Use in hepatic impairment.

There is limited clinical experience in patients with severe hepatic impairment and/or cholestasis. Use in patients with severe hepatic impairment is contraindicated. Caution is advised in patients with mild to moderate hepatic impairment. There have been reports of clinically significant liver disease occurring with other angiotensin II receptor antagonists. No such cases have been reported to date with candesartan.

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. When candesartan is used in hypertensive patients with severe renal impairment, periodic monitoring of serum potassium and creatinine levels should be considered. There is very limited experience in patients with very severe or endstage renal impairment (i.e. creatinine clearance < 15 mL/min/1.73 m2 BSA). Evaluation of patients with heart failure should include periodic assessments of renal function. During dose titration of candesartan, monitoring of serum creatinine and potassium is recommended.

Haemodialysis.

During dialysis the blood pressure may be particularly sensitive to AT1 receptor blockade as a result of reduced plasma volume and activation of the renin angiotensin aldosterone system. Therefore, candesartan should be carefully titrated with thorough monitoring of blood pressure in patients on haemodialysis (see Section 4.2 Dose and Method of Administration).

Use in the elderly.

An initial dose of 8 mg is recommended.

Paediatric use.

The safety and efficacy of candesartan have not been established in children.

Effects on laboratory tests.

In general there were no clinically important effects of candesartan on routine laboratory variables. As for other inhibitors of the renin angiotensin aldosterone system, small decreases in haemoglobin have been seen. Increases in creatinine, urea or potassium and decreases in sodium have been observed. In clinical trials, elevations of ALT occurred in 1.3% of candesartan treated patients and 0.5% of those treated with placebo. The incidence of AST elevation was 0.4% with candesartan and 0% with placebo. No routine monitoring of laboratory variables is usually necessary for patients receiving candesartan. However, in patients with severe renal impairment, periodic monitoring of serum potassium and creatinine levels should be considered.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Dual blockade of the renin angiotensin aldosterone system (RAAS) with aliskiren containing medicines.

The combination of candesartan cilexetil with aliskiren-containing medicine is contraindicated in patients with diabetes mellitus (type I or II) or moderate to severe renal impairment (GFR < 60 mL/min/1.73 m2) and is not recommended in other patients. 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).

Food.

Food increases the rate of absorption of candesartan however the extent of absorption of candesartan is not affected by food.

Lithium.

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

Other medicines.

Compounds which have been investigated in clinical pharmacokinetic studies include hydrochlorothiazide, warfarin, digoxin, oral contraceptives (i.e. ethinyloestradiol/ levonorgestrel), glibenclamide and nifedipine and enalapril. No pharmacokinetic interactions of clinical significance were identified in these studies.
Attenuation of the antihypertensive effect may occur when simultaneously administering AIIRAs and nonsteroidal anti-inflammatory drugs (NSAIDs; i.e. selective COX-2 inhibitors, acetylsalicylic acid (> 3 g/day) and nonselective NSAIDs).
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). Available interaction studies indicate no effect on CYP2C9 and CYP3A4 but the effect on other cytochrome P450 isoenzymes is presently unknown.
Candesartan may be administered with other antihypertensive agents.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Candesartan cilexetil had no adverse effects on the reproductive performance of male or female rats at oral doses up to 300 mg/kg/day.
(Category D1)
The use of candesartan is contraindicated during pregnancy (see Section 4.3 Contraindications). Patients receiving candesartan 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 must be stopped immediately and if appropriate, alternate therapy should be started.
Drugs that act on the renin angiotensin system (RAS) can cause fetal and neonatal morbidity and death when administered to pregnant women. Exposure to angiotensin II receptor antagonist therapy is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia).
1Category D - Drugs which have caused, are suspected to have caused or may be expected to cause, an increased incidence of human fetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects. Accompanying texts should be consulted for further details.
 It is not known whether candesartan is excreted in human milk. However, candesartan is excreted in the milk of lactating rats. Because of the potential for adverse effects on the nursing infant, breastfeeding should be discontinued if the use of candesartan 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.

4.8 Adverse Effects (Undesirable Effects)

Hypertension.

Candesartan was well tolerated in clinical studies showing an adverse event profile comparable to that of placebo. Generally adverse events were mild and transient. The overall incidence of adverse effects showed no association with dose, age or gender. Withdrawals from treatment due to adverse events were similar with candesartan cilexetil (3.1%) and placebo (3.2%).
Information on adverse events was obtained from 39 phase I to phase III clinical studies, involving a total of 5,464 subjects. Candesartan was administered as mono or combination therapy to 2,061 hypertensive patients. The crude frequency of the most commonly occurring adverse events, irrespective of causality, reported for those patients and the 573 placebo comparators are given in Table 1.

Laboratory findings.

In general there were no clinically important effects of candesartan cilexetil on routine laboratory variables. As for other inhibitors of the renin-angiotensin-aldosterone system, small decreases in haemoglobin have been seen. Increases in creatinine, urea or potassium and decreases in sodium have been observed. In clinical trials, elevations of ALT occurred in 1.3% of candesartan-treated patients and 0.5% of those treated with placebo. The incidence of AST elevation was 0.4% with candesartan and 0% with placebo. No routine monitoring of laboratory variables is usually necessary for patients receiving candesartan cilexetil. However, in patients with severe renal impairment, periodic monitoring of serum potassium and creatinine levels should be considered.

Heart failure.

The adverse experience profile of candesartan in heart failure patients was consistent with the pharmacology of the drug and the health status of the patients. In the CHARM clinical programme, comparing candesartan in doses up to 32 mg (n = 3,803) to placebo (n = 3,796), 21.0% of the candesartan group and 16.1% of the placebo group discontinued treatment because of adverse events. Adverse reactions commonly (≥ 1/100, < 1/10) seen were:

Vascular disorders.

Hypotension.

Metabolism and nutrition disorders.

Hyperkalaemia.

Renal and urinary disorders.

Renal impairment.

Laboratory findings.

Increases in creatinine, urea and potassium. Periodic monitoring of serum creatinine and potassium is recommended (see Section 4.4 Special Warnings and Precautions for Use).

Post marketing experience.

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

Blood and lymphatic system disorders.

Leukopenia, neutropenia and agranulocytosis.

Metabolism and nutrition disorders.

Hyperkalaemia, hyponatraemia.

Hepatobiliary disorders.

Increased liver enzymes, abnormal hepatic function or hepatitis.

Skin and subcutaneous tissue disorders.

Angioedema, rash, urticaria, pruritus.

Musculoskeletal, connective tissue and bone disorders.

Back pain, myalgia.

Renal and urinary disorders.

Renal impairment, including renal failure in susceptible patients (see Section 4.4 Special Warnings and Precautions for Use).
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 and cardiovascular adverse reactions have been very rarely reported during postmarketing surveillance. These were: agitation, anxiety, depression, insomnia, somnolence, nervousness, nightmare, sleep disorder and palpitations.

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 http://www.tga.gov.au/reporting-problems.

4.9 Overdose

Symptoms.

Based on pharmacological considerations, the main manifestation of an overdose is likely to be symptomatic hypotension, and dizziness. In single case reports of overdose (up to 672 mg candesartan cilexetil) patient recovery was uneventful.

Management.

If symptomatic hypotension should occur, symptomatic treatment should be instituted and vital signs monitored. The patients should be placed supine with the legs elevated. If this is not sufficient, plasma volume should be increased by the infusion of, for example, isotonic saline solution. Sympathomimetic drugs may be administered if the above mentioned measures are not sufficient.
Candesartan is not removed by haemodialysis. Contact the Poisons Information Centre for advice on management.
For information on the management of overdose, contact the Poison Information Centre on 131126 (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, heart failure 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 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.
In hypertension, candesartan causes a dose dependent, long lasting reduction in arterial blood pressure. The antihypertensive action is due to decreased systemic peripheral resistance, while heart rate, stroke volume and cardiac output are not affected. There is no indication of serious or exaggerated first dose hypotension or rebound effect after cessation of treatment.
Candesartan is effective in hypertension. After administration of a single dose, onset of antihypertensive effect generally occurs within two hours. With continuous treatment, the maximum reduction in blood pressure with any dose is generally attained within four weeks and is sustained during long-term treatment. It provides effective and smooth blood pressure reduction over the 24 hours dosing interval, with a trough/ peak ratio confirming once daily dosing.
Candesartan can be used as monotherapy, or in combination with other antihypertensive drugs, such as thiazide diuretics, calcium antagonists and lisinopril, for improved blood pressure control. Age and gender have no influence on the efficacy of candesartan.
Candesartan has favourable renal haemodynamic effects. It increases renal blood flow and maintains or increases glomerular filtration rate while renal vascular resistance and filtration fraction are reduced.
Candesartan reduces urinary protein excretion in hypertensive patients with microalbuminuria or nephropathy of different aetiology. Candesartan has no adverse effect on blood glucose or lipid profile. 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. Fetotoxicity has been observed in late pregnancy (see Section 4.6 Fertility, Pregnancy and Lactation).

Clinical trials.

Hypertension. The Candesartan and Lisinopril Microalbuminuria (CALM) study was a 24 week double blind, parallel group trial (n = 199) to evaluate the effects of candesartan and lisinopril alone and in combination on urinary albumin excretion (UAE) in patients with type II diabetes mellitus, hypertension and microalbuminuria. Patients were randomly allocated to four treatment regimens: 1) 24 weeks of candesartan monotherapy (1/3 of the patients); 2) 24 weeks of lisinopril monotherapy (1/3 of the patients); 3) 12 weeks of candesartan monotherapy, followed by 12 weeks of candesartan + lisinopril combination therapy (1/6 of the patients); and 4) 12 weeks of lisinopril monotherapy, followed by 12 weeks of lisinopril + candesartan combination therapy (1/6 of the patients). Thus, after 12 weeks, half of the patients were treated with candesartan monotherapy (n = 99) and half with lisinopril monotherapy (n = 98). After 24 weeks, 1/3 of the patients still in the study were on candesartan monotherapy (n = 49), 1/3 on lisinopril monotherapy (n = 46), and 1/3 on combination therapy (candesartan + lisinopril, n = 25; lisinopril + candesartan, n = 24).
Significant reduction in urinary albumin/ creatinine ratio (UACR), in both monotherapy treatment groups was observed, although no significant difference between treatment groups was seen. Combination therapy following monotherapy for 12 weeks showed significantly greater reduction in UACR (mean reduction of 50%) than candesartan cilexetil 16 mg monotherapy (mean reduction in UACR 24%) and numerically greater reduction than lisinopril 20 mg monotherapy (mean reduction in UACR 39%).
All treatment regimens reduced both systolic and diastolic blood pressure significantly. The blood pressure reductions were significantly greater with combination therapy than with monotherapy, whether lisinopril was added to candesartan, or candesartan was added to lisinopril (see Table 2).
The antihypertensive effects of candesartan cilexetil and losartan potassium at their highest recommended doses administered once daily were compared in two randomised, double blind trials. In a total of 1,268 patients with mild to moderate hypertension who were not receiving other antihypertensive therapy, candesartan cilexetil 32 mg lowered systolic and diastolic blood pressure by 2 to 3 mmHg on average more than losartan potassium 100 mg, when measured at the time of either peak or trough effect.
Heart failure. In patients with chronic heart failure (CHF) and depressed left ventricular systolic function (left ventricular ejection fraction, LVEF ≤ 40%), candesartan decreases systemic vascular resistance and pulmonary capillary wedge pressure, increases plasma renin activity and angiotensin II concentration, and decreases aldosterone levels.
Treatment with candesartan reduces mortality and hospitalisation due to CHF and improves symptoms as shown in the Candesartan in Heart failure-Assessment of Reduction in Mortality and morbidity (CHARM) programme comprising 3 studies (CHARM-Alternative, CHARM-Added and CHARM-Preserved). In all 3 studies, patients on optimal baseline therapy were randomised to placebo or candesartan (titrated from 4 mg or 8 mg once daily to 32 mg once daily or the highest tolerated dose, mean dose 24 mg) and followed for a median of 37.7 months.

CHARM-Alternative.

CHARM-Alternative was a multinational, randomised, double blind placebo controlled study in CHF patients (NYHA class II-IV, n = 2,028) with a LVEF ≤ 40% not treated with an ACE inhibitor because of intolerance. See Table 3.

CHARM-Added.

CHARM-Added was a multinational, randomised, double blind placebo controlled study in CHF patients (NYHA class II-IV, n = 2,548) with a LVEF ≤ 40% treated with ACE inhibitors. See Table 4.

CHARM-Preserved.

CHARM-Preserved was a multinational, randomised, double blind placebo controlled study in CHF patients (n = 3,023, NYHA class II-IV) with a LVEF > 40%, approximately 20% of whom received an ACE inhibitor. In the CHARM-Preserved study there was no effect of candesartan upon mortality. See Table 5.
All cause mortality was also assessed in pooled populations, CHARM-Alternative and CHARM-Added (HR 0.88, 95% CI 0.79-0.98, p = 0.018) and all three studies (HR 0.91, 95% CI 0.83-1.00, p = 0.055). This corresponds to a relative risk reduction of 12% and 9% respectively and an absolute risk reduction of 2.9 and 1.6% respectively.
Treatment with candesartan resulted in improved NYHA functional class in CHARM-Alternative and CHARM-Added (p = 0.008 and p = 0.020 respectively).
The beneficial effects of candesartan cilexetil on cardiovascular mortality and CHF hospitalisation were consistent irrespective of age, gender and concomitant medication. Candesartan was effective also in patients taking both beta-blockers and ACE inhibitors at the same time, and the benefit was obtained whether or not patients were taking ACE inhibitors at the target dose recommended by treatment guidelines.

5.2 Pharmacokinetic Properties

In studies comparing candesartan 8 mg and 32 mg tablets with the innovator, the two products were shown to be bioequivalent.

Absorption.

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 serum concentration (Cmax) is reached 3-4 hours after taking a tablet. The candesartan serum concentrations increase linearly with increasing doses in the therapeutic dose range. The area under the serum 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.

Distribution.

Candesartan is highly bound to plasma protein (more than 99%). The apparent volume of distribution (Vss) of candesartan is 0.1 L/kg.

Metabolism.

Candesartan is mainly eliminated unchanged via urine and bile and is eliminated by hepatic metabolism only to a minor extent.

Excretion.

The terminal half-life of candesartan is approximately 9 hours. There is no accumulation following multiple doses.
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.

Pharmacokinetics in special populations.

In the elderly (over 65 years) both Cmax and AUC of candesartan are increased in comparison to young subjects. An initial dose of 8 mg is recommended (see Section 4.2 Dose and Method of Administration).
In patients with mild to moderate renal impairment Cmax and AUC of candesartan increased during repeated dosing by approximately 50% and 70% respectively, but t1/2 was not altered, compared to patients with normal renal function. The corresponding changes in patients with severe renal impairment was approximately 50% and 110% respectively. The terminal t1/2 of candesartan was approximately doubled in patients with severe renal impairment. AUC of candesartan in patients undergoing haemodialysis was similar to that 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.

5.3 Preclinical Safety Data

Genotoxicity.

Candesartan showed no evidence of genotoxic potential in a series of assay for gene mutations (Salmonella typhimurium, Escherichia coli, mouse L5178Y cells and CHO cells), chromosomal aberrations (mouse nucleus assay) and unscheduled DNA synthesis. The active metabolite, candesartan, caused an increase in chromosomal aberrations in vitro (CHL cells) but not in vivo (mouse micronucleus assay).

Carcinogenicity.

There was no evidence of carcinogenicity when candesartan cilexetil was orally administered to mice and rats for up to 104 weeks at doses up to 100 and 1000 mg/kg/day, respectively. Rats received the drug by gavage whereas mice received the drug by dietary administration. These (maximally tolerated) doses of candesartan cilexetil provided systemic exposures to candesartan (AUCs) that were, in mice, approximately 7 times and, in rats, more than 70 times the exposure in man at the maximum recommended daily human dose (32 mg).

6 Pharmaceutical Particulars

6.1 List of Excipients

Each candesartan tablet contains candesartan cilexetil as the active ingredient. In addition, each candesartan tablet contains the following inactive ingredients: lactose, carmellose calcium, maize starch, macrogol 8000, hydroxypropylcellulose, magnesium stearate and Pigment Blend PB-24880 Pink (ARTG 108327) which contains iron oxide red and lactose. The tablets are gluten free.
See Section 2 Qualitative and Quantitative Composition.

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

4 mg tablets.

Blister pack (PVC/PE/PVDC/Al) of 7, 28 and 30 tablets. AUST R 210529.

8 mg tablets.

Blister pack (PVC/PE/PVDC/Al) blister packs 7, 28 and 30 tablets. AUST R 210530.

16 mg tablets.

Blister pack (PVC/PE/PVDC/Al) of 7, 28 and 30 tablets. AUST R 210531.

32 mg tablets.

Blister pack (PVC/PE/PVDC/Al) of 7, 28 and 30 tablets. AUST R 210532.
Not all strengths and/or pack sizes may be available.

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

It is a white to off white powder and is practically insoluble in water. It has a pKa of 6.3, corresponding to deprotonation of the tetrazole ring. The partition coefficient of candesartan cilexetil is as follows (see Table 6):
Three polymorphic forms have been identified; crystal form I, crystal form II and an amorphous form. Crystalline form I is used in APO-Candesartan.

Chemical structure.


Chemical Name: (±)-1-(cyclohexyloxycarbonyl-oxy) ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl]-1H-benzimadozole-7-carboxylate.
Molecular Formula: C33H34N6O6.
Molecular Weight: 610.7.

CAS number.

145040-37-5.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes