Consumer medicine information

Candesartan Sandoz

Candesartan cilexetil

BRAND INFORMATION

Brand name

Candesartan Sandoz

Active ingredient

Candesartan cilexetil

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Candesartan Sandoz.

What is in this leaflet

This leaflet answers some common questions about Candesartan Sandoz.

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

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

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

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

What Candesartan Sandoz is used for

Candesartan cilexetil belongs to a group of medicines called angiotensin II receptor antagonists (or blocker).

This medicine is used to treat:

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

It contains the active ingredient candesartan cilexetil.

When taking this medicine for hypertension, it works by:

Lowering blood pressure by dilating (expanding) small blood vessels from the heart, letting the blood be pumped around the body more easily.

All people have blood pressure. This pressure helps to push blood all around your body. Your blood pressure changes during the day, depending on how busy you are or how you are feeling. You have hypertension (high blood pressure) when your blood pressure stays higher than is needed, even when you are calm and relaxed.

Regular blood pressure checks are the only way of knowing that you have hypertension. There are usually no symptoms of hypertension and you may feel fine. If hypertension is not treated, serious health problems such as stroke or heart attack and heart or kidney failure may occur.

When taking this medicine for heart failure, it works by:

Widening the blood vessels, so that the heart does not have to pump as hard to move the blood around the body. This also means that when you place extra demands on your heart, such as during exercise, the heart may cope better so you may not get short of breath as easily.

When used to treat heart failure, this medicine is almost always used with other medicines called diuretics or fluid tablets. These medicines help the kidney to get rid of excess fluid from the body.

Heart failure means that the heart muscle cannot pump blood strongly enough to supply all the blood needed throughout the body. Heart failure is not the same as heart attack and does not mean that the heart stops working. Heart failure may start off with no symptoms, but as the condition progresses, patients may feel short of breath or may get tired easily after light physical activity such as walking. Some patients may wake up short of breath at night. Fluid may collect in different parts of the body, often first noticed as swollen ankles and feet. This medicine helps to treat heart failure and may improve your symptoms.

Your doctor will have explained why you are being treated with this medicine and told you what dose to take.

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

This medicine is not addictive.

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

There is not enough information to recommend the use of this medicine for children.

Before you take Candesartan Sandoz

When you must not take it

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

  • candesartan cilexetil, the active ingredient or to any of the other ingredients listed at the end of this leaflet under Product Description.
  • any medicine containing an angiotensin II receptor antagonist (blocker).

Some of the symptoms of an allergic reaction may include:

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

Do not use Candesartan Sandoz if you have:

  • severe liver disease and/or conditions associated with impaired bile flow (cholestasis)

Do not use Candesartan Sandoz if you are taking blood pressure medicine containing aliskiren, especially if you have diabetes mellitus or have kidney problems.

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

Do not breast-feed if you are taking this medicine. It is not known if this medicine passes into breast milk.

Do not give this medicine to children. There is no information about its use in children, so Candesartan Sandoz is not recommended for children.

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

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

Before you start to take it

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

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

  • kidney problems
  • liver problems
  • heart problems
  • recent excessive vomiting or diarrhoea
  • a condition called primary hyperaldosteronism.

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

You may have to take a lower dose of Candesartan Sandoz if you have these conditions.

Taking other medicines

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

Some medicines and Candesartan Sandoz 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 Candesartan Sandoz or may affect how well it 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 this medicine.

How to take Candesartan Sandoz

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

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

How much to take

The usual dose is 8 or 16 mg taken once daily. Sometimes an increase in dose to 32 mg once daily is needed.

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

Follow the instructions they give you. If you take the wrong dose, Candesartan Sandoz may not work as well and your problem may not improve.

How to take it

Swallow the tablets whole with a full glass of water.

It does not matter whether you take this medicine with food or on an empty stomach.

When to take Candesartan Sandoz

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

How long to take Candesartan Sandoz

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

If you forget to take it

Take your dose as soon as you remember (as long as it is at least 12 hours before your next dose is due), and continue to take it as you would normally.

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

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

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

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

If you take too much (overdose)

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

Symptoms of an overdose may include a headache, feel sick (nausea), dizziness and tiredness.

While you are taking Candesartan Sandoz

Things you must do

Take Candesartan Sandoz 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 Candesartan Sandoz.

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

If you are going to have surgery (even at the dentist) that needs a general anaesthetic, tell the surgeon or anaesthetist that you are taking this medicine.

If you become pregnant while taking this medicine, tell your doctor immediately. You should not take this medicine if you are pregnant or thinking about becoming pregnant. Your doctor can discuss different treatment options with you.

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 test (eg blood tests, blood pressure) from time to time. These tests may help to prevent side effects.

Things you must not do

Do not take Candesartan Sandoz to treat any other complaints unless your doctor tells you to.

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

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

Things to be careful of

Move slowly when getting out of bed or standing up if you feel faint, dizzy or light-headed.

Be careful driving or operating machinery until you know how Candesartan Sandoz affects you. This medicine may cause nausea, dizziness and tiredness in some people. If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous.

If you are taking this medicine 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 this medicine, you may faint or feel light-headed or sick. This is because your body doesn't have enough fluid and your blood pressure is low. If you continue to feel unwell, tell your doctor.

If you are taking this medicine for heart failure, restricted fluid intake is generally recommended. Speak with your doctor about how much water you should drink.

Side effects

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

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

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

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

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

  • headache
  • chest or throat infection
  • flu-like symptoms
  • feeling sick (nausea, vomiting)
  • back pain
  • dizziness

These are all mild side effects of candesartan cilexetil. Tell your doctor as soon as possible if you notice any of the following:

  • aching muscles, tenderness or weakness in the muscle

The above list includes serious side effects that may require medical attention. Serious side effects are rare.

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

  • swelling of the face, lips, tongue or throat which may cause difficulty in swallowing or breathing
  • swelling of the hands, feet or ankles
  • harsh sounds when breathing
  • signs of frequent infections such as fever, severe chills, sore throat or mouth ulcers
  • jaundice (yellowing of the skin and /or eyes).
  • unusual skin reactions (severe and sudden onset of rash, itchiness, hives (itchy swellings on the skin)
  • easy bruising or bleeding more easily than normal
  • extreme fatigue, tiredness, weakness
  • 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 changes in heart rhythm.

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

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above may also occur in some people.

After taking Candesartan Sandoz

Storage

Keep your medicine in the original container. If you take it out of its original container it may not keep well.

Keep your medicine in a cool dry place where the temperature stays below 30°C.

Do not store Candesartan Sandoz or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep it where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

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

Product description

What it looks like

Candesartan Sandoz comes in four types of tablets:

Candesartan Sandoz 4 mg - white, round biconvex tablet, debossed with 4 on one side and scored on the other side.

Candesartan Sandoz 8 mg - pink, mottled, round biconvex tablet, debossed with 8 on one side and scored on the other side.

Candesartan Sandoz 16 mg - pink, mottled, round biconvex tablet, debossed with 16 on one side and scored on the other side.

Candesartan Sandoz 32 mg - pink, mottled, round biconvex tablet, debossed with 32 on one side and scored on the other side.

Available in blisters of 30 tablets.

Ingredients

Active ingredients:

  • Candesartan Sandoz 4 mg - 4 mg candesartan cilexetil
  • Candesartan Sandoz 8 mg - 8 mg candesartan cilexetil
  • Candesartan Sandoz 16 mg - 16 mg candesartan cilexetil
  • Candesartan Sandoz 32 mg - 32 mg candesartan cilexetil

Inactive ingredients:

  • Lactose monohydrate
  • iron oxide red (8 mg, 16 mg and 32 mg tablets only)
  • titanium dioxide (8 mg, 16 mg and 32 mg tablets only)
  • maize starch
  • povidone
  • carrageenan
  • croscarmellose sodium
  • magnesium stearate.

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

Supplier

Candesartan Sandoz is supplied in Australia by:

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

This leaflet was revised in April 2019.

Australian Register Numbers

  • Candesartan Sandoz 4mg tablets - AUST R 147497
  • Candesartan Sandoz 8mg tablets - AUST R 147493
  • Candesartan Sandoz 16mg tablets - AUST R 147498
  • Candesartan Sandoz 32mg tablets - AUST R 147496

Published by MIMS June 2019

BRAND INFORMATION

Brand name

Candesartan Sandoz

Active ingredient

Candesartan cilexetil

Schedule

S4

 

1 Name of Medicine

Candesartan cilexetil.

6.7 Physicochemical Properties

The chemical name of candesartan cilexetil is (±)-1-(cyclohexyloxycarbonyl-oxy) ethyl 2-ethoxy- 1-[[2'-(1H-tetrazol-5-yl)-biphenyl-4-yl] methyl]-1H-benzimadozole-7-carboxylate. Its empirical formula is C33H34N6O6 (MW: 610.7).

Chemical structure.

Its chemical structure is:

CAS number.

145040-37-5.

2 Qualitative and Quantitative Composition

Each Candesartan Sandoz 4 mg tablet contains 4 mg candesartan cilexetil.
Each Candesartan Sandoz 8 mg tablet contains 8 mg candesartan cilexetil.
Each Candesartan Sandoz 16 mg tablet contains 16 mg candesartan cilexetil.
Each Candesartan Sandoz 32 mg tablet contains 32 mg candesartan cilexetil.

Excipient with known effect.

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

3 Pharmaceutical Form

Candesartan Sandoz 4 mg tablets are white, round biconvex tablets, debossed with 4 on one side and scored on the other.
Candesartan Sandoz 8 mg tablets are pink, mottled, round biconvex tablets, debossed with 8 on one side and scored on the other.
Candesartan Sandoz 16 mg tablets are pink, mottled, round biconvex tablets, debossed with 16 on one side and scored on the other.
Candesartan Sandoz 32 mg tablets are pink, mottled, round biconvex tablets, debossed with 32 on one side and scored on the other.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Candesartan cilexetil is an AIIRA.
Angiotensin II is the primary vasoactive hormone of the RAAS 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 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 AIIRA, selective for AT1 receptors, with tight binding to and slow dissociation from the receptor. It has no agonist activity.
Candesartan does not inhibit 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, AIIRAs are unlikely to be associated with cough. This has been confirmed in controlled clinical studies with candesartan cilexetil. Candesartan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.
In hypertension, candesartan cilexetil 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 cilexetil 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-hour dosing interval, with a trough/ peak ratio confirming once daily dosing.
Candesartan can be used as monotherapy or in combination with other antihypertensive medicines, such as thiazide diuretics, calcium antagonists and lisinopril, for improved blood pressure control. Age and gender have no influence on the efficacy of candesartan cilexetil.
Candesartan cilexetil 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 cilexetil reduces urinary protein excretion in hypertensive patients with microalbuminuria or nephropathy of different aetiology. Candesartan cilexetil 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 RAAS 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, Use in pregnancy, Use in 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 2 diabetes mellitus, hypertension and microalbuminuria. Patients were randomly allocated to four treatment regimens: 1) 24 weeks of candesartan monotherapy (one-third of the patients); 2) 24 weeks of lisinopril monotherapy (one-third of the patients); 3) 12 weeks of candesartan monotherapy, followed by 12 weeks of candesartan + lisinopril combination therapy (one-sixth of the patients); and 4) 12 weeks of lisinopril monotherapy, followed by 12 weeks of lisinopril and candesartan combination therapy (one-sixth 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, one-third of the patients still in the study were on candesartan monotherapy (n = 49), one-third on lisinopril monotherapy (n = 46), and one-third on combination therapy (candesartan and lisinopril (n = 25), lisinopril and candesartan (n = 24). (See Table 2.)
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 less than or equal to 40%), candesartan cilexetil decreases systemic vascular resistance and pulmonary capillary wedge pressure, increases plasma renin activity and angiotensin II concentration, and decreases aldosterone levels.
Treatment with candesartan cilexetil 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) program comprising three studies (CHARM-Alternative, CHARM-Added and CHARM-Preserved). In all three studies, patients on optimal baseline therapy were randomised to placebo or candesartan cilexetil (titrated from 4 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 (New York Heart Association (NHYA) class II to IV, n = 2,028) with a LVEF less than or equal to 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 to IV, n = 2,548) with a LVEF less than or equal to 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 to 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 to 0.98, p = 0.018) and all three studies (HR 0.91, 95% CI: 0.83 to 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 cilexetil resulted in improved NYHA functional class in CHARM-Alternative and CHARM-Added (p = 0.008 and 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 cilexetil 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

Absorption and distribution.

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 three to four hours after taking a tablet. The point estimate of Cmax is 103.83% with associated confidence interval of [96.65%, 111.55%]. 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.
In case of AUC0-t, the point estimate is 95.45% with associated confidence interval of [91.14%, 99.96%] and AUC0-∞ has point estimate of 94.96% and corresponding associated confidence interval of [90.73%, 99.37%].
Candesartan is highly bound to plasma protein (more than 99%). The apparent volume of distribution (Vss) of candesartan is 0.1 L/kg.

Metabolism and elimination.

Candesartan is mainly eliminated unchanged via urine and bile and is eliminated by hepatic metabolism only to a minor extent. The terminal half-life of candesartan is approximately nine hours. There is no accumulation following multiple doses.
Total plasma clearance of candesartan is about 0.37 mL/minute/kg, with a renal clearance of about 0.19 mL/minute/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 were 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.
Following oral administration of Candesartan Sandoz 16 mg to healthy subjects under fasting conditions, a mean peak plasma concentration (Cmax) of candesartan of approximately 118.18 nanogram/mL was achieved within approximately 4.02 hours (Tmax).

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 medicine by gavage whereas mice received the medicine by dietary administration. These (maximally tolerated) doses of candesartan cilexetil provided systematic exposures to candesartan (AUCs) that were, in mice, approximately 7 times and, in rats, more than 70 times the exposure in humans at the maximum recommended daily human dose (32 mg).

4 Clinical Particulars

4.1 Therapeutic Indications

Treatment of hypertension.
Treatment of patients with heart failure and impaired left ventricular systolic function (left ventricular ejection fraction ≤ 40%) as add on therapy to angiotensin converting enzyme (ACE) inhibitors or when ACE inhibitors are not tolerated.

4.3 Contraindications

Hypersensitivity to any component of Candesartan Sandoz.
Pregnancy and lactation (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy).
Severe hepatic impairment and/or cholestasis.
The use of candesartan 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

In patients whose vascular tone and renal function depend predominantly on the activity of the renin-angiotensin-aldosterone-system (RAAS) (e.g. patients with severe congestive heart failure or underlying renal disease, including renal artery stenosis), treatment with medicines 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 medicines that affect the RAAS, i.e. 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 (AIIRAs).

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 medicines acting through inhibition of the RAAS. 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 RAAS, it may also occur in hypertensive patients with intravascular volume depletion. Caution should be observed when initiating therapy and correction of hypovolaemia should be attempted.

Dual blockade of the RAAS.

There is evidence that the concomitant use of ACE-inhibitors, AIIRAs or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of the RAAS through the combined use of candesartan with and 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 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 medicines that affect the RAAS, concomitant use of candesartan with potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium, or other medicines that may increase potassium levels (e.g. heparin, trimethoprim/sulfamethoxazole) 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 AIIRAs due to blockade of the renin-angiotensin system (RAS). 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 medicine (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 medicine. Combined use of these medications should be accompanied by increased monitoring of serum creatinine, particularly at the institution of the combination. The combination of medicines 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 AIIRAs. No such cases have been reported to date with candesartan.

Use in renal impairment.

As with other agents inhibiting the RAAS, 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 end-stage renal impairment (i.e. creatinine clearance < 15 mL/minute/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 RAAS. 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.

No data available.

Paediatric use.

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

Effects on laboratory tests.

In general, there were no clinically important effects of candesartan cilexetil on routine laboratory variables. As for other inhibitors of the RAAS, 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 alanine aminotransferase (ALT) occurred in 1.3% of candesartan treated patients and 0.5% of those treated with placebo. The incidence of aspartate aminotransferase (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.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Dual blockade of the RAAS.

The combination of candesartan 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/1.7 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 blocker 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 AIIRAs 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, nifedipine and enalapril. No pharmacokinetic interactions of clinical significance were identified in these studies.
The antihypertensive effect of AIIRAs, 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). 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 D)
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, alternative therapy should be started.
Drugs that act on the 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).
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.

4.8 Adverse Effects (Undesirable Effects)

Hypertension.

Candesartan cilexetil 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 cilexetil was administered as monotherapy 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.

Heart failure.

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

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).

Postmarketing.

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

Blood and lymphatic system disorders.

Leucopenia, 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, Use in renal impairment).
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 www.tga.gov.au/reporting-problems.

4.2 Dose and Method of Administration

Dosage.

Candesartan Sandoz should be taken once daily with or without food.

Hypertension.

The recommended maintenance dose of Candesartan Sandoz is 8 or 16 mg once daily. The maximal antihypertensive effect is attained within four 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 Sandoz, combination with a thiazide diuretic is recommended.

Heart failure.

The usual recommended initial dose of Candesartan Sandoz 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).

Dosage adjustment.

Renal impairment.

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

Hepatic impairment.

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 Sandoz should not be used in patients with severe hepatic impairment and/or cholestasis (see Section 4.3 Contraindications).

Elderly.

An initial dose of 8 mg is recommended.

Paediatrics.

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

Concomitant therapy.

Candesartan Sandoz can be administered with other heart failure treatment, including ACE inhibitors, beta-blockers, diuretics and digitalis or a combination of these medicines (see Section 4.4 Special Warnings and Precautions for Use; Section 5.1 Pharmacodynamic Properties).

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.

4.9 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.

Treatment.

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, e.g. isotonic saline solution. Sympathomimetic medicines may be administered if the above-mentioned measures are not sufficient.
Candesartan is not removed by haemodialysis.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Lactose monohydrate, iron oxide red (8 mg, 16 mg and 32 mg tablets only), titanium dioxide (8 mg, 16 mg and 32 mg tablets only), maize starch, povidone, carrageenan, croscarmellose sodium, magnesium stearate.

6.2 Incompatibilities

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

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 30°C. Store in the original packaging.

6.5 Nature and Contents of Container

Candesartan Sandoz is available in Al/Al blister packs of 30 tablets.

6.6 Special Precautions for Disposal

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

Summary Table of Changes