Consumer medicine information

Inspra

Eplerenone

BRAND INFORMATION

Brand name

Inspra

Active ingredient

Eplerenone

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Inspra.

What is in this leaflet

This leaflet answers some common questions about Inspra.

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 Inspra against the benefits it is expected to 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 Inspra is used for

What Inspra does

  • This medicine is used to treat heart failure in patients who have experienced a heart attack.
    A heart attack occurs when one of the major blood vessels supplying blood to your heart becomes blocked. This means that your heart cannot receive the oxygen it needs and becomes damaged. This may lead to further problems, such as heart failure, irregular heart rhythms and blood clots.
    Heart failure means that the heart muscle is weak and cannot pump blood strongly enough to supply all the blood needed throughout the body. Heart failure is not the same as heart attack, and may start off with mild or 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, or have to prop their heads up during sleep to avoid this problem. Fluid may collect in different parts of the body, often first noticed as swollen ankles and feet.
  • This medicine is also used to reduce the risk of death or need for hospitalisations due to heart failure in patients with chronic heart failure.

How Inspra works

Your body makes a substance called aldosterone. It is important for regulating blood pressure and is one of the factors involved in heart function. Sometimes aldosterone can cause changes in our body that lead to heart failure. Inspra works by blocking the action of aldosterone, and slowing the progression of heart failure by reducing heart damage.

Inspra belongs to a group of medicines called 'selective aldosterone blockers' that stop the action of aldosterone.

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.

There is no evidence that this medicine is addictive.

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

Use in children

The safety and effectiveness of Inspra in children have not been established.

Before you take Inspra

When you must not take it

Do not take Inspra if you have an allergy to:

  • any medicine containing eplerenone
  • any medicine containing any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

  • skin rash
  • itchiness
  • shortness of breath
  • swelling of the face, lips or tongue
  • muscle pain or tenderness
  • joint pain.

Do not take Inspra if you have or have had any of the following medical conditions:

  • very high levels of potassium in your blood
  • severely reduced kidney function. Your doctor will determine your kidney function.
  • Severe liver problems.

Do not take Inspra if you are currently taking any of the following medicines:

  • potassium-sparing diuretics (e.g. spironolactone, amiloride), used to help the kidneys get rid of salt and water by increasing the amount of urine produced
  • ketoconazole and itraconazole used to treat fungal infections
  • clarithromycin, used to treat bacterial infections
  • saquinavir, ritonavir, for the treatment of HIV infections.

Taking Inspra together with the above medicines can lead to serious side effects.

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

Do not breast-feed if you are taking this medicine. The active ingredient in Inspra may pass into breast milk and there is a possibility that your baby may be affected.

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:

  • high levels of potassium in your blood
  • diabetes
  • long term kidney disease
  • liver problems.

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

If you have not told your doctor about any of the above, tell them before you start taking Inspra.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including:

  • all prescription medicines
  • all medicines you buy over the counter from a pharmacy or supermarket
  • all complementary and alternative therapies
  • anything you buy from a health food shop.

Some medicines may be affected by Inspra or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines. Your doctor will advise you.

Tell your doctor or pharmacist if you are taking any of the following:

  • medicines known as angiotensin converting enzyme (ACE) inhibitor and/or angiotensin receptor blocker (ARB), such as quinapril, losartan. These are used to treat high blood pressure and some other heart conditions and may increase the risk of high potassium levels in your blood.
  • non-steroidal anti-inflammatory drugs (NSAIDs), medicines used to relieve pain, swelling and other symptoms of inflammation including aspirin and ibuprofen.
  • lithium, a medicine used to treat mood swings
  • neuroleptics, used to treat certain mental illnesses
  • tricyclic antidepressants, used to treat certain mental illnesses
  • St John's Wort, used in the management of depression
  • carbamazepine, used to control seizures, facial pain or certain types of mood disorders
  • phenytoin and phenobarbitone, medicines used to control seizures
  • potassium-sparing diuretics, such as spironolactone, amiloride
  • potassium supplements, or salt substitutes which contain potassium
  • medicines used to treat fungal infections such as ketoconazole, itraconazole
  • certain antibiotics used to treat bacterial infections, such as erythromycin, trimethoprim, rifampicin
  • saquinavir, ritonavir, for the treatment of HIV infections
  • immunosupressive agents such as cyclosporin, tacrolimus
  • baclofen, a muscle relaxant
  • prazosin, used to treat high blood pressure and other medical conditions
  • alfuzosin, for the treatment of benign prostatic hyperplasia
  • amifostine, used in combination with cancer treatments
  • any other medicines used to treat high blood pressure or heart failure.

If you are not sure if you are taking any of these medicines mentioned in this leaflet, check with your doctor or pharmacist.

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

Tell your doctor if you are taking salt tablets. Taking Inspra together with salt tablets can lead to serious side effects.

How to take Inspra

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 on the box, ask your doctor or pharmacist for help.

How much to take

Your doctor will tell you how many tablets you need to take each day. This may depend upon your age, your kidney condition, the potassium level in your blood, and whether or not you are taking any other medicines.

The usual starting dose of Inspra is 25 mg taken once a day. After about 4 weeks, your doctor may increase the dose to 50 mg once a day.

Your doctor will do blood tests to help determine the correct dose of Inspra for you.

How to take it

Swallow the tablets whole with a full glass of water.

When to take it

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

Your tablets may be taken with or after a meal, or on an empty stomach.

How long to take it

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

If it is less than 12 hours before your next dose, skip the dose you missed and take your next dose when you are meant to.

Otherwise, take it as soon as you remember, and then go back to taking your medicine as you would normally.

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

If you take too much Inspra, you may feel light-headed.

While you are taking Inspra

Things you must do

Keep all of your doctor's appointments so that your progress can be checked. Your doctor may occasionally do a blood test to check your potassium levels and see how your kidneys are working. Your dose of Inspra may be adjusted by your doctor, depending on the potassium levels in your blood.

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

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

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine. It may affect other medicines used during surgery.

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

Make sure you drink enough water during exercise and hot weather when you are taking this medicine, especially if you sweat a lot. If you do not drink enough water while taking Inspra, you may feel faint, light-headed or sick. This is because your blood pressure is dropping suddenly. If you continue to feel unwell, tell your doctor.

If you have excess vomiting or diarrhoea while taking Inspra, tell your doctor. You may lose too much water and salt and your blood pressure may drop too much.

If you feel light-headed or dizzy after taking your first dose of Inspra, or when your dose is increased, tell your doctor immediately.

Things you must not do

Do not take Inspra 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. If you stop taking it suddenly, your condition may worsen or you may have unwanted side effects.

Things to be careful of

Be careful driving or operating machinery until you know how Inspra affects you. This medicine may cause dizziness and feeling faint in some people. If you have this symptom, do not drive, operate machinery or do anything else that could be dangerous.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Inspra or your condition changes. Tell your doctor even if you think the problem is not connected with the medicine or is not listed in this leaflet.

This medicine helps most people with heart failure, but it may have unwanted side effects in some people. 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.

It is often difficult to tell whether side effects are the result of taking Inspra, or the effects of your heart failure or side effects of other medicines you may be taking. For this reason it is important to report any change in your condition. Your doctor may want to change your dose or advise you to stop taking Inspra.

If you are over 65 years of age you may have an increased chance of having some side effects, as you may be more sensitive to the effects of the medication.

Do not be alarmed by the following list 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 if...

The following list includes the more common or noticeable side effects of your medicine.

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

  • feeling light-headed, dizzy or faint
  • stomach or bowel problems
    - feeling sick (nausea) or vomiting
    - diarrhoea
    - constipation
    - flatulence or wind
  • cough
  • sore throat
  • headache
  • rash, itchy skin
  • high temperature, signs of an infection
  • back pain.

Tell your doctor as soon as possible if...

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

Tell your doctor as soon as possible if you notice any of the following:

  • heart flutters, increased heart rate
  • unusual tiredness, weakness
  • muscle spasms and pain
  • abdominal pain
  • enlargement of the breasts in men
  • reduced sense of touch
  • increased sweating
  • feeling weak and generally unwell
  • problems with sleeping.

Go to hospital if...

Tell your doctor immediately or go to Accident and Emergency at your nearest hospital, if you notice any of the following:

  • shortness of breath, swelling of the feet or legs due to fluid build up
  • chest pain which may spread to the neck and shoulders
  • swelling of the face, lips, mouth, tongue or throat which may cause difficulty in swallowing or breathing.

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 patients.

Some of these side effects (for example, changes in potassium levels, thyroid function, or cholesterol level) can only be found when your doctor does tests from time to time to check your progress.

After taking Inspra

Storage

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

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

Do not store Inspra 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

Inspra is a yellow, arc diamond, film-coated tablet.

Packs contain 30 tablets.

25 mg tablet
Marked with 'NSR' over '25' on one side and 'Pfizer' on the other.

50 mg tablet
Marked with 'NSR' over '50' on one side and 'Pfizer' on the other.

Ingredients

The active ingredient in Inspra is eplerenone.

  • Inspra 25 tablet contains 25 mg eplerenone
  • Inspra 50 tablet contains 50 mg eplerenone.

Inspra tablets also contain:

  • lactose
  • microcrystalline cellulose
  • croscarmellose sodium
  • hydromellose
  • sodium lauryl sulfate
  • talc-purified
  • magnesium stearate
  • titanium dioxide
  • macrogol 400
  • polysorbate 80
  • iron oxide yellow (CI77492)
  • iron oxide red (CI77491).

This medicine does not contain sucrose, gluten, or tartrazine.

Supplier

Inspra is supplied in Australia by:

Viatris Pty Ltd
Level 1, 30 The Bond
30-34 Hickson Road
Millers Point NSW 2000
www.viatris.com.au
Phone: 1800 274 276

Australian registration numbers

25 mg AUST R 100162

50 mg AUST R 100163

This leaflet was prepared in August 2021.

INSPRA® is a Viatris company trade mark

ujcinspt10821

Published by MIMS December 2021

BRAND INFORMATION

Brand name

Inspra

Active ingredient

Eplerenone

Schedule

S4

 

1 Name of Medicine

Eplerenone.

2 Qualitative and Quantitative Composition

Each Inspra tablet contains 25 or 50 mg eplerenone.

Excipient(s) with known effect.

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

3 Pharmaceutical Form

Tablet, film coated.
Inspra is supplied as yellow, arc diamond, film-coated tablets containing 25 or 50 mg eplerenone.

25 mg tablet.

Stylised with 'NSR' over '25' on one side and 'Pfizer' on the other.

50 mg tablet.

Stylised with 'NSR' over '50' on one side and 'Pfizer' on the other.

4 Clinical Particulars

4.1 Therapeutic Indications

Inspra is indicated:
to reduce the risk of cardiovascular death in combination with standard therapy in patients who have evidence of heart failure and left ventricular impairment within 3-14 days of an acute myocardial infarction (see Section 4.2 Dose and Method of Administration; Section 5.1 Pharmacodynamic Properties, Clinical trials);
to reduce the risk of cardiovascular mortality and morbidity in adult patients with NYHA class II (chronic) heart failure and left ventricular systolic dysfunction (LVEF ≤ 30% or LVEF ≤ 35% in addition to QRS duration of > 130 msec), in addition to standard optimal therapy (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

4.2 Dose and Method of Administration

For postmyocardial infarction heart failure patients.

Inspra is usually administered in combination with standard therapies. The recommended dose of Inspra is 50 mg once daily. Treatment should be initiated at 25 mg once daily and titrated to the target dose of 50 mg once daily within 4 weeks as tolerated by the patient.
In the pivotal clinical study EPHESUS, eplerenone was added to standard medical therapy within 3-14 days after an acute qualifying myocardial infarction. There is evidence that the reduction in mortality occurred mostly within the first 12 months of Inspra treatment. Patients with chronic heart failure should be reassessed no longer than 12 months after commencing therapy and options for the management of chronic heart failure considered.

For patients with NYHA class II (chronic) heart failure.

Patients with eGFR ≥ 50 mL/min/1.73 m2 (CKD stages 1, 2 and partly 3). Treatment should be initiated at a dose of 25 mg once daily and titrated to the target dose of 50 mg once daily preferably within 4 weeks; taking into account the serum potassium levels (see Table 1).

Serum potassium levels.

Serum potassium should be measured before initiating Inspra therapy, within the first week and at 1 month after the start of treatment or dosage adjustment. Serum potassium should be assessed periodically thereafter, and the dose of eplerenone adjusted based on the serum potassium level (see Table 1).
Inspra should be suspended when serum potassium is ≥ 6.0 mmol/L. It can be restarted at a dose of 25 mg every other day when serum potassium levels have fallen below 5.0 mmol/L. Serum potassium monitoring should continue once eplerenone has been restarted again.

Concomitant treatment.

In case of concomitant treatment with mild to moderate CYP3A4 inhibitors, e.g. amiodarone, diltiazem, erythromycin, saquinavir, fluconazole and verapamil, dosing should not exceed 25 mg once daily.
Inspra may be administered with or without food.

Special populations.

Children.

There are insufficient data to recommend the use of Inspra in the paediatric population and, therefore, use in this age group is not recommended.

Elderly patients.

No dose adjustment is required in the elderly.

Patients with chronic kidney disease.

Periodic monitoring of serum potassium is recommended, in particular in patients with chronic kidney disease, to avoid serum potassium levels > 5.5 mmol/L (see Section 4.2 Dose and Method of Administration, Serum potassium levels; Section 4.4 Special Warnings and Precautions for Use, Use in renal impairment).
Dosage should be initiated as shown in Table 2 and adjusted based on serum potassium levels as described in Table 1.
Doses above 25 mg daily have not been studied in patients with eGFR < 50 mL/min/1.73 m2.
Eplerenone is not dialysable.

Patients with hepatic insufficiency.

No initial dosage adjustment is necessary for patients with mild to moderate hepatic impairment. Inspra is contraindicated in patients with severe hepatic insufficiency (see Section 4.3 Contraindications).

4.3 Contraindications

Hypersensitivity to eplerenone or any of the excipients.
Inspra should not be administered to patients with clinically significant hyperkalaemia (serum potassium > 5.0 mmol/L at initiation) (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
Inspra should not be administered to patients with severe renal insufficiency (eGFR < 30 mL per minute per 1.73 m2, CKD stages 4 and 5) (see Section 4.2 Dose and Method of Administration; Section 5.1 Pharmacodynamic Properties, Clinical trials).
Inspra should not be administered to patients with severe hepatic insufficiency (see Section 4.2 Dose and Method of Administration).
Inspra should not be coadministered to patients receiving potassium sparing diuretics or strong inhibitors of CYP3A4, e.g. itraconazole, ketoconazole, ritonavir and clarithromycin (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

4.4 Special Warnings and Precautions for Use

Hyperkalaemia.

The principal risk of Inspra is hyperkalaemia. Hyperkalaemia can cause serious, sometimes fatal, arrhythmias. Patients who develop hyperkalaemia (> 5.5 mmol/L) may still benefit from Inspra with proper dose adjustment.
Serum potassium should be measured before initiating Inspra therapy, and measured periodically thereafter, as clinically warranted (see Section 4.2 Dose and Method of Administration).
Hyperkalaemia can be minimised by patient selection, avoidance of certain concomitant treatments and periodic monitoring until the effect of Inspra has been established. Inspra should generally not be administered to patients taking potassium supplements, or salt substitutes containing potassium. For patient selection and avoidance of certain concomitant medications, see Section 4.3 Contraindications; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions; Section 4.8 Adverse Effects (Undesirable Effects), Clinical laboratory test findings, Potassium. Dose reduction of Inspra has been shown to decrease potassium levels (see Section 4.2 Dose and Method of Administration).
Diabetic patients with CHF post-MI, including those with proteinuria, should also be treated with caution. The subset of patients in EPHESUS with both diabetes and proteinuria on the baseline urinalysis had increased rates of hyperkalaemia (see Section 4.8 Adverse Effects (Undesirable Effects), Clinical laboratory test findings, Potassium).
The risk of hyperkalaemia may increase when eplerenone is used in combination with an angiotensin converting enzyme (ACE) inhibitor and an angiotensin receptor blocker (ARB) and therefore this combination is not recommended.

Use in hepatic impairment.

Due to an increased systemic exposure to eplerenone in patients with mild-to-moderate hepatic impairment, frequent and regular monitoring of serum potassium is recommended in these patients, especially when elderly. In 16 subjects with mild to moderate hepatic impairment who received 400 mg of eplerenone no elevations of serum potassium above 5.5 mmol/L were observed. The mean increase in serum potassium was 0.12 mmol/L in patients with hepatic impairment and 0.13 mEq/L in normal controls. The use of Inspra in patients with severe hepatic impairment has not been evaluated and is therefore contraindicated (see Section 4.2 Dose and Method of Administration; Section 4.3 Contraindications; Section 5.2 Pharmacokinetic Properties, Special populations).

Use in renal impairment.

Inspra should not be administered to patients with severe renal insufficiency (CKD stages 4 and 5, eGFR < 30 mL/min/1.73 m2), the risk of hyperkalaemia increases with declining renal function. Eplerenone cannot be removed by haemodialysis. (See Section 4.2 Dose and Method of Administration; Section 4.3 Contraindications; Section 5.1 Pharmacodynamic Properties, Clinical trials.)

Use in the elderly.

Of the total number of patients in EPHESUS, 3,340 (50%) were 65 and over, while 1,326 (20%) were 75 and over. Patients greater than 75 years did not appear to benefit from the use of Inspra (see Section 5.1 Pharmacodynamic Properties, Clinical trials). No differences in overall incidence of adverse events were observed between elderly and younger patients. However, due to age related decreases in creatinine clearance, the incidence of laboratory documented hyperkalaemia was increased in patients 65 and older (see Section 4.4 Special Warnings and Precautions for Use, Hyperkalaemia).
Post hoc analyses in the EMPHASIS-HF study to explore potential age related blood pressure (BP) changes suggest that there may be a greater sensitivity to treatment in older individuals and thus potentially greater reductions in blood pressure with the use of eplerenone, compared to younger patients. In patients aged below 75 years, 28.3% treated with eplerenone recorded (maximum drop, at any time during study) systolic BP reductions from baseline of greater than 20 mmHg, while patients with placebo had a 23.9% incidence of these reductions. Of those aged at or over 75, the respective observations were 37.9% for eplerenone and 24.4% for placebo.
These blood pressure reductions noted in the EMPHASIS-HF study were independent of any reports of adverse events reported in the EMPHASIS-HF study (see Section 4.8 Adverse Effects (Undesirable Effects)).

Paediatric use.

The safety and effectiveness of Inspra have not been established in paediatric patients.

Effects on laboratory tests.

See Section 4.8 Adverse Effects (Undesirable Effects), Post-marketing experience, Clinical laboratory test findings.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Inhibitors of CYP3A4.

Eplerenone metabolism is predominantly mediated via CYP3A4. A pharmacokinetic study evaluating the administration of a single dose of Inspra 100 mg with ketoconazole 200 mg twice daily, a potent inhibitor of the CYP3A4 pathway, showed a 1.7-fold increase in Cmax of eplerenone and a 5.4-fold increase in AUC of eplerenone. Inspra should not be used with drugs described as strong inhibitors of CYP3A4 in their labelling (see Section 4.3 Contraindications). Administration of eplerenone with other CYP3A4 inhibitors (e.g. erythromycin 500 mg twice daily, verapamil 240 mg once daily, saquinavir 1,200 mg three times daily, fluconazole 200 mg once daily) resulted in increases in Cmax of eplerenone ranging from 1.4 to 1.6-fold and AUC from 2.0 to 2.9-fold.

Inducers of CYP3A4.

Coadministration of St John's wort (a potent CYP3A4 inducer) with eplerenone caused a decrease in eplerenone AUC. A more pronounced decrease in eplerenone AUC may occur with more potent CYP3A4 inducers and the concomitant use of potent CYP3A4 inducers (rifampicin, carbamazepine, phenytoin, phenobarbitone, St John's wort) with eplerenone is not recommended.

ACE inhibitors and angiotensin II receptor antagonists.

In EPHESUS, 3,020 (91%) patients receiving Inspra 25 to 50 mg also received ACE inhibitors or angiotensin II receptor antagonists (ACEI/ARB). Rates of patients with maximum potassium levels > 5.5 mmol/L were similar regardless of the use of ACEI/ARB.
The risk of hyperkalaemia may increase when eplerenone is used in combination with an angiotensin converting enzyme (ACE) inhibitor and/or an angiotensin receptor blocker (ARB). A close monitoring of serum potassium and renal function is recommended, especially in patients at risk for impaired renal function, e.g. the elderly (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use).

Lithium.

A drug interaction study of eplerenone with lithium has not been conducted. Lithium toxicity has been reported in patients receiving lithium concomitantly with diuretics and ACE inhibitors. Coadministration of Inspra and lithium should be avoided. If this combination appears necessary, serum lithium levels should be monitored frequently.

Cyclosporin and tacrolimus.

Cyclosporin and tacrolimus may lead to impaired renal function and increase the risk of hyperkalaemia. The concomitant use of Inspra and cyclosporin or tacrolimus should be avoided. If needed, close monitoring of serum potassium and renal function are recommended when cyclosporin and tacrolimus are to be administered during treatment with eplerenone.

Trimethoprim.

The concomitant administration of trimethoprim with Inspra increases the risk of hyperkalaemia. Monitoring of serum potassium and renal function should be made, particularly in patients with renal impairment and in the elderly.

Alpha-1 blockers.

When alpha-1 blockers (e.g. prazosin, alfuzosin) are combined with Inspra, there is the potential for increased hypotensive effect and/or postural hypotension. Clinical monitoring for postural hypotension is recommended during alpha-1 blocker coadministration.

Tricyclic antidepressants, neuroleptics, amifostine and baclofen.

Coadministration of these drugs with Inspra may potentially increase antihypertensive effects and risk of postural hypotension.

Nonsteroidal anti-inflammatory drugs (NSAIDs).

A drug interaction study of eplerenone with an NSAID has not been conducted. The administration of other potassium sparing antihypertensives with NSAIDs has been shown to reduce the antihypertensive effect in some patients and result in severe hyperkalaemia in patients with impaired renal function. Therefore, when Inspra and NSAIDs are used concomitantly, patients should be observed to determine whether the desired effect on blood pressure is obtained.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Male rats treated with eplerenone at 1000 mg/kg/day for 10 weeks (AUC 24 times that at the clinical dose of 50 mg/day) had decreased weights of seminal vesicles and epididymides and slightly decreased fertility; the no effect dose was 300 mg/kg/day (10 times clinical AUC at 50 mg/day). Dogs administered eplerenone at dosages of 15 mg/kg/day and higher (AUC six times that at the clinical dose of 50 mg/day) had dose related prostate atrophy, and the NOEL (5 mg/kg/day) for prostate atrophy in dogs resulted in plasma AUC approximately three times the clinical value at 50 mg/day. Androgen receptor binding was identified as a possible cause of prostate atrophy. The effect was reversible following drug withdrawal. Dogs with prostate atrophy showed no decline in libido, sexual performance or semen quality. Testicular weight and histology were not affected by eplerenone in mouse, rat or dog studies.
(Category B3)
There are no adequate data on the use of eplerenone in pregnant women. Studies in rats and rabbits showed no teratogenic effects, although decreased maternal and fetal weights in rats and decreased maternal bodyweights and postimplantation loss in rabbits were observed at the highest administered dose of 1,000 mg/kg/day in rats and 300 mg/kg/day in rabbits (for both species approximately 40 times the clinical exposure based on AUC). The potential risk for humans is unknown. Inspra should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
It is unknown if eplerenone is excreted in human breast milk after oral administration. Preclinical data show that eplerenone and/or metabolites are present in rat breast milk and that rat pups exposed by this route had decreased bodyweight gain at a maternal dose of 1,000 mg/kg/day (maternal exposure 43 times the clinical AUC). Because many drugs are excreted in human milk and because of the unknown potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

4.7 Effects on Ability to Drive and Use Machines

Dizziness and syncope have been reported to occur in some patients. Caution is advised when driving or operating machinery until the response to initial treatment has been determined.

4.8 Adverse Effects (Undesirable Effects)

Inspra has been evaluated for safety in 1,360 patients with heart failure and 3,307 patients treated for heart failure postmyocardial infarction (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
In the EPHESUS study, the overall incidence of adverse events reported with Inspra (78.9%) was similar to placebo (79.5%). The discontinuation rate due to adverse events in this study was 4.4% for patients receiving Inspra and 4.3% for patients receiving placebo.
In the EMPHASIS-HF study, the overall incidence of adverse events (% subjects) reported with Inspra (72%) was similar to placebo (73.6%). The discontinuation rate due to adverse events in this study was 13.8% for patients receiving Inspra and 16.2% for patients receiving placebo.
Adverse events reported are those with suspected relationship to treatment and in excess of placebo, or are serious and significantly in excess of placebo, or have been observed during post-marketing surveillance. Adverse events are listed by body system and absolute frequency. Frequencies are defined as common (> 1% to ≤ 10%) or uncommon (> 0.1% to ≤ 1%).

Blood and lymphatic system disorders.

Uncommon: eosinophilia.

Cardiac disorders.

Common: myocardial infarction. Uncommon: left ventricular failure, atrial fibrillation, tachycardia.

Endocrine disorders.

Uncommon: hypothyroidism.

Gastrointestinal disorders.

Common: diarrhoea, nausea, constipation. Uncommon: flatulence, vomiting.

General disorders and administration site conditions.

Uncommon: asthenia, malaise.

Hepatobiliary disorders.

Uncommon: cholecystitis.

Infections and infestations.

Common: infection. Uncommon: pyelonephritis, pharyngitis.

Investigations.

Common: blood urea increased. Uncommon: blood creatinine increased, epidermal growth factor receptor decreased, blood glucose increased.

Metabolic and nutrition disorders.

Common: hyperkalaemia, dehydration. Uncommon: hypercholesterolaemia, hypertriglyceridaemia, hyponatraemia.

Musculoskeletal and connective tissue disorders.

Common: muscle spasms, musculoskeletal pain. Uncommon: back pain.

Nervous system disorders.

Common: dizziness, syncope. Uncommon: headache, hypoaesthesia.

Psychiatric disorders.

Uncommon: insomnia.

Renal and urinary disorders.

Common: renal impairment.

Reproductive system and breast disorders.

Uncommon: gynaecomastia.

Respiratory, thoracic and mediastinal disorders.

Common: cough.

Skin and subcutaneous tissue disorders.

Common: pruritus. Uncommon: hyperhidrosis.

Vascular disorders.

Common: hypotension. Uncommon: arterial thrombosis limb, orthostatic hypotension.
The rates of sex hormone related events are shown in Table 3.
See Tables 4 and 5.
A total of 3,353 patients have been treated with Inspra in clinical studies of hypertension. The overall rates of adverse events in placebo controlled studies were similar between Inspra (49%) and placebo (48%). Adverse events with suspected relationship to treatment and in excess of placebo from the monotherapy arms of five placebo controlled studies for patients who received Inspra 25 to 400 mg are listed below by absolute frequency. Frequencies are defined as common (> 1% to ≤ 10%) or uncommon (> 0.1% to ≤ 1%).
Common: ALT increased, GGT increased.
Uncommon: anaemia, angina pectoris, arthralgia, AST increased, bilirubinaemia, coughing, creatine phosphokinase increased, dyspepsia, dyspnoea, ECG abnormal, flushing, gastroesophageal reflux, haematuria, hyperuricaemia, libido decreased, menstrual disorder, myalgia, prothrombin decreased, tinnitus, urine abnormal, URT infection.

Post-marketing experience.

In post-marketing experience, the following additional undesirable effects have been reported.

Skin and subcutaneous tissues disorders.

Angioedema, rash.

Clinical laboratory test findings.

Creatinine.

Increases of more than 44.2 micromol/dL were reported for 6.5% of patients administered Inspra and for 4.9% of placebo treated patients.

Potassium.

In EPHESUS, the frequency of patients with changes in potassium (< 3.5 mmol/L or > 5.5 mmol/L or ≥ 6.0 mmol/L) receiving Inspra compared with placebo are displayed in Table 6.
Table 7 shows the rates of hyperkalaemia in EPHESUS as assessed by baseline renal function (creatinine clearance).
Table 8 shows the rates of hyperkalaemia in EPHESUS as assessed by two baseline characteristics: presence/ absence of proteinuria from baseline urinalysis and presence/ absence of diabetes (see Section 4.4 Special Warnings and Precautions for Use, Hyperkalaemia).

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

No cases of adverse events associated with overdosage of eplerenone in humans have been reported.The most likely manifestation of human overdosage would be anticipated to be hypotension or hyperkalaemia.
There is no specific antidote; treatment is symptomatic and supportive. Eplerenone cannot be removed by haemodialysis. Eplerenone has been shown to bind extensively to charcoal. Activated charcoal is most effective when administered within 1 hour of ingestion. In patients who are not fully conscious or have impaired gag reflex, consideration should be given to administering activated charcoal via nasogastric tube once the airway is protected. If symptomatic hypotension should occur, supportive treatment should be initiated. If hyperkalaemia develops, standard treatment should be initiated.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Eplerenone is a relatively selective mineralocorticoid receptor antagonist with weak binding to androgen, glucocorticoid and progesterone receptors. Eplerenone prevents the binding of aldosterone, a key hormone in the renin angiotensin aldosterone system (RAAS), which is involved in the regulation of blood pressure and the pathophysiology of cardiovascular disease.
Eplerenone has been shown to produce sustained increases in plasma renin and serum aldosterone, consistent with inhibition of the negative regulatory feedback of aldosterone on renin secretion. The resulting increased plasma renin activity and aldosterone circulating levels do not overcome the effects of eplerenone on blood pressure.
Eplerenone attenuates progression of heart failure in animal models with both ischaemic and nonischaemic aetiologies. Independent of blood pressure lowering, eplerenone preserves diastolic and systolic function and reduces left ventricular remodelling. In animal models, eplerenone reduces vascular inflammation and injury in the heart and kidney.

Clinical trials.

EPHESUS trial.

Eplerenone was studied in the Eplerenone Postacute myocardial infarction Heart failure Efficacy and SUrvival Study (EPHESUS). EPHESUS was a large multicentre, double blind, placebo controlled study, of 3 year duration, in 6,632 patients with acute myocardial infarction (AMI), left ventricular dysfunction (as measured by left ventricular ejection fraction [LVEF] ≤ 40%), and clinical evidence of heart failure. Patients were randomised 3 to 14 days after an acute MI. Following randomisation, patients received eplerenone or placebo in addition to standard therapies at an initial dose 25 mg once daily and titrated to the target dose of 50 mg once daily after 4 weeks if serum potassium was < 5.0 mmol/L. Dosage was reduced or suspended anytime during the study if serum potassium levels were ≥ 5.5 mmol/L.
In EPHESUS, the coprimary endpoints were all-cause mortality and the combined endpoint of cardiovascular (CV) death (defined as sudden cardiac death or death due to progression of congestive heart failure [CHF], stroke, or other CV causes) or CV hospitalisation (defined as hospitalisation for progression of CHF, ventricular arrhythmias, AMI or stroke). Because of the increased CV risk associated with diabetes, patients with diabetes and LV dysfunction were eligible for randomization in the absence of symptoms of heart failure; 10% of the population met this criterion. Patients with CHF of valvular or congenital aetiology or patients with unstable postinfarct angina and patients with serum potassium > 5.0 mmol/L or serum creatinine > 221 micromol/L were excluded. Patients were also allowed to undergo revascularization by angioplasty or coronary artery bypass graft surgery.
The mean time to enrolment was 7 days and the mean duration of follow-up was approximately 16 months. During the study patients received standard post-MI drug therapy including aspirin (92%), ACE inhibitors (90%), β-blockers (83%), nitrates (72%), loop diuretics (66%), or HMG-CoA reductase inhibitors (60%).
For the coprimary endpoint for all-cause mortality, 478 (14.4%) patients on eplerenone and 554 (16.7%) on placebo died. Consequently, a significant (p = 0.008) risk reduction (RR = 15%; HR = 0.85; 95% CI: 0.75-0.96) was observed with eplerenone when compared to placebo. The risk benefit for all-cause mortality was primarily due to CV mortality (12.3%). Most CV deaths were attributed to sudden death, AMI and CHF. Kaplan-Meier curves for all-cause mortality are shown in Figure 2, and the efficacy analyses for the components of mortality are provided in Table 9.
With respect to the composite endpoint of CV death or CV hospitalisation, 885 (26.7%) patients on eplerenone and 993 (30%) on placebo experienced the endpoint. With respect to the above endpoint, a significant (p = 0.002) risk reduction (RR = 13%; HR = 0.87; 95% CI: 0.79-0.95) was observed with eplerenone when compared to placebo (see Table 10; Figure 3).
Most CV deaths were attributed to sudden death, AMI and congestive heart failure (CHF).
The reduction in mortality observed in patients treated with Inspra compared to those who received placebo is mainly the result of a reduction in the rate of sudden death after myocardial infarction. In the first 12 months of treatment the rate of all cause mortality was 11.68% among patients treated with Inspra compared to 13.63% for patients treated with placebo. Among patients who remained alive after 12 months of therapy, the all-cause mortality rates at month 27 in the eplerenone and placebo groups were 7.97% and 9.58%, respectively.
Mortality hazard ratios varied for some subgroups as shown in Figure 1. Mortality hazard ratios appeared favourable for Inspra for both genders and for all races or ethnic groups, although the numbers of non-Caucasians was low (10%). Patients with diabetes without clinical evidence of CHF and patients greater than 75 years did not appear to benefit from the use of Inspra. Such subgroup analyses must be interpreted cautiously.
Analyses conducted for a variety of CV biomarkers did not confirm a mechanism of action by which mortality was reduced.
In dose ranging studies of chronic heart failure (NYHA classification II-IV), the addition of eplerenone to standard therapy resulted in expected dose dependent increases in aldosterone. Similarly, in a cardiorenal substudy of EPHESUS, therapy with eplerenone led to a significant increase in aldosterone. These results confirm the blockade of mineralocorticoid receptors in these populations.
No consistent effects of eplerenone on heart rate, QRS duration or PR or QT interval were observed in 147 normal subjects evaluated for electrocardiographic changes during pharmacokinetic studies.

EMPHASIS-HF trial.

In the Eplerenone in Mild Patients Hospitalisation And SurvIval Study in Heart Failure trial, the effect of eplerenone when added to standard therapy was investigated on clinical outcomes in patients with systolic heart failure and mild symptoms (NYHA functional class II).
Patients were included if they were at least 55 years old, had a left ventricular ejection fraction (LVEF) ≤ 30% or LVEF ≤ 35% in addition to QRS duration of > 130 msec and were either hospitalised for cardiovascular (CV) reasons 6 months prior to inclusion or had a plasma level of B-type natriuretic peptide (BNP) of at least 250 picogram/mL or a plasma level of N-terminal pro-BNP of at least 500 picogram/mL in men (750 picogram/mL in women). Subjects were required to have a serum potassium level ≤ 5.0 mmoL/L and an eGFR ≥ 30 mL/min/1.73 m2 within 24 hours prior to randomisation. Eplerenone was started at a dose of 25 mg once daily and was increased after 4 weeks to 50 mg once daily if the serum potassium level was < 5.0 mmol/L. Alternatively, if the estimated GFR was 30-49 mL/min/1.73 m2, eplerenone was started at 25 mg on alternate days, and increased to 25 mg once daily.
In total, 2,737 patients were randomised (double blind) to the treatment with eplerenone (1,364 patients) or placebo (1,373 patients) including baseline therapy of diuretics (85%), ACE inhibitors (78%), angiotensin II receptor blockers (19%), beta blockers (87%), antithrombotic drugs (88%), and lipid lowering agents (63%).
Out of the randomised patients (1,360 treated with eplerenone, 1,369 treated with placebo; four patients in each group were not treated), the majority were white (1141 subjects; 83.1% in the placebo group and 1127 subjects; 82.6% in the eplerenone group). Subjects were predominately male (78.1% and 77.3% in the placebo and eplerenone groups, respectively). The mean age was 68.6 years in the placebo group and 68.7 years in eplerenone group. The two treatment groups were comparable with respect to the baseline characteristics and the use of various cardiac medications at enrolment. The mean follow-up time was 21.1 months, the median was 20.6 months and the maximum follow-up time was 49.7 months.
The primary endpoint, death from cardiovascular causes or hospitalisation for heart failure occurred in 249 patients (18.3%) in the eplerenone group and 356 patients (25.9%) in the placebo group resulting in a relative risk reduction of 37% (hazard ratio 0.63, 95% CI: 0.54-0.74; p < 0.0001), as shown in Table 11. A Kaplan-Meier plot of time to first event is provided in Figure 4 and a summary of the hazard ratios of the primary endpoint by sub-groups is presented in Figure 5.
The secondary endpoint of all cause mortality was met by 171 patients (12.5%) in the eplerenone group and 213 patients (15.5%) in the placebo group resulting in a relative risk reduction of 24% (hazard ratio 0.76; 95% CI: 0.62-0.93; p = 0.008). Death from CV causes was reported in 147 (10.8%) patients in the eplerenone group and 185 (13.5%) patients in the placebo group resulting in a relative risk reduction of 24% (hazard ratio 0.76; 95% CI: 0.61-0.94; p = 0.01).

Serum potassium levels.

Serum potassium levels were assessed periodically during the study and the dosage adjusted accordingly (see Section 4.2 Dose and Method of Administration). During the EMPHASIS-HF study, hyperkalaemia (serum potassium level > 5.5 mmol/L) was reported in 158 patients (11.8%) in the eplerenone group and 96 patients (7.2%) in the placebo group (p < 0.001). Hypokalaemia, defined as serum potassium levels < 3.5 mmol/L, was statistically lower with eplerenone when compared to placebo (7.5% for eplerenone compared to 11.0% for placebo, p < 0.002). There is limited data available on the patient population with baseline serum potassium levels between 5.0 and 5.5 mmol/L.

Chronic kidney disease (CKD).

The distribution of subjects enrolled in the EMPHASIS-HF study based on renal function stratification is shown in Table 12.
Patients with stage 1 and 2 CKD were started on eplerenone 25 mg or matching placebo daily. They could be uptitrated to eplerenone 50 mg daily, or matching placebo, if serum potassium at 4 weeks was < 5.0 mmol/L. Subsequently, patients received a maintenance dose that ensured that serum potassium did not exceed 5.0 mmol/L. If serum potassium rose above 5.0 mmol/L, patients were down titrated to a daily dose of 25 mg or matching placebo. Similarly, patients taking 25 mg or matching placebo, daily, were down titrated to 25 mg or matching placebo, every other day, if serum potassium was > 5.0 mmol/L.
Patients with stage 3 CKD and eGFR 50-59 mL/min/1.73 m2 were started on a dose of eplerenone 25 mg, or matching placebo, daily. At the end of 4 weeks, they were uptitrated to 50 mg or matching placebo, daily, if serum potassium was < 5.0 mmol/L. However, if serum potassium was > 5.0 mmol/L, patients were down titrated to a dose of 25 mg or matching placebo, every other day.
Patients with stage 3 CKD and eGFR 30-49 mL/min/1.73 m2 were started on eplerenone 25 mg, or matching placebo, every other day. They were uptitrated to 25 mg or matching placebo daily, if serum potassium was < 5.0 mmol/L at the end of 4 weeks. However, if serum potassium was > 5.0 mmol/L, dosing was temporarily withheld and serum potassium repeated after 72 hours. If the repeated value of serum potassium was < 5.0 mmol/L, eplerenone was reintroduced at 25 mg every other day, or if serum potassium increased again, eplerenone was discontinued.
While stratification to a dosing group at baseline was based on renal function, dose adjustments were always and solely based on serum potassium, a value of serum potassium > 5.0 mmol/L always necessitating a downward dose adjustment.
Eplerenone has not been evaluated in subjects with severe (stage 4 and 5) CKD (eGFR less than 30 mL/min/1.73 m2).

Open label phase.

The EMPHASIS-HF study protocol included prespecified interim analyses. During the second interim analysis, the Data Safety Monitoring Committee confirmed that the study had reached its primary efficacy endpoint early and that the prespecified stopping rules regarding early attainment of positive efficacy results had been met. A recommendation was made to terminate the double blind (DB) study and to provide a mechanism to make eplerenone available to all participating subjects. As a result, enrolment into the study was stopped and all subjects who were participating in the double blind phase of EMPHASIS-HF were given the opportunity to receive open label treatment for 12 months.
All efficacy data collected during the DB phase up to termination of enrolment were analysed according to the prespecified protocol and are presented in Table 11 and Figures 4 and 5. Although enrolment was stopped, the DB phase of the study continued until all consenting patients were transitioned into the open label extension (OLE) phase of the study. The all cause mortality figures collected up to start of the OLE phase are 205/1367 (15.0%) for eplerenone and 253/1376 (18.4%) for placebo. These figures were not subject to statistical analysis.
A total of 1245 subjects were treated in the OLE phase, and 56 (4.5%) deaths were reported during the 12 months. No efficacy evaluations were conducted on the open label extension (OLE) phase.

5.2 Pharmacokinetic Properties

Eplerenone is cleared predominantly by cytochrome P450 (CYP) 3A4 metabolism, with an elimination half-life of 3 to 5 hours. Steady-state is reached within 2 days. Absorption is not affected by food. Inhibitors of CYP3A4 (e.g. ketoconazole, saquinavir) increase blood levels of eplerenone.

Absorption.

Mean peak plasma concentrations of eplerenone are reached approximately 1.5 hours following oral administration. The absolute bioavailability of eplerenone 100 mg tablet is 69%. Both peak plasma levels (Cmax) and area under the curve (AUC) are dose proportional for doses of 25 to 100 mg and less than proportional at doses above 100 mg.

Distribution.

The plasma protein binding of eplerenone is about 50% and is primarily bound to alpha-1-acid glycoproteins. The apparent volume of distribution at steady-state ranged from 43 to 90 L. Eplerenone does not preferentially bind to red blood cells.

Metabolism.

Eplerenone metabolism is primarily mediated via CYP3A4. No active metabolites of eplerenone have been identified in human plasma.

Excretion.

Less than 5% of an eplerenone dose is recovered as unchanged drug in the urine and faeces. Following a single oral dose of radiolabelled drug, approximately 32% of the dose was excreted in the faeces and approximately 67% was excreted in the urine. The elimination half-life of eplerenone is approximately 3 to 5 hours. The apparent plasma clearance is approximately 10 L/hour.

Special populations.

Age, gender and race.

The pharmacokinetics of eplerenone at a dose of 100 mg once daily have been investigated in the elderly (≥ 65 years), in males and females and in blacks. The pharmacokinetics of eplerenone did not differ significantly between males and females. At steady-state, elderly subjects had increases in Cmax (22%) and AUC (45%) compared with younger subjects (18 to 45 years). At steady-state, Cmax was 19% lower and AUC was 26% lower in blacks (see Section 4.2 Dose and Method of Administration).

Chronic kidney disease.

The pharmacokinetics of eplerenone were evaluated in patients with varying degrees of chronic kidney disease and in patients undergoing haemodialysis. Compared with control subjects, steady-state AUC and Cmax were increased by 38% and 24%, respectively, in patients with severe chronic kidney disease and were decreased by 26% and 3%, respectively, in patients undergoing haemodialysis. No correlation was observed between plasma clearance of eplerenone and creatinine clearance. Eplerenone is not removed by haemodialysis (see Section 4.4 Special Warnings and Precautions for Use).

Hepatic insufficiency.

The pharmacokinetics of eplerenone 400 mg have been investigated in patients with moderate (Child-Pugh class B) hepatic impairment and compared with normal subjects. Steady-state Cmax and AUC of eplerenone were increased by 3.6% and 42%, respectively (see Section 4.2 Dose and Method of Administration).

Heart failure.

The pharmacokinetics of eplerenone 50 mg were evaluated in patients with heart failure (NYHA classification II-IV). Compared with healthy subjects matched according to age, weight and gender, steady-state AUC and Cmax in heart failure patients were 38% and 30% higher, respectively. Consistent with these results, a population pharmacokinetic analysis of eplerenone based on a subset of patients from EPHESUS indicates that clearance of eplerenone in patients with heart failure was similar to that in healthy elderly subjects.

5.3 Preclinical Safety Data

Genotoxicity.

Eplerenone was nongenotoxic in a battery of assays including in vitro bacterial gene mutation (Salmonella typhimurium and E. coli), in vitro mammalian cell gene mutation (mouse lymphoma cells), in vitro chromosomal aberration (Chinese hamster ovary cells), in vivo rat bone marrow micronucleus formation, and in vivo/ ex vivo unscheduled DNA synthesis in rat hepatocytes.

Carcinogenicity.

There was no drug related tumour response in heterozygous P53 deficient mice when tested for 6 months at oral dosages up to 1,000 mg/kg/day (systemic AUC exposures up to 10-15 times the exposure in humans receiving the 50 mg/day therapeutic dose, based on unbound AUC). Statistically significant increases in benign thyroid tumours were observed after 2 years in both male and female rats when administered eplerenone 250 mg/kg/day (highest dose tested) and in male rats only at 75 mg/kg/day. The incidence of renal tubular adenomas was increased in females at 250 mg/kg/day. These dosages provided systemic AUC exposures three to 16 times the average human therapeutic exposure at 50 mg/day. The thyroid tumours were associated with thyroid hypertrophy resulting from increases in the hepatic enzyme responsible for conjugation and clearance of thyroxine, which results in increased levels of TSH by a compensatory mechanism. The benign renal tumours were associated with chronic progressive nephropathy, which commonly occur in ageing rats and which is exacerbated by some human therapeutic agents. Drugs that have produced thyroid tumours and renal tubular adenomas by these rodent specific mechanisms have not shown a similar effect in humans.

6 Pharmaceutical Particulars

6.1 List of Excipients

Lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, hypromellose, sodium lauryl sulfate, purified talc, magnesium stearate, titanium dioxide, macrogol 400, polysorbate 80, iron oxide yellow (CI77492), iron oxide red (CI77491).

6.2 Incompatibilities

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

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25 degrees Celsius.

6.5 Nature and Contents of Container

Inspra tablets are available in blister packs of 30.

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

Eplerenone is an odourless, white to off white crystalline powder. It is very slightly soluble in water, with its solubility essentially pH independent. The octanol/ water partition coefficient of eplerenone is approximately 7.1 at pH 7.0.

Chemical structure.

Eplerenone is pregn-4-ene-7,21-dicarboxylic acid, 9,11- epoxy-17-hydroxy-3-oxo, γ-lactone, methyl ester, (7α,11α,17α). The empirical formula of eplerenone is C24H30O6 and its molecular weight 414.50. The structural formula of eplerenone is shown below:

CAS number.

107724-20-9.

7 Medicine Schedule (Poisons Standard)

Prescription only medicine (S4).

Summary Table of Changes