Consumer medicine information

APO-Eplerenone Tablets

Eplerenone

BRAND INFORMATION

Brand name

APO-Eplerenone

Active ingredient

Eplerenone

Schedule

SUMMARY CMI

APO-Eplerenone tablets

Consumer Medicine Information (CMI) summary

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

1. Why am I using APO-Eplerenone?

APO-Eplerenone contains the active ingredient Eplerenone. APO-Eplerenone is used to treat heart failure in patients who have experienced heart attack.

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

2. What should I know before I use APO-Eplerenone?

Do not use it if you have ever had an allergic reaction to Eplerenone or any of the ingredients listed at the end of the CMI.

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

For more information, see Section 2. What should I know before I use APO-Eplerenone? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Eplerenone and affect how it works.

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

4. How do I use APO-Eplerenone?

Take your medicine at about the same time each day. Taking at the same time each day will have the best effect. It will also help you remember when to take it.
Swallow the tablet whole with a full glass of water.

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

5. What should I know while using APO-Eplerenone?

Things you should do	Remind any doctor, dentist, or pharmacist you visit that you are using APO-Eplerenone. Tell your doctor if you have excess vomiting or diarrhoea while taking APO-Eplerenone
Things you should not do	Do not take this medicine 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.
Driving or using machines	This medicine may cause dizziness and feeling faint in some people. If you do not drive, operate machinery or do anything else that could be dangerous.
Drinking alcohol	Tell your doctor if you drink alcohol. Alcohol may have some effects with APO-Eplerenone.
Looking after your medicine	Keep the medicine in the pack until it is time to take them. If you take the tablets out of the pack, they may not keep well

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

6. Are there any side effects?

The common side effects include feeling light headed, dizzy or faint, headache, stomach or bowel problems, feeling sick (nausea), vomiting, diarrhea, constipation, flatulence, cough, back pain.

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

FULL CMI

APO-Eplerenone tablets

Active ingredient(s): Eplerenone

Consumer Medicine Information (CMI)

This leaflet provides important information about using Eplerenone. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using APO-Eplerenone.

Where to find information in this leaflet:

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

1. Why am I using APO-Eplerenone?

APO-Eplerenone contains the active ingredient eplerenone. APO-Eplerenone belongs to a group of medicines called ‘selective aldosterone, a substance made by your body. Aldosterone 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. Eplerenone works by blocking the action of aldosterone and slowing the progression of heart failure by reducing heart damage.

APO-Eplerenone is used to

Treat heart failure in patients who have experienced a heart attack.
Reduce the risk of death or need for hospitalization due to heart failures in patients with chronic heart failure.

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.

2. What should I know before I use APO-Eplerenone?

Warnings

Do not use APO-Eplerenone if:

You are allergic to eplerenone, or any of the ingredients listed at the end of this leaflet.
Always check the ingredients to make sure you can use this medicine.
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.

Check with your doctor if you:

Have or had any other medical conditions
- Very high levels of potassium in your blood
- Severely reduced kidney function
- Severe liver problems
take any medicines for any other condition
- potassium-sparing diuretics (e.g., spironolactone, amiloride), used to remove fluid from the body
- ketoconazole and itraconazole, used to treat fungal functions
- clarithromycin, used to treat bacterial infections
- saquinavir and ritonavir, used to treat HIV infections

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

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

Before you start to take it

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

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

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

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

3. What if I am taking other medicines?

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

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

Angiotensin converting enzymes (ACE)inhibitors and sartans (e.g., quinapril and losartan), used to treat high blood pressure.
Non-steroidal anti-inflammatory drugs (NSAIDs) (e.g., aspirin and ibuprofen), used to treat pain and inflammation.
Lithium, a medicine used to treat mood swings.
Neuroleptics and tricyclic anti-depressants, used to treat pain and inflammation.
Lithium, a medicine used to treat mood swings.
Neuroleptics and tricyclic antidepressants, used to treat certain medical illness.
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 (e.g., spironolactone, amiloride)
Potassium supplements, salt substitutes which contain potassium or salt tablets.
Medicines used to treat fungal infections (e.g., ketoconazole, itraconazole, fluconazole)
Certain antibiotics used to treat bacterial infections (e.g., erythromycin, trimethoprim, rifampicin)
Saquinavir and ritonavir, medicines used to treat HIV infections
Immunosuppressive agents (e.g., cyclosporin, tacrolimus)
Baclofen, a muscle relaxant
Prazosin, used to treat high blood pressure
Alfuzosin, used to treat benign prostatic hyperplasia
Amifostine, used to combination with cancer treatments
Any other medicines used to treat high blood pressure or hear failure (e.g., verapamil)

These medicines may be affected by this medicine or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

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

Other medicines not listed above may interact with eplerenone.

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

4. How do I use APO-Eplerenone?

How much to take / use

Your doctor will tell you how much of this medicine you should take. This may depend on your age, your kidney condition, the potassium level in your blood, and whether you are taking any other medicine.
The usual starting dose is one 25mg tablet taken once a day. After about four weeks, your doctor may increase the dose to one 50mg tablet once a day.

When to take / use APO-Eplerenone

APO-Eplerenone should be used at 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.
It does not matter if this medicine is taken before or after food.

How to take APO-Eplerenone

Swallow the tablets whole with a full glass of water.

If you forget to use APO-Eplerenone

APO-Eplerenone should be used regularly at the same time each day. 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 normally.

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

Do not take a double dose to make up for the dose you missed.

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 use too much APO-Eplerenone

If you think that you have used too much APO-Eplerenone, you may need urgent medical attention.

You should immediately:

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

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

5. What should I know while using APO-Eplerenone?

Things you should do

Call your doctor straight away if you:

Remind any doctor, dentist, or pharmacist you visit that you are using APO-Eplerenone.

If you are about to start on any new medicine, remind your doctor and pharmacist that you are taking APO-Eplerenone.
Tell any other doctors, dentists and pharmacists who treat you that you are taking this medicine.
If you become pregnant while taking this medicine, tell your doctor immediately.
If you are going to have surgery, tell the surgeon or anesthetist that you are taking this medicine.
If you are about to have any blood tests, tell your doctor that you are taking this medicine.
Tell your doctor if you feel light-headed or dizzy after taking your first dose of this medicine, or when your dose is increased.
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 APO-Eplerenone, 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.

Tell your doctor if you have excess vomiting or diarrhea while taking eplerenone.

You may loose too much water and salt and your blood pressure may drop too much.

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

Keep all of your doctors' 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 doctor may adjust your dose of this medicine depending on the potassium levels in your blood.

Things you should not do

Do not take this medicine 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

Driving or using machines

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

APO-Eplerenone may cause dizziness and feeling faint in some people. If you have any of these symptoms, do not drive or operate machinery or do anything else that could be dangerous.

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

Standing up slowly, especially when you get up from bed or chairs, will help your body get used to the change in position and blood pressure. If this problem continues or gets worse, talk to your doctor.

Drinking alcohol

Tell your doctor if you drink alcohol.

Alcohol may have some effects with APO-Eplerenone.

Looking after your medicine

Keep your tablets in the pack until it is time to take them.
If you take the tablets out of the pack, they may not keep well.
Keep your medicine in a cool dry place where the temperature stays below 25°C.
Do not store this medicine or any other medicine in the bathroom or near the sink.

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

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

in the bathroom or near a sink, or
in the car or on windowsills.

Heat and dampness can destroy some medicines.

Keep it where young children cannot reach it.

A locked cupboard at least one-and-a -half-meters above the ground is a good place to store medicine.

Getting rid of any unwanted medicine

If your doctor tells you to stop taking the medicine or the If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

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

If you are over 65 years of age you may have an increased chance of having some side effects.

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

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

Less serious side effects

Less serious side effects	What to do
Feeling light-headed, dizzy, or faint headache Stomach or bowel problems, feeling sick (nausea), vomiting, diarrhoea, constipation, flatulence. Cough Back pain	Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effects	What to do
Rash, itchy skin Sore throat, high temperature, signs of an infection Heart flutters, increased heart rate Unusual tiredness, weakness, feeling weak and generally unwell Muscle spasms and pain, abdominal pain Enlargement of the breasts in men Reduced sense of touch Increased sweating Problems with sleeping	Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Very serious side effects

Serious side effects	What to do
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 may cause difficulty in swallowing or breathing.	Call your doctor straight away or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects you my need urgent medical attention or hospitalization.

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

Some side effects (such as changes in potassium or cholesterol levels, thyroid function) can only be found when your doctor does blood tests to check your progress.

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

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

Reporting side effects

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

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

7. Product details

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

What APO-Eplerenone contains

Active ingredient (Main ingredient)	Eplerenone
Other ingredients (Inactive ingredients)	Lactose monohydrate Microcrystalline cellulose Croscarmellose sodium Hypromellose Magnesium stearate Purified talc Titanium dioxide Macrogol 6000 Iron oxide yellow Iron oxide red
Potential allergens	Contain lactose

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

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

What APO-Eplerenone looks like

25mg tablet:

APO-Eplerenone is yellow, round, biconvex, film coated tablet, engraved with “E25” on one side. AUST R 295709. Pack size of 30 tablets.

50mg tablet:

APO-Eplerenone is a yellow, round, biconvex, film coated tablet, engraved with “E50” on one side. AUST R 295708. Pack size of 30 tablets.

Who distributes APO-Eplerenone

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

This leaflet was prepared in September 2023.

Published by MIMS November 2023

BRAND INFORMATION

Brand name

APO-Eplerenone

Active ingredient

Eplerenone

Schedule

1 Name of Medicine

Eplerenone.

2 Qualitative and Quantitative Composition

Each tablet contains 25 mg or 50 mg eplerenone, as the active ingredient.

Excipients with known effect.

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

3 Pharmaceutical Form

APO-Eplerenone tablets.

25 mg.

Yellow, round, biconvex film coated tablet, engraved with "E25" on one side.

50 mg.

Yellow, round, biconvex film coated tablet, engraved with "E50" on one side.

4 Clinical Particulars

4.1 Therapeutic Indications

Eplerenone 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 5.1 Pharmacodynamic Properties, Clinical trials; Section 4.2 Dose and Method of Administration);
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

APO-Eplerenone tablets are intended for oral administration.

Dosage.

For post-myocardial infarction heart failure patients.

Eplerenone is usually administered in combination with standard therapies. The recommended dose of eplerenone 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 eplerenone 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 eplerenone therapy, within the first week and at one 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).

Eplerenone 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 re-started 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.
Eplerenone may be administered with or without food.

Special populations.

Children.

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

Elderly patients.

No dose adjustment is required in the elderly.

Renal impairment.

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 Serum potassium levels; see 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.

Hepatic impairment.

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

4.3 Contraindications

Hypersensitivity to eplerenone or any of the excipients in the tablet.
Eplerenone 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).
Eplerenone should not be administered to patients with severe renal insufficiency (eGFR < 30 mL/min/1.73 m², CKD stages 4 and 5) (see Section 5.1 Pharmacodynamic Properties, Clinical trials; Section 4.2 Dose and Method of Administration).
Eplerenone should not be administered to patients with severe hepatic insufficiency (see Section 4.2 Dose and Method of Administration).
Eplerenone should not be co-administered 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 eplerenone is hyperkalaemia. Hyperkalaemia can cause serious, sometimes fatal, arrhythmias. Patients who develop hyperkalaemia (> 5.5 mmol/L) may still benefit from eplerenone with proper dose adjustment.
Serum potassium should be measured before initiating eplerenone therapy, and measured periodically thereafter, as clinically warranted (see Section 4.2 Dose and Method of Administration).
Hyperkalaemia can be minimized by patient selection, avoidance of certain concomitant treatments and periodic monitoring until the effect of eplerenone has been established. Eplerenone 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 eplerenone 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 ACE inhibitor and an angiotensin receptor blocker (ARB) and therefore this combination is not recommended.

Use in renal impairment.

Eplerenone 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 5.1 Pharmacodynamic Properties, Clinical trials; Section 4.3 Contraindications; Section 4.2 Dose and Method of Administration).

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 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 eplerenone in patients with severe hepatic impairment has not been evaluated and is therefore contraindicated (see Section 5.2 Pharmacokinetic Properties, Special populations; Section 4.3 Contraindications; Section 4.2 Dose and Method of Administration).

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 eplerenone (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 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 eplerenone has not been established in paediatric patients.

Effects on laboratory tests.

No data available.

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 eplerenone 100 mg with ketoconazole 200 mg twice daily, a potent inhibitor of the CYP3A4 pathway, showed a 1.7-fold increase in C_max of eplerenone and a 5.4-fold increase in AUC of eplerenone. Eplerenone 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 C_max of eplerenone ranging from 1.4- to 1.6-fold and AUC from 2.0- to 2.9-fold.

Inducers of CYP3A4.

Co-administration 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 eplerenone 25-50 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 ACE inhibitor and/or an 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 4.4 Special Warnings and Precautions for Use; Section 4.2 Dose and Method of Administration).

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. Co-administration of eplerenone 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 eplerenone and cyclosporin or tacrolimus should be avoided. If needed, close monitoring of serum potassium and renal function are recommended when cyclosporine and tacrolimus are to be administered during treatment with eplerenone.

Trimethoprim.

The concomitant administration of trimethoprim with eplerenone 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 eplerenone, there is the potential for increased hypotensive effect and/or postural hypotension. Clinical monitoring for postural hypotension is recommended during alpha-1-blocker co-administration.

Tricyclic anti-depressants, neuroleptics, amifostine and baclofen.

Co-administration of these drugs with eplerenone may potentially increase antihypertensive effects and risk of postural hypotension.

Non-steroidal 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 eplerenone 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 1,000 mg/kg/day for 10 weeks (AUC 24x 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 (10x clinical AUC at 50 mg/day). Dogs administered eplerenone at dosages of 15 mg/kg/day and higher (AUC 6x 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 3x 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 body weights and post-implantation 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 40x the clinical exposure based on AUC). The potential risk for humans is unknown. Eplerenone 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 body weight gain at a maternal dose of 1,000 mg/kg/day (maternal exposure 43x 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)

Eplerenone has been evaluated for safety in 1,360 patients with heart failure and 3,307 patients treated for heart failure post-myocardial infarction (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
In the EPHESUS study, the overall incidence of adverse events reported with eplerenone (78.9%) was similar to placebo (79.5%). The discontinuation rate due to adverse events in this study was 4.4% for patients receiving eplerenone and 4.3% for patients receiving placebo.
In the EMPHASIS-HF study, the overall incidence of adverse events (% subjects) reported with eplerenone (72%) was similar to placebo (73.6%). The discontinuation rate due to adverse events in this study was 13.8% for patients receiving eplerenone 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 eplerenone in clinical studies of hypertension. The overall rates of adverse events in placebo-controlled studies were similar between eplerenone (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 eplerenone 25-400 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/d were reported for 6.5% of patients administered eplerenone 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 eplerenone 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 and contact Apotex Medical Information Enquiries/Adverse Drug Reaction Reporting on 1800 195 055.

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 131126 (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, 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 non-ischaemic 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 Post-acute myocardial infarction Heart failure Efficacy and SUrvival Study (EPHESUS). EPHESUS was a large multi-centre, double-blind, placebo-controlled study, of 3-year duration, in 6,632 patients with acute myocardial infarction (MI), left ventricular dysfunction [as measured by left ventricular ejection fraction (LVEF) ≤ 40%] and clinical evidence of heart failure. Patients were randomized 3-14 days after an acute MI. Following randomization, 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 co-primary 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, acute MI 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 post-infarct 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%), angiotensin converting enzyme (ACE) inhibitors (90%), β-blockers (83%), nitrates (72%), loop diuretics (66%) or HMG CoA reductase inhibitors (60%).
For the co-primary 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, acute MI 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 (Table 10; Figure 3).

Most CV deaths were attributed to sudden death, acute MI and CHF.

The reduction in mortality observed in patients treated with eplerenone 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 eplerenone 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 eplerenone 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 eplerenone. 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 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 randomization. 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 randomized (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 randomized patients (1,360 treated with eplerenone, 1,369 treated with placebo; four patients in each group were not treated), the majority were white (1,141 subjects; 83.1% in the placebo group and 1,127 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 up-titrated 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 up-titrated 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 up-titrated 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 pre-specified 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 pre-specified 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 pre-specified 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 205/1,367 (15.0%) for eplerenone and 253/1,376 (18.4%) for placebo. These figures were not subject to statistical analysis.
A total of 1,245 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 OLE phase.

5.2 Pharmacokinetic Properties

Eplerenone is cleared predominantly by cytochrome P450 (CYP) 3A4 metabolism, with an elimination half-life of 3-5 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 (C_max) and area under the curve (AUC) are dose proportional for doses of 25-100 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 43-90 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 3-5 hours. The apparent plasma clearance is approximately 10 L/hr.

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 C_max (22%) and AUC (45%) compared with younger subjects (18-45 years). At steady state, C_max 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 C_max 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 C_max 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 C_max 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 non-genotoxic 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 10-15x 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 16x 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, magnesium stearate, purified talc, titanium dioxide, macrogol 6000, iron oxide yellow, iron oxide red.

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°C.