Consumer medicine information

Yonsa Mpred

Abiraterone acetate; Methylprednisolone

BRAND INFORMATION

Brand name

Yonsa Mpred

Active ingredient

Abiraterone acetate; Methylprednisolone

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Yonsa Mpred.

SUMMARY CMI

YONSA MPRED™

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 YONSA MPRED?

YONSA MPRED is a combination pack which contains two different medicines, YONSA tablets and Methylprednisolone tablets. YONSA tablets contain the active ingredient abiraterone acetate and Methylprednisolone tablets contain the active ingredient methylprednisolone. YONSA MPRED is used to treat prostate cancer that has spread to other parts of the body

For more information, see Section 1. Why am I using YONSA MPRED? in the full CMI.

2. What should I know before I use YONSA MPRED?

Do not use if you have ever had an allergic reaction to abiraterone acetate, methylprednisolone 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 YONSA MPRED? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with YONSA MPRED 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 YONSA MPRED?

YONSA MPRED should be used regularly each day. The dosage recommended by the doctor will depend on your condition

More instructions can be found in Section 4. How do I use YONSA MPRED? in the full CMI.

5. What should I know while using YONSA MPRED?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using YONSA MPRED.
  • Keep all of your doctor's appointments so that your condition can be monitored.
Things you should not do
  • Do not stop using this medicine suddenly.
Driving or using machines
  • YONSA MPRED may cause dizziness in some people. Be careful before you drive or use any machines or tools until you know how YONSA MPRED affects you
Drinking alcohol
  • Alcohol may increase the chance of you experiencing stomach problems
Looking after your medicine
  • Store your medicine in a cool dry place where the temperature stays below 25°C, away from moisture, heat or sunlight.

For more information, see Section 5. What should I know while using YONSA MPRED? in the full CMI.

6. Are there any side effects?

Common side effects include diarrhoea, fluid in legs and feet, low blood potassium, urinary tract infection and high blood pressure. Other side effects include high fat levels in your blood, liver function test increases, indigestion, blood in urine, chest pain, heartbeat disorders, heart failure, rapid heart rate and muscle pains. Some side effects can only be found when your doctor does tests from time to time to check your progress.

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

YONSA MPRED™

Active ingredients: Abiraterone acetate and methylprednisolone

Consumer Medicine Information (CMI)

This leaflet provides important information about using YONSA MPRED. 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 YONSA MPRED.

Where to find information in this leaflet:

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

1. Why am I using YONSA MPRED?

YONSA MPRED is a combination pack which contains two different medicines, YONSA tablets and Methylprednisolone tablets. YONSA tablets contain the active ingredient abiraterone acetate and Methylprednisolone tablets contain the active ingredient methylprednisolone.

  • Abiraterone acetate works by reducing the levels of male sex hormones in your body, including testosterone.
  • Methylprednisolone is a corticosteroid that must be taken to reduce the chance of developing high blood pressure, heart effects or low levels of potassium in your blood while you are using YONSA tablets.

YONSA MPRED is used to treat prostate cancer that has spread to other parts of the body.

2. What should I know before I use YONSA MPRED?

Warnings

Do not use YONSA MPRED if:

  • you are allergic to abiraterone acetate, methylprednisolone or any of the ingredients listed at the end of this leaflet. Always check the ingredients to make sure you can use this medicine.
  • if you have severe liver failure.
  • If you are being treated with XOFIGO (radium 223 dichloride), a radiation therapy used for prostate cancer
  • If you are pregnant or may potentially be pregnant
  • if you have an infection or if you have recently been given a vaccine

Check with your doctor if you:

  • have any other medical conditions, especially the following:
    - problems with your liver or kidneys
    - high blood pressure
    - heart problems
    - low levels of potassium in your blood
    - fluid retention (bloating, swollen legs, feet, ankles, puffiness in the abdomen, face and hips, sudden unexplained increase in weight)
    - tuberculosis
    - underactive thyroid gland
    - herpes in the eye
    - hypoprothrombinaemia (a blood clotting disorder)
    - disease of the bowel, e.g., ulcerative colitis or diverticulitis
    - stomach ulcers
    - diabetes
    - emotional problems or mental disorders
    - infections
    - Cushing's disease (a hormone disorder)
    - seizures/epilepsy
    - myasthenia gravis (ongoing muscle weakness and chronic fatigue)
    - thin or weak bones
    - blood clots
    - systemic sclerosis
    - lactose, galactose or glucose intolerance
  • take any medicines for any other condition

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

Pregnancy and breastfeeding

Do not take YONSA MPRED if you are pregnant or may potentially be pregnant.

YONSA MPRED is not for use in women and children.

Problems with your liver

  • You should not take YONSA MPRED if you have moderate or severe liver disease. Your doctor will decide whether YONSA MPRED can be used if you have a mild liver problem.
  • YONSA MPRED may affect your liver. When you are taking YONSA MPRED your doctor will check your blood to look for any effects on your liver

High blood pressure and heart problems

  • YONSA can make high blood pressure or heart failure or low blood potassium worse. Taking methylprednisolone with YONSA helps to avoid worsening of these conditions. If you have these conditions, or other heart or blood vessel problems, discuss them with your doctor.

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 YONSA MPRED may interfere with each other. These include:

  • medicines for bacterial infections (antibiotics) such as rifampicin, erythromycin, clarithromycin and isoniazid
  • cough medicines such as dextromethorphan
  • medicines used to treat diabetes, low blood sugar may occur to patients with pre-existing diabetes receiving pioglitazone or repaglinide.
  • medicines used to suppress the immune system such as ciclosporin, cyclophosphamide, tacrolimus and methotrexate
  • medicines to relieve pain and inflammation such as aspirin, ibuprofen and naproxen
  • some medicines for fungal infections such as ketoconazole and itraconazole
  • medicines for epilepsy such as phenobarbitone, phenytoin and carbamazepine
  • medicines to reduce blood clotting ('thin' the blood) such as warfarin and heparin
  • some immunisations and vaccinations
  • medicines for myasthenia gravis (ongoing muscle weakness and chronic fatigue), glaucoma, Alzheimer's disease
  • medicines for psychiatric disorders and anxiety
  • medicines to help you breathe when you have lung diseases such as asthma, bronchitis, emphysema
  • medicines for nausea such as aprepitant and fosaprepitant
  • medicines for HIV (AIDS) such as indinavir, ritonavir and cobicistat
  • some medicines for blood pressure, stroke and other heart conditions such as digoxin and diltiazem
  • diuretics used to help kidneys get rid of salt and water from the body by increasing the amount of urine, such as frusemide, spironolactone and acetazolamide.
  • XOFIGO (radium 223 dichloride) for treating prostate cancer
  • grapefruit juice
  • medicines for breast cancer and hormone disorders

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these can be used while you are taking YONSA MPRED.

4. How do I use YONSA MPRED?

How much to take / use

YONSA MPRED contains two different medicines that need to be taken each day.

YONSA 125 mg tablets

  • The usual daily dose of YONSA is four 125 mg tablets taken as a single dose.

Methylprednisolone 4 mg tablets

  • Depending on your condition, the usual dose of the methylprednisolone 4 mg tablets in the YONSA MPRED pack is either, one tablet once a day or one tablet twice a day.

Follow the instructions provided and use YONSA MPRED until your doctor tells you to stop.

When to take YONSA MPRED

  • YONSA tablets and methylprednisolone tablets can be taken with or without food. The tablets should be swallowed whole with water. Do not crush or chew tablets.

If you forget to use YONSA MPRED

YONSA MPRED should be used regularly each day.

If you miss your daily dose of YONSA or a dose of methylprednisolone, skip the dose you missed and take your next dose when you are meant to.

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

If more than one daily dose is missed, talk to your doctor

If you use too much YONSA MPRED

If you think that you have used too much YONSA MPRED, 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 YONSA MPRED?

Things you should do

  • Keep all of your doctor's appointments so that your progress can be checked. Your doctor will do some blood and other tests from time to time to check your progress and monitor for side effects
  • Remind any doctor (including surgeons and anaesthetists), dentist or pharmacist you visit that you are using YONSA MPRED.

Call your doctor straight away if you:

  • are diabetic and notice a change in the results of the blood sugar tests.
  • notice signs of infection such as fever, swelling or inflammation.
  • notice signs that your blood potassium may be low such as, muscle weakness, muscle twitching or heart palpitations

Things you should not do

  • Do not stop using this medicine suddenly. Your doctor may reduce the dose of methylprednisolone gradually if you have been on long-term treatment.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how YONSA MPRED affects you.

YONSA MPRED may cause dizziness in some people

Drinking alcohol

Tell your doctor if you drink alcohol.

Alcohol may increase the chance of you experiencing stomach problems.

Looking after your medicine

Keep YONSA MPRED where the temperature stays below 25°C.

Keep the tablets in the bottle until it is time to take them.

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 window sills.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

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

Do not use this medicine after the expiry date.

6. Are there any side effects?

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

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

Less serious side effects

Less serious side effectsWhat to do
  • fatigue
  • cough
  • hot flushes
  • nausea
  • headache, dizziness or lightheadedness
  • muscle weakness, pain or loss of muscle mass
  • problems with your joints, including pain
  • thin fragile skin or bruising easily
  • itchy or peeling skin, rashes, acne, hives
  • slow wound healing
  • increased sweating
  • diarrhoea or constipation
  • indigestion
  • increased appetite, loss of appetite or weight loss
  • persistent hiccups
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
  • signs of an allergic reaction such as skin rash, itching; difficulty breathing, wheezing or coughing; swelling of the face, lips or tongue
  • signs of infection such as fever, severe chills, sore throat or mouth ulcers
  • heart palpitations (heart racing or pounding) or irregular heartbeat
  • pain or discomfort in your chest
  • blurred or distorted vision or loss of vision, eye infections
  • pain when urinating or blood in your urine
  • fluid retention (swelling or bloating)
  • swelling or discomfort in your joints, feet, ankles or legs
  • severe stomach pains
  • convulsions or fits
  • mood changes e.g. excitement, depression, suicidal thoughts, hallucinations, anxiety
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.

Some side effects can only be found when your doctor does tests from time to time to check your progress, for example:

  • changes in liver function
  • increases in blood sugar (glucose) levels
  • increase in blood fat levels
  • changes in blood pressure
  • loss of bone density
  • reduced potassium levels in the blood
  • changes in the function of the adrenal glands, which make the body's own steroids

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

YONA MPRED is only available with a doctor's prescription.

YONSA tablets and Methylprednisolone 4 mg tablets are not available separately.

What YONSA MPRED contains

YONSA tablets

Active ingredient
(main ingredient)		abiraterone acetate
Other ingredients
(inactive ingredients)		lactose monohydrate
sodium lauryl sulphate
butylated hydroxyanisole
butylated hydroxytoluene
microcrystalline cellulose
croscarmellose sodium
sodium stearyl fumarate.
Potential allergensLactose monohydrate

Methylprednisolone tablets

Active ingredient
(main ingredient)		methylprednisolone
Other ingredients
(inactive ingredients)		lactose monohydrate
maize starch
gelatin
magnesium stearate
talc
Potential allergenslactose monohydrate

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

What YONSA MPRED looks like

YONSA MPRED is a combination pack which contains two different medicines supplied together in a cardboard carton.

YONSA tablets are white to off-white and oval shaped, marked with ‘125 FP’. YONSA tablets are supplied in a white plastic bottle containing 120 tablets.

Methylprednisolone 4 mg tablets are white to almost white, round, flat and scored tablets. Methylprednisolone 4 mg tablets are supplied in a white plastic bottle containing 60 tablets or 30 tablets.

YONSA MPRED is available in two pack sizes. Each carton of YONSA MPRED contains 120 YONSA tablets and either 60 or 30 methylprednisolone tablets.

YONSA MPRED registration number: Aust R 346890.

Not all pack sizes may be available.

Who distributes YONSA MPRED

Sun Pharma ANZ Pty Ltd
ABN 17 110 871 826
Macquarie Park Sydney NSW 2113
Telephone 1800 726229

This leaflet was prepared in September 2024.

Published by MIMS November 2024

BRAND INFORMATION

Brand name

Yonsa Mpred

Active ingredient

Abiraterone acetate; Methylprednisolone

Schedule

S4

 

1 Name of Medicine

Abiraterone acetate and methylprednisolone.

2 Qualitative and Quantitative Composition

Yonsa Mpred contains 125 mg abiraterone acetate tablets (Yonsa) and 4 mg methylprednisolone tablets.

Excipients with known effects.

Sugars as lactose (both tablets) and sulfites (methylprednisolone tablets only).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Abiraterone acetate 125 mg tablet (Yonsa).

White to off‐white modified oval shaped tablet debossed with '125 FP'.

Methylprednisolone 4 mg tablet.

White to almost white, round, flat, beveled edge, scored tablets.

4 Clinical Particulars

4.1 Therapeutic Indications

Yonsa Mpred is indicated for the treatment of patients with:
newly diagnosed high‐risk metastatic hormone sensitive prostate cancer (mHSPC) in combination with androgen deprivation therapy (ADT); or
patients with metastatic advanced prostate cancer (castration resistant prostate cancer, mCRPC) who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy (ADT); or
patients with mCRPC who have received prior chemotherapy containing a taxane.

4.2 Dose and Method of Administration

The recommended dose of Yonsa abiraterone acetate tablets is 500 mg (four 125 mg tablets) administered orally once daily in combination with methylprednisolone.
The recommended dose of methylprednisolone for metastatic hormone sensitive prostate cancer is 4 mg administered once daily. The recommended dose of methylprednisolone for metastatic castration resistant prostate cancer is 4 mg administered twice daily. (See Section 4.4 Special Warnings and Precautions for Use, Corticosteroid withdrawal and coverage of stress situations.)

Important administration instructions.

To avoid medication errors and overdose, be aware that Yonsa tablets may have different dosing and food effects than other abiraterone acetate products.
Yonsa tablets can be taken with or without food (see Section 5.2 Pharmacokinetic Properties). The tablets should be swallowed whole with water. Do not crush or chew tablets.
Patients started on Yonsa Mpred who were receiving a LHRH agonist should continue to receive a LHRH agonist.

Recommended monitoring.

Serum transaminases and bilirubin should be measured prior to starting treatment with Yonsa Mpred, every two weeks for the first three months of treatment and monthly thereafter. Blood pressure, serum potassium and fluid retention should be monitored monthly (see Section 4.4 Special Warnings and Precautions for Use).

Special populations.

Abiraterone acetate.

Renal insufficiency.

No dosage adjustment is necessary for patients with renal impairment.

Hepatic insufficiency.

No dosage adjustment is necessary for patients with pre‐existing mild hepatic impairment. There are no data on the clinical safety and efficacy of multiple doses of abiraterone acetate when administered to patients with moderate or severe hepatic impairment (Child‐Pugh Class B or C). No dose adjustment can be predicted. Abiraterone acetate tablets should be used with caution in patients with moderate hepatic impairment, only if the benefit clearly outweighs the possible risk. Abiraterone acetate tablets should not be used in patients with pre‐existing severe hepatic impairment (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties).
For patients who develop hepatotoxicity during treatment with abiraterone acetate tablets (alanine aminotransferase (ALT) or aspartate aminotransferase (AST) increases above 5 times the upper limit of normal or bilirubin increases above 3 times the upper limit of normal) treatment should be withheld immediately until liver function tests normalise (see Section 4.4 Special Warnings and Precautions for Use). Re‐treatment following return of liver function tests to the patient's baseline may be given at a reduced dose of 250 mg (two 125 mg tablets) once daily. For patients being re‐treated, serum transaminases and bilirubin should be monitored at a minimum of every two weeks for three months and monthly thereafter. If hepatotoxicity recurs at the reduced dose of 250 mg daily, discontinue treatment with abiraterone acetate.
If patients develop severe hepatotoxicity (ALT or AST 20 times the upper limit of normal) anytime while on therapy, abiraterone acetate tablets should be discontinued and patients should not be re‐treated with abiraterone acetate tablets.

4.3 Contraindications

Abiraterone acetate.

Abiraterone acetate is contraindicated in women who are or may potentially be pregnant.
Abiraterone acetate is contraindicated in patients with severe hepatic impairment [Child Pugh Class C].
Abiraterone acetate is contraindicated in combination with Xofigo (radium 223 dichloride; see Section 4.4 Special Warnings and Precautions for Use).
Known hypersensitivity to abiraterone acetate or any excipient in the formulation.

Methylprednisolone.

Known hypersensitivity to methylprednisolone or any excipient in the formulation.

4.4 Special Warnings and Precautions for Use

Lactose.

Yonsa abiraterone acetate tablets and methylprednisolone 4 mg tablets in Yonsa Mpred contain lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Abiraterone acetate.

Hypertension, hypokalaemia and fluid retention due to mineralocorticoid excess.

Abiraterone acetate should be used with caution in patients with a history of cardiovascular disease. The safety of abiraterone acetate in patients with left ventricular ejection fraction (LVEF) < 50% or New York Heart Association (NYHA) Class III or IV heart failure (in study 301) or NYHA Class II to IV heart failure (in studies 3011 and 302) was not established. Before treatment with abiraterone acetate, hypertension must be controlled and hypokalaemia must be corrected.
Abiraterone acetate may cause hypertension, hypokalaemia and fluid retention (see Section 4.8 Adverse Effects (Undesirable Effects)) as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition (see Section 5.1 Pharmacodynamic Properties). Co‐administration of a corticosteroid suppresses adrenocorticotropic hormone (ACTH) drive, resulting in a reduction in the incidence and severity of these adverse reactions. Caution is required in treating patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalaemia or fluid retention, e.g. those with heart failure, recent myocardial infarction or ventricular arrhythmia. In postmarketing experience, QT prolongation and torsades de pointes have been observed in patients who develop hypokalaemia or have underlying cardiovascular conditions while taking abiraterone acetate.
Blood pressure, serum potassium and fluid retention should be monitored at least monthly.

Hepatotoxicity.

Marked increases in liver enzymes leading to drug discontinuation or dosage modification occurred in controlled clinical studies (see Section 4.8 Adverse Effects (Undesirable Effects)). Very rarely, hepatitis fulminant and hepatic failure has been seen. Serum transaminase and bilirubin levels should be measured prior to starting treatment with abiraterone acetate, every two weeks for the first three months of treatment, and monthly thereafter. If clinical symptoms or signs suggestive of hepatotoxicity develop, serum transaminases, should be measured immediately. If at any time the ALT or AST rises above 5 times the upper limit of normal or the bilirubin rises above 3 times the upper limit of normal, treatment with abiraterone acetate should be interrupted immediately and liver function closely monitored.
Re‐treatment with abiraterone acetate tablets may only take place after the return of liver function tests to the patient's baseline and at a reduced dose level (see Section 4.2 Dose and Method of Administration).
If patients develop severe hepatotoxicity (ALT or AST 20 times the upper limit of normal) anytime while on therapy, abiraterone acetate should be discontinued and patients should not be re‐treated with abiraterone acetate.
Patients with active or symptomatic viral hepatitis were excluded from clinical trials; thus, there are no data to support the use of abiraterone acetate tablets in this population.
There are no data on the clinical safety and efficacy of multiple doses of abiraterone acetate when administered to patients with moderate or severe hepatic impairment (Child‐Pugh Class B or C). The use of abiraterone acetate tablets should be cautiously assessed in patients with moderate hepatic impairment, in whom the benefit clearly should outweigh the possible risk. Abiraterone acetate tablets should not be used in patients with severe hepatic impairment (see Section 4.3 Contraindications; Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties).

Hypoglycaemia.

Hypoglycaemia may occur when abiraterone plus methylprednisolone is administered to patients with pre-existing diabetes receiving pioglitazone or repaglinide (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Potential for abiraterone to affect exposures to other drugs). Blood glucose should be monitored in patients with diabetes.

Use with chemotherapy.

The safety and efficacy of concomitant use of abiraterone acetate with cytotoxic chemotherapy has not been established.

Use in combination with radium 223 dichloride.

In a randomised clinical trial in patients with asymptomatic or mildly symptomatic bone‐predominant metastatic castration resistant prostate cancer, at the time of unblinding, the addition of radium 223 dichloride to abiraterone acetate plus prednisone/prednisolone showed an increase in mortality and an increased rate of fracture. Radium 223 dichloride is not recommended for use in combination with Yonsa Mpred. It is recommended that subsequent treatment with radium 223 dichloride is not initiated for at least 5 days after the last administration of Yonsa Mpred.

Paediatric use.

This medicine is not for use in children.

Effects on laboratory tests.

No data available.

Methylprednisolone.

Corticosteroid withdrawal and coverage of stress situations.

Caution is advised and monitoring for adrenocortical insufficiency should occur if patients need to be withdrawn from methylprednisolone. If abiraterone acetate is continued after corticosteroids are withdrawn, patients should be monitored for symptoms of mineralocorticoid excess.
In patients on methylprednisolone who are subjected to unusual stress, increased dosage of a corticosteroid may be indicated before, during and after the stressful situation. 17α hydroxylase inhibition by abiraterone acetate decreases glucocorticoid production.

Hyperglycaemia.

The use of glucocorticoids could increase hyperglycaemia, therefore blood sugar should be measured frequently in patients with diabetes.

Immune system effects.

Allergic reactions may occur. Because rare instances of skin reactions and anaphylactic/anaphylactoid reactions have occurred in patients receiving corticosteroid therapy, appropriate precautionary measures should be taken prior to administration, especially when the patient has a history of allergy to any drug.

Cardiac effects.

Adverse effects of glucocorticoids on the cardiovascular system, such as dyslipidemia and hypertension, may predispose treated patients with existing cardiovascular risk factors to additional cardiovascular effects if high doses and/or prolonged courses are used. When using corticosteroids in these patients, attention should be paid to risk modification and additional cardiac monitoring should be considered.
Use of systemic corticosteroid is not recommended in patients with congestive heart failure.
Particular care is required when considering the use of systemic corticosteroids in patients with recent myocardial infarction (myocardial rupture has been reported) and frequent patient monitoring is necessary.
Care should be taken for patients receiving cardioactive drugs such as digoxin because of steroid induced electrolyte disturbance/potassium loss (see Section 4.8 Adverse Effects (Undesirable Effects)).

Vascular effects.

Thrombosis including venous thromboembolism has been reported to occur with corticosteroids. As a result corticosteroids should be used with caution in patients who have or may be predisposed to thromboembolic disorders.
Corticosteroids should be used with caution in patients with hypertension.

Endocrine effects.

Because glucocorticoids can produce or aggravate Cushing syndrome, glucocorticoids should be avoided in patients with Cushing disease.
There is an enhanced effect of corticosteroids in patients with hypothyroidism.
Pheochromocytoma crisis, which can be fatal, has been reported after administration of systemic corticosteroids. Corticosteroids should only be administered to patients with suspected or identified pheochromocytoma after an appropriate risk/benefit evaluation.

Hepatobiliary effects.

There is an enhanced effect of corticosteroids in patients with cirrhosis (see Section 4.2 Dose and Method of Administration, Recommended monitoring).

Ocular effects.

Corticosteroids should be used cautiously in patients with ocular herpes simplex because of possible corneal perforation.
Prolonged use of corticosteroids may produce posterior subcapsular cataracts and nuclear cataracts, exophthalmos or increased intraocular pressure which may result in glaucoma with possible damage to the optic nerves and may enhance the establishment of secondary ocular infections due to fungi or viruses.
Corticosteroid therapy has been associated with central serous chorioretinopathy, which may lead to retinal detachment.
If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes.

Psychiatric effects.

Psychic derangements may appear when corticosteroids are used, ranging from euphoria, insomnia, mood swings, personality changes and severe depression to frank psychotic manifestations. Also, existing emotional instability or psychotic tendencies may be aggravated by corticosteroids.
Potentially severe psychiatric adverse reactions may occur with systemic steroids (see Section 4.8 Adverse Effects (Undesirable Effects)). Symptoms typically emerge within a few days or weeks of starting treatment. Most reactions recover after either dose reduction or withdrawal, although specific treatment may be necessary.
Psychological effects have been reported upon withdrawal of corticosteroids; the frequency is unknown. Patients/caregivers should be encouraged to seek medical attention if psychological symptoms develop in the patient, especially if depressed mood or suicidal ideation is suspected. Patients/caregivers should be alert to possible psychiatric disturbances that may occur either during or immediately after dose tapering/withdrawal of systemic steroids.

Gastrointestinal effects.

Corticosteroid therapy may mask the symptoms of peptic ulcer so that perforation or hemorrhage may occur without significant pain. Glucocorticoid therapy may mask peritonitis or other signs or symptoms associated with gastrointestinal disorders such as perforation, obstruction or pancreatitis. In combination with NSAIDs, the risk of developing gastrointestinal ulcers is increased.
Corticosteroids should be used with caution in non‐specific ulcerative colitis if there is a probability of impending perforation, abscess, or other pyogenic infection, diverticulitis, fresh intestinal anastomoses, or active or latent peptic ulcer.

Nervous system effects.

Use of corticosteroids is not recommended in patients with seizure disorders.
Corticosteroids should be used with caution in patients with myasthenia gravis.

Use with NSAIDs.

Non‐steroidal anti‐inflammatory agents should be used cautiously in conjunction with corticosteroids (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Other.

In post marketing experience tumour lysis syndrome (TLS) has been reported in patients with malignancies, including haematological malignancies and solid tumours, following the use of systemic corticosteroids alone or in combination with other chemotherapeutic agents. Patients at high risk of TLS, such as patients with tumours that have a high proliferative rate, high tumour burden and high sensitivity to cytotoxic agents, should be monitored closely and appropriate precautions should be taken.

Use in renal impairment.

Caution is required in patients with systemic sclerosis because an increased incidence of scleroderma renal crisis has been observed with corticosteroids, including methylprednisolone. Corticosteroids should be used with caution in patients with renal insufficiency.

Use in the elderly.

Caution is recommended with prolonged corticosteroid treatment in the elderly due to a potential increased risk for osteoporosis, diabetes, susceptibility to infection and thinning of the skin, as well as increased risk for fluid retention with possible resultant hypertension.

Paediatric use.

No data available for use in combination with abiraterone acetate.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Abiraterone acetate.

In vitro studies. In vitro studies with human hepatic microsomes showed that abiraterone acetate is a strong inhibitor of CYP1A2, CYP2D6 and CYP2C8 and a moderate inhibitor of CYP2C9, CYP2C19 and CYP3A4/5. The major metabolites, abiraterone sulphate and N‐oxide abiraterone sulphate are also strong inhibitors of CYP2C8 in vitro. In vitro abiraterone acetate, abiraterone sulphate and N‐oxide abiraterone sulphate are inhibitors of OATP1B1. The clinical relevance of this inhibition is not clear.
Clinical studies.

CYP2D6.

In a study to determine the effects of abiraterone acetate (plus prednisone) on a single dose of the CYP2D6 substrate dextromethorphan, the systemic exposure (AUC) of dextromethorphan was increased approximately 200%. The AUC24 for dextrorphan, the active metabolite of dextromethorphan, increased approximately 33%.
Caution is advised when abiraterone acetate is administered with drugs activated by or metabolised by CYP2D6, particularly with drugs that have a narrow therapeutic index. Dose reduction of narrow therapeutic index drugs metabolised by CYP2D6 should be considered the same.

CYP3A4.

Abiraterone acetate is a substrate of CYP3A4. In a clinical pharmacokinetic interaction study of 20 healthy subjects pre‐treated with a strong CYP3A4 inducer (rifampicin, 600 mg daily for 6 days) followed by a single dose of 1000 mg of another abiraterone acetate product, the mean plasma Cmax and AUC∞ of abiraterone were decreased by 55%.
Strong inducers of CYP3A4 (e.g. phenytoin, carbamazepine, rifampicin, rifabutin, rifapentine, phenobarbital) during treatment with abiraterone acetate tablets are to be avoided, or used with careful evaluation of clinical efficacy, if there is no therapeutic alternative.
In a separate clinical pharmacokinetic interaction study of 19 healthy subjects, co‐administration of ketoconazole, a strong inhibitor of CYP3A4 (ketoconazole 400 mg for 6 days), had no clinically meaningful effect on the pharmacokinetics of abiraterone acetate.

CYP2C8.

In a CYP2C8 drug‐drug interaction trial in healthy subjects, the AUC of pioglitazone was increased by 46% and the AUCs for M‐III and M‐IV, the active metabolites of pioglitazone, each decreased by 10%, when pioglitazone was given together with a single dose of 1000 mg abiraterone acetate.
Patients should be monitored for signs of toxicity related to a CYP2C8 substrate with a narrow therapeutic index if used concomitantly with abiraterone acetate tablets. Examples of medicinal products metabolized by CYP2C8 include pioglitazone and repaglinide (see Section 4.4 Special Warnings and Precautions for Use, Hypoglycaemia).

CYP1A2.

In a clinical study to determine the effects of abiraterone acetate (plus prednisone) on a single dose of the CYP1A2 substrate theophylline, no increase in systemic exposure of theophylline was observed.
Use with spironolactone. Spironolactone binds to the androgen receptor and may increase prostate specific antigen (PSA) levels. Use with abiraterone acetate tablets is not recommended (see Section 5.1 Pharmacodynamic Properties, Pharmacodynamic effects).

Methylprednisolone.

Methylprednisolone has a wide spectrum of clinical use and is therefore used with numerous concurrent drugs. The interactions summarised in Table 1 and Table 2 are of known or likely clinical significance. The need for dosage adjustment of either medication will depend on the clinical situation, the dose regimen prescribed and the observed clinical response. The interactions listed have either pharmacokinetic or pharmacodynamic basis.
Methylprednisolone is a cytochrome P450 enzyme (CYP) substrate and is mainly metabolised by the CYP3A4 enzyme. CYP3A4 catalyses 6β‐hydroxylation of steroids, the essential Phase I metabolic step for both endogenous and synthetic corticosteroids. Many other compounds are also substrates of CYP3A4, some of which (as well as other drugs) have been shown to alter glucocorticoid metabolism by induction (upregulation) or inhibition of the CYP3A4 enzyme.

CYP3A4 inhibitors.

Drugs that inhibit CYP3A4 activity generally decrease hepatic clearance, resulting in increased plasma concentrations of corticosteroids. Co‐administration of these substances may require titration of corticosteroid dosage to reduce the risk of adverse effects and avoid steroid toxicity.

CYP3A4 inducers.

Drugs that induce CYP3A4 activity generally increase hepatic clearance, resulting in decreased plasma concentrations of corticosteroids. Coadministration of these substances may require an increase in corticosteroid dosage to achieve the desired result.

CYP3A4 substrates.

In the presence of another CYP3A4 substrate, the hepatic clearance of methylprednisolone may be affected, with corresponding dosage adjustments required. It is possible that adverse events associated with the use of either drug alone may be more likely to occur with coadministration.
The most common and/or clinically important drug interactions or effects resulting from co‐administration of methylprednisolone and examples of CYP3A4 inhibitors, inducers and substrates are provided in Table 1 and 2. Table 1 and 2 should be used in conjunction with the detailed information provided above.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Abiraterone acetate.

In fertility studies in both male and female rats (4‐and 3‐weeks), abiraterone acetate reduced fertility, which was completely reversible in 4 to 16 weeks after abiraterone acetate was stopped.
In studies in mice (4 weeks), rats (4 up to 26‐weeks) and monkeys (up to 39‐weeks), decreases in testosterone levels, atrophy, aspermia/hypospermia, and/or hyperplasia in the reproductive system were observed at > 125 mg/kg/day in mice, ≥ 30 mg/kg/day in rats and ≥ 250 mg/kg/day in monkeys and were consistent with the antiandrogenic pharmacological activity of abiraterone acetate. These effects were observed at exposure levels similar to or lower than the human clinical exposure, based on abiraterone AUC.

Methylprednisolone.

Animal studies on the effects of methylprednisolone did not show an adverse impact on fertility in male and female rats treated with methylprednisolone aceponate at subcutaneous doses up to 0.1 mg/kg/day, although there was an increase in the number of non‐viable fetuses. Other corticosteroids have been shown to impair fertility and reduce embryonic viability in studies in mice and rats.
(Category D)
Yonsa Mpred is contraindicated in women who are or may potentially be pregnant (see Section 4.3 Contraindications).

Abiraterone acetate.

There are no human data on the use of abiraterone acetate in pregnancy and abiraterone acetate is not for use in women of child‐bearing potential. Maternal use of a CYP17 inhibitor is expected to produce changes in hormone levels that could affect development of the fetus.
In an embryofetal developmental study in the rat, abiraterone acetate at ≥ 10 mg/kg/day affected pregnancy including reduced fetal weight and survival, delayed ossification, and increases in late resorptions and post implantation loss with a subsequent reduction in live fetuses. Effects on the external genitalia (decreased fetal ano‐genital distance) were observed though abiraterone acetate was not teratogenic.
In these fertility and developmental toxicity studies performed in the rat, all effects were related to the pharmacological activity of abiraterone acetate.
It is not known if abiraterone acetate or its metabolites are present in semen. A condom is required if the patient is engaged in sexual activity with a pregnant woman. If the patient is engaged in sex with a woman of child‐bearing potential, a condom is required along with another effective contraceptive method.
To avoid inadvertent exposure, women who are pregnant or women who may be pregnant should not handle abiraterone acetate tablets without protection, e.g. gloves.

Methylprednisolone.

There are no data for use of methylprednisolone in combination with abiraterone acetate in women.

Abiraterone acetate.

Abiraterone acetate tablets are not for use in women. It is not known if either abiraterone acetate or its metabolites are excreted in human breast milk.

Methylprednisolone.

There are no data for use of methylprednisolone in combination with abiraterone acetate in women.

4.7 Effects on Ability to Drive and Use Machines

Abiraterone acetate.

No studies on the effects of abiraterone acetate on the ability to drive or use machines have been performed. It is not anticipated that abiraterone acetate will affect the ability to drive and use machines.

Methylprednisolone.

The effect of corticosteroids on the ability to drive or use machinery has not been systematically evaluated. Undesirable effects, such as dizziness, vertigo, visual disturbances, and fatigue are possible after treatment with corticosteroids. If affected, patients should not drive or operate machinery.

4.8 Adverse Effects (Undesirable Effects)

Abiraterone acetate.

Adverse drug reactions from clinical trials. In an analysis of adverse reactions of composite Phase 3 studies with abiraterone acetate, adverse reactions that were observed in ≥ 10% of patients were peripheral oedema, hypokalaemia, hypertension, urinary tract infection, and alanine aminotransferase increased, and/or aspartate aminotransferase increased.
Abiraterone acetate may cause hypertension, hypokalaemia and fluid retention as a pharmacodynamic consequence of its mechanism of action. In Phase 3 studies anticipated mineralocorticoid effects were seen more commonly in patients treated with abiraterone acetate versus patients treated with placebo; hypokalaemia 18% versus 8%, hypertension 22% versus 16% and fluid retention (peripheral oedema) 23% versus 17%, respectively. Grades 3/4 hypokalaemia were observed in 6% versus 1%, grades 3/4 hypertension were observed in 7% versus 5%, and grades 3/4 fluid retention oedema were observed in 1% versus 1% of patients treated with abiraterone acetate versus patients treated with placebo, respectively. Mineralocorticoid effects generally were able to be successfully managed medically. Concomitant use of a corticosteroid reduces the incidence and severity of these adverse drug reactions (see Section 4.4 Special Warnings and Precautions for Use).
In a Phase 3 study of patients with newly diagnosed high‐risk mHNPC or mHSPC (Study 3011) who were receiving and remained on ADT (a luteinising hormone‐releasing hormone [LHRH] agonist or orchiectomy), abiraterone acetate was administered at a dose equivalent to 500 mg of Yonsa (abiraterone acetate tablets contained in Yonsa Mpred) once daily in combination with low dose prednisone (5 mg daily) and ADT in the active treatment arm; ADT and placebo were given to control patients. The median duration of treatment with abiraterone acetate was 24 months.
Adverse reactions that occurred at a rate of ≥ 1% (all grades) are shown in Table 3.
In a Phase 3 study of patients with metastatic castration resistant prostate cancer who had received prior chemotherapy (study 301) who were using a LHRH agonist, or were previously treated with orchiectomy, abiraterone acetate was administered at a dose equivalent to 500 mg of Yonsa (abiraterone acetate tablets contained in Yonsa Mpred) once daily in combination with low dose prednisone or prednisolone (10 mg daily) in the active treatment arm; placebo plus low dose prednisone or prednisolone (10 mg daily) was given to control patients. Patients were intolerant to or had failed up to two prior chemotherapy regimens, one of which contained a taxane. The average duration of treatment with abiraterone acetate was 8 months.
Adverse drug reactions that occurred at a rate of ≥ 1% (all grades) are shown in Table 4.
In a second placebo‐controlled, multicentre Phase 3 clinical study (study 302), in asymptomatic or mildly symptomatic, chemotherapy naïve patients with metastatic advanced prostate cancer who were using a LHRH agonist or were previously treated with orchiectomy, abiraterone acetate was also administered at a dose equivalent to 500 mg of Yonsa (abiraterone acetate tablets contained in Yonsa Mpred) once daily in combination with low dose prednisone or prednisolone 10 mg daily in the active treatment arm. Placebo plus low dose prednisone or prednisolone 10 mg daily was given to control patients. The average duration of treatment with abiraterone acetate in study 302 was 13.8 months.
Adverse drug reactions that occurred at a rate of ≥ 1% (all grades) are shown in Table 5.
The most common adverse drug reactions that resulted in drug discontinuation in combined data from phase 3 studies were alanine aminotransferase increased, aspartate aminotransferase increased, and hypokalaemia (each in < 1% of patients taking abiraterone acetate).
The adverse drug reaction, adrenal insufficiency, occurred in the Phase 3 clinical studies at a rate 0.3% in patients taking abiraterone acetate and at a rate of 0.1% inpatients taking placebo.
In the Phase 3 studies, 70% of patients were 65 years and over, and 27% were 75 years and over for patients taking abiraterone acetate. Adverse effects were more common in patients ≥ 75 years old in both the abiraterone acetate and placebo groups.
Cardiovascular effects. The three Phase 3 studies excluded patients with uncontrolled hypertension, clinically significant heart disease as evidenced by myocardial infarction, arterial thrombotic events in the past 6 months, severe or unstable angina, or NYHA Class III or IV heart failure (study 301) or Class II to IV heart failure (studies 3011 and 302) or cardiac ejection fraction measurement of < 50%. All patients enrolled (both active and placebo‐treated patients) were concomitantly treated with androgen deprivation therapy, predominately with the use of LHRH agonists, which has been associated with diabetes, myocardial infarction, cerebrovascular accident and sudden cardiac death. The incidence of cardiovascular adverse reactions in the Phase 3 studies in patients taking abiraterone acetate versus patients taking placebo were as follows: atrial fibrillation 2.6% vs. 2.0%, tachycardia 1.9% vs. 1.0%, angina pectoris 1.7% vs. 0.8%, cardiac failure 0.7% vs. 0.2% and arrhythmia 0.7% vs. 0.5%.
Hepatotoxicity. Drug‐associated hepatotoxicity with elevated ALT, AST and total bilirubin has been reported in patients treated with abiraterone acetate. Across Phase 3 clinical studies, hepatotoxicity grades 3 and 4 (e.g. ALT or AST increases of > 5 X ULN or bilirubin increases > 1.5 X ULN) were reported in approximately 4% of patients who received abiraterone acetate, typically during the first 3 months after starting treatment. In Study 3011, grade 3 or 4 hepatotoxicity was observed in 8.4% of patients treated with abiraterone acetate. Ten patients who received abiraterone acetate were discontinued because of hepatotoxicity; two had Grade 2 hepatotoxicity, six had Grade 3 hepatotoxicity, and two had Grade 4 hepatotoxicity. No patient died of hepatotoxicity in Study 3011. In the 301 clinical study, patients whose baseline ALT or AST were elevated were more likely to experience liver function test elevations than those beginning with normal values. When elevations of either ALT or AST > 5 X ULN, or elevations in bilirubin > 3 X ULN were observed, abiraterone acetate was withheld or discontinued. Hepatic metastases and baseline elevations in alkaline phosphatase associated with prostate cancer were present in a few of these patients. In two instances marked increases in liver function tests occurred (see Section 4.4 Special Warnings and Precautions for Use). These two patients with normal baseline hepatic function, experienced ALT or AST elevations 15 to 40 X ULN and bilirubin elevations 2 to 6 X ULN. Upon discontinuation of abiraterone acetate, both patients had normalisation of their liver function tests and one patient was re‐treated with abiraterone acetate without recurrence of the elevations. In study 302, grade 3 or 4 ALT or AST elevations were observed in 35 (6.5%) patients treated with abiraterone acetate. Aminotransferase elevations resolved in all but 3 patients (2 with new multiple liver metastases and 1 with AST elevation approximately 3 weeks after the last dose of abiraterone acetate). In Phase 3 clinical studies, treatment discontinuations due to ALT and AST increases or abnormal hepatic function were reported in 1.1% of patients treated with abiraterone acetate and 0.6% of patients treated with placebo. No deaths were reported due to hepatotoxicity events.
In clinical trials, the risk for hepatotoxicity was mitigated by exclusion of patients with baseline hepatitis or significant abnormalities of liver function tests. In the 3011 trial, patients with baseline ALT and AST > 2.5 X ULN, bilirubin > 1.5 X ULN or those with active or symptomatic viral hepatitis or chronic liver disease; ascites or bleeding disorders secondary to hepatic dysfunction were excluded. In the 301 trial, patients with baseline ALT and AST ≥ 2.5 X ULN in the absence of liver metastases and > 5 X ULN in the presence of liver metastases were excluded. In the 302 trial patients with liver metastases were not eligible and patients with baseline ALT and AST ≥ 2.5 X ULN were excluded. Abnormal liver function tests developing in patients participating in clinical trials were vigorously managed by requiring treatment interruption and permitting re‐treatment only after return of liver function tests to the patient's baseline (see Section 4.2 Dose and Method of Administration). Patients with elevations of ALT or AST > 20 X ULN were not re‐treated. The safety of re‐treatment in such patients is unknown. The mechanism for hepatotoxicity associated with abiraterone acetate is not understood.
Post‐marketing data. Adverse drug reactions identified during the post‐marketing experience based on spontaneous reports with abiraterone acetate used with a different corticosteroid are described below. The frequencies are provided according to the following convention:
Very common: ≥ 1/10; common: ≥ 1/100 and < 1/10; uncommon: ≥ 1/1,000 and < 1/100; rare: ≥ 1/10,000 and < 1/1,000; very rare: < 1/10,000; isolated reports: frequency unknown.

System organ class: respiratory, thoracic and mediastinal disorders.

Rare: allergic alveolitis.

System organ class: musculoskeletal and connective tissue disorders.

Uncommon: rhabdomyolysis, myopathy.

System organ class: gastrointestinal disorders.

Very common: diarrhoea.

System organ class: hepatobiliary disorders.

Very rare: hepatitis fulminant, hepatic failure.

System organ class: cardiac disorders.

Very rare: QT prolongation and torsades de pointes (observed in patients who developed hypokalaemia or had underlying cardiovascular conditions).

System organ class: immune system disorders - hypersensitivity.

Very rare: anaphylactic reaction (severe allergic reactions that include, but are not limited to difficulty swallowing or breathing, swollen face, lips, tongue or throat, or an itchy rash (urticaria)).

Methylprednisolone.

The adverse effects listed in Table 6 are typical for all systemic corticosteroids. Their inclusion in this list does not necessarily indicate that the specific event has been observed with methylprednisolone in combination with abiraterone acetate tablets.
The adverse effects are listed below by system organ class and frequency. Common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); not known (frequency cannot be estimated from the available data).

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

Abiraterone acetate.

Human experience of overdose with abiraterone acetate tablets is limited. There is no specific antidote. In the event of an overdose, stop abiraterone acetate tablets, undertake general supportive measures, including monitoring for arrhythmias and cardiac failure and assess liver function.

Methylprednisolone.

Reports of acute toxicity and metabolic disturbances with glucocorticoids are rare but do occur. There is no clinical syndrome of acute overdosage with methylprednisolone. Acute overdose may possibly aggravate pre‐existing disease states such as ulceration of the gastrointestinal tract, electrolyte disturbances, infections, diabetes and oedema. Repeated high doses of methylprednisolone have caused hepatic necrosis and an increase in amylase. Bradyarrhythmias, ventricular arrhythmias and cardiac arrest have been observed in cases of intravenous administration of high doses of methylprednisolone.
Repeated frequent doses (daily or several times per week) over a protracted period may result in a Cushingoid state. The possibility of adrenal suppression should be guarded against by gradual diminution of dose levels over a period of time.
In the event of an overdose, treatment is symptomatic and supportive, including respiratory and cardiovascular function. In chronic toxicity, fluids and electrolytes should be monitored closely. Serum levels are not clinically useful.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Abiraterone acetate.

Mechanism of action.

Abiraterone acetate is converted in vivo to abiraterone, an androgen biosynthesis inhibitor. Specifically, abiraterone selectively inhibits the enzyme 17α hydroxylase/C17,20‐lyase (CYP17). This enzyme is expressed in and is required for androgen biosynthesis in testicular, adrenal and in prostatic tumour tissues. It catalyses the conversion of pregnenolone and progesterone into testosterone precursors, DHEA and androstenedione, respectively, by 17α hydroxylation and cleavage of the C17,20 bond. CYP17 inhibition also results in increased mineralocorticoid production by the adrenals (see Section 4.4 Special Warnings and Precautions for Use).
Androgen‐sensitive prostatic carcinoma responds to treatment that decreases androgen levels. Androgen deprivation therapies, such as treatment with luteinising hormone‐releasing hormone (LHRH) agonists or orchiectomy, decrease androgen production in the testes but do not affect androgen production by the adrenals or in the tumour. Treatment with abiraterone acetate decreases serum testosterone to undetectable levels (using commercial assays) when given with LHRH agonists (or orchiectomy).

Pharmacodynamic effects.

Abiraterone acetate decreases serum testosterone and other androgens to levels lower than those achieved by the use of LHRH agonists alone or by orchiectomy. Prostate specific antigen (PSA) serves as a biomarker in patients with prostate cancer. In a Phase 3 clinical study of patients who failed prior chemotherapy with taxanes, 29% of patients treated with abiraterone acetate, versus 6% of patients treated with placebo, had at least a 50% decline from baseline in PSA levels.

Use of spironolactone.

Patients in pivotal clinical trials with abiraterone acetate were not allowed to use spironolactone as spironolactone binds to the androgen receptor and may increase PSA levels.

Effects on the QT interval.

In a cardiovascular safety study in patients with metastatic advanced prostate cancer there were no significant effects of abiraterone acetate on the cardiac QT/QTc interval.

Clinical trials.

The efficacy of abiraterone acetate was established in three randomised placebo controlled multicentre Phase 3 clinical studies (studies 3011, 301 and 302) of patients with hormone naïve metastatic prostate cancer and metastatic castration resistant prostate cancer.
Study 3011 enrolled patients who were newly diagnosed (within 3 months of randomisation) mHNPC who had high‐risk prognostic factors. High‐risk prognosis was defined as having at least 2 of the following 3 risk factors: (1) Gleason score of ≥ 8; (2) presence of 3 or more lesions on bone scan; (3) presence of measurable visceral (excluding lymph node disease) metastasis. In the active arm, abiraterone acetate was administered at a dose equivalent to 500 mg of Yonsa (abiraterone acetate tablets contained in Yonsa Mpred) once daily in combination with low dose prednisone 5 mg once daily in addition to ADT (LHRH agonist or orchiectomy), which was the standard of care treatment. Patients in the control arm received ADT and placebos for both abiraterone acetate and prednisone.
Study 302 enrolled patients who were asymptomatic or mildly symptomatic and had not received prior chemotherapy, whereas study 301 enrolled patients who received prior chemotherapy containing a taxane. In both studies patients were using a LHRH agonist or were previously treated with orchiectomy. In the active treatment arms, abiraterone acetate was administered at a dose equivalent to 500 mg of Yonsa (abiraterone acetate tablets contained in Yonsa Mpred) once daily in combination with low dose prednisone or prednisolone 5 mg twice daily. Control patients received placebo and low dose prednisone or prednisolone 5 mg twice daily.
Because changes in PSA serum concentration do not always predict clinical benefit, in all studies patients were maintained on abiraterone acetate until specific discontinuation criteria were met for each study below.
Study 3011 (patients with newly diagnosed high‐risk metastatic hormone naïve prostate cancer (mHNPC) or hormone sensitive prostate cancer (mHSPC). In Study 3011, (n=1199) the median age of enrolled patients was 67 years. The ECOG performance status was 0 or 1 for 97% of patients. Patients with uncontrolled hypertension, significant heart disease, or NYHA Class II or worse heart failure were excluded. Co‐primary efficacy endpoints were overall survival (OS) and radiographic progression‐free survival (rPFS). The median baseline pain score, as measured by the Brief Pain Inventory Short Form (BPI‐SF) was 2.0 in both the treatment and placebo groups. In addition to the co primary endpoint measures, benefit was also assessed using time to skeletal‐related event (SRE), time to subsequent therapy for prostate cancer, time to initiation of chemotherapy, time to pain progression and time to PSA progression.
In the 3011 study, treatment continued until disease progression, withdrawal of consent, the occurrence of unacceptable toxicity, or death.
Radiographic progression‐free survival was defined as the time from randomisation to the occurrence of radiographic progression or death from any cause.
Radiographic progression included progression by bone scan (according to modified PCWG2) or progression of soft tissue lesions by CT or MRI (according to RECIS 1.1).
At the planned rPFS analysis there were 593 events; 239 (40.0%) of patients treated with abiraterone acetate and 354 (58.8%) of patients treated with placebo had radiographic evidence of progression or had died. A significant difference in rPFS between treatment groups was observed (see Table 7 and Figure 1).
At the planned first interim analysis (IA‐1) for overall survival, four hundred and six (406; 47.7% of the total number of deaths required at the final analysis) deaths had occurred (169 subjects in the AA‐P group and 237 subjects in the placebo group). A statistically significant improvement in OS in favour of AA‐P plus ADT was observed with a 38% reduction in the risk of death (HR=0.621; 95% CI: 0.509, 0.756) compared to placebo plus ADT. Median survival was not reached in the AA‐P group versus 34.7 months in the placebo group (p < 0.0001, crossing the pre‐specified boundary for OS at Interim Analysis 1 of 0.010) (see Table 8 and Figure 2). The study was un‐blinded based on the magnitude of clinical benefit observed and patients in the placebo group were offered treatment with abiraterone acetate. Survival continued to be followed after this IA.
Subgroup analyses consistently favour treatment with abiraterone acetate (see Figure 3).
In addition to the observed improvements in overall survival and rPFS, benefit was demonstrated for abiraterone acetate vs placebo treatment in all prospectively defined secondary endpoint measures as follows:

Time to skeletal‐related event (SRE).

There was a 30% reduction in the risk of skeletal‐related events (HR = 0.703; 95% CI: [0.539, 0.916] p < 0.0086). The median time to SRE has not been reached for the abiraterone acetate or placebo study arm.

Time to PSA progression based on PCWG2 criteria.

The median time to PSA progression was 33.2 months for patients receiving abiraterone acetate and 7.4 months for patients receiving placebo (HR = 0.299; 95% CI: [0.255, 0.352], p < 0.0001).

Time to subsequent therapy.

The median time to subsequent therapy at the time of interim analysis was not reached for patients receiving abiraterone acetate and was 21.6 months for patients receiving placebo (HR = 0.415; 95% CI: [0.346, 0.497], p < 0.0001).

Time to initiation of chemotherapy.

The median time to initiation of chemotherapy was not reached for patients receiving abiraterone acetate and was 38.9 months for patients receiving placebo (HR = 0.443; 95% CI: [0.349, 0.561], p < 0.0001).

Time to pain progression.

The median time to pain progression was not reached for patients receiving abiraterone acetate and was 16.6 months for patients receiving placebo (HR = 0.695; 95% CI: [0.583, 0.829], p = < 0.0001).
The majority of exploratory endpoints favored treatment with abiraterone acetate and prednisone (AA‐P) over placebo. A statistically significant improvement in prostate cancer‐specific OS was observed for AA‐P treatment compared with placebo (HR=0.547, p < 0.0001). A confirmed PSA response was observed in 91.0% of subjects in the AA‐P group and 66.8% of subjects in the placebo group (relative risk=1.362; p < 0.0001). The overall response rate (complete plus partial response) in subjects with measurable disease at baseline was significantly higher in the AA‐P group compared with those in the placebo group (p=0.0002).
The time to degradation analyses of patient reported outcome (PRO) measures consistently demonstrated that treatment with AA‐P delayed degradation and progression of pain, functional status, fatigue and health‐related quality of life. Based on the change from baseline using repeated measures mixed‐effect model statistically significant differences were observed between AA‐P and placebo as early as Cycle 2 and maintained throughout the study.
Study 302 (asymptomatic or mildly symptomatic patients who did not receive prior chemotherapy). In study 302, (n=1088) the median age of enrolled patients was 71 years for patients treated with abiraterone acetate plus prednisone or prednisolone and 70 years for patients treated with placebo plus prednisone or prednisolone. The ECOG performance status was 0 for 76% of patients, and 1 for 24% of patients in both arms. Co‐primary efficacy endpoints were overall survival and radiographic progression free survival (rPFS). In addition to the co‐primary endpoint measures, benefit was also assessed using time to opiate use for cancer pain, time to initiation of cytotoxic chemotherapy, time to deterioration in ECOG performance score by ≥ 1 point and time to PSA progression based on Prostate Cancer Working Group‐2 (PCWG2) criteria.
In study 302, treatments were discontinued at the time of unequivocal clinical progression. Treatments could also be discontinued at the time of confirmed radiographic progression at the discretion of the investigator. Patients should not be discontinued based on PSA progression alone and should remain on treatment until fully confirmed clinical progression utilising multiple assessment criteria.
Radiographic progression free survival was assessed with the use of sequential imaging studies as defined by PCWG2 criteria (for bone lesions) and modified Response Evaluation Criteria in Solid Tumours (RECIST) criteria (for soft tissue lesions). PCWG2 criteria require a confirmatory bone scan to document progression. Analysis of rPFS utilised centrally‐reviewed radiographic assessment of progression.
At the planned rPFS analysis there were 401 radiographic progression events; 150 (28%) of patients treated with abiraterone acetate and 251 (46%) of patients treated with placebo had radiographic evidence of progression or had died. A significant difference in rPFS between treatment groups was observed (see Table 9 and Figure 4).
Subgroup analyses of rPFS are presented in Figure 5. The treatment effect of abiraterone acetate on the co‐primary endpoint of the independent review of rPFS was consistently favourable and highly robust across all subgroups.
A planned interim analysis for overall survival was conducted after 333 deaths were observed. The study was unblinded, following the recommendation of the Independent Data Monitoring Committee (IDMC), based on the magnitude of clinical benefit observed. Twenty seven percent (147 of 546) of patients treated with abiraterone acetate, compared with 34% (186 of 542) of patients treated with placebo, had died. Overall survival was longer for abiraterone acetate than placebo with a 25% reduction in risk of death (Hazard Ratio = 0.752; 95% CI: 0.606‐0.934). The p value was 0.0097 which did not meet the pre‐specified level (0.0008) to claim statistical significance (see Table 10 and Figure 6).
Subgroup analyses of overall survival are presented in Figure 7. The treatment effect of abiraterone acetate on overall survival was favorable across all subgroups (all HR < 1.0).
In addition to the observed improvements in overall survival and rPFS, benefit was demonstrated for abiraterone acetate versus placebo treatment in all the secondary endpoint measures as follows.

Time to PSA progression based on PCWG2 criteria.

Median time to PSA progression was 11.1 months for patients receiving abiraterone acetate and 5.6 months for patients receiving placebo (HR=0.488; 95%CI: [0.420, 0.568], p < 0.0001). Time to PSA progression was approximately doubled with abiraterone acetate treatment. The proportion of subjects with a confirmed PSA response was greater in the abiraterone acetate group than in the placebo group (62% versus 24%; p < 0.0001).

Time to opiate use for cancer pain.

The median time to opiate use for prostate cancer pain was not reached for patients receiving abiraterone acetate and was 23.7 months for patients receiving placebo (HR=0.686; 95%CI: [0.566, 0.833], p=0.0001).

Time to initiation of cytotoxic chemotherapy.

The median time to initiation of cytotoxic chemotherapy was 25.2 months for patients receiving abiraterone acetate and 16.8 months for patients receiving placebo (HR=0.580; 95% CI: [0.487, 0.691], p < 0.0001).

Time to deterioration in ECOG performance score by ≥ 1 point.

The median time to deterioration in ECOG performance score by ≥ 1 point was 12.3 months for patients receiving abiraterone acetate and 10.9 months for patients receiving placebo (HR=0.821; 95% CI: [0.714, 0.943], p=0.0053).
The following study endpoints demonstrated a statistically significant advantage in favour of abiraterone acetate treatment:

Objective response.

Objective response was defined as the proportion of subjects with measurable disease achieving a complete or partial response according to RECIST criteria (baseline lymph node size was required to be ≥ 2 cm to be considered a target lesion). The proportion of subjects with measurable disease at baseline who had an objective response was 36% in the abiraterone acetate group and 16% in the placebo group (p < 0.0001).

Pain.

Treatment with abiraterone acetate significantly reduced the risk of average pain intensity progression by 18% compared with placebo (p=0.0490). The median time to progression was 26.7 months in the abiraterone acetate group and 18.4 months in the placebo group.

Time to degradation in the FACT‐P (total score).

Treatment with abiraterone acetate decreased the risk of FACT‐P (Total Score) degradation by 22% compared with placebo (p=0.0028). The median time to degradation in FACT‐P (Total Score) was 12.7 months in the abiraterone acetate group and 8.3 months in the placebo group.
Study 301 (patients who had received prior chemotherapy). Eleven percent of patients enrolled in study 301 had an ECOG performance score of 2; 70% had radiographic evidence of disease progression with or without PSA progression; 70% had received one prior cytotoxic chemotherapy and 30% received two. Liver metastasis was present in 11% of patients treated with abiraterone acetate.
It was recommended that patients be maintained on their study drugs until there was PSA progression (confirmed 25% increase over the patient's baseline/nadir) together with protocol‐ defined radiographic progression and symptomatic or clinical progression. The primary efficacy endpoint was overall survival.
In a planned analysis conducted after 552 deaths were observed, 42% (333 of 797) of patients treated with abiraterone acetate compared with 55% (219 of 398) of patients treated with placebo had died. A statistically significant improvement in median overall survival was seen in patients treated with abiraterone acetate (see Table 11).
At all evaluation time points after the initial few months of treatment, a higher proportion of patients treated with abiraterone acetate remained alive compared with the proportion of patients treated with placebo (see Figure 8).
Subgroup survival analyses showed a consistent survival benefit for treatment with abiraterone acetate (see Figure 9).
In addition to the observed improvement in overall survival, all secondary study endpoints favoured abiraterone acetate and were statistically significant after adjusting for multiple testing as follows.
Patients receiving abiraterone acetate demonstrated a significantly higher total PSA response rate (defined as a ≥ 50% reduction from baseline), compared with patients receiving placebo: 29% versus 6%, p < 0.0001.
The median time to PSA progression was 10.2 months for patients treated with abiraterone acetate and 6.6 months for patients treated with placebo (HR= 0.580; 95% CI: [0.462, 0.728], p < 0.0001).
The median radiographic progression free survival was 5.6 months for patients treated with abiraterone acetate and 3.6 months for patients who received placebo (HR= 0.673; 95% CI: [0.585, 0.776], p < 0.0001).

Pain.

The proportion of patients with pain palliation was statistically significantly higher in the abiraterone acetate group than in the placebo group (44% versus 27%, p=0.0002).
A lower proportion of patients treated with abiraterone acetate had pain progression compared to patients taking placebo at 6 (22% vs. 28%), 12 (30% vs. 38%) and 18 months (35% vs. 46%). The time to pain progression at the 25th percentile was 7.4 months in the abiraterone acetate group, versus 4.7 months in the placebo group.

Skeletal‐related events.

A lower proportion of patients in the abiraterone acetate group had skeletal‐related events compared with the placebo group at 6 months (18% vs. 28%), 12 months (30% vs 40%), and 18 months (35% vs. 40%). The time to first skeletal‐related event at the 25th percentile in the abiraterone acetate group was twice that of the control group at 9.9 months vs 4.9 months.

Methylprednisolone.

Mechanism of action.

Naturally occurring glucocorticoids (hydrocortisone), which also have salt‐retaining properties, are used in replacement therapy in adrenocortical deficiency states. Their synthetic analogues are used primarily for their potent anti‐inflammatory effects in disorders of many organ systems. Glucocorticoids cause profound and varied metabolic effects. In addition, they modify the body's immune response to diverse stimuli.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Abiraterone acetate.

Following administration of abiraterone acetate, the pharmacokinetics of abiraterone and abiraterone acetate have been studied in healthy subjects, patients with metastatic advanced prostate cancer and subjects without cancer with hepatic or renal impairment. Abiraterone acetate is rapidly converted in vivo to abiraterone.
Geometric mean ±SD abiraterone Cmax was 73 ± 44 nanogram/mL and AUCINF was 373 ± 249 nanogram.hr/mL following a single dose of abiraterone 500 mg in overnight fasted healthy volunteers. Dose proportionality was observed in single doses of abiraterone in a range of 125 mg to 625 mg.
Absorption. Following oral administration of abiraterone to healthy volunteers and patients with metastatic CRPC, the mean time to reach maximum plasma abiraterone concentrations is approximately 2 hours.

Effect of food.

Abiraterone Cmax was approximately 6.5‐fold higher and AUC0‐∞ was 4.4‐fold higher when a single dose of abiraterone tablets 500 mg was administered with a high‐fat meal (56‐60% fat, 900‐1000 calories) compared to overnight fasting in healthy volunteers. These differences are not considered significant and abiraterone can be taken with or without food (see Section 4.2 Dosage and Method of Administration).
Other formulations of abiraterone acetate may differ in their food effects and dose. This may impact the ability to take other abiraterone acetate formulations with food.
Distribution. The plasma protein binding of 14C abiraterone in human plasma is 99.8%. The apparent volume of distribution is approximately 5630 L, suggesting that abiraterone extensively distributes to peripheral tissues.
Metabolism. Following oral administration of 14C‐abiraterone acetate as capsules, abiraterone acetate is hydrolysed to abiraterone, which then undergoes metabolism including sulphation, hydroxylation and oxidation primarily in the liver. The majority of circulating radioactivity (approximately 92%) is found in the form of metabolites of abiraterone. Of 15 detectable metabolites, 2 main metabolites, abiraterone sulphate and N‐oxide abiraterone sulphate, each represent approximately 43% of total radioactivity.
The major enzymes involved in the metabolism of abiraterone are CYP3A4 for phase I (oxidative) metabolites, the sulfotransferase (SULT) isozyme SULT2A1, and UDP‐glucuronosyl transferase (UGT) UGT1A4. No studies have been conducted to determine if drugs that induce or inhibit these enzymes affect the metabolism of abiraterone.
Excretion. The mean half‐life of abiraterone in plasma is approximately 15 hours based on data from healthy subjects. Following oral administration of 14C abiraterone acetate, approximately 88% of the radioactive dose is recovered in faeces and approximately 5% in urine. The major compounds present in faeces are unchanged abiraterone acetate and abiraterone (approximately 55% and 22% of the administered dose, respectively).
Additional information on special populations.

Hepatic impairment.

The pharmacokinetics of abiraterone acetate was examined in subjects with pre‐existing mild or moderate hepatic impairment (Child‐Pugh class A and B, respectively) and in healthy control subjects. Systemic exposure to abiraterone after a single oral 1000 mg dose of another abiraterone acetate product increased by approximately 11% and 260% in subjects with mild and moderate pre‐existing hepatic impairment, respectively. The mean half‐life of abiraterone is prolonged to approximately 18 hours in subjects with mild hepatic impairment and to approximately 19 hours in subjects with moderate hepatic impairment. No dosage adjustment is necessary for patients with pre‐existing mild hepatic impairment. There are no data on the clinical safety and efficacy of multiple doses of abiraterone acetate when administered to patients with moderate or severe hepatic impairment (Child‐Pugh Class B or C). No dose adjustment can be predicted. Abiraterone acetate tablets should be used with caution in patients with moderate hepatic impairment, only if the benefit clearly outweighs the possible risk. Abiraterone acetate tablets should not be used in patients with pre‐ existing severe hepatic impairment (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use; Section 4.2 Dose and Method of Administration).
For patients who develop hepatotoxicity during treatment with abiraterone acetate, suspension of treatment and dosage adjustment may be required (see Section 4.4 Special Warnings and Precautions for Use; Section 4.2 Dose and Method of Administration).

Renal impairment.

The pharmacokinetics of abiraterone acetate was compared in patients with end‐stage renal disease on a stable haemodialysis schedule versus matched control subjects with normal renal function. Systemic exposure to abiraterone after a single oral 1000 mg dose of another abiraterone acetate product did not increase in patients with end‐stage renal disease on dialysis.
Administration of abiraterone acetate in patients with renal impairment including severe renal impairment does not require dose reduction (see Section 4.2 Dose and Method of Administration).

Methylprednisolone.

Methylprednisolone pharmacokinetics are linear, independent of route of administration.

Absorption.

Methylprednisolone is rapidly absorbed and the maximum plasma methylprednisolone concentration is achieved around 1.5 to 2.3 hours across doses following oral administration in normal healthy adults. The absolute bioavailability of methylprednisolone in normal healthy subjects is generally high (82% to 89%) following oral administration.
The mean oral time of peak concentration is 1.1 ‐ 2.2 hours.

Distribution.

Methylprednisolone is widely distributed into the tissues, crosses the blood‐brain barrier, and is secreted in breast milk. Its apparent volume of distribution is approximately 1.4 L/kg.
The plasma protein binding of methylprednisolone in humans is approximately 77%.

Metabolism.

Corticosteroids are metabolised mainly in the liver but also in the kidney and are excreted in the urine.
In humans, methylprednisolone is metabolized in the liver to inactive metabolites; the major ones are 20α-hydroxymethylprednisolone and 20β‐hydroxymethylprednisolone. Metabolism in the liver occurs primarily via the CYP3A4 enzyme. Methylprednisolone, like many CYP3A4 substrates, may also be a substrate for the ATP‐binding cassette (ABC) transport protein p‐glycoprotein, influencing tissue distribution and interactions with other medicines.

Excretion.

The mean elimination half‐life for total methylprednisolone is in the range of 1.8 to 5.2 hours. Total clearance is approximately 5 to 6 mL/min/kg.

5.3 Preclinical Safety Data

Abiraterone acetate.

Genotoxicity.

Abiraterone acetate and abiraterone were devoid of genotoxic potential in the standard panel of genotoxicity tests including, an in vitro bacterial reverse mutation assay (the Ames test), an in vitro mammalian chromosome aberration test (using human lymphocytes) and an in vivo rat micronucleus assay. Genotoxicity studies have not been conducted with the main human metabolites of abiraterone.

Carcinogenicity.

Carcinogenicity studies were not conducted with abiraterone acetate.

Methylprednisolone.

Genotoxicity.

Methylprednisolone acetate has not been formally evaluated for genotoxicity. However, methylprednisolone sulfonate, which is structurally similar to methylprednisolone, was not mutagenic in bacteria (Ames test), or in a mammalian cell gene mutation assay using Chinese hamster ovary cells. Methylprednisolone suleptanate did not induce unscheduled DNA synthesis in primary rat hepatocytes. Prednisolone farnesylate, which is also structurally similar to methylprednisolone, was not mutagenic in bacteria, but displayed weak clastogenic activity in vitro in Chinese hamster lung fibroblasts in the presence of metabolic activation.

Carcinogenicity.

Methylprednisolone has not been formally evaluated in rodent carcinogenicity studies. Negative results for carcinogenicity have been obtained with various other glucocorticoids including budesonide, prednisolone and triamcinolone acetonide, in mice. However, all three of these compounds were shown to increase the incidence of hepatocellular adenomas and carcinomas after oral administration in a 2‐year study in male rats. These tumorigenic effects occurred at doses that are less than the typical clinical doses on a mg/m2 basis. Hepatocarcinogenicity is likely to involve an interaction with the glucocorticoid receptor.

6 Pharmaceutical Particulars

6.1 List of Excipients

Yonsa abiraterone acetate 125 mg tablets.

Lactose monohydrate, sodium lauryl sulfate, butylated hydroxyanisole, butylated hydroxytoluene, microcrystalline cellulose, croscarmellose sodium, sodium stearyl fumarate.

Methylprednisolone 4 mg tablets.

Lactose monohydrate, maize starch, gelatin, magnesium stearate, talc.

6.2 Incompatibilities

Not applicable.

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 at or below 25°C.

6.5 Nature and Contents of Container

Yonsa abiraterone acetate 125 mg tablets are available in high‐density polyethylene bottles with child resistant closure. Each bottle contains 120 tablets.
Methylprednisolone 4 mg tablets are available in high‐density polyethylene bottles. Each bottle contains 30 or 60 tablets.

6.6 Special Precautions for Disposal

Handling.

In Australia, any unused medicine or waste material should be disposed of by taking to your local Pharmacy. Women who are pregnant or women who may be pregnant should not handle abiraterone acetate tablets without protection, e.g. gloves (see Section 4.6 Fertility, Pregnancy and Lactation).

6.7 Physicochemical Properties

Abiraterone acetate.

Abiraterone acetate is a white to off‐white, non‐hygroscopic, crystalline powder. It is a lipophilic compound with an octanol‐water partition coefficient of 5.12 (Log P) and is practically insoluble in water. The pKa of the aromatic nitrogen is 5.19.

Chemical structure.


CAS number.

154229‐18‐2.

Methylprednisolone.

Methylprednisolone is a white to practically white, odourless, crystalline powder. It is sparingly soluble in alcohol, in dioxane, and in methanol, slightly soluble in acetone, and in chloroform, and very slightly soluble in ether. It is practically insoluble in water.

Chemical structure.


CAS number.

83‐43‐2.

7 Medicine Schedule (Poisons Standard)

Prescription Medicine - S4.

Summary Table of Changes