Consumer medicine information

Mycophenolic Acid ARX

Mycophenolic acid

BRAND INFORMATION

Brand name

Mycophenolic Acid ARX

Active ingredient

Mycophenolic acid

Schedule

SUMMARY CMI

MYCOPHENOLIC ACID ARX

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 MYCOPHENOLIC ACID ARX?

MYCOPHENOLIC ACID ARX contains the active ingredient mycophenolic acid (as sodium). MYCOPHENOLIC ACID ARX is used for people who have had a kidney transplant, to prevent the body from rejecting the new kidney.

For more information, see Section 1. Why am I using MYCOPHENOLIC ACID ARX? in the full CMI.

2. What should I know before I use MYCOPHENOLIC ACID ARX?

Do not use if you have ever had an allergic reaction to MYCOPHENOLIC ACID ARX 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 MYCOPHENOLIC ACID ARX? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with MYCOPHENOLIC ACID ARX 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 MYCOPHENOLIC ACID ARX?

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

More instructions can be found in Section 4. How do I use MYCOPHENOLIC ACID ARX? in the full CMI.

5. What should I know while using MYCOPHENOLIC ACID ARX?

Things you should do	Remind any doctor, dentist, or pharmacist you visit that you are using MYCOPHENOLIC ACID ARX. You must not take this medicine while you are pregnant or breast-feeding. If you become pregnant while taking MYCOPHENOLIC ACID ARX, tell your doctor immediately
Things you should not do	Do not stop taking this medicine unless your doctor tells you to. Do not have any vaccinations without first checking with your doctor.
Driving or using machines	MYCOPHENOLIC ACID ARX may cause dizziness in some people. Be careful driving, operating machinery or doing jobs that require you to be alert while you are taking MYCOPHENOLIC ACID ARX until you know how it affects you.
Drinking alcohol	Alcohol may have some effects while taking MYCOPHENOLIC ACID ARX
Looking after your medicine	Keep your tablets in the foil blister pack until it is time to take them. If you take the tablets out of the blister pack, they will not keep well.

For more information, see Section 5. What should I know while using MYCOPHENOLIC ACID ARX? in the full CMI.

6. Are there any side effects?

The common side effects include diarrhea, indigestion, bloating, muscle pain, weakness, pain in joint, pain in stomach.

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

MYCOPHENOLIC ACID ARX

Active ingredient(s): mycophenolic acid (as sodium) enteric coated tablets

Consumer Medicine Information (CMI)

This leaflet provides important information about using MYCOPHENOLIC ACID ARX. 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 MYCOPHENOLIC ACID ARX.

Where to find information in this leaflet:

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

1. Why am I using MYCOPHENOLIC ACID ARX?

MYCOPHENOLID ACID ARX contains the active ingredient mycophenolic acid. It belongs to a group of medicines called immunosuppressive. These medicines work by stopping your immune system from rejecting the transplanted organ.

MYCOPHENOLIC ACID ARX is used for people who have had a kidney transplant, to prevent the body from rejecting the new kidney.

MYCOPHENOLIC ACID ARX is used for people who have inflammatory kidney disease associated with a chronic autoimmune disorder known as systemic lupus erythematosus (also called lupus or SLE).

MYCOPHENOLIC ACID is used in combination with other medicines.

2. What should I know before I use MYCOPHENOLIC ACID ARX?

Warnings

Do not use MYCOPHENOLIC ACID ARX if:

you are allergic to mycophenolic acid, or any of the ingredients listed at the end of this leaflet.
Always check the ingredients to make sure you can use this medicine.
Symptoms of allergic reaction include:
- Shortness of breath;
- Wheezing or difficulty.
- Breathing or faintness;
- Swelling of face, lips, tongue, or other parts of the body;
- Rash, itching, hives on the skin

Check with your doctor if you:

have any other medical conditions
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 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.

Use of MYCOPHENOLIC ACID ARX in pregnancy causes a very high frequency of loss of pregnancy (miscarriage) and of severe birth defects in the unborn baby.

Do not take MYCOPHENOLIC ACID ARX if you are not using effective contraception.

Your doctor should advise you about contraception before you start taking MYCOPHENOLIC ACID ARX. Reliable contraception must be used before starting MYCOPHENOLIC ACID ARX.

MYCOPHENOLIC ACID ARX may reduce blood levels of the hormones in oral contraceptive pills and could theoretically reduce their effectiveness. Use of two methods of contraception is advised. The two methods can be a double barrier method or a barrier method plus a hormonal method. Adequate barrier methods of contraception include diaphragm, condom (by the partner), intrauterine device, sponge, or spermicide.

Do not take MYCOPHENOLID ACID ARX if you are breast-feeding during treatment with MYCOPHENOLIC ACID ARX. This is because small amounts of the medicine can pass into the mother's milk.

Sexually active men are recommended to use condoms during treatment and for total of 13 weeks after their last dose of Mycophenolate sodium. Condom use applies for both reproductively for competent and vasectomized men, because the risks associated with the transfer of seminal fluids also apply to men who have had a vasectomy.

In addition, female partners of male patients are recommended to use highly effective contraception during treatment and for a total of 13 week after the last dose of Mycophenolate sodium.

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 may interfere with MYCOPHENOLIC ACID ARX. These medicines include:

antacids that contain magnesium or aluminium hydroxide
azathioprine, tacrolimus, or any other immunosuppressive medicine
certain live vaccines
cholestyramine (used to treat high blood cholesterol levels)
aciclovir or ganciclovir (used to treat viral infections)
oral contraceptives. These may not work as well while you are taking MYCOPHENOLIC ACID ARX and you could become pregnant. Talk to your doctor about other birth control methods that can be used while you are taking MYCOPHENOLIC ACID ARX.

You may need to take different amounts of your medicines, or you may need to take different medicines.

Tell your doctor if you have or have had:

Sunspots or skin cancers
Low neutrophil (a type of white blood cell) blood count
Serious problems with your stomach or bowel, such as ulcers or bleeding.
Lesch-Nyhan or Kelly-Seegmiller syndrome 9a rare hereditary disorder that affects males only and is caused by a deficiency of a specific enzyme).

Your doctor may not want you to take MYCOPHENOLIC ACID ARX or may want to take special precautions if you have any of the above conditions.

If you are a woman who could become pregnant, you must provide a negative pregnancy test before starting treatment and must follow the contraceptive advice given to you by your doctor. Your doctor may request more than one test to ensure you are not pregnant before starting MYCOPHENOLIC ACID ARX.

If you are planning to have a child, your doctor will talk to you about the risks and alternative treatment you can take to prevent rejection of your transplant organ.

Tell your doctor if you are lactose intolerant. MYCOPHENOLIC ACID ARX tablets contain lactose.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect MYCOPHENOLIC ACID ARX.

4. How do I use MYCOPHENOLIC ACID ARX?

How much to take / use

Do not exceed the recommended dosage. The usual dose is 1,440 mg, take 720 mg twice a day. Your doctor may have prescribed a different dose, particularly for the initial treatment of inflammatory kidney disease.
Take MYCOPHENOLIC ACID ARX as prescribed by your doctor.
This will ensure that this medicine will work properly and prevent any unwanted side effects.
Remove the tablets from the foil blister pack when you are ready to take them.
Swallow the tablets whole with a full glass of water.
Do not chew or crush the tablets. Do not take any tablets that are broken or split.
You may take MYCOPHENOLIC ACID ARX tablets with or without food. It does not matter if you take them after food or on an empty stomach, as long as you take it the same way each day.
If you take them with food, always take them with food.If you take them without food, always take them without food.

When to take / use MYCOPHENOLIC ACID ARX

MYCOPHENOLIC ACID ARX should be used twice a day, 12 hours apart if possible. Taking your dose 12 hours apart will have the best effect.
Take them at about the same time each day. This will help you remember when to take them.
If you have had a renal transplant, your first dose will usually be given within 48 hours after your transplant.

How long to take MYCOPHENOLIC ACID ARX

Keep taking this medicine for as long as your doctor recommends.

It is important to keep taking MYCOPHENOLIC ACID ARX to prevent rejection of your transplanted kidney.

If you forget to use MYCOPHENOLIC ACID ARX

MYCOPHENOLIC ACID ARX should be used regularly at the same time each day.

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

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

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

If you use too much MYCOPHENOLIC ACID ARX

If you think that you have used too much MYCOPHENOLIC ACID ARX, 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 MYCOPHENOLIC ACID ARX?

Things you should do

Call your doctor straight away if you:

Make sure that you keep all of your doctor's appointments and have any tests done that are ordered by your doctor.
Your doctor may ask you to have blood tests from time to time to check your progress and prevent side effects.
You must not take this medicine while you are pregnant or breast-feeding. If you become pregnant while taking MYCOPHENOLIC ACID ARX, tell your doctor immediately.
Your doctor will discuss the potential risks of taking MYCOPHENOLIC ACID ARX during pregnancy such as miscarriage and a higher risk of birth defects.
If you are a woman of child-bearing age, you must use effective contraception measures before you take MYCOPHENOLIC ACID ARX, while you are taking MYCOPHENOLIC ACID ARX, and for 6 weeks after you stop taking MYCOPHENOLIC ACID ARX. If you are taking oral contraceptives, you must also use another form of birth control.
If you are a sexually active man, you should use condoms during treatment with MYCOPHENOLIC ACID ARX and for 13 weeks after stopping treatment even if you have had a vasectomy. Your partner should also use effective contraception during your treatment and for 13 weeks after you have stopped MYCOPHENOLIC ACID ARX.
Contact your doctor as soon as possible if you think your contraception may not have been effective or if you have forgotten to take your contraceptive pill.
Tell your doctor immediately if your partner becomes pregnant while you are taking MYCOPHENOLIC ACID ARX.
Do not breast-feed during treatment with MYCOPHENOLIC ACID ARX and for 6 weeks after you have stopped taking MYCOPHENOLIC ACID ARX.
If you develop lumps anywhere in your body, or develop any moles, or you notice changes in existing moles, tell your doctor.
This may be an early sign of cancer. Immunosuppressant medicines, including MYCOPHENOLIC ACID ARX, may increase the risk of developing certain cancers, including skin cancer and lymphoma (cancer of the lymphatic system.
Take special care during exposure to sunlight. If you go out in the sun, limit your exposure to sunlight and UV light by wearing a hat, protective clothing, and sunscreen with a high protection factor.
This will help to prevent the development of skin cancer.
Take special care of your teeth and gums. People taking immunosuppressant medicines are at a greater risk of getting infections.
Taking good care of your teeth and gums will help to prevent dental and mouth infections.
If you experience any symptoms of infection (e.g., fever, sore throat), unexpected bruising and/or bleeding you should inform your doctor immediately.
If you have already had hepatitis B or C, MYCOPHENOLIC ACID ARX may increase the risk of these diseases re-appearing.
Your doctor may perform blood analysis and check for symptoms of these diseases. If you experience any symptoms (yellow skin and eyes, nausea, loss of appetite, dark urine) you should inform your doctor immediately.
You must not donate blood during treatment with MYCOPHENOLIC ACID ARX and for at least 6 weeks after stopping treatment.
Men must not donate semen during treatment with MYCOPHENOLIC ACID ARX and for at least 90 days after stopping treatment.
If you are about to be started on any new medicine remind your doctor or pharmacist that you are taking MYCOPHENOLIC ACID ARX.
Remind any doctor, dentist, or pharmacist you visit that you are using MYCOPHENOLIC ACID ARX.

Things you should not do

Do not stop taking this medicine unless your doctor tells you to.
Do not have any vaccinations without first checking with your doctor.
Some vaccines may be less effective, or they may cause unwanted side effects while you are taking MYCOPHENOLIC ACID ARX.
Do not give this medicine to anyone else even if their condition seems like yours.
Do not take it to treat any other complaints unless your doctor tells you to.

Things to be careful of

Driving or using machines

Be careful before you drive or use any machines or tools until you know how MYCOPHENOLIC ACID ARX affects you.

MYCOPHENOLIC ACID ARX may cause dizziness in some people.

Be careful driving, operating machinery or doing jobs that require you to be alert while you are taking MYCOPHENOLIC ACID ARX until you know how it affects you.

This medicine is not expected to affect your ability to drive a car or operate machinery.

Drinking alcohol

Tell your doctor if you drink alcohol.

Alcohol may affect the effects of MYCOPHENOLIC ACID ARX.

Looking after your medicine

Keep your tablets in the foil blister pack until it is time to take them. If you take the tablets out of the blister pack, they will not keep well.
Store the pack in a cool dry place where the temperature stays below 25°C.
Always keep the tablets away from direct sunlight and keep the tablets away from moisture.

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.

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

When to discard your medicine (as relevant)

If your doctor tells you to stop taking MYCOPHENOLIC ACID ARX or it has passed its expiry date, ask your pharmacist what to do with any medicine you have left over.

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 effects	What to do
Diarrhoea Constipation Indigestion Flatulence Loose stools Nausea (feeling sick), or vomiting Pain in the stomach Pain in the joints Weakness Muscle pain Feeling bloated or tenderness in the abdomen Headache Dizziness Unusual bleeding or bruising (signs of low level of blood platelets) Cough Anxiety Fever temperature above 37°C Tiredness	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

Symptoms of infection including fever, chills, sweating, feelings of tiredness, drowsiness, or lack of energy.
vision changes, loss of coordination, clumsiness, memory loss, difficulty speaking or understanding what others say, and muscle weakness. These can be the signs of an infection of the brain called progressive multifocal leukoencephalopathy.
signs of allergy such as rash, itching or hives on the skin; swelling of the face, lips, tongue or other part of the body; shortness of breath, wheezing or troubled breathing or you feel congested.
enlarged glands, a new lump or mole on your skin, or changes to existing moles, anywhere on the body. A very small number of MYCOPHENOLIC ACID ARX patients have developed cancer of the skin or lymph nodes. Lymph nodes are the bean-shaped organs found in the underarm, groin, neck, chest and abdomen that act as filters for the lymph fluid as it circulates through the body.
any symptoms of anemia (decrease in red blood cells), such as unusual tiredness, headache, shortness of breath at rest or with exercise, dizziness, chest pain, looking pale.
signs of peripheral oedema such as swollen hands, ankles or feet.
signs of severe high blood pressure such as headache, dizziness, possibly with nausea.
signs of high levels of potassium in the blood (hyperkalaemia) such as muscle spasms, abnormal heart rhythm.
signs of interstitial lung disease including fatal pulmonary fibrosis) such as cough, difficulty breathing, painful breathing
General disorders and administration site conditions: de novo purine synthesis inhibitors-associated acute inflammatory syndrome.

Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

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

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

Reporting side effects

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

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

7. Product details

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

What MYCOPHENOLIC ACID ARX contains

Active ingredient (main ingredient)	Mycophenolic acid (as sodium) 180mg or 360mg
Other ingredients (inactive ingredients)	Microcrystalline cellulose Croscarmellose sodium Povidone Croscarmellose sodium Purified talc Colloidal anhydrous silica Magnesium stearate Isopropyl alcohol Purified water PI: Opacode Black S-1-1782. PI: Acryl-Eze Green 93O510003 aqueous acrylic enteric system
Potential allergens	N/A

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

What MYCOPHENOLIC ACID ARX looks like

MYCOPHENOLIC ACID ARX tablets 180 mg are lime green, round shaped, biconvex bevelled edged enteric-coated tablets imprinted with M1 on one side with black ink and plain on the other side (AUST R 338491).

Available in 20, 50, 100 and 120 tablets pack sizes

MYCOPHENOLIC ACID ARX tablets 360 mg are peach, oblong shaped, biconvex enteric-coated tablets imprinted with M2 on one side with black ink and plain on the other side (AUST R 338496).

Available in 50, 100 and 120 tablets pack sizes

* Not all strengths or pack sizes may be available.

Who distributes MYCOPHENOLIC ACID ARX

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

This leaflet was prepared in November 2024.

Published by MIMS January 2025

BRAND INFORMATION

Brand name

Mycophenolic Acid ARX

Active ingredient

Mycophenolic acid

Schedule

1 Name of Medicine

Mycophenolic acid as sodium salt.

2 Qualitative and Quantitative Composition

Mycophenolic Acid ARX enteric coated tablets are available in 180 mg and 360 mg. Mycophenolic Acid ARX enteric coated tablets contain the active mycophenolic acid (as sodium salt), equivalent to 192.4 mg and 384.7 mg mycophenolate sodium, respectively.

Excipients with known effects.

Sodium. Each 180 mg and 360 mg tablet contains 15 mg and 360 mg of elemental sodium respectively.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Mycophenolic Acid ARX enteric coated tablets 180 mg are lime green, round shaped, biconvex bevelled edged enteric-coated tablets imprinted with M1 on one side with black ink and plain on the other side.
Mycophenolic Acid ARX enteric coated tablets 360 mg are peach, oblong shaped, biconvex enteric-coated tablets imprinted with M2 on one side with black ink and plain on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Mycophenolic Acid ARX tablets are indicated for the prophylaxis of acute transplant rejection in adult patients receiving allogeneic renal transplants.
Mycophenolic Acid ARX tablets are indicated for induction and maintenance treatment of adult patients with WHO Class III, IV or V lupus nephritis.
This indication is based on the evidence in literature reports of studies of treatment in patients with lupus nephritis, the majority of whom were ISN/RPS (2003) Class IV. The evidence for efficacy was based on surrogate endpoints.

4.2 Dose and Method of Administration

Treatment with Mycophenolic Acid ARX tablets should be initiated and maintained by appropriately qualified specialists who are expert in managing the safety risks associated with the contraindication for use in pregnancy. Consideration should be given to therapeutic drug monitoring of mycophenolate because of the variable pharmacokinetic profile and narrow therapeutic margin.
Mycophenolic Acid ARX tablets should not be initiated in women of child-bearing potential until a negative pregnancy test has been obtained. For information on use in pregnancy and contraceptive requirements, see Section 4.4 Special Warnings and Precautions for Use, Women of child-bearing potential, Male patients; Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy, Male patients.
A dose of 1440 mg/day of mycophenolate sodium has been shown to be equivalent to 2 g/day of mycophenolate mofetil. Mycophenolic Acid ARX tablets and CellCept (mycophenolate mofetil) should not be indiscriminately interchanged or substituted because of their different pharmacokinetic profiles.
Mycophenolic Acid ARX tablets should not be crushed and should be swallowed whole. Patients should be advised to take Mycophenolic Acid ARX tablets consistently either with or without food, but not switch between fed and fasted states because of the risk of increased MPA AUC variability.

Renal transplant patients.

Mycophenolic Acid ARX tablets should be initiated in de novo patients within 48 hours following transplantation. The recommended dose is 720 mg administered twice daily (1440 mg daily dose).

Paediatric patients.

Safety and efficacy in paediatric patients have not been established.

Elderly patients.

No dose adjustment is required in elderly patients.

Patients with renal insufficiency.

No dose adjustments are needed in patients experiencing delayed renal graft function post-operatively. Patients with severe chronic renal impairment (glomerular filtration rate < 25 mL.min^-1.1.73 m^-2) should be carefully monitored.

Patients with hepatic insufficiency.

No dose adjustments are needed for renal transplant patients with severe hepatic parenchymal disease.

Treatment during rejection episodes.

Dosage reduction or interruption of Mycophenolic Acid ARX tablets is not required during episodes of renal transplant rejection.

Lupus nephritis patients.

Adequate dose finding studies have not been performed. The prescriber should adjust the dose based on clinical response.
Induction treatment with Mycophenolic Acid ARX tablets is usually initially administered in combination with corticosteroids. The recommended dose is 720 mg administered twice daily (1440 mg daily dose). A daily dose of greater than 1440 mg/day has been used for induction therapy in some studies, see Section 5.1 Pharmacodynamic Properties, Clinical trials. This dose may be tapered for maintenance purposes following a complete or partial response.

4.3 Contraindications

Mycophenolic Acid ARX tablets are contraindicated in pregnancy unless there is no suitable alternative treatment to prevent transplant rejection, since it is associated with increased risks of pregnancy loss including spontaneous abortion and congenital malformations, see Section 4.6 Fertility, Pregnancy and Lactation.
Mycophenolic Acid ARX tablets are contraindicated in women who are breast-feeding, see Section 4.6 Fertility, Pregnancy and Lactation and in women of child-bearing potential who are not using highly effective contraception methods and should not be initiated without providing a pregnancy test to rule out unintended pregnancy, see Section 4.4 Special Warnings and Precautions for Use, Women of child-bearing potential.
It is also contraindicated in patients with a hypersensitivity to mycophenolate sodium, mycophenolic acid or mycophenolate mofetil or to any of the excipients of the formulation, see Section 6.1 List of Excipients.

4.4 Special Warnings and Precautions for Use

Identified precautions.

Embryofoetal toxicity.

Mycophenolic acid can cause foetal harm when administered to a pregnant woman. Use of mycophenolic acid during pregnancy is associated with an increased risk of pregnancy loss including spontaneous abortion and an increased risk of congenital malformations, especially external ear and other facial abnormalities including cleft lip and palate, and anomalies of the distal limbs, heart, esophagus, and kidney.

Women of child-bearing potential.

Mycophenolic acid therapy should not be initiated until a negative pregnancy test has been obtained to exclude unintended exposure of the embryo to mycophenolate. Two serum or urine pregnancy tests with a sensitivity of at least 25 mIU/mL are recommended; the second test should be performed 8-10 days after the first one and immediately before starting mycophenolate. Pregnancy test should be repeated as clinically required (e.g. after any gap in contraception is reported). Results of all pregnancy tests should be discussed with the patient. Patients should be instructed to consult their physician immediately should pregnancy occur.
Women of child-bearing potential must use highly effective contraception. Two types of reliable contraception should start simultaneously before beginning mycophenolic acid therapy, during therapy and for six weeks after their last dose of mycophenolic acid; unless abstinence is the chosen method of contraception. Given that mycophenolate mofetil reduces blood levels of the hormones in the oral contraceptive pill, it is possible that mycophenolic acid could reduce the efficacy of oral contraceptives, see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

Pregnancy and breast-feeding, fertility and male patients.

For information on use in pregnancy, breast-feeding and contraceptive requirements see sections entitled (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy, Use in lactation, Effects on fertility, Male patients; Section 4.4 Special Warnings and Precautions for Use, Women of child-bearing potential).

Malignancies.

Patients receiving immunosuppressive regimens involving combinations of drugs, including mycophenolic acid, are at increased risk of developing lymphomas and other malignancies, particularly of the skin, see Section 4.8 Adverse Effects (Undesirable Effects). The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent. In order to minimise the risk for skin cancer, exposure to sunlight and UV light should be limited by wearing protective clothing and using a sunscreen with a high protection factor.

Infections.

Patients receiving mycophenolic acid should be instructed to immediately report any evidence of infection, unexpected bruising, bleeding or any other manifestation of bone marrow depression.
Over suppression of the immune system increases the susceptibility to infection, including opportunistic infections, fatal infections and sepsis, see Section 4.8 Adverse Effects (Undesirable Effects).
Reactivation of hepatitis B (HBV) or hepatitis C (HCV) have been reported in patients treated with immunosuppressants, including the mycophenolic acid (MPA) derivatives and MMF. Monitoring infected patients for clinical and laboratory signs of active HBV or HCV infection is recommended.
Cases of progressive multifocal leukoencephalopathy (PML), sometimes fatal, have been reported in patients treated with MPA derivatives which include mycophenolate mofetil (MMF) and mycophenolate sodium, see Section 4.8 Adverse Effects (Undesirable Effects). Hemiparesis, apathy, confusion, cognitive deficiencies and ataxia were the most frequent clinical features observed. Mycophenolate mofetil is metabolized to mycophenolic acid, the active ingredient in Mycophenolic Acid ARX tablets and the active form of the drug. The reported cases generally had risk factors for PML, including immunosuppressant therapies and impairment of immune functions. In immunosuppressed patients, physicians should consider PML in the differential diagnosis in patients reporting neurological symptoms and consultation with a neurologist should be considered as clinically indicated. Polyomavirus associated nephropathy (PVAN) especially due to BK virus infection, should be included in the differential diagnosis in immunosuppressed patients with deteriorating renal function, see Section 4.8 Adverse Effects (Undesirable Effects). Consideration should be given to reducing the total immunosuppression in patients who develop PML or PVAN. In transplant patients, however, reduced immunosuppression may place the graft at risk.

Blood dyscrasias.

Patients receiving mycophenolic acid should be monitored for blood dyscrasias (e.g. neutropenia or anaemia, see Section 4.8 Adverse Effects (Undesirable Effects), which may be related to MPA itself, concomitant medications, viral infections or some combination of these causes. Patients taking mycophenolic acid should have complete blood counts weekly during the first month, twice monthly for the second and third months of treatment, then monthly through the first year. If blood dyscrasias occur (e.g. neutropenia with absolute neutrophil count < 1.5 x 10⁹/L or anaemia), it may be appropriate to interrupt or discontinue mycophenolic acid.
Cases of pure red cell aplasia (PRCA) have been reported in patients treated with MPA derivatives in combination with other immunosuppressive agents, see Section 4.8 Adverse Effects (Undesirable Effects). MMF is metabolized to mycophenolic acid (MPA), the active ingredient in Mycophenolic Acid ARX tablets and the active form of the drug. The mechanism for MPA derivatives induced PRCA is unknown; the relative contribution of other immunosuppressants and their combinations in an immunosuppressive regimen is also unknown. However, MPA derivatives may cause blood dyscrasias. In some cases PRCA was found to be reversible with dose reduction or cessation of therapy with MPA derivatives. In transplant patients, however, reduced immunosuppression may place the graft at risk. Changes to mycophenolic therapy should only be undertaken under appropriate supervision in transplant recipients in order to minimise the risk of graft rejection.

Vaccination.

Patients should be advised that, during treatment with MPA, vaccinations may be less effective and the use of live attenuated vaccines should be avoided, see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions. Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination.

Donation of blood or semen.

Patients should not donate blood during therapy or for at least 6 weeks following discontinuation of mycophenolate. Men should not donate semen during therapy or for 90 days following discontinuation of mycophenolate.

Gastrointestinal disorders.

Because MPA derivatives have been associated with an increased incidence of digestive system adverse events, including infrequent cases of gastrointestinal tract ulceration and haemorrhage, and perforation, mycophenolic acid should be administered with caution in patients with active serious digestive system disease.

Patients with rare hereditary deficiency of hypoxanthine-guanine phosphoribosyl-transferase (HGPRT).

Mycophenolic acid is an IMPDH (inosine monophosphate dehydrogenase) inhibitor and therefore, on theoretical grounds, it should be avoided in patients with rare hereditary deficiency of hypoxanthine-guanine phosphoribosyl-transferase (HGPRT) such as Lesch-Nyhan and Kelley-Seegmiller syndrome.

Male patients.

Sexually active men are recommended to use condoms during treatment, and for a total of 13 weeks after their last dose of mycophenolic acid. Condom use applies for both reproductively competent and vasectomized men, because the risks associated with the transfer of seminal fluid also apply to men who have had a vasectomy. In addition, female partners of male patients are recommended to us highly effective contraception during treatment and for a total of 13 weeks after the last dose of mycophenolic acid.

Use in hepatic impairment.

Not available.

Use in renal impairment.

Not available.

Use in the elderly.

See Section 4.8 Adverse Effects (Undesirable Effects), Elderly patients.

Paediatric use.

Safety and efficacy in paediatric patients have not been established.

Effects on laboratory tests.

Not available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Mycophenolic acid has been administered in combination with the following agents in clinical trials: antithymocyte globulin, basiliximab, ciclosporin and corticosteroids. The efficacy and safety of the use of mycophenolic acid with other immunosuppressive agents have not been studied.

Oral contraceptives.

Concomitant use of mycophenolic acid with oral contraceptives has not been studied. Oral contraceptives undergo oxidative metabolism while mycophenolic acid is metabolised by glucuronidation. Given the different metabolism of mycophenolic acid and oral contraceptives, no drug interaction between these two classes of drug is expected. However, in a drug-drug interaction study, mean levonorgestrel AUC was decreased by 15% when coadministered with mycophenolate mofetil. Therefore, it is recommended that oral contraceptives are coadministered with mycophenolic acid with caution and additional birth control methods be considered, see Section 4.4 Special Warnings and Precautions for Use, Women of child-bearing potential, Male patients; Section 4.6 Fertility, Pregnancy and Lactation.

Azathioprine.

It is recommended that mycophenolic acid should not be administered concomitantly with azathioprine because such concomitant administration has not been studied.

Live vaccines.

Live vaccines should not be given to patients with an impaired immune response. The antibody response to other vaccines may be diminished.

Aciclovir.

Concomitant use of mycophenolic acid with aciclovir has not been studied. After co-administration of mycophenolate mofetil (which delivers MPA to the systemic circulation) and aciclovir, higher plasma concentrations of MPAG and aciclovir have been observed compared with administration of each drug alone. In renal impairment, the two drugs may compete for tubular secretion resulting in further increases in MPAG and aciclovir plasma concentration. In this situation, patients should be carefully monitored.

Ciclosporin.

When studied in stable renal transplant patients, ciclosporin (Neoral) pharmacokinetics were unaffected by steady state dosing of mycophenolic acid.

Ganciclovir.

Concomitant use of mycophenolic acid with ganciclovir has not been studied. In patients taking mycophenolate mofetil, MPA and MPAG pharmacokinetics are unaffected by the addition of ganciclovir. The clearance of ganciclovir is unchanged in the setting of therapeutic MPA exposure. However, in patients with renal impairment in whom mycophenolic acid and ganciclovir are coadministered, the potential exists for the two drugs to compete for tubular secretion, resulting in increased plasma concentrations of both drugs. Therefore, in patients with renal impairment, the dose recommendations for ganciclovir should be observed and patients carefully monitored.

Tacrolimus.

In a calcineurin cross-over study in stable renal transplant patients, steady state mycophenolic acid pharmacokinetics were determined during concomitant ciclosporin (Neoral) and tacrolimus (Prograf) treatments. Mean MPA AUC was 19% higher and C_max about 20% lower, and mean MPAG AUC and C_max were about 30% lower on tacrolimus treatment compared to Neoral treatment.

Conditions of decreased protein binding sites.

MPA concentration may increase under conditions of decreased protein binding sites, which may occur when mycophenolic acid is administered concomitantly with highly protein bound drugs and/or in the setting of uraemia. This may put patients at increased risk of MPA-related adverse effects.

Gastroprotective agents.

Antacids with magnesium and aluminium hydroxides.

The absorption of mycophenolic acid was decreased when administered with antacids containing magnesium and aluminium hydroxide, resulting in a 37% decrease in MPA systemic exposure and a 25% decrease in MPA maximal concentration. Caution should be used when co-administering antacids containing magnesium and aluminium hydroxide with mycophenolic acid.

Proton pump inhibitors.

In healthy volunteers, no changes in the pharmacokinetics of MPA were observed following concomitant administration of mycophenolic acid and pantoprazole given at 40 mg twice daily during the four previous days.

Cholestyramine and drugs that interfere with enterohepatic circulation.

Due to its capacity to block the enteric circulation of drugs, cholestyramine may decrease the systemic exposure of MPA. Caution should be used when co-administering cholestyramine or drugs that interfere with enterohepatic circulation because of the potential to reduce the efficacy of mycophenolic acid.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Mycophenolate sodium had no effect on fertility of male rats at oral doses up to 18 mg/kg/day. The systemic exposure to MPA (plasma AUC) at this dose represents approximately 2 times the clinical exposure at the recommended dose of 1.44 g/day. No effects on female fertility were seen up to a dose of 20 mg/kg/day, a dose at which embryotoxicity was observed, with estimated systemic exposure to MPA (plasma AUC) approximately 3 times clinical exposure.

Male patients.

Sexually active men are recommended to use condoms during treatment, and for total of 13 weeks after their last dose of mycophenolate sodium. Condom use applies for both reproductively for competent and vasectomized men, because the risks associated with the transfer of seminal fluid also apply to men who have had a vasectomy. In addition, female partners of male patients are recommended to use highly effective contraception during treatment and for a total of 13 weeks after the last dose of mycophenolate sodium.
(Category D)
The use of mycophenolic acid is contraindicated during pregnancy unless there is no suitable alternative treatment available. Treatment should not be initiated without providing a negative pregnancy test result to rule out unintended use in pregnancy.
Female and male patients of reproductive potential must be made aware of the increased risk of pregnancy loss and congenital malformations at the beginning of the treatment and must be counseled regarding pregnancy prevention and planning.
Mycophenolate is a powerful human teratogen, with an increased risk of spontaneous abortions and congenital malformations in case of exposure during pregnancy.
Spontaneous abortions have been reported in 45 to 49% of pregnant women exposed to mycophenolate mofetil, compared to a reported rate of between 12 and 33% in solid organ transplant patients treated with immunosuppressants other than mycophenolate mofetil.
Based on literature reports, malformations occurred in 23 to 27% of live births in women exposed to mycophenolate mofetil during pregnancy (compared to 2 to 3% of live births in the overall population and approximately 4 to 5% of live births in solid organ transplant recipients treated with immunosuppressants other than mycophenolate mofetil).
Congenital malformations, including reports of multiple malformations, have been observed post-marketing in children of patients exposed to mycophenolate mofetil during pregnancy in combination with other immunosuppressants. The following malformations were most frequently reported:
Abnormalities of the ear (e.g. abnormally formed or absent external/middle ear), external auditory canal artesia;
Congenital heart disease such as atrial and ventricular septal defects;
Facial malformations such as cleft lip, cleft palate, micrognathia and hypertelorism of the orbits;
Abnormalities of the eye (e.g. coloboma);
Malformations of the fingers (e.g. polydactyly, syndactyly);
Tracheo-oesophageal malformations (e.g. oesophageal atresia);
Nervous system malformations such as spina bifida;
Renal abnormalities.
In addition there have been isolated reports of the following malformations:
Microphthalmia;
Congenital choroid plexus cyst;
Septum pellucidum agenesis;
Olfactory nerve agenesis.
Adverse effects on fetal development (including malformations) occurred when pregnant rats and rabbits were dosed with mycophenolate sodium or mycophenolate mofetil during organogenesis. In a teratology study performed with mycophenolate sodium in rats at 1 mg/kg/day (the lowest dose tested), there was an increase in resorptions, and malformations in the offspring were observed including anophthalmia, exencephaly and umbilical hernia.
The estimated systemic exposure to MPA at this dose is about 0.1 times the clinical exposure (plasma AUC) at the recommended dose of 1.44 g/day.
It is not known whether MPA is excreted in human milk but studies in rats given radiolabelled mycophenolate mofetil have shown the excretion of radioactivity into milk.
Mycophenolic acid is contraindicated in women who are breast-feeding because of the potential for serious adverse reactions in breastfed newborns/infants.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects of mycophenolic acid on the ability to drive and use machines have been performed. The mechanism of action and pharmacodynamic profile and the reported adverse reactions indicate that an effect is unlikely.

4.8 Adverse Effects (Undesirable Effects)

Adverse effects from clinical trials in renal transplant patients.

Malignancies.

Patients receiving immunosuppressive regimens involving combinations of drugs, including MPA, are at increased risk of developing lymphomas and other malignancies, particularly of the skin, see Section 4.4 Special Warnings and Precautions for Use, Malignancies. Overall rates of malignancies observed in mycophenolic acid clinical trials are as follows: lymphoproliferative disease or lymphoma developed in 2 de novo patients (0.9%) and in 2 maintenance patients (1.3%) receiving mycophenolic acid for up to 1 year; non-melanoma skin carcinomas occurred in 2 de novo patients (0.9%) and 3 maintenance patients (1.9%) receiving mycophenolic acid for up to 1 year; other types of malignancy occurred in 0.5% of de novo and 0.6% of maintenance patients.

Opportunistic infections.

All transplant patients are at increased risk of opportunistic infections. The risk increases with total immunosuppressive load, see Section 4.4 Special Warnings and Precautions for Use, Infections. The most common opportunistic infections in de novo renal transplant patients receiving mycophenolic acid with other immunosuppressants in controlled clinical trials of renal transplant patients followed for one year were CMV, candidiasis and herpes simplex. The overall rate of CMV infections (serology, viraemia or disease) observed in mycophenolic acid clinical trials was 21.6% in de novo and 1.9% in maintenance renal transplant patients.

Other adverse drug reactions.

Table 1 contains adverse drug reactions, possibly or probably related to mycophenolic acid, reported in the two phase III randomised, double blind, controlled, multi-centre trials: 1 in de novo renal transplant patients and 1 in maintenance renal transplant patients, in which mycophenolic acid was administered at a dose of 1440 mg/day for 12 months together with ciclosporin microemulsion (Neoral) and corticosteroids. It is compiled according to MedDRA system organ class.
Adverse reactions are listed according to the following categories: very common ≥ 10% (≥ 1/10); common ≥ 1% and < 10% (≥ 1/100 and < 1/10); uncommon ≥ 0.1% and < 1% (≥ 1/1000 and < 1/100); rare ≥ 0.01% and < 0.1% (≥ 1/10000 and < 1/1000); very rare < 0.01% (< 1/10000).

Renal transplant patients were treated with 1440 mg mycophenolic acid daily up to one year. A similar profile was seen in the de novo and maintenance transplant population although the incidence tended to be lower in the maintenance patients.

Elderly patients.

Elderly patients may generally be at increased risk of adverse drug reactions due to immunosuppression. Elderly patients receiving mycophenolic acid as part of a combination immunosuppressive regimen did not show an increased risk of adverse reactions compared to younger individuals in the mycophenolic acid clinical trials.

Adverse effects from a clinical trial in lupus nephritis patients (A2420).

Mycophenolic acid was administered at a dose of 720 mg twice daily for 2 weeks and then 1080 mg twice daily (or 720 mg three times daily) for 22 weeks in an open-label trial comparing the efficacy and safety of mycophenolic acid and a standard corticosteroid regimen (prednisolone 1 mg/kg bodyweight/day, tapered) with mycophenolic acid and a reduced corticosteroid regimen (prednisolone 0.5 mg/kg bodyweight/day, tapered) for induction treatment of lupus nephritis. Adverse events were reported by 35/42 (83.3%) patients in the mycophenolic acid and standard corticosteroid group and by 30/39 (76.9%) patients in the mycophenolic acid and reduced corticosteroid group. The incidence of gastrointestinal events (standard: 18/42, 42.9%; reduced: 13/39, 33.3%), infections (standard: 25/42, 59.5%; reduced: 14/39, 35.9%), and general disorders (standard: 14/42, 33.3%; reduced: 8/39, 20.5%) were higher in the mycophenolic acid and standard corticosteroid group compared with the mycophenolic acid and reduced corticosteroid group.

Adverse effects from post marketing experience.

Immune system disorders.

Hypersensitivity reactions (including anaphylaxis).
Rash has been identified as an adverse effect from post-approval clinical trials, post marketing surveillance and spontaneous reports.

General disorders and administration site conditions.

De novo purine synthesis inhibitors-associated acute inflammatory syndrome.
The following additional adverse reactions are attributed to MPA derivatives as a class effect.

Pregnancy, puerperium and perinatal conditions.

Cases of spontaneous abortion have been reported in patients exposed to mycophenolate mainly in the first trimester.

Congenital malformations.

Congenital malformations have been reported in offspring of patients exposed to mycophenolate mofetil (MMF) during pregnancy, see Section 4.6 Fertility, Pregnancy and Lactation.

Infections and infestations.

Serious, sometimes life-threatening infections, including meningitis, infectious endocarditis, tuberculosis and atypical mycobacterial infection. Polyomavirus associated nephropathy (PVAN), especially due to BK virus infection. Cases of progressive multifocal leukoencephalopathy (PML), sometimes fatal, have been reported, see Section 4.4 Special Warnings and Precautions for Use.

Blood and lymphatic system disorders.

Agranulocytosis, neutropenia, pancytopenia. Cases of pure red cell aplasia (PRCA) have been reported in patients treated with MPA derivatives in combination with other immunosuppressive agents. See Section 4.4 Special Warnings and Precautions for Use.

Gastrointestinal disorders.

Colitis, oesophagitis (including CMV-colitis and -oesophagitis), CMV gastritis, pancreatitis, intestinal perforation, gastrointestinal haemorrhage, gastric ulcers, duodenal ulcers, ileus.

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

Signs and symptoms.

There has been no reported experience of overdosage of mycophenolic acid in humans.

Treatment.

Although dialysis may be used to remove the inactive metabolite MPAG, it would not be expected to remove clinically significant amounts of the active moiety, MPA. This is in large part due to the very high plasma protein binding of MPA. By interfering with enterohepatic circulation of MPA, bile acid sequestrants such as cholestyramine may reduce the systemic exposure of MPA.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Mycophenolic acid (MPA) is a non-nucleoside, non-competitive, reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH). IMPDH is the rate limiting enzyme in the de novo synthesis pathway of guanosine triphosphate. Both T- and B-lymphocytes are highly dependent on this pathway for the generation of guanosine nucleotides whereas non-lymphoid cells can utilise a salvage pathway for the generation of guanosine triphosphate.
MPA selectively decreases the lymphocyte nucleotide pool, which effectively impairs the capacity of T- and B-lymphocytes to proliferate. MPA inhibits glycosylation of adhesion molecules on lymphocytes and monocytes (a process requiring guanosine triphosphate). This action could potentially decrease the recruitment of lymphocytes and monocytes into sites of chronic inflammation, an important process in ongoing rejection.

Clinical trials.

Renal transplant. Two multi-centre, randomised, double-blind, parallel group studies were conducted in renal transplant patients. The first study was conducted in newly transplanted patients and in the second study, maintenance renal transplant patients were randomised 1:1 to either remain on mycophenolate mofetil (MMF) or be switched to mycophenolic acid. Both pivotal studies were reference therapy-controlled clinical studies using commercially marketed MMF as the comparator.

De novo renal transplant patients.

A total of 423 patients were randomised within 48 hours of renal transplantation, 213 to mycophenolic acid (1.44 g/day, 720 mg bid) and 210 to MMF (2 g/day, 1 g bid) as part of triple immunosuppressive therapy with Neoral and steroids. The aim of the study was to show therapeutic equivalence of mycophenolic acid to MMF as measured by the incidence of biopsy-proven acute rejection, graft loss, death or lost to follow-up at 6 and 12 months of treatment. All patients contributed data at 6 and 12 months. Efficacy results are reported in Table 2 for the intent-to-treat population. Similar results were obtained for the per protocol analysis an analysis which excluded patients with serious protocol violations.

Maintenance renal transplant patients.

A total of 322 patients who were at least 6 months post-renal transplant and stabilised on 2 g MMF and Neoral, were randomised, 159 to mycophenolic acid (1.44 g/day, 720 mg bid) and 163 to MMF (2 g/day, 1 g bid) plus Neoral, with or without steroids. The primary objective was to demonstrate safety and tolerability of mycophenolic acid compared to MMF and this objective was met. Evaluation of efficacy was a secondary objective. The incidence rate of biopsy-proven acute rejection, graft loss, death or lost to follow-up, and the incidence of suspected or biopsy-proven acute rejections within 6 and 12 months post-randomisation, were compared across treatment groups. All patients contributed data at 6 months, and 223 patients contributed data at 12 months. Efficacy results are shown in Table 3.

Lupus nephritis. One exploratory randomised open-label 6-month study (A2420; Zeher et al., 2011) has been conducted comparing the efficacy and safety of mycophenolic acid and a standard corticosteroid regimen (prednisolone 1 mg/kg bodyweight/day, tapered) with mycophenolic acid and a reduced corticosteroid regimen (prednisolone 0.5 mg/kg bodyweight/day, tapered) for induction treatment of lupus nephritis. Male and female patients aged ≥ 18 years were eligible to enter the study if they met the following criteria: diagnosed with SLE, defined as meeting at least four classification criteria of the American College of Rheumatology; presence of proliferative lupus nephritis flare class III or IV (ISN/RPS classification of lupus nephritis) documented by a renal biopsy performed within 24 months preceding the study entry; proteinuria defined as > 0.5 gram urine protein per gram urine creatinine at screening and baseline and clinical activity defined by serum creatinine > 1.0 mg/dL (88.4 micromol/L), microscopic hematuria (> 5 red cells per high power field) or presence of cellular casts were the other key inclusion criteria. The key exclusion criteria were patients with calculated creatinine clearance < 30 mL/min (using the Cockcroft-Gault formula); patients having received i.v. CS bolus, oral or i.v. cyclophosphamide or MMF during the last 3 months; use of any antibodies during the last 6 months. Mycophenolic acid was administered at a dose of 720 mg twice daily for 2 weeks and then 1080 mg twice daily (or 720 mg three times daily) for 22 weeks. A total of 81 patients with biopsy proven lupus nephritis WHO class III, IV, or V and clinical activity were treated in this study.
The primary efficacy variable was the complete remission rate at 24 weeks defined as the proportion of patients with urine protein/urine creatinine ratio < 0.5 gram urine protein per gram urine creatinine, urine sediment normalized (no cellular casts, < 5 red cells per high power field), and serum creatinine is within 10% of normal value. Secondary efficacy variables included the proportion patients in partial remission after 24 weeks of treatment, with partial response defined as reduction in urine protein:creatinine ratio of ≥ 50% compared with base line, and serum creatinine within 10% of baseline value; proportion of patients with mild SLE flare after 12 and 24 weeks of treatment; disease activity index measured with BILAG score and SLEDAI index; renal function assessed by serum creatinine, creatinine clearance, glomerular filtration rate (GFR) and urine protein:creatinine ratio.
The demographic and other baseline characteristics were balanced between the two dose groups. Most patients had a histological diagnosis of class IV lupus nephritis. At 6 months, 8/42 (19.0%) of mycophenolic acid and standard corticosteroid-treated patients and 8/39 (20.5%) of mycophenolic acid and reduced corticosteroid-treated patients achieved complete remission. Partial response occurred in 20/42 (47.6%) of patients in the standard dose group and 14/39 (35.9%) of patients in the low dose group. Patients in whom treatment failed included those without complete or partial remission at 6 months or who prematurely discontinued treatment during the first 24 weeks for any reason, yielding failure rates of 21/42 (50%) in the standard dose group and 23/39 (59.0%) in the low dose group. At 6 months, the mean change from baseline for urine protein to creatinine ratio decreased by 1.1 in the standard dose group and by 0.8 in the low dose group. Only one patient in the standard-dose group reported a moderate to severe SLE flare at 24 weeks. The mean BILAG and SLEDI scores decreased from Week 4 to Week 24 in both treatment groups.

Published studies.

Studies comparing the use of mycophenolate (sodium or mofetil) with intravenous cyclophosphamide (IVC) and azathioprine (AZA) in patients with proliferative lupus nephritis have been reported in the literature. Results from the two pivotal published studies with MMF in induction and maintenance therapy are given below.
The ALMs study (Appel et al., 2009) compared MMF and IVC as induction treatment for active lupus nephritis in a 24 week open-label parallel group multicentre study. 370 patients with Class III to V lupus nephritis were randomly assigned to a target dose of 3 g/day MMF or 0.5 to 1.0 g/m² IVC. Both groups received prednisone, tapered from a maximum starting dose of 60 mg/day. The primary endpoint was a pre-specified decrease in urine protein/creatinine ratio and stabilization or improvement in serum creatinine. Secondary endpoints included complete renal remission, systemic disease activity and damage, and safety. No significant difference in response rate between the two groups was detected. The primary efficacy endpoint was achieved in 104 (56.2%) patients receiving MMF, compared with 98 (53.0%) patients receiving IVC. No significant differences were detected between the MMF and IVC groups with regard to the rates of adverse events, serious adverse events or infections.
Dooley et al., 2011 conducted a 36 month randomized, double-blind, double dummy study comparing MMF (2 g per day) plus placebo and AZA (2 mg per kg per day) plus placebo for the maintenance of remission in 227 patients who met the response criteria during the ALMS 6-month induction trial with either MMF or IVC. 116 patients were randomly assigned to MMF and 111 to AZA. The primary endpoint was the time to treatment failure measured as the time until the first event defined as death, end-stage renal disease, sustained doubling of the serum creatinine level, renal flare, or the need for rescue therapy. Secondary assessments included the time to the individual components of treatment failure and adverse events. MMF was superior to AZA with respect to the primary end point, time to treatment failure (hazard ratio, 0.44; 95% confidence interval, 0.25 to 0.77; P = 0.003), and with respect to time to renal flare and time to rescue therapy (hazard ratio, < 1.00; P < 0.05). Observed rates of treatment failure were 16.4% (19 of 116 patients) in the MMF group and 32.4% (36 of 111) in the AZA. Adverse events, most commonly minor infections and gastrointestinal disorders, occurred in more than 95% of the patients in both groups (P = 0.68). Serious adverse events occurred in 33.3% of patients in the AZA group and in 23.5% of those in the MMF group (P = 0.11), and the rate of withdrawal due to adverse events was higher with AZA than with MMF (39.6% vs. 25.2%, P = 0.02).

Doses used in clinical studies.

The doses of mycophenolate sodium (or the equivalent doses when administered as mycophenolate mofetil) used in the published clinical studies were varied. Doses used for induction: In the pivotal 24-week ALMS study (Appel et al., 2009) the target dose of MMF was 3 g per day (equivalent of 2.16 g mycophenolate sodium or 720 mg three times daily). The median dosage of MMF was calculated as 2.6 g/day. In another 24-week published study (Ginzler et al., 2005), patients were treated with escalating doses of MMF up to 3 g per day (equivalent of 2.16 g mycophenolate sodium or 720 mg three times daily). In this study the mean maximum tolerated dose of MMF was 2.68 g per day (equivalent to 1.93 g mycophenolate sodium or nearly 720 mg three times daily). Doses used for maintenance: In the pivotal long term maintenance study (Dooley et al., 2011), the target dose of MMF was 2 g/day (equivalent to mycophenolate sodium 720 mg twice daily); 80% of patients received a daily dose of 1.6 mg or more.

5.2 Pharmacokinetic Properties

Absorption.

Following oral administration, mycophenolate sodium is extensively absorbed. The median time to maximum MPA plasma concentration (t_max) is 2 hours (Table 4) but there is significant variability, especially with food, with values up to 16 hours fasting and 24 hours fed. In vitro studies demonstrated that the enteric-coated formulation of mycophenolic acid prevents the release of MPA under acidic condition, as in the stomach.
In stable renal transplant patients on ciclosporin (Neoral) based immunosuppression, the mean absolute bioavailability of mycophenolic acid tablets was 71% (range: 38-98%). Mycophenolic acid pharmacokinetics are dose proportional and linear over the studied dose range of 180 to 2160 mg. Compared to the fasting state, administration of mycophenolic acid 720 mg with a high fat meal had no effect on the systemic exposure (AUC) of MPA, which is the most relevant pharmacokinetic parameter linked to efficacy. However, there was a 33% decrease in the maximal plasma concentration (C_max) of MPA and a delay in t_max when mycophenolic acid was given with a high fat meal.

Distribution.

The volume of distribution at steady state for MPA is 50 litres. Both MPA and its major metabolite, mycophenolic acid glucuronide (MPAG), are highly protein bound, 97% and 82%, respectively. The free MPA concentration may increase under conditions of decreased protein binding sites (uraemia, hepatic failure, hypoalbuminaemia, concomitant use of drugs with high protein binding) and this may put patients at increased risk of MPA-related adverse effects.

Metabolism.

The half life of MPA (mean ± SD) is 11.7 ± 3.2 hours and the clearance (mean ± SD) is 8.4 ± 1.8 L/hr. MPA is metabolised principally by glucuronyl transferase to form the phenolic glucuronide of MPA, mycophenolic acid glucuronide. MPAG is the predominant metabolite of MPA and is pharmacologically inactive. In stable renal transplant patients on Neoral based immunosuppression, approximately 28% of the oral mycophenolic acid dose is converted to MPAG by presystemic metabolism. The half-life of MPAG (mean ± SD) is approximately 15.7 ± 3.9 hours and its clearance (CL/f_m) is about 0.45 ± 0.15 L/hr (mean ± SD).

Excretion.

Although negligible amounts of MPA are present in the urine (< 1%), the majority of MPA is eliminated in the urine as MPAG. MPAG secreted in the bile is available for deconjugation by gut flora. The MPA resulting from this deconjugation may then be reabsorbed.
Approximately 6-8 hours after mycophenolic acid dosing, a second peak of MPA concentration can be measured, consistent with reabsorption of the deconjugated MPA.

Pharmacokinetics in renal transplant patients on ciclosporin based immunosuppression.

Table 4 shows the mean pharmacokinetic parameters for MPA following administration of mycophenolic acid. In the early post-transplant period, mean MPA AUC and mean MPA C_max were approximately one-half of that measured six months post-transplant.

Pharmacokinetics in special patient groups.

Gender.

There are no clinically significant gender differences in mycophenolic acid pharmacokinetics.

Elderly.

Pharmacokinetics in the elderly have not been formally studied. The exposure of MPA does not appear to vary to a clinically significant degree by age.

Impaired renal function.

There are no data for mycophenolic acid. After a single dose of mycophenolate mofetil containing an equivalent amount of MPA to 720 mg of mycophenolic acid, clearance of MPA appeared to be reduced with increasing levels of renal impairment. The area under the MPA plasma concentration time curve (MPA exposure) increased by up to 30% in patients with mild to moderate renal impairment (GFR 25-80 mL/min/1.73 m²) and 75% in patients with severe renal impairment (GFR < 25 mL/min/1.73 m²). However, there was considerable variability and small numbers of subjects (6-7 at each level of renal impairment). MPAG exposure was 3 to 6-fold higher in subjects with moderate to severe renal impairment, which was consistent with renal elimination of MPAG.
At higher MPAG concentrations (observed in patients with renal impairment or delayed graft function), plasma protein binding of MPA may be reduced as a result of competition between MPAG and MPA for binding sites. This would result in increased free MPA in plasma.

Impaired hepatic function.

There are no data for mycophenolic acid. After a single dose of mycophenolate mofetil equivalent to 720 mg MPA in patients with alcoholic cirrhosis, hepatic MPA glucuronidation processes were relatively unaffected by hepatic parenchymal disease. Effects of hepatic disease on this process probably depend on the particular disease. However, hepatic disease with predominantly biliary damage, such as primary biliary cirrhosis, may show a different effect.

5.3 Preclinical Safety Data

Genotoxicity.

Mycophenolate sodium and mycophenolate mofetil were genotoxic in the mouse lymphoma/thymidine kinase assay, the micronucleus test in V79 Chinese hamster cells in vitro and in the in vivo mouse micronucleus assay. They were not genotoxic in the bacterial mutation assay. Mycophenolate sodium showed weak evidence of genotoxicity in the chromosome aberration assay in human lymphocytes. There were no relevant qualitative or quantitative differences in the genotoxic potential of mycophenolate sodium and mycophenolate mofetil. The genotoxic activity of MPA may be due to a shift in the relative abundance of the nucleotides in the cellular pool used for DNA synthesis.

Carcinogenicity.

In a 104-week oral carcinogenicity study in rats, mycophenolate sodium at daily doses up to 9 mg/kg was not tumorigenic. The highest dose tested resulted in approximately 0.6-1.2 times the systemic exposure observed in renal transplant patients at the recommended dose of 1.44 g/day. Similar results were observed in a parallel study in rats performed with mycophenolate mofetil. In a 26-week oral carcinogenicity assay in a P53 (heterozygous) transgenic mouse model, mycophenolate sodium at daily doses up to 200 mg/kg was not tumorigenic. The highest dose tested resulted in approximately 5 times the systemic exposure (plasma AUC) observed in renal transplant patients taking 1.44 g/day. The results of this study, however, remain equivocal because of the lack of a response to the positive control compound, benzene.
In a 2-year carcinogenicity study in rats, administration of oral doses of 6 and 9 mg/kg/day mycophenolate sodium resulted in an increase in the incidence of benign thymomas in the thymus in females. Systemic exposure (plasma AUC) at these respective doses was about 0.5 and 1 times that observed in renal transplant patients taking 1.44 g/day.

6 Pharmaceutical Particulars

6.1 List of Excipients

Mycophenolic acid enteric coated tablets contain excipients microcrystalline cellulose, croscarmellose sodium, povidone, purified talc, colloidal anhydrous silica, magnesium stearate, black ink and enteric film coating.
The black ink contains shellac, iron oxide black and propylene glycol.
The enteric film coating contains methacrylic acid - ethyl acrylate copolymer (1:1), purified talc, titanium dioxide, triethyl citrate, colloidal anhydrous silica, sodium bicarbonate, sodium lauryl sulfate, iron oxide yellow, indigo carmine aluminium lake (180 mg tablets only) and iron oxide red (360 mg tablets only).

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 in original package and container below 25°C. Protect from moisture. Keep out of reach of children.

6.5 Nature and Contents of Container

Mycophenolic Acid ARX tablets are packed in Al/Al (Aluminium/Aluminium) blister packs.
Mycophenolic Acid ARX tablets 180 mg are available in 20, 50, 100, and 120 tablets pack sizes.
Mycophenolic Acid ARX tablets 360 mg are available in 50, 100 and 120 tablets pack sizes.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.

Chemical name: (E)-6-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methyl-hex-4-enoic acid sodium salt.
Molecular formula: C₁₇H₁₉O₆Na.
Molecular weight: 342.32.

CAS number.

37415-62-6.
Mycophenolate sodium is the sodium salt of the active moiety, mycophenolic acid, and is a white to off-white, fine crystalline powder. It is freely soluble in aqueous media at physiological pH, as in the upper intestine, but practically insoluble in 0.1 M HCl.

7 Medicine Schedule (Poisons Standard)

Prescription only medicine - S4.

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Consumer medicine information

Mycophenolic Acid ARX

Mycophenolic acid

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