Consumer medicine information

Mycotex

Mycophenolate sodium

BRAND INFORMATION

Brand name

Mycotex

Active ingredient

Mycophenolate sodium

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Mycotex.

SUMMARY CMI

MYCOTEX

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 MYCOTEX?

MYCOTEX contains the active ingredient mycophenolate sodium. MYCOTEX is used in adult patients: 1) to prevent the body from rejecting a transplanted kidney; 2) It is also used to treat inflammatory kidney disease associated with chronic autoimmune disorder known as systemic lupus erythematosis (also called lupus or SLE). MYCOTEX is used in combination with other medicines. For more information, see Section 1. Why am I using MYCOTEX? in the full CMI.

2. What should I know before I use MYCOTEX?

Do not use if you have ever had an allergic reaction to mycophenolate sodium 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 MYCOTEX? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with MYCOTEX 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 MYCOTEX?

  • The usual dose is 1,440 mg, taken as 720 mg twice a day.
  • Doctor may prescribe a different dose, particularly for the initial treatment of inflammatory kidney disease.

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

5. What should I know while using MYCOTEX?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using MYCOTEX.
  • Ensure you keep all your doctor's appointments and have any tests (including blood tests) ordered by your doctor.
  • Use effective contraception measures while you are taking MYCOTEX.
  • Tell your doctor immediately, if you have COVID-19 or if you become pregnant while taking MYCOTEX.
  • Tell your doctor immediately, if you develop lumps or notice any moles anywhere in your body or if you notice changes in existing moles – this may be a sign of cancer.
Things you should not do
  • Do not stop using this medicine without first checking with your doctor.
  • Do not have any vaccinations without first checking with your doctor.
Driving or using machines
  • Be careful driving, operating machinery or doing jobs that require you to be alert while you are taking MYCOTEX 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.
Looking after your medicine
  • Store below 25°C. Store in original container to protect from moisture.
  • Keep your tablets in the foil blister pack until it is time to take them.

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

6. Are there any side effects?

Less serious side effects: diarrhoea, constipation, indigestion, flatulence, loose stools, nausea (feeling sick), or vomiting, pain in the stomach, pain or swelling in the joints, weakness.

Serious side effects: symptoms of infection including fever, chills, sweating, feelings of tiredness, drowsiness, or lack of energy. 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

MYCOTEX

Active ingredient(s): mycophenolate sodium

Consumer Medicine Information (CMI)

This leaflet provides important information about using MYCOTEX. 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 MYCOTEX.

Where to find information in this leaflet:

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

1. What am I using MYCOTEX?

MYCOTEX contains the active ingredient, mycophenolate sodium.

MYCOTEX belongs to a group of medicines called immunosuppressives. These medicines work by stopping your immune system from rejecting the transplanted organ.

MYCOTEX is used for people who have had a kidney transplant, to prevent the body from rejecting the new kidney. It is also used for people who have inflammatory kidney disease associated with a chronic autoimmune disorder known as systemic lupus erythematosis (also called lupus or SLE). MYCOTEX is used in combination with other medicines.

2. What should I know before I use MYCOTEX?

Warnings

Do not use MYCOTEX if:

  • you are allergic to mycophenolate sodium (the active ingredient in MYCOTEX), or any of the ingredients listed at the end of this leaflet.
  • you are pregnant, think you may be pregnant, or intend to become pregnant.
  • you are not using effective contraception.
  • you are breastfeeding.
  • the package is torn or shows signs of tampering
  • the expiry date printed on the pack has passed

Always check the ingredients to make sure you can use this medicine.

Check with 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 Kelley-Seegmiller syndrome (a 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 MYCOTEX or may want to take precautions if you have any of the above conditions.

  • plan to have vaccinations.
  • are lactose intolerant as MYCOTEX tablets contain lactose.
  • are allergic to any other medicines, foods, dyes or preservatives.

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant. You must not take MYCOTEX if you are pregnant. 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 MYCOTEX.

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

  • Talk to your doctor if you are breastfeeding or intend to breastfeed. You must not breastfeed during treatment with MYCOTEX. This is because small amounts of the medicine can pass into the mother's milk.

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?

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 a pharmacy, supermarket or health food shop.

Some medicines may interfere with MYCOTEX. 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 MYCOTEX and you could become pregnant. Talk to your doctor about other birth control methods that can be used while you are taking MYCOTEX.

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

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

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

4. How do I use MYCOTEX?

How much to take

  • The usual dose is 1,440 mg, taken as 720 mg twice a day. Your doctor may have prescribed a different dose, particularly for the initial treatment of inflammatory kidney disease.
  • Take MYCOTEX exactly as your doctor has prescribed.
    This will ensure that this medicine will work properly and prevent any unwanted side effects.

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

When to take MYCOTEX

  • MYCOTEX should be taken twice a day, 12 hours apart if possible. Taking your doses 12 hours apart will have the best effect.
  • If you have had a renal transplant, your first dose will usually be given within 48 hours after your transplant.

How to take MYCOTEX

  • 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 MYCOTEX with or without food.
    It does not matter if you take MYCOTEX after food or on an empty stomach, if you take it the same way each day.
  • If you take it with food, always take it with food.
  • If you take it without food, always take it without food.

If you forget to use MYCOTEX

MYCOTEX should be used regularly at the same time each day. This will also help you remember when to take it.

If it is almost time for your next dose, skip the dose you missed and take the next dose when you are meant to. Otherwise, take it as soon as you remember, and then go back to taking it as you would normally.

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

If you miss more than one dose, contact your doctor as soon as possible.

If you take too much MYCOTEX

If you think that you have used too much MYCOTEX, 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 MYCOTEX?

Things you should do

  • Make sure to keep all of your doctor's appointments and have any tests done that are ordered by your doctor.
  • If you are about to be started on any new medicine, remind your doctor, dentist or pharmacist you visit that you are using MYCOTEX.
  • If you are a woman of child-bearing age, you must use effective contraception measures before you take MYCOTEX, while you are taking MYCOTEX, and for 6 weeks after you stop taking MYCOTEX. 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 MYCOTEX 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 MYCOTEX.
  • 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

Call your doctor straight away if you:

  • Have COVID-19. Increased severity of COVID-19 may occur with MYCOTEX.
  • are a woman or child-bearing age, taking effective contraception measures and you think your contraception may not have been effective or if you have forgotten to take your contraceptive pill
  • are a sexually active man, and your partner becomes pregnant while you are taking MYCOTEX.
  • develop lumps anywhere in your body, or develop any moles, or you notice changes in existing moles. This may be an early sign of a cancer. Immunosuppressant medicines, including MYCOTEX, may increase the risk of developing certain cancers, including skin cancer and lymphoma (cancer of the lymphatic system).

Things you should not do

  • Do not stop using this medicine without first checking with your doctor.
  • Do not have any vaccinations without first checking with your doctor.
  • Do not give MYCOTEX to anyone else even if their condition seems similar to yours.
  • Do not donate blood during treatment with MYCOTEX and for at least 6 weeks after stopping treatment.
  • Do not breastfeed during treatment with MYCOTEX and for 6 weeks after you have stopped taking MYCOTEX.
  • Men must not donate semen during treatment with MYCOTEX and for at least 90 days after stopping treatment.

Driving or using machines

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

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

Drinking alcohol

Tell your doctor if you drink alcohol.

Looking after your medicine

  • Keep your tablets in the foil blister pack until it is time to take them.
  • Store below 25°C.

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
  • Diarrhea, nausea (feeling sick), constipation, vomiting, loose stools, indigestion, flatulence, stomach pain, feeling bloated, tenderness in the stomach
  • Headache, dizziness, anxiety
  • Weakness, muscle pain, pain or swelling in the joints, tiredness
  • Cough, fever
  • Unusual bleeding or bruising
Speak to your doctor if you have any of these less serious side and they worry you:

Serious side effects

Serious side effectsWhat to do
  • Signs of severe allergic reactions including rash, itching, hives on the skin, swelling of the face, lips, tongues or other part of the body, breathlessness or difficulty breathing, wheezing or coughing, light-headedness, dizziness, changes in levels of consciousness, hypotension with or without mild generalized itching, skin reddening and facial/ throat swelling.
  • Enlarged glands, a new lump or mole on your skin, or changes to existing moles, anywhere on the body.
  • Vision changes, loss of coordination, clumsiness, memory loss, difficulty speaking or understanding what others say and muscle weakness.
  • Signs of infection including fever, chills, sweating, tiredness, drowsiness, urinary infections, respiratory tract infections and skin infections
  • Signs of anemia (decrease in red blood cells) including unusual tiredness, headache, shortness of breath, chest pain, looking pale.
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 if you notice anything else that is 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 MYCOTEX contains

Active ingredient
(main ingredient)		Mycophenolic Acid (as Mycophenolate Sodium USP) 360 mg
Other ingredients
(inactive ingredients)
  • Silicon Dioxide
  • Povidone
  • Lactose
  • Maize starch
  • Crospovidone
  • Magnesium Stearate
  • Hypromellose Phthalate
  • Triethyl Citrate
  • OPADRY II complete film coating system 85F540054 PINK
  • OPACODE monogramming ink S-1-17823 BLACK.
  • OPADRY II complete film coating system 85F540054 PINK contains polvinyl alcohol, titanium dioxide, macrogol, talc, iron oxide yellow and iron oxide red
  • OPACODE monogramming ink S-1-17823 BLACK contains shellac, iron oxide black, and propylene glycol

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

What MYCOTEX looks like

MYCOTEX 360 mg are pale orange-red colored, oval shaped, biconvex, film coated tablets imprinted “MA 360” with black ink on one side and plain on other side.

The film-coated tablets are packed in

  • Alu-Alu Blister Pack of 50's, 120's Tablets
  • HDPE Bottle Pack of 120's Tablets

Who distributes MYCOTEX

Pharmacor Pty Ltd.
CHATSWOOD, NSW 2067,
Australia

Australian Registration Numbers:

360 mg enteric-coated tablet bottle pack: 391535

360 mg enteric-coated tablet blister pack: 391538

This leaflet was prepared in 12/2024

Published by MIMS March 2025

BRAND INFORMATION

Brand name

Mycotex

Active ingredient

Mycophenolate sodium

Schedule

S4

 

1 Name of Medicine

Mycophenolate sodium.

2 Qualitative and Quantitative Composition

Each enteric coated 360 mg tablet contains Mycophenolic acid 360 mg (as sodium).

Excipients with known effect.

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

3 Pharmaceutical Form

Mycotex 360 mg.

Pale orange-red colored, oval shaped, biconvex, film-coated tablets imprinted "MA 360" with black ink on one side and plain on other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Mycotex is indicated for the prophylaxis of acute transplant rejection in adult patients receiving allogeneic renal transplants.
Mycotex is 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

Mycotex is unavailable in the 180 mg tablet strength. The 180 mg tablet is available in other brands.
Treatment with Mycotex 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.
Mycotex should not be initiated in women of childbearing 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 childbearing potential; 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. Mycotex and CellCept (mycophenolate mofetil) should not be indiscriminately interchanged or substituted because of their different pharmacokinetic profiles.
Mycotex tablets should not be crushed and should be swallowed whole. Patients should be advised to take Mycotex 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.

Mycotex 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 postoperatively. Patients with severe chronic renal impairment (glomerular filtration rate < 25 mL.min-1.1.73 m2) 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 Mycotex 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 Mycotex 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

Mycotex is 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, Use in pregnancy). Mycotex is contraindicated in women who are breastfeeding (see Section 4.6 Fertility, Pregnancy and Lactation, Use in lactation) and in women of childbearing 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 childbearing 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

Embryofoetal toxicity.

Mycotex can cause foetal harm when administered to a pregnant woman. Use of Mycotex 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 childbearing potential.

Mycotex 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 tests 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 childbearing potential must use highly effective contraception. Two types of reliable contraception should start simultaneously before beginning Mycotex therapy, during therapy and for six weeks after their last dose of Mycotex; 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 Mycotex could reduce the efficacy of oral contraceptives (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Pregnancy and breastfeeding, fertility and male patients.

For information on use in pregnancy, breastfeeding and contraceptive requirements, 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 childbearing potential.

Malignancies.

Patients receiving immunosuppressive regimens involving combinations of drugs, including Mycotex, 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 Mycotex should be instructed to immediately report any evidence of infection, unexpected bruising, bleeding or any other manifestation of bone marrow depression.
Oversuppression 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 mycophenolate sodium 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 Mycotex 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.
Mycophenolic acid has a cytostatic effect on B- and T-lymphocytes, therefore an increased severity of COVID-19 may occur, and appropriate clinical action should be considered.

Blood dyscrasias.

Patients receiving Mycotex 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 Mycotex 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 x109/L or anaemia), it may be appropriate to interrupt or discontinue Mycotex.
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 metabolised to mycophenolic acid (MPA), the active ingredient in Mycotex 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 (see above). 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 Mycotex therapy should only be undertaken under appropriate supervision in transplant recipients in order to minimise the risk of graft rejection.

Vaccinations.

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, Mycotex should be administered with caution in patients with active serious digestive system disease.

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

Mycotex 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.

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.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Mycophenolate sodium 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 Mycotex with other immunosuppressive agents have not been studied.

Oral contraceptives.

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

Azathioprine.

It is recommended that Mycotex 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 Mycotex with aciclovir has not been studied. After coadministration 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 Mycotex.

Ganciclovir.

Concomitant use of Mycotex 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 Mycotex 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 Mycotex pharmacokinetics were determined during concomitant ciclosporin (Neoral) and tacrolimus (Prograf) treatments. Mean MPA AUC was 19% higher and Cmax about 20% lower, and mean MPAG AUC and Cmax 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 Mycotex 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 mycophenolate sodium 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 coadministering antacids containing magnesium and aluminium hydroxide with Mycotex.

Proton pump inhibitors.

In healthy volunteers, no changes in the pharmacokinetics of MPA were observed following concomitant administration of mycophenolate sodium 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 coadministering cholestyramine or drugs that interfere with enterohepatic circulation because of the potential to reduce the efficacy of Mycotex.

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 a total of 13 weeks after their last dose of Mycotex. 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 use highly effective contraception during treatment and for a total of 13 weeks after the last dose of Mycotex.
(Category D)
The use of Mycotex 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 counselled 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 postmarketing in children of patients exposed to mycophenolate mofetil in combination with other immunosuppressants during pregnancy. The following malformations were most frequently reported:
abnormalities of the ear (e.g. abnormally formed or absent external/middle ear), external auditory canal atresia;
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.
Mycotex is contraindicated in women who are breastfeeding 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 Mycotex 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 mycophenolate sodium 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 mycophenolate sodium for up to 1 year; non-melanoma skin carcinomas occurred in 2 de novo patients (0.9%) and 3 maintenance patients (1.9%) receiving mycophenolate sodium 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 mycophenolate sodium 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 mycophenolate sodium 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 mycophenolate sodium, reported in the two phase III randomised, double blind, controlled, multicentre trials: 1 in de novo renal transplant patients and 1 in maintenance renal transplant patients, in which mycophenolate sodium 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% (≥ 1/10,000 and < 1/1000); very rare: < 0.01% (< 1/10,000).
Renal transplant patients were treated with 1440 mg mycophenolate sodium 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 Mycotex as part of a combination immunosuppressive regimen did not show an increased risk of adverse reactions compared to younger individuals in the mycophenolate sodium clinical trials.

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

Mycophenolate sodium 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 mycophenolate sodium and a standard corticosteroid regimen (prednisolone 1 mg/kg bodyweight/day, tapered) with mycophenolate sodium 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 mycophenolate sodium and standard corticosteroid group and by 30/39 (76.9%) patients in the mycophenolate sodium 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 mycophenolate sodium and standard corticosteroid group compared with the mycophenolate sodium 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 4.4 Special Warnings and Precautions for Use; Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy).

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, Infections).

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 Mycotex 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 nonlymphoid 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 multicentre, 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 mycophenolate sodium. 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 mycophenolate sodium (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 mycophenolate sodium 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 mycophenolate sodium (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 mycophenolate sodium 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 postrandomisation, 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 mycophenolate sodium and a standard corticosteroid regimen (prednisolone 1 mg/kg bodyweight/day, tapered) with mycophenolate sodium 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. Mycophenolate sodium 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 a 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 mycophenolate sodium and standard corticosteroid-treated patients and 8/39 (20.5%) of mycophenolate sodium 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 gram 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 g or more.

5.2 Pharmacokinetic Properties

Absorption.

Following oral administration, mycophenolate sodium is extensively absorbed. The median time to maximum MPA plasma concentration (tmax) is 2 hours (see 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 mycophenolate sodium 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 mycophenolate sodium tablets was 71% (range: 38-98%). mycophenolate sodium pharmacokinetics are dose proportional and linear over the studied dose range of 180 to 2160 mg. Compared to the fasting state, administration of mycophenolate sodium 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 (Cmax) of MPA and a delay in tmax when mycophenolate sodium 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 mycophenolate sodium 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/fm) 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 Mycotex 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 mycophenolate sodium. In the early post transplant period, mean MPA AUC and mean MPA Cmax 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 Mycotex 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 Mycotex. After a single dose of mycophenolate mofetil containing an equivalent amount of MPA to 720 mg of Mycotex, 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 Mycotex. 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

Excipients: silicon dioxide, povidone, lactose, maize starch, crospovidone, magnesium stearate, hypromellose phthalate, triethyl citrate, Opadry II complete film coating system 85F540054 pink, Opacode monogramming ink S-1-17823 black.
Opadry II complete film coating system 85F540054 pink contains polyvinyl alcohol, titanium dioxide, macrogol, talc, iron oxide yellow and iron oxide red.
Opacode monogramming ink S-1-17823 black contains shellac, iron oxide black, and propylene glycol.

6.2 Incompatibilities

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

6.3 Shelf Life

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

6.4 Special Precautions for Storage

Store below 25°C. Store in original container to protect from moisture. Keep out of reach of children.

6.5 Nature and Contents of Container

Alu-Alu blister pack of 50's and 120's tablets.
HDPE bottle pack of 120's tablets.

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

Mycophenolate sodium is the sodium salt of the active moiety, mycophenolic acid, and is a white to off-white, fine crystalline powder.
Mycophenolate sodium is freely soluble in aqueous media at physiological pH, as in the upper intestine, but practically insoluble in 0.1 M HCl.
Chemical name: (E)-6-(4- Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4methyl-hex-4-enoic acid sodium salt.
Empirical formula: C17H19O6Na.
Molecular weight: 342.32.

Chemical structure.


CAS number.

37415-62-6.

7 Medicine Schedule (Poisons Standard)

Schedule 4.

Summary Table of Changes