Consumer medicine information

Mycophenolate Sandoz

Mycophenolate mofetil

BRAND INFORMATION

Brand name

Mycophenolate Sandoz

Active ingredient

Mycophenolate mofetil

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Mycophenolate Sandoz.

What is in this leaflet

This leaflet answers some common questions about Mycophenolate Sandoz.

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking this medicine against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may want to read it again.

What Mycophenolate Sandoz is used for

Mycophenolate Sandoz contains the active ingredient mycophenolate mofetil.

Mycophenolate Sandoz belongs to a group of medicines called immunosuppressants.

Immunosuppressants are used to prevent rejection of transplanted organ and works by stopping your immune system from reacting to the transplanted organ.

There are many different types of medicines used to prevent rejection of a transplanted organ.

Mycophenolate Sandoz may be used together with other medicines known as ciclosporin and corticosteroids.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

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

Mycophenolate Sandoz is not addictive.

Before you take Mycophenolate Sandoz

When you must not take it

Do not take this medicine if you have an allergy to:

  • mycophenolate mofetil, the active ingredient, or to any of the other ingredients listed at the end of this leaflet under Product description.

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin.

Do not take this medicine if you are pregnant. Mycophenolate Sandoz is harmful to an unborn baby when taken by a pregnant woman. There have been cases of miscarriage and severe birth defects reported when patients have taken mycophenolate mofetil during pregnancy. You must tell your doctor if you are pregnant or plan to become pregnant.

Do not take this medicine if you are breastfeeding. Mycophenolate Sandoz may pass into human breast milk and cause serious side effects in your baby if you breastfeed.

Do not take this medicine if you are a woman who could become pregnant and you are not using two reliable forms of contraception. You must use two reliable forms of contraception at the same time before beginning mycophenolate mofetil therapy, during therapy and for at least six weeks after stopping mycophenolate mofetil, unless you are not sexually active.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

If you take this medicine after the expiry date has passed it may not work as well.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

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

Tell your doctor if you are pregnant or plan to become pregnant.

If you are a woman of child bearing potential, you must have two negative pregnancy tests 8-10 days apart just prior to starting treatment with mycophenolate mofetil.

Repeat pregnancy tests will be performed during routine follow-up visits with your doctor.

Tell your doctor if you are breastfeeding or plan to breastfeed.

Tell your doctor if you are a sexually active man.

You are recommended to use condoms during treatment and for 90 days after stopping treatment, even if you have had a vasectomy. Your female partner(s) are recommended to use reliable contraception while you are being treated with mycophenolate mofetil and for 90 days after you have stopped receiving mycophenolate mofetil.

You should not donate semen while you are being treated with Mycophenolate Sandoz and for 90 days after you have stopped receiving this medicine.

You should not donate blood while you are being treated with Mycophenolate Sandoz and for at least 6 weeks after you stop receiving this medicine.

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

  • a history of sun spots or skin cancers
  • a history of low blood counts of neutrophils (a type of white blood cell)
  • a history of serious stomach or bowel problems (such as ulcers or bleeding)
  • rare diseases due to a deficiency of the HGPRT enzyme such as Lesch-Nyhan or Kelley-Seegmiller syndrome
  • kidney disease.

If you have not told your doctor about any of the above, tell him/her before you start taking Mycophenolate Sandoz.

Taking other medicines

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

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

  • azathioprine, tacrolimus and sirolimus, medicines used to suppress the immune system which can be used to prevent organ rejection after a transplant
  • acyclovir, ganciclovir, valaciclovir or valganciclovir, medicines used to treat viral infections
  • isavuconazole, a medicine used to treat fungal infections
  • antacids, medicines used to treat heartburn and indigestion
  • proton pump inhibitors, medicines used to treat indigestion and stomach ulcers such as lansoprazole and pantoprazole
  • cholestyramine, a medicine used to treat high cholesterol
  • ciprofloxacin, amoxicillin plus clavulanic acid, norfloxacin plus metronidazole and rifampicin, medicines used to treat infections
  • iron supplements, medicines used to treat low iron levels in the blood
  • certain vaccines, (especially live vaccines), medicines that work by causing your body to produce its own protection against an infectious disease
  • calcium-free phosphate binders (such as sevelamer), medicines used to treat high phosphate levels in the blood.

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

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

How to take Mycophenolate Sandoz

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions, ask your doctor or pharmacist for help.

How much to take

Take Mycophenolate Sandoz exactly as your doctor has prescribed. Your doctor will tell you how many Mycophenolate Sandoz capsules or tablets to take each day.

Ask your doctor or pharmacist if you are unsure of the correct dose for you. They will tell you exactly how much to take.

Follow the instructions they give you. If you take the wrong dose, Mycophenolate Sandoz may not work as well and your problem may not improve.

The dose to prevent organ rejection is usually 1 g to 1.5 g in the morning and 1 g to 1.5 g at night (2 g to 3 g per day) depending on which organ has been transplanted.

How to take it

Swallow the tablets/capsules whole with a glass of water.

Do not crush tablets or open or crush capsules. If a capsule breaks open accidentally, wash any powder off your skin with soap and water.

When to take Mycophenolate Sandoz

It is best to take doses of Mycophenolate Sandoz approximately 12 hours apart.

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

How long to take Mycophenolate Sandoz

This medicine should be taken every day. It is important to keep taking Mycophenolate Sandoz to ensure your new transplant keeps working properly.

Continue taking your medicine for as long as your doctor tells you.

If you forget to take it

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

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

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

If you are not sure what to do, ask your doctor or pharmacist.

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

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone Australia 13 11 26 or New Zealand 0800 POISON or 0800 764766) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much Mycophenolate Sandoz. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

If you are not sure what to do, contact your doctor or pharmacist.

While you are taking Mycophenolate Sandoz

Things you must do

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

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

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

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

If you are a woman of child bearing potential, you must use two reliable forms of contraception at the same time before beginning mycophenolate mofetil therapy, during therapy and for at least six weeks after stopping mycophenolate mofetil, unless you are not sexually active.

If you are a sexually active male, you are recommended to use condoms during treatment and for 90 days after stopping treatment, even if you have had a vasectomy.

Your female partner(s) are recommended to use reliable contraception while you are being treated with mycophenolate mofetil and for 90 days after you have stopped receiving mycophenolate mofetil.

Tell your doctor if, for any reason, you have not taken your medicine exactly as prescribed. Otherwise, your doctor may think that it was not effective and change your treatment unnecessarily.

Tell your doctor if you feel your medicine is not helping your condition.

Keep all of your doctor's appointments so that your progress can be checked. Your doctor will need to give you regular blood tests.

Wear protective clothing and a broad-spectrum sunscreen when outdoors. Medicines that prevent rejection of transplants can increase the risk of skin cancers.

Things you must not do

Do not stop taking your medicine or change the dose without checking with your doctor.

Do not let yourself run out of medicine over the weekend or on holidays.

Do not give your medicine to anyone else, even if they have the same condition as you.

Do not take Mycophenolate Sandoz to treat any other complaints unless your doctor tells you to.

Do not crush Mycophenolate Sandoz tablets or open Mycophenolate Sandoz capsules.

Do not take any other medicines whether they require a prescription or not without first telling your doctor or consulting a pharmacist.

Things to be careful of

Be careful driving or operating machinery until you know how Mycophenolate Sandoz affects you experience somnolence, confusion, dizziness, tremor or hypotension. Mycophenolate Sandoz may affect your ability to drive a car or operate machinery.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Mycophenolate Sandoz.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Mycophenolate Sandoz helps most people who have transplants but it may have unwanted side effects in a few people.

To stop you rejecting your organ, transplant medications reduce your body's own defence mechanisms. This means your body will not be as good at fighting infection. People taking this medicine therefore develop more infections than usual.

Patients who receive immunosuppressant medicines may also have a small increase in their risk of developing some types of cancer. You should discuss this with your doctor.

If you are over 65 years of age you may have an increased chance of side effects occurring due to immunosuppression.

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

Ask your doctor or pharmacist to answer any questions you may have.

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

  • diarrhoea, constipation, nausea (feeling sick) or indigestion
  • stomach, chest, back or other pain
  • headache
  • urinary infections.

The above list includes the more common side effects of Mycophenolate Sandoz.

If any of the following happen, tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

  • signs of other infections e.g. fevers, chills, sore throat or ulcers of the mouth, abdominal pain or bloody stools.
  • unexpected bruising or bleeding
  • signs of anaemia such as excessive tiredness, dizziness or looking pale
  • swelling of the hands, ankles or feet, lymph nodes.
  • Hypersensitivity
  • Breathing difficulties, pain in the chest, chronic cough with blood

The above list includes serious side effects. You may need urgent medical attention or hospitalisation. Serious side effects are rare.

This is not a complete list of all possible side effects. Others may occur in some people and there may be some side effects not yet known.

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

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

After taking Mycophenolate Sandoz

Storage

Keep your medicine in the original container.

If you take it out of its original container it may not keep well.

Keep your medicine in a cool dry place where the temperature stays below 30°C.

Do not store Mycophenolate Sandoz or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep it where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product description

What Mycophenolate Sandoz capsules look like

Mycophenolate Sandoz 250 mg - capsules, blue on one end and orange on the other.

Available in blister packs of 100 capsules.

Ingredients

Active ingredients:

  • Mycophenolate Sandoz 250 mg - 250 mg mycophenolate mofetil

Inactive ingredients:

The capsule fill contains:

  • pregelatinised maize starch
  • croscarmellose sodium
  • povidone
  • magnesium stearate.

The capsule shell contains:

  • gelatin
  • titanium dioxide
  • iron oxide red
  • iron oxide yellow
  • indigo carmine.

What Mycophenolate Sandoz tablets look like

Mycophenolate Sandoz 500 mg - lavender coloured, capsule shaped tablets, plain on both sides.

Available in blister packs of 50 tablets.

Ingredients

Active ingredients:

  • Mycophenolate Sandoz 500mg - 500mg mycophenolate mofetil

Inactive ingredients:

  • microcrystalline cellulose
  • povidone
  • purified talc
  • croscarmellose sodium
  • magnesium stearate
  • hypromellose
  • hyprolose
  • titanium dioxide
  • macrogol 400
  • iron oxide black
  • iron oxide red.

Mycophenolate Sandoz tablets and capsules do not contain lactose, sucrose, gluten, tartrazine or any other azo dyes.

Not all strengths or presentations may be marketed.

Supplier

Sandoz Pty Ltd
ABN 60 075 449 553
54 Waterloo Road
Macquarie Park, NSW 2113
Australia
Tel: 1800 726 369

Novartis New Zealand Ltd
PO Box 99102
Newmarket, Auckland 1149
New Zealand
Tel: 0800 354 335

This leaflet was revised in April 2021.

Australian Register Number(s)

  • Mycophenolate Sandoz 250 mg capsules - AUST R 148227 (blisters)
  • Mycophenolate Sandoz 500 mg tablets - AUST R 148225 (blisters)

Published by MIMS June 2021

BRAND INFORMATION

Brand name

Mycophenolate Sandoz

Active ingredient

Mycophenolate mofetil

Schedule

S4

 

1 Name of Medicine

Mycophenolate mofetil (MMF).

2 Qualitative and Quantitative Composition

Each Mycophenolate Sandoz 250 mg capsules contains 250 mg mycophenolate mofetil.
Each Mycophenolate Sandoz 500 mg tablets contains 500 mg mycophenolate mofetil.
MMF is a white to off-white crystalline powder.
For the full list of excipients, see Section 6.1 List of Excipients.
Not all strengths may be marketed in Australia.

3 Pharmaceutical Form

Mycophenolate Sandoz 250 mg capsules.

Blue opaque cap with orange opaque body, containing white to off white coloured powder.

Mycophenolate Sandoz 500 mg tablets.

Capsule shaped, lavender coloured, film-coated biconvex tablet, plain on both sides.
Not all strengths may be marketed in Australia.

4 Clinical Particulars

4.1 Therapeutic Indications

Mycophenolate Sandoz is indicated for the prophylaxis of solid organ rejection in adults receiving allogeneic organ transplants.
Mycophenolate Sandoz is indicated for the prophylaxis of organ rejection in paediatric patients (6 to 18 years) receiving allogeneic renal transplants.

4.2 Dose and Method of Administration

Dosage.

The initial dose of Mycophenolate Sandoz should be given as soon as clinically feasible following transplantation.

Adults.

Renal transplantation.

The recommended dose in renal transplant patients is 1 g twice daily (2 g daily dose).

Cardiac transplantation.

The recommended dose in cardiac transplant patients is 1.5 g administrated orally twice daily (3 g daily dose).

Hepatic transplantation.

The recommended dose in hepatic transplant patients is 1 g twice daily (2 g daily dose) followed by 1.5 g twice daily (3 g daily dose).

Other transplants.

The recommended dose in other transplants is 2 to 3 g per day depending on the level of immunosuppression required.

Children (6-18 years).

The recommended dose for renal transplant patients is 600 mg/m2 of MMF administered twice daily (up to a maximum of 2 g daily).

Monitoring advice.

Complete blood counts should be performed weekly during the first month, twice monthly for the second and third months of treatment, then monthly through the first year. If neutropenia develops (Absolute Neutrophil Count (ANC) < 1.3 x 109/L), dosing with Mycophenolate Sandoz should be interrupted or the dose reduced and the patient carefully observed (see Section 4.4 Special Warnings and Precautions for Use). Patients should be advised to report immediately any evidence of infection, unexpected bruising, bleeding or any other manifestation of bone marrow depression.

Method of administration.

For oral administration.
Mycophenolate Sandoz may be administered in combination with ciclosporin and corticosteroids.

Dosage adjustment.

Renal impairment.

In renal transplant patients with severe chronic renal impairment (GFR < 25 mL/min/1.73 m2) outside of the immediate post-transplant period, doses of Mycophenolate Sandoz greater than 1 g administered twice a day should be avoided. No data are available in cardiac or hepatic allograft recipients with severe chronic renal impairment. These patients should also be carefully observed. No dose adjustments are needed in patients experiencing delayed renal allograft function postoperatively.

Hepatic impairment.

No data are available for cardiac transplant patients with severe hepatic parenchymal disease.
No dosage adjustment is required in the elderly or in renal transplant patients with hepatic parenchymal disease.

4.3 Contraindications

Allergic reactions to MMF have been observed, therefore, Mycophenolate Sandoz is contraindicated in patients with a hypersensitivity to MMF, mycophenolic acid (MPA) or any component of the capsules and tablets.
Mycophenolate Sandoz is contraindicated during pregnancy due to its mutagenic and teratogenic potential (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy).
Mycophenolate Sandoz is contraindicated in women of childbearing potential not using highly effective contraceptive methods (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy).
Mycophenolate Sandoz is contraindicated in women who are breastfeeding (see Section 4.6 Fertility, Pregnancy and Lactation, Use in lactation).

4.4 Special Warnings and Precautions for Use

General.

Female patients of childbearing potential must use effective contraception before, during and for six weeks after receiving MMF. MMF is contraindicated during pregnancy and during breastfeeding (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy, Use in lactation).
Men should not donate semen during therapy and for 90 days following discontinuation of MMF.

Neoplasms.

As with other patients receiving immunosuppressive regimes involving combinations of medicines, patients receiving MMF as part of an immunosuppressive regime are at an increased risk of developing lymphomas and other malignancies, particularly of the skin. The risk appears to be related to the intensity and duration of immunosuppression rather than the use of any specific agent. Approximately 1% of patients receiving MMF with other immunosuppressive agents in the controlled studies of prevention of rejection have developed lymphoproliferative disease or lymphoma. As immunosuppression increases the risk of skin cancer, patients should also be advised to limit their exposure to sunlight and other sources of UV light by wearing protective clothing and using sunscreen with a high protection factor.

Infections.

Oversuppression of the immune system can also increase susceptibility to infection, including opportunistic infections, fatal infections and sepsis. In the controlled studies for the prevention of rejection, the incidence of fatal infection was similar in patients receiving MMF or control therapy in combination with other immunosuppressive agents. There was a higher incidence of fatal infection in the liver transplant study (5%) compared with the other studies (2%).
Such infections include latent viral reactivation, such as hepatitis B or hepatitis C reactivation or infections caused by polyomaviruses. Cases of hepatitis due to reactivation of hepatitis B or hepatitis C have been reported in carrier patients treated with immunosuppressants. Cases of Progressive Multifocal Leukoencephalopathy (PML) associated with the JC virus, sometimes fatal, have been reported in patients treated with MMF. Hemiparesis, apathy, confusion, cognitive deficiencies and ataxia were the most frequent clinical features observed. The reported cases generally had risk factors for PML, including concomitant immunosuppressant therapies and impaired immune function. 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. Consideration should be given to reducing the amount of immunosuppression in patients who develop PML. In transplant patients, physicians should also consider the risk that reduced immunosuppression represents to the graft.
BK virus associated nephropathy has been observed during the use of MMF in patients postrenal transplant. This infection can be associated with serious outcomes, sometimes leading to renal graft loss. Patient monitoring may help detect patients at risk of BK virus associated nephropathy. Reduction in immunosuppression should be considered for patients who develop evidence of BK virus associated nephropathy.

Blood and immune system.

Cases of pure red cell aplasia (PRCA) have been reported in patients treated with MMF in combination with other immunosuppressive agents. The mechanism for MMF induced PRCA is unknown; the relative contribution of other immunosuppressants and their combinations in an immunosuppression regimen are also unknown. In some cases, PRCA was found to be reversible with dose reduction or cessation of MMF therapy. In transplant patients however, reduced immunosuppression may place the graft at risk.
Patients receiving MMF should be instructed to immediately report any evidence of infection, unexpected bruising, bleeding or any other manifestation of bone marrow depression.
Patients on MMF should have complete blood counts weekly during the first month of treatment, twice monthly for the second and third months, then monthly through the first year. In particular, patients receiving MMF should be monitored for neutropenia. The development of neutropenia may be related to MMF, concomitant medications, viral infection, or some combination of these causes. If neutropenia develops (ANC < 1.3 x 103/microL), dosing with MMF should be interrupted or the dose reduced and the patient should be carefully observed.
0.5% of patients receiving MMF 2 g for prevention of rejection in renal transplantation, 2.8% of patients receiving MMF 3 g in cardiac transplantation and 3.6% of patients receiving MMF 3 g in hepatic transplantation, developed severe neutropenia (ANC < 5 x 108/L).
Patients should be advised that during treatment with MMF, 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. Physicians should refer to the national guidelines for influenza vaccination.
Patients should not donate blood during therapy and for at least 6 weeks following discontinuation of MMF.

Hypogammaglobulinaemia.

There have been reports of hypogammaglobulinaemia in association with recurrent infections in patients receiving MMF in combination with other immunosuppressants. In some of these cases switching MMF to an alternative immunosuppressant resulted in serum IgG levels returning to normal. Patients on MMF who develop recurrent infections should have their serum immunoglobulins measured. In cases of sustained, clinically relevant hypogammaglobulinaemia, appropriate clinical action should be considered taking into account the potent cytostatic effects that MPA has on T and B-lymphocytes. There have been published reports of bronchiectasis in adults and children who received MMF in combination with other immunosuppressants. In some of these cases switching MMF to another immunosuppressant resulted in improvement in respiratory symptoms. The risk of bronchiectasis may be linked to hypogammaglobulinaemia or to a direct effect on the lung. There have also been isolated reports of interstitial lung disease and pulmonary fibrosis, some of which were fatal (see Section 4.8 Adverse Effects (Undesirable Effects)). It is recommended that patients who develop persistent pulmonary symptoms, such as cough and dyspnoea, are investigated.

Gastrointestinal.

MMF has been associated with an increased incidence of digestive system adverse events, including uncommon cases of gastrointestinal tract ulceration, haemorrhage, and perforation (colon, gall bladder) in postmarketing surveillance, MMF should be administered with caution in patients with active serious digestive system disease. Gastrointestinal tract bleeding (requiring hospitalisation) has been observed in approximately 1.4% of patients treated with MMF 2 g in renal transplantation, 2.8% of patients receiving 3 g in cardiac transplantation and in 5.4% of patients receiving MMF 3 g in hepatic transplantation. Gastrointestinal tract perforations have rarely been observed. Most patients were also receiving other medicines that are associated with these complications (see Section 4.8 Adverse Effects (Undesirable Effects)). It should be noted that patients with active peptic ulcer disease were excluded from enrolment in studies with MMF.
Since MMF is an IMPDH (inosine monophosphate dehydrogenase) inhibitor, 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.

Interactions.

Caution should be exercised when switching combination therapy from regimens containing immunosuppressants which interfere with MPA enterohepatic recirculation e.g. ciclosporin, to others devoid of this effect e.g. tacrolimus, sirolimus, belatacept, or vice versa, as this might result in changes of MPA exposure. Drugs which interfere with MPA's enterohepatic cycle e.g. cholestyramine, antibiotics should be used with caution due to their potential to reduce the plasma levels and efficacy of MMF (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Therapeutic drug monitoring of MPA may be appropriate when switching combination therapy (e.g. from ciclosporin to tacrolimus or vice versa) or to ensure adequate immunosuppression in patients with high immunological risk (e.g. risk of rejection, treatment with antibiotics, addition or removal of an interacting medication).

Azathioprine.

It is recommended that MMF should not be administered concomitantly with azathioprine because both have the potential to cause bone marrow suppression and such concomitant administration has not been studied.

Use in renal impairment.

Patients with severe chronic renal impairment (GFR < 25 mL/min/1.73 m2) who have received single doses of MMF showed increased plasma AUCs of MPA and Mycophenolic Acid Glucuronide (MPAG) relative to subjects with lesser degrees of renal impairment or normal healthy subjects. Patients with severe chronic renal impairment should be carefully monitored and administration of doses of MMF greater than 1 g twice daily should be avoided (see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties).
In patients with delayed graft function post-transplant, mean MPA AUC0-12 was comparable, but MPAG AUC0-12 was 2-3 fold higher, compared to that seen in post-transplant patients without delayed graft function. In the three controlled studies of prevention of rejection, there were 298 of 1,483 patients (20%) with delayed graft function. Although patients with delayed renal allograft function have a higher incidence of certain adverse events (anaemia, thrombocytopenia, hyperkalaemia) than patients without delayed graft function, these events were not more frequent in patients receiving MMF than azathioprine or placebo. No dose adjustment is recommended for these patients, however, they should be carefully observed.
In renal transplant patients with severe chronic renal impairment, administration of doses greater than 1 g twice daily should be avoided.

Use in the elderly.

Elderly patients may be at an increased risk of certain infections (including cytomegalovirus (CMV) tissue invasive disease) and possible gastrointestinal haemorrhage and pulmonary oedema, compared with younger individuals. Elderly patients (over 65 years) may generally be at increased risk of adverse reactions due to immunosuppression. Pharmacokinetic behaviour of MMF in the elderly has not been formally evaluated.

Paediatric use.

Based on a safety and pharmacokinetics study in renal paediatric patients, no significant differences in pharmacokinetic parameters in comparison to adult patients were observed. Paediatric patients experienced a higher incidence of certain adverse events (see Section 4.8 Adverse Effects (Undesirable Effects)). Data are insufficient to establish safety and efficacy in children below the age of two years.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Medicine interaction studies with MMF have been conducted with aciclovir, antacids, belatacept, cholestyramine, ciclosporin, ganciclovir, oral contraceptives, proton pump inhibitors (PPIs), sirolimus, tacrolimus, telmisartan and trimethoprim/sulfamethoxazole. Medicine interaction studies have not been conducted with other medicines that may be commonly administered to renal, cardiac or hepatic transplant patients.

Aciclovir.

Following single dose administration of MMF (1 g) and aciclovir (800 mg) to normal healthy subjects, higher MPAG (8.6%) and aciclovir (17.4%) plasma AUCs were observed when MMF was administered with aciclovir in comparison to the administration of each medicine alone. As MPAG plasma concentrations are increased in the presence of renal impairment, as are aciclovir concentrations, the potential exists for the mycophenolate and aciclovir or its prodrugs, e.g. valaciclovir to compete for tubular secretion and thus further increases in concentrations of both medicines may occur.

Antacids with magnesium and aluminium hydroxides.

Absorption of a single dose of MMF (2.0 g) was decreased when aluminium/magnesium hydroxide antacids were administered concomitantly to rheumatoid arthritis patients. The Cmax and 24 hour AUC values for MPA were 33% and 17% lower, respectively than when MMF was administered alone under fasting conditions.

Antibiotics.

Antibiotics eliminating β-glucuronidase producing bacteria in the intestine (e.g. aminoglycoside, cephalosporin, fluoroquinolone, and penicillin classes of antibiotics) may interfere with MPAG/MPA enterohepatic recirculation thus leading to reduced systemic MPA exposure. Information concerning the following antibiotics is available:

Ciprofloxacin or amoxicillin plus clavulanic acid.

Reductions in predose (trough) MPA concentrations of 54% have been reported in renal transplant recipients in the days immediately following commencement of oral ciprofloxacin or amoxicillin plus clavulanic acid. Effects tended to diminish with continued antibiotic use and cease after discontinuation. The change in predose level may not accurately represent changes in overall MPA exposure, therefore, clinical relevance of these observations is unclear.

Norfloxacin and metronidazole.

In healthy volunteers, no significant interaction was observed when MMF was concomitantly administered with norfloxacin and metronidazole separately. The combination of norfloxacin and metronidazole reduced the MPA AUC following a single dose of MMF.

Rifampicin.

After correction for dose a 70% decrease in MPA exposure (AUC0-12h) has been observed with concomitant rifampicin administration in a single heart-lung transplant patient. It is therefore recommended to monitor MPA exposure levels and to adjust MMF doses accordingly to maintain clinical efficacy when the medicines are administered concomitantly.

Trimethoprim and sulfamethoxazole.

Following single dose administration of MMF (1.5 g) to healthy male volunteers pretreated for 10 days with trimethoprim 160 mg/sulfamethoxazole 800 mg, no effect on the bioavailability of MPA was observed.

Cholestyramine.

Following single dose administration of 1.5 g MMF in normal healthy subjects pretreated with 4 g three times daily of cholestyramine for 4 days, there was a mean 40% reduction in the AUC of MPA (see Section 5.2 Pharmacokinetic Properties). In view of the significant reduction in the AUC of MPA by cholestyramine, caution should be used with the concomitant use of MMF and any medicine which interferes with enterohepatic circulation because of the potential to reduce the efficacy of MMF.

Ciclosporin.

Ciclosporin pharmacokinetics (at doses of 275 to 415 mg/day) were unaffected by single and multiple doses of 1.0 g MMF twice daily in stable renal transplant patients. The mean (± SD) dose normalised AUC0-12h of MPA after 14 days and 3 months of multiple doses of MMF and ciclosporin in 17 renal transplant patients were 43 ± 11 microgram.h/mL.g and 56 ± 31 microgram.h/mL.g, respectively. However, ciclosporin interferes with MPA enterohepatic recycling, resulting in reduced MPA exposures by 30-50% in renal transplant patients treated with MMF and ciclosporin compared with patients receiving sirolimus or belatacept and similar doses of MMF. Conversely, changes of MPA exposure should be expected with switching patients from ciclosporin to one of the immunosuppressants which do not interfere with MPA's enterohepatic cycle. If concomitant ciclosporin treatment is stopped, a significant increase in the concentration of MPA should be expected.

Drugs affecting glucuronidation.

Concomitant administration of drugs inhibiting glucuronidation of MPA may increase MPA exposure (e.g. increase of MPA AUC0-∞ by 35% was observed with concomitant administration of isavuconazole). Caution is therefore recommended when administering these drugs concomitantly with MMF.

Ganciclovir.

Following single dose administration in stable renal transplant patients, no pharmacokinetic interaction was observed between MMF (1.5 g) and IV ganciclovir (5 mg/kg). However, as MPAG plasma and ganciclovir concentrations are increased in the presence of renal impairment, the potential exists for the two medicines to compete for tubular secretion and thus further increases in concentrations of both medicines may occur. In patients with renal impairment in which MMF and ganciclovir or its prodrugs (e.g. valganciclovir) are coadministered, patients should be carefully monitored. However, with MPA, no substantial alteration of MPA pharmacokinetics is anticipated and dose adjustment of MMF is not required.

Iron.

In a study involving 16 healthy volunteers, no clinically relevant interaction was found between MMF and iron supplements when administered in a fasting state. In the same study, a 15% reduction in MPA AUC was observed when MMF and iron were administered simultaneously with food. In an earlier study involving 7 healthy volunteers, a significant reduction in MPA AUC was observed when MMF and iron were administered in a fasting state. To avoid any possible interactions, iron supplements should be administered at least 3 hours following MMF.

Live vaccines.

Live vaccines should not be given to patients with an impaired immune response. The antibody response to other vaccines may be diminished (see Section 4.4 Special Warnings and Precautions for Use, Blood and immune system).

Oral contraceptives.

A study of coadministration of MMF (1 g twice daily) and combined oral contraceptives containing ethinylestradiol (0.02-0.04 mg) and levonorgestrel (0.05-0.20 mg), desogestrel (0.15 mg) or gestodene (0.05-0.1 mg) conducted in 18 women with psoriasis over 3 menstrual cycles showed no clinically relevant influence of MMF on serum levels of progesterone, LH and FSH, thus indicating no influence of MMF on the ovulation suppressing action of the oral contraceptives. The pharmacokinetics of oral contraceptives were not affected to a clinically relevant degree by co-administration of MMF (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy).

Proton pump inhibitors (PPIs).

Decreased MPA exposure has been observed when PPIs, including lansoprazole and pantoprazole, were administered with MMF. The clinical impact of reduced MPA exposure on organ rejection has not been established in transplant patients receiving PPIs and MMF. Because clinical relevance has not been established, PPIs should be used with caution when co-administered to transplant patients being treated with MMF.

Sevelamer and other calcium free phosphate binders.

Concomitant administration of sevelamer and MMF in adults and paediatric patients decreased the Cmax and AUC0-12 of MPA by 30% and 25%, respectively. There are no data on MMF with phosphate binders other than sevelamer. This data suggest that sevelamer and other calcium free phosphate binders should preferentially be given two hours after MMF intake to minimise impact on the absorption of MPA.

Sirolimus.

A study in 36 renal transplant patients demonstrated that concomitant administration of MMF (1 g twice daily) and sirolimus resulted in the mean (± SD) AUC0-12h of MPA after 14 days and 3 months were 81 ± 36 microgram.h/mL.g and 71 ± 26 microgram.h/mL.g, respectively. Another study using 45 renal transplant patients demonstrated that a significant proportion of patients (10 of 30) who received the combination of sirolimus and MMF were withdrawn with symptoms consistent with MPA or sirolimus toxicity.
Monitoring of MPA levels should be performed in renal graft recipients cotreated with sirolimus because of the risk of overexposure to this immunosuppressive agent.

Tacrolimus.

The AUC and Cmax of MPA, the active metabolite of MMF, were not significantly affected by coadministration with tacrolimus, in stable hepatic transplant patients initiated on MMF and tacrolimus. In contrast, there was an increase of approximately 20% in tacrolimus AUC when multiple doses of MMF (1.5 g twice daily) were administered to patients taking tacrolimus.
However, in renal transplant patients, tacrolimus concentration did not appear to be altered by MMF.

Telmisartan.

Concomitant administration of telmisartan and MMF resulted in an approximately 30% decrease of MPA concentrations. Telmisartan changes MPA's elimination by enhancing PPAR gamma (peroxisome proliferator-activated receptor gamma) expression which in turn results in an enhanced UGT1A9 expression and activity.

Other interactions.

The measured value for renal clearance of MPAG indicates removal occurs by renal tubular secretion as well as glomerular filtration. Consistent with this, coadministration of probenecid, a known inhibitor of tubular secretion, with MMF in monkeys raises plasma AUC of MPAG by 3-fold. Thus, other medicines known to undergo renal tubular secretion may compete with MPAG and thereby raise plasma concentrations of MPAG or the other medicine undergoing tubular secretion.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

MMF had no effect on fertility of male rats at oral doses up to 20 mg/kg/day or on female rats at oral doses up to 4.5 mg/kg/day (0.8 and 0.1 times the expected maximum clinical dose based on AUC values respectively). A female fertility and reproduction study conducted in rats caused malformations (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy). Malformations (including anophthalmia, agnathia, and hydrocephaly) occurred in the first generation offspring of female rats treated with oral doses of MMF in the absence of maternal toxicity. No effect was seen on the fertility of male rats treated with MMF.
(Category D)
MMF is contraindicated during pregnancy and in women of childbearing potential not using highly effective contraceptive methods due to its mutagenic and teratogenic potential (see Section 4.3 Contraindications). MMF is a human teratogen with an increased risk of spontaneous abortions (mainly in the first trimester) and congenital malformations in case of maternal exposure during pregnancy (see Section 4.8 Adverse Effects (Undesirable Effects)). In the medical literature, the risk of spontaneous abortions have been reported as 45% to 49% following MMF exposure, compared to a reported rate between 12% and 33% in solid organ transplant patients treated with other immunosuppressants.
Congenital malformations (including multiple malformations in individual newborns) have been reported in 23% to 27% of live births in MMF exposed pregnancies in published literature. For comparison, the risk of malformations is estimated at approximately 2% of live births in the overall population and at approximately 4% to 5% in solid organ transplant patients treated with immunosuppressants other than MMF.
Congenital malformations, including multiple malformations have been reported post-marketing in children of patients exposed to MMF in combination with other immunosuppressants during pregnancy. The following malformations were most frequently reported:
Facial malformations such as cleft lip, cleft palate, micrognathia and hypertelorism of the orbits;
Abnormalities of the ear (e.g. abnormally formed or absent external/middle ear) and eye (e.g. coloboma, microphthalmos);
Malformations of the fingers (e.g. polydactyly, syndactyly, brachydactyly);
Cardiac abnormalities such as atrial and ventricular septal defects;
Oesophageal malformations (e.g. oesophageal atresia);
Nervous system malformations (such as spina bifida).
These findings were consistent with teratology studies performed in rats and rabbits where fetal resorptions and malformations occurred in absence of maternal toxicity.
Embryofoetal development studies were conducted with MMF in rats (0.6, 2, 6 mg/kg/day on gestation days 7-16, and 0.5, 1.5 and 4.5 mg/kg/day from prior to conception to weaning) and rabbits (10, 30, 90 mg/kg/day on gestation days 7-19). Foetal resorptions and malformations occurred in rats at doses of 4.5 mg/kg/day (0.1 times the expected maximum human dose based on AUC values) and in rabbits at 90 mg/kg/day (0.1 times the expected maximum human dose based on AUC values), in the absence of maternal toxicity.
The observed malformations in rats or rabbits were highly predictive of human malformations. Animal malformations with reported human correlates can be broadly classified as facial defects (including cleft palate, agnathia), eye abnormalities (including anophthalmia, microphthalmia), cardiac malformations (including ectocardia), nervous system malformations (including hydrocephaly), abdominal and thoracic wall defects (including umbilical and diaphragmatic hernia), kidney and lung defects (including renal agenesis, ectopic kidney and lung hypoplasia), reproductive organ defects (cryptorchidism) and skeletal malformations. Additional animal malformations included spleen and adrenal gland defects (aplasia, dysplasia).
The no-effect levels for teratogenicity in rats and rabbits were 2 and 30 mg/kg/day, respectively. A peri and postnatal study in rats administered MMF 1, 3 or 10 mg/kg/day from gestation day 17 to weaning showed no adverse effects.
Before the start of treatment, female and male patients of reproductive potential must be made aware of the increased risk of pregnancy loss and congenital malformations and must be counselled regarding pregnancy prevention, and planning.

Pregnancy testing.

Prior to starting therapy with MMF, female patients of childbearing potential must have two negative serum or urine pregnancy tests with a sensitivity of at least 25 mIU/mL; The second test should be performed 8-10 days after the first one and immediately before starting MMF. Repeat pregnancy tests should be performed during routine follow-up visits. Results of all pregnancy tests should be discussed with the patient. Patients should be instructed to consult their physician immediately should they become pregnant.

Contraception.

Females.

Women of child bearing potential should use two reliable forms of contraception simultaneously, at least one of which must be highly effective, before beginning MMF therapy, during therapy, and for six weeks following discontinuation of therapy, unless abstinence is the chosen method of contraception.

Males.

Limited clinical evidence is currently available on paternal exposure to MMF.
Non-clinical evidence shows that the dose of mycophenolate that could be transferred via the seminal fluid to a potentially pregnant partner is 30-fold lower than the concentration without teratogenic effects in rats, and 200-fold lower than the lowest teratogenic concentration in rats. Therefore, the risk of harm mediated via seminal fluid is considered negligible. However, genotoxic effects have been observed in animal studies at exposures exceeding the human therapeutic exposures by approximately 2.5-times. Thus, the risk of genotoxic effects on sperm cells cannot completely be excluded.
In absence of sufficient data to exclude a risk of harm to the fetus conceived during or directly after the treatment of the father, the following precautionary measure is recommended. Sexually active men are recommended to use condoms during treatment and for at least 90 days after cessation of treatment. 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 total 90 days after the last dose of MMF.
MMF is contraindicated during breastfeeding due to the potential for serious adverse reactions in nursing infants (see Section 4.3 Contraindications).
It is not known whether this medicine is excreted in human milk. Although the relevance to humans is unknown, studies in rats have shown MMF to be excreted in milk.

4.7 Effects on Ability to Drive and Use Machines

MMF may have a moderate influence on the ability to drive and use machines.
Patients should be advised to use caution when driving or using machines if they experience adverse drug reactions such as somnolence, confusion, dizziness, tremor or hypotension during treatment with MMF (see Section 4.8 Adverse Effects (Undesirable Effects)).

4.8 Adverse Effects (Undesirable Effects)

The adverse event profile associated with the use of immunosuppressive medicines is often difficult to establish owing to the presence of underlying disease and the concurrent use of many other medications. The principal adverse effects associated with the administration of MMF in combination with ciclosporin and steroids include diarrhoea, leucopenia, sepsis and vomiting, and there is evidence of a higher frequency of certain types of infections, such as tuberculosis and atypical mycobacterial infection. Uncommon but serious life threatening infections such as meningitis and infectious endocarditis have been reported.
The incidence of adverse events for MMF was determined in 3 randomised comparative double blind trials in prevention of rejection in renal transplant patients. However, due to the lower overall reporting of events in the placebo controlled prevention of rejection study, these data were not combined with the other two active controlled prevention trials, but are instead presented separately.
Patients in the double blind studies of the prevention of renal allograft rejection were treated for up to a minimum of 1 year, with approximately 53% of the patients having been treated for more than 1 year. The adverse events, reported as probably or possibly related to study medication at an incidence of greater than or equal to 3% of patients in either of the MMF 2 g or 3 g treatment groups are presented in Table 1, for the two active controlled studies combined, and for the one placebo controlled study.
Patients in a double blind study of the prevention of cardiac allograft rejection were treated for up to a minimum of 1 year. The adverse events, reported as probably or possibly related to study medication at an incidence of greater than or equal to 3% of patients in either of the MMF 3 g or azathioprine treatment groups are presented in Table 2.
Patients in a double blind study of the prevention of hepatic allograft rejection were followed for up to a minimum of 1 year. The adverse events reported as probably or possibly related to study medication at an incidence of greater than or equal to 3% of patients in either of the MMF 3 g or azathioprine treatment groups are presented in Table 3.
The following adverse events, considered by the investigator to be possibly or probably related to medicine treatment and not mentioned in any of the tables above or in text pertaining to infections or malignancy following, were reported with an incidence of less than 3% in one or more of the MMF 2 g or 3 g (renal) active controlled cohorts (n = 336, n = 330), the MMF 2 g or 3 g (renal) placebo controlled cohorts (n = 165, n = 160), less than 1.4% in the MMF 3 g (cardiac) active controlled cohort (n = 289), or less than 1.4% in the MMF 3 g (hepatic) active controlled cohort study (n = 277).

Digestive system.

Colitis (sometimes caused by CMV), ileus, duodenal ulcer, rectal disorder, stomach ulcer, duodenitis, gastrointestinal haemorrhage, mouth ulceration, dysphagia, peptic ulcer, cholecystitis, gastrointestinal disorder, ulcerative stomatitis, cheilitis, large intestine perforation, periodontal abscess, haemorrhagic gastritis, gum hyperplasia, stomatitis, eructation, haemorrhagic pancreatitis, intestinal necrosis, intestinal perforation, intestinal ulcer, gingivitis, glossitis, oesophageal ulcer, pancreatitis, aphthous stomatitis, enteritis, faecal impaction, stomach atony, haematemesis, duodenal ulcer haemorrhage, proctitis, rectal haemorrhage, gastrointestinal carcinoma, faecal incontinence, pancreas disorder, stomach ulcer haemorrhage, cholangitis, hepatic failure, perforated peptic ulcer, ulcerative colitis.

Body as a whole.

Back pain, ciclosporin level increased, chest pain, reaction unevaluable, accidental injury, abscess, lab test abnormal, cyst, neoplasm, chills, face oedema, malaise, substernal chest pain, carcinoma, moniliasis, chills and fever, sarcoma, adenoma, granuloma, lack of medicine effect, syncope, pelvis pain, pain, oedema, drug level increased, drug level decreased.

Urogenital system.

Dysuria, cystitis, haematuria, infection, oliguria, urinary frequency, pyuria, kidney abscess, abnormal kidney function, urethritis, urogenital carcinoma, kidney pain, nephritis, urethral pain, urinary urgency, urinary tract disorder, hydronephrosis, epididymitis, kidney tubular necrosis, urogenital occlusion, bladder neoplasm, urinary incontinence, vaginal moniliasis, kidney failure, urine abnormality.

Reproductive system.

Vaginal moniliasis, metrorrhagia, prostatic disorder, amenorrhoea, balanitis, cervix disorder, endometrial carcinoma, vaginal haemorrhage, impotence, breast pain, gynaecomastia, penis disorder.

Skin and appendages.

Alopecia, fungal dermatitis, skin benign neoplasm, rash, acne, cutaneous moniliasis, pruritus, infection, urticaria, cellulitis, sweating, haemorrhage (skin and appendages), vesiculobullous rash, skin disorder, skin hypertrophy, skin ulcer, furunculosis, maculopapular rash, petechial rash, seborrhoea, skin carcinoma, skin discolouration.

Haemic and lymphatic system.

Pancytopenia, polycythemia, thrombocythemia, agranulocytosis, lymphoma-like reaction, decreased immunoglobulins, ecchymosis, thrombotic thrombocytopenic purpura, epistaxis, haemorrhage, petechia, abnormal WBC, blood dyscrasia, haemolytic anaemia, lymphadenopathy, hepatitis B serum antigen positive, reticuloendothelial hyperplasia, marrow hyperplasia, coagulation disorder, haemolysis.

Respiratory system.

Sinusitis, cough increased, dyspnoea, rhinitis, respiratory abscess, interstitial pneumonia, lung carcinoma, lung disorder, asthma, laryngismus, laryngitis, pneumothorax, hypoxia, atelectasis, lung oedema, lung fibrosis, pleural effusion, pleural disorder.
There have also been reports of bronchiectasis in children and adults.

Metabolic and nutritional disorders.

Gamma glutamyl transpeptidase increased, hypercholesterolaemia, hypokalemia, acidosis, increased creatinine, bilirubinaemia, peripheral oedema, increased amylase, healing abnormal, hypocalcaemia, hyperglycaemia, albuminuria, weight loss, BUN increased, dehydration, decreased gamma globulin, hypercalcaemia, hypervolaemia, hypoproteinaemia, uraemia, hyperkalemia, hyperchloraemia, enzymatic abnormality, hypomagnesaemia, increased creatine phosphokinase, hyperuricaemia, hyponatraemia, diabetes mellitus, gout, respiratory acidosis, oedema, hypoglycaemia, cachexia, hyperphosphatemia.

Liver and biliary system.

Liver damage, cholestatic jaundice, cholelithiasis.

Cardiovascular system.

Pulmonary embolus, thrombosis, palpitation, angina pectoris, vasodilatation, arterial thrombosis, cerebrovascular accident, phlebitis, atrial fibrillation, supraventricular tachycardia, cyanosis, cerebral ischaemia, hypotension, peripheral gangrene, tachycardia, arrhythmia, heart arrest, occlusion, shock, gangrene, deep thrombophlebitis, myocardial infarct, cardiomegaly, ventricular extrasystoles, ventricular tachycardia, cerebral ischaemia, myocarditis, endocarditis, heart failure, pulmonary hypertension, cardiomyopathy, electrocardiogram abnormal, pericardial effusion.

Central and peripheral nervous system.

Hypertonia, dizziness, anxiety, vocal cord paralysis, neuropathy, paraesthesia, convulsion, depression, confusion, amnesia, depersonalisation, encephalitis, psychosis, agitation, hallucinations, aphasia, delirium, encephalopathy, hyperaesthesia, nystagmus, speech disorder, thinking abnormal, vertigo, apathy, catatonic reaction, CNS neoplasia, delusions, hemiplegia, hostility, hypokinesia, opisthotonos, paranoid reaction, personality disorder, somnolence, hypesthesia, emotional lability, hyperkinesia, manic reaction.

Special senses.

Otitis media, infection, conjunctivitis, eye haemorrhage, blepharitis, ear pain, visual disturbance, lacrimation disorder, corneal ulcer, deafness, diplopia, retinal disorder, taste loss, keratitis, retinitis, ear disorder, vestibular disorder, eye disorder, taste perversion, tinnitus, otitis externa, amblyopia, abnormal vision, eye pain, photophobia.

Musculo-skeletal system.

Arthralgia, bone pain, leg cramps, myalgia, bone necrosis, joint disorder, myasthenia, myopathy, osteoporosis.

Endocrine.

Sialadenitis, hormone level altered, hypothyroidism.
Up to 0.5% (regardless of investigator assessment of causality) of patients receiving MMF 2 g for prevention of renal allograft rejection developed severe neutropenia (ANC < 5 x 108/L). Up to 2.8% (regardless of investigator assessment of causality) of cardiac transplant patients receiving MMF 3 g and up to 3.6% (regardless of investigator assessment of causality) of patients receiving MMF 3 g in hepatic transplantation developed severe neutropenia.
CMV tissue invasive disease was more common in renal transplant patients receiving MMF 3 g/day (8-12%) than in those receiving MMF 2 g/day (4-8%) or control therapy (2-6%) in the three controlled studies for prevention of renal allograft rejection (percentage incidences have been determined regardless of investigator assessment of causality). In the placebo controlled renal study, there was an increased incidence of Herpes simplex and Herpes zoster infections in patients receiving MMF compared to placebo. In addition, the incidence of overall infection with Candida and CMV viraemia/ syndrome were similar in the three treatment groups. Table 4 shows the incidence of select opportunistic infections in the prevention of rejection trials.
The following other opportunistic infections occurred with an incidence of less than 4% in MMF patients in the above azathioprine controlled studies: Herpes zoster, visceral disease; Candida, urinary tract infection, fungemia/ disseminated disease, tissue invasive disease; Cryptococcosis; Aspergillus/ Mucor; Pneumocystis carinii.
In the placebo controlled renal transplant study, the same pattern of opportunistic infection was observed compared to the azathioprine controlled renal study, with a notably lower incidence of Herpes simplex and CMV tissue invasive disease.
In the three controlled studies for prevention of rejection in renal transplantation, similar rates of fatal infections/ sepsis (< 2%) have occurred in patients receiving MMF or control therapy in combination with other immunosuppressive agents. In the controlled cardiac transplant study, fatal infections occurred in 2.4% of patients receiving MMF 3 g compared to 4.5% of patients receiving azathioprine, both in combination with other immunosuppressive agents. In the controlled hepatic transplant study, fatal infection/ sepsis occurred in 5.4% of patients receiving MMF 3 g compared to 7.3% receiving azathioprine, both in combination with other immunosuppressive agents.
As with other patients receiving immunosuppressive regimes involving combinations of medicines, patients receiving MMF as part of an immunosuppressive regime are at an increased risk of developing lymphomas and other malignancies, particularly of the skin. Within 3 years post-transplant, lymphoproliferative disease or lymphoma developed in patients receiving MMF in immunosuppressive regimes in 0.6% of patients receiving 2 g daily in the controlled studies of prevention of renal rejection compared to placebo (0%) and azathioprine groups (0.6%).
The incidence of malignancies among the 1,483 patients enrolled in controlled trials for the prevention of renal allograft rejection was low, and similar to the incidence reported in the literature for renal allograft recipients. There was a slight increase in the incidence of lymphoproliferative disease in the MMF treatment groups compared to the placebo and azathioprine groups. Table 5 summarises the incidence of malignancies observed in the prevention of rejection trials.
Three year safety data in renal and cardiac transplant patients indicated that the overall incidence of malignancy was comparable between MMF and azathioprine groups. Hepatic transplant patients were followed for at least 1 year but less than 3 years.

Paediatric adverse events.

The type and frequency of adverse medicine effects in a clinical study of 100 paediatric patients 3 months to 18 years of age given 600 mg/m2 MMF orally twice daily were generally similar to those observed in adult patients given 1 g MMF twice daily with the exception that paediatric patients had a higher proportion of diarrhoea, anaemia, sepsis and leucopenia.

Postmarketing experience.

Infections.

Uncommon: serious life threatening infections such as meningitis, protozoal infections and infectious endocarditis have been reported occasionally and there is evidence of a higher frequency of certain types of serious infections such as tuberculosis and atypical mycobacterial infection.
Cases of PML, sometimes fatal, have been reported in patients treated with MMF. The reported cases generally had risk factors for PML, including treatment with concomitant immunosuppressant therapies and impaired immune function.
BK virus associated nephropathy has been observed in patients treated with MMF. This infection can be associated with serious outcomes, sometimes leading to renal graft loss.

Respiratory, thoracic and mediastinal disorders.

Bronchiectasis, interstitial lung disease, and pulmonary fibrosis. Interstitial lung disorders, including fatal pulmonary fibrosis, have been reported rarely and should be considered in the differential diagnosis of pulmonary symptoms ranging from dyspnea to respiratory failure in post-transplant patients receiving mycophenolate.

Resistance mechanism disorders.

Uncommon: serious life threatening infections such as meningitis and infectious endocarditis have been reported occasionally and there is evidence of a higher frequency of certain types of serious infections such as tuberculosis and atypical mycobacterial infections.

Neoplasm benign, malignant and unspecified (including cysts and polyps).

Lymphoma, lymphoproliferative disorder.

Gastrointestinal.

Uncommon: pancreatitis, isolated cases of intestinal villous atrophy, colitis (sometimes caused by CMV).

Congenital disorders.

Congenital malformations including ear malformations have been reported postmarketing in children of patients exposed to MMF in combination with other immunosuppressants during pregnancy (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy).

Pregnancy, puerperium and perinatal conditions.

Cases of spontaneous abortions mainly in the first trimester in patients exposed to MMF have been reported (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy).

Blood and immune system.

Cases of pure red cell aplasia (PRCA) and hypogammaglobulinemia have been reported in patients treated with MMF in combination with other immunosuppressive agents, hypersensitivity. Isolated cases of abnormal neutrophil morphology, including the acquired Pelger-Huet anomaly, have been observed in patients treated with MMF. These changes are not associated with impaired neutrophil function. These changes may suggest a 'left shift' in the maturity of neutrophils in haematological investigations, which may be mistakenly interpreted as a sign of infection in immunosuppressed patients such as those that receive MMF.

Vascular disorders.

Lymphocele.

General disorders and administration site conditions.

De novo purine synthesis inhibitors associated acute inflammatory syndrome is a newly described paradoxical pro-inflammatory reaction associated with mycophenolate and other purine synthesis inhibitors, characterised by fever, arthralgias, arthritis, muscle pain and elevated inflammatory markers. Anecdotal literature reports showed rapid improvements following discontinuation of the medication.

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

Reports of overdoses with MMF have been received from clinical trials and during post-marketing experience. In many of these cases no adverse events were reported. In those overdose cases in which adverse events were reported, the events fall within the known safety profile of the medicine.
It is expected that an overdose of MMF could possibly result in over-suppression of the immune system and increase susceptibility to infections and bone marrow suppression (see Section 4.4 Special Warnings and Precautions for Use). If neutropenia develops, dosing with MMF should be interrupted or the dose reduced (see Section 4.4 Special Warnings and Precautions for Use).
MPA cannot be removed by haemodialysis. However, at high MPAG plasma concentrations (> 100 microgram/mL), small amounts of MPAG are removed. Bile acid sequestrants, such as cholestyramine, can remove MPA by increasing excretion of the drug (see Section 5.2 Pharmacokinetic Properties).
Treatment of overdosage should consist of general supportive measures.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

MPA is a potent, selective, uncompetitive and reversible inhibitor of IMPDH which inhibits the de novo pathway of guanosine nucleotide synthesis without incorporation into DNA. Based on Chinese hamster IMPDH in complex with inosine-5'-monophosphate (IMP) and MPA, the mechanism by which MPA inhibits the enzymatic activity of IMPDH (human type II) appears to be related to the ability of MPA to structurally mimic both the nicotinamide adenine dinucleotide cofactor and a catalytic water molecule. This prevents the oxidation of IMP to xanthos-5'-monophosphate, the committed step in the de novo guanosine nucleotide biosynthesis. Human type II and Chinese hamster IMPDH differ by six amino acids but have similar enzymatic characteristics. MPA has more potent cytostatic effects on lymphocytes than on other cells because T and B lymphocytes are dependent for their proliferation on de novo synthesis of purines, whereas other cell types can utilise salvage pathways. Depletion of guanosine nucleotides leads to the inhibition of glycosylation of adhesion molecules on lymphocytes, a process also considered an action of MMF.
MMF has been demonstrated in experimental animal models to prolong the survival of allogeneic transplants (kidney, heart, liver, intestine, limb, small bowel, pancreatic islets, and bone marrow). MMF has also been shown to reverse ongoing acute rejection in the canine renal and rat cardiac allograft models. MMF also inhibited proliferative arteriopathy in experimental models of aortic and heart allografts in rats, as well as in primate cardiac xenografts. MMF was used alone or in combination with other immunosuppressive agents in these studies.
In experimental animals, MMF has been demonstrated to prevent inflammatory responses that are immunologically mediated, and to delay tumour development and prolong survival in models of xenogeneic human to mouse and syngeneic murine tumours in vivo.
MMF, the 2-morpholinoethyl ester of MPA, is rapidly absorbed following oral administration and hydrolysed to form free MPA, which is the active metabolite. MPA inhibits proliferative responses of T and B lymphocytes to both mitogenic and allospecific stimulation.
Addition of guanosine or deoxyguanosine reverses the cytostatic effects of MPA on lymphocytes, showing the specificity of action of the medicine. MPA also suppresses antibody formation by B lymphocytes. By depletion of guanosine nucleotides, MPA prevents the glycosylation of lymphocyte and monocyte glycoproteins that are involved in intercellular adhesion to endothelial cells. By this mechanism, MPA may inhibit recruitment of leucocytes into sites of inflammation and graft rejection.
MMF did not inhibit early events in the activation of human peripheral blood mononuclear cells such as the production of interleukin 1 (IL-1) and interleukin 2 (IL-2), but did block the coupling of these events to DNA synthesis and proliferation.
Animal studies have shown that mortality in rats with Pneumocystis carinii pneumonia is higher during combined treatment with MMF and trimethoprim/ sulfamethoxazole than with either medicine alone. MMF did not interfere with the ability of trimethoprim/ sulfamethoxazole to reduce the incidence of P. carinii cysts in surviving animals, and reduced the incidence of cysts when administered by itself.

Clinical trials.

Prevention of acute renal rejection episodes.

The safety and efficacy of MMF as adjunctive therapy for the prevention of organ rejection following allogeneic renal transplants were assessed in three randomised, double blind, multicentre trials.
These studies compared two dose levels of MMF (1 g twice daily and 1.5 g twice daily) with azathioprine (2 studies) or placebo (1 study) when administered in combination with ciclosporin and corticosteroids to prevent acute rejection episodes. One study also included antithymocyte globulin (Atgam) induction therapy.
The primary efficacy endpoint was the proportion of patients in each treatment group who experienced biopsy proven acute rejection or treatment failure (defined as early termination from the study for any reason without prior biopsy proven rejection) within the first six months after transplantation. MMF, when administered with Atgam induction (one study) and with ciclosporin and corticosteroids (all three studies) was shown to be superior to the following three therapeutic regimens: (1) Atgam induction/ azathioprine/ ciclosporin/ corticosteroids, (2) azathioprine/ ciclosporin/ corticosteroids, and (3) ciclosporin/ corticosteroids. The superior efficacy of MMF as adjunctive therapy, when compared to azathioprine or placebo, was demonstrated by a reduction in the incidence of first biopsy proven acute rejection episode or treatment failure within the first 6 months after transplantation. In addition, MMF reduced the incidence of first biopsy proven acute rejection episodes within the first six months after transplantation.
In Table 6, the percentages for first biopsy proven rejection alone have not been adjusted for patients who terminated prematurely before experiencing a biopsy proven rejection episode.
In these three studies, the proportion of patients requiring antilymphocyte therapy for treatment of rejection during the first 6 months following transplantation was smaller among patients receiving MMF 2 g per day (5.5 to 10.3%) or MMF 3 g per day (3.1 to 5.4%) than among patients receiving azathioprine or placebo (15 to 21%).
Six and twelve month patient survival and graft survival was somewhat higher in the patients receiving MMF in comparison to either azathioprine or placebo. The cumulative proportions of patients who had died or lost their graft by 6 and 12 months post-transplant are shown in Table 7.

Treatment of refractory renal rejection.

The safety and efficacy of MMF as adjunctive therapy for the treatment of refractory organ rejection following allogeneic renal transplants was assessed in one randomised, open label, multicentre trial. This study was designed to evaluate whether MMF at a dose of 1.5 g twice daily was superior to high dose IV steroids. In this study, all patients continued to receive concomitant maintenance oral corticosteroids and ciclosporin. The control group received IV methylprednisolone (5 mg/kg/day for 5 days followed by an oral course with tapered doses of corticosteroids); the control patients also generally received azathioprine. A total of 150 patients were enrolled (73 assigned to receive IV steroids; 77 assigned to receive MMF). Patients enrolled in this study had recurrent or persistent allograft rejection following treatment with either Orthoclone OKT3, Atgam or antilymphocyte globulin for at least 7 days, the last day of which occurred within 28 days prior to entry into the study. In addition, patients showed renal biopsy findings consistent with acute rejection at study entry. Serum creatinine concentrations were 442 micromol/L or lower at study entry.
The primary efficacy endpoint was graft and patient survival at 6 months post-enrolment. MMF was shown to be clinically effective in this study as evidenced by a 45% reduction in the number of patients who died or lost their graft. By 6 months post-enrolment, 26% of the IV steroid group and 14.3% of the MMF group had died or experienced graft loss. Eighteen patients (25%) receiving high dose IV steroids and 9 patients (12%) receiving MMF lost their graft in the 6 months after enrolment. One patient (1.4%) receiving high dose IV steroids and 2 patients (2.6%) receiving MMF died in the 6 months after enrolment. Fewer patients receiving MMF (10.4%) required treatment with anti-lymphocyte preparations in the 6 months after enrolment, compared to those receiving high dose IV steroids (24.7%).

Prevention of renal rejection in paediatrics.

In a multicentre open label safety, tolerability and pharmacokinetic study of MMF oral suspension 600 mg/m2 twice daily (up to 1 g twice daily) in combination with ciclosporin and corticosteroids in the US, Europe and Australia, 100 patients aged 3 months to 18 years of age received treatment for the prevention of renal allograft rejection. The primary efficacy endpoint was the proportion of patients experiencing an acute rejection episode in the first 6 months post-transplant. Results were analysed after 1 year and it was shown that MMF was well tolerated in paediatric patients (see Section 4.8 Adverse Effects (Undesirable Effects)), and the pharmacokinetics profile was similar to that seen in adult patients dosed with 1 g twice daily MMF capsules (see Section 5.2 Pharmacokinetic Properties, Pharmacokinetics in special populations). The rate of biopsy proven rejection was similar across the age groups (3 months to < 6 years, 6 to < 12 years, 12 to 18 years). The overall biopsy proven rejection rate at 6 months and the combined incidence of graft loss (5%) and patient death (2%) at 12 months post-transplant were similar to the rates observed in adult renal transplant patients. Results out to 36 months post-transplant in children are currently under investigation.

Prevention of cardiac allograft rejection.

In a randomised, double blind, parallel active controlled multicentre study to compare the safety and efficacy of MMF 1.5 g twice daily with azathioprine 1.5-3 mg/kg/day, both in combination with ciclosporin and corticosteroids, 650 patients were randomised to the two arms. The primary endpoints investigated were (1) prevention of biopsy proven acute rejection with haemodynamic compromise during the first six months following transplantation and (2) prevention of death or retransplantation during the first year following cardiac transplantation. 72 patients were withdrawn prior to administration and without knowledge of the assigned therapy primarily because of perioperative adverse events, inability to take oral medication or death. Therefore 289 patients received study medication in each arm.
Patients in the MMF arm had a lower incidence of death or retransplantation, however this difference was within the protocol defined range of equivalence, being a ± 10% mortality difference.
MMF and azathioprine did not differ significantly at 6 months in biopsy proven acute rejection with haemodynamic compromise. Survival, acute rejection and composite endpoints are listed in Table 8.

Prevention of hepatic allograft rejection.

The safety and efficacy of MMF was assessed in a randomised, double blind, parallel, active controlled, multicentre study in hepatic transplant patients. This study compared the use of MMF 1 g twice daily intravenously for up to 14 days followed by 1.5 g twice daily orally against azathioprine 1-2 mg/kg/day intravenously followed by 1-2 mg/kg/day orally, both in combination with ciclosporin and corticosteroids. 565 patients were randomised into the two arms, 278 patients in the MMF group and 287 patients in the azathioprine group.
The two primary endpoints investigated were (1) the proportion of patients who experienced, in the first 6 months post-transplantation, (a) one or more episodes of biopsy proven and treated rejection or (b) death/ retransplantation, and (2) the proportion of patients with graft loss (death/ retransplantation) during the first 12 months post-transplantation. Patients who prematurely discontinued treatment were followed for the occurrence of allograft rejection and for the occurrence of graft loss (death/ retransplantation) for 1 year.
In the primary analyses MMF in combination with corticosteroids and ciclosporin was superior to azathioprine for prevention of acute rejection (p = 0.02) in the 6 months following transplant and equivalent to azathioprine for survival or graft loss in the 12 months following transplant (see Table 9).
The superiority of MMF to azathioprine in the time to biopsy proven and treated rejection or death/ retransplantation in the 6 months following transplant approached statistical significance (log rank p = 0.06). The time to death/ retransplantation in the 12 months following transplant was similar in the two treatment groups (log rank p = 0.86).

5.2 Pharmacokinetic Properties

Absorption.

Following oral and intravenous administration, MMF undergoes rapid and extensive absorption and complete presystemic metabolism to the active metabolite, MPA. MMF is not measurable systemically in plasma following oral administration. Modest concentrations of the parent drug are detected in plasma samples during intravenous infusion, but concentrations decline rapidly after the completion of the infusion. The mean extent of absorption of MPA during multiple dosing (as measured by the area under the plasma concentration time curve, AUC) increases in a dose proportionate manner over a daily dose range of 1 g to 4 g in renal transplant patients.
The administration of a 1.5 g dose of MMF by the intravenous (IV) and oral routes to healthy volunteers resulted in similar plasma MPA and inactive MPAG total AUC values. Recovery of MPAG in urine was the same for both routes indicating complete absorption of oral MMF. The mean bioavailability of orally administered MMF, based on MPA AUC, was 94% relative to IV administration.
In a steady state study, the administration of 1 g twice daily of MMF by the IV and oral routes to renal transplant patients in the immediate post-transplant period, resulted in a MPA AUC that was approximately 29% higher for the IV formulation than achieved by the capsule. Cmax was approximately 20% greater for IV.
The results of a single dose bioequivalence study in 47 healthy volunteers indicated that the 500 mg tablet (x 2) was equivalent to the 250 mg capsule (x 4) with respect to the extent of absorption (AUC), but not the rate of absorption (Cmax). The Cmax for MPA of the tablet was 28% lower than that for the capsule.
In a two way, randomised, crossover, bioequivalence study of MMF oral suspension and capsules, a 1 g dose of MMF suspension was bioequivalent to the 250 mg capsule (x 4) with respect to Cmax, t1/2, AUClast, AUC0-∞; and Kel. Tmax was marginally shorter for the oral suspension.
Food had no effect on the extent of absorption (MPA AUC) of MMF when administered as 1.5 g twice daily doses to renal transplant patients. However, the Cmax for MPA was lowered by 40% in the presence of food.
The pharmacokinetic profile of MPA in cardiac patients is similar to that in renal patients.
Following oral administration of one MMF 250 mg capsule to healthy male subjects under fasting conditions, a mean peak plasma concentration (Cmax) of MMF of approximately 1.7 ± 1.6 nanogram/mL was achieved within 0.50 hrs (Tmax). Cmax and Tmax for MPA were approximately 10.3 ± 3.8 microgram/mL and 0.50 hrs, respectively.
Following oral administration of one MMF 500 mg tablet to healthy male subjects under fasting conditions, a mean peak plasma concentration (Cmax) of MMF of approximately 2.5 ± 2.7 nanogram/mL was achieved within 0.50 hrs (Tmax). Cmax and Tmax for MPA were approximately 15.9 ± 6.7 microgram/mL and 0.50 hrs, respectively.

Distribution.

As a result of enterohepatic recirculation, secondary increases in plasma MPA concentration are usually observed approximately 6 to 12 hrs post-dose. Co-administration of cholestyramine (4 g three times daily) with MMF is associated with a reduction in the AUC of MPA of approximately 40% as a result of decreased enterohepatic recirculation. The majority of the difference in the AUC is in the terminal portion of the MPA plasma concentration time profile.
At clinically relevant concentrations, MPA is 97% bound to plasma albumin.

Metabolism.

MPA is metabolised principally by glucuronyl transferases (predominantly isoform UGT1A9) to form the pharmacologically inactive phenolic glucuronide of MPA (MPAG). In vivo, MPAG is converted to free MPA via enterohepatic recirculation. A minor acylglucuronide (AcMPAG) is also formed. AcMPAG is pharmacologically active and is suspected to be responsible for some of MMF's side effects (diarrhoea, leucopenia).

Excretion.

After oral administration, 93% of the dose was recovered from the urine and 6% from the faeces. The major metabolite of MMF excreted in urine is MPAG, which accounts for 87% of the oral MMF dose. Less than 1% of the dose was excreted as MPA in the urine. The following metabolites of the morpholino moiety are also recovered in the urine following oral administration of MMF: N-(2-carboxymethyl)-morpholine, N-(2-hydroxyethyl)-morpholine, and the N-oxide of N-(2-hydroxyethyl)-morpholine.
Mean ± SD apparent half-life and plasma clearance of MPA are 17.9 ± 6.5 hours and 193 ± 48 mL/min respectively following oral administration.
MPA's disposition depends on several transporters. Organic anion-transporting polypeptides (OATPs) and multidrug resistance-associated protein 2 (MRP2) are involved in MPA's disposition; OATP isoforms, MRP2 and breast cancer resistance protein (BCRP) are transporters associated with the glucuronides' biliary excretion. Multidrug resistance protein 1 (MDR1) is also able to transport MPA, but its contribution seems to be confined to the absorption process. In the kidney MPA and its metabolites inhibit renal organic anion transporters, with MPAG also being a substrate for OAT3.

Pharmacokinetics in special populations.

Renal, cardiac and hepatic transplant patients.

In renal, cardiac and hepatic transplant patients, mean steady state MPA AUC and Cmax were up to 40% lower in the early post-transplant period (< 40 days post-transplant) compared to the late transplant period (3-6 months post-transplant).
In renal transplant patients, in the immediate post-transplant phase, mean steady state MPA AUC was 24% higher following 1 g twice daily intravenous MMF (over 2 hours) for 5 days compared with the same dose orally.
In cardiac transplant patients, administration of 1.5 g twice daily oral MMF resulted in mean steady state MPA AUC values similar to those found in renal transplant patients administered the same dose.
In hepatic transplant patients, administration of 1 g twice daily intravenous MMF followed by 1.5 g twice daily oral MMF resulted in mean steady state MPA AUC values similar to those found in renal transplant patients administered 1 g twice daily oral MMF.

Renal impairment.

In a single dose study (6 subjects per group), plasma MPA AUCs were up to 30% higher in subjects with mild to moderate renal impairment (GFR 25-80 mL/min/1.73 m2) and 75% higher in subjects with severe renal impairment (GFR < 25 mL/min/1.73 m2) than those subjects with normal renal function (GFR > 80 mL/min/1.73 m2). The mean increase in MPA AUC observed in subjects with severe renal impairment was comparable to the increase in MPA AUC seen when the dose of MMF is increased from a daily dose of 2 to 3 g (see Section 4.2 Dose and Method of Administration). Multiple dosing of MMF in patients with severe chronic renal impairment has not been studied. In addition, the single dose plasma AUC of MPAG was 3 to 6-fold higher in subjects with severe renal impairment than in subjects with mild renal impairment or normal healthy subjects consistent with the known renal elimination of MPAG. No data are available on the safety of long-term exposure to this level of MPAG.

Delayed renal graft function post-transplant.

In patients with delayed renal graft function post-transplant, mean AUC0-12 of MPA was comparable to that seen in post-transplant patients without delayed graft function. However, mean plasma AUC0-12 of MPAG was 2 to 3-fold higher than post-transplant patients without delayed graft function. Also, with repeated dosing, plasma concentrations of MPAG accumulated, whereas accumulation of MPA occurred to a lesser degree, if at all. High plasma concentrations of MPAG may displace MPA from its protein binding sites resulting in a transient increase in the plasma concentration of free MPA in patients with delayed graft function. No dose adjustment is recommended although close monitoring is advised.

Haemodialysis.

The pharmacokinetics of MMF during haemodialysis are not altered. Haemodialysis does not remove MPA or MPAG. At high concentrations (> 100 microgram/mL), haemodialysis removes only small amounts of MPAG.

Hepatic impairment.

In volunteers with alcoholic cirrhosis, hepatic MPA glucuronidation was relatively unaffected by hepatic parenchymal disease. Effects of hepatic disease on these processes probably depend on the particular disease. Hepatic disease with predominantly biliary damage, such as primary biliary cirrhosis, may show a different effect.

Elderly patients.

Pharmacokinetics in the elderly have not been formally evaluated.

Paediatric patients.

The pharmacokinetic parameters of the MPA and MPAG were evaluated in 55 paediatric renal transplant patients aged 1 to 18 years given 600 mg/m2 MMF orally twice daily (up to a maximum of 1 g twice daily). This dose achieved MPA AUC values similar to those seen in adult renal transplant patients receiving MMF at a dose of 1 g twice daily in the early and late post-transplant period. MPA AUC levels across age groups were similar in the early post-transplant period out to 9 months post-transplant. There is limited pharmacokinetic data available for children aged less than 2 years.

Plasma binding.

MPA, at clinically relevant concentrations, is 97% bound to plasma albumin. MPAG is 82% bound to plasma albumin at MPAG concentration ranges such as those normally seen in stable renal transplant patients; however, at higher concentrations of MPAG, which are seen in patients with delayed graft function or with severe renal insufficiency, the bound fraction in vitro decreases to 62%.
In vitro studies to evaluate the effect of several agents on the binding of MPA to human serum albumin (HSA) or plasma proteins showed that salicylate (at 250 microgram/mL with HSA) and MPAG (≥ 460 microgram/mL with plasma proteins) increased the free fraction of MPA. At concentrations that exceeded what is encountered clinically, naproxen, digoxin, ciclosporin, theophylline, tacrolimus, tolbutamide, propranolol, warfarin, and prednisone did not increase the free fraction of MPA. MPA at concentrations as high as 100 microgram/mL had little effect on the binding of warfarin, digoxin or propranolol but decreased the binding of theophylline from 53% to 45% and decreased the binding of phenytoin from 90% to 87%.

5.3 Preclinical Safety Data

Genotoxicity.

MMF did not induce point mutations (Ames assay) or primary DNA damage (yeast mitotic gene conversion assay) in the presence or absence of metabolic activation. MMF did not cause chromosomal damage in vivo at oral doses up to 3000 mg/kg (mouse micronucleus aberration assay) or in vitro with or without metabolic activation at concentrations up to 5 microgram/mL (Chinese hamster ovary cell [CHO] chromosomal aberration assay). Chromosome aberrations were present without metabolic activation in an initial CHO cell assay, but only at concentrations (249 to 300 microgram/mL) that cause excessive cytotoxicity.

Carcinogenicity.

A 104 week oral carcinogenicity study in mice with MMF at daily doses of 25, 75 or 180 mg/kg showed an increase above control levels in the incidence of lymphosarcomas in females at the highest two dose levels and in males at the highest dose level (1.1-1.9 times the expected maximum clinical dose based on AUC values). The incidence of lymphosarcomas in all mice remained within the range of that observed historically in this strain of mice. In a 104 week oral carcinogenicity study in rats, MMF in daily doses up to 15 mg/kg (0.6 times the expected maximum clinical dose based on AUC values) was not tumourigenic.
The incidence of lymphoma/ lymphoproliferative disease and other malignancies is also increased in patients on immunosuppressive agents, and this appears to be related to the intensity or duration of immunosuppression rather than any specific immunosuppressant agent (see Section 4.4 Special Warnings and Precautions for Use).

6 Pharmaceutical Particulars

6.1 List of Excipients

Capsules.

Croscarmellose sodium, povidone, magnesium stearate, titanium dioxide, iron oxide red, pregelatinised maize starch, gelatin, iron oxide yellow, indigo carmine.

Tablets.

Microcrystalline cellulose, povidone, purified talc, croscarmellose sodium, magnesium stearate, titanium dioxide, hypromellose, hyprolose, macrogol 400, iron oxide black, iron oxide red.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.
For information on interactions with other medicines and other forms of interactions, see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

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 30°C.

6.5 Nature and Contents of Container

Mycophenolate Sandoz 250 mg capsules are available in blister packs (PVC/PE/PVDC/Al) and bottles (HDPE) containing 100 and 300 capsules.
Mycophenolate Sandoz 500 mg tablets are available in blister packs (PVC/PE/PVDC/Al) and bottles (HDPE) containing 50 and 150 tablets.
Not all presentations may be marketed in Australia.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

Handling and disposal.

MMF has demonstrated teratogenic effects (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy), therefore, Mycophenolate Sandoz tablets should not be crushed and Mycophenolate Sandoz capsules should not be opened or crushed. Patients should also avoid inhalation or contact with skin or mucous membranes of the powder contained in Mycophenolate Sandoz capsules. If contact occurs, wash thoroughly with soap and water; should the eyes be affected, rinse eyes with plain water.

6.7 Physicochemical Properties

MMF is freely soluble in dimethyl sulfoxide, tetrahydrofuran, acetone, acetonitrile, dichloromethane and ethyl acetate; soluble in methanol and propylene carbonate; sparingly soluble in anhydrous ethanol; slightly soluble in 2-propanol, diethyl ether and very slightly soluble in hexane. It is practically insoluble in water (43 microgram/mL at pH 7.4); the solubility increases in acidic medium (4.27 mg/mL at pH 3.6).

Chemical structure.


Chemical name: 2-morpholinoethyl(E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoate.
Molecular formula: C23H31NO7.
Molecular weight: 433.5.

CAS number.

115007-34-6.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes