Consumer medicine information

Cellcept

Mycophenolate mofetil

BRAND INFORMATION

Brand name

CellCept

Active ingredient

Mycophenolate mofetil

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Cellcept.

What is in this leaflet

This leaflet answers some common questions about CellCept. 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 CellCept against the benefits expected for you.

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

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

What CellCept is used for

CellCept contains the active ingredient mycophenolate mofetil.

CellCept belongs to a group of medicines called immunosuppressants.

Immunosuppressants are used to prevent the rejection of a transplanted organ and work 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.

CellCept may be used together with other medicines known as cyclosporin and corticosteroids.

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

CellCept is not addictive.

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

Before you take or are given CellCept

When you must not take it

Do not take CellCept if:

  1. you have an allergy to:
  • CellCept or any of the ingredients listed at the end of this leaflet.
    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
    CellCept IV solution should not be given if you have an allergy to polysorbate 80.
  1. you are pregnant
  • CellCept 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 CellCept during pregnancy.
  • You must tell your doctor if you are pregnant or plan to become pregnant.
  1. you are breastfeeding
  • CellCept may pass into human breast milk and could cause serious side effects in your baby if you breastfeed.
  1. 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 CellCept therapy, during therapy and for at least six weeks after stopping CellCept, unless you are not sexually active.
  1. The package is torn or shows signs of tampering
  2. The expiry date (EXP) printed on the pack has passed.
  • 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 CellCept

Tell your doctor if:

  1. 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 CellCept.
  • repeat pregnancy tests will be performed during routine follow-up visits with your doctor.
  1. you are breast feeding or plan to breast feed
  2. 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 CellCept and for 90 days after you have stopped receiving CellCept.
  • you should not donate semen while you are being treated with CellCept and for 90 days after you have stopped receiving CellCept.
  1. You should not donate blood while you are being treated with CellCept and for at least 6 weeks after you stop receiving CellCept
  2. you have any other health problems, especially the following:
  • 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 ulceration or bleeding)
  • rare diseases due to a deficiency of the HGPRT enzyme such as Lesch-Nyhan or Kelley-Seegmiller syndrome
  • kidney disease
  • phenylketonuria. You may not be able to take CellCept oral suspension as it is a source of phenylalanine
  1. you have allergies to any other medicines, foods, preservatives or dyes

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

Taking other medicines

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

Some medicines and CellCept 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 certain viral infections
  • isavuconazole, a medicine used to treat fungal infections
  • antacids, medicines used to treat heartburn and indigestion
  • cholestyramine, a medicine used to treat high cholesterol
  • ciprofloxacin, amoxicillin plus calvulanic 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
  • proton-pump inhibitors, medicines used to treat indigestion and stomach ulcers such as lansoprazole and pantoprazole
  • calcium-free phosphate binders (such as sevelamer), medicines used to treat high phosphate levels in the blood

These medicines may be affected by CellCept 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 CellCept

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 on the packet ask your doctor or pharmacist for help.

CellCept infusion is only given in a hospital setting by specially trained doctors or nurses.

How much to take

Take CellCept exactly as your doctor has prescribed.

Your doctor will tell you how many CellCept capsules or tablets or how much CellCept suspension to take each day.

Your doctor will work out how much CellCept infusion will be given to you.

CellCept Capsules and Tablets

The dose to prevent organ rejection is usually 1g 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.

CellCept Suspension

Adult

The dose to prevent organ rejection is usually 2 g or 3 g per day depending on which organ has been transplanted. This should be taken as 5 mL or 7.5 mL in the morning and 5 mL or 7.5 mL at night using the oral dispenser provided.

Children

For renal transplant only.

For children 2 to 18 years of age, the dose to prevent organ rejection is dependent on the child's height and weight. The maximum dose is usually 1 g in the morning and 1 g at night (2 g daily).

CellCept Infusion

The dose to prevent organ rejection is usually 2 g to 3 g per day depending on which organ has been transplanted.

Your doctor may adjust your dose depending on your response.

How to take it

CellCept Capsules and Tablets

Swallow the capsules or tablets whole with a full 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.

CellCept Suspension

Shake the suspension well before you measure out your dose. Shaking the bottle will make sure that you get the correct dose.

Just before the suspension was given to you, water was added to the powder in the bottle. The bottle will only be about three-quarters full when you receive it.

After the addition of water, the amount of suspension that can be withdrawn from the bottle is 165 mL. However, each bottle will contain a little more than 165 mL to allow for the small amount of suspension that cannot be withdrawn from the bottle with the oral dispenser.

After each dose of the suspension have a glass of water.

If you accidentally spill the suspension on yourself, wash off any liquid thoroughly with soap and water.

CellCept Infusion

CellCept is added to an infusion bag and given as a 'drip' into a vein, usually over a period of two or more hours.

It is only given in a hospital setting and doses are usually approximately 12 hours apart.

If contact with the infusion solution occurs, wash off any liquid thoroughly with soap and water.

When to take CellCept

It is best to take doses of CellCept capsules, tablets or suspension approximately 12 hours apart.

Take your medicine at about the same time each day. Taking CellCept 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 CellCept

CellCept should be taken every day. It is important to keep taking CellCept to ensure your new transplant keeps working properly.

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

If you are receiving CellCept infusion, your doctor will most likely change this medication to CellCept capsules, tablets or suspension once you are able to take these.

If you forget to take CellCept tablets, capsules or suspension

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.

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 13 11 26) 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 CellCept. 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 using CellCept

Things you must do

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

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

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.

Tell your doctor if you become pregnant while taking CellCept.

If you are a woman of child bearing potential, you must use two reliable forms of contraception at the same time before beginning CellCept therapy, during therapy and for at least six weeks after stopping CellCept, 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 CellCept and for 90 days after you have stopped receiving CellCept.

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.

Be sure to keep all of your appointments with your doctor so that your progress can be checked. Your doctor will need to give you regular blood tests.

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

Things you must not do

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

Do not use CellCept to treat any other complaints unless your doctor tells you to.

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

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

Do not crush CellCept tablets or open CellCept capsules.

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

Things to be careful of

Be careful driving or operating machinery until you know how CellCept affects you or if you experience somnolence, confusion, dizziness, tremor or hypotension. CellCept 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 CellCept.

This medicine helps most people who have organ transplants, but it may have unwanted side effects in some people.

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.

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 receiving CellCept 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 increase chance of side effects occurring due to immunosuppression.

Do not be alarmed by the following list 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), vomiting or indigestion
  • stomach, chest or back pain
  • headache
  • urinary infections

The above list includes the more common side effects of CellCept.

Tell your doctor immediately or go to Accident and Emergency at your nearest hospital if you notice any of the following:

  • signs of other infections, e.g. fevers, chills, sore throat, 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. Serious side effects are rare.

This is not a complete list of all possible side effects. Other side effects may occur in some people and there may be some others that are 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 using CellCept

Storage

CellCept Capsules and Tablets

Keep your capsules or tablets in the blister pack until it is time to take them. If you take the capsules or tablets out of the blister pack they may not keep well.

Keep CellCept capsules in a cool dry place where the temperature stays below 30°C.

Keep CellCept tablets in a cool dry place where the temperature stays below 25°C.

CellCept Suspension

Discard the suspension after 60 days. The suspension only lasts for 60 days once water has been added. After this time it may not work as well.

Keep CellCept suspension in a cool dry place where the temperature stays below 25°C. It may be stored in a refrigerator but should not be frozen.

CellCept Infusion

The infusion will be stored by the hospital pharmacy or on the ward until it is time to use it.

Do not store CellCept 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 CellCept or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product description

Availability

CellCept 250 mg capsules come in packs of 100 capsules.

CellCept 500 mg tablets come in packs of 50 tablets.

CellCept 200 mg/mL suspension comes in a 225 mL bottle with an adapter and two oral dispensers.

CellCept 500 mg infusion comes in packs of 4 vials. CellCept vials will be kept in the hospital pharmacy or on the ward.

What CellCept capsules look like

CellCept capsules are oblong, blue on one end and brown on the other, printed with black ink 'CellCept 250' on the cap and 'Roche' on the body.

Ingredients

CellCept capsules contain 250 mg of mycophenolate mofetil as the active ingredient.

Inactive ingredients:

  • Pregelatinised maize starch
  • Croscarmellose sodium
  • Povidone
  • Magnesium sterate

The capsule shell contains:

  • Gelatine
  • Sodium lauryl sulphate
  • Shellac
  • Potassium hydroxide
  • Silicon dioxide

The dyes in the capsule shell are:

  • Indigo carmine (132)
  • Iron oxide red (172)
  • Titanium dioxide (171)
  • Iron oxide yellow (172)
  • Iron oxide black (172)

CellCept capsules are gluten and lactose free.

What CellCept tablets look like

CellCept tablets are lavender coloured and capsule shaped, engraved with 'CellCept 500' on one side and 'Roche' on the other.

Ingredients

CellCept tablets contain 500 mg of mycophenolate mofetil as the active ingredient.

Inactive ingredients:

  • Microcrystalline cellulose (460)
  • Croscarmellose sodium
  • Povidone
  • Magnesium sterate (470)
  • Talc (553)
  • The proprietary ingredient Opadry Lavender Y-5R-10272-A (includes 464, 171, 132 and 172).

CellCept tablets are gluten and lactose free.

What CellCept suspension looks like

CellCept suspension is a white to off-white powder.

Ingredients

CellCept suspension contains 1 g of mycophenolate mofetil per 5 mL as the active ingredient when reconstituted.

Inactive ingredients:

  • Sorbitol (420)
  • Silicon dioxide (551)
  • Sodium citrate (331)
  • Soybean lecithin
  • Mixed fruit flavour
  • Xanthan gum (415)
  • Aspartame (951)
  • Methyl hydroxybenzoate (218)
  • Citric acid anhydrous (330)

What CellCept infusion looks like

CellCept infusion is a sterile white to off-white powder in a clear glass vial. It will be made up into an infusion bag before being given to you. The solution in the infusion bag should be clear to slightly yellow.

Ingredients

CellCept infusion contains 500 mg of mycophenolate mofetil as the hydrochloride salt.

Inactive ingredients:

  • Polysorbate 80
  • Citric acid (330)
  • Sodium chloride

Manufacturer

CellCept is distributed in Australia by:

Roche Products Pty Limited
ABN 70 000 132 865
Level 8, 30-34 Hickson Road
Sydney NSW 2000
AUSTRALIA

Medical enquiries: 1800 233 950

Please check with your pharmacist for the latest Consumer Medicine Information.

Australian Registration Numbers

  • CellCept 250 mg capsules AUST R 67313
  • CellCept 500 mg tablets AUST R 82372
  • CellCept 200 mg/mL suspension AUST R 72582
  • CellCept 500 mg vials AUST R 68233

This leaflet was prepared on 17 October 2018.

Published by MIMS December 2018

BRAND INFORMATION

Brand name

CellCept

Active ingredient

Mycophenolate mofetil

Schedule

S4

 

1 Name of Medicine

Mycophenolate mofetil.

6.7 Physicochemical Properties

Mycophenolate mofetil is the 2-morpholinoethyl ester of mycophenolic acid. The chemical name for mycophenolate mofetil is 2-morpholinoethyl-(E)6-(1, 3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5- isobenzofuranyl) -4-methyl-4-hexenoate. It has an empirical formula of C23H31NO7 and a molecular weight of 433.50.
Mycophenolate mofetil is a white to off-white crystalline powder. It 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.


CAS number.

115007-34-6.

2 Qualitative and Quantitative Composition

CellCept 250 mg capsules contain 250 mg mycophenolate mofetil.
CellCept 500 mg tablets contain 500 mg mycophenolate mofetil.
CellCept 500 mg powder for concentrate for solution for infusion contains 500 mg mycophenolate mofetil (as hydrochloride salt).
CellCept 1 g/5 mL powder for oral suspension contains 1 g mycophenolate mofetil per 5 mL when reconstituted.
For the full list of excipients, see Section 6.1. List of Excipients.

3 Pharmaceutical Form

CellCept 250 mg capsules.

Capsules, hard.
CellCept capsules: oblong, blue/brown, branded with black "CellCept 250" on the capsule cap and "Roche" name on the capsule body.

CellCept 500 mg tablets.

Film coated tablets.
CellCept tablets: lavender coloured caplet-shaped tablet, engraved with "CellCept 500" on one side and "Roche" name on the other.

CellCept 500 mg powder for concentrate for solution for infusion.

Powder for concentrate for solution for infusion.
Sterile lyophilised white to off-white powder for infusion.
CellCept 500 mg powder for concentrate for solution for infusion must be reconstituted and further diluted with glucose intravenous infusion 5% prior to administration to the patient. Reconstitution and dilution with 5% glucose intravenous infusion as recommended yields a slightly yellow solution of mycophenolate mofetil, 6 mg/mL.

CellCept 1 g/5 mL powder for oral suspension.

Powder for oral suspension.
White to off-white powder for oral suspension.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: immunosuppressive agents. ATC code L04AA06.

Mechanism of action.

Mycophenolic acid (MPA) is a potent, selective, uncompetitive and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH) which inhibits the de novo pathway of guanosine nucleotide synthesis without incorporation into DNA. Based on Chinese hamster inosine-5'-monophosphate dehydrogenase (IMPDH) in complex with inosine-5'-monophosphate (IMP) and mycophenolic acid (MPA), the mechanism by which MPA inhibits the enzymic 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 mycophenolate mofetil.
Mycophenolate mofetil (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. Mycophenolate mofetil 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 drug. 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 drug 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 CellCept 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 CellCept (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. CellCept, 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 CellCept 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 following transplantation. In addition, CellCept 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 CellCept 2 g per day (5.5 to 10.3%) or CellCept 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 CellCept 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 CellCept 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 CellCept 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 CellCept). 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. CellCept 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 CellCept group had died or experienced graft loss. Eighteen patients (25%) receiving high dose IV steroids and 9 patients (12%) receiving CellCept lost their graft in the 6 months after enrolment. One patient (1.4%) receiving high dose IV steroids and 2 patients (2.6%) receiving CellCept died in the 6 months after enrolment. Fewer patients receiving CellCept (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 CellCept 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 CellCept 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 CellCept 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 CellCept 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.
CellCept and azathioprine did not differ significantly at 6 months in biopsy-proven acute rejection with haemodynamic compromise. (See Table 8.)

Prevention of hepatic allograft rejection.

The safety and efficacy of CellCept 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 CellCept 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 CellCept 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 CellCept 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, mycophenolic acid (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 glucuronide of MPA (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, cross-over, 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 decreased by 40% in the presence of food.
The pharmacokinetic profile of MPA in cardiac patients is similar to that in renal patients.

Distribution.

As a result of enterohepatic recirculation, secondary increases in plasma MPA concentration are usually observed approximately 6 to 12 hours 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 back 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 and 16.6 ± 5.8 hours and 177 ± 31 mL/min, respectively, following intravenous 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 CellCept 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 (at greater than or equal to 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).

4 Clinical Particulars

4.1 Therapeutic Indications

CellCept is indicated for the prophylaxis of solid organ rejection in adults receiving allogeneic organ transplants.
CellCept is indicated for the prophylaxis of organ rejection in paediatric patients (2 to 18 years) receiving allogeneic renal transplants.

4.3 Contraindications

Allergic reactions to CellCept have been observed, therefore, CellCept is contraindicated in patients with a hypersensitivity to mycophenolate mofetil (MMF) or to mycophenolic acid.
CellCept intravenous (IV) solution is contraindicated in patients with known hypersensitivity to polysorbate 80.
CellCept is contraindicated during pregnancy due to its mutagenic and teratogenic potential (see Section 4.6 Fertility, Pregnancy and Lactation).
CellCept is contraindicated in women of childbearing potential not using highly effective contraceptive methods (see Section 4.6 Fertility, Pregnancy and Lactation).
CellCept is contraindicated in women who are breastfeeding (see Section 4.6 Fertility, Pregnancy and 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 CellCept. CellCept is contraindicated during pregnancy and during breastfeeding (see Section 4.6 Fertility, Pregnancy and Lactation).
Men should not donate semen during therapy and for 90 days following discontinuation of CellCept.

Caution.

CellCept IV solution must not be administered by rapid or bolus intravenous injection.

Neoplasms.

As with other patients receiving immunosuppressive regimes involving combinations of medicines, patients receiving CellCept 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 CellCept 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 CellCept 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 CellCept-treated patients. 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 CellCept in patients post-renal 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 CellCept in combination with other immunosuppressive agents. The mechanism for mycophenolate mofetil-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 CellCept therapy. In transplant patients however, reduced immunosuppression may place the graft at risk.
Patients receiving CellCept should be instructed to immediately report any evidence of infection, unexpected bruising, bleeding or any other manifestation of bone marrow depression.
Patients on CellCept 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 CellCept should be monitored for neutropenia. The development of neutropenia may be related to CellCept, concomitant medications, viral infection or some combination of these causes. If neutropenia develops (absolute neutrophil count < 1.3 x 103/microL), dosing with CellCept should be interrupted or the dose reduced and the patient should be carefully observed.
0.5% of patients receiving CellCept 2 g for prevention of rejection in renal transplantation, 2.8% of patients receiving CellCept 3 g in cardiac transplantation and 3.6% of patients receiving CellCept 3 g in hepatic transplantation, developed severe neutropenia (absolute neutrophil count [ANC] < 5 x 108/L).
Patients should be advised that during treatment with CellCept 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 CellCept.

Gastrointestinal.

CellCept 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 post-marketing surveillance, CellCept 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 CellCept 2 g in renal transplantation, 2.8% of patients receiving 3 g in cardiac transplantation and in 5.4% of patients receiving CellCept 3 g in hepatic transplantation. Gastrointestinal tract perforations have rarely been observed. Most patients were also receiving other drugs 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 CellCept 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 CellCept (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 CellCept 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.

Phenylketonurics.

CellCept oral suspension contains aspartame, a source of phenylalanine (0.56 mg phenylalanine per mL suspension). Therefore, care should be taken if CellCept oral suspension is administered to patients with phenylketonuria.

Use in renal impairment.

Patients with severe chronic renal impairment (GFR < 25 mL/min/1.73 m2) who have received single doses of CellCept showed increased plasma AUCs of MPA and MPAG relative to patients with lesser degrees of renal impairment or normal healthy patients. Patients with severe chronic renal impairment should be carefully monitored and administration of doses of CellCept greater than 1 g twice daily should be avoided (see Section 4.2 Dose and Method of Administration and 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 CellCept 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.

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.

Use in the elderly.

Elderly patients may be at an increased risk of adverse events such as certain infections (including CMV tissue invasive disease) and possibly 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 CellCept in the elderly has not been formally evaluated.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Drug interaction studies with MMF have been conducted with aciclovir, antacids, belatacept, cholestyramine, ciclosporin, ganciclovir, oral contraceptives, proton pump inhibitors, sirolimus, tacrolimus, telmisartan and trimethoprim/sulfamethoxazole. Drug 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 drug 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 drugs 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 pre-dose (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 pre-dose level may not accurately represent changes in overall MPA exposure; therefore, clinical relevance of these observations is unclear.

Norfloxacin and metronidazole.

The combination of norfloxacin and metronidazole reduced the MPA AUC following a single dose of CellCept.

Trimethoprim and sulfamethoxazole.

Following single dose administration of MMF (1.5 g) to healthy male volunteers pretreated for 10 days with trimethoprim 160 mg and 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 CellCept and any drug which interferes with enterohepatic circulation because of the potential to reduce the efficacy of CellCept.

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 CellCept 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 CellCept and ciclosporin compared with patients receiving sirolimus or belatacept and similar doses of CellCept. Conversely, changes of MPA exposure should be expected when switching patients from ciclosporin to one of the immunosuppressants which do not interfere with MPA's enterohepatic cycle.

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 CellCept.

Telmisartan.

Concomitant administration of telmisartan and CellCept resulted in an approximately 30% decrease of mycophenolic acid (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.

Sirolimus.

A study in 36 renal transplant patients demonstrated that concomitant administration of CellCept (1 g twice daily) and sirolimus resulted in the mean (± SD) AUC0-12h of MPA after 14 days and 3 months were 81 ± 36 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 CellCept were withdrawn with symptoms consistent with MPA or sirolimus toxicity.
Monitoring of MPA levels should be performed in renal graft recipients co-treated with sirolimus because of the risk of overexposure to this immunosuppressive agent.

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 co-administered, 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 CellCept and iron supplements when administered in a fasting state. In the same study, a 15% reduction in MPA AUC was observed when CellCept and iron were administered simultaneously with food. In an earlier study involving 7 healthy volunteers, a significant reduction in MPA AUC was observed when CellCept and iron were administered in a fasting state. To avoid any possible interactions, iron supplements should be administered at least 3 hours following CellCept.

Live vaccines.

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

Oral contraceptives.

A study of co-administration of CellCept (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 CellCept on serum levels of progesterone, LH and FSH, thus indicating no influence of CellCept on the ovulation-suppressing action of the oral contraceptives. The pharmacokinetics of oral contraceptives were not affected to a clinically relevant degree by coadministration of CellCept (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 CellCept. The clinical impact of reduced MPA exposure on organ rejection has not been established in transplant patients receiving PPIs and CellCept. Because clinical relevance has not been established, PPIs should be used with caution when co-administered to transplant patients being treated with CellCept.

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 CellCept doses accordingly to maintain clinical efficacy when the drugs are administered concomitantly.

Tacrolimus.

The AUC and Cmax of MPA, the active metabolite of CellCept, were not significantly affected by co-administration with tacrolimus, in stable hepatic transplant patients initiated on CellCept and tacrolimus. In contrast, there was an increase of approximately 20% in tacrolimus AUC when multiple doses of CellCept (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 CellCept.

Sevelamer and other calcium-free phosphate binders.

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

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, co-administration 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 drug 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 Use in pregnancy below). Malformations (including anophthalmia, agnathia, and hydrocephaly) occurred in the first generation offspring of female rats treated with oral doses of mycophenolate mofetil in the absence of maternal toxicity. No effect was seen on the fertility of male rats treated with mycophenolate mofetil.
(Category D)
CellCept 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). CellCept 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 mycophenolate mofetil 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 mycophenolate mofetil 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 mycophenolate mofetil.
Congenital malformations, including multiple malformations have been reported post-marketing in children of patients exposed to mycophenolate mofetil 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 or more (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 anopthalmia, micropthalmia), 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 counseled regarding pregnancy prevention, and planning.
It is not known whether the drug is excreted in human milk. Due to the potential for serious adverse reactions in nursing infants, CellCept is contraindicated during breastfeeding (see Section 4.3 Contraindications).
Although the relevance to humans is unknown, studies in rats have shown MMF to be excreted in milk.

Pregnancy testing.

Prior to starting therapy with CellCept, 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 CellCept. 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 CellCept 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 CellCept.
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 a total of 90 days after the last dose of CellCept.

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 reactions associated with the administration of CellCept 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 CellCept 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 CellCept 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 CellCept 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 CellCept 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 drug treatment and not mentioned in any of the tables or in text pertaining to infections or malignancy following, were reported with an incidence of less than 3% in one or more of the CellCept 2 g or 3 g (renal) active-controlled cohorts (n = 336, n = 330), the CellCept 2 g or 3 g (renal) placebo-controlled cohorts (n = 165, n = 160), less than 1.4% in the CellCept 3 g (cardiac) active-controlled cohort (n = 289), or less than 1.4% in the CellCept 3 g (hepatic) active-controlled cohort study (n = 277).

Digestive system.

Colitis (sometimes caused by cytomegalovirus), 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 drug effect, syncope, pelvis pain, pain, oedema, drug level increased, drug level decreased, injection site reaction, injection site inflammation, injection site hypersensitivity.

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, injection site inflammation, 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.

Metabolic and nutritional disorders.

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

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.

Musculoskeletal 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 CellCept 2 g for prevention of renal allograft rejection developed severe neutropenia (absolute neutrophil count (ANC) < 5 x 108/L). Up to 2.8% (regardless of investigator assessment of causality) of cardiac transplant patients receiving CellCept 3 g and up to 3.6% (regardless of investigator assessment of causality) of patients receiving CellCept 3 g in hepatic transplantation developed severe neutropenia.
Cytomegalovirus (CMV) tissue invasive disease was more common in renal transplant patients receiving CellCept 3 g/day (8 - 12%) than in those receiving CellCept 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 CellCept 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 CellCept 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 CellCept or control therapy in combination with other immunosuppressive agents. In the controlled cardiac transplant study, fatal infections occurred in 2.4% of patients receiving CellCept 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 CellCept 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 drugs, patients receiving CellCept as part of an immunosuppressive regimen 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 CellCept in immunosuppressive regimens 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 CellCept and azathioprine groups. Hepatic transplant patients were followed for at least 1 year but less than 3 years.

Adverse events profile for intravenous administration.

The adverse event profile of CellCept administered intravenously was determined from a single, double blind, controlled comparative study of the safety of CellCept 2 g/day administered intravenously or orally in the immediate post-transplant period (administered for the first 5 days). The potential venous irritation of CellCept administered intravenously was evaluated by comparing the adverse events attributable to a peripheral venous infusion of CellCept with those observed in the IV placebo group; patients in the latter group received active medication by the oral route.
Adverse events attributable to peripheral venous infusion were phlebitis and thrombosis, both observed at 4% in patients treated with CellCept intravenously.
In the active controlled study in hepatic transplant patients, 2 g daily of CellCept intravenous were administered in the immediate post-transplant period (up to 14 days). The safety profile of intravenous CellCept was similar to that of intravenous azathioprine.

Paediatric adverse events.

The type and frequency of adverse drug reactions 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 CellCept twice daily with the exception that paediatric patients had a higher proportion of diarrhoea, anaemia, sepsis and leucopenia.

Post-marketing 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 infections.
Cases of Progressive Multifocal Leukoencephalopathy (PML), sometimes fatal, have been reported in CellCept treated patients. The reported cases generally had risk factors for PML, including concomitant immunosuppressant therapies and impaired immune function.
BK virus-associated nephropathy has been observed in patients treated with CellCept. This infection can be associated with serious outcomes, sometimes leading to renal graft loss.

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 cytomegalovirus).

Congenital disorders.

Congenital malformations have been reported post marketing in children of patients exposed to CellCept in combination with other immunosuppressants during pregnancy (see Section 4.6 Fertility, Pregnancy and Lactation).

Pregnancy, puerperium and perinatal conditions.

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

Blood and immune system.

Cases of pure red cell aplasia (PRCA) and hypogammaglobulinemia have been reported in patients treated with CellCept in combination with other immunosuppressive agents, hypersensitivity.

Respiratory, thoracic and mediastinal disorders.

Bronchiectasis, interstitial lung disease, pulmonary fibrosis.

Vascular disorders.

Lymphocele.

Reporting of suspected adverse reactions.

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.

4.2 Dose and Method of Administration

Dosage.

The initial dose of CellCept should be given as soon as clinically feasible following transplantation. Intravenous administration is recommended in those patients unable to take oral medication. However, oral administration should be initiated as soon as possible.

Adults.

Renal transplantation.

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

Cardiac transplantation.

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

Hepatic transplantation.

The recommended dose in hepatic transplant patients is 1 g administered intravenously twice daily (2 g daily dose) followed by 1.5 g administered orally twice daily (3 g daily dose) (see Preparation and administration of CellCept IV, below).

Other transplants.

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

Paediatrics (2 to 18 years).

The recommended dose for renal transplant patients is 600 mg/m2 of mycophenolate mofetil (MMF) administered orally twice daily (up to a maximum of 2 g daily).
CellCept may be administered in combination with ciclosporin and corticosteroids.
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 (ANC < 1.3 x 109/L), dosing with CellCept should be interrupted or the dose should be 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.
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 CellCept 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 post-operatively.
No dosage adjustment is required in the elderly or in renal transplant patients with hepatic parenchymal disease.
No data are available for cardiac transplant patients with severe hepatic parenchymal disease.

Method of administration.

Preparation and administration of CellCept IV.

CellCept IV is an alternative dosage form recommended for patients unable to take CellCept capsules, tablets and oral suspension. CellCept IV should be administered within 24 hours following transplantation. Although CellCept IV administration has been studied for up to 14 days, patients should be switched to oral CellCept as soon as they can tolerate oral medication.
CellCept IV should be reconstituted and diluted to a concentration of 6 mg/mL with 5% glucose intravenous infusion prior to use. A two-step reconstitution and dilution process is required to prepare the infusion solution to the recommended concentration of 6 mg/mL (see below). It must be administered by slow intravenous infusion over a period of no less than 2 hours.

Caution.

CellCept IV solution must not be administered by rapid or bolus intravenous injection.
Two vials of CellCept IV are used for preparing each 1 g dose. Three vials of CellCept IV are used for preparing each 1.5 g dose.

1 gram dose (two vials).

Step 1. 1. Withdraw 5% glucose intravenous infusion from the bag so that 140 mL remains (e.g. for a 250 mL bag, withdraw 110 mL).
2. Use 28 mL of this withdrawn glucose solution to reconstitute the two vials by injecting 14 mL of 5% glucose intravenous infusion into each vial (using aseptic techniques).
3. Gently shake the vials to dissolve the drug.
4. Inspect the resulting solution for particulate matter and discolouration prior to further dilution. Discard any vial in which particulate matter or discolouration are observed.
Step 2. 1. Further dilute the contents of the two reconstituted vials (prepared in step 1) by adding both to the 140 mL bag of 5% glucose intravenous infusion for a total volume of 168 mL and a final concentration of 6 mg/mL.
2. Inspect the infusion solution for particulate matter or discolouration. Discard the infusion solution if particulate matter or discolouration is observed.

1.5 gram dose (three vials).

Step 1. 1. Withdraw 5% glucose intravenous infusion from the bag so that 210 mL remains (e.g. for a 250 mL bag, withdraw 40 mL and discard).
2. Prepare 42 mL of 5% glucose intravenous infusion to reconstitute the three vials by injecting 14 mL of 5% glucose intravenous infusion into each vial (using aseptic techniques).
3. Gently shake the vials to dissolve the medicine.
4. Inspect the resulting solution for particulate matter and discolouration prior to further dilution. Discard any vial in which particulate matter or discolouration are observed.
Step 2. 1. Further dilute the contents of the three reconstituted vials (prepared in step 1) by adding them to the 210 mL bag of 5% glucose intravenous infusion for a total volume of 252 mL and a final concentration of 6 mg/mL.
2. Inspect the infusion solution for particulate matter or discolouration. Discard the infusion solution if particulate matter or discolouration are observed.

Preparation and administration of oral suspension.

It is recommended that CellCept oral powder for suspension be reconstituted by the pharmacist prior to dispensing to the patient.
CellCept powder for oral suspension should not be mixed with any other medication.
1. Tap the closed bottle several times to loosen the powder.
2. Measure 94 mL of purified water in a graduated cylinder.
3. Add approximately half of the total amount of purified water to the bottle and shake well for about 1 minute.
4. Add the remainder of water and shake the closed bottle well for about 1 minute.
5. Remove the cap and push bottle adapter into neck of the bottle.
6. Close bottle with cap tightly. This will assure the proper seating of the bottle adapter in the bottle.
7. Write the date of expiration of the constituted oral suspension on the bottle label. (The shelf life of the reconstituted oral suspension is 60 days from date of preparation.)

Note.

If required CellCept Oral Suspension can be administered via a nasogastric tube with a minimum interior diameter of 1.7 mm.
The deliverable volume of the oral suspension is 165 mL and contains 33 doses of 1 g/5 mL mycophenolate mofetil. After reconstitution, each bottle will contain a volume greater than 165 mL to allow for wastage due to inaccessible suspension. Each dose is administered using the 5 mL plastic oral dispenser provided (2 per carton). Discard any unused suspension 60 days after reconstitution.

4.7 Effects on Ability to Drive and Use Machines

CellCept 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 CellCept (see Section 4.8 Adverse Effects (Undesirable Effects)).

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 drug.
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 CellCept 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 13 11 26 (Australia) or the National Poisons Centre on 0800 POISON (0800 764766) (New Zealand).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

CellCept 250 mg capsules.

Pregelatinised maize starch; Croscarmellose sodium; Povidone; Magnesium stearate.

Capsule shell.

Gelatin; Sodium lauryl sulphate; Shellac; Potassium hydroxide; Silicon dioxide.

Capsule shell dyes.

Indigo carmine; Iron oxide red; Titanium dioxide; Iron oxide yellow; Iron oxide black.

CellCept 500 mg tablets.

Microcrystalline cellulose; Croscarmellose sodium; Povidone; Magnesium stearate; Talc; Opadry Lavender Y-5R-10272-A.

CellCept 500 mg powder for concentrate for solution for infusion.

Polysorbate 80; Citric acid; Sodium chloride.

CellCept 1 g/5 mL powder for oral suspension.

Sorbitol; Silicon dioxide; Sodium citrate; Soybean lecithin; Mixed fruit flavour; Xanthan gum; Aspartame; Methyl hydroxybenzoate; Citric acid anhydrous.

6.2 Incompatibilities

CellCept IV infusion solution should not be mixed or administered concurrently via the same catheter with other intravenous drugs or infusion admixtures.
CellCept IV is physically incompatible with the following infusion solutions: 0.9% Normal Saline, Ringer’s and lactated Ringer’s solutions.

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

CellCept 250 mg capsules should be stored below 30°C.
CellCept 500 mg tablets should be stored below 25°C and protected from light.
CellCept 500 mg powder for solution for infusion should be stored below 30°C. Reconstituted IV solution should be stored between 15 - 30°C for up to four hours.
CellCept oral suspension should be stored below 25°C before reconstitution. The reconstituted oral suspension should be stored below 25°C or may be refrigerated (2 - 8°C) but should not be frozen. Discard any unused suspension 60 days after reconstitution.

6.5 Nature and Contents of Container

CellCept 250 mg capsules.

Blister platforms of 10 (pack of 100).

CellCept 500 mg tablets.

Blister platforms of 10 (pack of 100).

CellCept 500 mg powder for solution for infusion.

20 mL clear glass vials with a grey rubber stopper and aluminium seals with plastic flip-off caps (pack of 4).

CellCept 1 g/5 mL powder for oral suspension.

Each bottle contains 35 g mycophenolate mofetil in a 110 g powder for oral suspension, yielding 33 doses of 1 g/5 mL once reconstituted.

6.6 Special Precautions for Disposal

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

CellCept oral administration.

Mycophenolate mofetil has demonstrated teratogenic effects (see Section 4.4 Special Warnings and Precautions for Use and Section 4.6 Fertility, Pregnancy and Lactation), therefore CellCept tablets and capsules should not be crushed or opened. Patients should also avoid inhalation or contact of the skin or mucous membranes with the powder contained in CellCept capsules and oral suspension (before and after reconstitution). If contact occurs, wash thoroughly with soap and water; should the eyes be affected, rinse eyes with plain water.

CellCept powder for oral suspension.

It is recommended that CellCept powder for suspension be reconstituted by the pharmacist prior to dispensing to the patient. Wearing disposable gloves is recommended during reconstitution and when wiping the outer surface of the bottle/cap and the table after reconstitution.

CellCept intravenous administration.

Caution should be exercised in the handling and preparation of solutions of CellCept IV to avoid direct contact of prepared solution with skin or mucous membranes. If contact occurs, wash thoroughly with soap and water; should the eyes be affected, rinse eyes with plain water.

Summary Table of Changes