Consumer medicine information

IMULATE

Mycophenolate mofetil

BRAND INFORMATION

Brand name

Imulate Capsules

Active ingredient

Mycophenolate mofetil

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using IMULATE.

What is in this leaflet

This leaflet answers some common questions about Imulate capsules and tablets.

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 Imulate against the benefits they expect it will have for you.

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

Keep this leaflet with the medicine.

You may need to read it again.

What Imulate is used for

Imulate contains the active ingredient mycophenolate mofetil.

Imulate belongs to a group of medicines called immunosuppressants.

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

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

Your doctor, however, may have prescribed Imulate for another purpose.

Ask your doctor if you have any questions about why Imulate has been prescribed for you.

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

Imulate is not addictive.

Before you take it

When you must not take it

Do not take Imulate if:

  1. you have had an allergic reaction to Imulate or any ingredients listed at the end of this leaflet.
    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, hives on the skin.
  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 if you should be taking Imulate, talk to your doctor.

Before you start to take it

Tell your doctor if:

  1. you are pregnant or plan to become pregnant
    It is not known whether Imulate is harmful to an unborn baby when taken by a pregnant woman. There have been cases of birth defects reported in patients exposed to Imulate in combination with other immunosuppressants during pregnancy. If there is a need to take Imulate when you are pregnant your doctor will discuss the risks and benefits to you and the unborn baby.
  2. you are breast-feeding or plan to breast-feed
    It is not known whether Imulate passes into breast milk. Your doctor will discuss the risks and benefits of taking Imulate if you are breast-feeding.
  3. 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 ulcers or bleeding).
  • kidney disease.
  1. you are allergic to any other medicines, foods, dyes or preservatives.

If you have not told your doctor about any of the above, tell them before you start taking Imulate.

Taking other medicines

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

Some medicines may interfere with Imulate. These medicines include:

  • aciclovir or ganciclovir, medicines used to treat viral infections
  • antacids, medicines used to treat heartburn and indigestion
  • azathioprine, a medicine used to suppress the immune system
  • calcium-free phosphate binders (such as sevelamer), medicines used to treat high phosphate levels in the blood
  • certain vaccines, medicines that work by causing your body to produce its own protection against an infectious disease
  • cholestyramine, a medicine used to treat high cholesterol levels in the blood
  • iron supplements, medicines used to treat low iron levels in the blood
  • norfloxacin plus metronidazole and amoxicillin plus clavulanic acid, combination antibiotics used to treat infections
  • rifampicin and ciprofloxacin, medicines used to treat infections
  • tacrolimus, a medicine used to suppress the immune system
  • sirolimus, a medicine used to prevent organ rejection after a transplant.

These medicines may be affected by Imulate, or may affect how well it works.

You may need to use different amounts of your medicine, or you may need to take different medicines. Your doctor will advise you.

Your doctor or pharmacist has more information on medicines to be careful with or avoid while taking Imulate.

Ask your doctor or pharmacist if you are not sure about this list of medicines.

How to take Imulate

Follow all directions given to you by your doctor or pharmacist carefully.

They may differ from the information contained in this leaflet.

How much to take

Take Imulate exactly as your doctor has prescribed.

Your doctor will tell you how many Imulate capsules and tablets to take each day.

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

Children

For renal transplant only.

For children (with a body surface area ≥ 1.25m2), the dose to prevent rejection is dependent on your child's height and weight. The maximum dose is usually 1 g in the morning and 1 g at night (2 g daily).

Your doctor may adjust your dose depending on your response.

How to take it

Imulate Capsules and Tablets

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

If a capsule breaks open accidentally, wash off any powder thoroughly with soap and water.

When to take it

It is best to take doses approximately 12 hours apart. Your dose can be taken with or without food.

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

How long to take Imulate

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

Continue taking Imulate until your doctor tells you to stop.

If you forget to take it

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

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

Do not double a dose to make up for one you have missed.

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

If you have trouble remembering your dose, ask your pharmacist for some hints.

If you take too much (overdose)

Immediately telephone your doctor, or Poisons Information Centre (telephone 13 11 26), or go to Accident and Emergency at your nearest hospital, if you think you or anyone else may have taken too much Imulate. Do this even if there are no signs of discomfort or poisoning.

Keep telephone numbers for these places handy. If you are not sure what to do, contact your doctor or pharmacist.

While you are taking Imulate

Things you must do

Tell all doctors, dentists and pharmacists who are treating you that you are taking Imulate.

Tell your doctor if you become pregnant while taking Imulate.

It is important to take effective contraceptive measures four weeks before you commence taking Imulate, while you are taking Imulate and for six weeks after you stop taking Imulate.

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 a broad-spectrum sunscreen when outdoors.

Medicines that prevent rejection of transplants can increase the risk of skin cancers.

Things you must not do

Do not stop taking Imulate or change the dose without first checking with your doctor. Do not let yourself run out of medicine over the weekend or on holidays.

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

Do not use Imulate to treat other complaints unless your doctor says to.

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

Things to be careful of

Be careful driving or operating machinery until you know how Imulate affects you.

However, Imulate is not expected to 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 Imulate.

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

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment 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 taking Imulate therefore develop more infections than usual.

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

If you are over 65 years of age you may have an increased chance of getting side effects.

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

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

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

These are the more common side effects of Imulate. Mostly these are mild.

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 or ulcers of the mouth
  • unexpected bruising or bleeding
  • clumsiness
  • weakness
  • changes in vision or speech
  • signs of anaemia such as excessive tiredness, dizziness or looking pale.

These are 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. Others may occur in some people and there may be some side effects not yet known.

Ask your doctor or pharmacist if you don't understand anything in this list.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

Tell your doctor if you notice anything else that is making you feel unwell, even if it is not on this list.

After taking Imulate

Storage

Imulate 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 Imulate capsules and tablets in a cool dry place where the temperature stays below 30 degrees C.

Always keep the tablets away from direct light and keep the capsules away from moisture. Light will cause Imulate tablets to fade.

Do not store Imulate capsules, tablets or suspension, or any other medicine, in a bathroom or near a sink. Do not leave your medicine in the car or on window sills.

Heat and dampness can destroy some medicines.

Keep Imulate where young children cannot reach it.

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

Disposal

If your doctor tells you to stop taking Imulate; or the capsules, tablets or suspension have passed their expiry date, ask your pharmacist what to do with any that is left over.

Product description

Availability

Imulate 250 mg capsules are available in a pack of 100 capsules packed in blister (10 capsules per blister).

Imulate 500 mg tablets are available in a pack of 50 tablets packed in blister (10 tablets per blister).

What Imulate capsules and tablets look like

Imulate is available as a mauve-coloured, capsule shaped film-coated tablet containing 500 mg of mycophenolate mofetil with the excipients: microcrystalline cellulose, croscarmellose sodium, povidone, magnesium stearate hypromellose, titanium dioxide, macrogol 400, iron oxide red, allura red AC aluminium lake and brilliant blue FCF.

The ivory coloured hard gelatin capsule contains 250 mg mycophenolate mofetil with the excipients: microcrystalline cellulose, croscarmellose sodium, povidone and magnesium stearate. The capsule shell contains gelatin, purified water, sodium lauryl sulphate, iron oxide yellow, erythrosine, titanium dioxide and Opacode black S-1-8152HV ink (ARTG no. 1560).

Imulate capsules are gluten and lactose free.

Supplier

Aspen Pharmacare Australia Pty Ltd
34-36 Chandos St
St Leonards NSW 2065
Australia

Australian Registration Numbers:
250 mg capsule AUST R 167225
500 mg tablet AUST R 167224

This leaflet was written in February 2012.

BRAND INFORMATION

Brand name

Imulate Capsules

Active ingredient

Mycophenolate mofetil

Schedule

S4

 

Name of the medicine

Mycophenolate mofetil.

Excipients.

Tablet.

Microcrystalline cellulose, croscarmellose sodium, povidone, magnesium stearate, hypromellose, titanium dioxide, macrogol 400, iron oxide red, allura red AC and brilliant blue FCF.

Capsule.

Microcrystalline cellulose, croscarmellose sodium, povidone and magnesium stearate. The capsule shell contains gelatin, purified water, sodium lauryl sulphate, iron oxide yellow, allura red AC, titanium dioxide and Opacode black S-1-8152HV ink (ARTG no. 1560).

Description

Chemical name: 2-morpholinoethyl(E)-6-(1, 3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl) -4-methyl4-hexenoate. Molecular formula: C23H31NO7. MW: 433.50. CAS: 115007-34-6. Mycophenolate mofetil is the 2-morpholinoethyl ester of mycophenolic acid. 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).

Pharmacology

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 dehydrongenase (IMPDH) in complex with inosine5’-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. MMF also inhibited proliferative arteriopathy in experimental models of aortic and heart allografts in rats, as well as in primate cardiac xenografts. MMF was used alone or in combination with other immunosuppressive agents in these studies.
In experimental animals, MMF has been demonstrated to prevent inflammatory responses that are immunologically mediated, and to delay tumour development and prolong survival in models of xenogeneic human to mouse and syngeneic murine tumours in vivo.
MMF, the 2-morpholinoethyl ester of MPA is rapidly absorbed following oral administration and hydrolysed to form free MPA, which is the active metabolite. MPA inhibits proliferative responses of T and B lymphocytes to both mitogenic and allospecific stimulation.
Addition of guanosine or deoxyguanosine reverses the cytostatic effects of MPA on lymphocytes, showing the specificity of action of the 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.

Pharmacokinetics.

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 (bd) of MMF by the IV and oral routes to renal transplant patients in the immediate post-transplant period, resulted in a MPA AUC that was approximately 29% higher for the IV formulation than achieved by the capsule. Cmax was approximately 20% greater for IV.
The results of a single dose bioequivalence study in 47 healthy volunteers indicated that the 500 mg tablet (x 2) was equivalent to the 250 mg capsule (x 4) with respect to the extent of absorption (AUC), but not the rate of absorption (Cmax). The Cmax for MPA of the tablet was 28% lower than that for the capsule.
In a two way, randomised, crossover, bioequivalence study of MMF oral suspension and capsules, a 1 g dose of MMF suspension was bioequivalent to the 250 mg capsule (x 4) with respect to Cmax, t1/2, AUClast, AUC0-∞ and Kel. Tmax was marginally shorter for the oral suspension.
Food had no effect on the extent of absorption (MPA AUC) of MMF when administered as 1.5 g bd 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 postdose. Coadministration of cholestyramine (4 g tid) 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 to form the pharmacologically inactive phenolic glucuronide of MPA (MPAG). In vivo, MPAG is converted to free MPA via enterohepatic recirculation.

Elimination.

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.

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 bd intravenous MMF (over 2 hours) for 5 days compared with the same dose orally.
In cardiac transplant patients, administration of 1.5 g bd 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 bd intravenous MMF followed by 1.5 g bd oral MMF resulted in mean steady state MPA AUC values similar to those found in renal transplant patients administered 1 g bd 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 Dosage and 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 bd). This dose achieved MPA AUC values similar to those seen in adult renal transplant patients receiving Imulate at a dose of 1 g bd 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, cyclosporin, 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%.

Clinical Trials

1. Prevention of acute renal rejection episodes.

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

2. Treatment of refractory renal rejection.

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

3. Prevention of renal rejection in paediatrics.

In a multicentre open label, safety, tolerability and pharmacokinetic study of MMF oral suspension 600 mg/m2 bd (up to 1 g bd) in combination with cyclosporin and corticosteroids in the US, Europe and Australia, 100 patients aged 3 months to 18 years of age received treatment for the prevention of renal allograft rejection. The primary efficacy endpoint was the proportion of patients experiencing an acute rejection episode in the first 6 months post-transplant. Results were analysed after 1 year and it was shown that MMF was well tolerated in paediatric patients (see Adverse Effects), and the pharmacokinetics profile was similar to that seen in adult patients dosed with 1 g bd Imulate capsules (see Pharmacology, Pharmacokinetics, 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.

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

5. Prevention of hepatic allograft rejection.

The safety and efficacy of MMF was assessed in a randomised, double blind, parallel, active controlled, multicentre study in hepatic transplant patients. This study compared the use of MMF 1 g bd intravenously for up to 14 days followed by 1.5 g bd orally against azathioprine 1-2 mg/kg/day intravenously followed by 1-2 mg/kg/day orally, both in combination with cyclosporin and corticosteroids.
565 patients were randomised into the two arms, 278 patients in the Imulate group and 287 patients in the azathioprine group. The two primary endpoints investigated were (1) the proportion of patients who experienced, in the first 6 months post-transplantation, (a) one or more episodes of biopsy proven and treated rejection or (b) death/ retransplantation, and (2) the proportion of patients with graft loss (death/ retransplantation) during the first 12 months post-transplantation. Patients who prematurely discontinued treatment were followed for the occurrence of allograft rejection and for the occurrence of graft loss (death/ retransplantation) for 1 year.
In the primary analyses MMF in combination with corticosteroids and cyclosporin 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 4.)
The superiority of MMF to azathioprine in the time to biopsy proven and treated rejection or death/ retransplantation in the 6 months following transplant approached statistical significance (log rank p = 0.06). The time to death/ retransplantation in the 12 months following transplant was similar in the two treatment groups (log rank p = 0.86).

Indications

Imulate is indicated for the prophylaxis of solid organ rejection in adults receiving allogeneic organ transplants.
Imulate is indicated for the prophylaxis of organ rejection in paediatric patients with a body surface area of ≥ 1.25 m2 receiving allogeneic renal transplants (see Dosage and Administration).

Contraindications

Allergic reactions to Imulate have been observed, therefore, Imulate is contraindicated in patients with a hypersensitivity to MMF or to mycophenolic acid.

Precautions

General.

Female patients of childbearing potential must use effective contraception before, during and for six weeks after receiving Imulate. The use of Imulate is not recommended during pregnancy and should be reserved for cases where no suitable alternate treatment is available. Imulate should be used in pregnant women only if the potential benefits outweigh the potential risks to the foetus (see Use in pregnancy).
As with other patients receiving immunosuppressive regimes involving combinations of medicines, patients receiving Imulate as part of an immunosuppressive regime are at an increased risk of developing lymphomas and other malignancies, particularly of the skin. The risk appears to be related to the intensity and duration of immunosuppression rather than the use of any specific agent.
Approximately 1% of patients receiving MMF with other immunosuppressive agents in the controlled studies of prevention of rejection have developed lymphoproliferative disease or lymphoma. As immunosuppression increases the risk of skin cancer, patients should also be advised to limit their exposure to sunlight and other sources of UV light by wearing protective clothing and using sunscreen with a high protection factor.
Patients receiving Imulate should be instructed to immediately report any evidence of infection, unexpected bruising, bleeding or any other manifestation of bone marrow depression.
Oversuppression of the immune system can also increase susceptibility to infection, including opportunistic infections, fatal infections and sepsis. In the controlled studies for the prevention of rejection, the incidence of fatal infection was similar in patients receiving MMF or control therapy in combination with other immunosuppresive 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 polyomaviruses. Cases of progressive multifocal leukoencephalopathy (PML) associated with the JC virus, sometimes fatal, have been reported in MMF 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 MMF in patients postrenal transplant. This infection can be associated with serious outcomes, sometimes leading to renal graft loss. Patient monitoring may help detect patients at risk of BK virus associated nephropathy. Reduction in immunosuppression should be considered for patients who develop evidence of BK virus associated nephropathy.
Cases of pure red cell aplasia (PRCA) have been reported in patients treated with MMF 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 MMF therapy. In transplant patients however, reduced immunosuppression may place the graft at risk.
0.5% of patients receiving MMF 2 g for prevention of rejection in renal transplantation, 2.8% of patients receiving MMF 3 g in cardiac transplantation and 3.6% of patients receiving MMF 3 g in hepatic transplantation, developed severe neutropenia (absolute neutrophil count [ANC] < 5 x 108/L). 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) Imulate dosing should be interrupted or the dose reduced. Appropriate diagnostic testing should be performed and the patient managed accordingly.
Since Imulate 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.
Patients should be advised that during treatment with Imulate, vaccinations may be less effective and the use of live attenuated vaccines should be avoided (see Interactions with Other Medicines). Influenza vaccination may be of value. Physicians should refer to the national guidelines for influenza vaccination.

Gastrointestinal.

Gastrointestinal tract bleeding (requiring hospitalisation) has been observed in approximately 1.4% of patients treated with MMF 2 g in renal transplantation, 2.8% of patients receiving 3 g in cardiac transplantation and in 5.4% of patients receiving Imulate 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 Adverse Effects). It should be noted that patients with active peptic ulcer disease were excluded from enrolment in studies with MMF. As MMF has been associated with an increased incidence of digestive system adverse events, including uncommon cases of gastrointestinal tract ulceration, haemorrhage, and perforation (colon, gall bladder) in postmarketing surveillance, Imulate should be administered with caution in patients with active serious digestive system disease.

Use in patients with severe chronic renal impairment.

Patients with severe chronic renal impairment (GFR < 25 mL/min/1.73 m2) who have received single doses of MMF showed increased plasma AUCs of MPA and 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 Imulate greater than 1g bd should be avoided (see Dosage and Administration and Pharmacokinetics).
In patients with delayed graft function post-transplant, mean MPA AUC0-12 was comparable, but MPAG AUC0-12 was 2 to 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 1483 patients (20%) with delayed graft function. Although patients with delayed renal allograft function have a higher incidence of certain adverse events (anaemia, thrombocytopenia, hyperkalaemia) than patients without delayed graft function, these events were not more frequent in patients receiving MMF than azathioprine or placebo. No dose adjustment is recommended for these patients, however, they should be carefully observed. In patients with severe chronic renal impairment, administration of doses greater than 1 g twice daily should be avoided.

Carcinogenicity, mutagenicity and impairment of fertility.

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 tumuorigenic.
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 Precautions).
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.
MMF had no effect on fertility of male rats at oral doses up to 20 mg/kg/day (0.8 times the expected maximum clinical dose based on AUC values). In a female fertility and reproduction study conducted in rats dosed orally at up to 4.5 mg/kg/day (0.1 times the maximum clinical dose based on AUC values), the 4.5 mg/kg/day dose caused malformations (principally of the head and eyes) in the first generation (F1) offspring in the absence of maternal toxicity. No effects on fertility were present in the treated females (P1 females), or in the subsequently mated first generation offspring (P2 females or P2 males).

Laboratory monitoring.

Patients on Imulate 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 Imulate should be monitored for neutropenia. The development of neutropenia may be related to Imulate, concomitant medications, viral infection or some combination of these causes. If neutropenia develops (absolute neutrophil count < 1.3 x 103/microL), dosing with Imulate should be interrupted or the dose reduced and the patient should be carefully observed.

Use in pregnancy.

(Category D)
There are limited data from the use of MMF in pregnant women. Imulate may be expected to cause foetal malformations and possibly foetal death in humans. Congenital malformations, including ear malformations, i.e. abnormally formed or absent external/ middle ear, have been reported in children of patients exposed to Imulate in combination with other immunosuppressants during pregnancy.
It is recommended that Imulate therapy not be initiated unless a negative pregnancy test has been obtained within one week prior to beginning therapy. Effective contraception must be used for four weeks before beginning Imulate therapy, during therapy, and for six weeks following discontinuation of therapy, even where there has been a history of infertility, unless due to hysterectomy. Patients should be instructed to consult their physician immediately should they become pregnant.
In teratology studies, foetal resorptions and malformations occurred in rats at 6 mg/kg/day (0.2 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 no effect levels for teratologic changes in rats and rabbits were 2 and 30 mg/kg/day, respectively.

Use in lactation.

Studies in rats have shown MMF to be excreted in milk. It is not known whether this medicine is excreted in human milk. Since many medicines are excreted in human milk; and because of the potential for serious adverse reactions in nursing infants from MMF, a decision should be made whether to discontinue nursing or to discontinue the medicine, taking into account the importance of the medicine to the mother.

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 Adverse 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 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. Elderly patients receiving Imulate as part of a combination immunosuppressive regimen may be at increased risk of certain infections (including cytomegalovirus tissue invasive disease) and possibly gastrointestinal haemorrhage and pulmonary oedema, compared to younger individuals. Pharmacokinetic behaviour of MMF in the elderly has not been formally evaluated.

Interactions

Drug interaction studies with MMF have been conducted with aciclovir, antacids, cholestyramine, cyclosporin A, ganciclovir, oral contraceptives, tacrolimus 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.

Azathioprine.

It is recommended that Imulate 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.

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.

Cholestyramine.

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

Ciprofloxacin and amoxicillin plus clavulanic acid.

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

Cyclosporin A.

Cyclosporin A (CsA) pharmacokinetics (at doses of 275 to 415 mg/day) were unaffected by single and multiple doses of 1.0 g MMF bd in stable renal transplant patients. The mean (± SD) dose normalised AUC0-12h of MPA after 14 days and 3 months of multiple doses of MMF and cyclosporin in 17 renal transplant patients were 43 ± 11 microgram.h/mL.g and 56 ± 31 microgram.h/mL.g, respectively.

Sirolimus.

A study in 36 renal transplant patients demonstrated that concomitant administration of MMF (1 g bd) 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 significant proportion of patients (10 of 30) who received the combination of sirolimus and MMF were withdrawn with symptoms consistent with MPA or sirolimus toxicity.
Monitoring of MPA levels should be performed in renal graft recipients cotreated with sirolimus because of the risk of overexposure to this immunosuppressive agent.

Ganciclovir.

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

Iron.

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

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.

The pharmacokinetics of oral contraceptives were unaffected by coadministration of MMF. A study of coadministration of MMF (1 g bd) and combined oral contraceptives containing ethinylestradiol (0.02-0.04 mg) and levonorgestrel (0.05-0.20 mg), desogestrel (0.15 mg) or gestodene (0.05-0.1 mg) conducted in 18 women with psoriasis over 3 menstrual cycles showed no clinically relevant influence of MMF on serum levels of progesterone, LH and FSH, thus indicating no influence of MMF on the ovulation suppressing action of the oral contraceptives (see Precautions, Use in pregnancy).

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

Tacrolimus.

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

Trimethoprim/ sulfamethoxazole.

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

Norfloxacin/ metronidazole.

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

Sevelamer and other calcium free phosphate binders.

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

Other interactions.

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

Adverse 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 MMF in combination with cyclosporin and steroids include diarrhoea, leucopenia, sepsis and vomiting, and there is evidence of a higher frequency of certain types of infections, such as tuberculosis and atypical mycobacterial infection. Uncommon but serious life threatening infections such as meningitis and infectious endocarditis have been reported.
The incidence of adverse events for MMF was determined in 3 randomised comparative double blind trials in prevention of rejection in renal transplant patients. However, due to the lower overall reporting of events in the placebo controlled prevention of rejection study, these data were not combined with the other two active controlled prevention trials, but are instead presented separately.
Patients in the double blind studies of the prevention of renal allograft rejection were treated for up to a minimum of 1 year, with approximately 53% of the patients having been treated for more than 1 year. The adverse events, reported as probably or possibly related to study medication at an incidence of greater than or equal to 3% of patients in either of the MMF 2 g or 3 g treatment groups are presented in Table 5, for the two active controlled studies combined, and for the one placebo controlled study.
Patients in a double blind study of the prevention of cardiac allograft rejection were treated for up to a minimum of 1 year. The adverse events, reported as probably or possibly related to study medication at an incidence of greater than or equal to 3% of patients in either of the MMF 3 g or azathioprine treatment groups are presented in Table 6.
Patients in a double blind study of the prevention of hepatic allograft rejection were followed for up to a minimum of 1 year. The adverse events reported as probably or possibly related to study medication at an incidence of greater than or equal to 3% of patients in either of the MMF 3 g or azathioprine treatment groups are presented in Table 7.
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 above or in text pertaining to infections or malignancy following, were reported with an incidence of less than 3% in one or more of the MMF 2 g or 3 g (renal) active controlled cohorts (n = 336, n = 330), the MMF 2 g or 3 g (renal) placebo controlled cohorts (n = 165, n = 160), less than 1.4% in the MMF 3 g (cardiac) active controlled cohort (n = 289), or less than 1.4 % in the MMF 3 g (hepatic) active controlled cohort study (n = 277).

Digestive system.

Colitis (sometimes caused by 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, apthous 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, cyclosporin 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, heart arrest, 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 MMF 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 MMF 3 g and up to 3.6% (regardless of investigator assessment of causality) of patients receiving MMF 3 g in hepatic transplantation developed severe neutropenia.
Cytomegalovirus (CMV) tissue invasive disease was more common in renal transplant patients receiving MMF 3 g/day (8-12%) than in those receiving MMF 2 g/day (4-8%) or control therapy (2-6%) in the three controlled studies for prevention of renal allograft rejection (percentage incidences have been determined regardless of investigator assessment of causality). In the placebo controlled renal study, there was an increased incidence of Herpes simplex and Herpes zoster infections in patients receiving MMF compared to placebo.
In addition, the incidence of overall infection with Candida and CMV viraemia/ syndrome were similar in the three treatment groups. Table 8 shows the incidence of select opportunistic infections in the prevention of rejection trials.
The following other opportunistic infections occurred with an incidence of less than 4% in MMF patients in the above azathioprine controlled studies: herpes zoster, visceral disease; Candida, urinary tract infection, fungemia/ disseminated disease, tissue invasive disease; Cryptococcosis; Aspergillus/ Mucor; Pneumocystis carinii.
In the placebo controlled renal transplant study, the same pattern of opportunistic infection was observed compared to the azathioprine controlled renal study, with a notably lower incidence of Herpes simplex and CMV tissue invasive disease.
In the three controlled studies for prevention of rejection in renal transplantation, similar rates of fatal infections/ sepsis (< 2%) have occurred in patients receiving MMF or control therapy in combination with other immunosuppressive agents. In the controlled cardiac transplant study, fatal infections occurred in 2.4% of patients receiving MMF 3 g compared to 4.5% of patients receiving azathioprine, both in combination with other immunosuppressive agents. In the controlled hepatic transplant study, fatal infection/ sepsis occurred in 5.4% of patients receiving MMF 3 g compared to 7.3% receiving azathioprine, both in combination with other immunosuppressive agents.
As with other patients receiving immunosuppressive regimes involving combinations of drugs, patients receiving MMF as part of an immunosuppressive regime are at an increased risk of developing lymphomas and other malignancies, particularly of the skin.
Within 3 years post-transplant, lymphoproliferative disease or lymphoma developed in patients receiving MMF in immunosuppressive regimes in 0.6% of patients receiving 2 g daily in the controlled studies of prevention of renal rejection compared to placebo (0%) and azathioprine groups (0.6%).
The incidence of malignancies among the 1483 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 9 summarises the incidence of malignancies observed in the prevention of rejection trials.
Three year safety data in renal and cardiac transplant patients indicated that the overall incidence of malignancy was comparable between MMF and azathioprine groups. Hepatic transplant patients were followed for at least 1 year but less than 3 years.

Paediatric adverse events.

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

Postmarketing experience.

Disorders of immunosuppression.

Uncommon: serious life threatening infections such as meningitis and infectious endocarditis have been reported occasionally and there is evidence of a higher frequency of certain types of serious infections such as tuberculosis and atypical mycobacterial infections.
Cases of progressive multifocal leukoencephalopathy (PML), sometimes fatal, have been reported in MMF 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 MMF. This infection can be associated with serious outcomes, sometimes leading to renal graft loss.

Gastrointestinal.

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

Congenital disorders.

Congenital malformations including ear malformations have been reported in offspring of patients exposed to MMF in combination with other immunosuppressants during pregnancy.
Cases of pure red cell aplasia (PRCA) have been reported in patients treated with MMF in combination with other immunosuppressive agents.

Dosage and Administration

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

Adults.

Renal transplantation.

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

Cardiac transplantation.

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

Hepatic transplantation.

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

Other transplants.

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

Paediatric patients (≥ 1.25 m2).

MMF capsules and tablets are not suitable for paediatric patients whose body surface area is < 1.25 m2. Patients with a body surface area of 1.25 m2 to 1.5 m2 may be dosed with MMF capsules at a dose of 750 mg twice daily (1.5 g daily dose). Patients with a body surface area of ≥ 1.5 m2 may be dosed with MMF capsules or tablets at a dose of 1 g twice daily (2 g daily dose).
Imulate may be administered in combination with cyclosporin 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 Imulate should be interrupted and the patient carefully observed (see Precautions). 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/1.73m2) outside of the immediate post-transplant period, doses of Imulate greater than 1 g administered twice a day should be avoided. No data are available in cardiac or hepatic allograft recipients with severe chronic renal impairment. These patients should also be carefully observed. No dose adjustments are needed in patients experiencing delayed renal allograft function postoperatively.
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.

Handling and disposal.

As MMF has demonstrated teratogenic effects in rat and rabbits studies, Imulate tablets should not be crushed and Imulate capsules should not be opened or crushed. Avoid inhalation or direct contact with skin or mucous membranes of the powder contained in Imulate capsules. If contact occurs, wash thoroughly with soap and water; should the eyes be affected, rinse eyes with plain water.

Overdosage

Reports of overdoses with MMF have been received from clinical trials and during postmarketing 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 oversuppression of the immune system and increase susceptibility to infections and bone marrow suppression (see Precautions). If neutropenia develops, dosing with Imulate should be interrupted or the dose reduced (see Precautions).
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 Pharmacokinetics).
Treatment of overdosage should consist of general supportive measures.
Contact the Poisons Information Centre for advice on management of overdosage.

Presentation

Capsules (ivory, marked SAL on cap, 726 on body), 250 mg: 100’s, 300's* (pack of 1 or 3 boxes containing 100 capsules in blister packs (10 capsules per blister)).
Tablets (mauve, capsule shaped, film coated, marked SAL on one side, 725 on reverse), 500 mg: 50’s, 150's* (pack of 1 or 3 boxes containing 50 tablets in blister packs (10 tablets per blister)).
*Not currently marketed in Australia.

Storage

Imulate 250 mg capsules should be stored below 30°C.
Imulate 500 mg tablets should be stored below 30°C and protected from light.

Poison Schedule

S4.