Consumer medicine information

Mycophenolate AN Tablets

Mycophenolate mofetil

BRAND INFORMATION

Brand name

Mycophenolate AN Tablets

Active ingredient

Mycophenolate mofetil

Schedule

What is in this leaflet

This leaflet answers some common questions about Mycophenolate AN.

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 Mycophenolate AN 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 Mycophenolate AN is used for

Mycophenolate AN contains the active ingredient mycophenolate mofetil.

Mycophenolate AN 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.

There are many different types of medicines used to prevent transplant rejection.

Mycophenolate AN belongs to a new group of these medicines.

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

Your doctor, however, may have prescribed Mycophenolate AN for another purpose.

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

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

Mycophenolate AN is not addictive.

Before you take Mycophenolate AN

When you must not take it

Do not take Mycophenolate AN if:

You have had an allergic reaction to Mycophenolate AN 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 face, lips, tongue or other parts of the body
rash, itching, hives on the skin

You are pregnant.
Mycophenolate AN is harmful to an unborn baby when taken by a pregnant woman.
There have been cases of miscarriage and severe birth defects reported when patients have taken Mycophenolate AN during pregnancy.
You must tell your doctor if you are pregnant or plan to become pregnant.
You are breastfeeding.
Mycophenolate AN may pass into human breast milk and could cause serious side effects in your baby if you breastfeed.
You are a woman who could become pregnant and you are not using two reliable forms of contraception.
You must use two reliable forms of contraception at the same time before beginning Mycophenolate AN therapy, during therapy and for at least six weeks after stopping Mycophenolate AN, unless you are not sexually active.
The package is torn or shows signs of tampering.
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 Mycophenolate AN, talk to your doctor.

Before you start to take it

Tell your doctor if:

You are pregnant or plan to become pregnant.
If you are a woman of child bearing potential, you must have two negative pregnancy tests 8-10 days apart just prior to starting treatment with Mycophenolate AN.
Repeat pregnancy tests will be performed during routine follow-up visits with your doctor.
You are breast-feeding or plan to breast-feed.
You are a sexually active man.
You are recommended to use condoms during treatment and for 90 days after stopping treatment, even if you have had a vasectomy.
Your female partner(s) are recommended to use reliable contraception while you are being treated with Mycophenolate AN and for 90 days after you have stopped receiving Mycophenolate AN.
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)
rare diseases due to a deficiency of the HGPRT enzyme such as Lesch-Nyhan or Kelly-Seegmiller syndrome
kidney disease

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 Mycophenolate AN.

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 Mycophenolate AN. These medicines include:

aciclovir or ganciclovir, valaciclovir or valganciclovir, 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 (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
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 of 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 Mycophenolate AN, 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 Mycophenolate AN.

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

How to take Mycophenolate AN

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 Mycophenolate AN exactly as your doctor has prescribed.

Your doctor will tell you how many tablets, to take each day.

Mycophenolate AN
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.

Mycophenolate AN is not suitable for paediatric patients whose body surface area is <1.50 m². Patients with a body surface area >1.5 m² may be dosed with Mycophenolate AN at a dose of 1 g twice daily (2 g daily dose).

Your doctor may adjust your dose depending on your response.

How to take it

Mycophenolate AN

Swallow the tablets whole with a glass of 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 Mycophenolate AN.

How long to take Mycophenolate AN

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

Continue taking Mycophenolate AN until your doctor tells you to stop.

If you forget to take Mycophenolate AN

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 Mycophenolate AN. 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 Mycophenolate AN

Things you must do

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

Tell your doctor if you become pregnant while taking Mycophenolate AN.

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

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

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

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 Mycophenolate AN 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 Mycophenolate AN to anyone else even if they have the same condition as you.

Do not use Mycophenolate AN 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 Mycophenolate AN affects you.

However, Mycophenolate AN 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 Mycophenolate AN.

Mycophenolate AN 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 Mycophenolate AN 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), vomiting 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 Mycophenolate AN. 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 excessiveness 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 Mycophenolate AN

Storage

Mycophenolate AN

Keep your tablets in the blister pack until it is time to take them.

If you take the tablets out of the blister pack they may not keep well.

Keep Mycophenolate AN in cool dry place where the temperature stays below 25°C. Protect from light.

Always keep the tablets away from direct light.

Light will cause Mycophenolate AN to fade.

Do not store Mycophenolate AN 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 Mycophenolate AN 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 Mycophenolate AN; or the tablets have passed their expiry date, ask your pharmacist what to do with any that are left over.

Product description

Availability

Mycophenolate AN is available in blister packs of 50 tablets.

What Mycophenolate AN looks like

Mycophenolate AN are purple colored, capsule shaped, biconvex, film coated tablets debossed ‘AHI’ on one side and ‘500’ on other side.

Ingredients

Active ingredient:

Each tablet contains 500 mg of Mycophenolate mofetil.

Inactive ingredients:

Microcrystalline cellulose
Povidone
Hydroxypropylcellulose
Croscarmellose sodium
Purified talc
Magnesium stearate
Opadry complete film coating system 03B50110 PURPLE (PI number: 12853) includes Hypromellose, Titanium dioxide (CI No. 77891), Macrogol 400, Iron oxide red (CI77491), Indigo carmine (CI73015) and Iron oxide black (CI77499)

Mycophenolate AN is gluten and lactose free.

Australian Registration Number

Mycophenolate AN:
AUST R 164416

Name and Address of the Sponsor

Amneal Pharma Australia Pty Ltd
12 River Street
Melbourne Victoria 3141
Australia

Date of Preparation

March 2016

BRAND INFORMATION

Brand name

Mycophenolate AN Tablets

Active ingredient

Mycophenolate mofetil

Schedule

Name of the medicine

Mycophenolate mofetil.

Excipients.

Microcrystalline cellulose, povidone, hydroxypropylcellulose, croscarmellose sodium, purified talc, magnesium stearate and Opadry complete film coating system 03B50110 purple (PI number: 12853).

Description

Chemical name: 2-morpholinoethyl(E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoate. Molecular formula: C₂₃H₃₁NO₇. MW: 433.50. CAS: 128794-94-5. 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 media (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 inosine-5'-monophosphate (IMP) and mycophenolic acid (MPA), the mechanism by which mycophenolic acid (MPA) inhibits the enzymatic activity of IMPDH (human type II) appears to be related to the ability of mycophenolic acid (MPA) to structurally mimic both the nicotinamide adenine dinucleotide cofactor and a catalytic water molecule. This prevents the oxidation of inosine-5'-monophosphate (IMP) to xanthos-5'-monophosphate, the committed step in the de novo guanosine nucleotide biosynthesis. Human type II and Chinese hamster inosine-5'-monophosphate dehydrongenase (IMPDH) differ by six amino acids but have similar enzymatic characteristics. Mycophenolic acid (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 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). Mycophenolate mofetil 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. Mycophenolate mofetil was used alone or in combination with other immunosuppressive agents in these studies.
In experimental animals, mycophenolate mofetil 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.
Mycophenolate mofetil, the 2-morpholinoethyl ester of mycophenolic acid (MPA) is rapidly absorbed following oral administration and hydrolysed to form free MPA, which is the active metabolite. Mycophenolic acid (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 mycophenolic acid (MPA) on lymphocytes, showing the specificity of action of the drug. Mycophenolic acid (MPA) also suppresses antibody formation by B lymphocytes. By depletion of guanosine nucleotides, mycophenolic acid (MPA) prevents the glycosylation of lymphocyte and monocyte glycoproteins that are involved in intercellular adhesion to endothelial cells. By this mechanism, mycophenolic acid (MPA) may inhibit recruitment of leucocytes into sites of inflammation and graft rejection.
Mycophenolate mofetil 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 mycophenolate mofetil and trimethoprim/ sulfamethoxazole than with either drug alone. Mycophenolate mofetil 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, mycophenolate mofetil undergoes rapid and extensive absorption and complete presystemic metabolism to the active metabolite, mycophenolic acid. Mycophenolate mofetil is not measurable systemically in plasma following oral administration. The mean extent of absorption of mycophenolic acid 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 to 4 g in renal transplant patients.
The administration of mycophenolate mofetil 1.5 g by the oral routes to healthy volunteers resulted in similar plasma mycophenolic acid and inactive glucuronide of mycophenolic acid total AUC values. Recovery of mycophenolic acid in urine was the same for both routes indicating complete absorption of oral mycophenolate mofetil. The mean bioavailability of orally administered mycophenolate mofetil, based on mycophenolic acid AUC, was 94%.
Food had no effect on the extent of absorption (mycophenolic acid AUC) of mycophenolate mofetil when administered as 1.5 g bd doses to renal transplant patients. However, the C_max for mycophenolic acid was decreased by 40% in the presence of food.
The pharmacokinetic profile of mycophenolic acid in cardiac patients is similar to that in renal patients.

Distribution.

As a result of enterohepatic recirculation, secondary increases in plasma mycophenolic acid concentration are usually observed approximately 6 to 12 hours postdose. CoA administration of cholestyramine (4 g three times daily) with mycophenolate mofetil is associated with a reduction in the AUC of mycophenolic acid 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 mycophenolic acid plasma concentration time profile.
At clinically relevant concentrations, mycophenolic acid is 97% bound to plasma albumin.

Metabolism.

Mycophenolic acid is metabolised principally by glucuronyl transferases to form the pharmacologically inactive phenolic glucuronide of mycophenolic acid. In vivo, glucuronide of mycophenolic acid, is converted to free mycophenolic acid via enterohepatic recirculation.

Excretion.

After oral administration, 93% of the dose was recovered from the urine and 6% from the faeces. The major metabolite of mycophenolate mofetil excreted in urine is glucuronide of mycophenolic acid, which accounts for 87% of the oral mycophenolate mofetil dose. Less than 1% of the dose was excreted as mycophenolic acid in the urine. The following metabolites of the morpholino moiety are also recovered in the urine following oral administration of mycophenolate mofetil: 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 mycophenolic acid are 17.9 ± 6.5 hours and 193 ± 48 mL/minute respectively following oral administration.

Pharmacokinetics in special populations.

Renal, cardiac and hepatic transplant patients.

In renal, cardiac and hepatic transplant patients, mean steady state (MPA AUC) and C_max were up to 40% lower in the early post-transplant period (< 40 days post-transplant) compared to the late transplant period (three to six months post-transplant).
In renal transplant patients, in the immediate post-transplant phase, mean steady state (MPA AUC) was 24% higher following mycophenolate mofetil 1 g bd intravenous (over two hours) for five days compared with the same dose orally.
In cardiac transplant patients, administration of mycophenolate mofetil 1.5 g bd oral 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 mycophenolate mofetil 1 g bd intravenous followed by 1.5 g bd oral mycophenolate mofetil resulted in mean steady state (MPA AUC) values similar to those found in renal transplant patients administered mycophenolate mofetil 1 g bd oral.

Renal impairment.

In a single dose study (six subjects per group), plasma (MPA AUCs) were up to 30% higher in subjects with mild to moderate renal impairment (GFR 25-80 mL/minute/1.73m²) and 75% higher in subjects with severe renal impairment (GFR < 25 mL/minute/1.73m²) than those subjects with normal renal function (GFR > 80 mL/minute/1.73m²). 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 mycophenolate mofetil is increased from a daily dose of 2 to 3 g (see Dosage and Administration). Multiple dosing of mycophenolate mofetil in patients with severe chronic renal impairment has not been studied. In addition, the single dose plasma AUC of glucuronide of mycophenolic acid, was three to sixfold 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 glucuronide of mycophenolic acid. No data are available on the safety of long-term exposure to this level of glucuronide of mycophenolic acid.

Delayed renal graft function post-transplant.

In patients with delayed renal graft function post-transplant, mean AUC_(0-12) of mycophenolic acid was comparable to that seen in post-transplant patients without delayed graft function. However, mean plasma AUC_(0-12) of glucuronide of mycophenolic acid was two to threefold higher than post-transplant patients without delayed graft function. Also, with repeated dosing, plasma concentrations of glucuronide of mycophenolic acid accumulated, whereas accumulation of mycophenolic acid occurred to a lesser degree, if at all. High plasma concentrations of glucuronide of mycophenolic acid may displace mycophenolic acid from its protein binding sites resulting in a transient increase in the plasma concentration of free mycophenolic acid in patients with delayed graft function. No dose adjustment is recommended although close monitoring is advised.

Haemodialysis.

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

Hepatic impairment.

In volunteers with alcoholic cirrhosis, hepatic glucuronide of mycophenolic acid 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 mycophenolic acid and glucuronide of mycophenolic acid were evaluated in 55 paediatric renal transplant patients aged 1 to 18 years given mycophenolate mofetil 600 mg/m² mycophenolate mofetil 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 mycophenolate mofetil 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 nine months post-transplant. There is limited pharmacokinetic data available for children aged less than 2 years.

Plasma binding.

Mycophenolic acid, at clinically relevant concentrations, is 97% bound to plasma albumin. Glucuronide of mycophenolic acid (MPAG) is 82% bound to plasma albumin at glucuronide of mycophenolic acid concentration ranges such as those normally seen in stable renal transplant patients; however at higher concentrations of glucuronide of mycophenolic acid 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 mycophenolic acid to human serum albumin (HSA) or plasma proteins showed that salicylate (at 250 microgram/mL with HSA) and glucuronide of mycophenolic acid (at greater than or equal to 460 microgram/mL with plasma proteins) increased the free fraction of mycophenolic acid. 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 mycophenolic acid. Mycophenolic acid 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 mycophenolate mofetil 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 mycophenolate mofetil (1 g twice daily (bd) and 1.5 g bd) with azathioprine (two studies) or placebo (one 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. Mycophenolate mofetil, 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; (3) cyclosporin/ corticosteroids. The superior efficacy of mycophenolate mofetil 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, mycophenolate mofetil reduced the incidence of first biopsy proven acute rejection episodes within the first 6 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 six months following transplantation was smaller among patients receiving mycophenolate mofetil 2 g per day (5.5 to 10.3%) or mycophenolate mofetil 3 g per day (3.1 to 5.4%) than among patients receiving azathioprine or placebo (15 to 21%).
6 and 12 month patient survival and graft survival was somewhat higher in the patients receiving mycophenolate mofetil 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 mycophenolate mofetil 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 mycophenolate mofetil at a dose of 1.5 g bd was superior to high dose intravenous steroids. In this study, all patients continued to receive concomitant maintenance oral corticosteroids and cyclosporin. The control group received intravenous methylprednisolone (5 mg/kg/day for five 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 intravenous steroids; 77 assigned to receive mycophenolate mofetil). Patients enrolled in this study had recurrent or persistent allograft rejection following treatment with either Orthoclone OKT3, ATGAM, or antilymphocyte globulin for at least seven 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 six months postenrolment. Mycophenolate mofetil 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 intravenous steroid group and 14.3% of the mycophenolate mofetil group had died or experienced graft loss. 18 patients (25%) receiving high dose intravenous steroids and nine patients (12%) receiving mycophenolate mofetil lost their graft in the 6 months after enrolment. One patient (1.4%) receiving high dose intravenous steroids and 2 patients (2.6%) receiving mycophenolate mofetil died in the six months after enrolment. Fewer patients receiving mycophenolate mofetil (10.4%) required treatment with antilymphocyte preparations in the six months after enrolment, compared to those receiving high dose intravenous steroids (24.7%).

3. Prevention of cardiac allograft rejection.

In a randomised, double blind, parallel active controlled multicentre study to compare the safety and efficacy of mycophenolate mofetil 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 mycophenolate mofetil 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.
Mycophenolate mofetil and azathioprine did not differ significantly at six months in biopsy proven acute rejection with haemodynamic compromise. Survival, acute rejection and composite endpoints are listed in Table 3.

4. Prevention of hepatic allograft rejection.

The safety and efficacy of mycophenolate mofetil was assessed in a randomised, double blind, parallel, active controlled, multicentre study in hepatic transplant patients. This study compared the use of mycophenolate mofetil 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 mycophenolate mofetil group and 287 patients in the azathioprine group.
The two primary endpoints investigated were (1) the proportion of patients who experienced, in the first six 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 one year.
In the primary analyses mycophenolate mofetil 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 mycophenolate mofetil to azathioprine in the time to biopsy proven and treated rejection or death/ retransplantation in the six 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

Prophylaxis of solid organ rejection in adults receiving allogeneic organ transplants.
Prophylaxis of organ rejection in paediatric patients (with a body surface area > 1.5 m²) receiving allogeneic renal transplants.

Contraindications

Allergic reactions to mycophenolate mofetil tablets have been observed; therefore, mycophenolate mofetil tablets are contraindicated in patients with hypersensitivity to mycophenolate mofetil or to mycophenolic acid.
Mycophenolate mofetil tablets are contraindicated during pregnancy due to its mutagenic and teratogenic potential (see Use in pregnancy).
Mycophenolate mofetil tablets are contraindicated in women of childbearing potential not using highly effective contraceptive methods (see Use in pregnancy).
Mycophenolate mofetil tablets are contraindicated in women who are breastfeeding (see Use in lactation).

Precautions

General.

Female patients of childbearing potential must use effective contraception before, during and for six weeks after receiving mycophenolate tablets. Mycophenolate mofetil tablets are contraindicated during pregnancy and during breastfeeding (see Use in pregnancy and Use in lactation).
As with other patients receiving immunosuppressive regimes involving combinations of medicines, patients receiving Mycophenolate AN as part of an immunosuppressive regimen 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 mycophenolate mofetil 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 Mycophenolate AN 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 mycophenolate mofetil 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 mycophenolate mofetil 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 reporting neurological symptoms, physicians should consider PML in the differential diagnosis in patients reporting neurological symptoms and consult 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 at risk.
BK virus associated neuropathy has been observed during the use of mycophenolate mofetil 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 mycophenolate mofetil 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 mycophenolate mofetil therapy. In transplant patients however, reduced immunosuppression may place with graft at risk.
0.5% of patients receiving mycophenolate mofetil 2 g for prevention of rejection in renal transplantation, 2.8% of patients receiving mycophenolate mofetil 3 g in cardiac transplantation and 3.6% of patients receiving mycophenolate mofetil 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) mycophenolate mofetil dosing should be interrupted or the dose reduced. Appropriate diagnostic testing should be performed and the patient managed accordingly.
Patients should be advised that during treatment with mycophenolate mofetil 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.
Since mycophenolate mofetil 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 syndromes.

Gastrointestinal.

Gastrointestinal tract bleeding (requiring hospitalisation) has been observed in approximately 1.4% of patients treated with mycophenolate mofetil 2 g in renal transplantation, 2.8% of patients receiving 3 g in cardiac transplantation and in 5.4% of patients receiving mycophenolate mofetil 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 mycophenolate mofetil. As mycophenolate mofetil 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, mycophenolate mofetil 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/minute/1.73m²) who have received single doses of mycophenolate mofetil showed increased plasma AUCs of mycophenolic acid and glucuronide of mycophenolic acid 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 mycophenolate mofetil greater than 1 g bd should be avoided (see Dosage and Administration and Pharmacology, Pharmacokinetics).
In patients with delayed graft function post-transplant, mean mycophenolic acid AUC_(0-12) was comparable, but MPAG AUC_(0-12) was two to threefold 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 graft 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 mycophenolate mofetil 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.

Laboratory monitoring.

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

Effects on fertility.

Mycophenolate mofetil 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).

Use in pregnancy.

(Category D)
Mycophenolate mofetil tablets are contraindicated during pregnancy and in women of childbearing potential not using highly effective contraceptive methods (see Contraindications).
Before the start of treatment, female and male patients of reproductive potential must be aware of the increased risk of pregnancy loss and congenital malformations and must be counselled regarding pregnancy prevention and planning.
Prior to starting therapy with mycophenolate mofetil tablets, 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 mycophenolate mofetil tablets. 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.
Due to the mutagenic and teratogenic potential of mycophenolate mofetil tablets, women of childbearing potential should use two reliable forms of contraception simultaneously, including at least one highly effective method, before beginning mycophenolate mofetil therapy, during therapy, and for six weeks following discontinuation of therapy, unless abstinence is the chosen method of contraception. Sexually active men are recommended to use condoms during treatment and for at least 90 days after cessation of treatment. Condom use applies for both reproductively competent and vasectomized men, because the risks associated with the transfer of seminal fluid also apply to men who have had a vasectomy. In addition, female partners of male patients are recommended to use highly effective contraception during treatment and for total of 90 days after the last dose of mycophenolate mofetil tablets.
Congenital malformations, including multiple malformations have been reported postmarketing 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).
In the medical literature, malformations in children from mycophenolate mofetil exposed pregnancies have been reported in 23% to 27% of live births. 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.
Cases of spontaneous abortions have also been reported in patients exposed to mycophenolate mofetil, mainly in the first trimester. In the medical literature, the risk has been reported at 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.
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.

Mycophenolate mofetil tablets are contraindicated during breastfeeding due to the potential for serious adverse reactions in nursing infants (see Contraindications).
Studies in rats have shown mycophenolate mofetil to be excreted in milk. It is not known whether this medicine is excreted in human milk.

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 2 years.

Use in the elderly.

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

Carcinogenicity.

A 104 week oral carcinogenicity study in mice with mycophenolate mofetil 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, mycophenolate mofetil in daily doses up to 15 mg/kg (0.6 times the expected maximum clinical dose based on AUC values) was not tumorigenic.
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).

Genotoxicity.

Mycophenolate mofetil did not induce point mutations (Ames assay) or primary DNA damage (yeast mitotic gene conversion assay) in the presence or absence of metabolic activation. Mycophenolate mofetil 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.

Interactions

Drug interaction studies with mycophenolate mofetil have been conducted with aciclovir, antacids, cholestyramine, cyclosporin A, ganciclovir, oral contraceptives, proton pump inhibitors, 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 Mycophenolate AN 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 mycophenolate mofetil (1 g) and aciclovir (800 mg) to normal healthy subjects, higher glucuronide of mycophenolic acid (8.6%) and aciclovir (17.4%) plasma AUCs were observed when mycophenolate mofetil was administered with aciclovir in comparison to the administration of each drug alone. As mycophenolate mofetil plasma concentrations are increased in the presence of renal impairment, as are aciclovir concentrations, the potential exists for the mycophenolate and acyclovir or the 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 mycophenolate mofetil (2 g) was decreased when aluminium/ magnesium hydroxide antacids were administered concomitantly to rheumatoid arthritis patients. The C_max and 24 hour AUC values for mycophenolic acid were 33% and 17% lower, respectively than when mycophenolate mofetil was administered alone under fasting conditions.

Cholestyramine.

Following single dose administration of mycophenolate mofetil 1.5 g in normal healthy subjects pretreated with cholestyramine three times daily 4 g for four days, there was a mean 40% reduction in the AUC of mycophenolic acid (see Pharmacology, Pharmacokinetics). In view of the significant reduction in the AUC of mycophenolic acid by cholestyramine, caution should be used with the concomitant use of Mycophenolate AN and any drug which interferes with enterohepatic circulation because of the potential to reduce the efficacy of mycophenolate tablets.

Ciprofloxacin and amoxicillin plus clavulanic acid.

Reductions in predose (trough) mycophenolic acid 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 mycophenolic acid 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 mycophenolate mofetil 1.0 g bd in stable renal transplant patients. The mean (± SD) dose normalised AUC_{(0-12 hours)} of mycophenolic acid after 14 days and 3 months of multiple doses of mycophenolate mofetil and cyclosporin in 17 renal transplant patients were 43 ± 11 and 56 ± 31 microgram, hour.mL, respectively.

Sirolimus.

A study in 36 renal transplant patients demonstrated that concomitant administration of mycophenolate mofetil (1 g bd) and sirolimus resulted in the mean (± SD) AUC_{(0-12 hours)} of mycophenolic acid after 14 days and 3 months were 81 ± 36 and 71 ± 26 microgram. hour/mL 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 mycophenolate mofetil were withdrawn with symptoms consistent with mycophenolic acid or sirolimus toxicity.
Monitoring of mycophenolic acid 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 mycophenolate mofetil (1.5 g) and intravenous ganciclovir (5 mg/kg). However, as glucuronide of mycophenolic acid (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 mycophenolate mofetil and ganciclovir or its prodrugs (e.g. valganciclovir) are coadministered, patients should be carefully monitored. However with mycophenolic acid no substantial alteration of MPA pharmacokinetics is anticipated and dose adjustment of mycophenolate mofetil is not required.

Iron.

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

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 mycophenolate mofetil. A study of coadministration of mycophenolate mofetil (1 g bd) and combined oral contraceptives containing ethinyloestradiol (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 three menstrual cycles showed no clinically relevant influence of mycophenolate mofetil on serum levels of progesterone, LH and FSH, thus indicating no influence of mycophenolate mofetil on the ovulation suppressing action of the oral contraceptives (see Precautions, Use in pregnancy).

Proton pump inhibitors (PPIs).

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

Rifampicin.

After correction for dose, a 70% decrease in mycophenolic acid exposure AUC_(0-12hours) has been observed with concomitant rifampicin administration in a single heart lung transplant patient. It is, therefore recommended to monitor mycophenolic acid exposure levels and to adjust mycophenolate tablets doses accordingly to maintain clinical efficacy when the drugs are administered concomitantly.

Tacrolimus.

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

Trimethoprim/ sulfamethoxazole.

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

Norfloxacin/ metronidazole.

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

Sevelamer and other calcium free phosphate binders.

Concomitant administration of sevelamer and mycophenolate mofetil in adults and paediatric patients decreased the C_max and AUC_(0-12) of mycophenolic acid by 30% and 25%, respectively. There are no data on mycophenolate mofetil with phosphate binders other than sevelamer. This data suggest that sevelamer and other calcium free phosphate binders should preferentially be given two hours after mycophenolate tablets intake to minimise impact on the absorption of mycophenolic acid.

Other interactions.

The measured value for renal clearance of glucuronide of mycophenolic acid 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 mycophenolate mofetil in monkeys raises the plasma AUC of glucuronide of mycophenolic acid by threefold. Thus, other medicines known to undergo renal tubular secretion may compete with glucuronide of mycophenolic acid and thereby raise plasma concentrations of glucuronide of mycophenolic acid 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 mycophenolate mofetil 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 mycophenolate mofetil was determined in three 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 one year, with approximately 53% of the patients having been treated for more than one 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 mycophenolate mofetil 2 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 one 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 mycophenolate mofetil 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 treated for up to a minimum of one 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 mycophenolate mofetil 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, were reported with an incidence of less than 3% in one or more of the mycophenolate mofetil 2 g or 3 g (renal) active controlled cohorts (n = 336, n = 330), the mycophenolate mofetil 2 g or 3 g (renal) placebo controlled cohorts (n = 165, n = 160), less than 1.4% in the mycophenolate mofetil 3 g (cardiac) active controlled cohort (n = 289), or less than 1.4 % in the mycophenolate mofetil 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, 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, benign skin 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, polycythaemia, thrombocythaemia, agranulocytosis, lymphoma like reaction, decreased immunoglobulins, ecchymosis, thrombotic thrombocytopenic purpura, epistaxis, haemorrhage, petechiae, 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, hypaesthesia, 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 mycophenolate mofetil 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 mycophenolate mofetil 3 g and up to 3.6% (regardless of investigator assessment of causality) of patients receiving mycophenolate mofetil 3 g in hepatic transplantation developed severe neutropenia.
Cytomegalovirus (CMV) tissue invasive disease was more common in renal transplant patients receiving mycophenolate mofetil 3 g/day (8-12%) than in those receiving mycophenolate mofetil 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 mycophenolate mofetil 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 mycophenolate mofetil 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 mycophenolate mofetil or control therapy in combination with other immunosuppressive agents. In the controlled cardiac transplant study, fatal infections occurred in 2.4% of patients receiving mycophenolate mofetil 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 mycophenolate mofetil 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 mycophenolate mofetil as part of an immunosuppressive regimen are at an increased risk of developing lymphomas and other malignancies, particularly of the skin. Within three years post-transplant, lymphoproliferative disease or lymphoma developed in patients receiving mycophenolate mofetil 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 mycophenolate mofetil 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 mycophenolate mofetil and azathioprine groups. Hepatic transplant patients were followed for at least one year but less than three 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 mycophenolate mofetil 600 mg/m² orally twice daily were generally similar to those observed in adult patients given mycophenolate mofetil 1 g twice daily with the exception that paediatric patients had a higher proportion of diarrhoea, anaemia, sepsis and leucopenia.

Postmarketing experience.

Infections.

Uncommon: serious life threatening infections such as meningitis 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 mycophenolate mofetil 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 mycophenolate mofetil. 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 have been reported postmarketing in children of patients exposed to mycophenolate mofetil in combination with other immunosuppressants during pregnancy (see Use in pregnancy).

Pregnancy, puerperium and perinatal conditions.

Cases of spontaneous abortions mainly in the first trimester in patients exposed to mycophenolate mofetil have been reported (see Use in pregnancy).

Blood and immune system.

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

Dosage and Administration

The initial dose of Mycophenolate AN 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.

Cardiac transplantation.

The recommended dose in cardiac transplant patients is 1.5 g administrated orally.

Hepatic transplantation.

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

Paediatrics (6 to 18 years).

Mycophenolate mofetil tablets are not suitable for paediatric patients whose body surface area is < 1.50 m². Patients with a body surface area > 1.5 m² may be dosed with mycophenolate mofetil tablets at a dose of 1 g twice daily (2 g daily dose).
Mycophenolate AN 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 mycophenolate mofetil tablets 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/minute/1.73m²) outside of the immediate post-transplant period, doses of mycophenolate mofetil tablets 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 mycophenolate mofetil has demonstrated teratogenic effects in rat and rabbit studies, Mycophenolate AN should not be crushed. Avoid inhalation or direct contact with skin or mucous membranes of the powder. If contact occurs, wash thoroughly with soap and water, should the eyes be affected, rinse eyes with plain water.

Overdosage

Symptoms.

Reports of overdoses with mycophenolate mofetil 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 mycophenolate mofetil could possibly result in over suppression of the immune system and increase susceptibility to infections and bone marrow suppression (see Precautions). If neutropenia develops, dosing with Mycophenolate AN should be interrupted or the dose reduced (see Precautions).

Treatment.

Mycophenolic acid cannot be removed by haemodialysis. However, at high glucuronide of mycophenolic acid plasma concentrations (> 100 microgram/mL), small amounts of glucuronide of mycophenolic acid are removed. Bile acid sequestrants, such as cholestyramine, can remove mycophenolic acid by increasing excretion of the drug (see Pharmacology, Pharmacokinetics).
Treatment of overdosage should consist of general supportive measures.
Contact the Poisons Information Centre (telephone 131 126) for advice regarding management of overdose.

Presentation

Tablets, 500 mg (purple, capsule shaped, biconvex, film coated, marked AHI, 500 on reverse): 50's (PVC/PVDC/Al blister pack).

Storage

Mycophenolate AN should be stored below 25°C and protected from light.

Poison Schedule

S4.

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Mycophenolate AN 500 mg Tablets

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