Myaccord

New Zealand - English - Medsafe (Medicines Safety Authority)

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Active ingredient:
Mycophenolate mofetil 500 mg;  
Available from:
Douglas Pharmaceuticals Limited
INN (International Name):
Mycophenolate mofetil 500 mg
Dosage:
500 mg
Pharmaceutical form:
Film coated tablet
Composition:
Active: Mycophenolate mofetil 500 mg   Excipient: Croscarmellose sodium Hyprolose Magnesium stearate Microcrystalline cellulose Opadry purple 03B50110 Povidone Purified talc
Units in package:
Blister pack, PVC/PVDC/aluminium foil, 50 tablets
Class:
Prescription
Prescription type:
Prescription
Manufactured by:
Concord Biotech Limited
Therapeutic indications:
for the prophylaxis of acute organ rejection in patients receiving allogeneic renal transplants.
Product summary:
Package - Contents - Shelf Life: Blister pack, PVC/PVDC/aluminium foil - 50 tablets - 3 years from date of manufacture stored at or below 25°C protect from light and moisture - Blister pack, PVC/PVDC/aluminium - 100 tablets - 3 years from date of manufacture stored at or below 25°C protect from light and moisture
Authorization number:
TT50-7702
Authorization date:
2006-06-22

ConsumerMedicineInformation

MYACCORD

Mycophenolatemofetil250mgcapsulesand500mgtablets

Whatisinthisleaflet

Thisleafletanswerssomeifnotallofthecommonquestionsabout

MYACCORDcapsulesandtablets.

Itwillnothavealltheavailableinformation.

Itdoesnottaketheplaceoftalkingtoyourdoctororpharmacist.

YourdoctorhasweighedtherisksofyoutakingMYACCORDagainstits

benefitsbeforeprescribingitforyou.

Ifyouhaveanyconcernsabouttakingthismedicinedoaskyourdoctor

orpharmacist.

Keepthisleafletwiththemedicine.Youmayneedtoreaditagain.

WhatisMYACCORDusedfor

MYACCORDcontainstheactiveingredientmycophenolatemofetilwhich

belongstoagroupofmedicinescalledimmunosuppressants.Itisthese

immunosuppressantsthatareusedtopreventrejectionoftransplanted

organs,andworkbystoppingyourimmunesystemfromreactingtothe

transplantedorgan.

MYACCORDmaybeusedtogetherwithothermedicinesknownas

ciclosporinandcorticosteroids.

AttimesyourdoctormayhaveprescribedMYACCORDforsomeother

purpose.

Ifindoubt,doaskyourdoctorifyouhaveanyquestionsabout

MYACCORD.

Thismedicineisavailableonlywithadoctor'sprescription.

BeforeyoutakeMYACCORD

Whenyoumustnottakeit

Themedicineshouldnotbetakenif:

1.thepackageistornorshowssignsoftampering

2.theexpirydateprintedonthepackhaspassed.Themedicine

maynotworkaswellifyoutakeitaftertheexpirydatehas

passed.

3.youhavehadanallergicreactiontoMYACCORDorany

ingredientslistedattheendofthisleaflet.

Allergicreactionsymptomsincludeswelling,itching,rash,

breathingdifficulties.

BeforeyoustarttotakeMYACCORDdoinformyourdoctorif:

1.youarepregnantorplantobecomepregnant

ItisnotknownwhetherMYACCORDisknowtocauseharmfuleffectsto

anunbornbaby.However,birthdefectshavebeenreportedinpatients

exposedtomycophenolatemofetil,incombinationwithother

immunosuppressants,duringpregnancy.Yourdoctorwilldiscussthe

risksandbenefitstoyouandtheunbornbabyifthereisaneedtotake

MYACCORDwhenyouarepregnant.

Womenofchildbearingpotentialshouldhaveapregnancytesttoshow

theyareNOTpregnantoneweekbeforestartingtotakeMYACCORD.

2.youarebreastfeedingorplantobreastfeed

yourdoctormayadviseyoutoeitherstopbreast-feeding,ortostop

takingMYACCORDasitisnotknownifMYACCORDpassesintobreast

milk.

3.youhaveanyotherhealthproblems,especiallythefollowing:

severekidneydisease

ahistoryofseriousstomachorbowelproblems(suchasulcersor

bleeding)

ahistoryofskincancersorsunspots

youhaveararediseasesuchasKelly-Seegmillersyndromeor

Lesch-Nyhan.

4.youareallergictoanyothermedicines,foods,dyesorpreservatives.

Ifyouhavenottoldyourdoctoraboutanyoftheabove,youshoulddosobefore

youstarttakingMYACCORD.

Takingothermedicines

Tellyourdoctorifyouaretakinganyothermedicinesincludinganythatyou

haveboughtfromapharmacy,healthfoodshoporsupermarket.

SomemedicinescouldinterferewithMyaccord.Thesemedicinesinclude:

antacids-aclassofmedicinesforindigestionorheartburn

azathioprine(Azamun ®

,Imuran ®

,Thioprine ®

):Thesemedicationsare

usedtosuppresstheimmunesystem.

tacrolimus(Prograf ® ):Anothermedicationusedtosuppresstheimmune

system.

aciclovir(Acicvir ®

,Lovir ®

,Zovirax ®

,Viraban ®

,Zolaten ®

),valaciclovir,

ganciclovir(Cymevene ®

),valganciclovir(Valcyte ®

):Thesemedications

areusedtotreatviralinfections.

cholestyramine(QuestranLight ®

):Thismedicationisusedtotreathigh

bloodcholesterollevels.

Rifampicin(Rifadin ®

,Rifinah ®

),ciprofloxacin(Cifran ®

,Ciproxin ®

,

Cipflox ® ),amoxicillinplusclavulanicacid(Augmentin ® ),norfloxacinplus

metronidazole.Thesearemedicinesusedtotreatinfections.

calcium-freephosphatebinders(sevelamer):Thesemedicationsare

usedtotreathighbloodphosphatelevels.

vaccinations-astheymaynotbeaseffectiveasnormal.Theseare

medicinesthatworkbycausingyourbodytoproduceitsownprotection

againstaninfectiousdisease.Vaccinationwithlivevaccinesshouldbe

avoided.

ThesemedicinesmayeitherbeaffectedbyMYACCORDoraffectitsaction.

Youmayneedtoalterthedosageofthemedicine,oryoumayberequiredto

changethemedicine.Yourdoctorwilladviseyouaccordingly.

Yourdoctororpharmacisthasmoreinformationonmedicinestobecarefulwith

oravoidwhiletakingMYACCORD.

Askyourdoctororpharmacistifyouarenotsureaboutthislistofmedicines.

HowtotakeMYACCORD

Youareadvisedtofollowallthedirectionsgiventoyoubyyourdoctoror

pharmacistverycarefully.Thedoctororpharmacist’sadvicemaydifferfrom

theinformationinthisleaflet.

Howmuchtotake

MYACCORDistobetakenexactlyasyourdoctorhasprescribed.

YourdoctorwilltellyouhowmuchMYACCORDtotakeeachday.

Thenormaladultdosetopreventrejectionisusually2gor3gperday,

dependingonwhichorganhasbeentransplanted.Thisshouldbetakenas1g

or1.5ginthemorning,andanother1gor1.5gatnight.

Thenormaldoseforchildrenandadolescents(aged3monthsto18years)to

preventrejectionofakidneytransplantdependsontheirbodysurfacearea.

Yourdoctorwilldeterminethedailydoseuptoausualmaximumof2gperday.

Yourdoctormayadjustyourdosedependingonyourresponse.

HowtotakeMYACCORD

Capsulesandtabletsshouldbeswallowedwholewithaglassofwater.

Ifatabletiscrushedorcapsulesbreaks,usingsoapandwater,washoffthe

powderthoroughly.Ifpowderentersyoureyes,usewatertorinse.

Whentotakeit

Itisbesttotakedosesapproximately12hoursapart.Yourdosecanbetaken

withorwithoutfood.

Takingyourmedicineatthesametimeeachdaywillhavethebesteffect.Itwill

alsohelpyoutorememberwhentotakeMYACCORD.

HowlongtotakeMYACCORD

MYACCORDshouldbetakeneveryday.Itisimportanttokeeptakingthe

medicationtoensureyourtransplantedorgankeepsworkingproperly.Itshould

betakenuntilthedoctortellsyoutostop.

Ifyouforgettotakeit

Ifitisalmosttimeforyournextdose,skipthedoseyoumissedandtakeyour

nextdosewhenyouaremeantto.Otherwise,takeitassoonasyouremember

andthengobacktotakingitasyouwouldnormally.

Donotdoubleadosetomakeupforoneyouhavemissed.

Ifindoubtdoaskyourdoctororpharmacist.Theycanalsohelpwithhintsif

youhavetroublerememberingyourdose.

Overdosage:

ImmediatelytelephoneyourdoctororNationalPoisonsInformationCentre

(telephone0800POISONor0800764766)foradviceorgotoyournearest

AccidentandEmergencycentreifyouthinkthatyouoranyoneelsemayhave

takentoomuchMYACCORD.Dosoeveniftherearenosignsofpoisoningor

discomfort.

Youmayneedurgentmedicalattention.

Keeptelephonenumbersfortheseplaceshandy.

Ifyouarenotsurewhattodo,contactyourdoctororpharmacist.

WhileyouareusingMYACCORD

WhileyouaretakingMYACCORDyoumust

Tellalldoctors,dentistsandpharmacistswhoaretreatingyouthatyou

aretakingMYACCORD.

InformyourdoctorifyoubecomepregnantwhiletakingMYACCORD.

Itisimportanttouseveryeffectivecontraceptivemeasuresfourweeks

priortotakingMYACCORD,whileyouaretakingMYACCORDandfor

sixweeksafteryoustoptakingMYACCORD.Itisrecommendedthattwo

reliableformsofcontraceptionbeusedatthesametimeifyouare

sexuallyactive.

TellyourdoctororgotoyournearestAccidentandEmergencycentre

immediatelyifyouthinkyoumayhaveaninfection(signsmayincludefever,

chills,localinflammation,sorethroatorulcersinthemouth,buttherecouldbe

othersymptoms),anyevidenceofunexpectedbruisingoranyunexpected

bleeding.AstheseareserioussideeffectswhiletakingMYACCORDandyou

mayneedurgentmedicalattention.

MYACCORDreducesyourbody'sowndefencemechanismstostopyou

rejectingyourtransplantedorgan.Yourbodywillnotbeaseffectiveatfighting

infectionasitnormallyis.PeopletakingMYACCORDoftendevelopmore

infectionsthantheynormallywould.

Whenoutdoors,wearprotectiveclothingandabroad-spectrumsunscreenwith

ahighprotectionfactor.

MedicinessuchasMYACCORDthatpreventrejectionoftransplants,cancause

asmallincreaseintheriskofgettingcancer,skincancersinparticular.You

shoulddiscussthiswithyourdoctorifitconcernsyou.

Tellyourdoctorifforanyreasonyouhavenottakenthemedicineas

prescribed.Yourdoctormayotherwisethinkthemedicationwasnoteffective

andchangethetreatmentprescribedunnecessarily.

Ifyoufeelyourmedicineisnothelpingyourconditionkindlydiscussthesame

withyourdoctor.

Ensureyoukeepallofyourappointmentswithyourdoctorsothatyourprogress

canbemonitored.Yourdoctormayrequireyoutogiveregularbloodtests.

Thingsyoumustnotdo

DonotgiveyourMYACCORDmedicationtoanyoneelseevenifthey

havethesameconditionasyou.

Donottakeanyothermedicines,whethertheyrequireaprescriptionor

not,withoutfirsttellingyourdoctororconsultingwithapharmacist.

DonotstoptakingMYACCORDorchangethedosewithoutfirst

checkingwithyourdoctor.Donotletyourselfrunoutofmedicineover

theweekendoronholidays.

DonotuseMYACCORDtotreatotherconditionsunlessyourdoctor

saysto.

Thingstobecarefulof

UntilyouknowhowMYACCORDaffectsyou,becarefuldrivingoroperating

machinery.

Aswithmanyothermedicinesusedtopreventrejectionoftransplantedorgans,

MYACCORDmaycausedrowsiness,dizziness,orlight-headednessinsome

people.MakesureyouknowhowyoureacttoMYACCORDbeforeyoudrivea

car,operatemachineryordoanythingelsethatcouldbedangerousifyouare

dizzy,drowsyorlight-headed.

Sideeffects

IfyoudonotfeelwellwhiletakingMYACCORD,tellyourdoctororpharmacist

assoonaspossible.

MYACCORDhelpsmostpeoplewhohavetransplantsbutitcouldhavesome

unwantedsideeffects.Allmedicinescanhavesideeffects.Sometimestheside

effectsareserious,mostofthetimetheyarenot.Someofthesideeffectsmay

requiremedicaltreatment.

Ifyouareover65yearsofageyoumayhaveanincreasedchanceofgetting

sideeffects.

Patientsreceivingimmunosuppressantmedicinesmayhaveasmallincreased

riskofdevelopingsometypesofcancers.Thisshouldbediscussedwithyour

doctor.

Askyourdoctororpharmacisttoansweranyquestionsyoumayhave.

Informyourdoctorifyounoticeanyofthefollowingandtheyconcernyou

(Thesearethemorecommon,mild,sideeffectsoftakingMYACCORD.):

dizzinessorshaking

diarrhoea,constipation,nausea(feelingsick)orindigestion

acne

hairlossoritchyskin

headache

inabilitytosleep(insomnia)

Informyourdoctorassoonaspossibleifyounoticeanyofthefollowing

(Thesemaybeserioussideeffectsandyoumayrequiremedicaltreatment):

fluid(swelling)inthelegs,armsorface

anxietyordepression

coldsores

signsofanaemiasuchasexcessivetiredness,dizzinessorlookingpale

stomach,back,muscleorotherpain

skinchanges,especiallychangesinmolesorfreckles.

Informyourdoctorimmediately,orgotoyournearestAccidentand

Emergencycentreifyounoticeanyofthefollowing(Theseareseriousside

effectsandyoumayneedurgentmedicalattention.Serioussideeffectsare

rare):

anysignsofinfectionsuchasfever,inflammation,sweating,chillsor'flu-

like’symptoms

vomiting

clumsiness

unexplainedbleeding

urinaryinfectionorbloodinyoururine

irregularheartbeatorchestpain

changesinvisionorspeech

weakness

Thisisnotacompletelistofallpossiblesideeffects.Othersmayoccurinsome

individualsandtheremayalsobesomesideeffectsthatarenotyetknown.

Tellyoudoctororpharmacistifyounoticeanythingelse,thatisnotonthelist,

thatismakingyoufeelunwell.

Doaskyourdoctororpharmacistifyoudon'tunderstandanythinginthislist.

Donotbealarmedbythislistofpossiblesideeffects.Youmaynotexperience

anyofthem.

AftertakingMYACCORD

Storage

Keepyourcapsulesortabletsintheblisterpackuntilitistimetotakethenext

dosage.

Donottakethecapsulesandtabletsoutoftheblisterpackastheymaynot

keepwell.

KeepMYACCORDcapsulesawayfrommoistureandkeepthetabletsinthe

cartonwheretheyareprotectedfromlight.

Lightmaycausethetabletstofade.

Themedicationshouldbestoredinacooldryplacewherethetemperature

staysbelow25°C.

Donotstorethem,oranyothermedicine,nearasinkorinabathroom.

DonotleaveMYACCORDonwindowsillsorinthecar.

Somemedicationscanbedestroyedbyheatanddampness.

KeepMYACCORDoutofreachofyoungchildren.

Agoodplacetostoremedicines,isalockedcupboardatleastone-and-a-half

metersabovetheground.

Disposal

IfyourdoctoradvisesyoutostoptakingMYACCORD,oriftheproductshave

passedtheirexpirydate,askyourpharmacistwhattodowithanyremaining

medicine.

Productdescription

WhatMYACCORDlookslike

MYACCORDcapsulesarelightblue/peachcoloured,hardgelatincapsuleswith

‘MMF’onthecapand‘250’onthebodycontainingwhitetooffwhitepowder.

Theycomeinpacksof30’s,90’sand100’s.

MYACCORDtabletsarepurplecolouredandcapsule-shaped,biconvexfilm

coateddebossedwith“ÄHI”engravedononesideand"500"ontheother.They

comeinpacksof50’sand100’s.

Ingredients

Activeingredient-mycophenolatemofetil

MYACCORDcapsulescontain250mgofmycophenolatemofetil

andtabletscontain500mgofmycophenolatemofetil.

Inactiveingredients–

Capsules:cellulosemicrocrystalline(AvicelPH101),hydroxyl

propylcellulose,povidoneK-90,croscarmellosesodium,talc,

magnesiumstearateandpurifiedwater.Thecapsuleshells

containgelatin,FD&Cblue,ironoxideyellow,ironoxidered,

titaniumdioxide,sodiumlaurylsulphateandpurifiedwater.The

printinginkcontainsblackironoxide,potassiumhydroxide,

shellac,dehydratedalcohol,isopropylalcohol,butylalcohol,

propyleneglycol,strongammoniasolutionandpurifiedwater.

Tablets:microcrystallinecellulose,croscarmellosesodium,

povidone,magnesiumstearate,hydroxypropylcellulose,talc,

opadry03B50110purpleandpurifiedwater.

MYACCORDcapsulesandtabletsareglutenandlactosefree.

Distributor

MYACCORDisdistributedby:

DouglasPharmaceuticalsLimited

POBox45027

Auckland0651

NewZealand

Ph:(09)8350660

Fax:(09)8350665

Thisleafletwaspreparedon17April2012

Data Sheet

MYACCORD

Mycophenolate mofetil

Immunosuppressant; inosine monophosphate dehydrogenase (IMPDH) inhibitor

Pharmaceutical Form

Oral administration

Myaccord is supplied as capsules and tablets.

Qualitative and Quantitative Composition

Active ingredient

Mycophenolate mofetil (MMF).

Oral administration

Each capsule contains 250 mg mycophenolate mofetil.

Each tablet contains 500 mg mycophenolate mofetil. Do not halve tablet. Dose

equivalence when the tablet is divided has not been established.

Appearance

Myaccord capsules 250 mg: Light blue/peach, hard gelatin capsules with ‘MMF’

on the cap and ‘250’ on the body containing white to off white powder.

Myaccord tablets 500 mg: Purple coloured, capsule shaped, biconvex, film

coated tablets engraved ‘AHI’ on one side and ‘500’ on the other side.

Clinical Particulars

Therapeutic Indications

Myaccord is indicated for the prophylaxis of acute organ rejection in patients

receiving allogeneic renal transplants.

Myaccord is indicated for the prophylaxis of acute organ rejection in patients

receiving allogeneic cardiac transplants. In the treated population, MMF

improved survival in the first year after transplantation.

Myaccord is indicated for the prophylaxis of acute organ rejection in patients

receiving allogeneic hepatic transplants.

Myaccord should be used concomitantly with ciclosporin and corticosteroids.

Dosage and Method of Administration

Do not halve tablet. Dose equivalence when the tablet is divided has not been

established.

Standard Dosage

Standard dosage for prophylaxis of renal rejection

Adults

A dose of 1 g administered orally twice a day (daily dose of 2 g) is

recommended for use in renal transplant patients. Although a dose of 1.5 g

administered twice daily (daily dose of 3 g) was used in clinical trials and was

shown to be safe and effective, no efficacy advantage could be established for

renal transplant patients. Patients receiving 2 g/day of mycophenolate mofetil

demonstrated an overall better safety profile compared to patients receiving

3g/day of mycophenolate mofetil.

Children (aged 3 months to 18 years)

Patients with a body surface area of 1.25 to 1.5 m

may be prescribed Myaccord

capsules at a dose of 750 mg twice daily (1.5 g daily dose). Patients with a body

surface area > 1.5 m

may be prescribed Myaccord tablets at a dose of 1g twice

daily (2 g daily dose).

Standard dosage for prophylaxis of cardiac rejection

Adults

A dose of 1.5 g administered orally twice a day (daily dose of 3 g) is

recommended for use in cardiac transplant patients.

Children

No data are available for paediatric cardiac transplant patients.

Standard dosage for prophylaxis of hepatic rejection

Adults

A dose of 1.5 g orally twice a day (daily dose of 3 g) is recommended for use in

hepatic transplant patients.

Children

No data are available for paediatric hepatic transplant patients.

Oral administration (see Bioequivalence)

The initial dose of Myaccord should be given as soon as possible following

renal, cardiac or hepatic transplantation.

Special Dosage Instructions

Patients with neutropenia

If neutropenia develops (absolute neutrophil count <1.3 x 10

/µl), dosing with

Myaccord should be interrupted or the dose reduced (See Warnings and

Precautions).

Contraindications

Allergic reactions to mycophenolate mofetil have been observed. Therefore,

Myaccord is contraindicated in patients with hypersensitivity to mycophenolate

mofetil or mycophenolic acid (MPA).

Warnings and Precautions

Female patients of childbearing potential must use effective contraception for

four weeks before, during and for six weeks after receiving Myaccord. The use

of Myaccord is not recommended during pregnancy and should be reserved for

cases where no suitable alternate treatment is available. Myaccord should be

used in pregnant women only if the potential benefits outweigh the potential

risks to the foetus (see Pregnancy and Nursing mothers).

As in all patients receiving immunosuppressive regimens involving

combinations of medicines, patients receiving Myaccord as part of an

immunosuppressive regimen are at increased risk of developing lymphomas

and other malignancies, particularly of the skin (see Undesirable Effects). The

risk appears to be related to the intensity and duration of immunosuppression

rather than to the use of any specific agent.

As with all patients at an increased risk for skin cancer, exposure to sunlight

and UV light should be limited by wearing protective clothing and using a

sunscreen with a high protection factor.

Patients receiving Myaccord should be instructed to report immediately 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 (see

Undesirable Effects).

Such infections included latent viral reactivation, such as by polyomaviruses.

Cases of Progressive Multifocal Leukoencephalopathy (PML), associated with

JC virus, 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. In

immunosuppressed patients reporting neurological symptoms, physicians

should consider PML in the differential diagnosis and consult with a Neurologist

as clinically indicated.

BK virus-associated nephropathy has been observed during the use of

mycophenolate mofetil in patients post renal transplant. This infection can be

associated with serious outcomes, sometimes leading to renal graft loss.

Patient monitoring may help detect patients at risk for 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 the graft at risk.

Patients should be advised that during treatment with Myaccord vaccinations

may be less effective and the use of live attenuated vaccines should be avoided

(See Interactions with other Medicinal Products and other Forms of Interaction).

Influenza vaccination may be of value. Prescribers should refer to national

guidelines for influenza vaccination.

Because mycophenolate mofetil has been associated with an increased

incidence of digestive system adverse events, including infrequent cases of

gastrointestinal tract ulceration, haemorrhage, and perforation, Myaccord

should be administered with caution in patients with active digestive system

disease.

Because Myaccord is an inosine monophosphate dehydrogenase (IMPDH)

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.

It is recommended that Myaccord 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.

In view of the significant reduction in the AUC of MPA by cholestyramine,

caution should be used in the concomitant administration of Myaccord with

medicines that interfere with enterohepatic recirculation because of their

potential to reduce the efficacy of Myaccord (see Interactions with other

Medicinal Products and other Forms of Interaction).

Administration of doses greater than 1 g bid to renal patients with severe

chronic renal impairment should be avoided (see Pharmacokinetic Properties

and Special Dosage Instructions).

No dose adjustment is recommended for post-transplant patients with delayed

renal graft function but patients should be carefully monitored (see

Pharmacokinetic Properties and Special Dosage Instructions). No data are

available for cardiac or hepatic transplant patients with severe renal impairment.

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.

Elderly patients may be at an increased risk of adverse events compared with

younger individuals (see Undesirable Effects).

Laboratory monitoring

Patients on Myaccord 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 Myaccord should

be monitored for neutropenia. The development of neutropenia may be related

to Myaccord, concomitant medications, viral infection or some combination of

these causes (see Special Dosage Instructions). If neutropenia develops

(absolute neutrophil count <1.3 x 10

/µl), dosing with Myaccord should be

interrupted or the dose reduced and the patient should be carefully observed

(see Special Dosage Instructions).

Interactions with other Medical Products and other Forms of Interaction

Aciclovir

Higher MPAG (the phenolic glucuronide of MPA) and aciclovir plasma

concentrations were observed when mycophenolate mofetil was administered

with aciclovir than when the medicines were administered alone. Because

MPAG plasma concentrations are increased in the presence of renal

impairment, as are aciclovir concentrations, the potential exists for

mycophenolate and aciclovir or its prodrugs e.g. valaciclovir to compete for

tubular secretion, further increasing the concentrations of both substances.

Antacids with magnesium and aluminium hydroxides

Absorption of mycophenolate mofetil was decreased when it was administered

with antacids.

Cholestyramine

Following single-dose administration of 1.5 g of mycophenolate mofetil to

normal healthy subjects pretreated with 4 g tid of cholestyramine for 4 days,

there was a 40% reduction in the AUC of MPA. Caution should be used during

concomitant administration or with medicines that interfere with enterohepatic

circulation (see Special Warnings and Special Precautions for Use).

Ciclosporin A (CsA)

CsA pharmacokinetics were unaffected by mycophenolate mofetil. However, in

renal transplant patients concomitant administration of mycophenolate mofetil

and CsA resulted in reduced MPA exposures by 30-50% compared with

patients receiving the combination of sirolimus and similar doses of

mycophenolate Mofetil.

Ganciclovir

Based on the results of a single dose administration study of recommended

doses of oral mycophenolate and IV ganciclovir and the known effects of renal

impairment on the pharmacokinetics of MMF (see Pharmacokinetic Properties

and Warnings and Precautions) and ganciclovir, it is anticipated that

coadministration of these agents (which compete for mechanisms of renal

tubular secretion) will result in increases in MPAG and ganciclovir

concentration. No substantial alteration of MPA pharmacokinetics is anticipated

and MMF dose adjustment is not required. In patients with renal impairment in

which MMF and ganciclovir or its prodrugs e.g. valganciclovir are co-

administered, patients should be monitored carefully.

Oral contraceptives

The pharmacokinetics of oral contraceptives were unaffected by

coadministration of mycophenolate mofetil. A study of co-administration of

mycophenolate mofetil (1 g bid) 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 - 0.10mg) conducted in 18 women

with psoriasis over 3 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. Although the long-term effect of

mycophenolate mofetil dosing on the pharmacokinetics of oral contraceptives is

not known, the free concentration of MPA remains relatively constant over time.

Therefore, it is unlikely the efficacy of oral contraceptives would be adversely

affected (see Pregnancy and Nursing mothers).

Rifampicin

After correction for dose, a 70% decrease in MPA exposure (AUC

0-12

h) 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 Myaccord doses accordingly to maintain clinical efficacy

when the medicines are administered concomitantly.

Tacrolimus

Exposure to tacrolimus concomitantly administered with mycophenolate mofetil

had no effect on the AUC or Cmax of MPA in liver transplant recipients. A

similar finding was observed in a recent study in kidney transplant recipients.

In renal transplant patients it was shown that the tacrolimus concentration did

not appear to be altered by mycophenolate mofetil.

However, in hepatic transplant patients, there was an increase of approximately

20% in tacrolimus AUC when multiple doses of mycophenolate mofetil (1.5 g

bid) were administered to patients taking tacrolimus.

Trimethoprim/sulphamethoxazole

No effect on the bioavailability of MPA was observed.

Norfloxacin and Metronidazole

No effect on the systemic exposure of MPA was observed when mycophenolate

mofetil was concomitantly administered with any antibiotic separately. In

contrast, the combination of norfloxacin and metronidazole reduced the MPA

0-48

by 30% following a single dose of mycophenolate mofetil.

Ciprofloxacin and amoxicillin plus clavulanic acid

Reductions in pre-dose (trough) MPA concentrations of 54% have been

reported in renal transplant recipients in the days immediately following

commencement of oral ciprofloxacin or amoxicillin plus clavulanic acid.

Effects tended to diminish with continued antibiotic use and cease after

discontinuation. The change in pre-dose level may not accurately

represent changes in overall MPA exposure, therefore, the clinical

relevance of these observations is unclear.

Other interactions

Coadministration of probenecid with mycophenolate mofetil in monkeys raises

the plasma AUC of MPAG 3-fold. Thus, other medicines known to undergo

renal tubular secretion may compete with MPAG and thereby raise plasma

concentrations of MPAG or the other medicine undergoing tubular secretion.

Concomitant administration of sevelamer and mycophenolate mofetil in adults

and paediatric patients decreased the MPA Cmax and AUC

0-12

by 30% and

25%, respectively. This data suggest that sevelamer and other calcium free

phosphate binders preferentially should be given 2 hours after Myaccord intake

to minimise the impact on the absorption of MPA.

Live vaccines

Live vaccines should not be given to patients with an impaired immune

response. The antibody response to other vaccines may be diminished (see

Warnings and Precautions).

Use in Special Populations

Pregnancy

Pregnancy Category D.

Adverse effects on foetal development (including malformations) occurred when

pregnant rats and rabbits were dosed during organogenesis. These responses

occurred at doses lower than those associated with maternal toxicity, and at

doses below the recommended clinical dose for renal, cardiac or hepatic

transplantation.

There are no adequate and well-controlled studies in pregnant women

conducted with mycophenolate mofetil. However, post-marketing data from the

US National Transplant Pregnancy Registry (NTPR) indicated that use of

mycophenolate mofetil is associated with an increased risk of congenital

malformations. Therefore, Myaccord should be avoided in pregnant women

unless the potential benefits outweigh the potential risks to the foetus.

Congenital malformations, including ear malformations i.e. abnormally formed

or absent external/middle ear, have been reported in children of patients

exposed to mycophenolate mofetil in combination with other

immunosuppressant agents during pregnancy.

Women of childbearing potential should have a negative serum or urine

pregnancy test with a sensitivity of at least 50 mIU/mL within 1 week prior to

beginning therapy. It is recommended that Myaccord therapy should not be

initiated by the physician until a report of a negative pregnancy test has been

obtained.

Mycophenolate mofetil may slightly reduce the blood levels of oral

contraceptives; however, there is no clinically relevant alteration in serum

progesterone, LH and FSH levels. This suggests that efficacy of the oral

contraceptives are unlikely to be reduced (see Interactions with other Medicinal

Products and other Forms of Interaction).

Effective contraception must be used for four weeks before beginning Myaccord

therapy, during therapy, and for 6 weeks following discontinuation of therapy,

even where there has been a history of infertility, unless due to hysterectomy.

Two reliable forms of contraception must be used simultaneously unless

abstinence is the chosen method (see Interactions with other Medicinal

Products and other Forms of Interaction). If pregnancy does occur during

treatment, the physician and patient should discuss the desirability of continuing

the pregnancy.

Nursing mothers

Studies in rats have shown mycophenolate mofetil to be excreted in milk. It is

not known whether it is excreted in human milk. Because many medicines are

excreted in human milk and because of the potential for serious adverse

reactions in nursing infants from mycophenolate mofetil, a decision should be

made whether to discontinue nursing or to discontinue the medicine, taking into

account the importance of mycophenolate mofetil to the mother.

Geriatric use

The recommended oral doses of 1 g bid for renal transplant patients and 1.5 g

bid for cardiac or hepatic transplant patients are appropriate for elderly patients

(see Warnings and Precautions).

Renal impairment

Patients with severe renal impairment

In renal transplant patients with severe chronic renal impairment (glomerular

filtration rate <25 ml/min/1.73m

) outside of the immediate post-transplant

period or after treatment of acute rejection, doses greater than 1 g administered

twice a day should be avoided (see Warnings and Precautions).

No data are available for cardiac or hepatic transplant patients with severe

chronic renal impairment.

Patients with delayed renal graft function post-transplant

No dose adjustments are needed in patients experiencing delayed renal graft

function post-operatively (see Pharmacokinetic Properties).

Hepatic impairment

Patients with severe hepatic impairment

No dose adjustments are needed for renal patients with severe hepatic

parenchymal disease (see Pharmacokinetic Properties).

No data are available for cardiac transplant patients with severe hepatic

parenchymal disease.

Undesirable Effects

The adverse event profile associated with the use of immunosuppressive

medicines is often difficult to establish owing to the presence of underlying

diseases and the concurrent use of many other medications.

Clinical Trials

The principal adverse reactions associated with the administration of

mycophenolate mofetil in the prevention of renal, cardiac and hepatic transplant

rejection in combination with ciclosporin and corticosteroids include diarrhoea,

leucopenia, sepsis and vomiting, and there is evidence of a higher frequency of

certain types of infection, e.g. opportunistic infections (see Warnings and

Precautions).

The safety profile of mycophenolate mofetil in patients treated for refractory

renal transplant rejection was similar to that observed in three controlled trials

for prevention of renal rejection at doses of 3 g per day. Diarrhoea and

leucopoenia, followed by anaemia, nausea, abdominal pain, sepsis, nausea and

vomiting, and dyspepsia were the predominant adverse events reported in

patients receiving mycophenolate mofetil in comparison to patients receiving IV

corticosteroids.

Malignancies

As in patients receiving immunosuppressive regimes involving combinations of

medicines, patients receiving mycophenolate mofetil as part of an

immunosuppressive regime are at increased risk of developing lymphomas and

other malignancies, particularly of the skin (see Warnings and Precautions).

Lymphoproliferative disease or lymphoma developed in 0.4% to 1% of patients

receiving mycophenolate mofetil (2 g or 3 g daily) in combination with other

immunosuppressants in controlled clinical trials of renal, cardiac and hepatic

transplant patients followed for at least 1 year. Non-melanoma skin carcinoma

occurred in 1.6% to 4.2% of patients; other types of malignancy occurred in

0.7% to 2.1% of patients. Three-year safety data in renal and cardiac transplant

patients did not reveal any unexpected changes in the incidence of malignancy

compared to the 1-year data. Hepatic transplant patients were followed for at

least 1 year, but less than 3 years.

In controlled trials of treatment of refractory renal rejection, the lymphoma rate

was 3.9% at an average follow-up of 42 months.

Opportunistic infections

All transplant patients are at increased risk of opportunistic infections. The risk

increased with total immunosuppressive load (see Warnings and Precautions).

The most common opportunistic infections in patients receiving mycophenolate

mofetil (2 g or 3 g daily) with other immunosuppressants in controlled clinical

trials of renal (2 g data), cardiac and hepatic transplant patients followed for at

least 1 year were candida mucocutaneous, CMV viraemia/syndrome and

Herpes simplex. The proportion of patients with CMV viraemia/syndrome was

13.5%.

Children (aged 3-months to 18 years)

The type and frequency of adverse reactions in a clinical study of 100 paediatric

patients aged 3 months to 18 years given 600 mg/m

mycophenolate mofetil

orally twice daily, were generally similar to those observed in adult patients

given 1 g mycophenolate mofetil twice daily. However, the following treatment-

related adverse events occurred with a frequency of ≥ 10% in children and were

more frequent in the paediatric population, particularly in children under 6 years

of age, when the frequency of treatment-related adverse events were compared

to adults: diarrhoea, leucopenia, sepsis, infection, anaemia.

Elderly patients (≥ 65 years)

Elderly patients, particularly those who are receiving Myaccord as part of a

combination immunosuppressive regimen, may be at greater increased risk of

certain infections (including cytomegalovirus tissue invasive disease) and

possibly gastrointestinal haemorrhage and pulmonary oedema, compared to

younger individuals (see Warnings and Precautions).

Safety profile of Mycophenolate Mofetil following oral administration

Adverse events reported in ≥ 10% and in 3 to < 10% of patients treated with

mycophenolate mofetil in controlled trials for prevention of renal transplant

rejection (3 trials, 2 g and 3 g data), one controlled cardiac transplant trial, and

one controlled hepatic transplant trial are listed in the table below.

Adverse Events Reported in ≥ 10 % and in 3 % to < 10 % of Patients

Treated with Mycophenolate Mofetil in Clinical Trials in Adults when Used

in Combination with Ciclosporin and Corticosteroids

Body System

Adverse Events

Reported in Renal

Transplant Patients

(n = 991) *

Adverse Events

Reported in Cardiac

Transplant Patients

(n = 289) **

Adverse Events

Reported in Hepatic

Transplant Patients

(n = 277) ***

Body as a

whole

≥ 10%

asthenia, fever,

headache, infection,

pain (includes

abdominal, back, and

chest), oedema, sepsis

asthenia, fever, chills,

headache, infection,

pain (includes

abdominal, back, and

chest), oedema, sepsis

ascites, asthenia,

chills, enlarged

abdomen, fever,

headache, hernia,

infection, pain

(includes abdominal,

back and chest),

oedema, peritonitis,

sepsis

3 - <

cysts (including

lymphocele and

hydrocele), enlarged

abdomen, facial

oedema, flu syndrome,

haemorrhage, hernia,

malaise, pelvic pain

cellulitis, cysts

(including lymphocele

and hydrocele),

enlarged abdomen,

facial oedema, flu

syndrome,

haemorrhage, hernia,

malaise, neck pain,

pallor, pelvic pain

abscess, cellulitis,

cyst (including

lymphocele and

hydrocele), flu

syndrome,

haemorrhage,

malaise, neck pain

Blood and

lymphatic

≥ 10%

anaemia (including

hypochromic

anaemia),

leucocytosis,

leucopenia,

thrombocytopenia

anaemia (including

hypochromic

anaemia), ecchymosis,

leucocytosis,

leucopenia,

thrombocytopenia

anaemia (including

hypochromic

anaemia),

leucocytosis,

leucopenia,

thrombocytopenia

3 - <

ecchymosis,

polycythaemia

petechia, prothrombin

time increased,

thromboplastin time

increased

ecchymosis,

pancytopenia,

prothrombin time

increased

Urogenital

≥ 10%

haematuria, renal

tubular necrosis,

urinary tract infection

abnormal kidney

function (decrease in

renal function, elevated

serum creatinine),

oliguria, urinary tract

infection

abnormal kidney

function (decrease in

renal function,

elevated serum

creatinine), oliguria,

urinary tract infection

3 - <

albuminuria, dysuria,

dysuria, haematuria,

acute renal failure,

Body System

Adverse Events

Reported in Renal

Transplant Patients

(n = 991) *

Adverse Events

Reported in Cardiac

Transplant Patients

(n = 289) **

Adverse Events

Reported in Hepatic

Transplant Patients

(n = 277) ***

hydronephrosis,

impotence,

pyelonephritis, urinary

frequency

impotence, nocturia,

renal failure, urinary

frequency, urinary

incontinence, urinary

retention

dysuria, haematuria

renal failure, scrotal

oedema, urinary

frequency, urinary

incontinence

Cardio-

vascular

≥ 10%

hypertension

arrhythmia,

bradycardia, cardiac

failure, hypertension,

hypotension,

pericardial effusion

hypertension,

hypotension,

tachycardia

3 - <

angina pectoris, atrial

fibrillation,

hypotension, postural

hypotension,

tachycardia,

thrombosis,

vasodilatation

angina pectoris,

arrhythmias (including

supraventricular and

ventricular

extrasystoles, atrial

flutter, supraventricular

and ventricular

tachycardias), atrial

fibrillation, cardiac

arrest, congestive

heart failure, postural

hypotension,

pulmonary

hypertension, syncope,

vasospasm, venous

pressure increased

arterial thrombosis,

atrial fibrillation,

arrhythmia,

bradycardia,

vasodilatation,

syncope

Metabolic/

Nutritional

≥ 10%

hypercholesterolaemia,

hyperglycaemia,

hyperkalaemia,

hypokalaemia,

hypophosphataemia

Acidosis (metabolic or

respiratory),

bilirubinaemia,

elevated BUN,

elevated creatinine,

elevated enzyme

levels (lactic

dehydrogenase, SGOT

and SGPT),

hypercholesterolaemia,

hyperglycaemia,

hyperkalaemia,

hyperlipaemia,

hyperuricaemia,

hypervolaemia,

hypokalaemia,

hypomagnesaemia,

hyponatraemia, weight

gain

bilirubinaemia,

elevated BUN,

elevated creatinine,

healing abnormal,

hyperglycaemia,

hyperkalaemia,

hypocalcaemia,

hypokalaemia,

hypoglycaemia,

hypomagnesaemia,

hypophosphataemia,

hypoproteinaemia,

Body System

Adverse Events

Reported in Renal

Transplant Patients

(n = 991) *

Adverse Events

Reported in Cardiac

Transplant Patients

(n = 289) **

Adverse Events

Reported in Hepatic

Transplant Patients

(n = 277) ***

3 - <

acidosis (metabolic or

respiratory), alkaline

phosphatase

increased,

dehydration, elevated

enzyme levels (gamma

glutamyl

transpeptidase, lactic

dehydrogenase, SGOT

and SGPT), elevated

creatinine,

hypercalcaemia,

hyperlipaemia,

hypervolaemia,

hypocalcaemia,

hypoglycaemia,

hypoproteinaemia,

hyperuricaemia, weight

gain

abnormal healing,

alkaline phosphatase

increased, alkalosis,

dehydration, gout,

hypocalcaemia,

hypochloraemia,

hypoglycaemia,

hypoproteinaemia,

hypophosphataemia,

hypovolaemia,

hypoxia, respiratory

acidosis, thirst, weight

loss

acidosis (metabolic

or respiratory),

alkaline phosphatase

increased,

dehydration, elevated

enzyme levels

(SGOT and SGPT),

hypercholesterolemia

, hyperlipaemia,

hyperphosphataemia,

hypervolaemia,

hyponatraemia,

hypoxia,

hypovolaemia, weight

gain, weight loss

Gastro-

intestinal

≥10%

constipation,

diarrhoea, dyspepsia,

nausea and vomiting,

oral moniliasis

constipation,

diarrhoea, dyspepsia,

flatulence, nausea and

vomiting, oral

moniliasis

elevated liver

function tests (incl.

AST, ALT), anorexia,

cholangitis,

cholestatic jaundice

constipation,

diarrhoea, dyspepsia,

flatulence, hepatitis,

nausea and vomiting,

oral moniliasis

3 - <

elevated liver function

tests (incl. AST, ALT),

anorexia, flatulence,

gastroenteritis,

gastrointestinal

haemorrhage,

gastrointestinal

moniliasis, gingivitis,

gum hyperplasia,

hepatitis, ileus,

oesophagitis,

stomatitis

elevated liver function

tests (incl. AST, ALT),

anorexia, dysphagia,

gastroenteritis,

gingivitis, gum

hyperplasia, jaundice,

melaena, oesophagitis,

stomatitis

dysphagia, gastritis,

gastrointestinal

haemorrhage, ileus,

jaundice, melaena,

mouth ulceration,

oesophagitis, rectal

disorder, stomach

ulcer

Respiratory ≥ 10%

cough increased,

dyspnoea, pharyngitis,

pneumonia, bronchitis

asthma, cough

increased, dyspnoea,

pharyngitis, pleural

effusion, pneumonia,

rhinitis, sinusitis

atelectasis, cough

increased, dyspnoea,

pharyngitis, pleural

effusion, pneumonia,

sinusitis

Body System

Adverse Events

Reported in Renal

Transplant Patients

(n = 991) *

Adverse Events

Reported in Cardiac

Transplant Patients

(n = 289) **

Adverse Events

Reported in Hepatic

Transplant Patients

(n = 277) ***

3 - <

asthma, pleural

effusion, pulmonary

oedema, rhinitis,

sinusitis

apnoea, atelectasis,

bronchitis, epistaxis,

haemoptysis,

hiccough, neoplasm,

pneumothorax,

pulmonary oedema,

sputum increased,

voice alteration

asthma, bronchitis,

epistaxis,

hyperventilation,

pneumothorax,

pulmonary oedema,

respiratory

moniliasis, rhinitis

Skin and

Appendage

≥ 10%

acne, herpes simplex

acne, herpes simplex,

herpes zoster, rash

pruritus, rash,

sweating

3 - <

alopecia, benign

neoplasm of skin,

fungal dermatitis,

herpes zoster,

hirsutism, pruritus, skin

carcinoma, skin

hypertrophy (incl.

actinic keratosis),

sweating, skin ulcer,

rash

benign neoplasm of

skin, fungal dermatitis,

haemorrhage, pruritus,

skin carcinoma, skin

hypertrophy, skin ulcer,

sweating

acne, fungal

dermatitis,

haemorrhage, herpes

simplex, herpes

zoster, hirsutism, skin

benign neoplasm,

skin ulcer,

vesiculobullous rash

Nervous

≥ 10%

dizziness, insomnia,

tremor

agitation, anxiety,

confusion, depression,

dizziness, hypertonia,

insomnia,

paraesthesia,

somnolence, tremor

anxiety, confusion,

depression,

dizziness, insomnia,

paraesthesia, tremor

3 - <

anxiety, depression,

hypertonia,

paraesthesia,

somnolence

convulsion, emotional

lability, hallucinations,

neuropathy, thinking

abnormal, vertigo

agitation, convulsion,

delirium, dry mouth,

hypertonia,

hypesthesia,

neuropathy,

psychosis,

somnolence, thinking

abnormal

Musculo-

skeletal

≥ 10%

leg cramps, myalgia,

myasthenia

3 - <

arthralgia, leg cramps,

myalgia, myasthenia

arthralgia

arthralgia, leg

cramps, myalgia,

myasthenia

osteoporosis

Special

Senses

≥ 10%

amblyopia

3 - <

amblyopia, cataract,

conjunctivitis

abnormal vision,

conjunctivitis,

deafness, ear pain,

abnormal vision,

amblyopia,

conjunctivitis,

Body System

Adverse Events

Reported in Renal

Transplant Patients

(n = 991) *

Adverse Events

Reported in Cardiac

Transplant Patients

(n = 289) **

Adverse Events

Reported in Hepatic

Transplant Patients

(n = 277) ***

eye haemorrhage,

tinnitus

deafness

Endocrine

≥ 10%

3 - <

diabetes mellitus,

parathyroid disorder

(elevated PTH level)

diabetes mellitus,

Cushing's syndrome,

hypothyroidism

diabetes mellitus

*(total n=1,483) ** (total n=578) *** (total n=564)

In the three controlled trials for prevention of renal transplant rejection, patients

receiving 2 g per day of mycophenolate mofetil demonstrated an overall better

safety profile than did patients receiving 3 g mycophenolate mofetil.

Post-Marketing Experience

Gastro-intestinal: colitis (sometimes caused by cytomegalovirus), pancreatitis,

isolated cases of intestinal villous atrophy.

Disorders of immunosuppression: 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 infections such as

tuberculosis and atypical mycobacterial infection.

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.

Cases of pure red cell aplasia (PRCA) have been reported in patients treated

with mycophenolate mofetil in combination with other immunosuppressive

agents.

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.

Congenital disorders: The use of mycophenolate mofetil in combination with

other immunosuppressant agents during pregnancy is associated with an

increased risk of congenital malformations, especially: external ear

abnormalities, facial abnormalities (including cleft lip and palate) and

abnormalities of the distal limbs, heart, oesophagus and kidney.

Other adverse reactions during post-marketing experience with mycophenolate

mofetil are similar to those seen in the controlled renal, cardiac and hepatic

transplant studies.

Overdose

Reports of overdoses with mycophenolate mofetil have been received from

clinical trials and during post-marketing experience. In many of these cases no

adverse events were reported. In those overdose cases in which adverse

events were reported, the events fall within the known safety profile of the

medicine.

It is expected that an overdose of mycophenolate mofetil could possibly result in

oversuppression of the immune system and increase susceptibility to infections

and bone marrow suppression (see Warnings and Precautions). If neutropenia

develops, dosing with Myaccord should be interrupted or the dose reduced (see

Warnings and Precautions).

MPA cannot be removed by haemodialysis. However, at high MPAG plasma

concentrations (> 100 µg/mL), small amounts of MPAG are removed. Bile acid

sequestrants, such as cholestyramine, can remove MPA by increasing

excretion of the medicine (see Pharmacokinetic Properties).

Pharmacological Properties & Effects

Pharmacodynamic Properties

Mechanism of Action

Mycophenolate mofetil (MMF) is the 2-morpholinoethyl ester of mycophenolic

acid (MPA). MPA is a potent, selective, uncompetitive and reversible inhibitor of

inosine monophosphate dehydrogenase (IMPDH), and therefore inhibits the de

novo pathway of guanosine nucleotide synthesis. The mechanism by which

MPA inhibits the enzymatic activity of IMPDH appears to be related to the ability

of MPA to structurally mimic both nicotinamide adenine dinucleotide cofactor

and a catalytic water molecule. This prevents the oxidation of IMP to xanthose-

5'-monophosphate which is the committed step in de novo guanosine

nucleotide biosynthesis. MPA has more potent cytostatic effects on

lymphocytes than on other cells, because T- and B-lymphocytes are critically

dependent for their proliferation on de novo synthesis of purines whereas other

cell types can utilise salvage pathways.

Efficacy / Clinical Studies

Mycophenolate mofetil has been administered in combination with the following

agents in clinical trials for the prevention of renal, cardiac and hepatic rejection

episodes: antithymocyte globulin, OKT3, ciclosporin and corticosteroids. Prior to

treatment with mycophenolate mofetil, patients may have also received

antilymphocyte globulin, antithymocyte globulin and OKT3. Mycophenolate

mofetil has further been used in clinical trials together with daclizumab and

tacrolimus.

Prevention of organ rejection

Adults

The safety and efficacy of mycophenolate mofetil in combination with

corticosteroids and ciclosporin for the prevention of organ rejection were

assessed in renal transplant patients in three randomised, double-blind,

multicentre trials, in cardiac patients in one randomised double-blind,

multicentre trial, and in hepatic patients in one randomised, double-blind,

multicentre trial.

Children

The safety, pharmacokinetics and efficacy of mycophenolate mofetil in

combination with corticosteroids and ciclosporin for the prevention of organ

rejection in paediatric renal transplant patients were assessed in an open-label,

multicentre study in 100 patients (aged 3-months to 18 years).

Renal transplant

Adults

The three studies compared two dose levels of oral mycophenolate mofetil (1 g

bid and 1.5 g bid) with azathioprine (2 studies) or placebo (1 study) when

administered in combination with ciclosporin and corticosteroids to prevent

acute rejection episodes.

The primary efficacy endpoint was the proportion of patients in each treatment

group who experienced treatment failure within the first 6 months after

transplantation (defined as biopsy-proven acute rejection on treatment or the

occurrence of death, graft loss or early termination from the study for any

reason without prior biopsy-proven rejection). Mycophenolate mofetil was

studied in the following three therapeutic regimens: (1) antithymocyte globulin

induction/MMF or azathioprine/ciclosporin/corticosteroids, (2) MMF or

azathioprine/ciclosporin/corticosteroids, and (3) MMF or placebo/ciclosporin/

corticosteroids.

Mycophenolate mofetil, in combination with corticosteroids and ciclosporin

reduced (statistically significant at the < 0.05 level) the incidence of treatment

failure within the first 6 months following transplantation. The following tables

summarise the results of these studies. Patients who prematurely discontinued

treatment were followed for the occurrence of death or graft loss, and the

cumulative incidence of graft loss and patient death are summarised separately.

Patients who prematurely discontinued treatment were not followed for the

occurrence of acute rejection after termination. More patients receiving

mycophenolate mofetil discontinued (without prior biopsy-proven rejection,

death or graft loss) than discontinued in the control groups, with the highest rate

in the mycophenolate mofetil 3 g/day group. Therefore, the acute rejection rates

may be underestimates, particularly in the mycophenolate mofetil 3 g/day

group.

Renal Transplant Studies

Incidence of Treatment Failure

(Biopsy-proven Rejection or Early Termination for Any Reason)

USA Study*

(N=499 patients)

Mycophenolate

Mofetil

2 g/day

(n=167 patients)

Mycophenolate

Mofetil

3 g/day

(n=166 patients)

Azathioprine

1 to 2

mg/kg/day

(n=166

patients)

All treatment failures

31.1%

31.3%

47.6%

Early termination

without prior acute

rejection**

9.6%

12.7%

6.0%

Biopsy-proven

rejection episode on

treatment

19.8%

17.5%

38.0%

* antithymocyte globulin induction/MMF or

azathioprine/ciclosporin/corticosteroids

Europe/Canada/Australia

Study*

(N=503 patients)

Mycophenolate

Mofetil

2 g/day

(n=173

patients)

Mycophenolate

Mofetil

3 g/day

(n=164

patients)

Azathioprine

100 to 150

mg/day

(n=166

patients)

All treatment failures

38.2%

34.8%

50.0%

Early termination without

prior acute rejection**

13.9%

15.2%

10.2%

Biopsy-proven rejection

episode on treatment

19.7%

15.9%

35.5%

* MMF or azathioprine/ciclosporin/corticosteroids

Europe Study*

(N=491 patients)

Mycophenolate

Mofetil

2 g/day

(n=165 patients)

Mycophenolate

Mofetil

3 g/day

(n=160 patients)

Placebo

(n=166

patients)

All treatment failures

30.3%

38.8%

56.0%

Early termination without

prior acute rejection**

11.5%

22.5%

7.2%

Biopsy-proven rejection

episode on treatment

17.0%

13.8%

46.4%

* MMF or placebo/ciclosporin/corticosteroids

** Does not include death and graft loss as reason for early termination.

Cumulative incidence of 12-month graft loss and patient death are presented

below. No advantage of mycophenolate mofetil with respect to graft loss and

patient death was established. Numerically, patients receiving mycophenolate

mofetil 2 g/day and 3 g/day experienced a better outcome than controls in all

three studies; patients receiving mycophenolate mofetil 2 g/day experienced a

better outcome than mycophenolate mofetil 3 g/day in two of the three studies.

Patients in all treatment groups who terminated treatment early were found to

have a poor outcome with respect to graft loss and patient death at 1 year.

Renal Transplant Studies

Cumulative Incidence of Combined Graft Loss

and Patient Death at 12 Months

Study

Mycophenolate

Mofetil

2 g/day

Mycophenolate

Mofetil

3 g/day

Control

(Azathioprine or

Placebo)

8.5%

11.5%

12.2%

Europe/Canada/Australia

11.7%

11.0%

13.6%

Europe

8.5%

10.0%

11.5%

Children (aged 3 months to 18 years)

One open-label, safety, pharmacokinetics and efficacy study of mycophenolate

mofetil in another dose form (powder for oral suspension) in combination with

ciclosporin and corticosteroids for the prevention of renal allograft rejection was

performed in 100 paediatric patients (aged 3 months to 18 years) at centres in

the US (9), Europe (5) and Australia (1). Mycophenolate mofetil was dosed at

600 mg/m

bid (up to 1 g bid) in all age groups.

The primary efficacy endpoint was the proportion of patients experiencing an

acute rejection episode in the first 6 months post transplant. The rate of biopsy-

proven rejection was similar across the age groups (3 months to < 6 years, 6

years to < 12 years, 12 years to 18 years). The overall biopsy-proven rejection

rate at 6 months was comparable to adults. The combined incidence of graft

loss (5%) and patient death (2%) at 12 months post-transplant was similar to

that observed in adult renal transplant patients.

Cardiac transplant

A double-blind, randomised, comparative, parallel-group, multicentre study was

performed in primary cardiac transplant recipients. The total number of patients

enrolled was 650; 72 never received the study medicine and 578 received the

study medicine. Patients received mycophenolate mofetil 1.5 g bid (n=289) or

azathioprine 1.5 to 3 mg/kg/day (n=289), in combination with ciclosporin and

corticosteroids as maintenance immunosuppressive therapy. The two primary

efficacy endpoints were: (1) the proportion of patients who, after transplantation,

had at least one endomyocardial biopsy-proven rejection with haemodynamic

compromise, or were retransplanted or died, within the first 6 months, and (2)

the proportion of patients who died or were transplanted during the first 12

months following transplantation. Patients who prematurely discontinued

treatment were followed for the occurrence of allograft rejection for up to 6

months and for the occurrence of death for 1 year.

Rejection: No difference was established between mycophenolate mofetil

and azathioprine (AZA) with respect to biopsy-proven rejection with

haemodynamic compromise, as presented below.

Rejection at 6 Months

All Patients

Treated Patients

AZA

N = 323

Mycophenolat

e Mofetil

N = 327

AZA

N = 289

Mycophenolat

e Mofetil

N = 289

Biopsy-proven

rejection with

haemodynami

c compromise*

121 (38%

120 (37%)

100 (35%

92 (32%)

* Haemodynamic compromise occurred if any of the following criteria were

met: pulmonary capillary wedge pressure ≥ 20mm or a 25% increase;

cardiac index < 2.0 l/min/m

or a 25% decrease; ejection fraction ≤30%;

pulmonary artery oxygen saturation ≤ 60% or a 25% decrease; presence of

new S

gallop; fractional shortening was ≤ 20% or a 25% decrease; inotropic

support required to manage the clinical condition.

Survival: In the enrolled patients, there were no statistically significant

differences between patients randomised to MMF and patients

randomised to AZA for death and retransplantation. In patients who

received study medicine, the lower limit of the 97.5% confidence interval

of the difference of death and retransplantation was 0.9 at 1 year,

indicating that MMF was superior to AZA in these patients, as presented

below.

Death or Retransplantation at 1 Year

All Patients

Treated Patients

AZA

N = 323

Mycophenolat

e Mofetil

N = 327

AZA

N = 289

Mycophenolat

e Mofetil

N = 289

Death or

Retransplantatio

49 (15.2%

42 (12.8%)

33 (11.4%

18 (6.2%)

Weighted

Treatment

Difference

2.6%

5.3%

Lower Limit of

97.5% one-

sided

Confidence

Interval

-2.5%

+0.9%

Hepatic transplant

A double-blind, randomised, comparative, parallel-group, multicentre study in

primary hepatic transplant recipients was performed at 16 centres in the United

States, 2 in Canada, 4 in Europe and 1 in Australia. The total number of

patients enrolled was 565 and 564 received study medicine. Patients either

received mycophenolate mofetil 1 g bid intravenously for up to 14 days followed

by mycophenolate mofetil 1.5 g bid orally or azathioprine 1 mg - 2 mg/kg/day

intravenously followed by azathioprine 1 mg - 2 mg/kg/day orally, in combination

with ciclosporin and corticosteroids as maintenance immunosuppressive

therapy. The two primary endpoints were: (1) the proportion of patients who

experienced, in the first 6 months post transplantation, one or more episodes of

biopsy-proven and treated rejection or death/retransplantation, and (2) the

proportion of patients who experienced 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. Results:

In the primary (intent-to-treat) analyses mycophenolate mofetil in combination

with corticosteroids and ciclosporin was superior to azathioprine for prevention

of acute rejection (p = 0.025) and equivalent to azathioprine for survival.

Rejection at 6 Months /

Death or Retransplantation at 1 Year

AZA

N = 287

Mycophenolate Mofetil

N = 278

Biopsy proven, treated rejection

at 6 months

137 (47.7%)

107 (38.5%)

Death or retransplantation at 1 year

42 (14.6%)

41 (14.7%)

Treatment of refractory organ rejection

A randomised, open-label comparison study of MMF 3 g per day against

intravenous corticosteroids was conducted in 150 renal transplant recipients

with refractory, acute, cellular allograft rejection. The primary endpoint was the

proportion of patients who were still alive with a functioning graft at 6 months

after study entry.

Results: The incidence of graft loss in the control group was unexpectedly low

and the primary analysis, based on the sequential probability ratio test showed

a trend toward improved graft survival in the MMF group (p = 0.081). A

secondary analysis, using the Cochran-Mantel-Haenzel test (not adjusted for

sequential monitoring) suggested a 45% reduction in the incidence of graft loss

or death at 6 months after study entry in the MMF arm (p = 0.062).

Graft Loss or Death at 6 Months

IV Steroids

N = 73

Mycophenolate Mofetil

N = 77

Graft Loss or death at 6 months

19 (26.0%)

11 (14.3%)

Pharmacokinetic Properties

The pharmacokinetics of MMF have been studied in renal, cardiac and hepatic

transplant patients.

In general, the pharmacokinetic profile of MPA is similar in renal and in cardiac

transplant patients. In the early transplant period, hepatic transplant patients

receiving a 1.5 g oral MMF dose or 1 g IV MMF dose have similar MPA levels

compared to renal transplant patients receiving 1 g oral or IV MMF.

Absorption

Following oral and intravenous administration, mycophenolate mofetil

undergoes rapid and extensive absorption and complete presystemic

metabolism to the active metabolite, MPA. The mean bioavailability of oral

mycophenolate mofetil, based on MPA AUC, is 94% relative to intravenous

mycophenolate mofetil. Mycophenolate mofetil can be measured systemically

during intravenous infusion; however, after oral administration it is below the

limit of quantitation (0.4 mcg/ml).

Immediately post-transplant (< 40 days) renal, cardiac and hepatic transplant

patients had mean MPA AUCs approximately 30% lower and Cmax

approximately 40% lower compared to the late transplant period (3 to 6 months

post-transplant). MPA AUC values obtained following administration of 1 g bid

intravenous mycophenolate mofetil at the recommended infusion rate to renal

patients in the immediate post-transplant phase are comparable to those

observed following oral dosing. In hepatic transplant patients, administration of

1 g bid intravenous mycophenolate mofetil followed by 1.5 g bid oral

mycophenolate mofetil resulted in MPA AUC values similar to those found in

renal transplant patients administered 1 g mycophenolate mofetil bid.

Food had no effect on the extent of absorption (MPA AUC) of mycophenolate

mofetil administered at doses of 1.5 g bid to renal transplant patients. However,

MPA Cmax was decreased by 40% in the presence of food.

Distribution

Secondary increases in plasma MPA concentrations are usually observed at

approximately 6-12 hours post-dose, consistent with enterohepatic recirculation.

A reduction of approximately 40% in the AUC of MPA is associated with

coadministration of cholestyramine (4 g tid), consistent with interruption of

enterohepatic recirculation.

At clinically relevant concentrations, MPA is 97% bound to plasma albumin.

Metabolism

MPA is conjugated primarily with glucuronyl transferase to form the phenolic

glucuronide of MPA (MPAG), which is not pharmacologically active. In vivo,

MPAG is converted to free MPA via enterohepatic recirculation.

Elimination

Oral administration of radiolabelled mycophenolate mofetil resulted in complete

recovery of the administered dose, with 93% of the dose recovered in the urine

and 6% recovered in the faeces. Most (about 87%) of a dose is excreted in the

urine as MPAG. A negligible amount of medicine (< 1% of dose) is excreted as

MPA in the urine.

At clinically encountered concentrations, MPA and MPAG are not removed by

haemodialysis. However, at high MPAG concentrations (> 100 mcg/mL), small

amounts of MPAG are removed. By interfering with enterohepatic circulation of

the medicine, bile acid sequestrants, such as cholestyramine, reduce MPA AUC

(see Overdose).

Bioequivalence

Bioequivalence of mycophenolate mofetil oral dosage forms have been

evaluated. Two 500 mg tablets have been shown to be bioequivalent to four

250 mg capsules.

Pharmacokinetics in Special Populations

Patients with severe renal impairment

In a single-dose study (6 subjects per group), mean plasma MPA AUCs

observed after oral dosing in subjects with severe chronic renal impairment

(glomerular filtration rate < 25 ml/min/1.73m

) were 28 to 75% higher than those

observed in normal healthy subjects or subjects with lesser degrees of renal

impairment. However, the mean single-dose MPAG AUC was 3- to 6-fold higher

in subjects with severe renal impairment than in subjects with mild renal

impairment and normal healthy subjects, consistent with the known renal

elimination of MPAG.

Multiple dosing of mycophenolate mofetil in patients with severe chronic renal

impairment has not been studied.

Patients with delayed renal graft function post-transplant

In patients with delayed renal graft function post-transplant, mean MPA AUC

0-12

was comparable to that seen in post-transplant patients without delayed renal

graft function. There may be a transient increase in the free-fraction and

concentration of plasma MPA in patients with delayed renal graft function. Dose

adjustment of mycophenolate mofetil does not appear to be necessary (see

Special Dosage Instructions). Mean plasma MPAG AUC

0-12

was 2- to 3-fold

higher than in post-transplant patients without delayed renal graft function.

In patients with primary non-functioning graft following renal transplantation,

plasma concentrations of MPAG accumulated; accumulation of MPA, if any,

was much smaller.

Patients with hepatic impairment

Overall, the pharmacokinetics of MPA and MPAG were relatively unaffected by

hepatic parenchymal disease in volunteers with alcoholic cirrhosis dosed with

oral or intravenous MMF. 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.

Children (aged ≤ 18 years)

Pharmacokinetic parameters were evaluated in 55 paediatric renal transplant

patients (ranging from 1 to 18 years of age) given 600 mg/m

mycophenolate

mofetil orally twice daily (up to a maximum of 1 g twice daily). This dose

achieved MPA AUC values similar to those seen in adult renal transplant

patients receiving mycophenolate mofetil at a dose of 1 g twice daily in the early

and late post transplant period. MPA AUC values across age groups were

similar in the early and late post-transplant period.

Elderly (≥ 65 years)

Pharmacokinetics in the elderly has not been formally evaluated.

Preclinical Safety

The haematopoietic and lymphoid systems were the primary organs affected in

toxicology studies conducted with mycophenolate mofetil in the rat, mouse, dog

and monkey. These effects occurred at systemic exposure levels that are

equivalent to or less than the clinical exposure at the recommended dose of 2

g/day for renal transplant recipients. Gastrointestinal effects were observed in

the dog at systemic exposure levels equivalent to or less than the clinical

exposure at the recommended doses. Gastrointestinal and renal effects

consistent with dehydration were also observed in the monkey at the highest

dose (systemic exposure levels equivalent to or greater than clinical exposure).

The nonclinical toxicity profile of mycophenolate mofetil appears to be

consistent with adverse events observed in human clinical trials which now

provide safety data of more relevance to the patient population (see

Undesirable Effects).

Mycophenolate mofetil had no effect on fertility of male rats at oral doses up to

20 mg/kg/day. The systemic exposure at this dose represents 2 to 3 times the

clinical exposure at the recommended clinical dose of 2 g/day in renal

transplant patients and 1.3 to 2 times the clinical exposure at the recommended

clinical dose of 3 g/day in cardiac transplant patients. In a female fertility and

reproduction study conducted in rats, oral doses of 4.5 mg/kg/day caused

malformations (including anophthalmia, agnathia, and hydrocephaly) in the first

generation offspring in the absence of maternal toxicity. The systemic exposure

at this dose was approximately 0.5 times the clinical exposure at the

recommended clinical dose of 2 g/day for renal transplant patients and

approximately 0.3 times the clinical exposure at the recommended clinical dose

of 3 g/day for cardiac transplant patients. No effects on fertility or reproductive

parameters were evident in the dams or in the subsequent generation.

In teratology studies in rats and rabbits, foetal resorptions and malformations

occurred in rats at 6 mg/kg/day (including anophthalmia, agnathia, and

hydrocephaly) and in rabbits at 90 mg/kg/day (including cardiovascular and

renal anomalies, such as ectopia cordis and ectopic kidneys, and diaphragmatic

and umbilical hernia), in the absence of maternal toxicity. The systemic

exposure at these levels are approximately equivalent to or less than 0.5 times

the clinical exposure at the recommended clinical dose of 2 g/day for renal

transplant patients and approximately 0.3 times the clinical exposure at the

recommended clinical dose of 3 g/day for cardiac transplant patients see

Pregnancy and Nursing mothers).

In experimental models, mycophenolate mofetil was not tumourigenic. The

highest dose tested in the animal carcinogenicity studies resulted in

approximately 2 - 3 times the systemic exposure (AUC or Cmax) observed in

renal transplant patients at the recommended clinical dose of 2 g/day and 1.3 -

2 times the systemic exposure (AUC or Cmax) observed in cardiac transplant

patients at the recommended clinical dose of 3 g/day. Two genotoxicity assays

(the mouse lymphoma/thymidine kinase assay and the mouse micronucleus

aberration assay) indicated a potential of mycophenolate mofetil to cause

chromosomal instability at severely cytotoxic dose levels. Other genotoxicity

tests (the bacterial mutation assay, the yeast mitotic gene conversion assay or

the Chinese hamster ovary cell chromosomal aberration assay) did not

demonstrate mutagenic activity.

Pharmaceutical Particulars

List of Excipients

Myaccord capsules 250 mg: contains the excipients cellulose microcrystalline

(Avicel PH 101), hydroxyl propyl cellulose, povidone K-90, croscarmellose

sodium, talc, magnesium stearate and purified water. The capsule shells

contain gelatin, FD & C blue, iron oxide yellow, iron oxide red, titanium dioxide,

sodium lauryl sulphate and purified water. The printing ink contains black iron

oxide, potassium hydroxide, shellac, dehydrated alcohol, isopropyl alcohol,

butyl alcohol, propylene glycol, strong ammonia solution and purified water.

Myaccord tablets 500 mg: contains the excipients microcrystalline cellulose,

croscarmellose sodium, povidone, talc, magnesium stearate, hydroxypropyl

cellulose, opadry 03B50110 purple and purified water.

Stability

This medicine should not be used after the expiry date shown on the pack. The

shelf-life of Myaccord 250 mg capsules is 3 years. The shelf-life of Myaccord

500 mg tablets is 3 years.

Special Remarks

Special Precautions for Storage

Myaccord capsules: Store below 25°C, store in the original package.

Myaccord tablets: Store below 25°C, store in the original container.

Instructions for Use, Handling and Disposal

Myaccord oral administration

Because mycophenolate mofetil has demonstrated teratogenic effects in rats

and rabbits (see Pregnancy and Nursing mothers), Myaccord tablets should not

be crushed or divided, and Myaccord capsules should not be opened or

crushed. Avoid inhalation or direct contact with skin or mucous membranes of

the powder contained in Myaccord capsules. If such contact occurs, wash

thoroughly with soap and water; rinse eyes with plain water.

Packs

Myaccord 250 mg capsules: Packs of 30, 90 and 100.

Myaccord 500 mg tablets: Packs of 50 and 100.

Medicine Classification

Prescription Medicine

Name and Address

Douglas Pharmaceuticals Ltd

P O Box 45 027

Auckland 0651

New Zealand

Phone: (09) 835 0660

Fax: (09) 835 0665

Date of Preparation

28 August 2015

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