MIRCERA DESCRIPTION. Methoxy polyethylene glycol-epoetin beta. CAS registry number:

Transcription

1 Copy fom GRASS MIRCERA Methoxy polyethylene glycol-epoetin beta CAS egisty numbe: DESCRIPTION MIRCERA (methoxy polyethylene glycol-epoetin beta) is a chemically synthesised Eythopoiesis Stimulating Agent (ESA) with a much longe half-life than eythopoietin. It is poduced by ecombinant DNA technology in Chinese Hamste Ovay (CHO) cells and diffes fom eythopoietin though the integation of an amide bond between eithe the N- teminal amino goup o the ε-amino goup of lysine, pedominantly Lys 52 and Lys 45 and methoxy polyethylene glycol butanoic acid. This esults in a molecula weight of appoximately 60 kda with the polyethylene glycol-moiety having an appoximate molecula weight of 30 kda. The dosage stength in µg indicates the quantity of the potein moiety of the methoxy polyethylene glycol-epoetin beta molecule without consideation of glycosylation. MIRCERA is available in pefilled syinges containing a steile, pesevative-fee solution with the following excipients; sodium phosphate-monobasic, monohydate; sodium sulfate; mannitol; methionine; Poloxame 188 and wate fo injection. The solution is clea, colouless to slightly yellowish and the ph is 6.2. Micea PI of 15

2 PHARMACOLOGY Copy fom GRASS Phamacodynamics MIRCERA shows diffeent activity to eythopoietin at the ecepto level. It is chaacteised by slowe association to the ecepto and slightly faste dissociation, esulting in a lowe affinity fo the ecepto. This lowe affinity may esult in less ecepto-mediated endocytosis and contibute togethe with educed subsequent lysosomal degadation and/o inceased ecycling to the slowe elimination. MIRCERA thus has a longe half-life than eythopoietin which enables MIRCERA to be administeed in a once monthly dosing egimen. Eythopoietin is a gowth facto fo eythoid development. It is poduced in the kidney and eleased into the bloodsteam in esponse to hypoxia, inteacting with eythoid pogenito cells to incease ed blood cell poduction. Poduction of endogenous eythopoietin is impaied in patients with chonic kidney disease (CKD), and eythopoietin deficiency is the pimay cause of thei anaemia. The onset of haemoglobin incease (defined as an incease > 4 g/l fom baseline) is obseved in CKD patients afte 7 to 15 days following a single dose of MIRCERA. Phamacokinetics The phamacokinetics of MIRCERA was studied in healthy voluntees and in anaemic CKD patients, including patients on dialysis and not on dialysis. A compaison of seum concentations of MIRCERA measued befoe and afte haemodialysis in 41 CKD patients showed that haemodialysis had no effect on MIRCERA seum concentations in-vivo. The esults of a study in 42 healthy voluntees indicated that the site of subcutaneous (SC) injection (abdomen, am o thigh) had no clinically elevant effect on the phamacokinetics, phamacodynamics, o local toleability of MIRCERA. Based on these esults, all thee sites ae consideed suitable fo SC injection with MIRCERA. An analysis in 126 CKD patients showed no phamacokinetic diffeence between patients on dialysis and patients not on dialysis. Multiple dosing in CKD patients was found to have no effect on the cleaance, volume of distibution and bioavailability of MIRCERA. Absoption and Bioavailability Following SC administation in CKD patients, the maximum seum concentations of MIRCERA wee obseved 72 hous (median value) afte administation. The absolute bioavailability of MIRCERA afte SC administation was 62% and 54%, in dialysis patients and patients not on dialysis, espectively. Distibution A study in 400 CKD patients showed that the volume of distibution of MIRCERA is appoximately 5 L. Afte administation evey 4 weeks in CKD patients, thee was vitually no accumulation of MIRCERA, as demonstated by a atio of accumulation of Afte administation evey 2 weeks, the atio of accumulation in seum was Micea PI of 15

3 Copy fom GRASS Elimination The phamacokinetic and the phamacological popeties of MIRCERA allow fo monthly administation due to the longe elimination half-life. The elimination half-life afte intavenous (IV) administation of MIRCERA is 15 to 20 times longe compaed to ecombinant human eythopoietin. Following IV administation in CKD patients, the obseved teminal elimination half-life (t 1/2 ) fo MIRCERA was 134 hous, and the total systemic cleaance was ml/h/kg. Following SC administation the t 1/2 was 139 hous. Data on methoxy polyethylene glycol-epoetin beta metabolism in animals is not available. In at, both unchanged methoxy polyethylene glycol-epoetin beta (about 1% of administeed dose) and polyethylene glycol-like mateial wee found in uine. In humans, it is unknown whethe a significant popotion of methoxy polyethylene glycol-epoetin beta is catabolised. In clinical tials with healthy voluntees, unchanged methoxy polyethylene glycol-epoetin beta was not detected in the uine. Due to its high molecula weight, enal excetion of methoxy polyethylene glycol-epoetin beta would not be expected. Phamacokinetics in Special Populations Population analyses evaluated the potential effects of demogaphic chaacteistics on the phamacokinetics of MIRCERA. Results of these analyses showed that no dose adjustments ae necessay fo age, gende, o ace. Fom a single dose study, it was shown that following IV administation, the phamacokinetics of MIRCERA ae simila in patients with sevee hepatic impaiment compaed to healthy subjects. CLINICAL TRIALS Chonic Kidney Disease The safety and efficacy of MIRCERA have been assessed in six phase III andomised, multicente clinical studies fo the teatment of anaemia in adult patients associated with CKD including patients on dialysis and not on dialysis. Two studies evaluated the safety and efficacy of MIRCERA in CKD patients not cuently teated with an ESA and fou studies assessed the ability of MIRCERA to maintain haemoglobin concentations in CKD patients who had been eceiving an ESA. Micea PI of 15

4 Copy fom GRASS Patients Not Cuently Teated with an Eythopoiesis Stimulating Agent (ESA) Table 1: Summay of phase III tials in anaemic CKD patients not cuently teated with an ESA ARCTOS (n = 324) AMICUS (n = 181) Study design / Patient goup Open label, andomised CKD patients not on dialysis Open label, andomised CKD patients on dialysis No pio ESA teatment Patient numbes MIRCERA (n = 162) Dabepoetin alfa (n = 162) Duation of teatment Route / Stating dose / Dosage egimen 52 wk 28 wk initiation, 24 wk maintenance MIRCERA: SC: 0.6 µg/kg Initiation: q2w Maintenance: q2w o q4w No pio ESA teatment MIRCERA (n = 135) Epo alfa o epo beta (n = 46) 52 wk 24 wk initiation, 28 wk maintenance MIRCERA: IV: 0.4 µg/kg Initiation: q2w Maintenance: q2w o q4w Efficacy esults Dabepoetin alfa: SC: 0.45 µg/kg Initiation: q1w Maintenance: q1w o q2w Taget Hb-110 to 130 g/l. Hb esponse* MIRCERA-97. (9 CI: 93.8, 99.3) Dabepoetin alfa-96.3% (9 CI: 92.1, 98.6) Hb change fom baseline MIRCERA-21.5 g/l Dabepoetin alfa-19.9 g/l (p < ) Incidence of RBC tansfusion MIRCERA-2. Dabepoetin alfa-6. Epo alfa o epo beta IV: dose pe label Initiation & maintenance: 3x/wk Taget Hb-110 to 130 g/l. Hb esponse* MIRCERA-93% (9 CI: 87.7, 96.9) Epo alfa o epo beta-91% (9 CI: 79.2, 97.6) Incidence of RBC tansfusion MIRCERA-5.2% Epo alfa o beta-4.3% * Hb esponse defined as at least a 10 g/l incease in Hb concentation to a level of at least 110 g/l without RBC tansfusion. CKD = Chonic Kidney Disease, ESA = Eythopoiesis Stimulating Agent, q1w = once weekly, q2w = once evey two weeks, Hb = haemoglobin, RBC = ed blood cell, Epo = epoetin, IV = intavenous, SC = subcutaneous, wk = week, CI = confidence inteval. The change in haemoglobin levels (fom baseline) obseved in these clinical tials demonstated MIRCERA to be clinically non-infeio to dabepoetin alfa (p < ). Fo both tials the obseved median dose of MIRCERA (once evey two weeks) was 0.6 µg/kg. A lowe popotion of patients teated with MIRCERA expeienced a haemoglobin level geate than 130 g/l duing the fist 8 weeks of teatment compaed to the efeence ams in both studies (7. in the MIRCERA goup compaed to 17. fo epoetin alfa o beta and 34% in the dabepoetin alfa am compaed to 11.4% fo MIRCERA). Micea PI of 15

5 Copy fom GRASS Patients Cuently Teated with an Eythopoiesis Stimulating Agent (ESA) CKD patients cuently eceiving an ESA wee andomised to stay on thei cuent teatment o switched to MIRCERA to maintain stable haemoglobin levels. Fo patients andomised to eceive MIRCERA (eithe once evey two weeks o once evey fou weeks) the initial dose was detemined based on the patient s pevious weekly ESA dose. Table 2: Summay of phase III tials in anaemic CKD patients cuently eceiving an ESA MAXIMA (n = 673) PROTOS (n = 572) STRIATA (n = 313) RUBRA (n = 336) Open-label, andomised Open-label, andomised Open-label, andomised CKD dialysis patients CKD dialysis patients CKD dialysis patients with stable Hb* with stable Hb* with stable Hb* eceiving epo (IV) eceiving epo (SC) on dabepoetin (IV) Study design / Patient goup Patient numbes Duation of teatment Route / Dosage egimen MIRCERA (n = 447) Epo alfa o epo beta (n = 226) MIRCERA (n = 381) Epo alfa o epo beta (n = 191) MIRCERA (n = 157) Dabepoetin alfa (n = 156) 52 wk 52 wk 52 wk 36 wk MIRCERA: IV: 30, 50, o 90 µg/wk. q2w, q4w MIRCERA: SC: 30, 50, o 90 µg/wk. q2w, q4w MIRCERA: IV: 60, 100, o 180 µg/ q2w Open-label, andomised CKD dialysis patients with stable Hb* eceiving epo (SC o IV) MIRCERA (n = 168) Epo alfa o epo beta (n = 168) MIRCERA: IV o SC: 60, 100, o 180 µg/q2w Epo alfa o epo beta IV at pevious dose and schedule Epo alfa o epo beta SC at pevious dose and schedule Dabepoetin alfa IV at pevious dose and schedule Epo alfa o epo beta IV o SC: at pevious dose and schedule Efficacy esults No diffeence in Hb change fom baseline (p < ) No diffeence in Hb change fom baseline (p < ) * stable Hb baseline Hb concentation between 105 and 130 g/l No diffeence in Hb change fom baseline (p < ) No diffeence in Hb change fom baseline (p < ) CKD = Chonic Kidney Disease, ESA = Eythopoiesis Stimulating Agent, q2w = once evey two weeks, q4w = once evey 4 weeks, Hb = haemoglobin, Epo = epoetin, IV = intavenous, SC = subcutaneous, wk = week. The esults fom these studies demonstated the ability of MIRCERA to maintain haemoglobin concentations within the study taget ange of g/l. The most fequently epoted advese effect in clinical tials (both compaatos and MIRCERA) was hypetension (see PRECAUTIONS). Othe Clinical Tials In a andomised, placebo-contolled, single-blind, thee-way cossove study, pain scoes afte SC injection with MIRCERA wee simila to placebo and significantly less compaed to othe ESAs. Micea PI of 15

6 Copy fom GRASS INDICATIONS MIRCERA is indicated fo the teatment of anaemia associated with chonic kidney disease (CKD). CONTRAINDICATIONS MIRCERA is containdicated in patients with: Uncontolled hypetension. Known hypesensitivity to the active substance o any of the excipients. PRECAUTIONS Cadiovascula and Thombotic Events / Inceased Motality Cadiovascula and thombotic events such as myocadial ischaemia and infaction, ceebovascula haemohage and infaction, tansient ischaemic attacks, deep venous thombosis, ateial thombosis, pulmonay emboli, etinal thombosis and haemodialysis gaft occlusion have been epoted in patients eceiving ESAs. In contolled clinical tials, ESAs inceased the isk fo death in oncology patients and fo seious cadiovascula events in oncology and CKD patients when administeed to taget a haemoglobin of > 120 g/l. Thee was an inceased isk of seious ateial and venous thomboembolic events, including myocadial infaction, stoke, congestive heat failue and haemodialysis gaft occlusion. A ate of haemoglobin ise of > 10 g/l ove 2 weeks may also contibute to these isks. MIRCERA is not appoved fo the teatment of anaemia in patients with cance. To educe cadiovascula isks, use the lowest dose of MIRCERA that will gadually incease the haemoglobin concentation. The haemoglobin concentation should not exceed 120 g/l and the ate of haemoglobin incease should not exceed 10 g/l in a 2 week peiod. Haemoglobin levels should be checked at egula intevals and dosages adjusted (see DOSAGE and ADMINISTRATION). Gowth Facto Potential / Inceased Tumou Pogession MIRCERA, like othe ESAs, is a gowth facto that pimaily stimulates ed blood cell (RBC) poduction. As with all gowth factos, thee is a theoetical concen that epoetins could act as a gowth facto fo any type of malignancy. ESAs, when administeed to taget haemoglobin of > 120 g/l, shotened the time to tumou pogession in patients with advanced head and neck cance eceiving adiation theapy. ESAs also shotened suvival in patients with metastatic beast cance eceiving chemotheapy when administeed to a taget haemoglobin of > 120 g/l. MIRCERA is not appoved fo the teatment of anaemia in patients with cance. Micea PI of 15

7 Copy fom GRASS Hypetension Patients with uncontolled hypetension should not be teated with MIRCERA; blood pessue should be adequately contolled befoe initiation of theapy. Blood pessue may ise duing teatment of anaemia with MIRCERA as with othe ESAs. Hypetensive encephalopathy and seizues have been obseved in patients teated with MIRCERA as with othe ESAs. Special cae should be taken to closely monito and contol blood pessue in patients teated with MIRCERA. Duing MIRCERA theapy, patients should be advised of the impotance of compliance with antihypetensive theapy and dietay estictions. If blood pessue is difficult to contol afte initiation of appopiate measues, the dose of MIRCERA should be educed o tempoaily withheld until haemoglobin begins to decease (see DOSAGE and ADMINISTRATION). Pue Red Cell Aplasia (PRCA) PRCA caused by neutalising anti-eythopoietin antibodies has been epoted in association with ESA theapy. These antibodies have been shown to coss-eact with all eythopoietic poteins, and patients suspected o confimed to have neutalising antibodies to eythopoietin should not be switched to MIRCERA. No cases of PRCA wee epoted in MIRCERA clinical tials. If anti-eythopoietin antibody-mediated PRCA develops whilst on MIRCERA, theapy with MIRCERA must be discontinued and patients should not be switched to anothe ESA. Seizues ESAs should be used with caution in patients with epilepsy. Geneal The safety and efficacy of MIRCERA theapy have not been established in patients with haemoglobinopathies o with a platelet level geate than 500 x 10 9 /L. Theefoe, caution should be used in these patients. Supplementay ion theapy is ecommended fo all patients with seum feitin values below 100 µg/l o whose tansfein satuation is below 20%, as pe Caing fo Austalasians with Renal Impaiment (CARI) Guidelines. To ensue effective eythopoiesis, ion status should be evaluated fo all patients pio to, and duing teatment. A lack of esponse o failue to maintain haemoglobin esponse with MIRCERA within the ecommended dose ange should pompt a seach fo causative factos. Deficiencies of ion, folic acid, and vitamin B 12 should be excluded o coected. The following conditions may also compomise the effectiveness of ESA theapy: chonic blood loss, bone maow fibosis, haemolysis, and sevee aluminium oveload due to teatment of enal failue. If all these conditions ae excluded and the patient has a sudden dop of haemoglobin associated with eticulocytopenia and anti-eythopoietin antibodies, examination of the bone maow fo the diagnosis of PRCA should be consideed. If PRCA is diagnosed, theapy with MIRCERA must be discontinued and patients should not be switched to anothe ESA. Effects on Fetility When MIRCERA was administeed subcutaneously to male and female ats pio to, and duing mating, at 6 times the clinical systemic exposue, based on AUC values, fetility, and spem count and motility wee not affected. Micea PI of 15

8 Copy fom GRASS Use in Pegnancy-Categoy B3 Methoxy polyethylene glycol-epoetin beta cossed the at placenta and was distibuted to foetal tissues, paticulaly the epoductive ogans, spleen and kidneys. A eduction in foetal weights occued in ats and abbits at systemic exposues 1 to 3 times clinical exposue, with an incease in evesible developmental delays, such as incomplete ossification, in both species. In abbits thee was an incease in the incidence of flat ibs at 29 times the clinical systemic exposue (based on AUC values). All doses tested in both species caused exaggeated phamacodynamic effects in dams. Post-implantation loss was inceased in abbits and sometimes in ats. MIRCERA should be used duing pegnancy only if the potential benefit justifies the potential isk to the foetus. Use in Lactation It is unknown whethe MIRCERA is exceted in human beast milk. Methoxy polyethylene glycol-epoetin beta was exceted into the milk of ats. MIRCERA teatment of lactating ats was associated with some advese effects on the offsping, which included educed pup bodyweight gain, developmental delay, slightly inceased pup motality, inceased incidence of pale lives and/o lungs and an incease in the incidence of abdominal distension post weaning. A decision on whethe to discontinue beast-feeding o theapy with MIRCERA should be made taking into account the benefit of MIRCERA theapy to the woman and the potential isks to the child. Paediatic Use MIRCERA is not ecommended fo use in patients aged less than 18 yeas due to a lack of data on safety and efficacy. Use in the Eldely Of the 1789 CKD patients teated with MIRCERA in clinical tials, 24% wee aged 65 to 74 yeas, while 20% wee aged 75 yeas and ove. Based on population analyses, no adjustment of the stating dose is equied in patients aged 65 yeas o olde. Cacinogenicity The cacinogenic potential of MIRCERA has not been evaluated in long-tem animal studies. As with all gowth factos, thee is a concen that ESAs could stimulate the gowth of any type of malignancy (see PRECAUTIONS, Gowth Facto Potential/Inceased Tumou Pogession). Genotoxicity The genotoxic potential of MIRCERA has not been evaluated. Inteactions with Othe Medicines No inteaction studies have been pefomed. The esults fom clinical tials do not indicate any inteaction of MIRCERA with othe medicinal poducts. Thee was no indication of an effect of concomitant medications on the phamacokinetics and phamacodynamics of MIRCERA using a population analysis appoach. Micea PI of 15

9 Copy fom GRASS Ability to Dive and Use Machines No studies on the effects on the ability to dive and use machines have been pefomed. Howeve, no effects ae expected based on the mechanism of action and the known safety pofile of MIRCERA. Effects on Laboatoy Tests Platelet counts and thombocytopenia Duing teatment with MIRCERA, a slight decease (median 5.) in platelet counts, emaining within the nomal ange, was obseved in clinical studies. The decline was obseved afte the fist dose and thee was a patial ecovey ove the couse of the studies. A platelet count below 100 x 10 9 /L was obseved in 9.0% of patients teated with MIRCERA and 6.2% of patients teated with othe ESAs. ADVERSE EFFECTS The safety database fo MIRCERA (based on data fom the completed phase II and III studies and long-tem follow-up infomation fom safety extension studies) compised of 2737 CKD patients, whee 1789 wee teated with MIRCERA and 948 with anothe ESA. Based on the esults of 1789 patients, appoximately of patients teated with MIRCERA expeienced advese eactions. The most fequently epoted advese eaction was hypetension. Advese events (iespective of causal elationship) with incidence in patients teated with MIRCERA o a efeence dug (epoetin o dabepoetin alfa) ae pesented in Table 3. Micea PI of 15

10 Copy fom GRASS Table 3 Advese events (iespective of causal elationship) occuing in of CKD patients Advese Event VASCULAR Hypetension Hypotension GASTROINTESTINAL Diahoea Vomiting Constipation Nausea Abdominal Pain Dyspepsia INFECTIONS AND INFESTATIONS Nasophayngitis Uppe Respiatoy Tact Infection Uinay Tact Infection Bonchitis Pneumonia Influenza Gastoenteitis NERVOUS SYSTEM Headache Dizziness INJURY, POISONING AND PROCEDURAL COMPLICATIONS Pocedual Hypotension Ateiovenous Fistula Thombosis Ateiovenous Fistula Site Complication Ateiovenous Gaft Thombosis Ateiovenous Fistula Site Haemohage Contusion MUSCULOSKELETAL AND CONNECTIVE TISSUE Muscle Spasms Back Pain Pain in Extemity Athalgia RESPIRATORY, THORACIC AND MEDIASTINAL Cough Dyspnoea METABOLISM AND NUTRITION Fluid Oveload Hypekalaemia Hypoglycaemia GENERAL AND ADMINISTRATION SITE COMPLICATIONS Pyexia Oedema Peipheal Asthenia MIRCERA (n = 1789) 1 1 4% 1 11% 13% 13% 4% 11% 10% 10% Epoetin o Dabepoetin alfa (n = 948) 21% 1 11% 1 12% 10% SKIN AND SUBCUTANEOUS TISSUE DISORDERS Puitus 10% 3% 4% 13% 11% 12% 10% 4% Micea PI of 15

11 Copy fom GRASS PSYCHIATRIC DISORDERS Insomnia CARDIAC DISORDERS Angina Pectois Cadiac Failue Congestive RENAL AND URINARY DISORDERS Renal Failue Chonic BLOOD AND LYMPHATIC SYSTEM DISORDERS Anaemia 4% 4% Some of the advese events epoted ae typically associated with CKD, o ecognised complications of dialysis, and may not necessaily be attibutable to MIRCERA theapy. The following desciptos ae used to descibe the fequency of advese eactions attibuted to teatment with MIRCERA in contolled clinical tials: Common ( 1/100 and < 1/10), Uncommon ( 1/1000 and < 1/100), and Rae ( 1/10,000 and < 1/1000). Vascula disodes: common hypetension Injuy, poisoning and pocedual complications: uncommon vascula access thombosis Immune system disodes: ae hypesensitivity Nevous system disodes: uncommon headache; ae hypetensive encephalopathy Skin and subcutaneous tissue disodes: ae ash (maculo-papula, seious) All othe events attibuted to MIRCERA wee epoted with ae fequency and wee of mild to modeate seveity in the majoity of patients. These events wee consistent with comobidities known in the population. Post-Maketing Expeience The safety infomation collected duing post maketing expeience eflects the expected advese event pofile in these populations and the advese eaction pofile of MIRCERA (see PRECAUTIONS, Geneal, and ADVERSE EFFECTS). DOSAGE AND ADMINISTRATION Geneal Use the lowest dose of MIRCERA that will gadually incease the haemoglobin concentation. MIRCERA is administeed less fequently than Aanesp, Epex and NeoRecomon due to the longe elimination half-life. Teatment with MIRCERA is to be initiated unde the supevision of a healthcae pofessional. Micea PI of 15

12 Copy fom GRASS Teatment of Anaemic Patients with Chonic Kidney Disease The solution can be administeed by subcutaneous (SC) o intavenous (IV) injection, accoding to clinical pefeence. MIRCERA can be injected SC in the abdomen, am o thigh. All thee injection sites ae equally suitable fo SC injection with MIRCERA. Patients being changed fom SC to IV administation of MIRCERA (o vice-vesa) should have thei haemoglobin levels monitoed to ensue that the haemoglobin concentation stays within the desied taget of 100 and 120 g/l. Patients not cuently teated with an Eythopoiesis Stimulating Agent (ESA): The ecommended stating dose of MIRCERA is 0.6 µg/kg body weight, administeed once evey two weeks as a single IV o SC injection in ode to taget a haemoglobin between g/l. It is ecommended that haemoglobin is monitoed evey two weeks until stabilised, and peiodically theeafte (see PRECAUTIONS, Cadiovascula and Thombotic Events/Inceased Motality). The dose of MIRCERA may be inceased by appoximately 25 to 50% of the pevious dose if the ate of ise in haemoglobin is less than 10 g/l ove a month. Futhe inceases of appoximately 25 to 50% may be made at monthly intevals until the individual taget haemoglobin level is obtained. Dose adjustments should not be made moe fequently than once a month. The dose fo each patient should be adjusted so that the haemoglobin level does not exceed 120 g/l. If the haemoglobin is inceasing and appoaching 120 g/l, the dose should be educed by appoximately 25 to 50%. If the haemoglobin continues to incease, the dose should be tempoaily withheld until the haemoglobin begins to decease, at which point theapy should be einitiated at a dose appoximately 25 to 50% below the pevious dose. If the haemoglobin inceases by moe than 10 g/l in any 2 week peiod, the dose should be deceased by appoximately 25 to 50%. Afte dose inteuption, a haemoglobin decease of appoximately 3.5 g/l pe week is expected. If the taget haemoglobin concentation is eached fo the individual patient, MIRCERA may be administeed once monthly using the dose equal to twice the pevious once evey two weeks dose. Patients cuently teated with an Eythopoiesis Stimulating Agent (ESA): When conveting fom epoetin o dabepoetin alfa, MIRCERA can be administeed once monthly o, if desied, once evey two weeks as a single IV o SC injection. The stating dose of MIRCERA is calculated based on the peviously-given ESA weekly dose at the time of convesion, as descibed in Table 4 below. The two-weekly dose should be appoximately half the once monthly dose. The fist injection of MIRCERA should be administeed at the next scheduled dose of the peviously administeed dabepoetin alfa o epoetin. Micea PI of 15

13 Copy fom GRASS Table 4. MIRCERA dose when conveting fom anothe ESA Pevious Weekly Dabepoetin Alfa Dose (µg/week) Pevious Weekly Epoetin Dose (Units/week) MIRCERA Stating Dose (µg/month) < 40 < > 80 > It is ecommended that haemoglobin is monitoed evey month until stabilised, and peiodically theeafte (see PRECAUTIONS, Cadiovascula and Thombotic Events/Inceased Motality). If a dose adjustment is equied to maintain the taget haemoglobin concentation between g/l, the monthly dose may be adjusted by appoximately 2. Dose adjustments should not be made moe fequently than once a month. The dose fo each patient should be adjusted so that the haemoglobin level does not exceed 120 g/l. If the haemoglobin is inceasing and appoaching 120 g/l, the dose should be educed by appoximately 25 to 50%. If the haemoglobin continues to incease, the dose should be tempoaily withheld until the haemoglobin begins to decease, at which point theapy should be einitiated at a dose appoximately 25 to 50% below the pevious dose. If the haemoglobin inceases by moe than 10 g/l in any 2 week peiod, the dose should be deceased by appoximately 25 to 50%. Afte dose inteuption, a haemoglobin decease of appoximately 3.5 g/l pe week is expected. Hepatic Impaiment No adjustments of the stating dose o dose modification ules ae equied in patients with any degee of hepatic impaiment. Teatment inteuption Teatment with MIRCERA is nomally long-tem. Howeve, it can be inteupted at any time, if necessay. Missed dose If one dose of MIRCERA is missed, the missed dose should be administeed as soon as possible and administation of MIRCERA estated at the pescibed dosing fequency. OVERDOSAGE The theapeutic ange of MIRCERA is wide and individual esponse to theapy must be consideed when MIRCERA teatment is initiated. Ovedose can esult in manifestations of an exaggeated phamacodynamic effect, e.g. excessive eythopoiesis. In case of excessive haemoglobin levels, MIRCERA should be tempoaily withheld. If clinically indicated, phlebotomy may be pefomed. Contact the Poisons Infomation Cente fo advice on management of ovedosage. Micea PI of 15

14 Copy fom GRASS PRESENTATION AND STORAGE CONDITIONS MIRCERA is supplied in a pack containing one single-use pefilled syinge and a 27 gauge, ½ inch needle. Each pefilled syinge is equipped with a needle guad that coves the needle duing disposal to educe the isk of needle stick injuy afte application. MIRCERA is available in the following stengths and plunges ae colou coded fo easy identification as indicated below: Stength Volume Colou (µg) (ml) tuquoise yellow ed aqua lime 150* 0.3 gey puple 250* 0.3 geen salmon * not cuently distibuted in Austalia Stoage conditions MIRCERA must not be used afte the expiy date. Stoe continuously in the efigeato at 2 C to 8 C. Do not feeze. Do not shake. Potect fom light. The pefilled syinges contain no antimicobial pesevative and ae fo single-use in one patient only. Discad any esidue. The end use may emove MIRCERA fom efigeation (2 C to 8 C) fo stoage at oom tempeatue (up to 30 C) fo one single peiod of 1 month. Once emoved fom the fidge, the poduct must be used within 1 month and not etuned to the fidge fo stoage. MIRCERA should not be mixed with othe poducts. Allow the poduct to each oom tempeatue befoe injecting. NAME AND ADDRESS OF SPONSOR Roche Poducts Pty Limited ABN Inman Road Dee Why NSW 2099 AUSTRALIA Custome enquiies: POISON SCHEDULE OF THE MEDICINE S4. Pesciption only medicine. Micea PI of 15

15 Copy fom GRASS TGA Appoval Date: 10 July 2009 Date of most ecent amendment: 1 Decembe 2010 Micea PI of 15