- Reduction  in  the  duration of  neutropenia  and the  incidence  of  febrile  neutropenia  in patients treated with established  cytotoxic  chemotherapy  for  malignancy  (with  the  exception of  chronic myeloid leukaemia  and myelodysplastic  syndromes)  and reduction  in  the  duration  of neutropenia  in patients  undergoing  myeloablative  therapy  followed by  bone  marrow transplantation  considered  to  be at  increased  risk  of  prolonged  severe  neutropenia. The  safety  and  efficacy  of  filgrastim  are  similar  in  adults and  children  receiving  cytotoxic chemotherapy.

- Mobilisation  of  peripheral  blood progenitor  cells  (PBPCs).

- In patients, children  or  adults, with severe  congenital,  cyclic, or  idiopathic  neutropenia  with an absolute  neutrophil  count  (ANC)  of  ≤  0.5  x  109/l,  and  a history  of  severe  or  recurrent  infections, long  term  administration of  filgrastim  is  indicated to  increase  neutrophil  counts  and to reduce the  incidence  and duration  of  infection-related  events. - - - Treatment  of  persistent  neutropenia (ANC  ≤  1.0  x  109/l)  in  patients with  advanced  HIV infection,  in order  to  reduce  the  risk  of  bacterial  infections  when other  options  to  manage neutropenia  are  inappropriate. 

Filgrastim  therapy  should only  be  given in collaboration with  an oncology  centre  which has experience in  G-CSF  treatment  and  haematology  and  has the necessary  diagnostic facilities.  The mobilisation and  apheresis  procedures  should  be  performed in collaboration  with an  oncologyhaematology  centre  with acceptable  experience  in this  field and where  the  monitoring  of haematopoietic progenitor  cells can  be  correctly  performed. Established  cytotoxic chemotherapy Posology The  recommended dose  of  filgrastim  is  0.5  MU/kg/day  (5  μg/kg/day). The  first  dose  of  filgrastim should be  administered at  least  24  hours  after  cytotoxic chemotherapy.  In  randomised  clinical  trials,  a subcutaneous  dose  of  230  μg/m2/day  (4.0 to 8.4  μg/kg/day)  was  used. Daily  dosing  with  filgrastim  should continue  until  the  expected  neutrophil  nadir  is  passed and the neutrophil  count  has  recovered  to the  normal  range. Following  established chemotherapy  for  solid tumours, lymphomas, and lymphoid leukaemia, it  is  expected that  the  duration of  treatment  required to fulfil  these  criteria will  be up  to  14  days. Following  induction and consolidation treatment  for  acute myeloid leukaemia  the  duration  of  treatment  may  be  substantially  longer  (up to 38  days)  depending  on the  type,  dose  and schedule  of  cytotoxic  chemotherapy  used. In  patients receiving  cytotoxic chemotherapy,  a transient  increase in  neutrophil  counts  is  typically  seen 1  -  2  days after  initiation  of  filgrastim  therapy.  However,  for  a  sustained  therapeutic response, filgrastim  therapy  should  not  be  discontinued before  the  expected nadir  has  passed  and the  neutrophil count  has  recovered  to the  normal  range. Premature  discontinuation of  filgrastim  therapy, prior  to  the time  of  the  expected neutrophil  nadir,  is  not  recommended. Method of  administration Filgrastim  may  be given  as a daily  subcutaneous  injection  or  as a daily  intravenous  infusion  diluted  in 5% glucose  solution given  over  30  minutes (see  section  6.6). The  subcutaneous  route  is  preferred in most  cases.  There is some evidence  from  a  study  of  single  dose  administration that  intravenous  dosing may  shorten  the  duration of  effect.  The  clinical  relevance  of  this  finding  to multiple  dose administration is  not  clear. The  choice  of  route  should depend on  the  individual  clinical  circumstance. In patients  treated with myeloablative  therapy  followed  by  bone  marrow  transplantation Posology The  recommended starting  dose  of  filgrastim  is  1.0  MU/kg/day  (10  μg/kg/day). The  first  dose  of filgrastim  should  be administered  at  least  24  hours  following  cytotoxic chemotherapy  and  at  least 24  hours  after  bone  marrow  infusion. Once  the  neutrophil  nadir  has  been passed,  the  daily  dose  of  filgrastim  should be  titrated  against  the neutrophil  response  as  follows: 

Method of  administration Filgrastim  may  be given  as a 30  minute  or  24  hour  intravenous  infusion or  given by  continuous 24  hour  subcutaneous  infusion. Filgrastim  should be  diluted in  20  ml  of  5%  glucose  solution (see section  6.6). For  the  mobilisation  of  PBPCs  in patients  undergoing  myelosuppressive  or  myeloablative  therapy followed by  autologous  PBPC  transplantation Posology The  recommended dose  of  filgrastim  for  PBPC  mobilisation when used alone  is 1.0  MU/kg/day  (10  μg/kg/day)  for  5  -  7  consecutive  days. Timing  of  leukapheresis: 1  or  2  leukaphereses on  days  5 and  6 are  often  sufficient. In other  circumstances, additional leukaphereses may  be necessary.  Filgrastim  dosing  should  be maintained  until  the last  leukapheresis. The  recommended dose  of  filgrastim  for  PBPC  mobilisation after  myelosuppressive  chemotherapy  is 0.5  MU/kg/day  (5  μg/kg/day)  from  the  first  day  after  completion of  chemotherapy  until  the  expected neutrophil  nadir  is  passed and the  neutrophil  count  has  recovered  to  the normal  range.  Leukapheresis should be  performed during  the  period when  the  ANC  rises  from  <  0.5  x  109/l  to  >  5.0  x  109/l.  For patients  who have  not  had extensive  chemotherapy, one  leukapheresis  is  often  sufficient.  In other circumstances,  additional  leukaphereses  are recommended. Method of  administration Filgrastim  for  PBPC  mobilisation when used alone: Filgrastim  may  be given  as a 24  hour  subcutaneous  continuous  infusion or  subcutaneous  injection. For infusions  filgrastim  should be  diluted in  20  ml  of  5%  glucose solution  (see section  6.6). Filgrastim  for  PBPC  mobilisation after  myelosuppressive  chemotherapy: Filgrastim  should be  given  by  subcutaneous  injection. For  the  mobilisation  of  PBPCs  in normal  donors  prior  to allogeneic  PBPC  transplantation Posology For  PBPC  mobilisation  in normal  donors, filgrastim  should be  administered  at 1.0  MU/kg/day  (10  μg/kg/day)  for  4  -  5  consecutive days.  Leukapheresis  should  be started  at  day  5 and continued until  day  6 if  needed in  order  to collect  4  x  106  CD34+  cells/kg  recipient  bodyweight. Method of  administration Filgrastim  should be  given  by  subcutaneous  injection. In  patients with  severe chronic neutropenia  (SCN) Posology Congenital  neutropenia The  recommended starting  dose  is  1.2  MU/kg/day  (12  μg/kg/day)  as  a  single  dose  or  in  divided doses. Idiopathic or cyclic neutropenia The  recommended starting  dose  is  0.5  MU/kg/day  (5  μg/kg/day)  as  a  single  dose  or  in divided  doses. Dose  adjustment Filgrastim  should be  administered daily  by  subcutaneous  injection until  the  neutrophil  count  has reached and can be  maintained at  more  than 1.5  x  109/l. When  the  response  has  been obtained,  the minimal  effective  dose  to  maintain  this  level  should  be  established. Long-term  daily  administration  is required to maintain an  adequate  neutrophil  count. After  1  -  2 weeks  of  therapy, the  initial  dose  may be  doubled or  halved depending  upon the  patient's  response. Subsequently  the  dose  may  be individually adjusted  every 1  -  2  weeks  to  maintain  the  average  neutrophil  count  between 1.5  x  109/l and 10  x  109/l. A  faster  schedule  of  dose  escalation may  be  considered in  patients  presenting  with severe  infections.  In  clinical  trials,  97%  of  patients who  responded  had  a complete  response  at  doses ≤  24  μg/kg/day. The  long-term  safety  of  filgrastim  administration above  24  μg/kg/day  in patients  with SCN has not  been  established. Method of  administration Congenital, idiopathic  or  cyclic  neutropenia:  Filgrastim  should be  given by  subcutaneous  injection. In patients  with HIV  infection Posology For reversal  of  neutropenia The  recommended starting  dose  of  filgrastim  is  0.1  MU/kg/day  (1  μg/kg/day), with titration up  to a maximum  of  0.4  MU/kg/day  (4  μg/kg/day)  until  a  normal  neutrophil  count  is  reached and  can be maintained  (ANC  >  2.0  x  109/l).  In  clinical  studies, >  90%  of  patients  responded at  these  doses, achieving  reversal  of  neutropenia in  a median  of  2  days. In a  small  number  of  patients  (<  10%), doses  up to  1.0  MU/kg/day  (10  μg/kg/day)  were  required to achieve reversal  of  neutropenia. For  maintaining  normal  neutrophil  counts When reversal  of  neutropenia has been  achieved,  the minimal  effective dose  to  maintain  a normal neutrophil  count  should be  established. Initial  dose  adjustment  to  alternate  day  dosing  with 30  MU/day  (300  μg/day)  is  recommended. Further  dose adjustment  may  be necessary,  as determined by  the  patient's  ANC, to maintain  the  neutrophil  count  at  >  2.0  x  109/l. In clinical  studies, dosing  with 30  MU/day  (300  μg/day)  on 1  -  7  days per  week  was required  to  maintain  the ANC  >  2.0  x  109/l,  with the  median  dose  frequency  being  3  days  per  week. Long-term  administration may  be  required  to maintain  the  ANC  >  2.0  x  109/l. Method of  administration Reversal  of  neutropenia  or  maintaining  normal  neutrophil  counts:  Filgrastim  should be  given by subcutaneous  injection. Elderly Clinical  trials with  filgrastim  have included  a small  number  of  elderly  patients but  special  studies have not  been performed in  this  group and therefore  specific  dosage  recommendations  cannot  be  made. Renal  impairment Studies  of  filgrastim  in  patients  with  severe  impairment  of  renal or  hepatic  function  demonstrate  that it exhibits  a  similar  pharmacokinetic  and  pharmacodynamic  profile  to  that  seen in normal  individuals. Dose  adjustment  is not  required  in  these circumstances. Paediatric  use  in  the SCN  and  cancer  settings Sixty-five  percent  of  the  patients  studied in  the  SCN  trial  program  were  under  18  years of  age.  The efficacy  of  treatment  was clear  for  this age-group, which included most  patients  with congenital neutropenia.  There were no  differences  in  the safety  profiles  for  paediatric patients treated  for  SCN. 

Data  from  clinical  studies in  paediatric patients indicate that  the safety  and  efficacy  of  filgrastim  are similar  in  both  adults  and  children  receiving  cytotoxic  chemotherapy. The  dosage recommendations in  paediatric patients are  the same as those  in  adults  receiving myelosuppressive  cytotoxic  chemotherapy. 

Special  warnings  and  precautions across indications Hypersensitivity Hypersensitivity, including  anaphylactic  reactions, occurring  on initial  or  subsequent  treatment  has been  reported  in  patients treated  with  filgrastim.  Permanently  discontinue  Zarzio  in  patients  with clinically  significant hypersensitivity.  Do  not administer  Zarzio  to  patients  with  a  history  of hypersensitivity  to  filgrastim  or  pegfilgrastim. Pulmonary  adverse  effects Pulmonary  adverse  effects,  in  particular  interstitial  lung  disease,  have been  reported  after  G-CSF administration.  Patients  with a  recent  history  of  lung  infiltrates  or  pneumonia  may  be  at  higher  risk. The  onset  of  pulmonary  signs, such as  cough, fever  and dyspnoea  in association  with  radiological signs  of  pulmonary  infiltrates  and  deterioration  in pulmonary  function may  be  preliminary  signs  of acute  respiratory  distress  syndrome  (ARDS). Filgrastim  should be  discontinued  and appropriate treatment  given  in  these cases. Glomerulonephritis Glomerulonephritis  has  been reported in patients  receiving  filgrastim  or  pegfilgrastim. Generally, events  of  glomerulonephritis  resolved after  dose  reduction or  withdrawal  of  filgrastim  or  pegfilgrastim. Urinalysis  monitoring  is  recommended. Capillary  leak  syndrome Capillary  leak  syndrome,  which  can  be life-threatening  if  treatment  is  delayed,  has  been  reported  after granulocyte  colony-stimulating  factor  administration  and is  characterised by  hypotension, hypoalbuminaemia, oedema  and hemoconcentration. Patients  who develop symptoms  of  capillary  leak syndrome  should be  closely  monitored  and  receive  standard  symptomatic  treatment, which may include  a need  for  intensive  care  (see section  4.8). Splenomegaly  and Splenic  rupture Generally  asymptomatic cases of  splenomegaly  and  cases of  splenic  rupture  have  been  reported  in patients  and normal  donors  following  administration  of  filgrastim.  Some cases of  splenic  rupture were fatal.  Therefore, spleen size  should be  carefully  monitored (e.g. clinical  examination, ultrasound). A diagnosis  of  splenic  rupture  should be  considered  in donors  and/or  patients  reporting  left  upper abdominal  pain  or  shoulder  tip  pain.  Dose reductions  of  filgrastim  have been  noted to slow  or  stop the progression of  splenic  enlargement  in  patients with  severe chronic  neutropenia, and in 3%  of  patients  a splenectomy  was required. Malignant  cell  growth G-CSF  can promote  growth  of  myeloid cells  in  vitro  and  similar  effects  may  be seen  on  some nonmyeloid  cells  in  vitro. 

Myelodysplastic syndrome or  Chronic  myeloid  leukemia The  safety  and efficacy  of  filgrastim  administration in  patients  with myelodysplastic  syndrome, or chronic  myelogenous  leukaemia  have  not  been established. Filgrastim  is  not  indicated  for  use  in  these conditions. Particular  care  should be  taken to distinguish the  diagnosis  of  blast  transformation of chronic myeloid  leukaemia from  acute myeloid  leukaemia. Acute  myeloid  leukaemia In  view  of  limited  safety  and  efficacy  data in  patients  with  secondary  acute myelogenous leukaemia (AML),  filgrastim  should be  administered with caution.  The safety  and  efficacy  of  filgrastim administration in  de  novo  AML  patients aged  <  55  years  with  good cytogenetics  [t(8;21),  t(15;17), and inv(16)]  have  not  been established. Thrombocytopenia Thrombocytopenia  has  been reported  in  patients  receiving  filgrastim.  Platelet counts  should  be monitored  closely,  especially  during  the first  few  weeks of  filgrastim  therapy.  Consideration  should be given  to  temporary  discontinuation or  dose  reduction  of  filgrastim  in  patients  with  severe  chronic neutropenia  who  develop thrombocytopenia  (platelet  count  <  100    x  109/l). Leukocytosis White  blood  cell  counts  of  100  x  109/l  or  greater  have  been  observed  in  less  than  5%  of  cancer  patients receiving  filgrastim  at  doses above 0.3  MU/kg/day  (3  μg/kg/day). No undesirable  effects  directly attributable to  this degree of  leukocytosis have been  reported.  However,  in  view  of  the potential  risks associated  with  severe leukocytosis,  a  white blood cell  count  should be  performed at  regular  intervals during  filgrastim  therapy. If  leukocyte  counts  exceed 50  x  109/l  after  the  expected  nadir, filgrastim should be  discontinued immediately.  When administered  for  PBPC  mobilisation,  filgrastim  should be discontinued or  its  dosage  should be  reduced if  the  leukocyte  counts  rise  to >  70  x  109/l. Immunogenicity As  with  all therapeutic  proteins,  there  is  a  potential for  immunogenicity.  Rates  of  generation of antibodies  against  filgrastim  is generally  low.  Binding  antibodies  do  occur  as expected  with  all biologics;  however,  they  have  not  been  associated with  neutralising  activity  at  present. Special  warning  and  precautions associated  with  co-morbidities Special  precautions  in sickle cell  trait  and  sickle  cell  disease Sickle cell  crises,  in  some cases  fatal,  have been  reported  with  the use of  filgrastim  in  patients with sickle  cell  trait  or  sickle  cell  disease.  Physicians should  use caution  when  prescribing  filgrastim  in patients  with  sickle cell  trait  or  sickle  cell  disease. Osteoporosis Monitoring  of  bone  density  may  be  indicated  in patients  with  underlying  osteoporotic  bone  diseases who undergo continuous  therapy  with filgrastim  for  more  than  6  months. Special  precautions in  cancer  patients Filgrastim  should not  be  used to  increase  the  dose  of  cytotoxic  chemotherapy  beyond established dosage regimens. 7  Pg. 7 Summary of Product Characteristics

Risks  associated  with  increased  doses  of  chemotherapy Special  caution  should  be used  when  treating  patients  with  high-dose  chemotherapy  because  improved tumour  outcome  has  not  been demonstrated  and  intensified  doses  of  chemotherapeutic agents may lead  to  increased  toxicities including  cardiac,  pulmonary,  neurologic,  and  dermatologic  effects (please refer  to  the  prescribing  information  of  the specific chemotherapy  agents  used). Effect  of  chemotherapy on  erythrocytes and  thrombocytes Treatment  with  filgrastim  alone  does  not  preclude  thrombocytopenia  and  anaemia  due  to myelosuppressive chemotherapy.  Because of  the potential  of  receiving  higher  doses of  chemotherapy (e.g. full  doses  on the  prescribed schedule)  the  patient  may  be  at  greater  risk  of  thrombocytopenia  and anaemia. Regular  monitoring  of  platelet  count  and  haematocrit  is  recommended. Special  care  should be  taken when administering  single  or  combination chemotherapeutic  agents  which are  known to cause  severe thrombocytopenia. The  use of  filgrastim-mobilised PBPCs  has  been  shown to reduce  the  depth  and duration  of thrombocytopenia  following  myelosuppressive  or  myeloablative  chemotherapy. Other special precautions The  effects  of  filgrastim  in patients  with substantially  reduced  myeloid progenitors  have  not  been studied. Filgrastim  acts  primarily  on neutrophil  precursors  to exert  its  effect  in elevating  neutrophil counts. Therefore,  in patients  with  reduced precursors,  neutrophil  response  may  be  diminished (such as  those  treated with extensive  radiotherapy  or  chemotherapy, or  those  with bone  marrow  infiltration by  tumour). Vascular  disorders,  including  veno-occlusive  disease  and fluid volume  disturbances,  have been reported occasionally  in patients  undergoing  high dose  chemotherapy  followed by  transplantation. There have  been  reports  of  Graft  versus  Host  Disease  (GvHD)  and  fatalities  in  patients  receiving G-CSF  after  allogeneic bone marrow  transplantation  (see section  4.8 and 5.1). Increased haematopoietic  activity  of  the  bone  marrow  in response  to growth  factor  therapy  has  been associated  with  transient  abnormal  bone  scans.  This should  be considered  when  interpreting  boneimaging  results. Aortitis  has  been reported  after  G-CSF  administration  in  healthy  subjects  and  in  cancer  patients.  The symptoms  experienced  included fever, abdominal  pain, malaise, back  pain and  inflammatory  markers (e.g. C-reactive protein  and  white  blood  cell  count)  were raised.  In  most  cases  aortitis was  diagnosed by  CT  scan  and  generally  resolved  after  withdrawal  of  G-CSF.  See also  section  4.8. Special  precautions  in  patients  undergoing  PBPC  mobilisation Mobilisation There  are  no prospectively  randomised  comparisons  of  the  two recommended mobilisation methods (Filgrastim  alone, or  in combination with myelosuppressive  chemotherapy)  within the  same  patient population.  The  degree  of  variation between individual  patients  and between  laboratory  assays  of CD34+  cells mean  that  direct  comparison  between  different  studies  is difficult.  It  is therefore difficult to recommend an optimum  method. The  choice  of  mobilisation  method  should be  considered in relation  to  the  overall  objectives  of  treatment for  an  individual  patient.

Prior exposure  to  cytotoxic agents Patients who  have undergone very  extensive prior  myelosuppressive  therapy  may  not  show  sufficient mobilisation of  PBPC  to achieve  the  recommended minimum  yield  (≥  2.0  x  106  CD34+  cells/kg)  or acceleration  of  platelet  recovery  to  the same degree. Some  cytotoxic  agents  exhibit  particular  toxicities  to the  haematopoietic  progenitor  pool  and may adversely  affect  progenitor  mobilisation. Agents  such  as  melphalan, carmustine  (BCNU)  and carboplatin, when  administered  over  prolonged periods  prior  to attempts  at  progenitor  mobilisation may  reduce  progenitor  yield. However, the  administration of  melphalan, carboplatin  or  BCNU together  with filgrastim  has  been shown to  be  effective  for  progenitor  mobilisation. When  a  PBPC transplantation  is  envisaged  it  is advisable  to  plan  the stem  cell  mobilisation  procedure early  in  the treatment course  of  the  patient.  Particular  attention  should be  paid to  the  number  of  progenitors mobilised in such  patients  before  the  administration  of  high-dose chemotherapy.  If  yields are inadequate, as  measured by  the  criteria  above, alternative  forms  of  treatment  not  requiring  progenitor support  should be  considered. Assessment  of  progenitor  cell  yields In  assessing  the number  of  progenitor  cells harvested  in  patients  treated  with  filgrastim,  particular attention  should be  paid to  the  method of  quantitation.  The  results  of  flow  cytometric  analysis  of CD34+  cell  numbers  vary  depending  on the  precise  methodology  used and, recommendations  of numbers  based on studies  in other  laboratories  need  to  be  interpreted with caution. Statistical  analysis  of  the relationship  between  the  number  of  CD34+  cells re-infused  and the  rate  of platelet  recovery  after  high-dose  chemotherapy  indicates  a  complex but  continuous  relationship. The  recommendation  of  a  minimum  yield of  ≥  2.0  x  106  CD34+  cells/kg  is  based  on published experience  resulting  in  adequate  haematologic reconstitution.  Yields  in  excess of  this  appear  to correlate with  more rapid  recovery,  those below  with  slower  recovery. Special  precautions in  normal  donors  undergoing  PBPC  mobilisation Mobilisation  of  PBPC  does  not  provide  a  direct  clinical  benefit  to normal  donors  and should only  be considered for  the  purposes  of  allogeneic  stem  cell  transplantation. PBPC mobilisation  should  be  considered  only  in  donors  who meet  normal  clinical  and laboratory eligibility  criteria  for  stem  cell donation  with  special attention  to  haematological  values  and  infectious disease. The  safety  and  efficacy  of  filgrastim  have not  been  assessed  in  normal  donors  <  16  years or  >  60  years. Transient  thrombocytopenia (platelets  <  100  x  109/l)  following  filgrastim  administration and leukapheresis was observed  in  35%  of  subjects  studied.  Among  these,  two  cases of  platelets <  50  x 109/l  were  reported  and  attributed to  the  leukapheresis  procedure. If  more  than one  leukapheresis  is  required, particular  attention should be  paid  to donors  with platelets  <  100  x  109/l  prior  to leukapheresis;  in general  apheresis  should not  be  performed if platelets  <  75  x  109/l. Leukapheresis  should not  be  performed in  donors  who  are  anticoagulated or  who have  known defects in  haemostasis. Donors  who  receive  G-CSFs  for  PBPC  mobilisation should be  monitored until  haematological  indices return to  normal. 

Transient  cytogenetic  abnormalities have been  observed in normal  donors  following  G-CSF  use. The significance of  these changes is unknown.  Nevertheless,  a risk  of  promotion  of  a  malignant  myeloid clone  cannot  be excluded.  It  is  recommended  that  the apheresis centre perform  a systematic record  and tracking  of  the  stem  cell  donors  for  at  least  10  years  to ensure  monitoring  of  long-term  safety. Special  precautions in  recipients  of  allogeneic  PBPCs  mobilised  with  filgrastim Current  data  indicate  that  immunological interactions  between  the  allogeneic  PBPC  graft and  the recipient  may  be associated  with  an  increased  risk  of  acute  and  chronic GvHD  when  compared  with bone  marrow  transplantation. Special  precautions in  SCN  patients Filgrastim  should not  be  administered  to patients  with  severe  congenital  neutropenia  who develop leukaemia or  have evidence  of  leukaemic evolution. Blood cell  counts Other  blood cell  changes  occur,  including  anaemia  and  transient  increases  in myeloid progenitors, which  require  close  monitoring  of  cell  counts. Transformation  to  leukaemia or  myelodysplastic  syndrome Special  care should  be taken  in  the diagnosis  of  SCNs  to distinguish  them  from  other  haematopoietic disorders such  as aplastic anaemia,  myelodysplasia,  and  myeloid  leukaemia.  Complete blood  cell counts  with differential  and  platelet  counts,  and an  evaluation of  bone  marrow  morphology  and karyotype  should be  performed prior  to treatment. There  was  a  low  frequency  (approximately  3%)  of  myelodysplastic  syndromes  (MDS)  or  leukaemia  in clinical  trial patients  with  SCN  treated  with  filgrastim.  This  observation  has  only  been  made  in patients  with congenital  neutropenia.  MDS  and  leukaemias are natural  complications of  the  disease and are  of  uncertain relation to filgrastim  therapy. A  subset  of  approximately  12%  of  patients  who  had normal  cytogenetic evaluations at  baseline was subsequently  found  to  have abnormalities, including monosomy  7, on routine  repeat  evaluation. It  is  currently  unclear  whether  long-term  treatment  of patients with  SCN  will  predispose patients  to  cytogenetic abnormalities,  MDS  or  leukaemic transformation. It  is  recommended to perform  morphologic  and cytogenetic  bone  marrow examinations  in  patients at  regular  intervals (approximately  every  12  months). Other special  precautions Causes  of  transient  neutropenia,  such  as viral  infections should  be  excluded. Haematuria  was common  and  proteinuria occurred  in  a  small  number  of  patients.  Regular  urinalysis should be  performed to monitor  these  events. The  safety  and  efficacy  in  neonates  and  patients  with autoimmune  neutropenia  have  not  been established. Special precautions  in  patients  with  HIV  infection Blood cell  counts Absolute  neutrophil  count  (ANC)  should be  monitored  closely, especially  during  the  first  few  weeks of  filgrastim  therapy. Some  patients may  respond  very  rapidly  and  with  a considerable  increase  in neutrophil  count  to  the  initial  dose  of  filgrastim.  It  is  recommended that  the  ANC  is  measured daily  for the first  2  -  3  days  of  filgrastim  administration.  Thereafter,  it  is  recommended that  the  ANC  is measured  at  least  twice  per  week  for  the first  2  weeks and  subsequently  once per  week  or  once every other  week  during  maintenance  therapy. During  intermittent  dosing  with 30  MU/day  (300  μg/day)  of filgrastim, there  can  be  wide  fluctuations  in  the  patient's  ANC  over  time. In order  to determine  a patient's  trough or  nadir  ANC, it  is  recommended that  blood  samples  are  taken for  ANC  measurement immediately  prior  to  any  scheduled  dosing  with  filgrastim. Risk associated  with  increased  doses of  myelosuppressive medicinal  products Treatment with  filgrastim  alone  does  not  preclude  thrombocytopenia  and  anaemia  due  to myelosuppressive treatments.  As  a result  of  the potential  to  receive higher  doses  or  a greater  number of  these  medicinal  products  with  filgrastim  therapy, the  patient  may  be  at  higher  risk  of  developing thrombocytopenia  and anaemia. Regular  monitoring  of  blood  counts  is  recommended (see  above). Infections  and malignancies  causing myelosuppression Neutropenia  may  be  due  to  bone  marrow-infiltrating  opportunistic  infections  such  as  Mycobacterium avium  complex or  malignancies  such as  lymphoma.  In  patients  with known bone  marrow  infiltrating infections  or  malignancy, consider  appropriate  therapy  for  treatment  of  the  underlying  condition in addition  to  administration  of  filgrastim  for  treatment of  neutropenia.  The effects of  filgrastim  on neutropenia  due  to  bone  marrow-infiltrating  infection  or  malignancy  have not  been  well  established. All patients Latex-sensitive  individuals The  removable  needle  cap  of  this  pre-filled  syringe  contains  a  derivative  of  natural  rubber  latex. No natural  rubber  latex  has to  date been  detected  in  the  removable  needle cap.  Nevertheless,  the  use  of Zarzio solution for  injection  in  pre-filled  syringe in  latex-sensitive  individuals  has  not  been studied and  thus  there is a potential  risk  for  hypersensitivity  reactions which  cannot  be completely  ruled  out. Excipients Zarzio  contains  sorbitol  (E420).  Patients  with hereditary  fructose  intolerance  (HFI)  must  not  be  given this medicine unless strictly  necessary. Babies  and young  children  (below  2 years  of  age)  may  not  yet  be  diagnosed  with  hereditary  fructose intolerance  (HFI). Medicines  (containing  sorbitol/fructose)  given  intravenously may be  lifethreatening  and  should be  contraindicated in  this  population unless  there  is  an overwhelming  clinical need  and  no  alternatives are  available. A detailed history  with  regard to HFI  symptoms  has to  be taken  of  each  patient  prior  to being  given this medicinal  product. In order  to  improve  the  traceability  of  granulocyte-colony  stimulating  factors  (G-CSFs), the  trade name  of  the  administered product  should  be  clearly  recorded  in  the  patient  file. 

The  safety  and  efficacy  of  filgrastim  given  on  the same day  as myelosuppressive cytotoxic chemotherapy  have  not  been definitively  established.  In view  of  the  sensitivity  of  rapidly  dividing myeloid cells  to myelosuppressive  cytotoxic  chemotherapy, the  use  of  filgrastim  is  not  recommended in the  period from  24  hours  before  to 24  hours  after  chemotherapy. Preliminary  evidence from  a small number  of  patients  treated  concomitantly  with  filgrastim  and 5-fluorouracil indicates  that  the  severity of  neutropenia may  be exacerbated. Possible  interactions with  other  haematopoietic growth  factors and  cytokines have not  yet  been investigated  in  clinical trials. 

Since  lithium  promotes  the  release  of  neutrophils,  lithium  is  likely  to  potentiate  the  effect of  filgrastim. Although this  interaction  has  not  been formally  investigated, there  is  no evidence  that  such an interaction is  harmful. 

Pregnancy There  are  no or  limited amount  of  data  from  the  use  of  filgrastim  in pregnant  women. Studies  in animals  have  shown reproductive  toxicity. An increased incidence  of  embryo-loss  has been  observed in  rabbits  at  high  multiples  of  the clinical  exposure  and  in  the presence  of  maternal  toxicity  (see section  5.3).  There are reports  in  the  literature  where the transplacental  passage of  filgrastim  in pregnant  women  has  been demonstrated. Zarzio is  not  recommended during  pregnancy. Breast-feeding It  is  unknown whether  filgrastim/metabolites  are  excreted  in human milk. A  risk  to the newborns/infants  cannot  be  excluded. A  decision must  be  made  whether  to discontinue  breast-feeding or  to discontinue/abstain from  Zarzio therapy  taking  into account  the  benefit  of  breast  feeding  for  the child and  the  benefit  of  therapy  for  the  woman. Fertility Filgrastim  did  not  affect  reproductive performance or  fertility  in  male or  female  rats  (see section  5.3). 

Filgrastim  may  have a minor  influence on  the  ability  to  drive and  use  machines.  Dizziness may  occur following  the  administration of  filgrastim  (see  section  4.8). 

a.Summary  of  the  safety  profile

The  most  serious adverse reactions  that  may  occur  during  filgrastim  treatment  include:  anaphylactic reaction,  serious pulmonary  adverse  events  (including  interstitial  pneumonia  and ARDS), capillary leak  syndrome, severe  splenomegaly/splenic  rupture, transformation to myelodysplastic  syndrome  or leukaemia in  SCN  patients,  GvHD  in  patients  receiving  allogeneic bone  marrow  transfer  or  peripheral blood cell  progenitor  cell  transplant  and  sickle  cell  crisis in  patients with  sickle cell  disease. The  most  commonly  reported adverse  reactions  are  pyrexia, musculoskeletal  pain  (which  includes bone  pain, back  pain,  arthralgia, myalgia, pain in extremity,  musculoskeletal  pain,  musculoskeletal chest  pain,  neck  pain),  anaemia,  vomiting,  and  nausea.  In  clinical  trials in  cancer  patients musculoskeletal  pain was  mild or  moderate  in  10%, and severe  in 3%  of  patients.

b. Tabulated  summary  of  adverse  reactions

The  data in  the tables below  describe  adverse reactions reported  from  clinical  trials and  spontaneous reporting. Within each frequency  grouping, undesirable effects  are  presented  in  order  of  decreasing seriousness.   

The effects of filgrastim overdosage have not been established. Discontinuation of filgrastim therapy usually results in a 50% decrease in circulating neutrophils within 1 to 2 days, with a return to normal levels in 1 to 7 days.

Pharmacotherapeutic group: Immunostimulants, colony stimulating factors, ATC Code: L03AA02

Zarzio is a biosimilar medicinal product. Detailed information is available on the website of the European Medicines Agency http://www.ema.europa.eu.

Human G-CSF is a glycoprotein which regulates the production and release of functional neutrophils from the bone marrow. Zarzio containing r-metHuG-CSF (filgrastim) causes marked increases in peripheral blood neutrophil counts within 24 hours, with minor increases in monocytes. In some SCN patients filgrastim can also induce a minor increase in the number of circulating eosinophils and basophils relative to baseline; some of these patients may present with eosinophilia or basophilia already prior to treatment. Elevations of neutrophil counts are dose-dependent at recommended doses. Neutrophils produced in response to filgrastim show normal or enhanced function as demonstrated by tests of chemotactic and phagocytic function. Following termination of filgrastim therapy, circulating neutrophil counts decrease by 50% within 1 - 2 days, and to normal levels within 1 - 7 days.

Use of filgrastim in patients undergoing cytotoxic chemotherapy leads to significant reductions in the incidence, severity and duration of neutropenia and febrile neutropenia. Treatment with filgrastim significantly reduces the duration of febrile neutropenia, antibiotic use and hospitalisation after induction chemotherapy for acute myelogenous leukaemia or myeloablative therapy followed by bone marrow transplantation. The incidence of fever and documented infections were not reduced in either setting. The duration of fever was not reduced in patients undergoing myeloablative therapy followed by bone marrow transplantation.

Use of filgrastim, either alone, or after chemotherapy, mobilises haematopoietic progenitor cells into the peripheral blood. These autologous PBPCs may be harvested and infused after high-dose cytotoxic therapy, either in place of, or in addition to bone marrow transplantation. Infusion of PBPC accelerates haematopoietic recovery reducing the duration of risk for haemorrhagic complications and the need for platelet transfusions.

Recipients of allogeneic PBPCs mobilised with filgrastim experienced significantly more rapid haematological recovery, leading to a significant decrease in time to unsupported platelet recovery when compared with allogeneic bone marrow transplantation.

One retrospective European study evaluating the use of G-CSF after allogeneic bone marrow transplantation in patients with acute leukaemias suggested an increase in the risk of GvHD, treatment related mortality (TRM) and mortality when G-CSF was administered. In a separate retrospective international study in patients with acute and chronic myelogenous leukaemias, no effect on the risk of GvHD, TRM and mortality was seen. A meta-analysis of allogeneic transplant studies, including the results of nine prospective randomized trials, eight retrospective studies and one case-controlled study, did not detect an effect on the risks of acute GvHD, chronic GvHD or early treatment-related mortality.

a Analysis includes studies involving BM transplant during this period; some studies used GM-CSF

b Analysis includes patients receiving BM transplant during this period

Use of filgrastim for the mobilisation of PBPCs in normal donors prior to allogeneic PBPC transplantation

In normal donors, a 1 MU/kg/day (10 μg/kg/day) dose administered subcutaneously for

4 - 5 consecutive days allows a collection of ≥ 4 x 106 CD34+ cells/kg recipient body weight in the majority of the donors after two leukaphereses.

Use of filgrastim in patients, children or adults, with SCN (severe congenital, cyclic, and idiopathic neutropenia) induces a sustained increase in ANCs in peripheral blood and a reduction of infection and related events.

Use of filgrastim in patients with HIV infection maintains normal neutrophil counts to allow scheduled dosing of antiviral and/or other myelosuppressive medication. There is no evidence that patients with HIV infection treated with filgrastim show an increase in HIV replication.

As with other haematopoietic growth factors, G-CSF has shown in vitro stimulating properties on human endothelial cells.

Randomised, double-blind, single and multiple dose, crossover studies in 204 healthy volunteers showed that the pharmacokinetic profile of Zarzio was comparable to that of the reference product after subcutaneous and intravenous administration.

Absorption

A single subcutaneous dose of 0.5 MU/kg (5 µg/kg) resulted in maximum serum concentrations after a tmax of 4.5 ± 0.9 hours (mean ± SD).

Distribution

The volume of distribution in blood is approximately 150 ml/kg. Following subcutaneous administration of recommended doses, serum concentrations were maintained above 10 ng/ml for 8 - 16 hours. There is a positive linear correlation between the dose and the serum concentration of filgrastim, whether administered intravenously or subcutaneously.

Elimination

The median serum elimination half-life (t1/2) of filgrastim after single subcutaneous doses ranged from

2.7 hours (1.0 MU/kg, 10 µg/kg) to 5.7 hours (0.25 MU/kg, 2.5 µg/kg) and was prolonged after 7 days of dosing to 8.5 - 14 hours, respectively.

Continuous infusion with filgrastim over a period of up to 28 days, in patients recovering from autologous bone-marrow transplantation, resulted in no evidence of drug accumulation and comparable elimination half-lives.

Filgrastim was studied in repeated dose toxicity studies up to 1 year in duration which revealed changes attributable to the expected pharmacological actions including increases in leukocytes, myeloid hyperplasia in bone marrow, extramedullary granulopoiesis and splenic enlargement. These changes all reversed after discontinuation of treatment.

Effects of filgrastim on prenatal development have been studied in rats and rabbits. Intravenous (80 µg/kg/day) administration of filgrastim to rabbits during the period of organogenesis was

maternally toxic and increased spontaneous abortion, post-implantation loss, and decreased mean live litter size and foetal weight were observed.

Based on reported data for another filgrastim product similar to the reference filgrastim product, comparable findings plus increased foetal malformations were observed at 100 µg/kg/day, a maternally toxic dose which corresponded to a systemic exposure of approximately 50 – 90 times the exposures observed in patients treated with the clinical dose of 5 µg/kg/day. The observed adverse effect level for embryo-foetal toxicity in this study was 10 µg/kg/day, which corresponded to a systemic exposure of approximately 3 – 5 times the exposures observed in patients treated with the clinical dose.

In pregnant rats, no maternal or foetal toxicity was observed at doses up to 575 µg/kg/day. Offspring of rats administered filgrastim during the peri-natal and lactation periods, exhibited a delay in external differentiation and growth retardation (≥20 µg/kg/day) and slightly reduced survival rate

(100 µg/kg/day).

Filgrastim had no observed effect on the fertility of male or female rats.

Glutamic acid

Sorbitol (E420)

Polysorbate 80

Water for injections

Zarzio must not be diluted with sodium chloride solution.

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

Diluted filgrastim may be adsorbed to glass and plastic materials, unless it is diluted in glucose 50 mg/ml (5%) solution (see section 6.6).

Store in a refrigerator (2°C - 8°C).

Keep the pre-filled syringe in the outer carton in order to protect from light.

Within its shelf-life and for the purpose of ambulatory use, the patient may remove the product from the refrigerator and store it at room temperature (not above 25°C) for one single period of up to

72 hours. At the end of this period, the product should not be put back in the refrigerator and should be disposed of.

For storage conditions after dilution of the medicinal product, see section 6.3.

 Pre-filled syringe (type I glass) with injection needle (stainless steel), with or without a needle safety guard, containing 0.5 ml solution.

Pack sizes of 1, 3, 5 or 10 pre-filled syringes. Not all pack sizes may be marketed.

The solution should be visually inspected prior to use. Only clear solutions without particles should be used.

The inner part of the needle cap of the syringe may contain dry rubber (latex). Persons sensitive to latex should take special care with Zarzio (see section 4.4).

Accidental exposure to freezing temperatures does not adversely affect the stability of filgrastim.

Zarzio contains no preservative. In view of the possible risk of microbial contamination, Zarzio syringes are for single use only.

Dilution prior to administration (optional)

If required, Zarzio may be diluted in glucose 50 mg/ml (5%) solution.

Dilution to a final concentration < 0.2 MU/ml (2 μg/ml) is not recommended at any time.

For patients treated with filgrastim diluted to concentrations < 1.5 MU/ml (15 μg/ml), human serum albumin (HSA) should be added to a final concentration of 2 mg/ml.

Example: In a final volume of 20 ml, total doses of filgrastim less than 30 MU (300 μg) should be given with 0.2 ml of human serum albumin 200 mg/ml (20%) solution Ph. Eur. added.

When diluted in glucose 50 mg/ml (5%) solution, filgrastim is compatible with glass and a variety of plastics including polyvinylchloride, polyolefin (a copolymer of polypropylene and polyethylene) and polypropylene.

Using the pre-filled syringe with a needle safety guard

The needle safety guard covers the needle after injection to prevent needle stick injury. This does not affect normal operation of the syringe. Depress the plunger slowly and evenly until the entire dose has been given and the plunger cannot be depressed any further. While maintaining pressure on the plunger, remove the syringe from the patient. The needle safety guard will cover the needle when releasing the plunger.

Using the pre-filled syringe without a needle safety guard

Administer the dose as per standard protocol. Disposal

Any unused product or waste material should be disposed of in accordance with local requirements.