Global Medical Cures™ | NEULASTA- Pediatric PostMarketing Adverse Event Review
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Global Medical Cures™ | NEULASTA- Pediatric PostMarketing Adverse Event Review



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Global Medical Cures™ | NEULASTA- Pediatric PostMarketing Adverse Event Review Global Medical Cures™ | NEULASTA- Pediatric PostMarketing Adverse Event Review Document Transcript

  • .,-:' Date: To: Thru: From: Subject: Drug Name(s): Pediatric Exclusivity Approval Date: Application Type/Number: Applicant/sponsor: OSE RCM #: Department of Health and Human Services Public Health Service Food and Drug Administration Center for Drug Evaluation and Research Offce of Surveilance and Epidemiology October 22, 2010 Lisa L. Mathis MD, Associate Director Pediatric and Maternal Health Staff (PMHS) Office of New Drugs (ON D), CDER and M, Dianne Murphy, MD, Director Office of Pediatric Therapeutics (OPT), OC ~. 1?-:i-l2-D l 0Bindi Nikhar, MD, Deputy Director.. ~ -' C 0 Division of Pharmacovigilance II (DPV II) ~ Office of Surveillance and Epidemiology (OSE),CDER Robert Pratt, PharmD, Team Leader Division of Pharmacovigilance II (DPV II) Offce of Surveillance and Epidemiology (OSE), CDER Corrinne Kulick, PharmD, Safety Evaluator Division of Pharmacovigilance II (DPV II) Office of Surveillance and Epidemiology (OS E), CDER PREA: Pediatric Postmarketing Adverse Event Review Neulasta (pegfilgrastim) injection BLA 125031 Amgen Inc. 2010-1804
  • CONTENTS EXECUTIVE SUMMARY ......................................... ........................... ........................... ..... ......... .... 1 1 BACKGROUND.......... ....................................... .............. ....... ................................. ................ 1 1.1 Product Formulations and Indications .............................. .............................................. 1 1.2 Pediatric Filing history............................ ...................................................... ..................2 1.3 Pediatric labeling ...................................... ............................................... .......................2 2 METHODS AND MATERIALS ................................................................................................2 2.1 AERS Search Criteria..................................................................................................... 2 3 AERS RESULTS FOR PEGFILGRASTIM ...... ........................................................................3 3.1 Crude Counts of All AERS Reports........................................................... .....................3 3.2 Characteristics From Pediatric Safety Review.... ........................................................... 4 4 DISCUSSION/SUMMARY OF PEDIATRIC CASES............................................................... 4 4.1 Deaths (n= 2) ........................ .................. ................................................... .....................4 4.2 Allergic-type events (n=4)............................. ..................................................................5 4.3 Miscellaneous events in the Unlabeled Indication Severe Chronic Neutropenia (n=5) .5 5 CONCLUSiONS...................................................................................................................... 6 6 RECOMMENDATIONS...........................................................................................................7 7 APPENDICES .........................................................................................................................7 7.1 Appendix A: Line listing of AERS cases associated with the use of pegfilgrastim in children 0-16 years old, received by the FDA from U.S. approval (31 January 2002) to 31 August 2010 (n=24) ..................................................................................................................... 1
  • EXECUTIVE SUMMARY In accordance with Pediatric Research Equity Act (PREA), the Division of Pharmacovigilance (DPV) was asked to summarize post-marketing reports of adverse events associated with the use of Neulasta (pegfilgrastim) in pediatric patients (0-16 years of age). The focus of this review is pediatric deaths and pediatric reports of serious unlabeled adverse events with pegfilgrastim. Pegfilgrastim is a chemically modified human granulocyte colony-stimulating factor (G-CSF) indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia. The safety and effectiveness of pegfilgrastim in pediatric patients has not been established. We searched the Adverse Event Reporting System (AERS) database for all reports of adverse events (serious and non-serious) up to the data lock date of 31 August 2010. AERS contained 3641 reports for pegfilgrastim; pediatric reports represented approximately 0.74 % of the total (27/3641). Among 24 unique pediatric cases, we observed the following: . All but one of the pediatric cases reported adverse events that are qualitatively similar to those currently found in the product label and described in the adult population or are not unexpected for the patient population. One case reported the unlabeled event glomerulonephritis coincident with filgrastim and pegfilgrastim, however, multiple medications and comorbidities, including inflammator~ bowel disease,1,2 as well as recurrent infections coincident with chronic cyclic neutropenia provide a plausible alterriative etiology. . Two cases reported death as an outcome. One case was attributed to cardiac arrest secondary to compression of the aortic arch by lymphadenopathy; the second lacked sufficient information to assess the causal role of pegfilgrastim. We did not identify any notable or unexpected safety concerns with pegfilgrastim use in pediatric patients. DPV II will continue routine monitoring of adverse events with the use of pegfilgrastim in pediatric patients. 1 BACKGROUND 1.1 PRODUCT FORMULATIONS AND INDICATIONS Pegfilgrastim is supplied in the U.S. às: 6 mg per 0.6 mL in single use prefied syringe Pegfilgrastim is approved for the following indication: Neulasta is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti- cancer drugs associated with a clinically significant incidence of febrile neutropenia. Neulasta is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation. 1 Takemura T, Okada M, Yagi K, Kuwajima H, Yanagida H. An adolescent with IgA nephropathy and Crohn disease: pathogenetic implications. Pediatr Nephrol 2002; 17:863-6. 2 Filiopoulos V, Trompouki S, Hadjiyannakos D, Paraskevakou H, Kamperoglou D, et at. IgA nephropathy in association with Crohn's disease: a case report and brief review of the literature. Ren Fail 2010; 32(4):523-7. 3 Dale DC, Cottle TE, Fier CJ, Bolyard AA, Bonilla MA, et al. Severe Chronic Neutropenia: Treatment and Follow-Up of Patients in the Severe Chronic Neutropenia International Registry American Journal of Hematology 2003; 72:82-93. i
  • 1.2 PEDIATRIC FILING HISTORY Pegfilgrastim, a leukocyte growth factor (marketed by Amgen Inc.), received approval on 31 January 2002, to decrease the incidence of infection; as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia. As a condition of approval Amgen committed to submit results from an ongoing study (990130) to evaluate the safety and efficacy of pegfilgrastim in pediatric patients. On 14 November 2008, safety and pharmacokinetic data from study 990130 was included in the Use in Specific Populations-Pediatric Use section of the labeL. Study 990130 did not provide suffcient data to enable extrapolation of efficacy to the pediatric population. 1.3 PEDIATRIC LABELING The labeling for pegfilgrastim includes the following information concerning pediatric patients4. Safety and effectiveness of Neulasta in pediatric patients have not been established. The adverse reaction profile and pharmacokinetics of pegfilgrastim were studied in 37 pediatric patients with sarcoma. The mean (:t standard deviation (SOl) systemic exposure (AUCo-in& of pegfilgrastim after subcutaneous administration at 100 meg/kg was 22. a (:t 13.1) mcg.hr/mL in the 6 to 11 years age group (n = 10), 29.3 (:t 23.2) mcg'hr/mL in the 12 to 21 years agé group (n = 13), and 47.9 (:t 22.5) mcg'hr/mL in the youngest age group (0 to 5 years, n = 11). The terminal elimination half-lives of the corresponding age groups were 20.2 (:t 11.3) hours, 21.2 (:t 16.0) hours, and 30.1 (:t 38.2) hours, respectively. The most common adverse reaction was bone pain. 2 METHODS AND MATERIALS 2.1 AERS SEARCH CRITERIA We searched the FDA's Adverse Event Reporting System (AERS) database for reports matching the following criteria: . Drug terms: Active ingredient (pegfilgrastim) and trade name (Neulasta) . Medical Dictionary for Regulatory Activities (MedDRA) terms: All terms . Time period: FDA received dates from 31 January 2002 to 31 August 2010 . Age ranges: all ages and 0 to 16 years The AERS search retrieved a total of 3641 adverse event reports for pegfilgrastim (crude counts, see Section 3.1). Twenty-seven reports involved pediatric patients ages 0 to 16 years. Of the 27 reports, two were duplicates and one (ISR 6930600) was an incorrectly submitted/coded adult patient. Therefore, we assessed 24 unique pediatric cases in this pediatric safety review. 4 Neulasta (pegfilgrastim) injection, for subcutaneous use Product Label, Amgen Inc., February 2010 2
  • 3 AERS RESULTS FOR PEGFILGRASTIM 3.1 CRUDE COUNTS OF ALL AERS REPORTS Table 1 presents crude counts of AERS reports with pegfilgrastim from U.S. approval (31 January 2002) to 31 August 2010. All reports (US)2 Serious3 (US) Death (US) Adults(~17 rs.) Pediatrics (0-16 rs.) A e unknown (Null values) Total 1 May include duplicates 2 US counts in parentheses 3 Serious adverse drug experiences per regulatory definition (CFR 314.80) include outcomes of death, life-threatening, hospitalization (initial or prolonged), disability, congenital anomaly and other serious important medical events. 2444 (1527) 27 (21) 1170 (773) 3641 (2321) 1955 (1063) 22 (16) 695 (321) 2672 (1400) 209 (102) 2 (1) 66 (26) 277 (129) Figure 1 depicts the number of pediatric AERS reports with pegfilgrastim received per year from US approval (31 January 2002) to 31 August 2010. Figure 1: Number of Pediatric AERS Reports with Pegfilgrastim by Year from U.S. Approval Date (31 January 2002) to 31 August 2010 5 4 3 AERS Reports 2 1 o 1-# Peds Reports I ~~~~~~~~~oooOOOOOOOCDO..NW,i01cn.. Year 3
  • 3.2 CHARACTERISTICS FROM PEDIATRIC SAFETY REVIEW Table 3 describes the characteristics of the 24 pediatric AERS cases reported from U.S. Approval (31 January 2002) to 31 August 2010. Gender (n) Male:12 Female:12 0- -:1 month: 0 1 month -:2 yrs: 1 2-5 yrs: 3 6-11 yrs: 6 12-16 yrs: 14 Mean 11 ears; Median 14 ears US 21, Forei n 3 1996: 1 2003: 4 2007: 1 2010: 1 2001: 1 2004: 4 2008: 1 2002: 1 2006: 2 2009: 4 Avera e 5 m ,Median 6 m Median 1 day Ran e 1 to 365 da s Chemotherapy induced neutropenia 18; Severe Chronic Neutropenia 5; neutropenia (NOS) 1 Death 2, Life-Threatening 3, Hospitalization 8 Disability 1, Other Medically Serious 5; Non-serious 5 Characteristics of the 24 individual pediatric cases is provided in Appendix A. Ori in (n) Event date (n=20) Age (n) Dose (subcutaneous) (n=22J Duration of therapy (n=14) Reasons for use (n) Outcomes(n) 4 DlSCUSSION/SUMMARY OF PEDIATRIC CASES The AERS search retrieved 27 reports of pediatric patients, ages 0 to 16 years. Of the 27 reports two were duplicates and one (ISR 6930600) was an incorrectly submitted/coded adult patient. We assessed 24 unique pediatric cases in this pediatric safety review. 4.1 DEATHS (N= 2) Two cases had an outcome of death. One case attributed death to cardiac arrest (an unlabeled event) secondary to compression of the aortic arch by lymphadenopathy and unrelated to pegfilgrastim. The second case had insufficient information to assess the event. A summary of these two cases is provided below. 1. ISR 5154157; Foreign; Expedited-15 day 2006; Cardiac Arrest A 14-year-old female patient with metastatic squamous cell lung cancer received carboplatin and docetaxel chemotherapy with pegfilgrastim support (6 mg subcutaneously). The patient developed noisy breathing within a few hours of commencing pegfilgrastim, went into cardiac arrest the same day, and died. The patient had no previous episodes of cardiac arrest but had masses on the aortic arch. The patient's lung function prior to pegfilgrastim administration was not reported. The patient appeared to be well following pegfilgrastim, with no signs or symptoms other than the noisy breathing. An autopsy was not performed but subsequent investigations identified the cause of death to be cardiac arrest, with compression of the aortic arch caused by massive mediastinal and hilar lymphadenopathy 4
  • the likely causative factor. The reporting physician felt that there was no possibility that the cardiac arrest may have been caused by pegfilgrastim. 2. ISR 6641459; US; Direct 201.0 An 8 year old female patient with malignant neoplasm of connective and other soft tissue received pegfilgrastim2 mg subcutaneously 24 hours after chemotherapy (not otherwise specified (NOS)) over a period of 120 days and died. Reviewer's comment: On 7 October 2010, this evaluator spoke with the reporter who stated it is their policy to submit a MedWatch form for any patient that expires, regardless of drug association. The reporter had phoned the patient's home prior to dispensing the next dose(s) of pegfilgrastim and was informed the patient was deceased. No additional information was provided. 4.2 ALLERGIC-TYPE EVENTS (N=4) Four cases reported allergic-type events occurring within 48 hours of the first dose of pegfilgrastim. All events resolved with medication. No patients were rechallenged. The current labeling appropriately reflects the postmarketing experience with allergic-type events (see Warnings and Precautions and Adverse Reactions - Postmarketing Experience). A summary of these four cases is provided below. 1. ISR 3962378- A 16 year old female with Hodgkin's disease, tape allergy, and a history of a bee sting 2-3 days previous received adriamycin, bleomycin, vinblastine and dacarbazine followed by the initial injection of pegfilgrastim 6 mg. She developed a wheal at the injection site which progressed to a generalized rash and hives. The patient was hospitalized and stabilized with epinephrine, dexamethasone, and diphenhydramine. The patient then developed shortness of breath (oxygen sáturation of 70%), hypotension(BP "60"), chest pain, tachycardia, nausea and vomiting. Epinephrine was re-administered and all symptoms except flushing resolved. Treatment with methylprednisolone and diphenhydramine continued. 2. ISR 6413084- A 15 year old male with acute lymphocytic leukemia received the initial injection of pegfilgrastim 6mg without complications. Approximately 6 hours later he complained of itching and the mother noticed large welts on his abdomen and legs and administered diphenhydramine. Upon arrival to the hospital the hives had spread to upper body and face. He was hospitalized and stabilized with epinephrine and steroids. All symptoms resolved within 24 hours. 3. ISR 6244513- A 6 year old female received an initial injection of pegfilgrastim 2 mg for neutropenia (NOS). She experienced headache, generalized erythema, dyspnea, hypotension and vomiting after the medication. Treatment included hydrocortisone, acetaminophen and epinephrine. The events resolved. 4. ISR 4656582- A 14 year old male with pelvic malignancy (NOS) received vincristine, doxorubicin, cyclophosphamide followed by an initial injection of 6 mg pegfilgrastim. He developed an injection site reaction characterized as localized, warm raised erythema 48 hours after pegfilgrastim administration. Treatment included cetirizine, diphenhydramine, and warm compresses. All symptoms resolved within 5 days. Pegfilgrastim was discontinued and filgrastim was administered with subsequent cycles of chemotherapy without recurrence of the event. 4.3 MISCELLANEOUS EVENTS IN THE UNLABELED INDICATION SEVERE CHRONIC NEUTROPENIA (N=5) Five cases involved pediatric patients with a variant of Severe Chronic Neutropenia, i.e., autoimmune, chronic cyclic, congenital, and severe congenital (n=2). Most events reported in these cases are not unexpected for the drug or the patient population and are labeled. 5
  • Three cases had an outcome of hospitalization; however, hospitalization occurred because of febrile neutropenia (n=2) or febrile infection (n=1). A summary of these three cases is provided below. 1. ISR 4412170- The 15 year old female was hospitalized for jaw abscess with fever and experienced leucocytosis (135,900/mm a labeled event, 3 days following pegfilgrastim administration. Leucocytosis could have also been influenced by the concurrent infection. Leucocytosis resolved in 4 days and she continued on pegfilgrastim. 2. ISR 67106095- The 2 year old male was hospitalized for febrile neutropenia and erroneously received 6 mg pegfilgrastim instead of 100 mcg/kg, a 937 mcg/kg overdose. He was discharged on day 11 without clinical sequela, and resumed daily filgrastim. 3. ISR 4242771- The 10 year old female was hospitalized for febrile neutropenia following 11 months of uneventful pegfilgrastim therapy (6 mg every 14 days). Three weeks following hospital discharge she was again hospitalized for febrile neutropenia with complaints of headache and "abnormal sensation of the tongue." She recovered and resumed pegfilgrastim but at weekly intervals (6 mg every 7 days). Of the remaining two cases, one was medically serious, however, multiple medications and comorbidities, including inflammatory bowel disease,1.2 as well as recurrent infections coincident with chronic cyclic neutropenia3 provide plausible alternative etiology. The remaining case was non-serious. A summary of these two cases is provided below. 1. ISR 4170505- A 15 year old male with depression, persistent anemiå, normal bone marrow biopsy, colon resection for typhlitis and multiple medical problems (NOS) experienced glomerulonephritis coincident with filgrastim. Prednisone, mycophenolate and a 12-month pulse regimen of methylprednisolone were administered with improvement in signs and symptoms over the following 9 months. Prednisone taper resulted in a flare in signs and symptoms. Filgrastim was discontinued and pegfilgrastim 6 mg every 23 days was initiated. He required several dose and frequency adjustments to prednisone and methylprednisone pulse therapy while on pegfilgrastim. Titers for neutralizing antibodies to filgrastim or pegfilgrastim were negative; renal biopsy performed at the onset of the event compared to the biopsy performed 19 months later were similar and both showed endothelial and mesangial immune complexes. 2. ISR 5279067- A 7 year old male experienced declining response to filgrastim after 2 years which lead to filgrastim discontinuation. Filgrastim was re-started some time later challenged with declining response after a year despite escalating doses. He was then started on pegfilgrastim and experienced declining response after a year. The disposition of pegfilgrastim was not provided. 5 CONCLUSIONS Among the 24 unique pediatric cases, we observed the following: . All but one of the pediatric cases reported adverse events that are qualitatively similar to those currently found in the product label and described in the adult population or are not unexpected for the patient population. One case reported the unlabeled event, Glomerulonephritis, coincident with filgrastim and pegfilgrastim, however, multiple medications and comorbidities, including inflammator~ bowel disease, 1.2 as well as recurrent infections coincident with chronic cyclic neutropenia provide a plausible alternative etiology. . Two cases reported death as an outcome. One was attributed to cardiac arrest secondary to compression of the aortic arch by lymphadenopathy; the second lacked sufficient information to assess the causal role of pegfilgrastim. 5 Dufour C, Cappelli B, Calvillo M, Fioredda F. et al. Similar favorable outcome of pegfilgrastim overdose in patients with different age and underlying disease. Haematologica 2010; 95: 684-5. 6
  • . Four cases reported allergic-type events, including one event of Anaphylactic Reaction and one event of Urticaria both requiring emergency treatment and hospitalization. The current labeling appropriately reflects the postmarketing experience with allergic-type events (see Warnings and Precautions and Adverse Reactions - Postmarketing Experience). . Five cases involved miscellaneous events in patients with a variant of Severe Chronic Neutropenia, which is an unlabeled indication. Most events reported in these cases are not unexpected for the drug or the patient population and are labeled. One of these five cases included the adverse event Glomerulonephritis discussed above. . Two cases reported Accidental Overdose (one serious), wherein each patient received the 6 mg adult dose in error. Both patients recovered without clinical sequela. These cases are under review by the Division of Medication Error Prevention and Analysis. 6 RECOMMENDATIONS Because we did not identify any notable or unexpected safety concerns with pegfilgrastim use in pediatric patients, we do not have any recommendations at this time. DPV II will continue routine monitoring of adverse events with the use of pegfilgrastim in pediatric patients. 7 APPENDICES Appendix A: Line listing of AERS cases associated with the use of pegfilgrastim in children 0-16 years old, received by the FDA from U.S. approval (31 January 2002) to 31 August 2010 (n=24). 7
  • 7.1ApPENDIXA:LINELISTINGOFAERSCASESASSOCIATEDWITHTHEUSEOFPEGFILGRASTIMINCHILDREN0-16YEARSOLD,RECEIVEDBYTHEFDA FROMU.S.APPROVAL(31JANUARY2002)TO31AUGUST2010(N=24) 5154157Expedited I 14/F iDE aorticocclusion,cardiac.iNeulasta,Carboplatin, IChemotherapy I6mgonce (15-Day)/GBarrest,hilarlymphadenopathy,Docetaxel(squamouscell lymphadenopathymediastinalcarcinomaofthe lung) 6641459IDirect/USI9/FIDEideathiNeulasta,NoOther ChemotherapyI2mgI120 MedicationsProvided(neoplasmof connectiveandother soft 3962378Expedited I 16/F ILT,HOIanaphylacticreaction Neulasta,Doxorubicin,mgonce (15-Day)/USBleomycin,Vinblastine, i(Hodgkin'sDacarbazinelymphoma) 4170505Expedited I 151M iOTIbloodalbumindecreased, Neulasta,Neupogen, IChronicSevere 6mgq23days270 (15-Day)/USdrugspecificantibodySomatropin,IronNeutropenia(chronic(ongoing) present,focalsegmentalSulfatethiaminCompoundcyclicneutropenia) glomerulosclerosis,Tab,FolicAcid,Sertraline glomerulonephritisrapidly progressive, hypocomplementaemia,lupus nephritis,whitebloodcells urinepositive 4172701IDirect/USI16/FiDSdysstasia,gaitdisturbance,Vincristine,Neulasta,ChemotherapyI6mgq25days neurotoxicity,peronealnerveDoxorubicin,Bleomycin,(hodgkin's palsyEtoposide,Prednisone,lymphoma) Cyclophosphamide, Neupogen 4238697Expedited131MHOdrugineffective,febrileNeulasta,NoOtherChemotherapy4.5mgUNK (15-Day)/USneutropeniaMedicationsReported(osteosarcoma) 4242771Expedited10/FHOdiseaserecurrence,febrileNeulasta,ConcertaChronicSevere6mgq14days330 (15-Day)/USneutropenia,headache,Neutropeniaincrease hypoaesthesiaoral(autoimmunefrequencytoq neutropenia)7days (ongoing)
  • 4258824Expedited I 151M IHOIescherichiasepsis,febrile Neulasta,Cytarabine, iChemotherapy i6mgonce (15-Day)/USneutropenia,septicshockAsparaginase,Fluticasone(acutelymphoid Propionate,Fexofenadine,leukemia) Trimethoprim- SuIfamethoxazole,Methotrex ate,Doxorubicin,Vincristine, Vancomycin,Tobramycin, Meropenem 4382430Expedited 181MILT,HO febrileneutropenia,abdominalNeulasta,Neurontin, IChemotherapy I2mgonce (15-Day)/USdistension,enterocolitis,Clotrimazole,Oxycodone,(Ewing'ssarcoma) tachycardia,tachypnoea,Senokot,Tylenol, atelectasis,clostridialVancomycin,Meropenem, infection,pleuraleffusionNilstat,Flagyl,Benadryl, Ondansetron,Cefepime, Septra,Ativan,Ambisome, Vincristine,Doxorubicin, Cyclophosphamide 4412170IExpedited I 15/F IHO febrileinfection,leukocytosis, INeulasta,Amoxicillinand ChronicSevere6mgq14days365 (15-Day)/UScellulitis,abscessjawc1avulanatepotassium,Neutropenia(ongoing) Ceftriaxonesodium, Vancomycin 4506566/4515088IExpedited I 16/F ILT,HOifebrilebonemarrowaplasia, ¡IfOSfamide,Mesna,ChemotherapyI6mgonce (15-Day)/USconfusionalstate,Etoposide,Carboplatin,(nephroblastoma) electroencephalogramNeulasta, abnormal,hallucination, tremor 4650551Expedited I 15/F lOTIanaemia,deafness,disease Cisplatin,Paclitaxel,Chemotherapy(renal6mgUNK (15-Day)/USprogression,hepaticGemcitabine,Neulasta,medullarycarcinoma) neoplasmmalignantrecurrent,Carboplatin,Methotrexate, hypokalaemia,Vinblastine,Doxorubicin hypomagnesaemia, hypophosphataemia,nausea, nephropathytoxic, neutropenia,thrombocytopenia 5126952Expedited i4.5/MiHO,OT pyrexia,febrileneutropenia,Neulasta,Ara-C,ChemotherapyI2.4mgonce (15-Day)/USblastcells,blastcellspresent,Asparaginase,Miralax,(lymphocytic shifttotheleftMorphine,Zantac,Zofran,leukemia) Senna 541348315428044IExpedited 131MiOT leukocytosisNeulasta,Temozolomide,Chemotherapy3mgIUNK (15-Day)/USEtoposide,(medulloblastoma) Cyclophosphamide,Mesna, Vincristine,Filgrastim 2
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