.,-:'

Date:

To:

Thru:

From:

Subject:

Drug Name(s):

Pediatric Exclusivity

Approval Date:

Application Type/Number:

Applicant/sponsor:

OSE RCM #:

Department of Health and Human ServicesPublic Health ServiceFood and Drug AdministrationCenter for Drug Evaluation and ResearchOffce of Surveilance and Epidemiology

October 22, 2010

Lisa L. Mathis MD, Associate DirectorPediatric and Maternal Health Staff (PMHS)Office of New Drugs (ON D), CDER

andM, Dianne Murphy, MD, DirectorOffice of Pediatric Therapeutics (OPT), OC

~. 1?-:i-l2-D l 0Bindi Nikhar, MD, Deputy Director.. ~ -' C 0Division of Pharmacovigilance II (DPV II) ~Office of Surveillance and Epidemiology (OSE),CDER

Robert Pratt, PharmD, Team LeaderDivision of Pharmacovigilance II (DPV II) Offce of Surveillance andEpidemiology (OSE), CDER

Corrinne Kulick, PharmD, Safety EvaluatorDivision 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 ......................................... ........................... ........................... ..... ......... .... 11 BACKGROUND.......... ....................................... .............. ....... ................................. ................ 1

1.1 Product Formulations and Indications .............................. .............................................. 1

1.2 Pediatric Filing history............................ ...................................................... ..................2

1.3 Pediatric labeling ...................................... ............................................... .......................22 METHODS AND MATERIALS ................................................................................................2

2.1 AERS Search Criteria..................................................................................................... 23 AERS RESULTS FOR PEGFILGRASTIM ...... ........................................................................3

3.1 Crude Counts of All AERS Reports........................................................... .....................3

3.2 Characteristics From Pediatric Safety Review.... ........................................................... 44 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...................................................................................................................... 66 RECOMMENDATIONS...........................................................................................................77 APPENDICES .........................................................................................................................7

7.1 Appendix A: Line listing of AERS cases associated with the use of pegfilgrastim inchildren 0-16 years old, received by the FDA from U.S. approval (31 January 2002) to 31August 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 useof Neulasta (pegfilgrastim) in pediatric patients (0-16 years of age). The focus of this review ispediatric 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 patientswith non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with aclinically significant incidence of febrile neutropenia. The safety and effectiveness of pegfilgrastimin pediatric patients has not been established.

We searched the Adverse Event Reporting System (AERS) database for all reports of adverseevents (serious and non-serious) up to the data lock date of 31 August 2010. AERS contained3641 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 thosecurrently found in the product label and described in the adult population or are not unexpectedfor the patient population. One case reported the unlabeled event glomerulonephritis coincidentwith filgrastim and pegfilgrastim, however, multiple medications and comorbidities, includinginflammator~ bowel disease,1,2 as well as recurrent infections coincident with chronic cyclicneutropenia provide a plausible alterriative etiology.

. Two cases reported death as an outcome. One case was attributed to cardiac arrest secondaryto compression of the aortic arch by lymphadenopathy; the second lacked sufficient information toassess the causal role of pegfilgrastim.

We did not identify any notable or unexpected safety concerns with pegfilgrastim use in pediatricpatients. DPV II will continue routine monitoring of adverse events with the use of pegfilgrastim inpediatric 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 febrileneutropenia, 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 forhematopoietic 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 RegistryAmerican 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 31January 2002, to decrease the incidence of infection; as manifested by febrile neutropenia, inpatients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associatedwith a clinically significant incidence of febrile neutropenia. As a condition of approval Amgencommitted to submit results from an ongoing study (990130) to evaluate the safety and efficacy ofpegfilgrastim in pediatric patients. On 14 November 2008, safety and pharmacokinetic data fromstudy 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 pediatricpopulation.

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. Theadverse reaction profile and pharmacokinetics of pegfilgrastim were studied in 37 pediatricpatients 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 21years agé group (n = 13), and 47.9 (:t 22.5) mcg'hr/mL in the youngest age group (0 to 5years, n = 11). The terminal elimination half-lives of the corresponding age groups were20.2 (:t 11.3) hours, 21.2 (:t 16.0) hours, and 30.1 (:t 38.2) hours, respectively. The mostcommon 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 matchingthe 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 27reports, 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 January2002) to 31 August 2010.

All reports (US)2 Serious3 (US) Death (US)

Adults(~17 rs.)

Pediatrics (0-16 rs.)

A e unknown (Null values)

Total1 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 otherserious 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 fromUS approval (31 January 2002) to 31 August 2010.

Figure 1: Number of Pediatric AERS Reports withPegfilgrastim by Year from U.S. Approval Date (31 January2002) to 31 August 2010

5

4

3AERS 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:12Female:12

0- -:1 month: 01 month -:2 yrs: 1

2-5 yrs: 3

6-11 yrs: 6

12-16 yrs: 14Mean 11 ears; Median 14 earsUS 21, Forei n 31996: 1 2003: 4 2007: 1 2010: 12001: 1 2004: 4 2008: 12002: 1 2006: 2 2009: 4Avera e 5 m ,Median 6 mMedian 1 dayRan e 1 to 365 da sChemotherapy induced neutropenia 18; Severe ChronicNeutropenia 5; neutropenia (NOS) 1

Death 2, Life-Threatening 3, Hospitalization 8Disability 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 unlabeledevent) secondary to compression of the aortic arch by lymphadenopathy and unrelated topegfilgrastim. The second case had insufficient information to assess the event. A summary ofthese 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 carboplatinand docetaxel chemotherapy with pegfilgrastim support (6 mg subcutaneously). The patientdeveloped noisy breathing within a few hours of commencing pegfilgrastim, went into cardiacarrest the same day, and died. The patient had no previous episodes of cardiac arrest buthad masses on the aortic arch. The patient's lung function prior to pegfilgrastimadministration was not reported. The patient appeared to be well following pegfilgrastim, withno signs or symptoms other than the noisy breathing. An autopsy was not performed butsubsequent investigations identified the cause of death to be cardiac arrest, withcompression 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 thecardiac 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 tissuereceived pegfilgrastim2 mg subcutaneously 24 hours after chemotherapy (not otherwisespecified (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 tosubmit a MedWatch form for any patient that expires, regardless of drug association. Thereporter had phoned the patient's home prior to dispensing the next dose(s) of pegfilgrastimand 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 ofpegfilgrastim. All events resolved with medication. No patients were rechallenged. The currentlabeling appropriately reflects the postmarketing experience with allergic-type events (seeWarnings and Precautions and Adverse Reactions - Postmarketing Experience). A summary ofthese four cases is provided below.

1. ISR 3962378- A 16 year old female with Hodgkin's disease, tape allergy, and a history ofa bee sting 2-3 days previous received adriamycin, bleomycin, vinblastine anddacarbazine followed by the initial injection of pegfilgrastim 6 mg. She developed a whealat the injection site which progressed to a generalized rash and hives. The patient washospitalized and stabilized with epinephrine, dexamethasone, and diphenhydramine. Thepatient then developed shortness of breath (oxygen sáturation of 70%), hypotension(BP"60"), chest pain, tachycardia, nausea and vomiting. Epinephrine was re-administeredand all symptoms except flushing resolved. Treatment with methylprednisolone anddiphenhydramine continued.

2. ISR 6413084- A 15 year old male with acute lymphocytic leukemia received the initialinjection of pegfilgrastim 6mg without complications. Approximately 6 hours later hecomplained of itching and the mother noticed large welts on his abdomen and legs andadministered diphenhydramine. Upon arrival to the hospital the hives had spread toupper 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 forneutropenia (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. Hedeveloped an injection site reaction characterized as localized, warm raised erythema 48hours after pegfilgrastim administration. Treatment included cetirizine, diphenhydramine,and warm compresses. All symptoms resolved within 5 days. Pegfilgrastim wasdiscontinued and filgrastim was administered with subsequent cycles of chemotherapywithout 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 inthese 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 offebrile neutropenia (n=2) or febrile infection (n=1). A summary of these three cases is providedbelow.

1. ISR 4412170- The 15 year old female was hospitalized for jaw abscess with fever andexperienced leucocytosis (135,900/mm\ a labeled event, 3 days following pegfilgrastimadministration. 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 anderroneously 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 following11 months of uneventful pegfilgrastim therapy (6 mg every 14 days). Three weeksfollowing hospital discharge she was again hospitalized for febrile neutropenia withcomplaints of headache and "abnormal sensation of the tongue." She recovered andresumed pegfilgrastim but at weekly intervals (6 mg every 7 days).

Of the remaining two cases, one was medically serious, however, multiple medications andcomorbidities, including inflammatory bowel disease,1.2 as well as recurrent infections coincidentwith chronic cyclic neutropenia3 provide plausible alternative etiology. The remaining case wasnon-serious. A summary of these two cases is provided below.

1. ISR 4170505- A 15 year old male with depression, persistent anemiå, normal bonemarrow biopsy, colon resection for typhlitis and multiple medical problems (NOS)experienced glomerulonephritis coincident with filgrastim. Prednisone, mycophenolateand a 12-month pulse regimen of methylprednisolone were administered withimprovement in signs and symptoms over the following 9 months. Prednisone taperresulted in a flare in signs and symptoms. Filgrastim was discontinued and pegfilgrastim6 mg every 23 days was initiated. He required several dose and frequency adjustmentsto prednisone and methylprednisone pulse therapy while on pegfilgrastim. Titers forneutralizing antibodies to filgrastim or pegfilgrastim were negative; renal biopsyperformed at the onset of the event compared to the biopsy performed 19 months laterwere similar and both showed endothelial and mesangial immune complexes.

2. ISR 5279067- A 7 year old male experienced declining response to filgrastim after 2years which lead to filgrastim discontinuation. Filgrastim was re-started some time laterchallenged with declining response after a year despite escalating doses. He was thenstarted on pegfilgrastim and experienced declining response after a year. The dispositionof 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 thosecurrently found in the product label and described in the adult population or are not unexpectedfor the patient population. One case reported the unlabeled event, Glomerulonephritis, coincidentwith filgrastim and pegfilgrastim, however, multiple medications and comorbidities, includinginflammator~ bowel disease, 1.2 as well as recurrent infections coincident with chronic cyclicneutropenia provide a plausible alternative etiology.

. Two cases reported death as an outcome. One was attributed to cardiac arrest secondary tocompression of the aortic arch by lymphadenopathy; the second lacked sufficient information toassess 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 oneevent of Urticaria both requiring emergency treatment and hospitalization. The current labelingappropriately reflects the postmarketing experience with allergic-type events (see Warnings andPrecautions and Adverse Reactions - Postmarketing Experience).

. Five cases involved miscellaneous events in patients with a variant of Severe ChronicNeutropenia, which is an unlabeled indication. Most events reported in these cases are notunexpected for the drug or the patient population and are labeled. One of these five casesincluded the adverse event Glomerulonephritis discussed above.

. Two cases reported Accidental Overdose (one serious), wherein each patient received the 6 mgadult dose in error. Both patients recovered without clinical sequela. These cases are underreview 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 inpediatric patients, we do not have any recommendations at this time. DPV II will continue routinemonitoring 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 0-16years old, received by the FDA from U.S. approval (31 January 2002) to 31 August 2010 (n=24).

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)

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