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`Drug Approval Package
`
` Neulasta (Pegfilgrastim) Injection
`Company: Amgen, Inc.
`Application No.: 125031
`Approval Date: 1/31/2002
`
`Approval Letter(s) (PDF)
`Printed Labeling (PDF)
`Medical Review(s)
`Part 1 (PDF)
`Part 2 (PDF)
`Part 3 (PDF)
`Chemistry Review(s) (PDF)
`Pharmacology Review(s) (PDF)
`Statistical Review(s) (PDF)
`Clinical Pharmacology Biopharmaceutics Review(s) (PDF)
`
`Date created: October 252004
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`Ex. 1031 - Page 1 of 29
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`AMGEN INC.
`Exhibit 1031
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`

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`Ex. 1031 - Page 2 of 29
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`

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`CENTER FOR DRUG EVALUATION AND
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`RESEARCH AND CENTER FOR BIOLOGICS
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`EVALUATION AND RESEARCH
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`APPLICA TION NUMBER:
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`125031/0
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`APPROVED LABELING
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`Ex. 1031 - Page 3 of 29
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`Ex. 1031 - Page 3 of 29
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`Physician Package Insert
`Neulastan‘ (PegfiIgrastim)
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`Page 1 of 17
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`[NeuIastaTM] (pegfilgrastim)
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`DESCRIPTION
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`NeulastaTM (pegfilgrastim) is a covalent conjugate of recombinant methionyl human
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`G-CSF (Filgrastim) and monomethoxypolyethylene glycol. Filgrastim is a water-soluble
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`175 amino acid protein with a molecular weight of approximately 19 kilodaltons (kD).
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`Filgrastim is obtained from the bacterial fermentation of a strain of Escherichia coli
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`transformed with a genetically engineered plasmid containing the human G—CSF gene.
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`To produce pegfilgrastim, a 20 kD monomethoxypolyethylene glycol molecule is
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`covalently bound to the N-terminal methionyl residue of Filgrastim. The average
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`molecular weight of pegfilgrastim is approximately 39 kD.
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`NeulastaTM is supplied in 0.6 mL prefilled syringes for subcutaneous (SC) injection.
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`Each syringe contains 6 mg pegfilgrastim (based on protein weight), in a sterile, clear,
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`colorless, preservative—free solution (pH 4.0) containing acetate (0.35 mg), sorbitol
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`(30.0 mg), polysorbate 20 (0.02 mg), and sodium (002 mg) in water for injection, USP.
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`CLINICAL PHARMACOLOGY
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`Both Filgrastim and pegfilgrastim are Colony Stimulating Factors that act on
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`hematopoietic cells by binding to specific cell surface receptors thereby stimulating
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`proliferation, differentiation, commitment, and end cell functional activation. 1’2 Studies
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`on cellular proliferation, receptor binding, and neutrophil fimction demonstrate that
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`Amgen Thousand Oaks
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`AMGEN
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`EX. 1031 - Page 4 of 29
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`Ex. 1031 - Page 4 of 29
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`Physician Package Insert
`Neulastam (Pegfilgrastim)
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`Page 2 of 17
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`22
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`23
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`Filgrastim and pegfilgrastim have the same mechanism of action. Pegfilgrastim has
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`reduced renal clearance and prolonged persistence in vivo as compared to Filgrastim.
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`24
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`Pharmacokinetics
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`25
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`The pharmacokinetics and pharmacodynamics of NeulastaTM were studied in 379 patients
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`with cancer. The pharmacokinetics of NeulastaTM were nonlinear in cancer patients and
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`clearance decreased with increases in dose. Neutrophil receptor binding is an important
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`component of the clearance of NeulastaTM, and serum clearance is directly related to the
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`number of neutrophils. For example, the concentration of NeulastaTM declined rapidly at
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`the onset of neutrophil recovery that followed myelosuppressive chemotherapy. In
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`addition to numbers of neutrophils, body weight appeared to be a factor. Patients with
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`higher body weights experienced higher systemic exposure to NeulastaTM after receiving
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`a dose normalized for body weight. A large variability in the pharmacokinetics of
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`NeulastaTM was observed in cancer patients. The half-life of NeulastaTM ranged from 15
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`to 80 hours after SC injection.
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`Special Populations
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`No gender-related differences were observed in the pharmacokinetics of NeulastaTM, and
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`no differences were observed in the pharmacokinetics of geriatric patients (2 65 years of
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`age) compared to younger patients (< 65 years of age) (see PRECAUTIONS, Geriatric
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`Use). The pharmacokinetic profile in pediatric populations or in patients with hepatic or
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`renal insufficiency has not been assessed.
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`Amgen Thousand Oaks
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`AMG EN
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`Ex. 1031 - Page 5 of 29
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`Physician Package Insert
`Neulasta‘m (Pegfilgrastim)
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`42
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`CLINICAL STUDIES
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`Page 3 of 17
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`43
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`45
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`NeulastaTM was evaluated in two randomized, double—blind, active control studies,
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`employing doxorubicin 60 mg/m2 and docetaxel 75 mg/mz administered every 21 days
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`for up to 4 cycles for the treatment of metastatic breast cancer. Study 1 investigated the
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`utility of a fixed dose of NeulastaTM. Study 2 employed a weight—adjusted dose. In the
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`absence of growth factor support, similar chemotherapy regimens have been reported to
`result in a 100% incidence of severe neutropenia (absolute neutrophil count [ANC]
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`< 0.5 x 109/L) with a mean duration of 5-7 days, and a 30—40% incidence of febrile
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`neutropenia. Based on the correlation between the duration of severe neutropenia and the
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`incidence of febrile neutropenia found in studies with Filgrastim, duration of severe
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`neutropenia was chosen as the primary endpoint in both studies, and the efficacy of
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`NeulastaTM was demonstrated by establishing comparability to Filgrastim
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`(NEUPOGEN®)-treated subjects in the mean days of severe neutropenia.
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`In study 1, 157 subjects were randomized to receive a single SC dose of 6 mg of
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`NeulastaTM on day 2 of each chemotherapy cycle or Filgrastim at 5 mcg/kg/day SC
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`beginning on day 2 of each cycle. In study 2, 310 subjects were randomized to receive a
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`single SC injection of NeulastaTM at 100 meg/kg on day 2 or Filgrastim at 5 mcg/kg/day
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`SC beginning on day 2 of each cycle of chemotherapy.
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`Both studies met the primary objective of demonstrating that the mean days of severe
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`neutropenia of NeulastaTM—treated patients did not exceed that of Filgrastim—treated
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`Amgen Thousand Oaks
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`AMG EN
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`Ex. 1031 - Pa e 6of29
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`Ex. 1031 - Page 6 of 29
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`Physician Package Insert
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`NeuIastam (Pegfilgrastim)
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`Page 4 of 17
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`64
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`patients by more than one day in cycle 1 of chemotherapy (see Table l). The rates of
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`65
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`febrile neutropenia in the two studies were comparable for NeulastaTM and Filgrastim (in
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`66
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`67
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`the range of 10 to 20%). Other secondary endpoints included days of severe neutropenia
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`in cycles 2—4, the depth of ANC nadir in cycles l-4, and the time to ANC recovery afier
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`68
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`nadir. In both studies, the results for the secondary endpoints were similar between the
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`69
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`two treatment groups.
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`70
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`Table 1. Mean Days of Severe Neutropenia (in Cycle 1)
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`Study
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`Study]
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`n = 157
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`Study 2
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`n z 310
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`Mean_aysof severe—eutropenia
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`Difference in means
`®
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`Neulastama
`NEUPOGEN
`(5 mcg/kg/day)
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`(95% CI)
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`
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`02
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`(-0.2, 0.6)
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`0.1
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`(4)2, 0.4)
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`71
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`a.
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`Study 1 dose— 6 mg x 1; study 2 dose—- 100 meg/kg x 1
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`INDICATIONS AND USAGE
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`73
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`NeulastaTM is indicated to decrease the incidence of infection, as manifested by febrile
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`75
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`neutropenia, in patients with non- myeloid malignancies receiving myelosuppressive
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`anti—cancer drugs associated with a clinically significant incidence of febrile neutropenia.
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`CONTRAINDICATIONS
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`77
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`NeulastaTM is contraindicated in patients with known hypersensitivity to E coli—derived
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`proteins, pegfilgrastim, Filgrastim, or any other component of the product.
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`Amgen Thousand Oaks
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`AMGEN
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`Ex. 1031 - Page 7 of 29
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`Ex. 1031 - Page 7 of 29
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`Physician Package Insert
`Neulastam (Pegfilgrastim)
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`79 WARNINGS
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`80
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`Splenic Rupture
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`Page 5 of 17
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`81
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`RARE CASES OF SPLENIC RUPTURE HAVE BEEN REPORTED
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`FOLLOWING THE ADMINISTRATION OF THE PARENT COMPOUND OF
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`NEULASTATM, FILGRASTIM, FOR PB PC MOBILIZATION IN BOTH
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`84
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`HEALTHY DONORS AND PATIENTS WITH CANCER. SOME OF THESE
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`85
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`CASES WERE FATAL. NEULASTATM HAS NOT BEEN EVALUATED IN THIS
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`86
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`SETTING, THEREFORE, NEULASTATM SHOULD NOT BE USED FOR PBPC
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`87 MOBILIZATION. PATIENTS RECEIVING NEULASTATM WHO REPORT
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`88
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`LEFT UPPER ABDOMINAL OR SHOULDER TIP PAIN SHOULD BE
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`89
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`EVALUATED FOR AN ENLARGED SPLEEN OR SPLENIC RUPTURE.
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`90 Adult Respiratory Distress Syndrome (ARDS)
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`91
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`Adult respiratory distress syndrome (ARDS) has been reported in neutropenic patients
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`92
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`with sepsis receiving Filgrastim, the parent compound of NeulastaTM, and is postulated to
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`93
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`be secondary to {an influx of neutrophils to sites of inflammation in the lungs.
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`94
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`Neutropenic patients receiving NeulastaTM who develop fever, lung infiltrates, or
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`95
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`respiratory distress should be evaluated for the possibility of ARDS. In the event that
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`96
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`ARDS occurs, NeulastaTM should be discontinued and/or withheld until resolution of
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`ARDS and patients should receive appropriate medical management for this condition.
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`Amgen Thousand Oaks
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`AMG EN
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`Ex. 1031 - Page 8 of 29
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`Ex. 1031 - Page 8 of 29
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`Physician Package Insert
`NeulastaTM (Pegfilgrastim)
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`Page 6 of 17
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`98 Allergic Reactidns
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`99
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`Allergic—type reactions, including anaphylaxis, skin rash and urticaria, occurring on
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`100
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`initial or subsequent treatment have been reported with the parent compound of
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`NeulastaTM, Filgrastim.
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`In some cases, symptoms have recurred with rechallenge,
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`suggesting a causal relationship. Allergic-type reactions to NeulastaTM have not been
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`103
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`observed in clinical trials. If a serious allergic reaction or an anaphylactic reaction
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`104
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`occurs, appropriate therapy should be administered and fiirther use of NeulastaTM should
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`105
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`be discontinued.
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`106
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`Sickle Cell Disease
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`107
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`Severe sickle cell crises have been reported in patients with sickle cell disease
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`108
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`(specifically homozygous sickle cell anemia, sickle/hemoglobin C disease, and sickle/13+
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`109
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`thalassemia) who received Filgrastim, the parent compound of pegfilgrastim, for PBPC
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`110 mobilization or following chemotherapy. One of these cases was fatal. Pegfilgrastim
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`111
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`should be used with caution in patients with sickle cell disease, and only after careful
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`112
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`consideration of the potential risks and benefits. Patients with sickle cell disease who
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`113
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`receive NeulastaTM should be kept well hydrated and monitored for the occurrence of
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`114
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`sickle cell crises. In the event of severe sickle cell crisis supportive care should be
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`115
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`administered, and interventions to ameliorate the underlying event, such as therapeutic
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`116
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`red blood cell exchange transfusion, should be considered.
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`Amgen Thousand Oaks
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`AMGEN
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`Ex. 1031 - Page 9 of 29
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`Ex. 1031 - Page 9 of 29
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`Physician Package Insert
`NeulastaTM (Pegfilgrastim)
`
`
`117
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`PRECAUTIONS
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`118 General
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`Page 7 of 17
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`119 Use With Chemotherapy and/or Radiation Therapy
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`120
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`NeulastaTM should not be administered in the period between 14 days before and 24 hours
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`121
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`after administration of cytotoxic chemotherapy (see DOSAGE AND
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`122
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`ADMINISTRATION) because of the potential for an increase in sensitivity of rapidly
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`dividing myeloid cells to cytotoxic chemotherapy.
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`125
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`The use of NeulastaTM has not been studied in patients receiving chemotherapy associated
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`126
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`with delayed myelosuppression (eg, nitrosoureas, mitomycin C).
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`127
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`128
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`The administration of NeulastaTM concomitantly with 5- fluorouracil or other
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`antimetabolites has not been evaluated in patients. Administration of pegfilgrastim at 0,
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`1 and 3 days before 5- fluorouracil resulted in increased mortality in mice; administration
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`of pegfilgrastim 24 hours after 5—fluorouracil did not adversely affect survival.
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`133
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`The use of NeulastaTM has not been studied in patients receiving radiation therapy.
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`Potential Effect on Malignant Cells
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`135
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`Pegfilgrastim is a growth factor that primarily stimulates neutrophils and neutrophil
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`' 136
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`precursors; however, the G—CSF receptor through which pegfilgrastim and Filgrastim act
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`AMGEN
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`EX. 1031 - Page 10 of 29
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`Ex. 1031 - Page 10 of 29
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`Physician Package Insert
`NeulastaTM (Pegfilgrastim)
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`Page 8 of 17
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`137
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`has been found on tumor cell lines, including some myeloid, T— lymphoid, lung, head and
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`138
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`neck, and bladder tumor cell lines. The possibility that pegfilgrastim can act as a growth
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`139
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`factor for any tumor type cannot be excluded. Use of NeulastaTM in myeloid
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`140
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`. malignancies and myelodysplasia (MDS) has not been studied. In a randomized study
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`141
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`comparing the effects of the parent compound of NeulastaTM, Filgrastim, to placebo in
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`142
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`patients undergoing remission induction and consolidation chemotherapy for acute
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`143 myeloid leukemia, important differences in remission rate between the two arms were
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`excluded. Disease— free survival and overall survival were comparable; however, the
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`study was not designed to detect important differences in these endpoints.3
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`Information for Patients
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`147
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`Patients should be informed of the possible side effects of NeulastaTM, and be instructed
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`148
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`to report them to the prescribing physician. Patients should be informed of the signs and
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`149
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`symptoms of allergic drug reactions and be advised of appropriate actions. Patients
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`150
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`should be counseled on the importance of compliance with their NeulastaTM treatment,
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`151
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`including regular monitoring of blood counts.
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`152
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`153
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`If it is determined that a patient or caregiver can safely and effectively administer
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`NeulastaTM (pegfilgrastim) at home, appropriate instruction on the proper use of
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`155
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`NeulastaTM (pegfilgrastim) should be provided for patients and their caregivers, including
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`156
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`careful review of the “Information for Patients and Caregivers” insert. Patients and
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`157
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`caregivers should be cautioned against the reuse of needles, syringes, or drug product,
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`Amgen Thousand Oaks
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`AMGEN
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`Ex. 1031 - Page 11 of 29
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`Ex. 1031 - Page 11 of 29
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`Physician Package Insert
`NeulastaTM (Pegfilgrastim)
`
`Page 9 of 17
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`158
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`and be thoroughly instructed in their proper disposal. A puncture—resistant container for
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`159
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`the disposal of used syringes and needles should be available.
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`160
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`Laboratory Monitoring
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`161
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`To assess a patient’s hematologic status and ability to tolerate myelosuppressive
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`162
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`chemotherapy, a complete blood count and platelet count should be obtained before
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`163
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`chemotherapy is administered. Regular monitoring of hematocrit value and platelet count
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`164
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`is recommended.
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`165 Drug Interaction
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`166 No formal drug interaction studies between NeulastaTM and other drugs have been
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`167 ' performed. Drugs such as lithium may potentiate the release of neutrophils; patients
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`168
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`receiving lithium and NeulastaTM should have more frequent monitoring of neutrophil
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`169
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`counts.
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`170 Carcinogenesis, Mutagenesis, Impairment of Fertility
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`171
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`No mutagenesis studies were conducted with pegfilgrastim. The carcinogenic potential
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`172
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`of pegfilgrastim has not been evaluated in long—term animal studies. In a toxicity study
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`173
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`of 6 months duration in rats given once weekly subcutaneous injections of up to
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`174
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`1000 meg/kg of pegfllgrastim (approximately 23—fold higher than the recommended
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`175
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`human dose), no precancerous or cancerous lesions were noted.
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`176
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`Ex. 1031 - Page 12 of 29
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`Ex. 1031 - Page 12 of 29
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`Physician Package Insert
`Neulastam (Pegfilgrastim)
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`Page 10 of 17
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`177 When administered once weekly via subcutaneous injections to male and female rats at
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`178
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`doses up to 1000 meg/kg prior to, and during mating, reproductive performance, fertility
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`179
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`and sperm assessment parameters were not affected.
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`180
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`Pregnancy Category C
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`181
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`Pegfilgrastim has been shown to have adverse effects in pregnant rabbits when
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`182
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`administered SC every other day during gestation at doses as low as 50 mcg/kg/dose
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`183
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`(approximately 4— fold higher than the recommended human dose). Decreased maternal
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`184
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`food consumption, accompanied by a decreased maternal body weight gain and decreased
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`185
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`fetal body weights were observed at 50 to 1000 mcg/kg/dose. Pegfilgrastim doses of 200
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`186
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`and 250 mcg/kg/dose resulted in an increased incidence of abortions. Increased
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`187
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`post-implantation loss due to early resorptions, was observed at doses of 200 to
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`188
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`1000 mcg/kg/dose and decreased numbers of live rabbit fetuses were observed at
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`189
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`pegfilgrastim doses of 200 to 1000 mcg/kg/dose, given every other day.
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`190
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`191
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`Subcutaneous injections of pegfilgrastim of up to 1000 mcg/kg/dose every other day
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`192
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`during the period of organogenesis in rats were not associated with an embryotoxic or
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`193
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`194
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`fetotoxic outcome. However, an increased incidence (compared to historical controls) of
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`wavy ribs was observed in rat fetuses at 1000 mcg/kg/dose every otler day. Very low
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`195
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`levels (< 0.5%) of pegfilgrastim crossed the placenta when administered subcutaneously
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`196
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`to pregnant rats every other day during gestation.
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`197
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`Amgen Thousand Oaks
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`AMG EN
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`EX. 1031 - Page 13 of 29
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`Ex. 1031 - Page 13 of 29
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`Physician Package insert
`NeulastaTM (Pegfilgrastim)
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`Page 11 of 17
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`198
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`Once weekly subcutaneous injections of pegfilgrastim to female rats from day 6 of
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`199
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`gestation through day 18 of lactation at doses up to 1000 mcg/kg/dose did not result in
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`200
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`any adverse maternal effects. There were no deleterious effects on the growth and
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`201
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`development of the offspring and no adverse effects were found upon assessment of
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`202
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`fertility indices.
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`203
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`204
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`There are no adequate and well—controlled studies in pregnant women. NeulastaTM should
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`205
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`be used during pregnancy only if the potential benefit to the mother justifies the potential
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`206
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`risk to the fetus.
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`207 Nursing Mothers
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`208
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`It is not known whether pegfilgrastim is excreted in human milk. Because many drugs
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`209
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`are excreted in human milk, caution should be exercised when NeulastaTM is administered
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`210
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`to a nursing woman.
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`211
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`Pediatric Use
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`212
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`The safety and effectiveness of NeulastaTM in pediatric patients have not been established.
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`213
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`The 6 mg fixed dose single-use syringe formulation should not be used in infants,
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`214
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`children and smaller adolescents weighing less than 45 kg.
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`215 Geriatric Use
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`216
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`Of the 465 subjects with cancer who received NeulastaTM in clinical studies, 85 (18%)
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`217
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`were age 65 and over, and 14 (3%) were age 75 and over. No overall differences in
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`Amgen Thousand Oaks
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`Ex. 1031 - Page 14 of 29
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`Ex. 1031 - Page 14 of 29
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`Physician Package Insert
`Neulastam (Pegfilgrastim)
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`Page 12 of 17
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`safety or effectiveness were observed between these patients and younger patients;
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`219
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`however, due to the small number of elderly subjects, small but clinically relevant
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`differences cannot be excluded.
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`ADVERSE REACTIONS
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`See WARNINGS sections regarding Splenic Rupture, ARDS, Allergic Reactions, and
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`Sickle Cell Disease.
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`Safety data are based upon 465 subjects with lymphoma and solid tumors (breast, lung,
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`and thoracic tumors) enrolled in six randomized clinical studies. Subjects received
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`NeulastaTM after nonmyeloablative cytotoxic chemotherapy. Most adverse experiences
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`were attributed by the investigators to the underlying malignancy or cytotoxic
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`chemotherapy and occurred at similar rates in subjects who received NeulastaTM (n = 465)
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`230
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`or Filgrastim (n = 331). These adverse experiences occurred at rates between 72% and
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`231
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`15% and included: nausea, fatigue, alopecia, diarrhea, vomiting, constipation, fever,
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`232
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`anorexia, skeletal pain, headache, taste perversion, dyspepsia, myalgia, insomnia,
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`abdominal pain, arthralgia, generalized weakness, peripheral edema, dizziness,
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`granulocytopenia, stomatitis, mucositis, and neutropenic fever.
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`236
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`The most common adverse event attributed to NeulastaTM in clinical triak was medullary
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`bone pain, reported in 26% of subjects, which was comparable to the incidence in
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`Filgrastim— treated patients, This bone pain was generally reported to be of
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`Physician Package Insert
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`Page 13 of 17
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`rnild—to— moderate severity. Approximately 12% of all subjects utilized nonnarcotic
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`analgesics and less than 6% utilized narcotic analgesics in association with bone pain.
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`No patient withdrew from study due to bone pain.
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`In clinical studies, leukocytosis (WBC counts > 100 x lOg/L) was observed in less than
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`1% of 465 subjects with no n— myeloid malignancies receiving NeulastaTM. Leukocytosis
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`was not associated with any adverse effects.
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`In subjects receiving NeulastalM in clinical trials, the only serious event that was not
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`deemed attributable to underlying or concurrent disease, or to concurrent therapy was a
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`case of hypoxia.
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`Reversible elevations in LDH, alkaline phosphatase, and uric acid, which did not require
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`treatment intervention, were observed. The incidences of these changes, presented for
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`NeulastaTM relative to Filgrastim, were: LDH (19% versus 29%), alkaline phosphatase
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`254
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`(9% versus 16%), and uric acid (8% versus 9% [1% of reported cases for both treatment
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`groups were classified as severe]).
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`lmmunogenicity
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`As with all therapeutic proteins, there is a potential for immunogenicity. The incidence
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`of antibody development in patients receiving NeulastaTM has not been adequately
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`determined. While available data suggest that a small proportion of patients developed
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`AMGEN
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`Ex. 1031 - Page 16 of29’
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`Physician Package Insert
`NeulastaTM (Pegfilgrastim)
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`Page 14 of 17
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`binding antibodies to Filgrastim or pegfilgrastim, the nature and specificity of these
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`261
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`antibodies has not been adequately studied. No neutralizing antibodies have been
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`detected using a cell—based bioassay in 46 patients who apparently developed binding
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`antibodies. The detection of antibody formation is highly dependent on the sensitivity
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`and specificity of the assay, and the observed incidence of antibody positivity in an assay
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`265 may be influenced by several factors including sample handling, concomitant
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`266
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`medications, and underlying disease. Therefore, comparison of the incidence of
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`antibodies to NeulastaTM with the incidence of antibodies to other products may be
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`misleading.
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`270
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`Cytopenias resulting from an antibody response to exogenous growth factors have been
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`reported on rare occasions in patients treated with other recombinant growth factors.
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`There is a theoretical possibility that an antibody directed against pegfilgrastim may
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`cross-react with endogenous G—CSF, resulting in immune- mediated neutropenia, but this
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`has not been observed in clinical studies.
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`OVERDOSAGE
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`The maximum amount of NeulastaTM that can be safely administered in single or multiple
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`doses has not been determined. Single doses of 300 mcg/kg have been administered SC
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`to 8 normal volunteers and 3 patients with non—small cell lung cancer without serious
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`adverse effects. These subjects experienced a mean maximum ANC of 55 x 109/L, with a
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`corresponding mean maximum WBC of 67 x 109/L. The absolute maximum ANC
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`observed was 96 x 109/L with a corresponding absolute maximum WBC observed of
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`AMGEN
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`Ex. 1031 - Page 17 of 29
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`Physician Package Insert
`NeulastaTM (Pegfilgrastim)
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`Page 15 of 17
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`120 x lOg/L. The duration ofleukocytosis ranged from 6 to 13 days. Leukapheresis
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`should be considered in the management of symptomatic individuals.
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`DOSAGE AND ADMINISTRATION
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`The recommended dosage of NeulastaTM is a single subcutaneous (SC) injection of 6 mg
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`administered once per chemotherapy cycle. NeulastaTM should not be administered in the
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`period between 14 days before and 24 hours after administration of cytotoxic
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`chemotherapy (see PRECAUTIONS).
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`The 6 mg fixed dose formulation should not be used in infants, children and smaller
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`adolescents weighing less than 45 kg.
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`NeulastaTM should be visually inspected for discoloration and particulate matter before
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`administration. NeulastaTM should not be administered if discoloration or particulates are
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`observed.
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`NeulastaTM is supplied in prefilled syringes with UltraSafe® Needle Guards. Following
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`administration of NeulastaTM from the prefilled syringe, the UltraSafe® Needle Guard
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`should be activated to prevent accidental needle sticks. To activate the UltraSafe®
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`Needle Guard, place your hands behind the needle, grasp the guard with one hand, and
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`slide the guard forward until the needle is completely covered and the guard clicks into
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`place. NOTE: If an audible click is not heard, the needle guard may not be completely
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`AMGEN
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`Physician Package Insert
`Neulastam (Pegfilgrastim)
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`Page 16 of 17
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`activated The prefilled syringe should be disposed of by placing the entire prefilled
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`syringe with guard activated into an approved puncture—proof container.
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`Storage
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`NeulastaTM should be stored refrigerated at 2° to 8°C (36° to 46°F); syringes should be
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`308
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`kept in their carton to protect from light until time of use. Shaking should be avoided.
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`Before injection, NeulastaTM may be allowed to reach room temperature for a maximum
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`of 48 hours but should be protected from light. NeulastaTM left at room temperature for
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`more than 48 hours should be discarded; Freezing should be avoided; however, if
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`accidentally frozen, NeulastaTM should be allowed to thaw in the refrigerator before
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`administration. If frozen 3 second time, NeulastaTM should be discarded.
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`HOW SUPPLIED
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`NeulastaTM is supplied as a preservative- free solution containing 6 mg (0.6 mL) of
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`pegfilgrastim (10 mg/mL) in a single—dose syringe with a 27 gauge, 1/2 inch needle with
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`an UltraSafe® Needle Guard.
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`NeulastaTM is provided in a dispensing pack containing one syringe
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`(NDC 55513—190—01).
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`AMG E N
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`REFERENCES
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`Page 17 of 17
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`l. Morstyn G, Dexter T, Foote M. Filgrastim (r—metHuG—CSF) in clinical practice.
`
`2nd Edition. 1998;3151-71.
`
`2. Valerius T, Elsasser D, Repp R, et al. HLA Class-II antibodies recruit G—CSF
`
`activated neutrophils for treatment of B—cell malignancies. Leukemia and Lymphoma.
`
`1997;26, 261-269.
`
`3. Heil G, Hoelzer D, Sanz MA, et al. A randomized, double-blind, placebo~controlled,
`
`phase III study of Filgrastim in remission induction and consolidation therapy for
`
`adults with de novo Acute Myeloid Leukemia. Blood. 1997;90:4710—4718.
`
`[Amgen Logo]
`
`Manufactured by:
`
`Amgen Inc.
`
`One Amgen Center Drive
`
`Thousand Oaks, California 91320-1799
`
`© ZOXX Amgen Inc. All rights reserved.
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`Issue Date: XX/XX/XX
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`Amgen Thousand Oaks
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`AM G E N
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`Patient Package Insert
`
`
`
`NeulastaTM (pegfilgrastim) Page 1 of 9
`
`NeulastaTM
`
`(pegfilgrastim)
`
`INFORMATION FOR PATIENTS AND CAREGIVERS
`
`This patient package insert provides information and instructions for people who will be
`receiving NeulastaTM or their caregivers. This patient package insert does not tell you
`
`everything about NeulastaTM. You should discuss any questions you have about
`treatment with NeulastaTM with your doctor.
`
`What is Neulastam?
`
`NeulastaTM is a man-made form of granulocyte colony-stimulating factor (G—CSF), which
`is made using the bacteria E coli. G-CSF is a substance naturally produced by the body.
`It stimulates the growth of neutrophils (nu-tro—fils), a type of white blood cell important in
`the body’s fight against infection.
`
`V What is Neulastam used for?
`
`NeulastaTM is used to treat neutropenia (nu-tro—peen-ee—ah), a condition where the body
`makes too few white blood cells. Neutropenia can be caused by drugs used to treat
`cancer.
`
`How does NeulastaTM work?
`
`NeulastaTM works by stimulating the growth of neutrophils, a type of white blood cell. To
`
`make sure NeulastaTM is working, the doctor will ask that the patient have blood tests to
`count the number of white blood cells.
`it is important to follow the doctor‘s instructions
`about these tests.
`
`Who should not take Neulastam?
`
`.
`
`People who have had an allergic reaction to other products made using the
`bacteria E coli should not take NeulastaTM.
`
`Talk to your doctor if you have any questions about this information.
`
`What important information do I need to know about receiving Neulasta’m?
`
`NeulastaTM can reduce the risk of infection, but it may not prevent all infections. An
`infection can still happen during the time when your white blood cell levels are low. You
`must be alert and look for some of the common signs of infection, such as fever, chills,
`rash, sore throat, diarrhea, or redness, swelling, or pain around a cut or sore.
`If you
`notice any of these symptoms during treatment with NeulastaTM, tell your doctor or nurse
`immediately.
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`AMG EN
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`Ex. 1031 - Page 21 of 29
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`Ex. 1031 - Page 21 of 29
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`Patient Package insert
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`
`
`NeulastaTM (pegfilgrastim) Page 2 of 9
`
`If there is a lump, swelling, or
`Occasionally a reaction may develop at the injection site.
`bruising at the injection site that does not go away, talk to the doctor.
`
`If you have sickle cell disease, make sure that your doctor knows about it before using
`NeulastaTM.
`it is important that you drink plenty of fluids if you receive NeulastaTM.
`If you
`
`have a sickle cell crisis after getting Neulastam, you need to tell your doctor right away.
`
`Make sure your doctor knows about all medications you are taking before starting
`NeulastaTM injections.
`if you are taking lithium, you may need more frequent blood tests.
`
`The doctor, nurse, or caregiver will usually inject the dose of NeulastaTM a day after the
`last dose of chemotherapy in each cycle. NeulastaTM should only be injected on the day
`the doctor has determined and should not be injected until approximately 24 hours after
`receiving chemotherapy.
`
`More information about NeulastaTM is available in the Physician Package insert.
`have any questions, talk to your doctor.
`
`if you
`
`What are possible or reasonably likely side effects of Neulastam?
`
`The most common side effect you may experience is aching in the bones and muscles.
`If this happens, it can usually be relieved with a non—aspirin pain reliever, such as
`acetaminophen.
`‘
`
`Some people experience redness, swelling, or itching at the site of injection. This may
`be an allergy to the ingredients in NeulastaTM, or it may be a local reaction.
`If you notice
`signs of a local reaction, call your doctor.
`
`It is possible that serious allergic reactions could also happen. These reactions can
`cause a rash over the whole body, shortness of breath, wheezing, a dro