ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling:Splenic Rupture [see Warnings and Precautions (5.1)] Acute Respiratory Distress Syndrome [see Warnings and Precautions (5.2)] Serious Allergic Reactions [see Warnings and Precautions (5.3)] Use in Patients with Sickle Cell Disorders [see Warnings and Precautions (5.4)] Glomerulonephritis [see Warnings and Precautions (5.5)] Leukocytosis [see Warnings and Precautions (5.6)] Thrombocytopenia [see Warnings and Precautions (5.7)] Capillary Leak Syndrome [see Warnings and Precautions (5.8)] Potential for Tumor Growth Stimulatory Effects on Malignant Cells [see Warnings and Precautions (5.9)] Myelodysplastic syndrome [see Warnings and Precautions (5.10)] Acute myeloid leukemia [see Warnings and Precautions (5.10)] Aortitis [see Warnings and Precautions (5.11)] Splenic Rupture [see Warnings and Precautions (5.1)] Acute Respiratory Distress Syndrome [see Warnings and Precautions (5.2)] Serious Allergic Reactions [see Warnings and Precautions (5.3)] Use in Patients with Sickle Cell Disorders [see Warnings and Precautions (5.4)] Glomerulonephritis [see Warnings and Precautions (5.5)] Leukocytosis [see Warnings and Precautions (5.6)] Thrombocytopenia [see Warnings and Precautions (5.7)] Capillary Leak Syndrome [see Warnings and Precautions (5.8)] Potential for Tumor Growth Stimulatory Effects on Malignant Cells [see Warnings and Precautions (5.9)] Myelodysplastic syndrome [see Warnings and Precautions (5.10)] Acute myeloid leukemia [see Warnings and Precautions (5.10)] Aortitis [see Warnings and Precautions (5.11)] Most common adverse reactions (>= 5% difference in incidence compared to placebo) are bone pain and pain in extremity. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.Pegfilgrastim clinical trials safety data are based upon 932 patients receiving pegfilgrastim in seven randomized clinical trials. The population was 21 to 88 years of age and 92% female. The ethnicity was 75% Caucasian, 18% Hispanic, 5% Black, and 1% Asian. Patients with breast (n 823), lung and thoracic tumors (n 53) and lymphoma (n 56) received pegfilgrastim after nonmyeloablative cytotoxic chemotherapy. Most patients received single 100 mcg/kg (n 259) or single mg (n 546) dose per chemotherapy cycle over cycles.The following adverse reaction data in Table are from randomized, double-blind, placebo-controlled study in patients with metastatic or non-metastatic breast cancer receiving docetaxel 100 mg/m2 every 21 days (Study 3). total of 928 patients were randomized to receive either mg pegfilgrastim (n 467) or placebo (n 461). The patients were 21 to 88 years of age and 99% female. The ethnicity was 66% Caucasian, 31% Hispanic, 2% Black, and 1% Asian, Native American, or other.The most common adverse reactions occurring in >= 5% of patients and with between-group difference of >= 5% higher in the pegfilgrastim arm in placebo-controlled clinical trials are bone pain and pain in extremity.Table 2. Adverse Reactions with >= 5% Higher Incidence in Pegfilgrastim Patients Compared to Placebo in Study 3Body System Adverse Reaction Placebo (N 461)Pegfilgrastim mg SC onDay (N 467)Musculoskeletal and connective tissue disorders Bone pain26%31% Pain in extremity4%9%. LeukocytosisIn clinical studies, leukocytosis (WBC counts 100 109/L) was observed in less than 1% of 932 patients with non-myeloid malignancies receiving pegfilgrastim. No complications attributable to leukocytosis were reported in clinical studies.. 6.2 Immunogenicity. As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other pegfilgrastim products may be misleading.Binding antibodies to pegfilgrastim were detected using BIAcore assay. The approximate limit of detection for this assay is 500 ng/mL. Pre-existing binding antibodies were detected in approximately 6% (51/849) of patients with metastatic breast cancer. Four of 521 pegfilgrastim-treated subjects who were negative at baseline developed binding antibodies to pegfilgrastim following treatment. None of these patients had evidence of neutralizing antibodies detected using cell-based bioassay.. 6.3 Postmarketing Experience. The following adverse reactions have been identified during post approval use of pegfilgrastim products. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Splenic rupture and splenomegaly (enlarged spleen) [see Warnings and Precautions (5.1)] Acute respiratory distress syndrome (ARDS) [see Warnings and Precautions (5.2)] Allergic reactions/hypersensitivity, including anaphylaxis, skin rash, urticaria, generalized erythema, and flushing [see Warnings and Precautions (5.3)] Sickle cell crisis [see Warnings and Precautions (5.4)] Glomerulonephritis [see Warnings and Precautions (5.5)] Leukocytosis [see Warnings and Precautions (5.6)] Thrombocytopenia [see Warnings and Precautions (5.7)] Capillary Leak Syndrome [see Warnings and Precautions (5.8)] Injection site reactionsSweets syndrome (acute febrile neutrophilic dermatosis), cutaneous vasculitisMyelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) in patients with breast and lung cancer receiving chemotherapy and/or radiotherapy [see Warnings and Precautions (5.10)]Aortitis [see Warnings and Precautions (5.11)] Alveolar hemorrhage. Splenic rupture and splenomegaly (enlarged spleen) [see Warnings and Precautions (5.1)] Acute respiratory distress syndrome (ARDS) [see Warnings and Precautions (5.2)] Allergic reactions/hypersensitivity, including anaphylaxis, skin rash, urticaria, generalized erythema, and flushing [see Warnings and Precautions (5.3)] Sickle cell crisis [see Warnings and Precautions (5.4)] Glomerulonephritis [see Warnings and Precautions (5.5)] Leukocytosis [see Warnings and Precautions (5.6)] Thrombocytopenia [see Warnings and Precautions (5.7)] Capillary Leak Syndrome [see Warnings and Precautions (5.8)] Injection site reactions. Sweets syndrome (acute febrile neutrophilic dermatosis), cutaneous vasculitis. Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) in patients with breast and lung cancer receiving chemotherapy and/or radiotherapy [see Warnings and Precautions (5.10)]. Aortitis [see Warnings and Precautions (5.11)] Alveolar hemorrhage.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. No carcinogenicity or mutagenesis studies have been performed with pegfilgrastim products.Pegfilgrastim did not affect reproductive performance or fertility in male or female rats at cumulative weekly doses approximately to times higher than the recommended human dose (based on body surface area).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Pegfilgrastim products are colony-stimulating factors that act on hematopoietic cells by binding to specific cell surface receptors, thereby stimulating proliferation, differentiation, commitment, and end cell functional activation.. 12.2 Pharmacodynamics. Animal data and clinical data in humans suggest correlation between pegfilgrastim products exposure and the duration of severe neutropenia as predictor of efficacy. Selection of the dosing regimen of Stimufend is based on reducing the duration of severe neutropenia.. 12.3 Pharmacokinetics. The pharmacokinetics of pegfilgrastim was studied in 379 patients with cancer. The pharmacokinetics of pegfilgrastim was nonlinear, and clearance decreased with increases in dose. Neutrophil receptor binding is an important component of the clearance of pegfilgrastim, and serum clearance is directly related to the number of neutrophils. In addition to numbers of neutrophils, body weight appeared to be factor. Patients with higher body weights experienced higher systemic exposure to pegfilgrastim after receiving dose normalized for body weight. large variability in the pharmacokinetics of pegfilgrastim was observed. The half-life of pegfilgrastim ranged from 15 to 80 hours after subcutaneous injection.. Specific PopulationsNo gender-related differences were observed in the pharmacokinetics of pegfilgrastim, and no differences were observed in the pharmacokinetics of geriatric patients (>= 65 years of age) compared with younger patients (< 65 years of age) [see Use in Specific Populations (8.5)].. Renal ImpairmentIn study of 30 subjects with varying degrees of renal dysfunction, including end stage renal disease, renal dysfunction had no effect on the pharmacokinetics of pegfilgrastim.. Pediatric Patients with Cancer Receiving Myelosuppressive ChemotherapyThe pharmacokinetics and safety of pegfilgrastim were studied in 37 pediatric patients with sarcoma in Study [see Clinical Studies 14.1]. The mean (+- standard deviation [SD]) systemic exposure (AUC0-inf) of pegfilgrastim after subcutaneous administration at 100 mcg/kg was 47.9 (+- 22.5) mcg.hr/mL in the youngest age group (0 to years, = 11), 22.0 (+- 13.1) mcg.hr/mL in the to 11 years age group (n 10), and 29.3 (+- 23.2) mcg.hr/mL in the 12 to 21 years age group (n 13). The terminal elimination half- lives of the corresponding age groups were 30.1 (+- 38.2) hours, 20.2 (+- 11.3) hours, and 21.2 (+- 16.0) hours, respectively.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. Patients with Cancer Receiving Myelosuppressive ChemotherapyPegfilgrastim was evaluated in three randomized, double-blind, controlled studies. Studies and were active-controlled studies that employed doxorubicin 60 mg/m2 and docetaxel 75 mg/m2 administered every 21 days for up to cycles for the treatment of metastatic breast cancer. Study investigated the utility of fixed dose of pegfilgrastim. Study employed weight-adjusted dose. In the absence of growth factor support, similar chemotherapy regimens have been reported to result in 100% incidence of severe neutropenia (ANC 0.5 109/L) with mean duration of to days and 30% to 40% incidence of febrile neutropenia. Based on the correlation between the duration of severe neutropenia and the incidence of febrile neutropenia found in studies with filgrastim, duration of severe neutropenia was chosen as the primary endpoint in both studies, and the efficacy of pegfilgrastim was demonstrated by establishing comparability to filgrastim-treated patients in the mean days of severe neutropenia.In Study 1, 157 patients were randomized to receive single subcutaneous injection of pegfilgrastim (6 mg) on day of each chemotherapy cycle or daily subcutaneous filgrastim (5 mcg/kg/day) beginning on day of each chemotherapy cycle. In Study 2, 310 patients were randomized to receive single subcutaneous injection of pegfilgrastim (100 mcg/kg) on day or daily subcutaneous filgrastim (5 mcg/kg/day) beginning on day of each chemotherapy cycle.Both studies met the major efficacy outcome measure of demonstrating that the mean days of severe neutropenia of pegfilgrastim-treated patients did not exceed that of filgrastim-treated patients by more than day in cycle of chemotherapy. The mean days of cycle severe neutropenia in Study were 1.8 days in the pegfilgrastim arm compared to 1.6 days in the filgrastim arm [difference in means 0.2 (95% CI 0.2, 0.6)] and in Study were 1.7 days in the pegfilgrastim arm compared to 1.6 days in the filgrastim arm [difference in means 0.1 (95% CI 0.2, 0.4)].A secondary endpoint in both studies was days of severe neutropenia in cycles through with results similar to those for cycle 1.Study was randomized, double-blind, placebo-controlled study that employed docetaxel 100 mg/m2 administered every 21 days for up to cycles for the treatment of metastatic or non-metastatic breast cancer. In this study, 928 patients were randomized to receive single subcutaneous injection of pegfilgrastim (6 mg) or placebo on day of each chemotherapy cycle. Study met the major trial outcome measure of demonstrating that the incidence of febrile neutropenia (defined as temperature >= 38.2C and ANC <= 0.5 109/L) was lower for pegfilgrastim-treated patients as compared to placebo-treated patients (1% versus 17%, respectively, < 0.001). The incidence of hospitalizations (1% versus 14%) and IV anti-infective use (2% versus 10%) for the treatment of febrile neutropenia was also lower in the pegfilgrastim-treated patients compared to the placebo-treated patients.Study was multicenter, randomized, open-label study to evaluate the efficacy, safety, and pharmacokinetics [see Clinical Pharmacology (12.3)] of pegfilgrastim in pediatric and young adult patients with sarcoma. Patients with sarcoma receiving chemotherapy age to 21 years were eligible. Patients were randomized to receive subcutaneous pegfilgrastim as single-dose of 100 mcg/kg (n 37) or subcutaneous filgrastim at dose mcg/kg/day (n 6) following myelosuppressive chemotherapy. Recovery of neutrophil counts was similar in the pegfilgrastim and filgrastim groups. The most common adverse reaction reported was bone pain.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.Pegfilgrastim clinical trials safety data are based upon 932 patients receiving pegfilgrastim in seven randomized clinical trials. The population was 21 to 88 years of age and 92% female. The ethnicity was 75% Caucasian, 18% Hispanic, 5% Black, and 1% Asian. Patients with breast (n 823), lung and thoracic tumors (n 53) and lymphoma (n 56) received pegfilgrastim after nonmyeloablative cytotoxic chemotherapy. Most patients received single 100 mcg/kg (n 259) or single mg (n 546) dose per chemotherapy cycle over cycles.The following adverse reaction data in Table are from randomized, double-blind, placebo-controlled study in patients with metastatic or non-metastatic breast cancer receiving docetaxel 100 mg/m2 every 21 days (Study 3). total of 928 patients were randomized to receive either mg pegfilgrastim (n 467) or placebo (n 461). The patients were 21 to 88 years of age and 99% female. The ethnicity was 66% Caucasian, 31% Hispanic, 2% Black, and 1% Asian, Native American, or other.The most common adverse reactions occurring in >= 5% of patients and with between-group difference of >= 5% higher in the pegfilgrastim arm in placebo-controlled clinical trials are bone pain and pain in extremity.Table 2. Adverse Reactions with >= 5% Higher Incidence in Pegfilgrastim Patients Compared to Placebo in Study 3Body System Adverse Reaction Placebo (N 461)Pegfilgrastim mg SC onDay (N 467)Musculoskeletal and connective tissue disorders Bone pain26%31% Pain in extremity4%9%. LeukocytosisIn clinical studies, leukocytosis (WBC counts 100 109/L) was observed in less than 1% of 932 patients with non-myeloid malignancies receiving pegfilgrastim. No complications attributable to leukocytosis were reported in clinical studies.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. Stimufend is contraindicated in patients with history of serious allergic reactions to pegfilgrastim products or filgrastim products. Reactions have included anaphylaxis [see Warnings and Precautions (5.3)].. Patients with history of serious allergic reactions to human granulocyte colony-stimulating factors such as pegfilgrastim products or filgrastim products. (4).

DESCRIPTION SECTION.

11 DESCRIPTION. Pegfilgrastim-fpgk is covalent conjugate of recombinant methionyl human G-CSF and monomethoxy polyethylene glycol. Recombinant methionyl human G-CSF is water-soluble 175 amino acid protein with molecular weight of approximately 19 kilodaltons (kD). Recombinant methionyl human G-CSF is obtained from the bacterial fermentation of strain of coli transformed with genetically engineered plasmid containing the human G-CSF gene. To produce pegfilgrastim-fpgk, 20 kD monomethoxy polyethylene glycol molecule is covalently bound to the N-terminal methionyl residue of recombinant methionyl human G-CSF. The average molecular weight of pegfilgrastim-fpgk is approximately 39 kD.Stimufend (pegfilgrastim-fpgk) injection is supplied in 0.6 mL pre-filled syringes for manual subcutaneous injection. The pre-filled syringe does not bear graduation marks and is designed to deliver the entire contents of the syringe (6 mg/0.6 mL).The delivered 0.6 mL dose from the prefilled syringe contains mg pegfilgrastim-fpgk (based on protein weight) in sterile, clear, colorless, preservative-free solution (pH 4.0) containing acetate (0.35 mg), polysorbate 20 (0.02 mg), sodium (0.02 mg), and sorbitol (30 mg) in Water for Injection, USP.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Patients with cancer receiving myelosuppressive chemotherapy6 mg administered subcutaneously once per chemotherapy cycle. (2.1)Do not administer between 14 days before and 24 hours after administration of cytotoxic chemotherapy. (2.1)Use weight based dosing for pediatric patients weighing less than 45 kg; refer to Table 1. (2.2) Patients with cancer receiving myelosuppressive chemotherapy6 mg administered subcutaneously once per chemotherapy cycle. (2.1)Do not administer between 14 days before and 24 hours after administration of cytotoxic chemotherapy. (2.1)Use weight based dosing for pediatric patients weighing less than 45 kg; refer to Table 1. (2.2) 6 mg administered subcutaneously once per chemotherapy cycle. (2.1). Do not administer between 14 days before and 24 hours after administration of cytotoxic chemotherapy. (2.1). Use weight based dosing for pediatric patients weighing less than 45 kg; refer to Table 1. (2.2). 2.1 Patients with Cancer Receiving Myelosuppressive Chemotherapy. The recommended dosage of Stimufend is single subcutaneous injection of mg administered once per chemotherapy cycle. For dosing in pediatric patients weighing less than 45 kg, refer to Table 1. Do not administer Stimufend between 14 days before and 24 hours after administration of cytotoxic chemotherapy.. 2.2 Administration. Stimufend is administered subcutaneously via single-dose prefilled syringe for manual use.Prior to use, remove the carton from the refrigerator and allow the Stimufend prefilled syringe to reach room temperature for minimum of 30 minutes. Discard any prefilled syringe left at room temperature for greater than 72 hours.Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not administer Stimufend if discoloration or particulates are observed.The needle cap on the pre-filled syringes contains dry natural rubber (derived from latex); persons with latex allergies should not administer these products.. Pediatric Patients weighing less than 45 kgThe Stimufend pre-filled syringe is not designed to allow for direct administration of doses less than 0.6 mL (6 mg). The syringe does not bear graduation marks, which are necessary to accurately measure doses of Stimufend less than 0.6 mL (6 mg) for direct administration to patients. Thus, the direct administration to patients requiring dosing of less than 0.6 mL (6 mg) is not recommended due to the potential for dosing errors. Refer to Table 1.Table 1. Dosing of Stimufend for Pediatric Patients Weighing Less Than 45 kgFor pediatric patients weighing less than 10 kg, administer 0.1 mg/kg (0.01 mL/kg) of Stimufend.Body WeightStimufend DoseVolume to AdministerLess than 10 kg See below See below 10 20 kg1.5 mg0.15 mL21 30 kg2.5 mg0.25 mL31 44 kg4 mg0.4 mL.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Stimufend is clear, colorless, preservative-free solution available as:Injection: mg/0.6 mL in single-dose pre-filled syringe for manual use only.. Injection: mg/0.6 mL in single-dose pre-filled syringe for manual use only.. Injection: mg/0.6 mL solution in single-dose pre-filled syringe for manual use only. (3).

GERIATRIC USE SECTION.

8.5 Geriatric Use. Of the 932 patients with cancer who received pegfilgrastim in clinical studies, 139 (15%) were aged 65 and over, and 18 (2%) were aged 75 and over. No overall differences in safety or effectiveness were observed between patients aged 65 and older and younger patients.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. Stimufend single-dose prefilled syringe for manual useStimufend (pegfilgrastim-fpgk) injection is clear, colorless, preservative-free solution supplied in pre-filled single-dose syringe for manual use containing mg pegfilgrastim-fpgk, supplied with 27-gauge, 1/2-inch needle with SafenSound(R) passive Needle Guard.The needle cap of the pre-filled syringe contains natural rubber (a derivative of latex).Stimufend is provided in dispensing pack containing one sterile mg/0.6 mL pre-filled syringe (NDC 65219-371-10).Stimufend pre-filled syringe does not bear graduation marks and is intended only to deliver the entire contents of the syringe (6 mg/0.6 mL) for direct administration. Use of the pre-filled syringe is not recommended for direct administration for pediatric patients weighing less than 45 kg who require doses that are less than the full contents of the syringe.Store refrigerated between 36F to 46F (2C to 8C) in the carton to protect from light. Do not shake. Discard syringes stored at room temperature for more than 72 hours. Do not freeze. Discard syringe if frozen.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Stimufend 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 clinically significant incidence of febrile neutropenia [see Clinical Studies (14.1)].. Stimufend is leukocyte growth factor 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 clinically significant incidence of febrile neutropenia. (1.1)Limitations of UseStimufend is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation.. Limitations of UseStimufend is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Advise patients of the following risks and potential risks with Stimufend:Splenic rupture and splenomegalyAcute Respiratory Distress SyndromeSerious allergic reactionsSickle cell crisisGlomerulonephritisIncreased risk of Myelodysplastic Syndrome and/or Acute Myeloid Leukemia in patients with breast and lung cancer who receive Stimufend in conjunction with chemotherapy and/or radiation therapyCapillary Leak SyndromeAortitisInstruct patients who self-administer Stimufend using the single-dose pre-filled syringe of the:Importance of following the Instructions for Use (see Instructions for Use).Dangers of reusing syringes.Importance of following local requirements for proper disposal of used syringes.Manufactured by: Fresenius Kabi USA, LLC Lake Zurich, Illinois 60047U.S. License No. 2146 Product of Italy. Splenic rupture and splenomegaly. Acute Respiratory Distress Syndrome. Serious allergic reactions. Sickle cell crisis. Glomerulonephritis. Increased risk of Myelodysplastic Syndrome and/or Acute Myeloid Leukemia in patients with breast and lung cancer who receive Stimufend in conjunction with chemotherapy and/or radiation therapy. Capillary Leak Syndrome. Aortitis. Importance of following the Instructions for Use (see Instructions for Use).. Dangers of reusing syringes.. Importance of following local requirements for proper disposal of used syringes.

INSTRUCTIONS FOR USE SECTION.

Instructions for UseSTIMUFEND(R) (STIM-yu-fend)(pegfilgrastim-fpgk)Injection, for subcutaneous useSingle-Dose Prefilled SyringeGuide to partsAfter Use (Clear needle guard locked in place) Important: The needle is covered by gray needle cap before use.Important:Read the Patient Information for important information you need to know about STIMUFEND before using these Instructions for Use.Before you use STIMUFEND prefilled syringe, read this important information.Storing the prefilled syringeStore STIMUFEND in the refrigerator between 36F and 46F (2C to 8C).Do not freeze. Throw away (dispose of) STIMUFEND that has been frozen.Keep the prefilled syringe in the original carton to protect from light or physical damage.Take the prefilled syringe out of the refrigerator 30 minutes before use and allow it to reach room temperature before preparing an injection.Throw away (dispose of) any STIMUFEND that has been left at room temperature, 68F to 77F (20C to 25C), for more than 72 hours.Keep the STIMUFEND prefilled syringe out of the reach of children.Using the prefilled syringeIt is important that you do not try to give the injection unless you or your caregiver has received training from your healthcare provider.Make sure the name STIMUFEND appears on the carton and prefilled syringe label.Check the carton and prefilled syringe label to make sure the dose strength is mg/0.6 mL.You should not inject dose of STIMUFEND to children weighing less than 45 kg from STIMUFEND prefilled syringe. dose less than 0.6 mL (6 mg) cannot be accurately measured using the STIMUFEND prefilled syringe.Do not use prefilled syringe after the expiration date on the label.Do not shake the prefilled syringe.Do not remove the gray needle cap from the prefilled syringe until you are ready to inject.Do not use the prefilled syringe if the carton is open or damaged.Do not use prefilled syringe if it has been dropped on hard surface. The prefilled syringe may be broken even if you cannot see the break. Use new prefilled syringe.The gray needle cap on the prefilled syringe contains dry natural rubber (made from latex). Tell your healthcare provider if you are allergic to latex. You should not give STIMUFEND using the prefilled syringe if you have latex allergies. The prefilled syringe has clear needle guard that automatically activates to cover the needle after the injection is given. Do not use prefilled syringe if the clear needle guard has been activated. Use another prefilled syringe that has not been activated and is ready to use.Call your healthcare provider if you have any questions.Step 1: Prepare1.1 Remove the prefilled syringe carton from the refrigerator. Remove the syringe tray from the carton.On clean, well-lit surface, place the syringe tray at room temperature for 30 minutes before you give an injection.Do not use the prefilled syringe if the carton is damaged.Do not try to warm the prefilled syringe by using heat source such as hot water or microwave.Do not leave the prefilled syringe in direct sunlight.Do not shake the prefilled syringe.Open the tray by peeling away the cover. Grab the clear needle guard to remove the prefilled syringe from the tray (see Figure C).For safety reasons:Do not grab the plunger rod.Do not grab the gray needle cap.1.2 Inspect the medicine and prefilled syringe.Make sure the medicine in the prefilled syringe is clear and colorless.Do not use the prefilled syringe if:The needle safety guard is activated (see Figure D).The medicine is cloudy or discolored, or contains flakes or particles (see Figure E).Any part appears cracked or broken.The prefilled syringe has been dropped.The gray needle cap is missing or not securely attached (see Figure E).The expiration date printed on the label has passed (see Figure E). In all cases use new syringe and call your healthcare provider.1.3 Gather all materials needed for the injection (see Figure F). Wash your hands thoroughly with soap and water.On clean, well-lit work surface, place the:Prefilled syringeAlcohol wipeCotton ball or gauze padAdhesive bandageSharps disposal containerStep 2: Get ready2.1 Prepare and clean the injection site(s). You can use:Stomach area (abdomen) except for 2-inch area away from the navel (belly button) (see Figure G)Thigh (see Figure G)Back area of the upper arm (only if someone else is giving you the injection) (See Figure H)Upper outer area of the buttocks (only if someone else is giving you the injection) (see Figure H)Clean the injection site with an alcohol wipe (see Figure I). Let the skin dry.Do not touch this area again before injecting.If you want to use the same injection site, make sure it is not the same spot on the injection site you used for previous injection.Do not inject into areas where the skin is tender, bruised, red, or hard. Avoid injecting into areas with scars or stretch marks.2.2 Hold the prefilled syringe by the clear needle guard. Carefully pull the gray needle cap straight off and away from the body (see Figure J).Do not remove the gray needle cap from the prefilled syringe until you are ready to inject.Do not twist or bend the gray needle cap.Do not hold the prefilled syringe by the plunger rod.Do not put the gray needle cap back onto the prefilled syringe.Important: Throw the gray needle cap into the sharps disposal container (see Figure K).Step 3: Subcutaneous (under the skin) injection3.1 Pinch the injection site to create firm surface (see Figure L).Important: Keep skin pinched while injecting.3.2 Hold the pinch. Insert the needle into the skin at 45 to 90 degrees (see Figure M).3.3 Using slow and constant pressure, push the plunger rod until it reaches the bottom (see Figure N).The plunger rod must be pushed down fully to ensure the full dose has been injected (see Figure O).Do not remove the needle from the skin when the plunger reaches the end and proceed with next step.Step 4: Finish4.1 Slowly release your thumb upward. This will allow the needle to move up into the clear needle guard and cover the entire needle (see Figure P).Do not try to recap the needle as it could lead to needle stick injury.Important: When you remove the syringe, if it looks like the medicine is still in the syringe barrel, this means you have not received full dose. Call your healthcare provider right away.4.2 Discard (throw away) your prefilled syringe.Put the used prefilled syringe in FDA-cleared sharps disposal container right away after use (see Figure Q).Do not throw away (dispose of) the prefilled syringe in your household trash.If you do not have FDA-cleared sharps disposal container, you may use household container that is:made of heavy-duty plastic,can be closed with tight-fitting, puncture-resistant lid, without sharps being able to come out,upright and stable during use,leak-resistant, andproperly labeled to warn of hazardous waste inside the container. When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDAs website at: http://www.fda.gov/safesharpsdisposal Do not reuse the prefilled syringe.Do not recycle the prefilled syringe or sharps disposal container or throw them in the household trash.Important: Always keep the sharps disposal container out of the reach of children.4.3 Examine the injection site.If there is blood, press cotton ball or gauze pad on the injection site. Do not rub the injection site. Apply an adhesive bandage if needed (see Figure R).This Instructions for Use has been approved by the U.S. Food and Drug Administration.Manufactured by: Fresenius Kabi USA, LLC Lake Zurich, Illinois 60047U.S. License No. 2146Issued: 09/2022. Store STIMUFEND in the refrigerator between 36F and 46F (2C to 8C).. Do not freeze. Throw away (dispose of) STIMUFEND that has been frozen.. Keep the prefilled syringe in the original carton to protect from light or physical damage.. Take the prefilled syringe out of the refrigerator 30 minutes before use and allow it to reach room temperature before preparing an injection.. Throw away (dispose of) any STIMUFEND that has been left at room temperature, 68F to 77F (20C to 25C), for more than 72 hours.. Keep the STIMUFEND prefilled syringe out of the reach of children.. It is important that you do not try to give the injection unless you or your caregiver has received training from your healthcare provider.. Make sure the name STIMUFEND appears on the carton and prefilled syringe label.. Check the carton and prefilled syringe label to make sure the dose strength is mg/0.6 mL.. You should not inject dose of STIMUFEND to children weighing less than 45 kg from STIMUFEND prefilled syringe. dose less than 0.6 mL (6 mg) cannot be accurately measured using the STIMUFEND prefilled syringe.. Do not use prefilled syringe after the expiration date on the label.. Do not shake the prefilled syringe.. Do not remove the gray needle cap from the prefilled syringe until you are ready to inject.. Do not use the prefilled syringe if the carton is open or damaged.. Do not use prefilled syringe if it has been dropped on hard surface. The prefilled syringe may be broken even if you cannot see the break. Use new prefilled syringe.. The gray needle cap on the prefilled syringe contains dry natural rubber (made from latex). Tell your healthcare provider if you are allergic to latex. You should not give STIMUFEND using the prefilled syringe if you have latex allergies. The prefilled syringe has clear needle guard that automatically activates to cover the needle after the injection is given. Do not use prefilled syringe if the clear needle guard has been activated. Use another prefilled syringe that has not been activated and is ready to use.. Do not use the prefilled syringe if the carton is damaged.. Do not try to warm the prefilled syringe by using heat source such as hot water or microwave.. Do not leave the prefilled syringe in direct sunlight.. Do not shake the prefilled syringe.. Do not grab the plunger rod.. Do not grab the gray needle cap.. Do not use the prefilled syringe if:The needle safety guard is activated (see Figure D).The medicine is cloudy or discolored, or contains flakes or particles (see Figure E).Any part appears cracked or broken.The prefilled syringe has been dropped.The gray needle cap is missing or not securely attached (see Figure E).The expiration date printed on the label has passed (see Figure E). The needle safety guard is activated (see Figure D).. The medicine is cloudy or discolored, or contains flakes or particles (see Figure E).. Any part appears cracked or broken.. The prefilled syringe has been dropped.. The gray needle cap is missing or not securely attached (see Figure E).. The expiration date printed on the label has passed (see Figure E).. Prefilled syringe. Alcohol wipe. Cotton ball or gauze pad. Adhesive bandage. Sharps disposal container. Stomach area (abdomen) except for 2-inch area away from the navel (belly button) (see Figure G). Thigh (see Figure G). Back area of the upper arm (only if someone else is giving you the injection) (See Figure H). Upper outer area of the buttocks (only if someone else is giving you the injection) (see Figure H). Do not touch this area again before injecting.. If you want to use the same injection site, make sure it is not the same spot on the injection site you used for previous injection.. Do not inject into areas where the skin is tender, bruised, red, or hard. Avoid injecting into areas with scars or stretch marks.. Do not remove the gray needle cap from the prefilled syringe until you are ready to inject.. Do not twist or bend the gray needle cap.. Do not hold the prefilled syringe by the plunger rod.. Do not put the gray needle cap back onto the prefilled syringe.. The plunger rod must be pushed down fully to ensure the full dose has been injected (see Figure O).. Do not remove the needle from the skin when the plunger reaches the end and proceed with next step.. Do not try to recap the needle as it could lead to needle stick injury.. Put the used prefilled syringe in FDA-cleared sharps disposal container right away after use (see Figure Q).. Do not throw away (dispose of) the prefilled syringe in your household trash.. If you do not have FDA-cleared sharps disposal container, you may use household container that is:made of heavy-duty plastic,can be closed with tight-fitting, puncture-resistant lid, without sharps being able to come out,upright and stable during use,leak-resistant, andproperly labeled to warn of hazardous waste inside the container. made of heavy-duty plastic,. can be closed with tight-fitting, puncture-resistant lid, without sharps being able to come out,. upright and stable during use,. leak-resistant, and. properly labeled to warn of hazardous waste inside the container.. When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDAs website at: http://www.fda.gov/safesharpsdisposal Do not reuse the prefilled syringe.. Do not recycle the prefilled syringe or sharps disposal container or throw them in the household trash.. If there is blood, press cotton ball or gauze pad on the injection site. Do not rub the injection site. Apply an adhesive bandage if needed (see Figure R).. Figure A. Figure B. Figure C. Figure D. Figure E. Figure F. Figures and H. Figure I. Figure J. Figure K. Figure L. Figure M. Figures and O. Figure P. Figure Q. Figure R. Fresenius Kabi Logo.

LACTATION SECTION.

8.2 Lactation. Risk SummaryThere are no data on the presence of pegfilgrastim products in human milk, the effects on the breastfed child, or the effects on milk production. Other filgrastim products are secreted poorly into breast milk, and filgrastim products are not absorbed orally by neonates. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for Stimufend and any potential adverse effects on the breastfed child from Stimufend or from the underlying maternal condition.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Pegfilgrastim products are colony-stimulating factors that act on hematopoietic cells by binding to specific cell surface receptors, thereby stimulating proliferation, differentiation, commitment, and end cell functional activation.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. No carcinogenicity or mutagenesis studies have been performed with pegfilgrastim products.Pegfilgrastim did not affect reproductive performance or fertility in male or female rats at cumulative weekly doses approximately to times higher than the recommended human dose (based on body surface area).

OVERDOSAGE SECTION.

10 OVERDOSAGE. Overdosage of pegfilgrastim products may result in leukocytosis and bone pain. Events of edema, dyspnea, and pleural effusion have been reported in single patient who administered pegfilgrastim on consecutive days in error. In the event of overdose, the patient should be monitored for adverse reactions [see Adverse Reactions (6)].

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE LABEL PRINCIPAL DISPLAY STIMUFEND -One 0.6 mL Single-Dose Prefilled Syringe CARTON PANELStimufendpegfilgrastim-fpgkInjection6 mg/0.6 mLNDC 65219-371-10Rx OnlyPegylated Recombinant Methionyl Human Granulocyte Colony-Stimulating Factor (PEG-r-methHuG-CSF) derived from ColiFor Subcutaneous Use Only1 single-dose pre-filled syringeThis product contains Dry Natural RubberSterile Solution-No Preservative. PACKAGE LABEL PRINCIPAL DISPLAY STIMUFEND -One 0.6 mL Single-Dose Prefilled Syringe CARTON PANEL.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness of pegfilgrastim have been established in pediatric patients. No overall differences in safety were identified between adult and pediatric patients based on postmarketing surveillance and review of the scientific literature.Use of pegfilgrastim in pediatric patients for chemotherapy-induced neutropenia is based on adequate and well-controlled studies in adults with additional pharmacokinetic and safety data in pediatric patients with sarcoma [see Clinical Pharmacology (12.3) and Clinical Studies (14.1)].

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Animal data and clinical data in humans suggest correlation between pegfilgrastim products exposure and the duration of severe neutropenia as predictor of efficacy. Selection of the dosing regimen of Stimufend is based on reducing the duration of severe neutropenia.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The pharmacokinetics of pegfilgrastim was studied in 379 patients with cancer. The pharmacokinetics of pegfilgrastim was nonlinear, and clearance decreased with increases in dose. Neutrophil receptor binding is an important component of the clearance of pegfilgrastim, and serum clearance is directly related to the number of neutrophils. In addition to numbers of neutrophils, body weight appeared to be factor. Patients with higher body weights experienced higher systemic exposure to pegfilgrastim after receiving dose normalized for body weight. large variability in the pharmacokinetics of pegfilgrastim was observed. The half-life of pegfilgrastim ranged from 15 to 80 hours after subcutaneous injection.. Specific PopulationsNo gender-related differences were observed in the pharmacokinetics of pegfilgrastim, and no differences were observed in the pharmacokinetics of geriatric patients (>= 65 years of age) compared with younger patients (< 65 years of age) [see Use in Specific Populations (8.5)].. Renal ImpairmentIn study of 30 subjects with varying degrees of renal dysfunction, including end stage renal disease, renal dysfunction had no effect on the pharmacokinetics of pegfilgrastim.. Pediatric Patients with Cancer Receiving Myelosuppressive ChemotherapyThe pharmacokinetics and safety of pegfilgrastim were studied in 37 pediatric patients with sarcoma in Study [see Clinical Studies 14.1]. The mean (+- standard deviation [SD]) systemic exposure (AUC0-inf) of pegfilgrastim after subcutaneous administration at 100 mcg/kg was 47.9 (+- 22.5) mcg.hr/mL in the youngest age group (0 to years, = 11), 22.0 (+- 13.1) mcg.hr/mL in the to 11 years age group (n 10), and 29.3 (+- 23.2) mcg.hr/mL in the 12 to 21 years age group (n 13). The terminal elimination half- lives of the corresponding age groups were 30.1 (+- 38.2) hours, 20.2 (+- 11.3) hours, and 21.2 (+- 16.0) hours, respectively.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryAlthough available data with Stimufend or pegfilgrastim product use in pregnant women are insufficient to establish whether there is drug associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes, there are available data from published studies in pregnant women exposed to filgrastim products. These studies have not established an association of filgrastim product use during pregnancy with major birth defects, miscarriage, or adverse maternal or fetal outcomes.In animal studies, no evidence of reproductive/developmental toxicity occurred in the offspring of pregnant rats that received cumulative doses of pegfilgrastim approximately 10 times the recommended human dose (based on body surface area). In pregnant rabbits, increased embryolethality and spontaneous abortions occurred at times the maximum recommended human dose simultaneously with signs of maternal toxicity (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.. Data. Animal DataPregnant rabbits were dosed with pegfilgrastim subcutaneously every other day during the period of organogenesis. At cumulative doses ranging from the approximate human dose to approximately times the recommended human dose (based on body surface area), the treated rabbits exhibited decreased maternal food consumption, maternal weight loss, as well as reduced fetal body weights and delayed ossification of the fetal skull; however, no structural anomalies were observed in the offspring from either study. Increased incidences of post-implantation losses and spontaneous abortions (more than half the pregnancies) were observed at cumulative doses approximately times the recommended human dose, which were not seen when pregnant rabbits were exposed to the recommended human dose.Three studies were conducted in pregnant rats dosed with pegfilgrastim at cumulative doses up to approximately 10 times the recommended human dose at the following stages of gestation: during the period of organogenesis, from mating through the first half of pregnancy, and from the first trimester through delivery and lactation. No evidence of fetal loss or structural malformations was observed in any study. Cumulative doses equivalent to approximately and 10 times the recommended human dose resulted in transient evidence of wavy ribs in fetuses of treated mothers (detected at the end of gestation but no longer present in pups evaluated at the end of lactation).

SPL PATIENT PACKAGE INSERT SECTION.

This Patient Information has been approved by the U.S. Food and Drug Administration. Issued: September 2022Patient Information Stimufend(R)(stim-yu-fend) (pegfilgrastim-fpgk) injectionSingle-Dose Prefilled SyringeWhat is StimufendStimufend is man-made form of granulocyte colony-stimulating factor (G-CSF). G-CSF is substance produced by the body. It stimulates the growth of neutrophils, type of white blood cell important in the bodys fight against infection.Do not take Stimufend if you have had serious allergic reaction to pegfilgrastim products or filgrastim products.Before you receive Stimufend, tell your healthcare provider about all of your medical conditions, including if you:have sickle cell disorder.have kidney problems.are allergic to latex. The needle cap on the prefilled syringe contains dry natural rubber (derived from latex). You should not give Stimufend using the prefilled syringe if you have latex allergies.are pregnant or plan to become pregnant. It is not known if Stimufend will harm your unborn baby.are breastfeeding or plan to breastfeed. It is not known if Stimufend passes into your breast milk.Tell your healthcare provider about all of the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.How will receive StimufendStimufend is given as an injection under your skin (subcutaneous injection) by healthcare provider. If your healthcare provider decides that the subcutaneous injections can be given at home by you or your caregiver, follow the detailed Instructions for Use that comes with your Stimufend for information on how to prepare and inject dose of Stimufend.You and your caregiver will be shown how to prepare and inject Stimufend before you use it.You should not inject dose of Stimufend to children weighing less than 45 kg from Stimufend prefilled syringe. dose less than 0.6 mL (6 mg) cannot be accurately measured using the Stimufend prefilled syringe.If you are receiving Stimufend because you are also receiving chemotherapy, the last dose of Stimufend should be injected at least 14 days before and 24 hours after your dose of chemotherapy.If you miss dose of Stimufend, talk to your healthcare provider about when you should give your next dose.What are possible side effects of StimufendStimufend may cause serious side effects, including:Spleen rupture. Your spleen may become enlarged and can rupture. ruptured spleen can cause death. Call your healthcare provider right away if you have pain in the left upper stomach area or your left shoulder.A serious lung problem called Acute Respiratory Distress Syndrome (ARDS). Call your healthcare provider or get emergency help right away if you have shortness of breath with or without fever, trouble breathing, or fast rate of breathing.Serious allergic reactions. Stimufend can cause serious allergic reactions. These reactions can cause rash over your whole body, shortness of breath, wheezing, dizziness, swelling around your mouth or eyes, fast heart rate, and sweating. If you have any of these symptoms, stop using Stimufend and call your healthcare provider or get emergency medical help right away.Sickle cell crises. You may have serious sickle cell crisis, which could lead to death, if you have sickle cell disorder and receive Stimufend. Call your healthcare provider right away if you have symptoms of sickle cell crisis such as pain or difficulty breathing.Kidney injury (glomerulonephritis). Stimufend can cause kidney injury. Call your healthcare provider right away if you develop any of the following symptoms:swelling of your face or anklesblood in your urine or dark colored urineyou urinate less than usual Increased white blood cell count (leukocytosis). Your healthcare provider will check your blood during treatment with Stimufend.Decreased platelet count (thrombocytopenia). Your healthcare provider will check your blood during treatment with Stimufend. Tell your healthcare provider if you have unusual bleeding or bruising during treatment with Stimufend. This could be sign of decreased platelet counts, which may reduce the ability of your blood to clot.Capillary Leak Syndrome. Stimufend can cause fluid to leak from blood vessels into your bodys tissues. This condition is called Capillary Leak Syndrome (CLS). CLS can quickly cause you to have symptoms that may become life-threatening. Get emergency medical help right away if you develop any of the following symptoms:swelling or puffiness and are urinating less than usualtrouble breathingswelling of your stomach area (abdomen) and feeling of fullnessdizziness or feeling fainta general feeling of tiredness Myelodysplastic syndrome and acute myeloid leukemia. If you have breast cancer or lung cancer, when Stimufend is used with chemotherapy and radiation therapy, or with radiation therapy alone, you may have an increased risk of developing precancerous blood condition called myelodysplastic syndrome (MDS) or blood cancer called acute myeloid leukemia (AML). Symptoms of MDS and AML may include tiredness, fever, and easy bruising or bleeding. Call your healthcare provider if you develop these symptoms during treatment with Stimufend.Inflammation of the aorta (aortitis). Inflammation of the aorta (the large blood vessel which transports blood from the heart to the body) has been reported in patients who received pegfilgrastim products. Symptoms may include fever, abdominal pain, feeling tired, and back pain. Call your healthcare provider if you experience these symptoms.The most common side effects of Stimufend are pain in the bones, arms, and legs.These are not all the possible side effects of Stimufend. Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store StimufendStore Stimufend in the refrigerator between 36F to 46F (2C to 8C).Do not freeze. Throw away (dispose of) Stimufend that has been frozen.Keep the prefilled syringe in the original carton to protect from light or physical damage.Do not shake the prefilled syringe.Take Stimufend out of the refrigerator 30 minutes before use and allow it to reach room temperature before preparing an injection.Throw away (dispose of) any Stimufend that has been left at room temperature, 68F to 77F (20C to 25C), for more than 72 hours.Keep the Stimufend prefilled syringe out of the reach of children.General information about the safe and effective use of Stimufend.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use Stimufend for condition for which it was not prescribed. Do not give Stimufend to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about Stimufend that is written for health professionals.What are the ingredients in StimufendActive ingredient: pegfilgrastim-fpgkInactive ingredients: acetate, polysorbate 20, sodium and sorbitol in Water for Injection, USP.Manufactured by: Fresenius Kabi USA, LLC Lake Zurich, Illinois 60047U.S. License No. 2146 Product of ItalyFor more information go to www.fresenius-kabi.com/us, or call 1-800-551-7176.. have sickle cell disorder.. have kidney problems.. are allergic to latex. The needle cap on the prefilled syringe contains dry natural rubber (derived from latex). You should not give Stimufend using the prefilled syringe if you have latex allergies.. are pregnant or plan to become pregnant. It is not known if Stimufend will harm your unborn baby.. are breastfeeding or plan to breastfeed. It is not known if Stimufend passes into your breast milk.. Stimufend is given as an injection under your skin (subcutaneous injection) by healthcare provider. If your healthcare provider decides that the subcutaneous injections can be given at home by you or your caregiver, follow the detailed Instructions for Use that comes with your Stimufend for information on how to prepare and inject dose of Stimufend.. You and your caregiver will be shown how to prepare and inject Stimufend before you use it.. You should not inject dose of Stimufend to children weighing less than 45 kg from Stimufend prefilled syringe. dose less than 0.6 mL (6 mg) cannot be accurately measured using the Stimufend prefilled syringe.. If you are receiving Stimufend because you are also receiving chemotherapy, the last dose of Stimufend should be injected at least 14 days before and 24 hours after your dose of chemotherapy.. If you miss dose of Stimufend, talk to your healthcare provider about when you should give your next dose.. Spleen rupture. Your spleen may become enlarged and can rupture. ruptured spleen can cause death. Call your healthcare provider right away if you have pain in the left upper stomach area or your left shoulder.. serious lung problem called Acute Respiratory Distress Syndrome (ARDS). Call your healthcare provider or get emergency help right away if you have shortness of breath with or without fever, trouble breathing, or fast rate of breathing.. Serious allergic reactions. Stimufend can cause serious allergic reactions. These reactions can cause rash over your whole body, shortness of breath, wheezing, dizziness, swelling around your mouth or eyes, fast heart rate, and sweating. If you have any of these symptoms, stop using Stimufend and call your healthcare provider or get emergency medical help right away.. Sickle cell crises. You may have serious sickle cell crisis, which could lead to death, if you have sickle cell disorder and receive Stimufend. Call your healthcare provider right away if you have symptoms of sickle cell crisis such as pain or difficulty breathing.. Kidney injury (glomerulonephritis). Stimufend can cause kidney injury. Call your healthcare provider right away if you develop any of the following symptoms:swelling of your face or anklesblood in your urine or dark colored urineyou urinate less than usual swelling of your face or ankles. blood in your urine or dark colored urine. you urinate less than usual. Increased white blood cell count (leukocytosis). Your healthcare provider will check your blood during treatment with Stimufend.. Decreased platelet count (thrombocytopenia). Your healthcare provider will check your blood during treatment with Stimufend. Tell your healthcare provider if you have unusual bleeding or bruising during treatment with Stimufend. This could be sign of decreased platelet counts, which may reduce the ability of your blood to clot.. Capillary Leak Syndrome. Stimufend can cause fluid to leak from blood vessels into your bodys tissues. This condition is called Capillary Leak Syndrome (CLS). CLS can quickly cause you to have symptoms that may become life-threatening. Get emergency medical help right away if you develop any of the following symptoms:swelling or puffiness and are urinating less than usualtrouble breathingswelling of your stomach area (abdomen) and feeling of fullnessdizziness or feeling fainta general feeling of tiredness swelling or puffiness and are urinating less than usual. trouble breathing. swelling of your stomach area (abdomen) and feeling of fullness. dizziness or feeling faint. general feeling of tiredness. Myelodysplastic syndrome and acute myeloid leukemia. If you have breast cancer or lung cancer, when Stimufend is used with chemotherapy and radiation therapy, or with radiation therapy alone, you may have an increased risk of developing precancerous blood condition called myelodysplastic syndrome (MDS) or blood cancer called acute myeloid leukemia (AML). Symptoms of MDS and AML may include tiredness, fever, and easy bruising or bleeding. Call your healthcare provider if you develop these symptoms during treatment with Stimufend.. Inflammation of the aorta (aortitis). Inflammation of the aorta (the large blood vessel which transports blood from the heart to the body) has been reported in patients who received pegfilgrastim products. Symptoms may include fever, abdominal pain, feeling tired, and back pain. Call your healthcare provider if you experience these symptoms.. Store Stimufend in the refrigerator between 36F to 46F (2C to 8C).. Do not freeze. Throw away (dispose of) Stimufend that has been frozen.. Keep the prefilled syringe in the original carton to protect from light or physical damage.. Do not shake the prefilled syringe.. Take Stimufend out of the refrigerator 30 minutes before use and allow it to reach room temperature before preparing an injection.. Throw away (dispose of) any Stimufend that has been left at room temperature, 68F to 77F (20C to 25C), for more than 72 hours.. Fresenius Kabi Logo.

SPL UNCLASSIFIED SECTION.

Limitations of UseStimufend is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryAlthough available data with Stimufend or pegfilgrastim product use in pregnant women are insufficient to establish whether there is drug associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes, there are available data from published studies in pregnant women exposed to filgrastim products. These studies have not established an association of filgrastim product use during pregnancy with major birth defects, miscarriage, or adverse maternal or fetal outcomes.In animal studies, no evidence of reproductive/developmental toxicity occurred in the offspring of pregnant rats that received cumulative doses of pegfilgrastim approximately 10 times the recommended human dose (based on body surface area). In pregnant rabbits, increased embryolethality and spontaneous abortions occurred at times the maximum recommended human dose simultaneously with signs of maternal toxicity (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.. Data. Animal DataPregnant rabbits were dosed with pegfilgrastim subcutaneously every other day during the period of organogenesis. At cumulative doses ranging from the approximate human dose to approximately times the recommended human dose (based on body surface area), the treated rabbits exhibited decreased maternal food consumption, maternal weight loss, as well as reduced fetal body weights and delayed ossification of the fetal skull; however, no structural anomalies were observed in the offspring from either study. Increased incidences of post-implantation losses and spontaneous abortions (more than half the pregnancies) were observed at cumulative doses approximately times the recommended human dose, which were not seen when pregnant rabbits were exposed to the recommended human dose.Three studies were conducted in pregnant rats dosed with pegfilgrastim at cumulative doses up to approximately 10 times the recommended human dose at the following stages of gestation: during the period of organogenesis, from mating through the first half of pregnancy, and from the first trimester through delivery and lactation. No evidence of fetal loss or structural malformations was observed in any study. Cumulative doses equivalent to approximately and 10 times the recommended human dose resulted in transient evidence of wavy ribs in fetuses of treated mothers (detected at the end of gestation but no longer present in pups evaluated at the end of lactation).. 8.2 Lactation. Risk SummaryThere are no data on the presence of pegfilgrastim products in human milk, the effects on the breastfed child, or the effects on milk production. Other filgrastim products are secreted poorly into breast milk, and filgrastim products are not absorbed orally by neonates. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for Stimufend and any potential adverse effects on the breastfed child from Stimufend or from the underlying maternal condition.. 8.4 Pediatric Use. The safety and effectiveness of pegfilgrastim have been established in pediatric patients. No overall differences in safety were identified between adult and pediatric patients based on postmarketing surveillance and review of the scientific literature.Use of pegfilgrastim in pediatric patients for chemotherapy-induced neutropenia is based on adequate and well-controlled studies in adults with additional pharmacokinetic and safety data in pediatric patients with sarcoma [see Clinical Pharmacology (12.3) and Clinical Studies (14.1)].. 8.5 Geriatric Use. Of the 932 patients with cancer who received pegfilgrastim in clinical studies, 139 (15%) were aged 65 and over, and 18 (2%) were aged 75 and over. No overall differences in safety or effectiveness were observed between patients aged 65 and older and younger patients.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Fatal splenic rupture: Evaluate patients who report left upper abdominal or shoulder pain for an enlarged spleen or splenic rupture. (5.1)Acute respiratory distress syndrome (ARDS): Evaluate patients who develop fever, lung infiltrates, or respiratory distress. Discontinue Stimufend in patients with ARDS. (5.2)Serious allergic reactions, including anaphylaxis: Permanently discontinue Stimufend in patients with serious allergic reactions. (5.3)Fatal sickle cell crises: Discontinue Stimufend if sickle cell crisis occurs. (5.4)Glomerulonephritis: Evaluate and consider dose- reduction or interruption of Stimufend if causality is likely. (5.5)Thrombocytopenia: Monitor platelet counts. (5.7)Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML): Monitor patients with breast and lung cancer using Stimufend in conjunction with chemotherapy and/or radiotherapy for signs and symptoms of MDS/AML. (5.10). Fatal splenic rupture: Evaluate patients who report left upper abdominal or shoulder pain for an enlarged spleen or splenic rupture. (5.1). Acute respiratory distress syndrome (ARDS): Evaluate patients who develop fever, lung infiltrates, or respiratory distress. Discontinue Stimufend in patients with ARDS. (5.2). Serious allergic reactions, including anaphylaxis: Permanently discontinue Stimufend in patients with serious allergic reactions. (5.3). Fatal sickle cell crises: Discontinue Stimufend if sickle cell crisis occurs. (5.4). Glomerulonephritis: Evaluate and consider dose- reduction or interruption of Stimufend if causality is likely. (5.5). Thrombocytopenia: Monitor platelet counts. (5.7). Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML): Monitor patients with breast and lung cancer using Stimufend in conjunction with chemotherapy and/or radiotherapy for signs and symptoms of MDS/AML. (5.10). 5.1 Splenic Rupture. Splenic rupture, including fatal cases, can occur following the administration of pegfilgrastim products. Evaluate for an enlarged spleen or splenic rupture in patients who report left upper abdominal or shoulder pain after receiving Stimufend.. 5.2 Acute Respiratory Distress Syndrome. Acute respiratory distress syndrome (ARDS) can occur in patients receiving pegfilgrastim products. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving Stimufend for ARDS. Discontinue Stimufend in patients with ARDS.. 5.3 Serious Allergic Reactions. Serious allergic reactions, including anaphylaxis, can occur in patients receiving pegfilgrastim products. The majority of reported events occurred upon initial exposure. Allergic reactions, including anaphylaxis, can recur within days after the discontinuation of initial anti-allergic treatment. Permanently discontinue Stimufend in patients with serious allergic reactions. Do not administer Stimufend to patients with history of serious allergic reactions to pegfilgrastim products or filgrastim products.. 5.4 Use in Patients with Sickle Cell Disorders. Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disorders receiving pegfilgrastim products. Discontinue Stimufend if sickle cell crisis occurs.. 5.5 Glomerulonephritis. Glomerulonephritis has occurred in patients receiving pegfilgrastim products. The diagnoses were based upon azotemia, hematuria (microscopic and macroscopic), proteinuria, and renal biopsy.Generally, events of glomerulonephritis resolved after dose-reduction or discontinuation of pegfilgrastim products. If glomerulonephritis is suspected, evaluate for cause. If causality is likely, consider dose- reduction or interruption of Stimufend.. 5.6 Leukocytosis. White blood cell (WBC) counts of 100 109/L or greater have been observed in patients receiving pegfilgrastim products. Monitoring of complete blood count (CBC) during Stimufend therapy is recommended.. 5.7 Thrombocytopenia. Thrombocytopenia has been reported in patients receiving pegfilgrastim products. Monitor platelet counts.. 5.8 Capillary Leak Syndrome. Capillary leak syndrome has been reported after G-CSF administration, including pegfilgrastim products, and is characterized by hypotension, hypoalbuminemia, edema and hemoconcentration. Episodes vary in frequency, severity and may be life-threatening if treatment is delayed. Patients who develop symptoms of capillary leak syndrome should be closely monitored and receive standard symptomatic treatment, which may include need for intensive care.. 5.9 Potential for Tumor Growth Stimulatory Effects on Malignant Cells. The granulocyte colony-stimulating factor (G-CSF) receptor through which pegfilgrastim products and filgrastim products act has been found on tumor cell lines. The possibility that pegfilgrastim products act as growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which pegfilgrastim products are not approved, cannot be excluded.. 5.10 Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML) in Patients with Breast and Lung Cancer. MDS and AML have been associated with the use of pegfilgrastim products in conjunction with chemotherapy and/or radiotherapy in patients with breast and lung cancer. Monitor patients for signs and symptoms of MDS/AML in these settings.. 5.11 Aortitis. Aortitis has been reported in patients receiving pegfilgrastim products. It may occur as early as the first week after start of therapy. Manifestations may include generalized signs and symptoms such as fever, abdominal pain, malaise, back pain, and increased inflammatory markers (e.g., c-reactive protein and white blood cell count). Consider aortitis in patients who develop these signs and symptoms without known etiology. Discontinue Stimufend if aortitis is suspected.. 5.12 Nuclear Imaging. Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes. This should be considered when interpreting bone imaging results.