PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. The time to the maximum ANC level was between to days and returned to baseline by 21 days following completion of chemotherapy. Doubling the tbo-filgrastim subcutaneous dose from mcg/kg to 10 mcg/kg resulted in 16% to 19% increase in the maximum ANC level and 33% to 36% increase in the area under the effect curve for ANC.Cardiac ElectrophysiologyAt an intravenous dose of mcg/kg, tbo-filgrastim did not prolong the QT interval to any clinically relevant extent.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenicity and genetic toxicology studies have not been conducted with tbo-filgrastim.A fertility study was not conducted with tbo-filgrastim. Toxicology studies of up to 26 weeks in rats or monkeys did not reveal findings in male or female reproductive organs that would suggest impairment of fertility.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following potential serious 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)] Sickle Cell Disorders [see Warnings and Precautions (5.4)] Glomerulonephritis [see Warnings and Precautions (5.5)] Capillary Leak Syndrome [see Warnings and Precautions (5.6)] Potential for Tumor Growth Stimulatory Effects on Malignant Cells [see Warnings and Precautions (5.7)] Myelodysplastic Syndrome and Acute Myeloid Leukemia [see Warnings and Precautions (5.8)] Leukocytosis [see Warnings and Precautions (5.9)] Simultaneous Use with Chemotherapy and Radiation Therapy Not Recommended [see Warnings and Precautions (5.10)] Aortitis [see Warnings and Precautions (5.12)] Alveolar Hemorrhage [see Warnings and Precautions (5.13)] 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)] Sickle Cell Disorders [see Warnings and Precautions (5.4)] Glomerulonephritis [see Warnings and Precautions (5.5)] Capillary Leak Syndrome [see Warnings and Precautions (5.6)] Potential for Tumor Growth Stimulatory Effects on Malignant Cells [see Warnings and Precautions (5.7)] Myelodysplastic Syndrome and Acute Myeloid Leukemia [see Warnings and Precautions (5.8)] Leukocytosis [see Warnings and Precautions (5.9)] Simultaneous Use with Chemotherapy and Radiation Therapy Not Recommended [see Warnings and Precautions (5.10)] Aortitis [see Warnings and Precautions (5.12)] Alveolar Hemorrhage [see Warnings and Precautions (5.13)] Most common adverse reaction (>=1%) to GRANIX is bone pain (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Teva Pharmaceuticals at 1-866-832-8537 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. Most common adverse reaction (>=1%) to GRANIX is bone pain (6.1). 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 to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.Adverse Reactions in Adult PatientsGRANIX clinical trials safety data are based upon the results of three randomized clinical trials in patients receiving myeloablative chemotherapy for breast cancer (N=348), lung cancer (N=240) and non-Hodgkins lymphoma (N=92). In the breast cancer study, 99% of patients were female, the median age was 50 years, and 86% of patients were Caucasian. In the lung cancer study, 80% of patients were male, the median age was 58 years, and 95% of patients were Caucasian. In the non-Hodgkins lymphoma study, 52% of patients were male, the median age was 55 years, and 88% of patients were Caucasian. In all three studies placebo (Cycle of the breast cancer study only) or non-U.S.-approved filgrastim product were used as controls. Both GRANIX and the non-U.S.-approved filgrastim product were administered at mcg/kg subcutaneously once daily beginning one day after chemotherapy for at least five days and continued to maximum of 14 days or until an ANC of >=10,000 106/L after nadir was reached.Bone pain was the most frequent treatment-emergent adverse reaction that occurred in at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group. The overall incidence of bone pain in Cycle of treatment was 3.4% (3.4% GRANIX, 1.4% placebo, 7.5% non-U.S.-approved filgrastim product).Leukocytosis In clinical studies, leukocytosis (WBC counts 100,000 106/L) was observed in less than 1% patients with non-myeloid malignancies receiving GRANIX. No complications attributable to leukocytosis were reported in clinical studies.Additional Adverse Reactions Other adverse reactions known to occur following administration of filgrastim products include myalgia, headache, vomiting, cutaneous vasculitis and thrombocytopenia.Adverse Reactions in Pediatric Patients GRANIX clinical trials safety data in pediatric patients are based upon the results of one single-arm clinical trial in 50 pediatric patients who received myelosuppressive chemotherapy for treatment of solid tumors without marrow involvement [see Use in Special Populations (8.4)]. In this study, GRANIX was administered at mcg/kg subcutaneously once daily beginning one day after chemotherapy. The most common (>5%) adverse reactions included thrombocytopenia (34%), pyrexia (8%), pain in extremity (6%), headache (6%) and diarrhea (6%).. 6.2 Postmarketing Experience. The following adverse reactions have been identified during post-approval use of GRANIX. 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.Sweets syndrome (acute febrile neutrophilic dermatosis), asthenia, diarrhea, and fatigue. Sweets syndrome (acute febrile neutrophilic dermatosis), asthenia, diarrhea, and fatigue.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenicity and genetic toxicology studies have not been conducted with tbo-filgrastim.A fertility study was not conducted with tbo-filgrastim. Toxicology studies of up to 26 weeks in rats or monkeys did not reveal findings in male or female reproductive organs that would suggest impairment of fertility.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Tbo-filgrastim is human granulocyte colony-stimulating factor (G-CSF) produced by recombinant DNA technology. Tbo-filgrastim binds to G-CSF receptors and stimulates proliferation of neutrophils. G-CSF is known to stimulate differentiation commitment and some end-cell functional activation, which increases neutrophil counts and activity.. 12.2 Pharmacodynamics. The time to the maximum ANC level was between to days and returned to baseline by 21 days following completion of chemotherapy. Doubling the tbo-filgrastim subcutaneous dose from mcg/kg to 10 mcg/kg resulted in 16% to 19% increase in the maximum ANC level and 33% to 36% increase in the area under the effect curve for ANC.Cardiac ElectrophysiologyAt an intravenous dose of mcg/kg, tbo-filgrastim did not prolong the QT interval to any clinically relevant extent.. 12.3 Pharmacokinetics. Tbo-filgrastim exhibits nonlinear pharmacokinetics. Increasing the dose of subcutaneous GRANIX from to 10 mcg/kg resulted in an approximate 2.5-fold increase in the maximum serum concentration (Cmax) and 3.0-fold increase in the area under the curve (AUC). In adult patients enrolled across three studies, subcutaneous GRANIX mcg/kg resulted in median time to maximal serum tbo-filgrastim concentrations (Tmax) within to hours. Geometric mean [coefficient of variation (CV%)] serum Cmax was 20 to 31 ng/mL [24% to 65%] within to hours. Geometric mean serum tbo-filgrastim area under the curve (AUC0-12h) ranged from 151 to 227 ng/mLh [24% to 60%]. No accumulation in serum tbo-filgrastim concentrations was observed after multiple dosing.AbsorptionThe absolute bioavailability of mcg/kg subcutaneous tbo-filgrastim was 33%.Metabolism/EliminationTbo-filgrastim clearance is primarily dependent on G-CSF receptor-mediated clearance which can be saturated by high serum concentrations of tbo-filgrastim and diminished in neutropenia. The median serum elimination half-life of tbo-filgrastim (5 mcg/kg sc) was 3.0 to 3.5 hours.Specific PopulationsNo sex-related differences were observed.Pediatric Patients:The geometric mean [coefficient of variation (CV%)] of Cmax was 18 ng/mL (56%) and AUC0-12h was 130 nghr/mL (52%) following subcutaneous administration of GRANIX mcg/kg in 49 pediatric patients (1.4 to 15.9 years) after chemotherapy. No clinically relevant differences in the pharmacokinetics of GRANIX were observed between infants, children and adolescents. Patients with Renal or Hepatic Impairment:Mild renal impairment (creatinine clearance 60 to 89 mL/min by Cockcroft-Gault) had no effect on tbo-filgrastim pharmacokinetics. The pharmacokinetics in patients with moderate and severe renal impairment has not been studied. The pharmacokinetics in patients with hepatic impairment has not been studied.. 12.6 Immunogenicity. The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of GRANIX or of other filgrastim products. While available data suggest that 1.4% of patients developed binding antibodies to filgrastim, the nature and specificity of these antibodies has not been adequately studied. Because of the low occurrence of anti- drug antibodies, the effect of these antibodies on the pharmacokinetics, pharmacodynamics, safety, and/or effectiveness of GRANIX is unknown. Cytopenias resulting from an antibody response to exogenous growth factors have been reported on rare occasions in patients treated with other recombinant growth factors.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. The efficacy of GRANIX was evaluated in multinational, multicenter, randomized and controlled Phase study in 348 chemotherapy-naive patients with high-risk stage II, stage III, or stage IV breast cancer receiving doxorubicin (60 mg/m2) and docetaxel (75 mg/m2) comparing GRANIX to placebo and non-U.S.-approved filgrastim product as controls. The median age of the patients was 50 years (range 25 to 75 years) with 99% female and 86% Caucasian.GRANIX, placebo, and the non-U.S.-approved filgrastim product were administered at mcg/kg subcutaneously once daily beginning one day after chemotherapy for at least five days and continued to maximum of 14 days or until an ANC of >=10,000 106/L after nadir was reached. GRANIX was superior to placebo in duration of severe neutropenia (DSN) with statistically significant reduction in DSN (1.1 days vs. 3.8 days, < 0.0001).

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 to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.Adverse Reactions in Adult PatientsGRANIX clinical trials safety data are based upon the results of three randomized clinical trials in patients receiving myeloablative chemotherapy for breast cancer (N=348), lung cancer (N=240) and non-Hodgkins lymphoma (N=92). In the breast cancer study, 99% of patients were female, the median age was 50 years, and 86% of patients were Caucasian. In the lung cancer study, 80% of patients were male, the median age was 58 years, and 95% of patients were Caucasian. In the non-Hodgkins lymphoma study, 52% of patients were male, the median age was 55 years, and 88% of patients were Caucasian. In all three studies placebo (Cycle of the breast cancer study only) or non-U.S.-approved filgrastim product were used as controls. Both GRANIX and the non-U.S.-approved filgrastim product were administered at mcg/kg subcutaneously once daily beginning one day after chemotherapy for at least five days and continued to maximum of 14 days or until an ANC of >=10,000 106/L after nadir was reached.Bone pain was the most frequent treatment-emergent adverse reaction that occurred in at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group. The overall incidence of bone pain in Cycle of treatment was 3.4% (3.4% GRANIX, 1.4% placebo, 7.5% non-U.S.-approved filgrastim product).Leukocytosis In clinical studies, leukocytosis (WBC counts 100,000 106/L) was observed in less than 1% patients with non-myeloid malignancies receiving GRANIX. No complications attributable to leukocytosis were reported in clinical studies.Additional Adverse Reactions Other adverse reactions known to occur following administration of filgrastim products include myalgia, headache, vomiting, cutaneous vasculitis and thrombocytopenia.Adverse Reactions in Pediatric Patients GRANIX clinical trials safety data in pediatric patients are based upon the results of one single-arm clinical trial in 50 pediatric patients who received myelosuppressive chemotherapy for treatment of solid tumors without marrow involvement [see Use in Special Populations (8.4)]. In this study, GRANIX was administered at mcg/kg subcutaneously once daily beginning one day after chemotherapy. The most common (>5%) adverse reactions included thrombocytopenia (34%), pyrexia (8%), pain in extremity (6%), headache (6%) and diarrhea (6%).

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. GRANIX is contraindicated in patients with history of serious allergic reactions to filgrastim products or pegfilgrastim products [see Warnings and Precautions (5.3) ].. Patients with history of serious allergic reactions to filgrastim products or pegfilgrastim products. (4).

DESCRIPTION SECTION.

11 DESCRIPTION. GRANIX (tbo-filgrastim) is non-glycosylated recombinant methionyl human granulocyte colony-stimulating growth factor (r-metHuG-CSF) manufactured by recombinant DNA technology using the bacterium strain coli K802. It has molecular weight of approximately 18.8 kDa and is composed of 175 amino acids. The endogenous human G-CSF is glycosylated and does not have the additional methionine amino acid residue in its NH2 terminal end.The product is sterile, clear, colorless, preservative-free solution containing tbo-filgrastim, glacial acetic acid, sorbitol, polysorbate 80, sodium hydroxide, and Water for Injection. The product is available in single-dose prefilled syringes that contain either 300 mcg or 480 mcg of tbo-filgrastim at fill volume of 0.5 mL or 0.8 mL, respectively and single-dose vials that contain either 300 mcg or 480 mcg of tbo-filgrastim at fill volume of mL or 1.6 mL, respectively. See table below for product composition of each presentation.Product Composition 300 mcg/0.5 mL Syringe 480 mcg/0.8 mL Syringe300 mcg/1 mL Vial 480 mcg/1.6 mL Vial Tbo-filgrastim 300 mcg 480 mcg 300 mcg 480 mcgGlacial Acetic Acid 0.3 mg 0.48 mg 0.6 mg0.96 mg Polysorbate 800.0275 mg0.044 mg 0.055 mg0.088 mg Sorbitol 25 mg40 mg 50 mg 80 mg Sodium Hydroxideq.s. to pH 4.2q.s. to pH 4.2q.s. to pH 4.2 q.s. to pH 4.2 Water for Injectionq.s. to 0.5 mL q.s. to 0.8 mLq.s. to mL q.s. to 1.6 mL q.s. quantity sufficient to make.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

Package/Label Display Panel 63459-910-11. NDC 63459-910-11Rx onlyGranix(R) (tbo-filgrastim) Injection 300 mcg/0.5 mLFor Subcutaneous Use OnlyA recombinant Granulocyte Colony-Stimulating Factor (rG-CSF) derived from Coli 300 mcg/0.5 mLFor Healthcare Professional Use Only1 Single-dose prefilled syringe with safety needle guardDiscard unused portion. 1.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness of GRANIX have been established for pediatric patients month to 17 years old (no data for the age group 1 month old). Use of GRANIX in these age groups is supported by evidence from adequate and well-controlled studies of GRANIX in adults [see Clinical Studies (14)] with additional safety and pharmacokinetics data from single-arm trial of 50 pediatric patients with solid tumors treated with GRANIX for chemotherapy-induced neutropenia. The 50 pediatric patients had median age of 9.2 years (range, 1.4 to 15.9 years); were infants (1 month to 2 years old), 30 were children (2 to 12 years old), and 18 were adolescents (12 to 17 years old). The pharmacokinetics and safety profile of GRANIX in the pediatric population were similar to those seen in adults [see Adverse Reactions (6.1), Clinical Pharmacology (12.3)].

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Recommended dose: mcg/kg per day administered as subcutaneous injectionAdminister the first dose no earlier than 24 hours following myelosuppressive chemotherapy. Do not administer within 24 hours prior to chemotherapy (2.1) Recommended dose: mcg/kg per day administered as subcutaneous injection. Administer the first dose no earlier than 24 hours following myelosuppressive chemotherapy. Do not administer within 24 hours prior to chemotherapy (2.1) 2.1 Recommended Dosage. The recommended dose of GRANIX is mcg/kg per day administered as subcutaneous injection. Administer the first dose of GRANIX no earlier than 24 hours following myelosuppressive chemotherapy. Do not administer GRANIX within 24 hours prior to chemotherapy.Daily dosing with GRANIX should continue until the expected neutrophil nadir is passed and the neutrophil count has recovered to the normal range. Monitor complete blood count (CBC) prior to chemotherapy and twice per week until recovery.. 2.2 General Considerations for Administration. GRANIX may be administered by either healthcare professional, patient or caregiver. Before decision is made to allow GRANIX to be administered by patient or caregiver, ensure that the patient is an appropriate candidate for self-administration or administration by caregiver. Proper training on storage, preparation, and administration technique should be provided. If patient or caregiver is not an appropriate candidate for any reason, then in such patients, GRANIX should be administered by healthcare professional.Dispense only the prefilled syringe without safety needle guard device to patient or caregiver. Instruct patients and caregivers to follow the Instructions for Use provided with the GRANIX prefilled syringe to properly administer an injection after training by healthcare professional. Visually inspect parenteral drug products for particulate matter and discoloration prior to administration. Do not administer GRANIX if discoloration or particulates are observed. The prefilled syringe and vial are for single-dose only. Discard unused portions. GRANIX and all its components are not made with natural rubber latex. Recommended sites for subcutaneous GRANIX injections include the abdomen (except for the two-inch area around the navel), the front of the middle thighs, the upper outer areas of the buttocks, or the upper back portion of the upper arms. The injection site should be varied daily. GRANIX should not be injected into an area that is tender, red, bruised, or hard, or that has scars or stretch marks. 2.3 Important Administration Instructions for Healthcare Professionals. Hold the syringe assembly by the open sides of the device and remove the needle shield.Expel any extra volume depending on dose needed.Inject GRANIX subcutaneously as recommended [see Dosage and Administration (2.2) ].Push the plunger as far as it will go to inject all the medication. Injection of the entire prefilled syringe contents is necessary to activate the needle guard. With the plunger still pressed all the way down, remove the needle from the skin.Slowly let go of the plunger and allow the empty syringe to move up inside the device until the entire needle is guarded.Discard the syringe assembly in approved containers.. needle image 1. needle image 2. needle image 3. needle image 4. needle image 5. needleimage 6.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. GRANIX is clear, colorless, preservative-free solution available as:Prefilled Syringe:Injection: 300 mcg/0.5 mL solution in single-dose prefilled syringeInjection: 480 mcg/0.8 mL solution in single-dose prefilled syringeVial:Injection: 300 mcg/mL solution in single-dose vialInjection: 480 mcg/1.6 mL (300 mcg/mL) solution in single-dose vial. Prefilled SyringeInjection: 300 mcg/0.5 mL solution in single-dose prefilled syringe (3)Injection: 480 mcg/0.8 mL solution in single-dose prefilled syringe (3)VialInjection: 300 mcg/mL solution in single-dose vials (3)Injection: 480 mcg/1.6 mL (300 mcg/mL) solution in single-dose vials (3) Injection: 300 mcg/0.5 mL solution in single-dose prefilled syringe (3). Injection: 480 mcg/0.8 mL solution in single-dose prefilled syringe (3). Injection: 300 mcg/mL solution in single-dose vials (3). Injection: 480 mcg/1.6 mL (300 mcg/mL) solution in single-dose vials (3).

GERIATRIC USE SECTION.

8.5 Geriatric Use. Among 677 cancer patients enrolled in clinical trials of GRANIX, total of 111 patients were 65 years of age and older, and 14 patients were 75 years and older. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. GRANIX solution for injection is supplied as single-dose, preservative-free clear solution, in either vial or, prefilled syringe made from Type glass which has permanently attached stainless steel needle. The active substance is tbo-filgrastim.Prefilled Syringes (UltraSafe Passive(R) Needle Guard)GRANIX 300 mcg/0.5 mL: Each prefilled syringe contains 300 mcg of tbo-filgrastim in 0.5 mL solution with blue plunger in:Pack of with safety needle guard in blister: NDC 63459-910-11Packs of 10 with safety needle guard in blisters: NDC 63459-910-15GRANIX 480 mcg/0.8 mL: Each prefilled syringe contains 480 mcg of tbo-filgrastim in 0.8 mL solution with clear plunger in:Pack of with safety needle guard in blister: NDC 63459-912-11Packs of 10 with safety needle guard in blisters: NDC 63459-912-15 Prefilled SyringesGRANIX 300 mcg/0.5 mL: Each prefilled syringe contains 300 mcg of tbo-filgrastim in 0.5 mL solution with blue plunger in:Pack of without safety needle guard (for patients and caregivers): NDC 63459-910-17Packs of without safety needle guard (for patients and caregivers): NDC 63459-910-36GRANIX 480 mcg/0.8 mL: Each prefilled syringe contains 480 mcg of tbo-filgrastim in 0.8 mL solution with clear plunger in:Pack of without safety needle guard (for patients and caregivers): NDC 63459-912-17Packs of without safety needle guard (for patients and caregivers): NDC 63459-912-36VialsGRANIX 300 mcg/mL: Each vial contains 300 mcg of tbo-filgrastim in mL solution.Packs of 10 single-dose vials: (NDC 63459-918-59)GRANIX 480 mcg/1.6 mL (300 mcg/mL): Each vial contains 480 mcg of tbo-filgrastim in 1.6 mL solution.Packs of 10 single-dose vials: (NDC 63459-920-59)GRANIX and all its components are not made with natural rubber latex [see Dosage and Administration (2.2)].Store GRANIX in refrigerator at 36F to 46F (2C to 8C). Protect from light. Within its shelf life, the product may be removed from 36F to 46F (2C to 8C) storage for single period of up to days between 73F to 81F (23C to 27C). If not used within days, the product may be returned to 36F to 46F (2C to 8C) up to the expiration date. Dispose of syringes if stored at room temperature for more than days.Avoid shaking. The solution should be visually inspected prior to use. Only clear solutions without particles should be used. Exposure to 23F to 30F (-1C to -5C) for up to 72 hours and temperatures as low as 5F to -13F (-15C to -25C) for up to 24 hours do not adversely affect the stability of GRANIX. Single-dose syringe and single-dose vial discard unused portion. Any unused product or waste material should be disposed of in accordance with local requirements.If GRANIX gets on the skin, wash the area with soap and water. If GRANIX gets in the eyes, thoroughly flush the exposed eye/eyes with water.. Pack of with safety needle guard in blister: NDC 63459-910-11. Packs of 10 with safety needle guard in blisters: NDC 63459-910-15. Pack of with safety needle guard in blister: NDC 63459-912-11. Packs of 10 with safety needle guard in blisters: NDC 63459-912-15. Pack of without safety needle guard (for patients and caregivers): NDC 63459-910-17. Packs of without safety needle guard (for patients and caregivers): NDC 63459-910-36. Pack of without safety needle guard (for patients and caregivers): NDC 63459-912-17. Packs of without safety needle guard (for patients and caregivers): NDC 63459-912-36. Packs of 10 single-dose vials: (NDC 63459-918-59). Packs of 10 single-dose vials: (NDC 63459-920-59).

IMMUNOGENICITY.

12.6 Immunogenicity. The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of GRANIX or of other filgrastim products. While available data suggest that 1.4% of patients developed binding antibodies to filgrastim, the nature and specificity of these antibodies has not been adequately studied. Because of the low occurrence of anti- drug antibodies, the effect of these antibodies on the pharmacokinetics, pharmacodynamics, safety, and/or effectiveness of GRANIX is unknown. Cytopenias resulting from an antibody response to exogenous growth factors have been reported on rare occasions in patients treated with other recombinant growth factors.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. GRANIX is indicated to reduce the duration of severe neutropenia in adult and pediatric patients month and older with non-myeloid malignancies receiving myelosuppressive anticancer drugs associated with clinically significant incidence of febrile neutropenia.. GRANIX (tbo-filgrastim) is leukocyte growth factor indicated in adult and pediatric patients month and older for reduction in the duration of severe neutropenia in patients with non-myeloid malignancies receiving myelosuppressive anticancer drugs associated with clinically significant incidence of febrile neutropenia. (1).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Availability of Patient Information and Instructions for UseAdvise all patients and/or caregivers to read the FDA-approved Patient Information. For patients that are candidates for self-administration, assist patients and caregivers in understanding the contents of the Patient Information as well as the GRANIX Instructions for Use that are included with the product, and give them the opportunity to ask questions prior to initiating therapy.Patient TrainingOnce it is determined that patient is an appropriate candidate for self-administration or administration by caregiver, instruct the patient or caregivers on the proper storage, preparation, and administration technique for GRANIX. Patients should be advised not to skip or change their dose or stop taking GRANIX without talking to their healthcare provider first. Advise the patients to read the FDA-approved Patient Information and Instructions for Use for further information.Bone PainBone pain is common. Analgesics such as acetaminophen or NSAIDS may be necessary [see Adverse Reactions (6.1)].Rupture or Enlargement of SpleenRupture or enlargement of the spleen may occur, which may be signaled by abdominal pain, left upper quadrant pain, or left shoulder pain. Advise patients to report onset of pain in these areas to their doctor immediately [see Warnings and Precautions (5.1)].DyspneaDyspnea with or without fever, progressing to Acute Respiratory Distress Syndrome, may occur. Advise patients to report dyspnea immediately to their doctor [see Warnings and Precautions (5.2)]. Allergic ReactionsSerious allergic reactions, including anaphylaxis, rash, and urticaria: Patients should report such reactions immediately to their doctor [see Warnings and Precautions (5.3)].Sickle Cell DisordersIn patients with sickle cell disorders, sickle cell crisis and death has occurred. Discuss the potential risks and benefits for patients with sickle cell disorders prior to the administration of GRANIX [see Warnings and Precautions (5.4)]. Glomerulonephritis Symptoms may include swelling of the face or ankles, dark colored urine or blood in the urine, or decrease in urine production. Advise patients to report signs or symptoms of glomerulonephritis to their physician immediately [see Warnings and Precautions (5.5)].Myelodysplastic Syndrome and Acute Myeloid LeukemiaThere may be an increased risk of Myelodysplastic Syndrome and/or Acute Myeloid Leukemia in patients with congenital neutropenia who receive GRANIX and in patients with breast and lung cancer who receive GRANIX in conjunction with chemotherapy and/or radiation therapy. Symptoms of MDS and AML may include tiredness, fever, and easy bruising or bleeding. Advise patients to report to their physician signs and symptoms of MDS/AML [see Warnings and Precautions (5.8)].PregnancyInform patients not to become pregnant while receiving GRANIX. If pregnancy occurs, advise patients of the possibility of fetal harm [see Use in Specific Populations (8.1)]. LactationAdvise women to avoid breastfeeding during treatment with GRANIX and for weeks after the final dose. [see Use in Specific Populations (8.2)].See FDA-approved Patient Labeling (Patient Information) and Instructions for Use.TBO-010(C)2023 Cephalon, Inc., wholly owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved.Manufactured by:UAB Teva BalticsVilnius, LithuaniaU.S. License No. 1803Distributed by:Teva Pharmaceuticals USA, Inc.North Wales, PA 19454Product of Israel. Teva logo.

INSTRUCTIONS FOR USE SECTION.

INSTRUCTIONS FOR USE Prefilled Syringe. GRANIX (GRAN-icks)(tbo-filgrastim)for subcutaneous injectionSingle-Dose Prefilled Syringe Important:Read the Prescribing information and Patient Package insert for important information about GRANIX.About the GRANIX syringe Depending on the prescription that your healthcare provider gave you, you will receive syringe that provides dose of either 0.1 mL to 0.5 mL or 0.1 mL to 0.8 mL. If you are prescribed dose over 0.8 mL, two syringes will be required to reach your prescribed dose. Your healthcare provider will determine how many syringes and the correct dose in milliliters (mL) you will need to give based on your body weight. You should continue to give GRANIX daily until your healthcare provider informs you that your white blood cell count has returned to normal. Make sure you understand the following:How to store your syringes.How to read the syringe markings.How to adjust the amount of GRANIX in the syringe for your prescribed dose.How to prepare and give the injection.Do not shake syringes.Do not remove the needle cap until you are ready to inject.Do not re-use syringe. The syringe is for single-use only.Your first dose of GRANIX is given at least 24 hours after you receive your chemotherapy.Do not inject GRANIX within 24 hours before your next dose of chemotherapy.Dosing schedule Inject your total daily dose time each day as prescribed by your healthcare provider, starting at least 24 hours (1 day) after the end of your chemotherapy cycle. You should continue to give GRANIX daily until your white blood cell count returns to normal. How to store your GRANIX syringes Store GRANIX in the refrigerator between 36F to 46F (2C to 8C).Store GRANIX in the original carton to protect it from light.Do not shake.Take GRANIX out of the refrigerator 30 minutes before use and allow it to reach room temperature before preparing an injection.GRANIX syringes can be left at room temperature for single period of up to days, and if not used can be returned to the refrigerator. Throw away (dispose of) any GRANIX syringes that have been left at room temperature for more than days.After you inject your dose, throw away (dispose of) any unused GRANIX left in the syringe. Do not save unused GRANIX in the syringe for later use.Keep GRANIX and all medicines out of the reach of children. Determining how many syringes you need for your daily dose If your prescribed daily dose is 0.5 mL or less, use syringe.If your prescribed daily dose is 0.8 mL or less, use syringe.If your prescribed daily dose is more than 0.8 mL you will need to prepare syringes in order to match your prescribed dose: Adjust your first syringe to 0.8 mL.Adjust your second syringe to the additional amount required to make up your total prescribed dose.Make sure the amounts in both syringes add up to your prescribed dose (See the table to the right to determine how much medicine should be in each syringe). For example: If your prescribed dose is mL you would prepare syringe with 0.8 mL and second syringe with 0.2 mL.Important: When using syringes always adjust the first syringe to 0.8 mL.How to read the syringe markings What the markings on the syringe mean:The syringe is labeled in 0.1 mL unit increments from 0.1 mL to 0.8 mL. There is line next to each 0.1 mL unit increment.To read the dose scale always hold the syringe with the needle-end facing up so that 0.1 mL is at the top and 0.8 mL is at the bottom. How to adjust the medicine level for your prescribed dose When setting your dose, (See 2C) you will line up the top edge of the grey rubber stopper with the line on the syringe scale that matches your prescribed dose. Note: The top edge of the grey rubber stopper is the edge directly below the dome at the top of the stopper. Do not use the top of the cone or the middle or lower edges of the grey stopper to measure your dose.Injection steps (follow the steps below for each day of dosing)1. Prepare for injection 1A Each time you inject dose gather the following supplies:GRANIX syringe(s)Alcohol swabsPaper towelCotton ball or gauze padAdhesive Bandage, if needed Sharps disposal container (hard-walled container for discarding syringes)Note: GRANIX and all of the parts of the prefilled syringe do not contain natural rubber latex.1B Take the carton with the syringe(s) out of the refrigerator1C Check the label and the expiration date on the side of the cartonImportant: Do not inject if:GRANIX(R) (tbo-filgrastim) is not listed on the carton.The expiration date on the syringe label has passed.1D Remove the syringe(s) from the carton Open the carton by breaking the tamper proof seal and lifting the lid. Remove the number of syringes required for your daily dose by grasping each at the middle of the syringe body.After removing your required number of syringes, place the carton back in the refrigerator.1E Look carefully at the syringe(s) and the medicine Hold the syringe body and check to make sure it is not damaged.Inspect the medicine in the syringe. GRANIX should be clear liquid.Important: Do not inject if:GRANIX(R) (tbo-filgrastim) is not listed on the syringe label.The medicine is cloudy, discolored, or foamy.The medicine contains lumps, flakes, or particles.1F Wait 30 minutes for the syringe(s) to warm to room temperature Wait 30 minutes for GRANIX to naturally warm to room temperature. This will provide more comfortable injection.1G Wash your handsWhen ready to inject, wash your hands with soap and warm water and dry thoroughly with clean towel.1H Choose an injection site The recommended injection sites are:If you are self-injecting:Stomach-area (abdomen): Except for 2-inch area around the navel (belly button).Thighs: Top or middle area of thighs.If caregiver is injecting GRANIX for you:Arms: Fleshy areas on upper, back part of the arm.Upper hip or buttock: Fleshy areas around the back of the upper hips and upper sides of the buttocks.If injections will be performed, then the second injection should be at least inch away from the first injection.Choose Injection SiteDo not inject into areas that are tender, red, bruised, hard, or have scars or stretch marks.Important:You should select different injection site each time you give yourself an injection.If you want to use the same injection site for dose requiring injections, make sure the second injection site is at least inch away from the first injection site.1I Clean the injection site using an alcohol swab Allow site to dry for 5-10 seconds to avoid stinging.If giving injections, then the distance between the injection sites should be at least inch apart.Do not touch or blow on site after cleaning.2. Adjust medicine level for your prescribed dose 2A Remove the needle cap from the syringePlace paper towel on the table.To remove the needle cap, hold the body of the syringe firmly with hand (with the needle facing away from you).Pull the needle cap straight off, extending your hand away from the needle.Note: Throw away the needle cap in sharps disposal container.Do not recap the needle now or after the injection.2B Hold the syringe upright and tap Hold the syringe upright (needle pointing up), as shown.Gently tap the barrel with your fingers to make sure any air bubbles rise to the top.2C Slowly and carefully adjust the medicine level Hold the syringe with the needle pointing up and slightly away from you, as shown. Make sure you can easily see the syringe markings and numbers.Holding the plunger as shown, very slowly and carefully push the plunger up until the top edge of the grey rubber stopper is even with the line that corresponds to your prescribed dose.Note:If GRANIX gets on your skin, wash your skin with soap and water.If GRANIX get in your eyes, flush well with water.Note: If you accidentally removed too much GRANIX, contact your healthcare provider before giving your injection.3. INJECT MEDICATION3A Pinch skinThe illustration below is an example onlyUse your free hand to firmly pinch the skin you previously cleaned.3B Insert the needle at 45 to 90 degree angle Hold the body of the syringe between your thumb and index finger.Use quick motion to fully insert the needle straight into the pinched skin at 45 to 90 degree angle.When the needle is inserted, you can release the pinched skin.Do not hold or push on the plunger while inserting the needle into the skin.3C Push the plunger down to inject all of the GRANIX Use your finger to gently push down on the plunger.When the plunger head is as far down as it will go, all of the GRANIX has been injected. When done, gently remove the needle from the skin.3D Throw away (dispose of) used syringe Put your used needles and syringes in FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose needles and syringes 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 dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container.3E Treat the injection site if needed and wash your handsIf you see drops of blood at the injection site, you can press cotton ball or gauze over the injection site for several seconds to stop the bleeding.Apply bandage, if needed.When you are finished, wash your hands with soap and warm water and dry thoroughly with clean towel.4. Repeat the injection steps with the second syringe (If dose is more than 0.8 mL) If your dose is more than 0.8 mL:Follow instructions 3A through 3E for injecting.Choose different site for your second injection. If you want to use the same part of your body, make sure the second injection site is at least inch away from the first injection site. If you have any questions or concerns about your dose of GRANIX or how to prepare and give your injections, call your healthcare provider.This Instructions for Use has been approved by the U.S. Food and Drug Administration.Manufactured by:UAB Teva BalticsVilnius, LithuaniaU.S. License No. 1803Distributed by:Teva Pharmaceuticals USA, Inc.North Wales, PA 19454Product of IsraelRevised: 11/2023TBOIFU-004(C)2023 Cephalon, Inc., wholly owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved.GRANIX is trademark of Teva Pharmaceutical Industries Ltd.. How to store your syringes.. How to read the syringe markings.. How to adjust the amount of GRANIX in the syringe for your prescribed dose.. How to prepare and give the injection.. Store GRANIX in the refrigerator between 36F to 46F (2C to 8C).. Store GRANIX in the original carton to protect it from light.. Do not shake.. Take GRANIX out of the refrigerator 30 minutes before use and allow it to reach room temperature before preparing an injection.. GRANIX syringes can be left at room temperature for single period of up to days, and if not used can be returned to the refrigerator. Throw away (dispose of) any GRANIX syringes that have been left at room temperature for more than days.. After you inject your dose, throw away (dispose of) any unused GRANIX left in the syringe. Do not save unused GRANIX in the syringe for later use.. If your prescribed daily dose is 0.5 mL or less, use syringe.. If your prescribed daily dose is 0.8 mL or less, use syringe.. If your prescribed daily dose is more than 0.8 mL you will need to prepare syringes in order to match your prescribed dose: Adjust your first syringe to 0.8 mL.Adjust your second syringe to the additional amount required to make up your total prescribed dose.Make sure the amounts in both syringes add up to your prescribed dose (See the table to the right to determine how much medicine should be in each syringe). Adjust your first syringe to 0.8 mL.. Adjust your second syringe to the additional amount required to make up your total prescribed dose.. Make sure the amounts in both syringes add up to your prescribed dose (See the table to the right to determine how much medicine should be in each syringe).. When setting your dose, (See 2C) you will line up the top edge of the grey rubber stopper with the line on the syringe scale that matches your prescribed dose. Note: The top edge of the grey rubber stopper is the edge directly below the dome at the top of the stopper. GRANIX syringe(s). Alcohol swabs. Paper towel. Cotton ball or gauze pad. Adhesive Bandage, if needed Sharps disposal container (hard-walled container for discarding syringes). GRANIX(R) (tbo-filgrastim) is not listed on the carton.. The expiration date on the syringe label has passed.. GRANIX(R) (tbo-filgrastim) is not listed on the syringe label.. The medicine is cloudy, discolored, or foamy.. The medicine contains lumps, flakes, or particles.. You should select different injection site each time you give yourself an injection.. If you want to use the same injection site for dose requiring injections, make sure the second injection site is at least inch away from the first injection site.. If GRANIX gets on your skin, wash your skin with soap and water.. If GRANIX get in your eyes, flush well with water.. 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.. Follow instructions 3A through 3E for injecting.. Choose different site for your second injection. If you want to use the same part of your body, make sure the second injection site is at least inch away from the first injection site. 1. ifu image 2. ifu image 3. ifu image 4. ifu image 5-new. 1. 1. ifu image 8. ifu image 9. 1. ifu image 11. ifu image 12. 1. ifu image 14. ifu image 15. ifu image 16. ifu image 17. 1. ifu image 19. ifu image 20. ifu image 21. ifu image 22. 1. ifu image 24. ifu image 25. ifu image 26. ifu image 27. ifu image 28. 1.

LACTATION SECTION.

8.2 Lactation. No data are available regarding the presence of tbo-filgrastim in human milk, the effects of the drug on the breastfed child, or the effects of the drug on milk production. Another filgrastim product was detected in human milk for up to days after filgrastim administration. Because of the potential for serious adverse reactions in the breastfed child, including splenic rupture, acute respiratory distress syndrome and serious allergic reactions, advise patients not to breastfeed during treatment with GRANIX and for weeks after the last dose.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Tbo-filgrastim is human granulocyte colony-stimulating factor (G-CSF) produced by recombinant DNA technology. Tbo-filgrastim binds to G-CSF receptors and stimulates proliferation of neutrophils. G-CSF is known to stimulate differentiation commitment and some end-cell functional activation, which increases neutrophil counts and activity.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Tbo-filgrastim exhibits nonlinear pharmacokinetics. Increasing the dose of subcutaneous GRANIX from to 10 mcg/kg resulted in an approximate 2.5-fold increase in the maximum serum concentration (Cmax) and 3.0-fold increase in the area under the curve (AUC). In adult patients enrolled across three studies, subcutaneous GRANIX mcg/kg resulted in median time to maximal serum tbo-filgrastim concentrations (Tmax) within to hours. Geometric mean [coefficient of variation (CV%)] serum Cmax was 20 to 31 ng/mL [24% to 65%] within to hours. Geometric mean serum tbo-filgrastim area under the curve (AUC0-12h) ranged from 151 to 227 ng/mLh [24% to 60%]. No accumulation in serum tbo-filgrastim concentrations was observed after multiple dosing.AbsorptionThe absolute bioavailability of mcg/kg subcutaneous tbo-filgrastim was 33%.Metabolism/EliminationTbo-filgrastim clearance is primarily dependent on G-CSF receptor-mediated clearance which can be saturated by high serum concentrations of tbo-filgrastim and diminished in neutropenia. The median serum elimination half-life of tbo-filgrastim (5 mcg/kg sc) was 3.0 to 3.5 hours.Specific PopulationsNo sex-related differences were observed.Pediatric Patients:The geometric mean [coefficient of variation (CV%)] of Cmax was 18 ng/mL (56%) and AUC0-12h was 130 nghr/mL (52%) following subcutaneous administration of GRANIX mcg/kg in 49 pediatric patients (1.4 to 15.9 years) after chemotherapy. No clinically relevant differences in the pharmacokinetics of GRANIX were observed between infants, children and adolescents. Patients with Renal or Hepatic Impairment:Mild renal impairment (creatinine clearance 60 to 89 mL/min by Cockcroft-Gault) had no effect on tbo-filgrastim pharmacokinetics. The pharmacokinetics in patients with moderate and severe renal impairment has not been studied. The pharmacokinetics in patients with hepatic impairment has not been studied.

POSTMARKETING EXPERIENCE SECTION.

6.2 Postmarketing Experience. The following adverse reactions have been identified during post-approval use of GRANIX. 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.Sweets syndrome (acute febrile neutrophilic dermatosis), asthenia, diarrhea, and fatigue. Sweets syndrome (acute febrile neutrophilic dermatosis), asthenia, diarrhea, and fatigue.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryThe limited published data on filgrastim product use during pregnancy are insufficient to inform drug-associated risk. In animal reproduction studies, administration of tbo-filgrastim to pregnant rabbits during organogenesis resulted in increased spontaneous abortion and fetal malformations at systemic exposures 50 to 90 times the human exposure expected at the recommended human dose (see Data). GRANIX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.The estimated background risk of major birth defects and miscarriage for the indicated population(s) are unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.DataAnimal DataIn an embryofetal developmental study, pregnant rabbits were administered subcutaneous doses of tbo-filgrastim during the period of organogenesis at 1, 10 and 100 mcg/kg/day. Increased abortions were evident in rabbits treated with tbo-filgrastim at 100 mcg/kg/day. This dose was maternally toxic as demonstrated by reduced body weight. Other embryofetal findings at this dose level consisted of post-implantation loss, decrease in mean live litter size and fetal weight, and fetal malformations such as malformed hind limbs and cleft palate. The dose of 100 mcg/kg/day corresponds to systemic exposure (AUC) of approximately 50 to 90 times the exposures observed in patients treated with the clinical tbo-filgrastim dose of mcg/kg/day.

RECENT MAJOR CHANGES SECTION.

Warnings and Precautions, Myelodysplastic Syndrome and Acute Myeloid Leukemia in Patients with Breast and Lung Cancer (5.8) 11/2023.

SPL PATIENT PACKAGE INSERT SECTION.

PATIENT INFORMATIONGRANIX (GRAN-icks) (tbo-filgrastim) injection, for subcutaneous use What is GRANIX GRANIX is prescription medicine: used in adults and children month of age and older with certain types of cancer (non-myeloid malignancies), who are receiving chemotherapy that affects the bone marrowgiven to help decrease the length of time that the number of certain white blood cells (neutrophils) are very low (severe neutropenia). Neutrophils are white blood cells that are important in fighting bacterial infections. It is not known if GRANIX is safe and effective in children younger than month of age. Do not take GRANIX if you have had serious allergic reaction to filgrastim products or pegfilgrastim products. Before you receive GRANIX, tell your healthcare provider about all of your medical conditions, including if you: have sickle cell disorderhave kidney problemsplan to have bone scans or tests are pregnant or plan to become pregnant. It is not known if GRANIX will harm your unborn baby. You should not become pregnant during treatment with GRANIX. are breastfeeding or plan to breastfeed. It is not known if GRANIX passes into your breast milk. Do not breastfeed during treatment with GRANIX and for weeks after the final dose. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. How will receive GRANIX GRANIX is given by an injection under your skin (subcutaneous) by healthcare provider. Your healthcare provider may decide injections can be given at home by you or your caregiver. If GRANIX is given at home, see the detailed Instructions for Use that comes with your GRANIX for information on how to prepare and inject dose of GRANIX.Your healthcare provider will show you and your caregiver how to prepare and inject GRANIX before you use it.Your healthcare provider will tell you how much GRANIX to inject and when to inject it. Do not stop using GRANIX or change your dose unless your healthcare provider tells you to.GRANIX injections are usually given time each day until your white blood cell count returns to normal.Your first dose of GRANIX is given at least 24 hours after you receive your chemotherapy.Do not inject GRANIX within 24 hours before your next dose of chemotherapy.Your healthcare provider will test your blood before your chemotherapy and during treatment with GRANIX. If GRANIX gets on your skin or your caregivers skin, wash the area with soap and water.If GRANIX gets in your eyes or your caregivers eyes, flush the eyes well with water. What are the possible side effects of GRANIX GRANIX can 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 your left upper stomach (abdomen)-area or your left shoulder during treatment with GRANIX.A serious lung problem called acute respiratory distress syndrome (ARDS). Call your healthcare provider or get emergency medical help right away if you have shortness of breath with or without fever, trouble breathing, or fast rate of breathing. Serious allergic reactions. GRANIX 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 GRANIX and call your healthcare provider or get emergency help right away. Sickle cell crisis. You may have serious sickle cell crisis, which could lead to death, if you have sickle cell disorder and use GRANIX. Call your healthcare provider right away if you have symptoms of sickle cell crisis such as pain or difficulty breathing.Kidney injury (glomerulonephritis). GRANIX can cause kidney injury. Call your healthcare provider right away if you develop any of the following symptoms: swelling of your face or ankles blood 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 GRANIX.Capillary Leak Syndrome. GRANIX 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 (MDS) and acute myeloid leukemia (AML).GRANIX may increase the risk of developing precancerous condition called MDS or type of blood cancer called AML in people who were born with low white blood cell counts (congenital neutropenia).If you have breast cancer or lung cancer, when GRANIX is used with chemotherapy and radiation therapy, or with radiation therapy only, you may have an increased risk of developing MDS or AML.Symptoms of MDS and AML may include tiredness, fever, and easy bruising or bleeding.Call your healthcare provider if you develop any of these symptoms during treatment with GRANIX.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 another filgrastim product. Symptoms may include fever, abdominal pain, feeling tired, and back pain. Call your healthcare provider if you experience these symptoms. Your healthcare provider may decrease your dose, temporarily stop, or permanently stop treatment with GRANIX if you have certain side effects. The most common side effect of GRANIX is bone pain. The most common side effects of GRANIX in children include: decreased platelet countfeverpain in the arms and legsheadachediarrhea These are not all of the possible side effects of GRANIX. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should store GRANIX Store GRANIX in the refrigerator between 36F to 46F (2C to 8C).Keep GRANIX away from light to protect it. If your GRANIX prefilled syringe or vial comes in carton, keep it in the carton until you are ready to use it, to protect from light. Do not shake.Take GRANIX out of the refrigerator 30 minutes before use and allow it to reach room temperature before preparing an injection.GRANIX can be left at room temperature for up to days. If not used within days, return GRANIX back to the refrigerator. Throw away (dispose of) GRANIX that has been left at room temperature for more than days.After you inject your dose, throw away (dispose of) any unused GRANIX left in the syringe or vial. Do not save unused GRANIX in the syringe or the vial for later use. Keep GRANIX and all medicines out of the reach of children. General information about the safe and effective use of GRANIX Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflets. Do not use GRANIX for condition for which it was not prescribed. Do not give GRANIX to other people, even if they have the same symptoms you have. It may harm them. You can ask your healthcare provider or pharmacist for information about GRANIX that is written for health professionals. What are the ingredients in GRANIX Active ingredient: tbo-filgrastim Inactive ingredients: glacial acetic acid, sorbitol, polysorbate 80, sodium hydroxide, and Water for Injection Manufactured by: UAB Teva Baltics Vilnius, Lithuania U.S. License No. 1803 Distributed by: Teva Pharmaceuticals USA, Inc. North Wales, PA 19454 Product of Israel TBOPL-008 (C)2023 Cephalon, Inc., wholly owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved. For more information, call 1-800-896-5855. This Patient Information has been approved by the U.S. Food and Drug Administration Revised: 11/2023. used in adults and children month of age and older with certain types of cancer (non-myeloid malignancies), who are receiving chemotherapy that affects the bone marrow. given to help decrease the length of time that the number of certain white blood cells (neutrophils) are very low (severe neutropenia). Neutrophils are white blood cells that are important in fighting bacterial infections. have sickle cell disorder. have kidney problems. plan to have bone scans or tests are pregnant or plan to become pregnant. It is not known if GRANIX will harm your unborn baby. You should not become pregnant during treatment with GRANIX. are breastfeeding or plan to breastfeed. It is not known if GRANIX passes into your breast milk. Do not breastfeed during treatment with GRANIX and for weeks after the final dose.. GRANIX is given by an injection under your skin (subcutaneous) by healthcare provider. Your healthcare provider may decide injections can be given at home by you or your caregiver. If GRANIX is given at home, see the detailed Instructions for Use that comes with your GRANIX for information on how to prepare and inject dose of GRANIX.. Your healthcare provider will show you and your caregiver how to prepare and inject GRANIX before you use it.. Your healthcare provider will tell you how much GRANIX to inject and when to inject it. Do not stop using GRANIX or change your dose unless your healthcare provider tells you to.. GRANIX injections are usually given time each day until your white blood cell count returns to normal.. Your first dose of GRANIX is given at least 24 hours after you receive your chemotherapy.. Do not inject GRANIX within 24 hours before your next dose of chemotherapy.. Your healthcare provider will test your blood before your chemotherapy and during treatment with GRANIX. If GRANIX gets on your skin or your caregivers skin, wash the area with soap and water.. If GRANIX gets in your eyes or your caregivers eyes, flush the eyes well with water.. 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 your left upper stomach (abdomen)-area or your left shoulder during treatment with GRANIX.. serious lung problem called acute respiratory distress syndrome (ARDS). Call your healthcare provider or get emergency medical help right away if you have shortness of breath with or without fever, trouble breathing, or fast rate of breathing. Serious allergic reactions. GRANIX 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 GRANIX and call your healthcare provider or get emergency help right away. Sickle cell crisis. You may have serious sickle cell crisis, which could lead to death, if you have sickle cell disorder and use GRANIX. Call your healthcare provider right away if you have symptoms of sickle cell crisis such as pain or difficulty breathing.. Kidney injury (glomerulonephritis). GRANIX can cause kidney injury. Call your healthcare provider right away if you develop any of the following symptoms: swelling of your face or ankles blood 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 GRANIX.. Capillary Leak Syndrome. GRANIX 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 (MDS) and acute myeloid leukemia (AML).GRANIX may increase the risk of developing precancerous condition called MDS or type of blood cancer called AML in people who were born with low white blood cell counts (congenital neutropenia).If you have breast cancer or lung cancer, when GRANIX is used with chemotherapy and radiation therapy, or with radiation therapy only, you may have an increased risk of developing MDS or AML.Symptoms of MDS and AML may include tiredness, fever, and easy bruising or bleeding.Call your healthcare provider if you develop any of these symptoms during treatment with GRANIX.. GRANIX may increase the risk of developing precancerous condition called MDS or type of blood cancer called AML in people who were born with low white blood cell counts (congenital neutropenia).. If you have breast cancer or lung cancer, when GRANIX is used with chemotherapy and radiation therapy, or with radiation therapy only, you may have an increased risk of developing MDS or AML.. Symptoms of MDS and AML may include tiredness, fever, and easy bruising or bleeding.. Call your healthcare provider if you develop any of these symptoms during treatment with GRANIX.. 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 another filgrastim product. Symptoms may include fever, abdominal pain, feeling tired, and back pain. Call your healthcare provider if you experience these symptoms.. decreased platelet count. fever. pain in the arms and legs. headache. diarrhea. Store GRANIX in the refrigerator between 36F to 46F (2C to 8C).. Keep GRANIX away from light to protect it. If your GRANIX prefilled syringe or vial comes in carton, keep it in the carton until you are ready to use it, to protect from light. Do not shake.. Take GRANIX out of the refrigerator 30 minutes before use and allow it to reach room temperature before preparing an injection.. GRANIX can be left at room temperature for up to days. If not used within days, return GRANIX back to the refrigerator. Throw away (dispose of) GRANIX that has been left at room temperature for more than days.. After you inject your dose, throw away (dispose of) any unused GRANIX left in the syringe or vial. Do not save unused GRANIX in the syringe or the vial for later use.. Teva logo.

SPL UNCLASSIFIED SECTION.

2.1 Recommended Dosage. The recommended dose of GRANIX is mcg/kg per day administered as subcutaneous injection. Administer the first dose of GRANIX no earlier than 24 hours following myelosuppressive chemotherapy. Do not administer GRANIX within 24 hours prior to chemotherapy.Daily dosing with GRANIX should continue until the expected neutrophil nadir is passed and the neutrophil count has recovered to the normal range. Monitor complete blood count (CBC) prior to chemotherapy and twice per week until recovery.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. GRANIX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. (8.1). 8.1 Pregnancy. Risk SummaryThe limited published data on filgrastim product use during pregnancy are insufficient to inform drug-associated risk. In animal reproduction studies, administration of tbo-filgrastim to pregnant rabbits during organogenesis resulted in increased spontaneous abortion and fetal malformations at systemic exposures 50 to 90 times the human exposure expected at the recommended human dose (see Data). GRANIX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.The estimated background risk of major birth defects and miscarriage for the indicated population(s) are unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.DataAnimal DataIn an embryofetal developmental study, pregnant rabbits were administered subcutaneous doses of tbo-filgrastim during the period of organogenesis at 1, 10 and 100 mcg/kg/day. Increased abortions were evident in rabbits treated with tbo-filgrastim at 100 mcg/kg/day. This dose was maternally toxic as demonstrated by reduced body weight. Other embryofetal findings at this dose level consisted of post-implantation loss, decrease in mean live litter size and fetal weight, and fetal malformations such as malformed hind limbs and cleft palate. The dose of 100 mcg/kg/day corresponds to systemic exposure (AUC) of approximately 50 to 90 times the exposures observed in patients treated with the clinical tbo-filgrastim dose of mcg/kg/day.. 8.2 Lactation. No data are available regarding the presence of tbo-filgrastim in human milk, the effects of the drug on the breastfed child, or the effects of the drug on milk production. Another filgrastim product was detected in human milk for up to days after filgrastim administration. Because of the potential for serious adverse reactions in the breastfed child, including splenic rupture, acute respiratory distress syndrome and serious allergic reactions, advise patients not to breastfeed during treatment with GRANIX and for weeks after the last dose. 8.4 Pediatric Use. The safety and effectiveness of GRANIX have been established for pediatric patients month to 17 years old (no data for the age group 1 month old). Use of GRANIX in these age groups is supported by evidence from adequate and well-controlled studies of GRANIX in adults [see Clinical Studies (14)] with additional safety and pharmacokinetics data from single-arm trial of 50 pediatric patients with solid tumors treated with GRANIX for chemotherapy-induced neutropenia. The 50 pediatric patients had median age of 9.2 years (range, 1.4 to 15.9 years); were infants (1 month to 2 years old), 30 were children (2 to 12 years old), and 18 were adolescents (12 to 17 years old). The pharmacokinetics and safety profile of GRANIX in the pediatric population were similar to those seen in adults [see Adverse Reactions (6.1), Clinical Pharmacology (12.3)]. 8.5 Geriatric Use. Among 677 cancer patients enrolled in clinical trials of GRANIX, total of 111 patients were 65 years of age and older, and 14 patients were 75 years and older. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. 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): Monitor for and manage immediately. Discontinue GRANIX if suspected (5.2)Serious Allergic Reactions Including Anaphylaxis: Permanently discontinue GRANIX in patients with serious allergic reactions (5.3)Sickle Cell Disorders: Severe and sometimes fatal crisis can occur. Discontinue GRANIX if suspected (5.4)Glomerulonephritis: Evaluate and consider dose reduction or interruption of GRANIX if causality is likely (5.5)Capillary Leak Syndrome: Monitor if symptoms develop and administer standard symptomatic treatment (5.6)Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML): Monitor patients with breast and lung cancer using GRANIX in conjunction with chemotherapy and/or radiotherapy for signs and symptoms of MDS/AML. (5.8). 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): Monitor for and manage immediately. Discontinue GRANIX if suspected (5.2). Serious Allergic Reactions Including Anaphylaxis: Permanently discontinue GRANIX in patients with serious allergic reactions (5.3). Sickle Cell Disorders: Severe and sometimes fatal crisis can occur. Discontinue GRANIX if suspected (5.4). Glomerulonephritis: Evaluate and consider dose reduction or interruption of GRANIX if causality is likely (5.5). Capillary Leak Syndrome: Monitor if symptoms develop and administer standard symptomatic treatment (5.6). Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML): Monitor patients with breast and lung cancer using GRANIX in conjunction with chemotherapy and/or radiotherapy for signs and symptoms of MDS/AML. (5.8). 5.1 Splenic Rupture. Splenic rupture, including fatal cases, can occur following administration of filgrastim products. Evaluate patients who report upper abdominal or shoulder pain for an enlarged spleen or splenic rupture. Discontinue GRANIX if splenic rupture is suspected or confirmed.. 5.2 Acute Respiratory Distress Syndrome. Acute respiratory distress syndrome (ARDS) can occur in patients receiving filgrastim products. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS.. 5.3 Serious Allergic Reactions. Serious allergic reactions, including anaphylaxis, can occur in patients receiving GRANIX. Reactions can occur on initial exposure. The administration of antihistamines, steroids, bronchodilators, and/or epinephrine may reduce the severity of the reactions. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with history of serious allergic reactions to filgrastim or pegfilgrastim.. 5.4 Sickle Cell Disorders. Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disorders receiving filgrastim products. Discontinue GRANIX if sickle cell crisis occurs.. 5.5 Glomerulonephritis. Glomerulonephritis can occur in patients receiving filgrastim products. The diagnoses were based on azotemia, hematuria (microscopic and macroscopic), proteinuria, and renal biopsy. Generally, events of glomerulonephritis resolved after dose reduction or discontinuation of the filgrastim product. If glomerulonephritis is suspected, evaluate for cause. If causality is likely, consider dose reduction or interruption of GRANIX.. 5.6 Capillary Leak Syndrome. Capillary leak syndrome (CLS) can occur in patients receiving filgrastim 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.. 5.7 Potential for Tumor Growth Stimulatory Effects on Malignant Cells. The granulocyte colony-stimulating factor (G-CSF) receptor through which GRANIX acts has been found on tumor cell lines. The possibility that GRANIX acts as growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded.. 5.8 Myelodysplastic Syndrome and Acute Myeloid Leukemiain Patients with Breast and Lung Cancer. Patients with Severe Chronic NeutropeniaConfirm the diagnosis of SCN before initiating GRANIX therapy.MDS and AML have been reported to occur in the natural history of congenital neutropenia without cytokine therapy. Cytogenetic abnormalities, transformation to MDS, and AML have also been observed in patients treated with GRANIX for SCN. Based on available data including postmarketing surveillance study, the risk of developing MDS and AML appears to be confined to the subset of patients with congenital neutropenia. Abnormal cytogenetics and MDS have been associated with the eventual development of myeloid leukemia. The effect of GRANIX on the development of abnormal cytogenetics and the effect of continued GRANIX administration in patients with abnormal cytogenetics or MDS are unknown. Monitor patients for signs and symptoms of MDS/AML in these settings. If patient with SCN develops abnormal cytogenetics or myelodysplasia, the risks and benefits of continuing GRANIX should be carefully considered.Patients with Breast and Lung CancerMDS and AML have been associated with the use of GRANIX 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.. 5.9 Leukocytosis. White blood cell counts of 100,000/mm3 or greater were observed in approximately 2% of patients receiving filgrastim products at dosages above mcg/kg/day. In patients with cancer receiving GRANIX as an adjunct to myelosuppressive chemotherapy, to avoid the potential risks of excessive leukocytosis, it is recommended that GRANIX therapy be discontinued if the ANC surpasses 10,000/mm3 after the chemotherapy-induced ANC nadir has occurred. Monitor CBCs at least twice weekly during therapy. Dosages of GRANIX that increase the ANC beyond 10,000/mm3 may not result in any additional clinical benefit. In patients with cancer receiving myelosuppressive chemotherapy, discontinuation of filgrastim products therapy usually resulted in 50% decrease in circulating neutrophils within to days, with return to pretreatment levels in to days. 5.10 Simultaneous Use with Chemotherapy and Radiation Therapy Not Recommended. The safety and efficacy of filgrastim products, including GRANIX, given simultaneously with cytotoxic chemotherapy have not been established. Because of the potential sensitivity of rapidly dividing myeloid cells to cytotoxic chemotherapy, do not use GRANIX in the period 24 hours before through 24 hours after the administration of cytotoxic chemotherapy [see Dosage and Administration (2.2)].The safety and efficacy of GRANIX have not been evaluated in patients receiving concurrent radiation therapy. Avoid the simultaneous use of GRANIX with chemotherapy and radiation therapy.. 5.11 Nuclear Imaging. Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone-imaging changes. Consider this when interpreting bone-imaging results. 5.12 Aortitis. Aortitis has been reported in patients receiving another filgrastim product. 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 GRANIX if aortitis is suspected. 5.13 Alveolar Hemorrhage. Alveolar hemorrhage manifesting as pulmonary infiltrates and hemoptysis requiring hospitalization has been reported in healthy donors undergoing peripheral blood progenitor cell (PBPC) collection treated with another filgrastim product. Hemoptysis resolved with discontinuation of filgrastim. The use of GRANIX for PBPC mobilization in healthy donors is not an approved indication.