GRANIX- filgrastim injection, solution
Cephalon, Inc
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HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use GRANIX safely and effectively. See full prescribing information for GRANIX .
GRANIXTM (tbo-filgrastim) Injection, for subcutaneous and intravenous use Initial U.S. Approval: 2012 INDICATIONS AND USAGEGRANIX (tbo-filgrastim) is a leukocyte growth factor indicated for reduction in the duration of severe neutropenia in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia. (1) DOSAGE AND ADMINISTRATION
DOSAGE FORMS AND STRENGTHS
CONTRAINDICATIONS
WARNINGS AND PRECAUTIONS
ADVERSE REACTIONS
To report SUSPECTED ADVERSE REACTIONS, contact TEVA at 1-866-832-8537 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. USE IN SPECIFIC POPULATIONSSee 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 1/2012 |
GRANIX is indicated to reduce the duration of severe neutropenia in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia.
The recommended dose of GRANIX is 5 mcg/kg per day administered as a 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 [see Warnings and Precautions (5)].
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.
GRANIX should be administered by a 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 is for single use only. Discard unused portions.
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.
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 General Considerations for 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.
300 mcg/0.5 mL in single-use prefilled syringe
480 mcg/0.8 mL in single-use prefilled syringe
Splenic rupture, including fatal cases, can occur following administration of human granulocyte colony-stimulating factors. In patients who report upper abdominal or shoulder pain after receiving GRANIX, discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture.
Acute respiratory distress syndrome (ARDS) can occur in patients receiving human granulocyte colony-stimulating factors. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS.
Serious allergic reactions including anaphylaxis can occur in patients receiving human granulocyte colony-stimulating factors. 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 a history of serious allergic reactions to filgrastim or pegfilgrastim.
Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving human granulocyte colony-stimulating factors. Consider the potential risks and benefits prior to the administration of human granulocyte colony-stimulating factors in patients with sickle cell disease. Discontinue GRANIX in patients undergoing a sickle cell crisis.
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 a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded.
The following serious adverse reactions are discussed in greater detail in other sections of the labeling:
The most common treatment-emergent adverse reaction that occurred at an incidence of 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 was bone pain.
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
GRANIX 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-Hodgkin’s 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-Hodgkin’s lymphoma study, 52% of patients were male, the median age was 55 years, and 88% of patients were Caucasian. In all three studies a placebo (Cycle 1 of the breast cancer study only) or a non-US-approved filgrastim product were used as controls. Both GRANIX and the non-US-approved filgrastim product were administered at 5 mcg/kg subcutaneously once daily beginning one day after chemotherapy for at least five days and continued to a maximum of 14 days or until an ANC of ≥10,000 x 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 1 of treatment was 3.4% (3.4% GRANIX, 1.4% placebo, 7.5% non-US-approved filgrastim product).
Leukocytosis
In clinical studies, leukocytosis (WBC counts > 100,000 x 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.
No formal drug interaction studies between GRANIX and other drugs have been performed.
Drugs which may potentiate the release of neutrophils‚ such as lithium‚ should be used with caution.
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.
Pregnancy Category C
There are no adequate and well-controlled studies of GRANIX in pregnant women. In an embryofetal developmental study, treatment of pregnant rabbits with tbo-filgrastim resulted in adverse embryofetal findings, including increased spontaneous abortion and fetal malformations at a maternally toxic dose. GRANIX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
In the 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 hindlimbs and cleft palate. The dose of 100 mcg/kg/day corresponds to a systemic exposure (AUC0-24) of approximately 50-90 times the exposures observed in patients treated with the clinical tbo-filgrastim dose of 5 mcg/kg/day.
It is not known whether tbo-filgrastim is secreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when GRANIX is administered to a nursing woman. Other recombinant G-CSF products are poorly secreted in breast milk and G-CSF is not orally absorbed by neonates.
The safety and effectiveness of GRANIX in pediatric patients have not been established.
Among 677 cancer patients enrolled in clinical trials of GRANIX, a total of 111 patients were 65 years of age and older. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients.
The safety and efficacy of GRANIX have not been studied in patients with moderate or severe renal impairment. No dose adjustment is recommended for patients with mild renal impairment [see Clinical Pharmacology (12.3)].
Tbo-filgrastim is a non-glycosylated recombinant methionyl human granulocyte colony-stimulating growth factor (r-metHuG-CSF) manufactured by recombinant DNA technology using the bacterium strain E coli K802. It has a 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 a 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-use prefilled syringes that contain either 300 mcg or 480 mcg of tbo-filgrastim at a fill volume of 0.5 mL or 0.8 mL, respectively. See table below for product composition of each single-use prefilled syringe.
Product Composition | ||
300 mcg/0.5 mL Syringe | 480 mcg/0.8 mL Syringe | |
Tbo-filgrastim | 300 mcg | 480 mcg |
Glacial Acetic Acid | 0.3 mg | 0.48 mg |
Sorbitol | 25 mg | 40 mg |
Polysorbate 80 | 0.0275 mg | 0.044 mg |
Sodium Hydroxide | q.s. to pH 4.2 | q.s. to pH 4.2 |
Water for Injection | q.s. to 0.5 mL | q.s. to 0.8 mL |
Tbo-filgrastim is a 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.
In the clinical trials of patients with cancer, the time to the ANCmax was between 3 to 5 days and returned to baseline by 21 days following completion of chemotherapy. In the healthy volunteer trials, doubling the tbo-filgrastim subcutaneous dose from 5 to 10 mcg/kg resulted in a 16%-19% increase in the ANCmax and a 33%-36% increase in the area under the effect curve for ANC.
In healthy subjects, the absolute bioavailability of 5 mcg/kg subcutaneous tbo-filgrastim was 33%. Increasing the dose of tbo-filgrastim from 5 to 10 mcg/kg in these healthy subjects resulted in an approximately 200% increase in both the maximum concentration (Cmax) and the area under the curve (AUC0-48h) of the drug.
In the clinical trials of patients with cancer, the AUC and Cmax were greater and more variable compared to healthy volunteers receiving the same dose of tbo-filgrastim subcutaneously. The median time to maximum concentration was between 4 to 6 hours and the median elimination half-life was between 3.2 to 3.8 hours. Accumulation was not observed after repeated dosing.
Pharmacokinetics in Specific Populations
Age: Not evaluated.
Gender: No gender-related differences were observed.
Renal Impairment: Mild renal impairment (creatinine clearance 60 - 89 mL/min) had no effect on tbo-filgrastim pharmacokinetics (N=11). The pharmacokinetic profile in patients with moderate and severe renal impairment has not been assessed.
Hepatic Impairment: The pharmacokinetic profile in patients with hepatic impairment has not been assessed.
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.
The efficacy of GRANIX was evaluated in a multinational, multicenter, randomized and controlled Phase 3 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 a non-US-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-US-approved filgrastim product were administered at 5 mcg/kg subcutaneously once daily beginning one day after chemotherapy for at least five days and continued to a maximum of 14 days or until an ANC of ≥10,000 x 106/L after nadir was reached.
GRANIX was superior to placebo in duration of severe neutropenia (DSN) with a statistically significant reduction in DSN (1.1 days vs. 3.8 days, p < 0.0001).
GRANIX solution for injection is supplied as a single-use, preservative-free, prefilled syringe of Type I glass which has a permanently attached stainless steel needle. Syringes may be supplied with or without an UltraSafe Passive® Needle Guard.
The active substance is tbo-filgrastim.
GRANIX 300 mcg/0.5 mL: Each prefilled syringe contains 300 mcg of tbo-filgrastim in 0.5 mL solution with a blue plunger in:
GRANIX 480 mcg/0.8 mL: Each prefilled syringe contains 480 mcg of tbo-filgrastim in 0.8 mL solution with a clear plunger in:
GRANIX syringes should be stored in a refrigerator at 36° to 46° F (2° to 8° C). Protect from light. Within its shelf life, the product may be removed from 36° to 46° F (2° to 8° C) storage for a single period of up to 5 days between 73° to 81° F (23° to 27° C). If not used within 5 days, the product may be returned to 36° to 46° F (2° to 8° C) up to the expiration date.
Avoid shaking. The solution should be visually inspected prior to use. Only clear solutions without particles should be used. Exposure to 23° to 30° F (-1° to -5 °C) for up to 72 hours and temperatures as low as 5° to -13° F (-15 to -25° C) for up to 24 hours do not adversely affect the stability of GRANIX.
Single-use syringe – discard unused portion. Any unused product or waste material should be disposed of in accordance with local requirements.
Advise patients of the following risks and potential risks with leukocyte growth factors such as GRANIX:
See FDA-Approved Patient Labeling (Patient Information)
TBO-003
©2013 Cephalon, Inc., a wholly owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved.
GRANIX is a trademark of Teva Pharmaceutical Industries Ltd.
Manufactured by:
Sicor Biotech UAB
Vilnius, Lithuania
U.S. License No. 1803
Distributed by:
Teva Pharmaceuticals USA, Inc.
North Wales, PA 19454
Product of Israel
Revision 05/2013
Patient Information
GRANIX(GRAN-icks)
(tbo-filgrastim)
Injection, for subcutaneous use
Read this Patient Information before you start receiving GRANIX and before each treatment course. There may be new information. This information does not take the place of you talking with your doctor about your medical condition or treatment.
What is GRANIX?
GRANIX is a prescription medicine:
It is not known if GRANIX is safe and effective in children under 18 years of age.
What should I tell my doctor before I receive GRANIX?
Before you receive GRANIX, tell your doctor if you:
Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements.
Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine.
How will I receive GRANIX?
What are the possible side effects of GRANIX?
GRANIX can cause serious side effects, including:
The most common side effect of GRANIX is bone pain.
Tell your doctor about any side effect that bothers you or that does not go away.
These are not all the possible side effects of GRANIX. For a complete list, ask your doctor or pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
General Information about GRANIX
Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflets. This Patient Information leaflet summarizes the most important information about GRANIX. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about GRANIX that is written for health professionals.
For more information, call 1-800-896-5855.
What are the ingredients in GRANIX?
Active ingredient: tbo-filgrastim
Inactive ingredient: glacial acetic acid, sorbitol, polysorbate 80, sodium hydroxide, and Water for Injection.
This Patient Information has been approved by the U.S. Food and Drug Administration.
TBO-003
.
©2013 Cephalon, Inc., a wholly owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved.
GRANIX is a trademark of Teva Pharmaceutical Industries Ltd.
Manufactured by:
Sicor Biotech UAB
Vilnius, Lithuania
U.S. License No. 1803
Distributed by:
Teva Pharmaceuticals USA, Inc.
North Wales, PA 19454
Product of Israel
Issued: May, 2013
GranixTM (tbo-filgrastim)
Injection
300 mcg/0.5 mL
For Subcutaneous Use Only
A recombinant Granulocyte Colony-Stimulating Factor (rG-CSF) derived from E coli
Inactive Ingredients: glacial acetic acid, sorbitol, polysorbate 80, and Water for Injection
Storage Conditions: Keep refrigerated (36° -46°F/2° -8°C)
Single-use prefilled syringe with safety needle guard
Discard unused portion
Rx only
NDC 63459-910-12
300 mcg/0.5 mL
Manufactured by:
Sicor Biotech UAB
Vilnius, Lithuania
U.S. License No. 1803
TEVA logo
GranixTM (tbo-filgrastim)
Injection
300 mcg/0.5 mL
For Subcutaneous Use Only
A recombinant Granulocyte Colony-Stimulating Factor (rG-CSF) derived from E coli
1 Single-use prefilled syringe with safety needle guard
Discard unused portion
NDC 63459-910-11
Rx only
300 mcg/0.5 mL
TEVA Oncology logo
NDC 63459-910-15
GranixTM (tbo-filgrastim)
Injection
300 mcg/0.5 mL
For Subcutaneous Use Only
A recombinant Granulocyte Colony-Stimulating Factor (rG-CSF) derived from E coli
Rx only
10 Single-use prefilled syringe with safety needle guard
Discard unused portion
300 mcg/0.5 mL
TEVA Oncology logo
GranixTM (tbo-filgrastim)
Injection
480 mcg/0.8 mL
For Subcutaneous Use Only
A recombinant Granulocyte Colony-Stimulating Factor (rG-CSF) derived from E coli
Inactive Ingredients: glacial acetic acid, sorbitol, polysorbate 80, and Water for Injection
Storage Conditions: Keep refrigerated (36° -46°F/2° -8°C)
Single-use prefilled syringe with safety needle guard
Discard unused portion
Rx only
NDC 63459-912-12
480 mcg/0.8 mL
Manufactured by:
Sicor Biotech UAB
Vilnius, Lithuania
U.S. License No. 1803
TEVA logo
GranixTM (tbo-filgrastim)
Injection
480 mcg/0.8 mL
For Subcutaneous Use Only
A recombinant Granulocyte Colony-Stimulating Factor (rG-CSF) derived from E coli
1 Single-use prefilled syringe with safety needle guard
Discard unused portion
NDC 63459-912-11
Rx only
480 mcg/0.8 mL
TEVA Oncology logo
NDC 63459-912-15
GranixTM (tbo-filgrastim)
Injection
480 mcg/0.8 mL
For Subcutaneous Use Only
A recombinant Granulocyte Colony-Stimulating Factor (rG-CSF) derived from E coli
Rx only
10 Single-use prefilled syringe with safety needle guard
Discard unused portion
480 mcg/0.8 mL
TEVA Oncology logo
GRANIX
tbo-filgrastim injection, solution |
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GRANIX
tbo-filgrastim injection, solution |
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Labeler - Cephalon, Inc (183236314) |
Establishment | |||
Name | Address | ID/FEI | Business Operations |
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TEVA Pharmaceutical Industries Ltd. | 533065814 | MANUFACTURE(63459-910, 63459-912) |
Establishment | |||
Name | Address | ID/FEI | Business Operations |
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Sicor Biotech UAB | 565487722 | ANALYSIS(63459-910, 63459-912) |