Drug Safety-related Labeling Changes (SrLC)

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Drug Safety-related Labeling Changes (SrLC) Database

ANDA	Abbreviated New Drug Application
BLA	Biologics License Application
CDER	Center for Drug Evaluation and Research
MG	Medication Guide
NDA	New Drug Application
PCI	Patient Counseling Information
PI	Patient Information
PLR	Physician Labeling Rule
PLLR	Pregnancy and Lactation Labeling Rule
Italics	For the most part, italics indicate an FDA comment such as: Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section.
Underlines	Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text.

Sections

BW	Box Warning
WP	Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format)
AR	Adverse Reactions (in pre-PLR format, this may be a subheading under precautions).
DI	Drug Interactions (in pre-PLR format, this may be a subheading under precautions).
USP	Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format.
PCI/PI/MG	Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events.

Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.

Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.

GRANIX (BLA-125294)

(TBO-FILGRASTIM)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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11/21/2023 (SUPPL-58)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.8 Myelodysplastic Syndrome and Acute Myeloid Leukemia in Patients with Breast and Lung Cancer

Newly added subsection:

Patients with Severe Chronic Neutropenia

Confirm 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 a 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 a patient with SCN develops abnormal cytogenetics or myelodysplasia‚ the risks and benefits of continuing GRANIX should be carefully considered.

Patients with Breast and Lung Cancer

MDS 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.

6 Adverse Reactions

ADVERSE REACTIONS

Additions and revisions underlined:

The following potential serious adverse reactions are discussed in greater detail in other sections of the labeling:

. . .

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)]

8 Use in Specific Populations

8.2 Lactation

Additions and revisions underlined:

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 3 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 2 weeks after the last dose.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and revisions underlined:

Myelodysplastic Syndrome and Acute Myeloid Leukemia

There 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)].

Lactation

Advise women to avoid breastfeeding during treatment with GRANIX and for 2 weeks after the final dose.

Patient Information

Additions and revisions underlined:

GRANIX is a prescription medicine:

- used in adults and children 1 month of age and older with certain types of cancer (nonmyeloid

malignancies), who are receiving chemotherapy that affects the bone marrow

Do not breastfeed during treatment with GRANIX and for 2 weeks after the final dose.

GRANIX can cause serious allergic reactions. These

reactions can cause a rash over your whole body, hives, shortness of breath, wheezing,

dizziness, swelling around your mouth or eyes, fast heart rate, and sweating.

You may have a serious sickle cell crisis, which could lead to death, if

you have a sickle cell disorder and use GRANIX.

Call yourhealthcare provider right away if you develop any of the following symptoms:

- 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.

Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).

o GRANIX may increase the risk of developing a precancerous condition called MDS or

a type of blood cancer called AML in people who were born with low white blood cell

counts (congenital neutropenia).

o 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.

o Symptoms of MDS and AML may include tiredness, fever, and easy bruising or

bleeding.

o Call your healthcare provider if you develop any of these symptoms during treatment

with GRANIX.

The most common side effects of GRANIX in children include:

- decreased platelet count

- fever

- pain in the arms and legs

- headache

- diarrhea

These are not all of the possible side effects of GRANIX.

03/28/2019 (SUPPL-46)

Approved Drug Label (PDF)

5 Warnings and Precautions

Newly Added Subsection:

5.12 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.

07/31/2018 (SUPPL-45)

Approved Drug Label (PDF)

5 Warnings and Precautions

Additions and/or revisions underlined:

5.1 Fatal Splenic Rupture

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.

5.3 Serious Allergic Reactions

5.4 Sickle Cell Disorders

Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disorders receiving filgrastim products …

Addition of the following 4 newly created subsections:

5.8 Leukocytosis

White blood cell counts of 100‚000/mm3 or greater were observed in approximately 2% of patients receiving filgrastim products at dosages above 5 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 a 50% decrease in circulating neutrophils within 1 to 2 days‚ with a return to pretreatment levels in 1 to 7 days.

5.9 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.

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.

5.10 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.

5.11 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.

6 Adverse Reactions

Additions and/or revisions underlined in bulleted line listing:

Fatal Splenic Rupture
Serious Allergic Reactions
Leukocytosis
Simultaneous Use with Chemotherapy and Radiation Therapy Not Recommended
Aortitis

Additions and/or revisions underlined:

6.1 Clinical Trials Experience

Adverse Reactions in Adult Patients

GRANIX clinical trials safety data …

Addition of the following:

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 a solid tumors without marrow involvement. In this study, GRANIX was administered at 5 mcg/kg subcutaneously once daily beginning one day after chemotherapy. The most common (greater than 5%) adverse reactions included thrombocytopenia (34%), pyrexia (8%), pain in extremity (6%),

headache (6%) and diarrhea (6%).

6.2 Immunogenicity

Additions and/or revisions underlined:

Binding antibodies to GRANIX were detected using a validated bridging immunoassay. Anti-drug antibodies to tbo-filgrastim occurred in 1.4 % of 486 adult and pediatric patients. None of these patients had cross-reactive antibodies to the native G-CSF …

8 Use in Specific Populations

8.1 Pregnancy

Addition of the following phrase:

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

8.2 Lactation

Child replaces infant in this subsection.

8.4 Pediatric Use

Newly added information:

… for pediatric patients 1 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 with additional safety and pharmacokinetics data from a single-arm trial of 50 pediatric patients with solid tumors treated with GRANIX for chemotherapy-induced neutropenia. The 50 pediatric patients had a median age of 9.2 years (range, 1.4-15.9 years); 2 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.

8.5 Geriatric Use

Newly added information following 65 years and older:

… and 14 patients were 75 years and older.

06/21/2017 (SUPPL-42)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Immunogenicity

Additions and/or revisions underlined:

As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay, and the observed incidence of antibody positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to GRANIX with the incidence of antibodies to other products may be misleading.

Binding antibodies to GRANIX were detected using a validated bridging immunoassay. In three clinical trials in oncology patients receiving prior chemotherapy, the incidence of antibody binding to tbo-filgrastim was 1.6 % (7/436). None of these 7 patients had cross-reactive antibodies to the native G-CSF. All antibody responses were transient and of low titers.

02/02/2017 (SUPPL-40)

Approved Drug Label (PDF)

4 Contraindications

Newly added:

GRANIX is contraindicated in patients with a history of serious allergic reactions to filgrastim or pegfilgrastim products.

5 Warnings and Precautions

5.1 Splenic Rupture

5.2 Acute Respiratory Distress Syndrome (ARDS)

Filgrastim products replaces human granulocyte colony-stimulating factors.

5.3 Allergic Reactions

GRANIX replaces human granulocyte colony-stimulating factors.

5.4 Use in Patients with Sickle Cell Disease

Filgrastim products replaces the first mention of human granulocte colony-stimulating factors and GRANIX replaces the second mention.

5.5 Glomerulonephritis

Newly added subsection:

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

Filgrastim products replaces human granulocyte colony-stimulating factors.

6 Adverse Reactions

6.1 Clinical Trials Experience

Additional Adverse Reactions

Filgrastim products replaces human granulocyte colony-stimulating factors.

6.3 Postmarketing Experience

Newly added subsection:

The following adverse reactions have been identified during post-approval use of GRANIX. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Sweet’s syndrome (acute febrile neutrophilic dermatosis), asthenia, diarrhea, and fatigue.

8 Use in Specific Populations

8.1 Pregnancy

PLLR conversion:

Risk Summary

The limited published data on filgrastim product use during pregnancy are insufficient to inform a 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 50-90 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. 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.

Data

Animal Data

In 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 a systemic exposure (AUC) of approximately 50-90 times the exposures observed in patients treated with the clinical tbo- filgrastim dose of 5 mcg/kg/day.

8.2 Lactation

PLLR conversion:

No data are available regarding the presence of tbo-filgrastim in human milk, the effects of the drug on the breast fed infant, or the effects of the drug on milk production. Another filgrastim product was detected in human milk for up to 3 days after filgrastim administration.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Patient Training

Additions and/or revisions underlined:

Once it is determined that a patient is an appropriate candidate for self-administration or administration by a 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.

Sickle Cell Disorders

GRANIX replaces human graulocyte colony-stimulating factors.

The following is newly added:

Glomerulonephritis

Symptoms may include swelling of the face or ankles, dark colored urine or blood in the urine, or a decrease in urine production. Advise patients to report signs or symptoms of glomerulonephritis to their physician immediately.

Lactation

Inform lactating women that filgrastim was detected in breast milk for up to 3 days after dosing.

PATIENT INFORMATION

Extensively changed; please refer to label.