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.

NEUPOGEN (BLA-103353)

(FILGRASTIM)

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

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04/18/2023 (SUPPL-5198)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Addition of the following to the bulleted line listing:

extramedullary hematopoiesis

01/05/2021 (SUPPL-5196)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.8 Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML)

(Additions and/or revisions underlined)

Patients with Severe Chronic Neutropenia

Confirm the diagnosis of SCN before initiating NEUPOGEN 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 NEUPOGEN 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 NEUPOGEN on the development of abnormal cytogenetics and the effect of continued NEUPOGEN 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 NEUPOGEN should be carefully considered.

Patients with Breast and Lung Cancer

MDS and AML have been associated with the use of NEUPOGEN 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

(Additions and/or revisions underlined)

The following 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)]
Alveolar Hemorrhage and Hemoptysis [see Warnings and Precautions (5.6)]
Capillary Leak Syndrome [see Warnings and Precautions (5.7)]

Myelodysplastic Syndrome [see Warnings and Precautions (5.8)]
Acute Myeloid Leukemia [see Warnings and Precautions (5.8)]

6.3 Postmarketing Experience

(Additions and/or revisions underlined)

The following adverse reactions have been identified during post-approval use of NEUPOGEN. 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.

splenic rupture and splenomegaly (enlarged spleen) [see Warnings and Precautions (5.1)]
acute respiratory distress syndrome [see Warnings and Precautions (5.2)]
anaphylaxis [see Warnings and Precautions (5.3)]
sickle cell disorders [see Warnings and Precautions (5.4)]
glomerulonephritis [see Warnings and Precautions (5.5)]
alveolar hemorrhage and hemoptysis [see Warnings and Precautions (5.6)]
capillary leak syndrome [see Warnings and Precautions (5.7)]
leukocytosis [see Warnings and Precautions (5.10)]
cutaneous vasculitis [see Warnings and Precautions (5.11)]
Sweet’s syndrome (acute febrile neutrophilic dermatosis)
decreased bone density and osteoporosis in pediatric patients receiving chronic treatment with NEUPOGEN
myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) in patients with breast and lung cancer receiving chemotherapy and/or radiotherapy [see Warnings and Precautions (5.8)]

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

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Review the steps for direct patient administration with patients and caregivers. Training by the healthcare provider should aim to ensure that patients and caregivers can successfully perform all of the steps in the Instructions for Use of NEUPOGEN vial and prefilled syringe, including showing the patient or caregiver how to measure the required dose, particularly if a patient is on a dose other than the entire prefilled syringe. If a patient or caregiver is not able to demonstrate that they can measure the dose and administer the product successfully, you should consider whether the patient is an appropriate candidate for self-administration of NEUPOGEN or whether the patient would benefit from a different NEUPOGEN presentation.

Advise patients of the following risks and potential risks with NEUPOGEN:

Rupture or enlargement of the spleen may occur. Symptoms include left upper quadrant abdominal pain or left shoulder pain. Advise patients to report pain in these areas to their physician immediately [see Warnings and Precautions (5.1)].
Dyspnea, with or without fever, progressing to Acute Respiratory Distress Syndrome, may occur. Advise patients to report dyspnea to their physician immediately [see Warnings and Precautions (5.2)].
Serious allergic reactions may occur, which may be signaled by rash‚ facial edema‚ wheezing‚ dyspnea‚ hypotension‚ or tachycardia. Advise patients to seek immediate medical attention if signs or symptoms of hypersensitivity reaction occur [see Warnings and Precautions (5.3)].
In patients with sickle cell disease, sickle cell crisis and death have occurred. Discuss potential risks and benefits for patients with sickle cell disease prior to the administration of human granulocyte colony-stimulating factors [see Warnings and Precautions (5.4)].
Glomerulonephritis may occur. Symptoms 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 [see Warnings and Precautions (5.5)].
There may be an increased risk of Myelodysplastic Syndrome and/or Acute Myeloid Leukemia in patients with congenital neutropenia who receive Neupogen and in patients with breast and lung cancer who receive Neupogen 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)].

06/18/2018 (SUPPL-5194)

Approved Drug Label (PDF)

5 Warnings and Precautions

Additions and/or revisions underlined:

5.4 Sickle Cell Disorders

Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disorders receiving filgrastim products. Discontinue NEUPOGEN if sickle cell crisis occurs.

Addition of the following:

5.15 Aortitis

Aortitis has been reported in patients receiving NEUPOGEN. 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 NEUPOGEN if aortitis is suspected.

6 Adverse Reactions

Addition of the following to the bulleted line listing:

Aortitis

6.3 Postmarketing Experience

Addition of the following to the bulleted line listing:

Aortitis

8 Use in Specific Populations

8.1 Pregnancy

PLLR conversion; additions and/or revisions underlined:

Risk Summary

Available data from published studies, including several observational studies of pregnancy outcomes in women exposed to filgrastim products and those who were unexposed, have not established an association with NEUPOGEN use during pregnancy and major birth defects, miscarriage, or adverse maternal or fetal outcomes. Reports in the scientific literature have described transplacental passage of NEUPOGEN in pregnant women when administered less than or equal to 30 hours prior to preterm delivery (less than or equal to 30 weeks gestation). In animal reproduction studies, effects of filgrastim on prenatal development have been studied in rats and rabbits. No malformations were observed in either species. No maternal or fetal effects were observed in pregnant rats at doses up to 58 times the human doses. Filgrastim has been shown to have adverse effects in pregnant rabbits at doses 2 to 10 times higher than the human doses.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15- 20%, respectively.

Data

Human Data

Several observational studies based on the Severe Chronic Neutropenia International Registry (SCNIR) described pregnancy outcomes in women with severe chronic neutropenia (SCN) who were exposed to filgrastim products during pregnancy and women with SCN who were unexposed. No major differences were seen between treated and untreated women with respect to pregnancy outcome (including miscarriage and preterm labor), newborn complications (including birth weight), and infections. Methodological limitations of these studies include small sample size and lack of generalizability due to the underlying maternal condition.

Animal Data

Effects of filgrastim on prenatal development … In pregnant rats, no maternal or fetal effects were observed at doses up to 575 mcg/kg/day, which is approximately 58 times higher than the human dose of 10 mcg/kg/day.

Offspring of rats administered filgrastim …

8.2 Lactation

PLLR conversion; newly added subsection:

Risk Summary

There is published literature documenting transfer of filgrastim into human milk. There are a few case reports describing the use of filgrastim in breastfeeding mothers with no adverse effects noted in the infants. There are no data on the effects of filgrastim on milk production. Other filgrastim products are secreted poorly into breast milk, and filgrastim products are not absorbed orally by neonates. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for NEUPOGEN and any potential adverse effects on the breastfed child from NEUPOGEN or from the underlying maternal condition.

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

PATIENT COUNSELING INFORMATION

Newly added information:

Aortitis may occur. Symptoms may include fever, abdominal pain, malaise, back pain, and increased inflammatory markers. Advise patients to report signs and symptoms of aortitis to their physician immediately.

06/29/2016 (SUPPL-5188)

Approved Drug Label (PDF)

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

PCI

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use). (addition): Review the steps for direct patient administration with patients and caregivers. Training by the healthcare provider should aim to ensure that patients and caregivers can successfully perform all of the steps in the Instructions for Use of NEUPOGEN vial and prefilled syringe, including showing the patient or caregiver how to measure the required dose, particularly if a patient is on a dose other than the entire prefilled syringe. If a patient or caregiver is not able to demonstrate that they can measure the dose and administer the product successfully, you should consider whether the patient is an appropriate candidate for self-administration of NEUPOGEN or whether the patient would benefit from a different NEUPOGEN presentation.

Addition of the following:

Instruct patients who self-administer NEUPOGEN using the prefilled syringe or single-dose vial of the:
- Importance of following the applicable Instructions for Use.
- Dangers of reusing needles, syringes, or unused portions of single-dose vials.
- Importance of following local requirements for proper disposal of used syringes, needles, and unused vials.

Importance of informing the healthcare provider if difficulty occurs when measuring or administering partial contents of the NEUPOGEN prefilled syringe. If difficulty occurs, use of the NEUPOGEN vial may be considered.
Difference in product concentration of the NEUPOGEN prefilled syringe in comparison to the NEUPOGEN vial. When switching patients from the NEUPOGEN prefilled syringe to the NEUPOGEN vial, or vice versa, ensure that patients understand the correct volume to be administered since the concentration of NEUPOGEN differs between the prefilled syringe and the vial.