Leukocyte Growth Factor

Fulphila

Approved 4 Jun 2018InjectionInjectable

Indications

Fulphila is a leukocyte growth factor indicated to

Decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia. ( 1.1 ) Limitations of Use Fulphila is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation.

1.1Patients with Cancer Receiving Myelosuppressive Chemotherapy

Fulphila is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia [see Clinical Studies (14.1) ] . Limitations of Use Fulphila is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation.

Contraindications

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

Warnings and precautions

Fatal splenic rupture: Evaluate patients who report left upper abdominal or shoulder pain for an enlarged spleen or splenic rupture. ( 5.1 )
Acute respiratory distress syndrome (ARDS): Evaluate patients who develop fever, lung infiltrates, or respiratory distress. Discontinue Fulphila in patients with ARDS. ( 5.2 )
Serious allergic reactions, including anaphylaxis: Permanently discontinue Fulphila in patients with serious allergic reactions. ( 5.3 )
Fatal sickle cell crises: Discontinue Fulphila if sickle cell crisis occurs. ( 5.4 )
Glomerulonephritis: Evaluate and consider dose-reduction or interruption of Fulphila if causality is likely. ( 5.5 )
Thrombocytopenia: Monitor platelet counts. ( 5.7 )
Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML): Monitor patients with breast and lung cancer using Fulphila in conjunction with chemotherapy and/or radiotherapy for signs and symptoms of MDS/AML. ( 5.10 )

At a glance

Brand name: Fulphila
Active substance: pegfilgrastim-jmdb
Pharmacologic class: Leukocyte Growth Factor
Route: Injection
Dosage form: Injectable
Applicant: Mylan GMBH
Status: Prescription
FDA approval: 4 Jun 2018
Application: BLA761075-001

Indications

Fulphila is a leukocyte growth factor indicated to

Decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia. ( 1.1 ) Limitations of Use Fulphila is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation.

1.1Patients with Cancer Receiving Myelosuppressive Chemotherapy

Contraindications

Warnings and precautions

Fatal splenic rupture: Evaluate patients who report left upper abdominal or shoulder pain for an enlarged spleen or splenic rupture. ( 5.1 )
Acute respiratory distress syndrome (ARDS): Evaluate patients who develop fever, lung infiltrates, or respiratory distress. Discontinue Fulphila in patients with ARDS. ( 5.2 )
Serious allergic reactions, including anaphylaxis: Permanently discontinue Fulphila in patients with serious allergic reactions. ( 5.3 )
Fatal sickle cell crises: Discontinue Fulphila if sickle cell crisis occurs. ( 5.4 )
Glomerulonephritis: Evaluate and consider dose-reduction or interruption of Fulphila if causality is likely. ( 5.5 )
Thrombocytopenia: Monitor platelet counts. ( 5.7 )
Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML): Monitor patients with breast and lung cancer using Fulphila in conjunction with chemotherapy and/or radiotherapy for signs and symptoms of MDS/AML. ( 5.10 )

Pregnancy and breastfeeding

8.1Pregnancy Risk Summary

Although available data with Fulphila or pegfilgrastim product use in pregnant women are insufficient to establish whether there is a drug associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes, there are available data from published studies in pregnant women exposed to filgrastim products. These studies have not established an association of filgrastim product use during pregnancy with major birth defects, miscarriage or adverse maternal or fetal outcomes.

In animal studies, no evidence of reproductive/developmental toxicity occurred in the offspring of pregnant rats that received cumulative doses of pegfilgrastim approximately 10 times the recommended human dose (based on body surface area). In pregnant rabbits, increased embryolethality and spontaneous abortions occurred at 4 times the maximum recommended human dose simultaneously with signs of maternal toxicity ( see Data ).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a 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 2-4% and 15-20%, respectively. Data Human Data Retrospective studies indicate that exposure to pegfilgrastim is without significant adverse effect on fetal outcomes and neutropenia.

Preterm deliveries have been reported in some patients. Animal Data Pregnant rabbits were dosed with pegfilgrastim subcutaneously every other day during the period of organogenesis. At cumulative doses ranging from the approximate human dose to approximately 4 times the recommended human dose (based on body surface area), the treated rabbits exhibited decreased maternal food consumption, maternal weight loss, as well as reduced fetal body weights and delayed ossification of the fetal skull; however, no structural anomalies were observed in the offspring from either study.

Increased incidences of post-implantation losses and spontaneous abortions (more than half the pregnancies) were observed at cumulative doses approximately 4 times the recommended human dose, which were not seen when pregnant rabbits were exposed to the recommended human dose. Three studies were conducted in pregnant rats dosed with pegfilgrastim at cumulative doses up to approximately 10 times the recommended human dose at the following stages of gestation: during the period of organogenesis, from mating through the first half of pregnancy, and from the first trimester through delivery and lactation.

No evidence of fetal loss or structural malformations was observed in any study. Cumulative doses equivalent to approximately 3 and 10 times the recommended human dose resulted in transient evidence of wavy ribs in fetuses of treated mothers (detected at the end of gestation but no longer present in pups evaluated at the end of lactation).

Adverse reactions

The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling:

Splenic Rupture [See Warnings and Precautions (5.1) ]
Acute Respiratory Distress Syndrome [See Warnings and Precautions (5.2) ]
Serious Allergic Reactions [See Warnings and Precautions (5.3) ]
Use in Patients with Sickle Cell Disorders [See Warnings and Precautions (5.4) ]
Glomerulonephritis [See Warnings and Precautions (5.5) ]
Leukocytosis [See Warnings and Precautions (5.6) ]
Thrombocytopenia [See Warnings and Precautions (5.7) ]
Capillary Leak Syndrome [See Warnings and Precautions (5.8) ]
Potential for Tumor Growth Stimulatory Effects on Malignant Cells [See Warnings and Precautions (5.9) ]
Myelodysplastic syndrome [See Warnings and Precautions (5.10) ]
Acute myeloid leukemia [See Warnings and Precautions (5.10) ]
Aortitis [see Warnings and Precautions (5.11) ] Most common adverse reactions (≥ 5% difference in incidence compared to placebo) are bone pain and pain in extremity. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Biocon Biologics Inc. at 1-833-986-1468 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . *Biosimilar means that the biological product is approved based on data demonstrating that it is highly similar to an FDA-approved biological product, known as a reference product, and that there are no clinically meaningful differences between the biosimilar product and the reference product. Biosimilarity of Fulphila has been demonstrated for the condition(s) of use (e.g. indication(s), dosing regimen(s)), strength(s), dosage form(s), and route(s) of administration described in its Full Prescribing Information.

6.1Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Pegfilgrastim clinical trials safety data are based upon 932 patients receiving pegfilgrastim in seven randomized clinical trials. The population was 21 to 88 years of age and 92% female.

The ethnicity was 75% Caucasian, 18% Hispanic, 5% Black, and 1% Asian. Patients with breast (n = 823), lung and thoracic tumors (n = 53) and lymphoma (n = 56) received pegfilgrastim after nonmyeloablative cytotoxic chemotherapy. Most patients received a single 100 mcg/kg (n = 259) or a single 6 mg (n = 546) dose per chemotherapy cycle over 4 cycles. The following adverse reaction data in Table 2 are from a randomized, double-blind, placebo-controlled study in patients with metastatic or non-metastatic breast cancer receiving docetaxel 100 mg/m 2 every 21 days (Study 3).

A total of 928 patients were randomized to receive either 6 mg pegfilgrastim (n = 467) or placebo (n = 461). The patients were 21 to 88 years of age and 99% female. The ethnicity was 66% Caucasian, 31% Hispanic, 2% Black, and < 1% Asian, Native American, or other. The most common adverse reactions occurring in ≥ 5% of patients and with a between-group difference of ≥ 5% higher in the pegfilgrastim arm in placebo-controlled clinical trials are bone pain and pain in extremity.

Table 2. Adverse Reactions with ≥ 5% Higher Incidence in Pegfilgrastim Patients Compared to Placebo in Study 3 Body System Adverse Reaction Placebo (N = 461) Pegfilgrastim 6 mg SC on Day 2 (N = 467) Musculoskeletal and connective tissue disorders Bone pain 26% 31% Pain in extremity 4% 9% Leukocytosis In clinical studies, leukocytosis (WBC counts > 100 x 10 9 /L) was observed in less than 1% of 932 patients with non-myeloid malignancies receiving pegfilgrastim.

No complications attributable to leukocytosis were reported in clinical studies.

6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease.

For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other pegfilgrastim products may be misleading. Binding antibodies to pegfilgrastim were detected using a BIAcore assay. The approximate limit of detection for this assay is 500 ng/mL. Pre-existing binding antibodies were detected in approximately 6% (51/849) of patients with metastatic breast cancer.

Four of 521 pegfilgrastim-treated subjects who were negative at baseline developed binding antibodies to pegfilgrastim following treatment. None of these 4 patients had evidence of neutralizing antibodies detected using a cell-based bioassay.

6.3Postmarketing Experience

The following adverse reactions have been identified during post approval use of pegfilgrastim products. 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 (ARDS) [see Warnings and Precautions (5.2) ]
Allergic reactions/hypersensitivity, including anaphylaxis, skin rash, and urticaria, generalized erythema, and flushing [see Warnings and Precautions (5.3) ]
Sickle cell crisis [see Warnings and Precautions (5.4) ]
Glomerulonephritis [see Warnings and Precautions (5.5) ]
Leukocytosis [see Warnings and Precautions (5.6) ]
Thrombocytopenia [see Warnings and Precautions (5.7) ]
Capillary Leak Syndrome [see Warnings and Precautions (5.8) ]
Injection site reactions
Sweet’s syndrome, (acute febrile neutrophilic dermatosis), cutaneous vasculitis
Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) in patients with breast and lung cancer receiving chemotherapy and/or radiotherapy [see Warnings and Precautions (5.10) ]
Aortitis [see Warnings and Precautions (5.11) ]
Alveolar hemorrhage

Fulphila

Indications

1.1Patients with Cancer Receiving Myelosuppressive Chemotherapy

Contraindications

Warnings and precautions

At a glance

Two medicines in one question?

Fulphila

Indications

1.1Patients with Cancer Receiving Myelosuppressive Chemotherapy

Contraindications

Warnings and precautions

At a glance

Two medicines in one question?

5.1Splenic Rupture

5.2Acute Respiratory Distress Syndrome

5.3Serious Allergic Reactions

5.4Use in Patients with Sickle Cell Disorders Severe

5.5Glomerulonephritis

5.6Leukocytosis

5.7Thrombocytopenia

5.8Capillary Leak Syndrome

5.9Potential for Tumor Growth Stimulatory Effects on Malignant Cells

5.11Aortitis

5.12Nuclear Imaging

Pregnancy and breastfeeding

8.1Pregnancy Risk Summary

Adverse reactions

6.1Clinical Trials Experience

6.3Postmarketing Experience

Composition

Official product information