NYVEPRIA (Page 2 of 5)
5.12 Nuclear Imaging
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.
6 ADVERSE REACTIONS
The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling:
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- Splenic Rupture [see Warnings and Precautions (5.1)]
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- Acute Respiratory Distress Syndrome [see Warnings and Precautions (5.2)]
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- Serious Allergic Reactions [see Warnings and Precautions (5.3)]
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- Use in Patients with Sickle Cell Disorders [see Warnings and Precautions (5.4)]
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- Glomerulonephritis [see Warnings and Precautions (5.5)]
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- Leukocytosis [see Warnings and Precautions (5.6)]
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- Thrombocytopenia [see Warnings and Precautions (5.7)]
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- Capillary Leak Syndrome [see Warnings and Precautions (5.8)]
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- Potential for Tumor Growth Stimulatory Effects on Malignant Cells [see Warnings and Precautions (5.9)]
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- Myelodysplastic Syndrome [see Warnings and Precautions (5.10)]
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- Acute Myeloid Leukemia [see Warnings and Precautions (5.10)]
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- Aortitis [see Warnings and Precautions (5.11)]
6.1 Clinical 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 to rates in the clinical trials of another drug and may not reflect the rates observed in 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/m2 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.
| 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 × 109 /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 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.
6.3 Postmarketing 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.
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- Splenic rupture and splenomegaly (enlarged spleen) [see Warnings and Precautions (5.1)]
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- Acute respiratory distress syndrome (ARDS) [see Warnings and Precautions (5.2)]
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- Allergic reactions/hypersensitivity, including anaphylaxis, skin rash, urticaria, generalized erythema, and flushing [see Warnings and Precautions (5.3)]
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- Sickle cell crisis [see Warnings and Precautions (5.4)]
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- Glomerulonephritis [see Warnings and Precautions (5.5)]
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- Leukocytosis [see Warnings and Precautions (5.6)]
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- Thrombocytopenia [see Warnings and Precautions (5.7)]
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- Capillary Leak Syndrome [see Warnings and Precautions (5.8)]
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- Injection site reactions
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- Sweet’s syndrome (acute febrile neutrophilic dermatosis), cutaneous vasculitis
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- 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)]
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- Aortitis [see Warnings and Precautions (5.11)]
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- Alveolar hemorrhage
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
Although available data with NYVEPRIA 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 to 4% and 15 to 20%, respectively.
Data
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).
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