IMPORTANT SAFETY INFORMATION AND INDICATIONS

CONTRAINDICATIONS

NIVESTYM^® is contraindicated in patients with a history of serious allergic reactions to human granulocyte-colony stimulating factors (G-CSF), such as filgrastim products or pegfilgrastim products.

WARNINGS AND PRECAUTIONS

Splenic Rupture

Splenic rupture, including fatal cases, has been reported following the administration of filgrastim products. Evaluate patients who report left upper abdominal or shoulder pain for an enlarged spleen or splenic rupture.

Acute Respiratory Distress Syndrome

Acute respiratory distress syndrome (ARDS) has been reported in patients receiving filgrastim products. Evaluate patients who develop fever and lung infiltrates or respiratory distress for ARDS. Discontinue NIVESTYM^® in patients with ARDS.

Serious Allergic Reactions

Serious allergic reactions, including anaphylaxis, have been reported in patients receiving filgrastim products. The majority of reported events occurred upon initial exposure. Provide symptomatic treatment for allergic reactions. Allergic reactions, including anaphylaxis, in patients receiving filgrastim products can recur within days after the discontinuation of initial anti-allergic treatment. Permanently discontinue NIVESTYM^® in patients with serious allergic reactions. NIVESTYM^® is contraindicated in patients with a history of serious allergic reactions to human G-CSF such as filgrastim or pegfilgrastim.

Sickle Cell Disorders

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

Glomerulonephritis

Glomerulonephritis has occurred in patients receiving filgrastim products. The diagnoses were based upon azotemia, hematuria (microscopic and macroscopic), proteinuria, and renal biopsy. Generally, events of glomerulonephritis resolved after dose reduction or discontinuation of filgrastim products. If glomerulonephritis is suspected, evaluate for cause. If causality is likely, consider dose-reduction or interruption of NIVESTYM^®.

Alveolar Hemorrhage and Hemoptysis

Alveolar hemorrhage manifesting as pulmonary infiltrates and hemoptysis requiring hospitalization has been reported in healthy donors treated with filgrastim products for peripheral blood progenitor cell (PBPC) mobilization. Hemoptysis resolved with discontinuation of filgrastim products. The use of NIVESTYM^® for PBPC mobilization in healthy donors is not an approved indication.

Capillary Leak Syndrome

Capillary leak syndrome (CLS) has been reported after G-CSF administration, including filgrastim products, and is characterized by hypotension, hypoalbuminemia, edema, and hemoconcentration. Episodes vary in frequency and severity and may be life-threatening if treatment is delayed. Patients who develop symptoms of CLS should be closely monitored and receive standard symptomatic treatment, which may include the need for intensive care.

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

Patients With Severe Chronic Neutropenia (SCN)
Confirm the diagnosis of SCN before initiating NIVESTYM^® 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 filgrastim products for SCN. Based on available data including a post-marketing 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 filgrastim products on the development of abnormal cytogenetics and the effect of continued filgrastim product 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 NIVESTYM^® should be carefully considered.

Patients with Breast and Lung Cancer
MDS and AML have been associated with the use of filgrastim products 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.

Thrombocytopenia

Thrombocytopenia has been reported in patients receiving filgrastim products. Monitor platelet counts.

Leukocytosis

Patients With Cancer Receiving Myelosuppressive Chemotherapy:
White blood cell counts of 100,000/mm³ or greater were observed in approximately 2% of patients who received filgrastim at dosages above 5 mcg/kg/day. In patients with cancer receiving NIVESTYM^® as an adjunct to myelosuppressive chemotherapy, to avoid the potential risks of excessive leukocytosis, it is recommended that NIVESTYM^® therapy be discontinued if the absolute neutrophil count (ANC) surpasses 10,000/mm³ after the chemotherapy-induced ANC nadir has occurred. Monitor CBCs at least twice weekly during therapy. Dosages of NIVESTYM^® 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 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.

Peripheral Blood Progenitor Cell Collection and Therapy:
During the period of administration of NIVESTYM^® for PBPC mobilization in patients with cancer, discontinue NIVESTYM^® if the leukocyte count rises to >100,000/mm³.

Cutaneous Vasculitis

Cutaneous vasculitis has been reported in patients treated with filgrastim products. In most cases, the severity of cutaneous vasculitis was moderate or severe. Most of the reports involved patients with SCN receiving long-term filgrastim therapy. Hold NIVESTYM^® therapy in patients with cutaneous vasculitis. NIVESTYM^® may be started at a reduced dose when the symptoms resolve and the ANC has decreased.

Potential Effect on Malignant Cells

NIVESTYM^® is a leukocyte growth factor that primarily stimulates neutrophils. The G-CSF receptor through which NIVESTYM^® acts has also been found on tumor cell lines. The possibility that NIVESTYM^® acts as a growth factor for any tumor type cannot be excluded. The safety of filgrastim products in chronic myeloid leukemia (CML) and myelodysplasia has not been established.

When NIVESTYM^® is used to mobilize PBPC, tumor cells may be released from the marrow and subsequently collected in the leukapheresis product. The effect of reinfusion of tumor cells has not been well studied, and the limited data available are inconclusive.

Simultaneous Use With Chemotherapy and Radiation Not Recommended

The safety and efficacy of NIVESTYM^® 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 NIVESTYM^® in the period of 24 hours before through 24 hours after the administration of cytotoxic chemotherapy.

The safety and efficacy of NIVESTYM^® have not been evaluated in patients receiving concurrent radiation therapy. Avoid the simultaneous use of NIVESTYM^® with chemotherapy and radiation therapy.

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.

Aortitis

Aortitis has been reported in patients receiving filgrastim products. 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 (eg, c-reactive protein and white blood cell count). Consider aortitis in patients who develop these signs and symptoms without known etiology. Discontinue NIVESTYM^® if aortitis is suspected.