WARNINGS
General
The safety and efficacy of Neulasta® for peripheral blood progenitor cell (PBPC) mobilization has not been evaluated in adequate and well-controlled studies. Neulasta® should not be used for PBPC mobilization.
Splenic Rupture
RARE CASES OF SPLENIC RUPTURE HAVE BEEN REPORTED FOLLOWING THE ADMINISTRATION OF NEULASTA®. SPLENIC RUPTURE, IN SOME CASES RESULTING IN DEATH, HAS ALSO BEEN ASSOCIATED WITH FILGRASTIM, THE PARENT COMPOUND OF NEULASTA®. PATIENTS RECEIVING NEULASTA® WHO REPORT LEFT UPPER ABDOMINAL AND/OR SHOULDER TIP PAIN SHOULD BE EVALUATED FOR AN ENLARGED SPLEEN OR SPLENIC RUPTURE.
Adult Respiratory Distress Syndrome (ARDS)
Adult respiratory distress syndrome (ARDS) has been reported in neutropenic patients with sepsis receiving Filgrastim, the parent compound of Neulasta®, and is postulated to be secondary to an influx of neutrophils to sites of inflammation in the lungs. Neutropenic patients receiving Neulasta® who develop fever, lung infiltrates, or respiratory distress should be evaluated for the possibility of ARDS. In the event that ARDS occurs, Neulasta® should be discontinued and/or withheld until resolution of ARDS and patients should receive appropriate medical management for this condition.
Allergic Reactions
Allergic reactions to Neulasta®, including anaphylaxis, skin rash, and urticaria, have been reported in postmarketing experience. The majority of reported events occurred upon initial exposure. In some cases, symptoms recurred with rechallenge, suggesting a causal relationship. In rare cases, allergic reactions including anaphylaxis, recurred within days after initial anti-allergic treatment was discontinued. If a serious allergic reaction occurs, appropriate therapy should be administered, with close patient follow-up over several days. Neulasta® should be permanently discontinued in patients with serious allergic reactions.
Sickle Cell Disease
Severe sickle cell crises have been associated with the use of Neulasta® in patients with sickle cell disease. Severe sickle cell crises, in some cases resulting in death, have also been associated with Filgrastim, the parent compound of pegfilgrastim. Only physicians qualified by specialized training or experience in the treatment of patients with sickle cell disease should prescribe Neulasta® for such patients, and only after careful consideration of the potential risks and benefits.
PRECAUTIONS
General
Use With Chemotherapy and/or Radiation Therapy
Neulasta® should not be administered in the period between 14 days before and 24 hours after administration of cytotoxic chemotherapy (see DOSAGE AND ADMINISTRATION) because of the potential for an increase in sensitivity of rapidly dividing myeloid cells to cytotoxic chemotherapy.
The use of Neulasta® has not been studied in patients receiving chemotherapy associated with delayed myelosuppression (eg, nitrosoureas, mitomycin C).
The administration of Neulasta® concomitantly with 5‑fluorouracil or other antimetabolites has not been evaluated in patients. Administration of pegfilgrastim at 0, 1, and 3 days before 5‑fluorouracil resulted in increased mortality in mice; administration of pegfilgrastim 24 hours after 5‑fluorouracil did not adversely affect survival.
The use of Neulasta® has not been studied in patients receiving radiation therapy.
Potential Effect on Malignant Cells
Pegfilgrastim is a growth factor that primarily stimulates neutrophils and neutrophil precursors; however, the G‑CSF receptor through which pegfilgrastim and Filgrastim act has been found on tumor cell lines, including some myeloid, T‑lymphoid, lung, head and neck, and bladder tumor cell lines. The possibility that pegfilgrastim can act as a growth factor for any tumor type cannot be excluded. Use of Neulasta® in myeloid malignancies and myelodysplasia (MDS) has not been studied. In a randomized study comparing the effects of the parent compound of Neulasta®, Filgrastim, to placebo in patients undergoing remission induction and consolidation chemotherapy for acute myeloid leukemia, important differences in remission rate between the two arms were excluded. Disease‑free survival and overall survival were comparable; however, the study was not designed to detect important differences in these endpoints.3
Information for Patients
Patients should be informed of the possible side effects of Neulasta®, and be instructed to report them to the prescribing physician. Patients should be informed of the signs and symptoms of allergic drug reactions and be advised of appropriate actions. Patients should be counseled on the importance of compliance with their Neulasta® treatment, including regular monitoring of blood counts.
If it is determined that a patient or caregiver can safely and effectively administer Neulasta® (pegfilgrastim) at home, appropriate instruction on the proper use of Neulasta® (pegfilgrastim) should be provided for patients and their caregivers, including careful review of the “Information for Patients and Caregivers” insert. Patients and caregivers should be cautioned against the reuse of needles, syringes, or drug product, and be thoroughly instructed in their proper disposal. A puncture-resistant container for the disposal of used syringes and needles should be available.
Laboratory Monitoring
To assess a patient’s hematologic status and ability to tolerate myelosuppressive chemotherapy, a complete blood count and platelet count should be obtained before chemotherapy is administered. Regular monitoring of hematocrit value and platelet count is recommended.
Drug Interaction
No formal drug interaction studies between Neulasta® and other drugs have been performed. Drugs such as lithium may potentiate the release of neutrophils; patients receiving lithium and Neulasta® should have more frequent monitoring of neutrophil counts.
Increased hematopoetic 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.
Carcinogenesis, Mutagenesis, Impairment of Fertility
No mutagenesis studies were conducted with pegfilgrastim. The carcinogenic potential of pegfilgrastim has not been evaluated in long‑term animal studies. In a toxicity study of 6 months duration in rats given once weekly subcutaneous injections of up to 1000 mcg/kg of pegfilgrastim (approximately 23‑fold higher than the recommended human dose), no precancerous or cancerous lesions were noted.
When administered once weekly via subcutaneous injections to male and female rats at doses up to 1000 mcg/kg prior to, and during mating, reproductive performance, fertility, and sperm assessment parameters were not affected.
Pregnancy Category C
Pegfilgrastim has been shown to have adverse effects in pregnant rabbits when administered subcutaneously every other day during gestation at doses as low as 50 mcg/kg/dose (approximately 4‑fold higher than the recommended human dose). Decreased maternal food consumption, accompanied by a decreased maternal body weight gain and decreased fetal body weights were observed at 50 to 1000 mcg/kg/dose. Pegfilgrastim doses of 200 and 250 mcg/kg/dose resulted in an increased incidence of abortions. Increased post‑implantation loss due to early resorptions was observed at doses of 200 to 1000 mcg/kg/dose, and decreased numbers of live rabbit fetuses were observed at pegfilgrastim doses of 200 to 1000 mcg/kg/dose, given every other day.
Subcutaneous injections of pegfilgrastim of up to 1000 mcg/kg/dose every other day during the period of organogenesis in rats were not associated with an embryotoxic or fetotoxic outcome. However, an increased incidence (compared to historical controls) of wavy ribs was observed in rat fetuses at 1000 mcg/kg/dose every other day. Very low levels (< 0.5%) of pegfilgrastim crossed the placenta when administered subcutaneously to pregnant rats every other day during gestation.
Once weekly subcutaneous injections of pegfilgrastim to female rats from day 6 of gestation through day 18 of lactation at doses up to 1000 mcg/kg/dose did not result in any adverse maternal effects. There were no deleterious effects on the growth and development of the offspring and no adverse effects were found upon assessment of fertility indices.
There are no adequate and well‑controlled studies in pregnant women. Neulasta® should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.
Nursing Mothers
It is not known whether pegfilgrastim is excreted in human milk. Because many drugs are excreted in human milk‚ caution should be exercised when Neulasta® is administered to a nursing woman.
Pediatric Use
The safety and effectiveness of Neulasta® in pediatric patients have not been established. The 6 mg fixed dose single‑use syringe formulation should not be used in infants, children, and smaller adolescents weighing less than 45 kg.
Geriatric Use
Of the 932 patients with cancer who received Neulasta® in clinical studies, 139 (15%) were age 65 and over, and 18 (2%) were age 75 and over. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients.
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