Neulasta Side Effects, and Drug Interactions - Pegfilgrastim

Neulasta Side Effects, and Drug Interactions - Pegfilgrastim

SIDE EFFECTS

See WARNINGS sections regarding Splenic Rupture, ARDS, Allergic Reactions, and Sickle Cell Disease.

Safety data are based upon 465 subjects with lymphoma and solid tumors (breast, lung, and thoracic tumors) enrolled in six random-izedclinical studies. Subjects received Neulasta^™ after nonmyelo-ablative cytotoxic chemotherapy. Most adverse experiences were attributed by the investigators to the underlying malignancy or cytotoxic chemotherapy and occurred at similar rates in subjects who received Neulasta^™ (n = 465) or Filgrastim (n = 331). These adverse experiences occurred at rates between 72% and 15% and included: nausea, fatigue, alopecia, diarrhea, vomiting, constipation, fever, anorexia, skeletal pain, headache, taste perversion, dyspepsia, myalgia, insomnia, abdominal pain, arthralgia, generalized weakness, peripheral edema, dizziness, granulocytopenia, stomatitis, mucositis, and neutropenic fever.

The most common adverse event attributed to Neulasta^™ in clinical trials was medullary bone pain, reported in 26% of subjects, which was comparable to the incidence of Filgrastim-treated patients. This bone pain was generally reported to be of mild-to-moderate severity. Approximately 12% of all subjects utilized non-narcotic analgesics and less than 6% utilized narcotic analgesics in association with bone pain. No patient withdrew from study due to bone pain. In clinical studies, leukocytosis (WBC counts >100 x 10⁹/_L) was observed in less than 1% of 465 subjects with non-myeloid malignancies receiving Neulasta^™. Leukocytosis was not associated with any adverse effects.

In subjects receiving Neulasta^™ in clinical trials, the only serious event that was not deemed attributable to underlying or concurrent disease, or to concurrent therapy was a case of hypoxia.

Reversible elevations in LDH, alkaline phosphatase, and uric acid, which did not require treatment intervention, were observed. The incidences of these changes, presented for Neulasta^™ relative to Filgrastim, were: LDH (19% vs 29%), alkaline phosphatase (9% vs 16%), and uric acid (8% vs 9% [1% of reported cases for both treatment groups were classified as severe]).

As with all therapeutic proteins, there is a potential for immuno-genicity. The incidence of antibody development in patients receiving Neulasta^™ has not been adequately determined. While available data suggest that a small proportion of patients developed binding antibodies to Filgrastim or pegfilgrastim, the nature and specificity of these antibodies has not been adequately studied. No neutralizing antibodies have been detected using a cell-based bioassay in 46 patients who apparently developed binding antibodies. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay, and the observed incidence of antibody positivity in an assay may be influenced by several factors including sample handling, concomitant medications, and underlying disease. Therefore, comparison of the incidence of antibodies to Neulasta^™ with the incidence of antibodies to other products may be misleading.

Cytopenias resulting from an antibody response to exogenous growthfactors have been reported on rare occasions in patients treated with other recombinant growth factors. There is a theoretical possibility that an antibody directed against pegfilgrastim may cross-react with endogenous G-CSF, resulting in immune-mediated neutropenia, but this has not been observed in clinical studies.

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.

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 SC 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 465 subjects with cancer who received Neulasta^™ in clinical studies, 85 (18%) were age 65 and over, and 14 (3%) were age 75 and over. No overall differences in safety or effectiveness were observed between these patients and younger patients; however, due to the small number of elderly subjects, small but clinically relevant differences cannot be excluded.