Sargramostim

(Category C)

Animal reproduction studies have not been conducted with sargramostim. It is not known whether sargramostim can cause fetal harm when administered to a pregnant woman or can affect reproductive capability. Sargramostim should be given to a pregnant woman only if clearly needed.

It is not known whether sargramostim is excreted in human milk. Because many drugs are excreted in human milk, sargramostim should be administered to a nursing woman only if clearly needed.

Animal studies have not been conducted with sargramostim to evaluate the carcinogenic potential or the effect on fertility.

Autologous and Allogeneic Bone Marrow Transplantation

Sargramostim is generally well tolerated. In three placebo-controlled studies enrolling a total of 156 patients after autologous BMT or peripheral blood progenitor cell transplantation, events reported in at least 10% of patients who received IV sargramostim or placebo were as reported in the following table.

Percent of AuBMT Patients Reporting Events:

No significant differences were observed between sargramostim and placebo-treated
patients in the type or frequency of laboratory abnormalities, including renal and hepatic parameters. In some patients with preexisting renal or hepatic dysfunction enrolled in uncontrolled clinical trials, administration of sargramostim has induced elevation of serum creatinine or bilirubin and hepatic enzymes. In addition, there was no significant difference in relapse rate and 24 month survival between the sargramostim and placebo-treated patients.

In the placebo-controlled trial of 109 patients after allogeneic BMT, events reported in at least 10% of patients who received IV sargramostim or placebo were as reported in the following table.

Percent of Allogeneic BMT Patients Reporting Events:

* Grade 3 and 4 laboratory abnormalities only. Denominators may vary due to missing laboratory measurements.

There were no significant differences in the incidence or severity of GVHD, relapse rates and survival between the sargramostim and placebo-treated patients. Adverse events observed for the patients treated with sargramostim in the historically-controlled BMT failure study were similar to those reported in the placebo-controlled studies. In addition, headache (26%), pericardial effusion (25%), arthralgia (21%) and myalgia (18%) were also reported in patients treated with sargramostim in the graft failure study.

In uncontrolled Phase I/II studies with sargramostim in 215 patients, the most frequent adverse events were fever, asthenia, headache, bone pain, chills and myalgia. These systemic events were generally mild or moderate and were usually prevented or reversed by the administration of analgesics and antipyretics such as acetaminophen. In these uncontrolled trials, other infrequent events reported were dyspnea, peripheral edema, and rash.

Reports of events occurring with marketed sargramostim include arrhythmia, fainting, eosinophilia, dizziness, hypotension, injection site reactions, pain (including abdominal, back, chest, and joint pain), tachycardia, thrombosis, and transient liver function abnormalities.

In patients with preexisting edema, capillary leak syndrome, pleural and/or pericardial effusion, administration of sargramostim may aggravate fluid retention. Body weight and hydration status should be carefully monitored during sargramostim administration.

Adverse events observed in pediatric patients in controlled studies were comparable to those observed in adult patients.

Acute Myelogenous Leukemia

Adverse events reported in at least 10% of patients who received LEUKINE or placebo were as reported in the following table.

Percent of AML Patients Reporting Events:

Nearly all patients reported leukopenia, thrombocytopenia and anemia. The frequency and type of adverse events observed following induction were similar between sargramostim and placebo groups. The only significant difference in the rates of these adverse events was an increase in skin associated events in the LEUKINE group (p=0.002). No significant differences were observed in laboratory results, renal or hepatic toxicity. No significant differences were observed between the sargramostim and placebo-treated patients for adverse events following consolidation. There was no significant difference in response rate or relapse rate.

In a historically-controlled study of 86 patients with acute myelogenous leukemia (AML), the sargramostim treated group exhibited an increased incidence of weight gain (p=0.007), low serum proteins and prolonged prothrombin time (p=0.02) when compared to the control group. Two sargramostim treated patients had progressive increase in circulating monocytes and promonocytes and blasts in the marrow which reversed when sargramostim was discontinued. The historical control group exhibited an increased incidence of cardiac events (p=0.018), liver function abnormalities (p=0.008), and neurocortical hemorrhagic events (p=0.025).