WARNINGS
Pediatric Use
Benzyl alcohol is a constituent of liquid LEUKINE and Bacteriostatic Water for Injection diluent. Benzyl alcohol has been reported to be associated with a fatal "Gasping Syndrome" in premature infants. Liquid solutions containing benzyl alcohol (including liquid LEUKINE) or lyophilized LEUKINE reconstituted with Bacteriostatic Water for Injection, USP (0.9% benzyl alcohol) should not be administered to neonates (see
PRECAUTIONS
and
DOSAGE AND ADMINISTRATION).
Fluid Retention
Edema, capillary leak syndrome, pleural and/or pericardial effusion have been reported in patients after LEUKINE administration. In 156 patients enrolled in placebo-controlled studies using LEUKINE at a dose of 250 mcg/m2/day by 2-hour IV infusion, the reported incidences of fluid retention (LEUKINE vs. placebo) were as follows: peripheral edema, 11% vs. 7%; pleural effusion, 1% vs. 0%; and pericardial effusion, 4% vs. 1%. Capillary leak syndrome was not observed in this limited number of studies; based on other uncontrolled studies and reports from users of marketed LEUKINE, the incidence is estimated to be less than 1%. In patients with preexisting pleural and pericardial effusions, administration of LEUKINE may aggravate fluid retention; however, fluid retention associated with or worsened by LEUKINE has been reversible after interruption or dose reduction of LEUKINE with or without diuretic therapy. LEUKINE should be used with caution in patients with preexisting fluid retention, pulmonary infiltrates or congestive heart failure.
Respiratory Symptoms
Sequestration of granulocytes in the pulmonary circulation has been documented following LEUKINE infusion12 and dyspnea has been reported occasionally in patients treated with LEUKINE. Special attention should be given to respiratory symptoms during or immediately following LEUKINE infusion, especially in patients with preexisting lung disease. In patients displaying dyspnea during LEUKINE administration, the rate of infusion should be reduced by half. If respiratory symptoms worsen despite infusion rate reduction, the infusion should be discontinued. Subsequent IV infusions may be administered following the standard dose schedule with careful monitoring. LEUKINE should be administered with caution in patients with hypoxia.
Cardiovascular Symptoms
Occasional transient supraventricular arrhythmia has been reported in uncontrolled studies during LEUKINE administration, particularly in patients with a previous history of cardiac arrhythmia. However, these arrhythmias have been reversible after discontinuation of LEUKINE. LEUKINE should be used with caution in patients with preexisting cardiac disease.
Renal and Hepatic Dysfunction
In some patients with preexisting renal or hepatic dysfunction enrolled in uncontrolled clinical trials, administration of LEUKINE has induced elevation of serum creatinine or bilirubin and hepatic enzymes. Dose reduction or interruption of LEUKINE administration has resulted in a decrease to pretreatment values. However, in controlled clinical trials the incidences of renal and hepatic dysfunction were comparable between LEUKINE (250 mcg/m2/day by 2-hour IV infusion) and placebo-treated patients. Monitoring of renal and hepatic function in patients displaying renal or hepatic dysfunction prior to initiation of treatment is recommended at least every other week during LEUKINE administration.
PRECAUTIONS
General
Parenteral administration of recombinant proteins should be attended by appropriate precautions in case an allergic or untoward reaction occurs. Serious allergic or anaphylactic reactions have been reported. If any serious allergic or anaphylactic reaction occurs, LEUKINE therapy should immediately be discontinued and appropriate therapy initiated.
A syndrome characterized by respiratory distress, hypoxia, flushing, hypotension, syncope, and/or tachycardia has been reported following the first administration of LEUKINE in a particular cycle. These signs have resolved with symptomatic treatment and usually do not recur with subsequent doses in the same cycle of treatment.
Stimulation of marrow precursors with LEUKINE may result in a rapid rise in white blood cell (WBC) count. If the ANC exceeds 20,000 cells/mm3 or if the platelet count exceeds 500,000/mm3, LEUKINE administration should be interrupted or the dose reduced by half. The decision to reduce the dose or interrupt treatment should be based on the clinical condition of the patient. Excessive blood counts have returned to normal or baseline levels within three to seven days following cessation of LEUKINE therapy. Twice weekly monitoring of CBC with differential (including examination for the presence of blast cells) should be performed to preclude development of excessive counts.
Growth Factor Potential
LEUKINE is a growth factor that primarily stimulates normal myeloid precursors. However, the possibility that LEUKINE can act as a growth factor for any tumor type, particularly myeloid malignancies, cannot be excluded. Because of the possibility of tumor growth potentiation, precaution should be exercised when using this drug in any malignancy with myeloid characteristics.
Should disease progression be detected during LEUKINE treatment, LEUKINE therapy should be discontinued.
LEUKINE has been administered to patients with myelodysplastic syndromes (MDS) in uncontrolled studies without evidence of increased relapse rates.13, 14, 15
Controlled studies have not been performed in patients with MDS.
Use in Patients Receiving Purged Bone Marrow
LEUKINE is effective in accelerating myeloid recovery in patients receiving bone marrow purged by anti-B lymphocyte monoclonal antibodies. Data obtained from uncontrolled studies suggest that if in vitro marrow purging with chemical agents causes a significant decrease in the number of responsive hematopoietic progenitors, the patient may not respond to LEUKINE. When the bone marrow purging process preserves a sufficient number of progenitors (>1.2 × 104/kg), a beneficial effect of LEUKINE on myeloid engraftment has been reported.16
Use in Patients Previously Exposed to Intensive Chemotherapy/Radiotherapy
In patients who before autologous BMT, have received extensive radiotherapy to hematopoietic sites for the treatment of primary disease in the abdomen or chest, or have been exposed to multiple myelotoxic agents (alkylating agents, anthracycline antibiotics and antimetabolites), the effect of LEUKINE on myeloid reconstitution may be limited.
Use in Patients with Malignancy Undergoing LEUKINE-Mobilized PBPC Collection
When using LEUKINE to mobilize PBPC, the limited in vitro data suggest that tumor cells may be released and reinfused into the patient in the leukapheresis product. The effect of reinfusion of tumor cells has not been well studied and the data are inconclusive.
Information for Patients
LEUKINE should be used under the guidance and supervision of a health care professional. However, when the physician determines that LEUKINE may be used outside of the hospital or office setting, persons who will be administering LEUKINE should be instructed as to the proper dose, and the method of reconstituting and administering LEUKINE (see
DOSAGE AND ADMINISTRATION). If home use is prescribed, patients should be instructed in the importance of proper disposal and cautioned against the reuse of needles, syringes, drug product, and diluent. A puncture resistant container should be used by the patient for the disposal of used needles.
Patients should be informed of the serious and most common adverse reactions associated with LEUKINE administration (see
ADVERSE REACTIONS). Female patients of childbearing potential should be advised of the possible risks to the fetus of LEUKINE (see
PRECAUTIONS, Pregnancy Category C).
Laboratory Monitoring
LEUKINE can induce variable increases in WBC and/or platelet counts. In order to avoid potential complications of excessive leukocytosis (WBC >50,000 cells/mm3; ANC >20,000 cells/mm3), a CBC is recommended twice per week during LEUKINE therapy. Monitoring of renal and hepatic function in patients displaying renal or hepatic dysfunction prior to initiation of treatment is recommended at least biweekly during LEUKINE administration. Body weight and hydration status should be carefully monitored during LEUKINE administration.
Drug Interaction
Interactions between LEUKINE and other drugs have not been fully evaluated. Drugs which may potentiate the myeloproliferative effects of LEUKINE, such as lithium and corticosteroids, should be used with caution.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Animal studies have not been conducted with LEUKINE to evaluate the carcinogenic potential or the effect on fertility.
Pregnancy (Category C)
Animal reproduction studies have not been conducted with LEUKINE. It is not known whether LEUKINE can cause fetal harm when administered to a pregnant woman or can affect reproductive capability. LEUKINE should be given to a pregnant woman only if clearly needed.
Nursing Mothers
It is not known whether LEUKINE is excreted in human milk. Because many drugs are excreted in human milk, LEUKINE should be administered to a nursing woman only if clearly needed.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established; however, available safety data indicate that LEUKINE does not exhibit any greater toxicity in pediatric patients than in adults. A total of 124 pediatric subjects between the ages of 4 months and 18 years have been treated with LEUKINE in clinical trials at doses ranging from 60–1,000 mcg/m2/day intravenously and 4–1,500 mcg/m2/day subcutaneously. In 53 pediatric patients enrolled in controlled studies at a dose of 250 mcg/m2/day by 2-hour IV infusion, the type and frequency of adverse events were comparable to those reported for the adult population. Liquid solutions containing benzyl alcohol (including liquid LEUKINE) or lyophilized LEUKINE reconstituted with Bacteriostatic Water for Injection, USP (0.9% benzyl alcohol) should not be administered to neonates (see
WARNINGS).
Geriatric Use
In the clinical trials, experience in older patients (age ≥65 years), was limited to the acute myelogenous leukemia (AML) study. Of the 52 patients treated with LEUKINE in this randomized study, 22 patients were age 65–70 years and 30 patients were age 55–64 years. The number of placebo patients in each age group were 13 and 33 patients respectively. This was not an adequate database from which determination of differences in efficacy endpoints or safety assessments could be reliably made and this clinical study was not designed to evaluate difference between these two age groups. Analyses of general trends in safety and efficacy were undertaken and demonstrate similar patterns for older (65–70 yrs) vs younger patients (55–64 yrs). Greater sensitivity of some older individuals cannot be ruled out.
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