openFDA text is shown for search and cross-checking; DailyMed SPL is canonical.
Warnings sections page 1 of 1 · 1 matching rows.
warnings
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/m 2 /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 infusion 12 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/m 2 /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.
ADVERSE REACTIONS Autologous and Allogeneic Bone Marrow Transplantation LEUKINE 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 LEUKINE or placebo were as reported in Table 6. Table 6 Percent of AuBMT Patients Reporting Events Events by Body System LEUKINE (n=79) Placebo (n=77) Events by Body System LEUKINE (n=79) Placebo (n=77) Body, General Metabolic, Nutritional Disorder Fever 95 96 Edema 34 35 Mucous membrane disorder 75 78 Peripheral edema 11 7 Asthenia 66 51 Respiratory System Malaise 57 51 Dyspnea 28 31 Sepsis 11 14 Lung disorder 20 23 Digestive System Hemic and Lymphatic System Nausea 90 96 Blood dyscrasia 25 27 Diarrhea 89 82 Cardiovascular System Vomiting 85 90 Hemorrhage 23 30 Anorexia 54 58 Urogenital System GI disorder 37 47 Urinary tract disorder 14 13 GI hemorrhage 27 33 Kidney function abnormal 8 10 Stomatitis 24 29 Nervous System Liver damage 13 14 CNS disorder 11 16 Skin and Appendages Alopecia 73 74 Rash 44 38 No significant differences were observed between LEUKINE 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 LEUKINE has induced elevation of serum creatinine or bilirubin and hepatic enzymes (see WARNINGS ). In addition, there was no significant difference in relapse rate and 24 month survival between the LEUKINE 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 LEUKINE or placebo were as reported in Table 7. Table 7 Percent of Allogeneic BMT Patients Reporting Events Events by Body System LEUKINE (n=53) Placebo (n=56) Events by Body System LEUKINE (n=53) Placebo (n=56) Body, General Metabolic/Nutritional Disorders Fever 77 80 Bilirubinemia 30 27 Abdominal pain 38 23 Hyperglycemia 25 23 Headache 36 36 Peripheral edema 15 21 Chills 25 20 Increased creatinine 15 14 Pain 17 36 Hypomagnesemia 15 9 Asthenia 17 20 Increased SGPT 13 16 Chest pain 15 9 Edema 13 11 Back pain 9 18 Increased alk. phosphatase 8 14 Digestive System Respiratory System Diarrhea 81 66 Pharyngitis 23 13 Nausea 70 66 Epistaxis 17 16 Vomiting 70 57 Dyspnea 15 14 Stomatitis 62 63 Rhinitis 11 14 Anorexia 51 57 Hemic and Lymphatic System Dyspepsia 17 20 Thrombocytopenia 19 34 Hematemesis 13 7 Leukopenia 17 29 Dysphagia 11 7 Petechia 6 11 GI hemorrhage 11 5 Agranulocytosis 6 11 Constipation 8 11 Urogenital System Skin and Appendages Hematuria 9 21 Rash 70 73 Nervous System Alopecia 45 45 Paresthesia 11 13 Pruritis 23 13 Insomnia 11 9 Musculo-skeletal System Anxiety 11 2 Bone pain 21 5 Laboratory Abnormalities Grade 3 and 4 laboratory abnormalities only. Denominators may vary due to missing laboratory measurements. Arthralgia 11 4 High glucose 41 49 Special Senses Low albumin 27 36 Eye hemorrhage 11 0 High BUN 23 17 Cardiovascular System Low calcium 2 7 Hypertension 34 32 High cholesterol 17 8 Tachycardia 11 9 There were no significant differences in the incidence or severity of GVHD, relapse rates and survival between the LEUKINE and placebo-treated patients. Adverse events observed for the patients treated with LEUKINE 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 LEUKINE in the graft failure study. In uncontrolled Phase I/II studies with LEUKINE 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 LEUKINE 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 LEUKINE may aggravate fluid retention (see WARNINGS ). Body weight and hydration status should be carefully monitored during LEUKINE 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 Table 8. Table 8 Percent of AML Patients Reporting Events Events by Body System LEUKINE (n=52) Placebo (n=47) Events by Body System LEUKINE (n=52) Placebo (n=47) Body, General Metabolic/Nutritional Disorder Fever (no infection) 81 74 Metabolic 58 49 Infection 65 68 Edema 25 23 Weight loss 37 28 Respiratory System Weight gain 8 21 Pulmonary 48 64 Chills 19 26 Hemic and Lymphatic System Allergy 12 15 Coagulation 19 21 Sweats 6 13 Cardiovascular System Digestive System Hemorrhage 29 43 Nausea 58 55 Hypertension 25 32 Liver 77 83 Cardiac 23 32 Diarrhea 52 53 Hypotension 13 26 Vomiting 46 34 Urogenital System Stomatitis 42 43 GU 50 57 Anorexia 13 11 Nervous System Abdominal distention 4 13 Neuro-clinical 42 53 Skin and Appendages Neuro-motor 25 26 Skin 77 45 Neuro-psych 15 26 Alopecia 37 51 Neuro-sensory 6 11 Nearly all patients reported leukopenia, thrombocytopenia and anemia. The frequency and type of adverse events observed following induction were similar between LEUKINE 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 LEUKINE 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 LEUKINE 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 LEUKINE treated patients had progressive increase in circulating monocytes and promonocytes and blasts in the marrow which reversed when LEUKINE 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). 15 Antibody Formation Serum samples collected before and after LEUKINE treatment from 214 patients with a variety of underlying diseases have been examined for immunogenicity based on the presence of antibodies. Neutralizing antibodies were detected in five of 214 patients (2.3%) after receiving LEUKINE by continuous IV infusion (three patients) or subcutaneous injection (SC)(two patients) for 28 to 84 days in multiple courses. All five patients had impaired hematopoiesis before the administration of LEUKINE and consequently the effect of the development of anti-GM-CSF antibodies on normal hematopoiesis could not be assessed. Antibody studies of 75 patients with Crohn's disease receiving LEUKINE by subcutaneous injection with normal hematopoiesis and no other immunosuppressive drugs showed one patient (1.3%) with detectable neutralizing antibodies. The clinical relevance of the presence of these antibodies are unknown. Drug-induced neutropenia, neutralization of endogenous GM-CSF activity and diminution of the therapeutic effect of LEUKINE secondary to formation of neutralizing antibody remain a theoretical possibility. Serious allergic and anaphylactoid reactions have been reported with LEUKINE but the rate of occurrence of antibodies in such patients has not been assessed. Overdosage The maximum amount of LEUKINE that can be safely administered in single or multiple doses has not been determined. Doses up to 100 mcg/kg/day (4,000 mcg/m 2 /day or 16 times the recommended dose) were administered to four patients in a Phase I uncontrolled clinical study by continuous IV infusion for 7 to 18 days. Increases in WBC up to 200,000 cells/mm 3 were observed. Adverse events reported were dyspnea, malaise, nausea, fever, rash, sinus tachycardia, headache and chills. All these events were reversible after discontinuation of LEUKINE. In case of overdosage, LEUKINE therapy should be discontinued and the patient carefully monitored for WBC increase and respiratory symptoms.