Leukine (Page 3 of 9)
6 ADVERSE REACTIONS
The following serious adverse reactions are discussed in greater detail in other sections of the labeling:
- Hypersensitivity Reactions [see Warnings and Precautions (5.1)]
- Infusion Related Reactions [see Warnings and Precautions (5.2)]
- Risk of Severe Myelosuppression when LEUKINE Administered within 24 Hours of Chemotherapy or Radiotherapy [see Warnings and Precautions (5.3)]
- Effusions and Capillary Leak Syndrome [see Warnings and Precautions (5.4)]
- Supraventricular Arrhythmias [see Warnings and Precautions (5.5)]
- Leukocytosis [see Warnings and Precautions (5.6)]
- Potential Effect on Malignant Cells [see Warnings and Precautions (5.7)]
- Immunogenicity [see Warnings and Precautions (5.8)]
- Risk of Serious Adverse Reactions in Infants Due to Benzyl Alcohol Preservative [see Warnings and Precautions (5.9)]
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
Autologous Peripheral Blood Progenitor Cell (PBPC) and Bone Marrow Transplantation
Studies 301, 302 and 303 enrolled a total of 156 patients after autologous or allogeneic marrow or PBPC transplantation. In these placebo-controlled studies, pediatric and adult patients received once-daily intravenous infusions of LEUKINE 250 mcg/m2 or placebo for 21 days.
In Studies 301, 302, and 303, there was no difference in relapse rate between the LEUKINE and placebo-treated patients. Adverse reactions reported in at least 10% of patients who received intravenous LEUKINE or at a rate that was at least 5% higher than the placebo arm are shown in Table 1.
Adverse Reactions by Body System | LEUKINE (n=79) % | Placebo (n=77) % | Adverse Reactions 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 | Blood and Lymphatic System | ||||
Nausea | 90 | 96 | Blood dyscrasia | 25 | 27 |
Diarrhea | 89 | 82 | Cardiovascular Vascular 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 | Nervous System | ||
Stomatitis | 24 | 29 | CNS disorder | 11 | 16 |
Liver damage | 13 | 14 | |||
Skin and Appendages | |||||
Alopecia | 73 | 74 | |||
Rash | 44 | 38 |
Additional Clinically Significant Adverse Reactions Occurring in Less than 10% Incidence
Investigations: Elevated creatinine, elevated bilirubin, elevate transaminases
Allogeneic Bone Marrow Transplantation
In the placebo-controlled trial of 109 patients after allogeneic BMT (Study 9002), acute graft-vs-host disease occurred in 55% on the LEUKINE arm and in 59% on the placebo arm. Adverse reactions reported in at least 10% of patients who received IV LEUKINE or at a rate at least 5% higher than the placebo arm are shown in Table 2.
* Grade 3 and 4 laboratory abnormalities only. Denominators may vary due to missing laboratory measures. | |||||
Adverse Reactions by Body System | LEUKINE (n=53) % | Placebo (n=56) % | Adverse Reactions by Body System | LEUKINE (n=53) % | Placebo (n=56) % |
Body, General | Eye hemorrhage | 11 | 0 | ||
Fever | 77 | 80 | Cardiovascular Vascular System | ||
Abdominal pain | 38 | 23 | Hypertension | 34 | 32 |
Headache | 36 | 36 | Tachycardia | 11 | 9 |
Chills | 25 | 20 | Metabolic / Nutritional Disorders | ||
Pain | 17 | 36 | Bilirubinemia | 30 | 27 |
Asthenia | 17 | 20 | Hyperglycemia | 25 | 23 |
Chest pain | 15 | 9 | Peripheral edema | 15 | 21 |
Digestive System | Increased creatinine | 15 | 14 | ||
Diarrhea | 81 | 66 | Hypomagnesemia | 15 | 9 |
Nausea | 70 | 66 | Increased SGPT | 13 | 11 |
Vomiting | 70 | 57 | Edema | 13 | 11 |
Stomatitis | 62 | 63 | Respiratory System | ||
Anorexia | 51 | 57 | Pharyngitis | 23 | 13 |
Dyspepsia | 17 | 20 | Epistaxis | 17 | 16 |
Hematemesis | 13 | 7 | Dyspnea | 15 | 14 |
Dysphagia | 11 | 7 | Rhinitis | 11 | 14 |
GI hemorrhage | 11 | 5 | Blood and Lymphatic System | ||
Skin and Appendages | Thrombocytopenia | 19 | 34 | ||
Rash | 70 | 73 | Leukopenia | 17 | 29 |
Alopecia | 45 | 45 | Nervous System | ||
Pruritus | 23 | 13 | Paresthesia | 11 | 13 |
Musculoskeletal System | Insomnia | 11 | 9 | ||
Bone pain | 21 | 5 | Anxiety | 11 | 2 |
Arthralgia | 11 | 4 | Laboratory Abnormalities* | ||
Special Senses | High glucose | 49 | 41 | ||
Low albumin | 36 | 27 | |||
High BUN | 17 | 23 |
Acute Myeloid Leukemia Following Induction Chemotherapy
Nearly all patients in both arms developed leukopenia, thrombocytopenia, and anemia. Adverse reactions reported in at least 10% of patients who received LEUKINE or at least 5% higher than the placebo arm are reported in Table 3.
Adverse Reactions by Body System | LEUKINE (n=52) % | Placebo (n=47) % | Adverse Reactions by Body System | LEUKINE (n=52) % | Placebo (n=47) % |
Body, General | Metabolic, Nutritional Disorder | ||||
Fever (no infection) | 81 | 74 | Metabolic Laboratory Abnormalities | 58 | 49 |
Infection | 65 | 68 | Edema | 25 | 23 |
Weight loss | 37 | 28 | Respiratory System | ||
Chills | 19 | 26 | Pulmonary toxicity | 48 | 64 |
Allergy | 12 | 15 | Blood and Lymphatic System | ||
Digestive System | Coagulation | 19 | 21 | ||
Nausea | 58 | 55 | Cardiovascular System | ||
Liver toxicity | 77 | 83 | Hemorrhage | 29 | 43 |
Diarrhea | 52 | 3 | Hypertension | 25 | 32 |
Vomiting | 46 | 34 | Cardiac | 23 | 32 |
Stomatitis | 42 | 43 | Hypotension | 13 | 26 |
Anorexia | 13 | 11 | Urogenital System | ||
Skin and Appendages | GU abnormalities | 50 | 57 | ||
Skin Reactions | 77 | 45 | Nervous System | ||
Alopecia | 37 | 51 | Neuro-clinical | 42 | 53 |
Neuro-motor | 25 | 26 | |||
Neuro-psych | 15 | 26 |
There was no significant difference between the arms in the proportion of patients achieving complete remission (CR; 69% in the LEUKINE group and 55% in the placebo group). There was also no significant difference in relapse rates; 12 of 36 patients who received LEUKINE and five of 26 patients who received placebo relapsed within 180 days of documented CR (p=0.26). The study was not sized to assess the impact of LEUKINE treatment on response.
Graft Failure
In a historically controlled study of 86 patients with 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). Headache (26%), pericardial effusion (25%), arthralgia (21%), and myalgia (18%) were also reported in patients treated with LEUKINE in the graft failure study.
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