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/m2/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/mm3 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.
To report SUSPECTED ADVERSE REACTIONS, contact Genzyme Corporation at 1-888-4RX-LEUKINE or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
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