LEUKINE SIDE EFFECTS

  • Generic Name: sargramostim
  • Brand Name: Leukine
  • Drug Class: Hematopoietic Growth Factors
Last updated on MDtodate: 10/7/2022

SIDE EFFECTS

The following serious adverse reactions are discussed in greater detail in other sections of the labeling:

  • Hypersensitivity Reactions.
  • Infusion Related Reactions.
  • Risk of Severe Myelosuppression when LEUKINE Administered within 24 Hours of Chemotherapy or Radiotherapy.
  • Effusions and Capillary Leak Syndrome.
  • Supraventricular Arrhythmias.
  • Leukocytosis.
  • Potential Effect on Malignant Cells.
  • Immunogenicity.
  • Risk of Serious Adverse Reactions in Infants Due to Benzyl Alcohol Preservative.

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.

Table 1: Adverse Reactions after Autologous Marrow or PBPC Transplantation in at Least 10% of Patients Receiving Intravenous LEUKINE or at Least 5% Higher than the Placebo Arm

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-vshost 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.

Table 2: Adverse Reactions after Allogeneic Marrow Transplantation in at Least 10% of Patients Receiving Intravenous LEUKINE or at Least 5% Higher than the Placebo Arm

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 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 16
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
* Grade 3 and 4 laboratory abnormalities only. Denominators may vary due to missing laboratory measures.

 

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.

Table 3: Adverse Reactions after Treatment of AML in at Least 10% of Patients Receiving Intravenous LEUKINE or at Least 5% Higher than the Placebo Arm

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 53 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.

Immunogenicity

As with all therapeutic proteins, there is the potential for immunogenicity with LEUKINE. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, duration of treatment, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to sargramostim in the studies described below with the incidence of antibodies in other studies or other products may be misleading.

In 214 patients with a variety of underlying diseases, neutralizing anti-sargramostim antibodies were detected in 5 patients (2.3%) after receiving LEUKINE by continuous IV infusion (3 patients) or SC injection (2 patients) for 28 to 84 days in multiple courses (as assessed by GMCSF dependent human cell-line proliferation assay). All 5 patients had impaired hematopoiesis before the administration of LEUKINE, and consequently the effect of the development of antisargramostim antibodies on normal hematopoiesis could not be assessed.

Antibody studies of 75 patients with Crohn’s disease (a disease for which LEUKINE is not indicated), with normal hematopoiesis and no other immunosuppressive drugs, receiving LEUKINE daily for 8 weeks by SC injection, showed 1 patient (1.3%) with detectable neutralizing anti-sargramostim antibodies (as assessed by GM-CSF dependent human cell-line proliferation assay).

In an experimental use trial where LEUKINE was given for an extended period, 53 patients with melanoma in complete remission (a disease for which LEUKINE is not indicated) received adjuvant therapy with LEUKINE 125 mcg/m² once daily (maximum dose 250 mcg) from day 1 to 14 every 28 days for 1 year. Serum samples from patients assessed at day 0, 2 weeks, 1 month, and 5 and/or 12 months were tested retrospectively for the presence of anti-sargramostim antibodies. Of 43 evaluable patients (having at least 3 timepoint samples post treatment), 42 (97.7%) developed anti-sargramostim binding antibody as assessed by ELISA and confirmed using an immunoprecipitation assay. Of these 42 patients, 41 had sufficient sample and were further tested: 34 patients (82.9%) developed anti-sargramostim neutralizing antibodies (as determined by a cell based luciferase reporter gene neutralizing antibody assay); 17 (50%) of these patients did not have a sustained pharmacodynamic effect of LEUKINE by day 155 as assessed by WBC counts. This study provided limited assessment of the impact of antibody formation on the safety and efficacy of LEUKINE.

Serious allergic and anaphylactoid reactions have been reported with LEUKINE, but the rate of occurrence of antibodies in such patients has not been assessed.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of LEUKINE in clinical trials and/or postmarketing surveillance. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

  • Infusion related reactions including dyspnea, hypoxia, flushing, hypotension, syncope and/or tachycardia
  • Serious allergic reactions/hypersensitivity, including anaphylaxis, skin rash, urticaria, generalized erythema, and flushing
  • Effusions and capillary leak syndrome
  • Supraventricular arrhythmias
  • Leukocytosis including eosinophilia
  • Thromboembolic events
  • Pain, including chest, abdominal, back, and joint pain
  • Injection site reactions.

 

SRC: NLM .