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8036 (05/09)
 
 
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use Clolar safely and effectively. See full prescribing information for Clolar.
Clolar® (clofarabine) Injection for intravenous use
Initial U.S. Approval: 2004

INDICATIONS AND USAGE

·
Clolar (clofarabine) Injection is a purine nucleoside metabolic inhibitor indicated for the treatment of pediatric patients 1 to 21 years old with relapsed or refractory acute lymphoblastic leukemia after at least two prior regimens. Randomized trials demonstrating increased survival or other clinical benefit have not been conducted. (1)

DOSAGE AND ADMINISTRATION

·
Administer the recommended pediatric dose of 52 mg/m2 as an intravenous infusion over 2 hours daily for 5 consecutive days of a 28-day cycle. Repeat cycles every 2-6 weeks. (2.1)
·
Provide supportive care, such as intravenous infusion fluids, allopurinol, and alkalinization of urine throughout the 5 days of Clolar administration to reduce the effects of tumor lysis and other adverse events. Discontinue Clolar if hypotension develops during the 5 days of administration. (2.1)
·
Monitor hepatic, renal, and cardiac function. (2.1)
·
Avoid use of certain medications. (2.2)
·
Use dose modification for toxicity. (2.3)
·
Filter Clolar through a sterile 0.2 micron syringe filter and then dilute with 5% Dextrose Injection, USP, or 0.9% Sodium Chloride Injection, USP, prior to intravenous infusion to a final concentration between 0.15 mg/mL and 0.4 mg/mL. (2.4)
·
To prevent drug incompatibilities, no other medications should be administered through the same intravenous line. (2.5)

DOSAGE FORMS AND STRENGTHS

·
20 mg/20 mL single-use vial. (3)

CONTRAINDICATIONS

·
None. (4)

WARNINGS AND PRECAUTIONS

Hematologic Toxicity
·
Monitor complete blood counts and platelet counts during Clolar therapy. (5.1)

Infections
·
Clolar use is likely to increase the risk of infection, including severe sepsis, as a result of bone marrow suppression. Monitor patients for signs and symptoms of infection and treat promptly. (5.2)

Hyperuricemia (Tumor Lysis)
·
Take precautions to prevent and monitor patients for signs and symptoms of tumor lysis syndrome, as well as signs and symptoms of cytokine release. (5.3)

Systemic Inflammatory Response Syndrome (SIRS) or Capillary Leak Syndrome
·
Discontinue Clolar immediately in the event of signs or symptoms of SIRS or Capillary Leak Syndrome
·
SIRS and Capillary Leak Syndrome may occur. Evaluate and monitor patients undergoing treatment for signs and symptoms of cytokine release. Consider use of steroids. (5.4)

Hepatic Enzymes
·
Monitor and discontinue treatment if necessary. (5.5)

Hepatic/Renal Impairment
·
Use with caution in patients with hepatic or renal impairment. Monitor hepatic and renal function. (5.6)

Use in Pregnancy
·
Fetal harm can occur when administered to a pregnant woman. Women should be advised to avoid becoming pregnant when receiving Clolar. (5.7, 8.1)

ADVERSE REACTIONS

Most common adverse reactions (≥ 10%): nausea, vomiting, diarrhea, febrile neutropenia, headache, rash, pruritus, pyrexia, fatigue, palmar-plantar erythrodysesthesia syndrome, anxiety, flushing, and mucosal inflammation (6).

To report SUSPECTED ADVERSE REACTIONS, contact Genzyme Corporation at 800-RX-CLOLAR or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

USE IN SPECIFIC POPULATIONS

·
Safety and effectiveness have not been established in adults. (8.6)
 
1
 
See 17 for PATIENT COUNSELING INFORMATION

Revised: [10/2008]

FULL PRESCRIBING INFORMATION: CONTENTS*

1
INDICATIONS AND USAGE
2
2
DOSAGE AND ADMINISTRATION
2
   
2.1
Recommended Dosage
2
   
2.2
Recommended Concomitant Medications and Medications to Avoid
2
   
2.3
Dose Modifications and Reinitiation of Therapy
2
   
2.4
Reconstitution/Preparation
2
   
2.5
Incompatibilities
2
3
DOSAGE FORMS AND STRENGTHS
2
4
CONTRAINDICATIONS
2
5
WARNINGS AND PRECAUTIONS
2
   
5.1
Hematologic Toxicity
3
   
5.2
Infections
3
   
5.3
Hyperuricemia (Tumor Lysis)
3
   
5.4
Systemic Inflammatory Response Syndrome (SIRS) and Capillary Leak Syndrome
3
   
5.5
Hepatic Enzymes
3
   
5.6
Hepatic and Renal Impairment
3
   
5.7
Use in Pregnancy
3
6
ADVERSE REACTIONS
3
   
6.1
Clinical Trials Experience
3
   
6.2
Post-marketing Experience
6
7
DRUG INTERACTIONS
6
8
USE IN SPECIFIC POPULATIONS
6
   
8.1
Pregnancy
6
   
8.3
Nursing Mothers
6
      8.4 
Pediatric Use 
 6
   
8.5
Geriatric Use
6
   
8.6
Adults with Hematologic Malignancies
6
10
OVERDOSAGE
6
11
DESCRIPTION
6
12
CLINICAL PHARMACOLOGY
6
   
12.1
Mechanism of Action
6
   
12.3
Pharmacokinetics
7
13
NONCLINICAL TOXICOLOGY
7
   
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
7
14
CLINICAL STUDIES
7
15
REFERENCES
8
16
HOW SUPPLIED/STORAGE AND HANDLING
8
17
PATIENT COUNSELING INFORMATION
8
 
*Sections or subsections omitted from the full prescribing information are not listed.
 
FULL PRESCRIBING INFORMATION

1.
INDICATIONS AND USAGE
Clolar® (clofarabine) Injection is indicated for the treatment of pediatric patients 1 to 21 years old with relapsed or refractory acute lymphoblastic leukemia after at least two prior regimens. This use is based on the induction of complete responses. Randomized trials demonstrating increased survival or other clinical benefit have not been conducted.

2.
DOSAGE AND ADMINISTRATION
2.1
Recommended Dosage
Administer the recommended pediatric dose of 52 mg/m2 as an intravenous infusion over 2 hours daily for 5 consecutive days.

 
·
Treatment cycles are repeated following recovery or return to baseline organ function, approximately every 2 to 6 weeks. The dosage is based on the patient’s body surface area (BSA), calculated using the actual height and weight before the start of each cycle. To prevent drug incompatibilities, no other medications should be administered through the same intravenous line.
 
·
Provide supportive care, such as intravenous fluids, allopurinol, and alkalinize urine throughout the 5 days of Clolar administration to reduce the effects of tumor lysis and other adverse events.
 
·
Discontinue Clolar if hypotension develops during the 5 days of administration.
 
·
Monitor renal and hepatic function during the 5 days of Clolar administration [see WARNINGS AND PRECAUTIONS (5.6)].
 
·
Monitor patients taking medications known to affect blood pressure. Monitor cardiac function during administration of Clolar.

2.2
Recommended Concomitant Medications and Medications to Avoid
 
·
Consider prophylactic anti-emetic medications as Clolar is moderately emetogenic.
 
·
Consider the use of prophylactic steroids to prevent signs or symptoms of Systemic Inflammatory Response Syndrome (SIRS) or capillary leak (e.g., hypotension, tachycardia, tachypnea, and pulmonary edema).
 
·
Consider avoiding drugs with known renal toxicity during the 5 days of Clolar administration.
 
·
Consider avoiding concomitant use of medications known to induce hepatic toxicity.

2.3
Dose Modifications and Reinitiation of Therapy
·
Hematologic Toxicity
 
·
Administer subsequent cycles no sooner than 14 days from the starting day of the previous cycle provided the patient’s ANC is ≥ 0.75 x 109/L.
 
·
If a patient experiences a Grade 4 neutropenia (ANC < 0.5 x 109/L) lasting ≥ 4 weeks, reduce dose by 25% for the next cycle.

·
Non-hematologic Toxicity
 
·
Withhold Clolar if a patient develops a clinically significant infection, until the infection is clinically controlled and then restart at the full dose.
 
·
Withhold Clolar if a Grade 3 non-infectious non-hematologic toxicity (excluding transient elevations in serum transaminases and/or serum bilirubin and/or nausea/vomiting that was controlled by antiemetic therapy) occurs. Re-institute Clolar administration at a 25% dose reduction when resolution or return to baseline.
 
·
Discontinue Clolar administration if a Grade 4 non-infectious non-hematologic toxicity occurs.
 
·
Discontinue Clolar administration if a patient shows early signs or symptoms of SIRS or capillary leak (e.g., hypotension, tachycardia, tachypnea, and pulmonary edema) occur and provide appropriate supportive measures.
 
·
Discontinue Clolar administration if Grade 3 or higher increases in creatinine or bilirubin are noted. Re-institute Clolar when the patient is stable and organ function has returned to baseline, generally with a 25% dose reduction. If hyperuricemia is anticipated (tumor lysis), prophylactically administer allopurinol.

2.4 
Reconstitution/Preparation
Clolar should be filtered through a sterile 0.2 micron syringe filter and then diluted with 5% Dextrose Injection, USP, or 0.9% Sodium Chloride Injection, USP, prior to intravenous (IV) infusion to a final concentration between 0.15 mg/mL and 0.4 mg/mL. Use within 24 hours of preparation. Store diluted Clolar at room temperature (15-30°C).

2.5 
Incompatibilities
Do not administer any other medications through the same intravenous line.

3.
DOSAGE FORMS AND STRENGTHS
20 mg/20 mL (1 mg/mL) single-use vial

4.
CONTRAINDICATIONS
None

5.
WARNINGS AND PRECAUTIONS
Clolar should be administered under the supervision of a qualified physician experienced in the use of antineoplastic therapy.

 
2
 

5.1 
Hematologic Toxicity
Monitor complete blood counts and platelet counts during Clolar therapy.

Suppression of bone marrow function should be anticipated. This is usually reversible and appears to be dose dependent. Severe bone marrow suppression, including neutropenia, anemia, and thrombocyto-penia, has been observed in patients treated with Clolar. At initiation of treatment, most patients in the clinical studies had hematological impairment as a manifestation of leukemia. Because of the pre-existing immunocompromised condition of these patients and prolonged neutropenia that can result from treatment with Clolar, patients are at increased risk for severe opportunistic infections.

5.2 
Infections
The use of Clolar is likely to increase the risk of infection, including severe sepsis, as a result of bone marrow suppression. Monitor patients for signs and symptoms of infection and treat promptly.

5.3 
Hyperuricemia (Tumor Lysis)
Administration of Clolar may result in a rapid reduction in peripheral leukemia cells. Evaluate and monitor patients undergoing treatment for signs and symptoms of tumor lysis syndrome. Provide intravenous infusion fluids throughout the five days of Clolar administration to reduce the effects of tumor lysis and other adverse events. Administer allopurinol if hyperuricemia (tumor lysis) is expected.

5.4 
Systemic Inflammatory Response Syndrome (SIRS) and Capillary Leak Syndrome
Evaluate and monitor patients undergoing treatment with Clolar for signs and symptoms of cytokine release (e.g., tachypnea, tachycardia, hypotension, pulmonary edema) that could develop into systemic inflammatory response syndrome (SIRS), capillary leak syndrome and organ dysfunction. Discontinue Clolar immediately in the event of clinically significant signs or symptoms of SIRS or capillary leak syndrome, either of which can be fatal, and consider use of steroids, diuretics, and albumin. Re-institute Clolar when the patient is stable, generally with a 25% dose reduction. The use of prophylactic steroids may be of benefit in preventing signs and symptoms of cytokine release.

5.5 
Hepatic Enzymes
Hepato-biliary enzyme elevations were frequently observed in pediatric patients during treatment with Clolar. Some patients discontinued treatment due to hepatic enzyme abnormalities [see ADVERSE REACTIONS (6.1)].

5.6 
Hepatic and Renal Impairment
Clolar has not been studied in patients with hepatic or renal dysfunction. Its use in such patients should be undertaken only with the greatest caution [see DOSAGE AND ADMINISTRATION (2.2)].

Patients who have previously received a hematopoietic stem cell transplant (HSCT) may be at higher risk for hepatotoxicity suggestive of veno-occlusive disease (VOD) following treatment with clofarabine (40 mg/m2) when used in combination with etoposide (100 mg/m2) and cyclophosphamide (440 mg/m2). Severe hepatotoxic events have been reported in an ongoing Phase 1/2 combination study of clofara-bine in pediatric patients with relapsed or refractory acute leukemia.

5.7 
Use in Pregnancy
Clolar can cause fetal harm when administered to a pregnant woman. Intravenous doses of clofarabine in rats and rabbits administered during organogenesis caused an increase in resorptions, malformations, and variations [see USE IN SPECIFIC POPULATIONS (8.1)]

6.
ADVERSE REACTIONS
The following adverse reactions are discussed in greater detail in other sections of the label:
 
·
Severe Bone Marrow Suppression [see WARNINGS AND PRECAUTIONS (5.1)]
 
·
Serious Infections [see WARNINGS AND PRECAUTIONS (5.2)]
 
·
Hyperuricemia (Tumor Lysis) [see WARNINGS AND PRECAUTIONS (5.3)]
 
·
Systemic Inflammatory Response Syndrome (SIRS) and Capillary Leak Syndrome [see WARNINGS AND PRECAUTIONS (5.4)]
 
·
Hepatic and Renal Impairment [see WARNINGS AND PRECAUTIONS (5.6)]
 
·
Use in Pregnancy [see WARNINGS AND PRECAUTIONS (5.7)]

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 to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described below reflect exposure to Clolar in 115 pediatric patients with relapsed or refractory Acute Lymphoblastic Leukemia (ALL) (70 patients) or Acute Myelogenous Leukemia (AML) (45 patients). One hundred and fifteen (115) of the pediatric patients treated in clinical trials received the recommended dose of Clolar 52 mg/m2 daily × 5. The median number of cycles was 2. The median cumulative amount of Clolar received by pediatric patients during all cycles was 540 mg.

The most common adverse reactions with Clolar are: nausea, vomiting, diarrhea, febrile neutropenia, headache, rash, pruritus, pyrexia, fatigue, palmar-plantar erythrodysesthesia syndrome, anxiety, flushing, and mucosal inflammation.

Table 1 lists adverse events regardless of causality by System Organ Class, including severe or life-threatening (NCI CTC grade 3 or grade 4), reported in ≥ 5% of the 115 patients in the 52 mg/m2/day dose group (pooled analysis of pediatric patients with ALL and AML). More detailed information and follow-up of certain events is given below.
 
Table 1: Most Commonly Reported (≥ 5% Overall) Adverse Events
Regardless of Causality by System Organ Class (N=115 pooled analysis)

               
Worst NCI Common
       
ALL/AML
  
Terminology Criteria Grade¹
       
(N=115)
  
3
  
4
  
5
System Organ Class¹
  
Preferred Term¹
  
N
  
%
  
N
  
%
  
N
  
%
  
N
  
%
Blood and Lymphatic
  
Febrile neutropenia
  
63
  
54.8
  
59
  
51.3
  
3
  
2.6
  
.
  
.
System Disorders
  
Neutropenia
  
11
  
9.6
  
3
  
2.6
  
8
  
7.0
  
.
  
.
Cardiac Disorders
  
Pericardial effusion
  
9
  
7.8
  
.
  
.
  
1
  
0.9
  
.
  
.
   
Tachycardia
  
40
  
34.8
  
6
  
5.2
  
.
  
.
  
.
  
.
 
¹
Patients with more than one preferred term within a SOC are counted only once in the SOC totals. Patients with more than one occurrence of the same preferred term are counted only once within that term and at the highest severity grade.
 
3

Table 1: Most Commonly Reported (≥ 5% Overall) Adverse Events
Regardless of Causality by System Organ Class (N=115 pooled analysis)

               
Worst NCI Common
       
ALL/AML
  
Terminology Criteria Grade¹
       
(N=115)
  
3
  
4
  
5
System Organ Class¹
  
Preferred Term¹
  
N
  
%
  
N
  
%
  
N
  
%
  
N
  
%
Gastrointestinal
  
Abdominal pain
  
40
  
34.8
  
8
  
7.0
  
.
  
.
  
.
  
.
Disorders
  
Abdominal pain upper
  
9
  
7.8
  
1
  
0.9
  
.
  
.
  
.
  
.
   
Diarrhea
  
64
  
55.7
  
14
  
12.2
  
.
  
.
  
.
  
.
   
Gingival bleeding
  
16
  
13.9
  
7
  
6.1
  
1
  
0.9
  
.
  
.
   
Mouth hemorrhage
  
6
  
5.2
  
2
  
1.7
  
.
  
.
  
.
  
.
   
Nausea
  
84
  
73.0
  
16
  
13.9
  
1
  
0.9
  
.
  
.
   
Oral mucosal petechiae
  
6
  
5.2
  
4
  
3.5
  
.
  
.
  
.
  
.
   
Proctalgia
  
9
  
7.8
  
2
  
1.7
  
.
  
.
  
.
  
.
   
Stomatitis
  
8
  
7.0
  
1
  
0.9
  
.
  
.
  
.
  
.
   
Vomiting
  
90
  
78.3
  
9
  
7.8
  
1
  
0.9
  
.
  
.
General Disorders
  
Asthenia
  
12
  
10.4
  
1
  
0.9
  
1
  
0.9
  
.
  
.
and Administration
  
Chills
  
39
  
33.9
  
3
  
2.6
  
.
  
.
  
.
  
.
Site Conditions
  
Fatigue
  
39
  
33.9
  
3
  
2.6
  
2
  
1.7
  
.
  
.
   
Irritability
  
11
  
9.6
  
1
  
0.9
  
.
  
.
  
.
  
.
   
Mucosal inflammation
  
18
  
15.7
  
2
  
1.7
  
.
  
.
  
.
  
.
   
Edema
  
14
  
12.2
  
2
  
1.7
  
.
  
.
  
.
  
.
   
Pain
  
17
  
14.8
  
7
  
6.1
  
1
  
0.9
  
.
  
.
   
Pyrexia
  
45
  
39.1
  
16
  
13.9
  
.
  
.
  
.
  
.
Hepatobiliary Disorder
  
Jaundice
  
9
  
7.8
  
2
  
1.7
  
.
  
.
  
.
  
.
Infections and
  
Bacteremia
  
10
  
8.7
  
10
  
8.7
  
.
  
.
  
.
  
.
Infestations
  
Candidiasis
  
8
  
7.0
  
1
  
0.9
  
.
  
.
  
.
  
.
   
Catheter related infection
  
14
  
12.2
  
13
  
11.3
  
.
  
.
  
.
  
.
   
Cellulitis
  
9
  
7.8
  
7
  
6.1
  
.
  
.
  
.
  
.
   
Clostridium colitis
  
8
  
7.0
  
6
  
5.2
  
.
  
.
  
.
  
.
   
Herpes simplex
  
11
  
9.6
  
6
  
5.2
  
.
  
.
  
.
  
.
   
Herpes zoster
  
8
  
7.0
  
6
  
5.2
  
.
  
.
  
.
  
.
   
Oral candidiasis
  
13
  
11.3
  
2
  
1.7
  
.
  
.
  
.
  
.
   
Pneumonia
  
11
  
9.6
  
6
  
5.2
  
1
  
0.9
  
1
  
0.9
   
Sepsis
  
11
  
9.6
  
5
  
4.4
  
2
  
1.7
  
4
  
3.5
   
Septic shock
  
8
  
7.0
  
1
  
0.9
  
2
  
1.7
  
5
  
4.4
   
Staphylococcal bacteremia
  
7
  
6.1
  
5
  
4.4
  
1
  
0.9
  
.
  
.
   
Staphylococcal sepsis
  
6
  
5.2
  
5
  
4.4
  
1
  
0.9
  
.
  
.
   
Upper respiratory tract
  
6
  
5.2
  
1
  
0.9
  
.
  
.
  
.
  
.
   
infection
                                
Metabolism and
Nutrition Disorders
  
Anorexia
  
34
  
29.6
  
6
  
5.2
  
8
  
7.0
  
.
  
.
Musculoskeletal and
  
Arthralgia
  
10
  
8.7
  
3
  
2.6
  
.
  
.
  
.
  
.
Connective Tissue
  
Back pain
  
12
  
10.4
  
3
  
2.6
  
.
  
.
  
.
  
.
Disorders
  
Bone pain
  
11
  
9.6
  
3
  
2.6
  
.
  
.
  
.
  
.
   
Myalgia
  
16
  
13.9
  
.
  
.
  
.
  
.
  
.
  
.
   
Pain in extremity
  
34
  
29.6
  
6
  
5.2
  
.
  
.
  
.
  
.
Neoplasms Benign,
Malignant and
Unspecified
(incl. cysts and polyps)
  
Tumor lysis syndrome
  
7
  
6.1
  
7
  
6.1
  
.
  
.
  
.
  
.
Nervous System
  
Headache
  
49
  
42.6
  
6
  
5.2
  
.
  
.
  
.
  
.
Disorders
  
Lethargy
  
12
  
10.4
  
1
  
0.9
  
.
  
.
  
.
  
.
   
Somnolence
  
11
  
9.6
  
1
  
0.9
  
.
  
.
  
.
  
.
Psychiatric Disorders
  
Agitation
  
6
  
5.2
  
1
  
0.9
  
.
  
.
  
.
  
.
   
Anxiety
  
24
  
20.9
  
2
  
1.7
  
.
  
.
  
.
  
.
Renal and Urinary
Disorders
  
Hematuria
  
15
  
13.0
  
2
  
1.7
  
.
  
.
  
.
  
.
Respiratory, Thoracic
  
Dyspnea
  
15
  
13.0
  
6
  
5.2
  
2
  
1.7
  
.
  
.
and Mediastinal
  
Epistaxis
  
31
  
27.0
  
15
  
13.0
  
.
  
.
  
.
  
.
Disorders
  
Pleural effusion
  
14
  
12.2
  
4
  
3.5
  
2
  
1.7
  
.
  
.
   
Respiratory distress
  
12
  
10.4
  
5
  
4.4
  
4
  
3.5
  
1
  
0.9
   
Tachypnea
  
10
  
8.7
  
4
  
3.5
  
1
  
0.9
  
.
  
.
 
¹
Patients with more than one preferred term within a SOC are counted only once in the SOC totals. Patients with more than one occurrence of the same preferred term are counted only once within that term and at the highest severity grade.

 
4
 

Table 1: Most Commonly Reported (≥ 5% Overall) Adverse Events
Regardless of Causality by System Organ Class (N=115 pooled analysis) (Continued)

               
Worst NCI Common
       
ALL/AML
  
Terminology Criteria Grade¹
       
(N=115)
  
3
  
4
  
5
System Organ Class¹
  
Preferred Term¹
  
N
  
%
  
N
  
%
  
N
  
%
  
N
  
%
Skin and
  
Erythema
  
13
  
11.3
  
.
  
.
  
.
  
.
  
.
  
.
Subcutaneous
  
Palmar-plantar
                                
Tissue Disorders
  
erythrodysesthesia
                                
   
syndrome
  
18
  
15.7
  
8
  
7.0
  
.
  
.
  
.
  
.
   
Petechiae
  
30
  
26.1
  
7
  
6.1
  
.
  
.
  
.
  
.
   
Pruritus
  
49
  
42.6
  
1
  
0.9
  
.
  
.
  
.
  
.
   
Rash
  
44
  
38.3
  
8
  
7.0
  
.
  
.
  
.
  
.
   
Rash pruritic
  
9
  
7.8
  
.
  
.
  
.
  
.
  
.
  
.
Vascular Disorders
  
Flushing
  
22
  
19.1
  
.
  
.
  
.
  
.
  
.
  
.
   
Hypertension
  
15
  
13.0
  
6
  
5.2
  
.
  
.
  
.
  
.
   
Hypotension
  
33
  
28.7
  
13
  
11.3
  
9
  
7.8
  
.
  
.

¹
Patients with more than one preferred term within a SOC are counted only once in the SOC totals. Patients with more than one occurrence of the same preferred term are counted only once within that term and at the highest severity grade.

The following less common adverse reactions have been reported in 1-4% of the 115 pediatric patients with ALL or AML:

Gastrointestinal Disorders: cecitis, pancreatitis
Hepatobiliary Disorders: hyperbilirubinemia
Immune System Disorders: hypersensitivity
Infections and Infestations: bacterial infection, Enterococcal bacteremia, Escherichia bacteremia, Escherichia sepsis, fungal infection, fungal sepsis, gastroenteritis adenovirus, infection, influenza, Parainfluenza virus infection, pneumonia fungal, pneumonia primary atypical, Respiratory syncytial virus infection, sinusitis, staphylococcal infection
Investigations: blood creatinine increased
Psychiatric Disorders: mental status change
Respiratory, Thoracic and Mediastinal Disorder: pulmonary edema

Table 2 lists the incidence of treatment emergent laboratory abnormalities after Clolar administration at 52 mg/m2 among pediatric patients with ALL and AML (N=115).

Table 2: Incidence of Treatment Emergent Laboratory Abnormalities
After Clolar® Administration

Parameter
  
Any Grade
    
Grade 3 or higher
  
Anemia (N=114)
     95 (83.3 )%     86 (75.4 )%
Leukopenia (N=114)
     100 (87.7 )%     100 (87.7 )%
Lymphopenia (N=113)
     93 (82.3 )%     93 (82.3 )%
Neutropenia (N=113)
     72 (63.7 )%     72 (63.7 )%
Thrombocytopenia (N=114)
     92 (80.7 )%     91 (79.8 )%
Elevated Creatinine (N=115)
     57 (49.5 )%     9 (7.8 )%
Elevated SGOT (N=100)
     74 (74.0 )%     36 (36.0 )%
Elevated SGPT (N=113)
     91 (80.5 )%     49 (43.4 )%
Elevated Total Bilirubin (N=114)
     51 (44.7 )%     15 (13.2 )%

Hematologic Toxicity
The most frequently reported hematologic adverse reactions in pediatric patients included febrile neutropenia (55%) and non-febrile neutropenia (10%).

Infection
At baseline, 48% of the pediatric patients had 1 or more concurrent infections. A total of 83% of patients experienced at least 1 infection after Clolar treatment, including fungal, viral and bacterial infections.

Hepatic
Hepato-biliary toxicities were frequently observed in pediatric patients during treatment with Clolar. Grade 3 or 4 elevated aspartate aminotransferase (AST) occurred in 36% of patients and grade 3 or 4 elevated alanine aminotransferase (ALT) occurred in 44% of patients. Grade 3 or 4 elevated bilirubin occurred in 13% of patients, with 2 events reported as grade 4 hyperbilirubinemia (2%), one of which resulted in treatment discontinuation, one patient had multi-organ failure and died. Two reports (2%) of veno-occlusive disease (VOD) were considered related to study drug.

For patients with follow-up data, elevations in AST and ALT were transient and typically ≤ 15 days duration. The majority of AST and ALT elevations occurred within 10 days of Clolar administration and returned to ≤ grade 2 within 15 days. Where follow-up data are available, the majority of bilirubin elevations returned to ≤ grade 2 within 10 days. Eight patients had grade 3 or 4 elevations in serum bilirubin at the last time point measured; these patients died due to sepsis and/or multi-organ failure.

Renal
The most prevalent renal toxicity in pediatric patients was elevated creatinine. Grade 3 or 4 elevated creatinine occurred in 8% of patients. Acute renal failure was reported in 3 patients (3%) at grade 3 and 2 patients (2%) with grade 4. Nephrotoxic medications, tumor lysis, and tumor lysis with hyperuricemia may contribute to renal toxicity. Hematuria was observed in 13% of patients overall.

Systemic Inflammatory Response Syndrome (SIRS)
Adverse reactions of SIRS were reported in 2 patients (2%) [see WARNINGS AND PRECAUTIONS (5.4)]

Capillary Leak Syndrome
Adverse reactions of capillary leak syndrome were reported in 4 patients (4%). Symptoms included rapid onset of respiratory distress, hypotension, pleural and pericardial effusion, and multi-organ failure.
 
5

Close monitoring for this syndrome and early intervention are recommended. The use of prophylactic steroids (e.g., 100 mg/m2 hydrocortisone on Days 1 through 3) may be of benefit in preventing signs or symptoms of SIRS or capillary leak. Physicians should be alert to early indications of this syndrome and should immediately discontinue Clolar administration if they occur and provide appropriate supportive measures. After the patient is stabilized and organ function has returned to baseline, re-treatment with Clolar can be considered with a 25% dose reduction.

6.2
Post-marketing Experience
The following adverse reactions have been identified during post-approval use of Clolar. 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. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) reported frequency of the reaction, or (3) strength of causal connection to Clolar.
 
·
Blood and lymphatic system disorders: bone marrow failure
 
·
Hepatobiliary disorders: Serious hepatotoxic adverse reactions of veno-occlusive disease have been reported in adult patients following HSCT. These patients received conditioning regimens that included busulfan, melphalan, and/or the combination of cyclophosphamide and total body irradiation.
 
·
Skin and subcutaneous tissue disorders: Occurrences of Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in patients who were receiving or had recently been treated with Clolar and other medications (e.g., allopurinol or antibiotics) known to cause these syndromes.

7.
DRUG INTERACTIONS
Although no clinical drug-drug interaction studies have been conducted to date, on the basis of the in vitro studies, cytochrome p450 inhibitors and inducers are unlikely to affect the metabolism of clofarabine. The effect of clofarabine on the metabolism of cytochrome p450 substrates has not been studied.

8.
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Pregnancy Category D

Clolar (clofarabine) may cause fetal harm when administered to a pregnant woman.

Clofarabine was teratogenic in rats and rabbits. Developmental toxicity (reduced fetal body weight and increased post-implantation loss) and increased incidences of malformations and variations (gross external, soft tissue, skeletal and retarded ossification) were observed in rats receiving 54 mg/m2/day (approximately equivalent to the recommended clinical dose on a mg/m2 basis), and in rabbits receiving 12 mg/m2/day (approximately 23% of the recommended clinical dose on a mg/m2 basis).

There are no adequate and well-controlled studies in pregnant women using clofarabine. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with clofarabine. All patients should be advised to use effective contraceptive measures to prevent pregnancy.

8.3
Nursing Mothers
It is not known whether clofarabine or its metabolites are excreted in human milk. Because of the potential for tumorigenicity shown for clofarabine in animal studies and the potential for serious adverse reactions, women treated with clofarabine should not nurse. Female patients should be advised to avoid breast-feeding during treatment with Clolar.

8.4
Pediatric Use
Safety and effectiveness have been established in pediatric patients 1 to 21 years old with relapsed or refractory acute lymphoblastic leukemia.

8.5
Geriatric Use
Safety and effectiveness of Clolar has not been established in geriatric patients aged 65 and older.

8.6
Adults with Hematologic Malignancies
Safety and effectiveness have not been established in adults.

10.
OVERDOSAGE
There were no known overdoses of Clolar. The highest daily dose administered to a human to date (on a mg/m2 basis) has been 70 mg/m2/day × 5 days (2 pediatric ALL patients). The toxicities included in these 2 patients included grade 4 hyperbilirubinemia, grade 2 and 3 vomiting, and grade 3 maculopapular rash. In a Phase I study of adults with refractory and/or relapsed hematologic malignancies, the recommended pediatric dose of 52 mg/m2/day was not tolerated.

11.
DESCRIPTION
Clolar (clofarabine) Injection contains clofarabine, a purine nucleoside metabolic inhibitor. Clolar (1 mg/mL) is supplied in a 20 mL, single-use vial. The 20 mL vial contains 20 mg clofarabine formulated in 20 mL unbuffered normal saline (comprised of Water for Injection, USP, and Sodium Chloride, USP). The pH range of the solution is 4.5 to 7.5. The solution is sterile, clear and practically colorless, and is preservative-free.

12.
12.1
CLINICAL PHARMACOLOGY
Mechanism of Action
Clofarabine is sequentially metabolized intracellularly to the 5’-monophosphate metabolite by deoxycytidine kinase and mono- and di-phospho-kinases to the active 5’-triphosphate metabolite. Clofarabine has high affinity for the activating phosphorylating enzyme, deoxycytidine kinase, equal to or greater than that of the natural substrate, deoxycytidine. Clofarabine inhibits DNA synthesis by decreasing cellular deoxynucleotide triphosphate pools through an inhibitory action on ribonucleotide reductase, and by terminating DNA chain elongation and inhibiting repair through incorporation into the DNA chain by competitive inhibition of DNA polymerases. The affinity of clofarabine triphosphate for these enzymes is similar to or greater than that of deoxyadenosine triphosphate. In preclinical models, clofarabine has demonstrated the ability to inhibit DNA repair by incorporation into the DNA chain during the repair process. Clofarabine 5’-triphosphate also disrupts the integrity of mitochondrial membrane, leading to the release of the pro-apoptotic mitochondrial proteins, cytochrome C and apoptosis-inducing factor, leading to programmed cell death. Clofarabine is cytotoxic to rapidly proliferating and quiescent cancer cell types in vitro.
 
6
 
12.3
Pharmacokinetics
The population pharmacokinetics of Clolar were studied in 40 pediatric patients aged 2 to 19 years (21 males/19 females) with relapsed or refractory acute lymphoblastic leukemia (ALL) or acute myelogenous leukemia (AML). At the given 52 mg/m2 dose, similar concentrations were obtained over a wide range of body surface areas (BSAs). Clofarabine was 47% bound to plasma proteins, predominantly to albumin. Based on non-compartmental analysis, systemic clearance and volume of distribution at steady-state were 28.8 L/h/m2 and 172 L/m2, respectively. The terminal half-life was 5.2 hours. No apparent difference in pharmacokinetics was observed between patients with ALL and AML or between males and females.
 
No relationship between clofarabine or clofarabine triphosphate exposure and toxicity or response was found in this population.

Based on 24-hour urine collections in the pediatric studies, 49-60% of the dose is excreted in the urine unchanged. In vitro studies using isolated human hepatocytes indicate very limited metabolism (0.2%). The pathways of non-hepatic elimination remain unknown.

The pharmacokinetics of clofarabine have not been evaluated in patients with renal or hepatic dysfunction.

13. 
NONCLINICAL TOXICOLOGY
13.1 
Carcinogenesis, Mutagenesis, Impairment of Fertility
Clofarabine has not been tested for carcinogenic potential.

Clofarabine showed clastogenic activity in the in vitro mammalian cell chromosome aberration assay (CHO cells) and in the in vivo rat micronucleus assay. It did not show evidence of mutagenic activity in the bacterial mutation assay (Ames test).

Studies in mice, rats, and dogs have demonstrated dose-related adverse effects on male reproductive organs. Seminiferous tubule and testicular degeneration and atrophy were reported in male mice receiving intraperitoneal (IP) doses of 3 mg/kg/day (9 mg/m2/day, approximately 17% of clinical recommended dose on a mg/m2 basis). The testes of rats receiving 25 mg/kg/day (150 mg/m2/day, approximately 3 times the recommended clinical dose on a mg/m2 basis) in a 6-month IV study had bilateral degeneration of the seminiferous epithelium with retained spermatids and atrophy of interstitial cells. In a 6-month IV dog study, cell degeneration of the epididymis and degeneration of the seminiferous epithelium in the testes were observed in dogs receiving 0.375 mg/kg/day (7.5 mg/m2/day, approximately 14% of the clinical recommended dose on a mg/m2 basis). Ovarian atrophy or degeneration and uterine mucosal apoptosis were observed in female mice at 75 mg/kg/day (225 mg/m2/day, approximately 4-fold of recommended human dose on a mg/m2 basis), the only dose administered to female mice. The effect on human fertility is unknown.

14.
CLINICAL STUDIES
Seventy-eight (78) pediatric patients with ALL were exposed to Clolar. Seventy (70) of the patients received the recommended pediatric dose of Clolar 52 mg/m2 daily x 5 as an intravenous (IV) infusion.

Dose Escalation Study in Pediatric Patients with Hematologic Malignancies
The safety and efficacy of Clolar were evaluated in pediatric patients with refractory or relapsed hematologic malignancies in an open-label, dose-escalation, noncomparative study. The starting dose of Clolar was 11.25 mg/m2/day IV infusion daily × 5 and escalated to 70 mg/m2/day IV infusion daily × 5. This dosing schedule was repeated every 2 to 6 weeks depending on toxicity and response. Nine of 17 ALL patients were treated with Clolar 52 mg/m2 daily × 5. In the 17 ALL patients there were 2 complete remissions (12%) and 2 partial remissions (12%) at varying doses. Dose-limiting toxicities (DLTs) in this study were reversible hyperbilirubinemia and elevated transaminase levels and skin rash, experienced at 70 mg/m2. As a result of this study, the recommended dose for subsequent study in pediatric patients was determined to be 52 mg/m2/day for 5 days.

Single Arm Study in Pediatric ALL
Clolar was evaluated in an open-label, single arm study of 61 pediatric patients with relapsed/refractory ALL. Patients received a dose of 52 mg/m2 over 2 hours for 5 consecutive days repeated every 2 to 6 weeks for up to 12 cycles. There was no dose escalation in this study.

All patients had disease that had relapsed after and/or was refractory to two or more prior therapies. Most patients, 38/61 (62%), had received > 2 prior regimens and 18/61 (30%) of the patients had undergone at least 1 prior transplant. The median age of the treated patients was 12 years, 61% were male, 39% were female, 44% were Caucasian, 38% were Hispanic, 12% were African-American, 2% were Asian and 5% were Other race.

The overall remission (OR) rate (Complete Remission [CR] + CR in the absence of total platelet recovery [CRp]) was evaluated. CR was defined as no evidence of circulating blasts or extramedullary disease, an M1 bone marrow (≤ 5% blasts), and recovery of peripheral counts [platelets ≥ 100 × 109/L and absolute neutrophil count (ANC) ≥ 1.0 × 109/L]. CRp was defined as meeting all criteria for CR except for recovery of platelet counts to ≥ 100 × 109/L. Partial Response (PR) was also determined, defined as complete disappearance of circulating blasts, an M2 bone marrow (≥ 5% and ≤ 25% blasts), and appearance of normal progenitor cells or an M1 marrow that did not qualify for CR or CRp. Duration of remission was also evaluated. Transplantation rate was not a study endpoint.

Response rates for these studies were determined by an unblinded Independent Response Review Panel (IRRP).

Table 3 summarizes results for the pediatric ALL study. Responses were seen in both pre-B and T-cell immunophenotypes of ALL. The median cumulative dose was 530 mg (range 29-2815 mg) in 1 (41%), 2 (44%) or 3 or more (15%) cycles. The median number of cycles was 2 (range 1-12). The median time between cycles was 28 days with a range of 12 to 55 days.

Table 3: Results in Single-Arm Pediatric ALL Study

   
N = 61
CR % (n) [95% CI]
  
11.5 (4.7, 22.2)
CRp % (n) [95% CI]
  
8.2 (2.7, 18.1)
Median Duration of CR plus CRp (range in weeks)1
  
10.7 (4.3 to 58.6)

CR = Complete response
CRp = Complete response without platelet recovery
1
Does not include 4 patients who were transplanted (duration of response, including response after transplant, in these 4 patients was 28.6 to 107.7 weeks).

Six (9.8%) patients achieved a PR; the clinical relevance of a PR in this setting is unknown.
 
Of 35 patients who were refractory to their immediately preceding induction regimen, 6 (17%) achieved a CR or CRp. Of 18 patients who had at least 1 prior hematopoietic stem cell transplant (HSCT), 5 (28%) achieved a CR or CRp.

Among the 12 patients who achieved at least a CRp, 6 patients achieved the best response after 1 cycle of clofarabine, 5 patients required 2 courses and 1 patient achieved a CR after 3 cycles of therapy.

 
7
 

15.
REFERENCES
 
1.
NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs in healthcare settings. 2004. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2004-165.
 
2.
OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999. http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html
 
3.
American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J Health-Syst Pharm. 2006; 63:1172-1193.
 
4.
Polovich, M., White, J. M., & Kelleher, L.O. (eds.) 2005. Chemotherapy and biotherapy guidelines and recommendations for practice (2nd. ed.) Pittsburgh, PA: Oncology Nursing Society.

16.
HOW SUPPLIED/STORAGE AND HANDLING
Clolar (clofarabine) Injection is supplied in single-use flint vials containing 20 mg of clofarabine in 20 mL of solution. Each box contains one Clolar vial (NDC 58468-0100-1) or four Clolar vials (NDC 58468-0100-2). The 20 mL flint vials contain 20 mL (20 mg) of solution. The pH range of the solution is 4.5 to 7.5.

Vials containing undiluted Clolar should be stored at 25°C (77°F); excursions permitted to 15-30°C (59-86°F).

Diluted admixtures may be stored at room temperature, but must be used within 24 hours of preparation.
 
Procedures for proper handling and disposal should be utilized. Handling and disposal of Clolar should conform to guidelines issued for cytotoxic drugs. Several guidelines on this subject have been published.1-4

17.
PATIENT COUNSELING INFORMATION
Hematologic Toxicity: Advise patients to return for regular blood counts and to report any symptoms associated with hematologic toxicity (such as weakness, fatigue, pallor, shortness of breath, easy bruising, petechiae, purpura, fever) to their physician [see WARNINGS AND PRECAUTIONS (5.1) and ADVERSE REACTIONS (6.1)].

Infection: Advise patients of the signs or symptoms of infection (e.g., fever) and report to the physician immediately if any occur [see WARNINGS AND PRECAUTIONS (5.2) and ADVERSE REACTIONS (6.1)].

Hepatic and Renal Impairment: Advise patients to avoid medications including over the counter and herbal medications, which may be hepatotoxic or nephrotoxic, during the 5 days of Clolar administration [see WARNINGS AND PRECAUTIONS (5.6)].

Systemic Inflammatory Response Syndrome (SIRS)/Capillary Leak Syndrome: Advise patients of the signs or symptoms of SIRS, such as fever, tachycardia, tachypnea, dyspnea and symptoms suggestive of hypotension [see WARNINGS AND PRECAUTIONS (5.4) and ADVERSE REACTIONS (6.1)].

Advise male and female patients with reproductive potential to use effective contraceptive measures to prevent pregnancy [see WARNINGS AND PRECAUTIONS (5.7), USE IN SPECIFIC POPULATIONS (8.1)]. Advise female patients to avoid breast-feeding during Clolar treatment [see USE IN SPECIFIC POPULATIONS (8.3)].

Rx Only

Manufactured by:
AAI Pharma Inc.
Charleston, SC 29405

Manufactured for:
Genzyme Corporation
4545 Horizon Hill Blvd.
San Antonio, TX 78229

Distributed by:
Genzyme Corporation
500 Kendall Street
Cambridge, MA 02142

www.clolar.com


©2008 Genzyme Corporation. All rights reserved.

Clolar is a registered trademark of Genzyme Corporation.

8036 (05/09)

 
8
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

6060   Revision date (07/09)
US License 1791
 

 
Rx only


DESCRIPTION
 
LEUKINE® (sargramostim) is a recombinant human granulocyte-macrophage colony stimulating factor (rhu GM-CSF) produced by recombinant DNA technology in a yeast (S. cerevisiae) expression system. GM-CSF is a hematopoietic growth factor which stimulates proliferation and differentiation of hematopoietic progenitor cells. LEUKINE is a glycoprotein of 127 amino acids characterized by three primary molecular species having molecular masses of 19,500,16,800 and 15,500 daltons. The amino acid sequence of LEUKINE differs from the natural human GM-CSF by a substitution of leucine at position 23, and the carbohydrate moiety may be different from the native protein. Sargramostim has been selected as the proper name for yeast-derived rhu GM-CSF.
 
The liquid LEUKINE presentation is formulated as a sterile, preserved (1.1% benzyl alcohol), injectable solution (500 mcg/mL) in a vial. Lyophilized LEUKINE is a sterile, white, preservative-free powder (250 mcg) that requires reconstitution with 1 mL Sterile Water for Injection, USP or 1 mL Bacteriostatic Water for Injection, USP. Liquid LEUKINE has a pH range of 6.7 - 7.7 and lyophilized LEUKINE has a pH range of 7.1 - 7.7.
 
Liquid LEUKINE and reconstituted lyophilized LEUKINE are clear, colorless liquids suitable for subcutaneous injection (SC) or intravenous infusion (IV). Liquid LEUKINE contains 500 mcg (2.8 x 106 IU/mL) sargramostim and 1.1% benzyl alcohol in a 1 mL solution. The vial of lyophilized LEUKINE contains 250 mcg (1.4 x 106 IU/vial) sargramostim. The liquid LEUKINE vial and reconstituted lyophilized LEUKINE vial also contain 40 mg/mL mannitol, USP; 10 mg/mL sucrose, NF; and 1.2 mg/mL tromethamine, USP, as excipients. Biological potency is expressed in International Units (IU) as tested against the WHO First International Reference Standard. The specific activity of LEUKINE is approximately 5.6 × 106 IU/mg.
 
CLINICAL PHARMACOLOGY
 
General   GM-CSF belongs to a group of growth factors termed colony stimulating factors which support survival, clonal expansion, and differentiation of hematopoietic progenitor cells. GM-CSF induces partially committed progenitor cells to divide and differentiate in the granulocyte-macrophage pathways which include neutrophils, monocytes/macrophages and myeloid-derived dendritic cells.
 
GM-CSF is also capable of activating mature granulocytes and macrophages. GM-CSF is a multilineage factor and, in addition to dose-dependent effects on the myelomonocytic lineage, can promote the proliferation of megakaryocytic and erythroid progenitors.1 However, other factors are required to induce complete maturation in these two lineages. The various cellular responses (i.e., division, maturation, activation) are induced through GM-CSF binding to specific receptors expressed on the cell surface of target cells.2
 
In vitro Studies of LEUKINE in Human Cells   The biological activity of GM-CSF is species-specific. Consequently, in vitro studies have been performed on human cells to characterize the pharmacological activity of LEUKINE. In vitro exposure of human bone marrow cells to LEUKINE at concentrations ranging from 1-100 ng/mL results in the proliferation of hematopoietic progenitors and in the formation of pure granulocyte, pure macrophage and mixed granulocyte-macrophage colonies.3 Chemotactic, anti-fungal and anti-parasitic4 activities of granulocytes and monocytes are increased by exposure to LEUKINE in vitro. LEUKINE increases the cytotoxicity of monocytes toward certain neoplastic cell lines3 and activates polymorphonuclear neutrophils to inhibit the growth of tumor cells.
 
In vivo Primate Studies of LEUKINE   Pharmacology/toxicology studies of LEUKINE were performed in cynomolgus monkeys. An acute toxicity study revealed an absence of treatment-related toxicity following a single IV bolus injection at a dose of 300 mcg/kg. Two subacute studies were performed using IV injection (maximum dose 200 mcg/kg/day × 14 days) and subcutaneous injection (SC) (maximum dose 200 mcg/kg/day × 28 days). No major visceral organ toxicity was documented. Notable histopathology findings included increased cellularity in hematologic organs and heart and lung tissues. A dose-dependent increase in leukocyte count, which consisted primarily of segmented neutrophils, occurred during the dosing period; increases in monocytes, basophils, eosinophils and lymphocytes were also noted. Leukocyte counts decreased to pretreatment values over a 1-2 week recovery period.
 
Pharmacokinetics   Pharmacokinetic profiles have been analyzed in controlled studies of 24 normal male volunteers. Liquid and lyophilized LEUKINE, at the recommended dose of 250 mcg/m2, have been determined to be bioequivalent based on the statistical evaluation of AUC.5
 
When LEUKINE (either liquid or lyophilized) was administered IV over two hours to normal volunteers, the mean beta half-life was approximately 60 minutes. Peak concentrations of GM-CSF were observed in blood samples obtained during or immediately after completion of LEUKINE infusion. For liquid LEUKINE, the mean maximum concentration (Cmax) was 5.0 ng/mL, the mean clearance rate was approximately 420 mL/min/m2 and the mean AUC (0-inf) was 640 ng/mL·min. Corresponding results for lyophilized LEUKINE in the same subjects were mean Cmax of 5.4 ng/mL, mean clearance rate of 431 mL/min/m2, and mean AUC (0-inf) of 677 ng/mL·min. GM-CSF was last detected in blood samples obtained at three or six hours.
 
When LEUKINE (either liquid or lyophilized) was administered SC to normal volunteers, GM-CSF was detected in the serum at 15 minutes, the first sample point. The mean beta half-life was approximately 162 minutes. Peak levels occurred at one to three hours post injection, and LEUKINE remained detectable for up to six hours after injection. The mean Cmax was 1.5 ng/mL. For liquid LEUKINE, the mean clearance was 549 mL/min/m2 and the mean AUC (0-inf) was 549 ng/mL·min. For lyophilized LEUKINE, the mean clearance was 529 mL/min/m2 and the mean AUC (0-inf) was 501 ng/mL·min.
 
INDICATIONS AND USAGE
 
Use Following Induction Chemotherapy in Acute Myelogenous Leukemia   LEUKINE is indicated for use following induction chemotherapy in older adult patients with acute myelogenous leukemia (AML) to shorten time to neutrophil recovery and to reduce the incidence of severe and life-threatening infections and infections resulting in death. The safety and efficacy of LEUKINE have not been assessed in patients with AML under 55 years of age.
 
The term acute myelogenous leukemia, also referred to as acute non-lymphocytic leukemia (ANLL), encompasses a heterogeneous group of leukemias arising from various non-lymphoid cell lines which have been defined morphologically by the French-American-British (FAB) system of classification.
 
Use in Mobilization and Following Transplantation of Autologous Peripheral Blood Progentior Cells   LEUKINE is indicated for the mobilization of hematopoietic progenitor cells into peripheral blood for collection by leukapheresis. Mobilization allows for the collection of increased numbers of progenitor cells capable of engraftment as compared with collection without mobilization. After myeloablative chemotherapy, the transplantation of an increased number of progenitor cells can lead to more rapid engraftment, which may result in a decreased need for supportive care. Myeloid reconstitution is further accelerated by administration of LEUKINE following peripheral blood progenitor cell transplantation.
 
Use in Myeloid Reconstitution After Autologous Bone Marrow Transplantation   LEUKINE is indicated for acceleration of myeloid recovery in patients with non-Hodgkin's lymphoma (NHL), acute lymphoblastic leukemia (ALL) and Hodgkin's disease undergoing autologous bone marrow transplantation (BMT). After autologous BMT in patients with NHL, ALL, or Hodgkin's disease, LEUKINE has been found to be safe and effective in accelerating myeloid engraftment, decreasing median duration of antibiotic administration, reducing the median duration of infectious episodes and shortening the median duration of hospitalization. Hematologic response to LEUKINE can be detected by complete blood count (CBC) with differential cell counts performed twice per week.
 
Use in Myeloid Reconstitution After Allogeneic Bone Marrow Transplantation   LEUKINE is indicated for acceleration of myeloid recovery in patients undergoing allogeneic BMT from HLA-matched related donors. LEUKINE has been found to be safe and effective in accelerating myeloid engraftment, reducing the incidence of bacteremia and other culture positive infections, and shortening the median duration of hospitalization.
 
Use in Bone Marrow Transplantation Failure or Engraftment Delay   LEUKINE is indicated in patients who have undergone allogeneic or autologous bone marrow transplantation (BMT) in whom engraftment is delayed or has failed. LEUKINE has been found to be safe and effective in prolonging survival of patients who are experiencing graft failure or engraftment delay, in the presence or absence of infection, following autologous or allogeneic BMT. Survival benefit may be relatively greater in those patients who demonstrate one or more of the following characteristics: autologous BMT failure or engraftment delay, no previous total body irradiation, malignancy other than leukemia or a multiple organ failure (MCF) score ≤ two (see CLINICAL EXPERIENCE). Hematologic response to LEUKINE can be detected by complete blood count (CBC) with differential performed twice per week.
 
 
CLINICAL EXPERIENCE
 
Acute Myelogenous Leukemia   The safety and efficacy of LEUKINE in patients with AML who are younger than 55 years of age have not been determined. Based on Phase II data suggesting the best therapeutic effects could be achieved in patients at highest risk for severe infections and mortality while neutropenic, the Phase III clinical trial was conducted in older patients. The safety and efficacy of LEUKINE in the treatment of AML were evaluated in a multi-center, randomized, double-blind placebo-controlled trial of 99 newly diagnosed adult patients, 55–70 years of age, receiving induction with or without consolidation.6 A combination of standard doses of daunorubicin (days 1–3) and ara-C (days 1–7) was administered during induction and high dose ara-C was administered days 1–6 as a single course of consolidation, if given. Bone marrow evaluation was performed on day 10 following induction chemotherapy. If hypoplasia with <5% blasts was not achieved, patients immediately received a second cycle of induction chemotherapy. If the bone marrow was hypoplastic with <5% blasts on day 10 or four days following the second cycle of induction chemotherapy, LEUKINE (250 mcg/m2/day) or placebo was given IV over four hours each day, starting four days after the completion of chemotherapy. Study drug was continued until an ANC ≥1500/mm3 for three consecutive days was attained or a maximum of 42 days. LEUKINE or placebo was also administered after the single course of consolidation chemotherapy if delivered (ara-C 3-6 weeks after induction following neutrophil recovery). Study drug was discontinued immediately if leukemic regrowth occurred.
 
LEUKINE significantly shortened the median duration of ANC <500/mm3 by 4 days and <1000/mm3 by 7 days following induction (see Table 1). 75% of patients receiving LEUKINE achieved ANC >500/mm3 by day 16, compared to day 25 for patients receiving placebo. The proportion of patients receiving one cycle (70%) or two cycles (30%) of induction was similar in both treatment groups; LEUKINE significantly shortened the median times to neutrophil recovery whether one cycle (12 versus 15 days) or two cycles (14 versus 23 days) of induction chemotherapy was administered. Median times to platelet (>20,000/mm3) and RBC transfusion independence were not significantly different between treatment groups.

Table 1

Hematological Recovery (in Days): Induction
  
Dataset
  
Sargramostim
n=52*
Median (25%, 75%)
    
Placebo
n=47
Median (25%, 75%)
    
p-value**
  
ANC>500/mm3 a
     13 (11,16 )     17 (13, 25 )     0.009  
ANC>1000/mm3 b
     14 (12, 18 )     21 (13, 34 )     0.003  
PLT>20,000/mm3 c
     11 (7,14 )  
12 (9, >42
 )      0.10  
RBCd
     12 (9,24 )     14 (9,42 )     0.53  
 
* Patients with missing data censored.
a 2 patients on sargramostim and 4 patients on placebo had missing values.
b 2 patients on sargramostim and 3 patients on placebo had missing values.
c 4 patients on placebo had missing values.
d 3 patients on sargramostim and 4 patients on placebo had missing values.
** p=Generalized Wilcoxon

During the consolidation phase of treatment, LEUKINE did not shorten the median time to recovery of ANC to 500/mm3 (13 days) or 1000/mm3 (14.5 days) compared to placebo. There were no significant differences in time to platelet and RBC transfusion independence.
 
The incidence of severe infections and deaths associated with infections was significantly reduced in patients who received LEUKINE. During induction or consolidation, 27 of 52 patients receiving LEUKINE and 35 of 47 patients receiving placebo had at least one grade 3, 4 or 5 infection (p=0.02). Twenty-five patients receiving LEUKINE and 30 patients receiving placebo experienced severe and fatal infections during induction only. There were significantly fewer deaths from infectious causes in the LEUKINE arm (3 versus 11, p=0.02). The majority of deaths in the placebo group were associated with fungal infections with pneumonia as the primary infection.
 
Disease outcomes were not adversely affected by the use of LEUKINE. The proportion of patients achieving complete remission (CR) was higher in the LEUKINE group (69% as compared to 55% for the placebo group), but the difference was not significant (p=0.21). There was 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 overall median survival was 378 days for patients receiving LEUKINE and 268 days for those on placebo (p=0.17). The study was not sized to assess the impact of LEUKINE treatment on response or survival.
 
Mobilization and Engraftment of PBPC   A retrospective review was conducted of data from patients with cancer undergoing collection of peripheral blood progenitor cells (PBPC) at a single transplant center. Mobilization of PBPC and myeloid reconstitution post-transplant were compared between four groups of patients (n=196) receiving LEUKINE for mobilization and a historical control group who did not receive any mobilization treatment [progenitor cells collected by leukapheresis without mobilization (n=100)]. Sequential cohorts received LEUKINE. The cohorts differed by dose (125 or 250 mcg/m2/day), route (IV over 24 hours or SC) and use of LEUKINE post-transplant. Leukaphereses were initiated for all mobilization groups after the WBC reached 10,000/mm3. Leukaphereses continued until both a minimum number of mononucleated cells (MNC) were collected (6.5 or 8.0 × 108/kg body weight) and a minimum number of phereses (5-8) were performed. Both minimum requirements varied by treatment cohort and planned conditioning regimen. If subjects failed to reach a WBC of 10,000 cells/mm3 by day five, another cytokine was substituted for LEUKINE; these subjects were all successfully leukapheresed and transplanted. The most marked mobilization and post-transplant effects were seen in patients administered the higher dose of LEUKINE (250 mcg/m2) either IV (n=63) or SC (n=41).
 
PBPCs from patients treated at the 250 mcg/m2/day dose had significantly higher number of granulocyte-macrophage colony-forming units (CFU-GM) than those collected without mobilization. The mean value after thawing was 11.41 × 104 CFU-GM/kg for all LEUKINE-mobilized patients, compared to 0.96 × 104/kg for the non-mobilized group. A similar difference was observed in the mean number of erythrocyte burst-forming units (BFU-E) collected (23.96 × 104/kg for patients mobilized with 250 mcg/m2 doses of LEUKINE administered SC vs. 1.63 × 104/kg for non-mobilized patients).
 
After transplantation, mobilized subjects had shorter times to myeloid engraftment and fewer days between transplantation and the last platelet transfusion compared to non-mobilized subjects. Neutrophil recovery (ANC >500/mm3) was more rapid in patients administered LEUKINE following PBPC transplantation with LEUKINE-mobilized cells (see Table 2). Mobilized patients also had fewer days to the last platelet transfusion and last RBC transfusion, and a shorter duration of hospitalization than did non-mobilized subjects.
 
Table 2

ANC and Platelet Recovery alter PBPC Transplant
  
   
 
  
 
  
ENGRAFTMENT
(median value in days)
  
   
Route for
Mobilization
  
Post-transplant
LEUKINE
  
ANC>500/mm3
    
Last platelet 
transfusion
  
No Mobilization
    
—   
  
no
    
29
      
28
  
LEUKINE
  
IV
  
no
    
21
      
24
  
250 mcg/m2
  
IV
  
yes
    
12
      
19
  
   
SC
  
yes
    
12
      
17
  
 
A second retrospective review of data from patients undergoing PBPC at another single transplant center was also conducted. LEUKINE was given SC at 250 mcg/m2/day once a day (n=10) or twice a day (n=21) until completion of the phereses. Phereses were begun on day 5 of LEUKINE administration and continued until the targeted MNC count of 9 × 108/kg or CD34+ cell count of 1 x 106/kg was reached. There was no difference in CD34+ cell count in patients receiving LEUKINE once or twice a day. The median time to ANC>500/mm3 was 12 days and to platelet recovery (>25,000/mm3) was 23 days.
 
Survival studies comparing mobilized study patients to the non-mobilized patients and to an autologous historical bone marrow transplant group showed no differences in median survival time.
 
Autologous Bone Marrow Transplantation7   Following a  dose-ranging Phase I/II trial in patients undergoing autologous BMT for lymphoid malignancies,8,9 three single center, randomized, placebo-controlled and double-blinded studies were conducted to evaluate the safety and efficacy of LEUKINE for promoting hematopoietic reconstitution following autologous BMT. A total of 128 patients (65 LEUKINE, 63 placebo) were enrolled in these three studies. The majority of the patients had lymphoid malignancy (87 NHL, 17 ALL), 23 patients had Hodgkin's disease, and one patient had acute myeloblastic leukemia (AML). In 72 patients with NHL or ALL, the bone marrow harvest was purged prior to storage with one of several monoclonal antibodies. No chemical agent was used for in vitro treatment of the bone marrow. Preparative regimens in the three studies included cyclophosphamide (total dose 120-150 mg/kg) and total body irradiation (total dose 1,200-1,575 rads). Other regimens used in patients with Hodgkin's disease and NHL without radiotherapy consisted of three or more of the following in combination (expressed as total dose): cytosine arabinoside (400 mg/m2) and carmustine (300 mg/m2), cyclophosphamide (140-150 mg/kg), hydroxyurea (4.5 grams/m2) and etoposide (375-450 mg/m2).
 
Compared to placebo, administration of LEUKINE in two studies (n=44 and 47) significantly improved the following hematologic and clinical endpoints: time to neutrophil engraftment, duration of hospitalization and infection experience or antibacterial usage. In the third study (n=37) there was a positive trend toward earlier myeloid engraftment in favor of LEUKINE. This latter study differed from the other two in having enrolled a large number of patients with Hodgkin's disease who had also received extensive radiation and chemotherapy prior to harvest of autologous bone marrow. A subgroup analysis of the data from all three studies revealed that the median time to engraftment for patients with Hodgkin's disease, regardless of treatment, was six days longer when compared to patients with NHL and ALL, but that the overall beneficial LEUKINE treatment effect was the same. In the following combined analysis of the three studies, these two subgroups (NHL and ALL vs. Hodgkin's disease) are presented separately.
 
Table 3

Autologous BMT: Combined Analysis from Placebo-Controlled Clinical Trials
of Responses in Patients with NHL and ALL
Median Values (days)
  
   
ANC
≥500/mm3
    
ANC
≥1000/mm3
    
Duration of
Hospitalization
    
Duration of
Infection
    
Duration of
Antibacterial Therapy
  
LEUKINE
(n=54)
    
18*#
      
24*#
      
25*
      
1*
      
21*
  
Placebo
(n=50)
    
24
      
32
      
31
      
4
      
25
  

* p <0.05 Wilcoxon or CMH ridit chi-squared
# p <0.05 Log rank
Note: The single AML patient was not included.
 
Patients with Lymphoid Malignancy (Non-Hodgkin's Lymphoma and Acute Lymphoblastic Leukemia)
 
Myeloid engraftment (absolute neutrophil count [ANC] ≥ 500 cells/mm3) in 54 patients receiving LEUKINE was observed 6 days earlier than in 50 patients treated with placebo (see Table 3). Accelerated myeloid engraftment was associated with significant clinical benefits. The median duration of hospitalization was six days shorter for the LEUKINE group than for the placebo group. Median duration of infectious episodes (defined as fever and neutropenia; or two positive cultures of the same organism; or fever >38°C and one positive blood culture; or clinical evidence of infection) was three days less in the group treated with LEUKINE. The median duration of antibacteria administration in the post-transplantation period was four days shorter for the patients treated with LEUKINE than for placebo-treated patients. The study was unable to detect a significant difference between the treatment groups in rate of disease relapse 24 months post-transplantation. As a group, leukemic subjects receiving LEUKINE derived less benefit than NHL subjects. However, both the leukemic and NHL groups receiving LEUKINE engrafted earlier than controls.
 
 
 
 

Patients with Hodgkin's Disease
 
If patients with Hodgkin's disease are analyzed separately, a trend toward earlier myeloid engraftment is noted. LEUKINE-treated patients engrafted earlier (by five days) than the placebo-treated patients (p=0.189, Wilcoxon) but the number of patients was small (n=22).
 
Allogeneic Bone Marrow Transplantation   A multi-center, randomized, placebo-controlled, and double-blinded study was conducted to evaluate the safety and efficacy of LEUKINE for promoting hematopoietic reconstitution following allogeneic BMT. A total of 109 patients (53 LEUKINE, 56 placebo) were enrolled in the study. Twenty-three patients (11 LEUKINE, 12 placebo) were 18 years old or younger. Sixty-seven patients had myeloid malignancies (33 AML, 34 CML), 17 had lymphoid malignancies (12 ALL, 5 NHL), three patients had Hodgkin's disease, six had multiple myeloma, nine had myelodysplastic disease, and seven patients had aplastic anemia. In 22 patients at one of the seven study sites, bone marrow harvests were depleted of T cells. Preparative regimens included cyclophosphamide, busulfan, cytosine arabinoside, etoposide, methotrexate, corticosteroids, and asparaginase. Some patients also received total body, splenic, or testicular irradiation. Primary graft-versus-host disease (GVHD) prophylaxis was cyclosporine A and a corticosteroid.
 
Accelerated myeloid engraftment was associated with significant laboratory and clinical benefits. Compared to placebo, administration of LEUKINE significantly improved the following: time to neutrophil engraftment, duration of hospitalization, number of patients with bacteremia and overall incidence of infection (see Table 4).
 
Table 4
 
Allogeneic BMT: Analysis of Data from Placebo -Controlled Clinic l Trial
Median Values (days or number of patients)
  
   
ANC ≥
500/mm3
    
ANC ≥
1000/mm3
    
Number of Patients
with Infections
    
Number of Patients
with Bacteremia
    
Days of
Hospitalization
  
LEUKINE
(n=53)
    
13*
      
14*
      
30*
      
9**
      
25*
  
Placebo
(n=56)
    
17
      
19
      
42
      
19
      
26
  

* p <0.05 generalized Wilcoxon test
**p<0.05s imple chi-square test
 
Median time to myeloid engraftment (ANC ≥ 500 cells/mm3) in 53 patients receiving LEUKINE was 4 four days less than in 56 patients treated with placebo (see Table 4). The number of patients with bacteremia and infection was significantly lower in the LEUKINE group compared to the placebo group (9/53 versus 19/56 and 30/53 versus 42/56, respectively). There were a number of secondary laboratory and clinical endpoints. Of these, only the incidence of severe (grade 3/4) mucositis was significantly improved in the LEUKINE group (4/53) compared to the placebo group (16/56) at p<0.05. LEUKINE-treated patients also had a shorter median duration of post-transplant IV antibiotic infusions, and shorter median number of days to last platelet and RBC transfusions compared to placebo patients, but none of these differences reached statistical significance.
 
Bone Marrow Transplantation Failure or Engraftment Delay   A historically-controlled study was conducted in patients experiencing graft failure following allogeneic or autologous BMT to determine whether LEUKINE improved survival after BMT failure.
 
Three categories of patients were eligible for this study:
 
1)
patients displaying a delay in engraftment (ANC ≤ 100 cells/mm3 by day 28 post-transplantation)
 
2) 
patients displaying a delay in engraftment (ANC ≤ 100 cells/mm3 by day 21 post-transplantation) and who had evidence of an active infection; and
 
3) 
patients who lost their marrow graft after a transient engraftment (manifested by an average of ANC ≥ 500 cells/mm3 for at least one week followed by loss of engraftment with ANC < 500 cells/mm3 for at least one week beyond day 21 post-transplantation).
 
A total of 140 eligible patients from 35 institutions were treated with LEUKINE and evaluated in comparison to 103 historical control patients from a single institution. One hundred sixty-three patients had lymphoid or myeloid leukemia, 24 patients had non-Hodgkin's lymphoma, 19 patients had Hodgkin's disease and 37 patients had other diseases, such as aplastic anemia, myelodysplasia or non-hematologic malignancy. The majority of patients (223 out of 243) had received prior chemotherapy with or without radiotherapy and/or immunotherapy prior to preparation for transplantation.
 
One hundred day survival was improved in favor of the patients treated with LEUKINE after graft failure following either autologous or allogeneic BMT. In addition, the median survival was improved by greater than two-fold. The median survival of patients treated with LEUKINE after autologous failure was 474 days versus 161 days for the historical patients. Similarly, after allogeneic failure, the median survival was 97 days with LEUKINE treatment and 35 days for the historical controls. Improvement in survival was better in patients with fewer impaired organs.
 
The MOF score is a simple clinical and laboratory assessment of seven major organ systems: cardiovascular, respiratory, gastrointestinal, hematologic, renal, hepatic and neurologic.10 Assessment of the MOF score is recommended as an additional method of determining the need to initiate treatment with LEUKINE in patients with graft failure or delay in engraftment following autologous or allogeneic BMT (see Table 5).
 
Table 5
 
Median Survival by Multiple Organ Failure (MOF) Category
Median Survival (days)
 
MOF ≤ 2 Organs
  
MOF > 2 Organs
  
MOF (Composite 
of Both Groups)
Autologous BMT
          
LEUKINE
474 (n=58)
  
78.5 (n=10)
  
474 (n=68)
Historical
165 (n=14)
  
39 (n=3)     
 
161 (n=17)
Allogeneic BMT
    
 
   
LEUKINE
174 (n=50)
  
27 (n=22)   
 
97 (n=72)
Historical
52.5 (n=60)
  
15.5 (n=26)
  
35 (n=86)
 
Factors that Contribute to Survival
 
The probability of survival was relatively greater for patients with any one of the following characteristics: autologous BMT failure or delay in engraftment, exclusion of total body irradiation from the preparative regimen, a non-leukemic malignancy or MOF score ≤ two (zero, one or two dysfunctional organ systems). Leukemic subjects derived less benefit than other subjects.
 
CONTRAINDICATIONS
 
LEUKINE is contraindicated:
 
1) 
in patients with excessive leukemic myeloid blasts in the bone marrow or peripheral blood (≥ 10%);
 
2) 
in patients with known hypersensitivity to GM-CSF, yeast-derived products or any component of the product;
 
3) 
for concomitant use with chemotherapy and radiotherapy.
 
Due to the potential sensitivity of rapidly dividing hematopoietic progenitor cells, LEUKINE should not be administered simultaneously with cytotoxic chemotherapy or radiotherapy or within 24 hours proceeding or following chemotherapy or radiotherapy. In one controlled study, patients with small cell lung cancer received LEUKINE and concurrent thoracic radiotherapy and chemotherapy or the identical radiotherapy and chemotherapy without LEUKINE. The patients randomized to LEUKINE had significantly higher incidence of adverse events, including higher mortality and a higher incidence of grade 3 and 4 infections and grade 3 and 4 thrombocytopenia.11
 
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 x 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 lor 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.
 
Table 6
   
Percent of AuBMT Patients Reporting Events
   
LEUKINE
  
Placebo
      
LEUKINE
  
Placebo
Events by Body System
  
(n=79)
  
(n=77)
  
Events by Body System
  
(n=79)
  
(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
            
 
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.
 
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 east 10% of patients who received IV LEUKINE or placebo were as reported in Table 7.
 
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%), pericardia 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 usualy 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.
 
4
 
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.
 
Table 7
Percent of Allogeneic BMT Patients Reporting Events
   
LEUKINE
  
Placebo
      
LEUKINE
  
Placebo
Events by Body System
  
(n=53)
  
(n=56)
  
Events by Body System
  
(n=53)
  
(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*
        
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
  
27
  
7
Hypertension
  
34
  
32
  
High cholesterol
  
17
  
8
Tachycardia
  
11
  
9
            

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

Table 8
Percent of AML Patients Reporting Events
   
LEUKINE
  
Placebo
      
LEUKINE
  
Placebo
Events by Body System
  
(n=52)
  
(n=47)
  
Events by Body System
  
(n=52)
  
(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
 
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
 
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
 
DOSAGE AND ADMINISTRATION
 
Neutrophil Recovery Following Chemotherapy in Acute Myelogenous Leukemia The recommended dose is 250 mcg/m2/day administered intravenously over a 4 hour period starting approximately on day 11 or four days following the completion of induction chemotherapy, if the day 10 bone marrow is hypoplastic with <5% blasts. If a second cycle of induction chemotherapyis necessary, LEUKINE should be administered approximatelyfour days after the completion of chemotherapy if the bone marrow is hypoplastic with <5% blasts. LEUKINE should be continued until an ANC >1500 cells/mm3 for 3 consecutive days or a maximum of 42 days. LEUKINE should be discontinued immediately if leukemic regrowth occurs. If a severe adverse reaction occurs, the dose can be reduced by 50% or temporarily discontinued until the reaction abates.
 
In order to avoid potential complications of excessive leukocytosis (WBC > 50,000 cells/mm3 or ANC > 20,000 cells/mm3) a CBC with differential is recommended twice per week during LEUKINE therapy. LEUKINE treatment should be interrupted or the dose reduced by half if the ANC exceeds 20,000 cells/mm3.
 
Mobilization of Peripheral Blood Progenitor Cells The recommended dose is 250 mcg/m2/day administered IV over 24 hours or SC once daily. Dosing should continue at the same dose through the period of PBPC collection. The optimal schedule for PBPC collection has not been established. In clinical studies, collection of PBPC was usually begun by day 5 and performed daily until protocol specified targets were achieved (see CLINICAL EXPERIENCE, Mobilization and Engraftment of PBPC). If WBC > 50,000 cells/mm3, the LEUKINE dose should be reduced by 50%. If adequate numbers of progenitor cells are not collected, other mobilization therapy should be considered.
 
Post Peripheral Blood Progenitor Cell Transplantation The recommended dose is 250 mcg/m2/day administered IV over 24 hours or SC once daily beginning immediately following infusion of progenitor cells and continuing until an ANC>1500 cells/mm3 for three consecutive days is attained.
 
5
 
Myeloid Reconstitution After Autologous or Allogeneic Bone Marrow Transplantation The recommended dose is 250 mcg/m2/day administered IV over a 2-hour period beginning two to four hours after bone marrow infusion, and not less than 24 hours after the last dose of chemotherapy or radiotherapy. Patients should not receive LEUKINE until the post marrow infusion ANC is less than 500 cells/mm3. LEUKINE should be continued until an ANC >1500 cells/mm3 for three consecutive days is attained. If a severe adverse reaction occurs, the dose can be reduced by 50% or temporarily discontinued until the reaction abates. LEUKINE should be discontinued immediately if blast cells appear or disease progression occurs.
 
In order to avoid potential complications of excessive leukocytosis (WBC > 50,000 cells/mm3, ANC > 20,000 cells/mm3) a CBC with differential is recommended twice per week during LEUKINE therapy. LEUKINE treatment should be interrupted or the dose reduced by 50% if the ANC exceeds 20,000 cells/mm3.
 
Bone Marrow Transplantation Failure or Engraftment Delay The recommended dose is 250 mcg/m2/day for 14 days as a 2-hour IV infusion. The dose can be repeated after 7 days off therapy if engraftment has not occurred. If engraftment still has not occurred, a third course of 500 mcg/m2/day for 14 days may be tried after another 7 days off therapy. If there is still no improvement, it is unlikely that further dose escalation will be beneficial. If a severe adverse reaction occurs, the dose can be reduced by 50% or temporarily discontinued until the reaction abates. LEUKINE should be discontinued immediately if blast cells appear or disease progression occurs.
 
In order to avoid potential complications of excessive leukocytosis (WBC > 50,000 cells/mm3, ANC > 20,000 cells/mm3) a CBC with differential is recommended twice per week during LEUKINE therapy. LEUKINE treatment should be interrupted or the dose reduced by half if the ANC exceeds 20,000 cells/mm3.
 
Preparation of LEUKINE
 
1.
Liquid LEUKINE is formulated as a sterile, preserved (1.1% benzyl alcohol), injectable solution (500 mcg/mL) in a vial. Lyophilized LEUKINE is a sterile, white, preservative-free powder (250 mcg) that requires reconstitution with 1 mL Sterile Water for Injection, USP, or 1 mL Bacteriostatic Water for Injection, USP
 
2.
Liquid LEUKINE may be stored for up to 20 days at 2-8°C once the vial has been entered. Discard any remaining solution after 20 days
 
3.
Lyophilized LEUKINE (250 mcg) should be reconstituted aseptically with 1.0 mL of diluent (see below). The contents of vials reconstituted with different diluents should not be mixed together.
 
Sterile Water for Injection, USP (without preservative): Lyophilized LEUKINE vials contain no antibacterial preservative, and therefore solutions prepared with Sterile Water for Injection, USP should be administered as soon as possible, and within 6 hours following reconstitution and/or dilution for IV infusion. The vial should not be re-entered or reused. Do not save any unused portion for administration more than 6 hours following reconstitution. Bacteriostatic Water for Injection, USP (0.9% benzyl alcohol): Reconstituted solutions prepared with Bacteriostatic Water for Injection, USP (0.9% benzyl alcohol) may be stored for up to 20 days at 2–8°C prior to use. Discard reconstituted solution after 20 days. Previously reconstituted solutions mixed with freshly reconstituted solutions must be administered within 6 hours following mixing. Preparations containing benzyl alcohol (including liquid LEUKINE and lyophilized LEUKINE reconstituted with Bacteriostatic Water for Injection) should not be used in neonates (see WARNINGS)
 
4.
During reconstitution of lyophilized LEUKINE the diluent should be directed at the side of the vial and the contents gently swirled to avoid foaming during dissolution. Avoid excessive or vigorous agitation; do not shake.
 
5.
LEUKINE should be used for SC injection without further dilution. Dilution for IV infusion should be performed in 0.9% Sodium Chloride Injection, USP. If the final concentration of LEUKINE is below 10 mcg/mL, Albumin (Human) at a final concentration of 0.1% should be added to the saline prior to addition of LEUKINE to prevent adsorption to the components of the drug delivery system. To obtain a final concentration of 0.1% Albumin (Human), add 1 mg Albumin (Human) per 1 mL 0.9% Sodium Chloride Injection, USP (e.g., use 1 mL 5% Albumin [Human] in 50 mL 0.9% Sodium Chloride Injection, USP).
 
6.
An in-line membrane filter should NOT be used for intravenous infusion of LEUKINE.
 
7. 
Store liquid LEUKINE and reconstituted lyophilized LEUKINE solutions under refrigeration at 2-8°C (36-46°F); DO NOT FREEZE
 
8.
In the absence of compatibility and stability information, no other medication should be added to infusion solutions containing LEUKINE. Use only 0.9% Sodium Chloride Injection, USP to prepare IV infusion solutions.
 
9.
Aseptic technique should be employed in the preparation of all LEUKINE solutions. To assure correct concentration following reconstitution, care should be exercised to eliminate any air bubbles from the needle hub of the syringe used to prepare the diluent. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. If particulate matter is present or the solution is discolored, the vial should not be used.
 
HOW SUPPLIED
 
Liquid LEUKINE is available in vials containing 500 mcg/mL (2.8 x 106 IU/mL) sargramostim. Lyophilized LEUKINE is available in vials containing 250 mcg (1.4 x 106 IU/vial) sargramostim.
 
Each dosage form is supplied as follows:
 
Lyophilized LEUKINE
  
Carton of five vials of lyophilized LEUKINE 250 mcg
(NDC 58468-0180-2)
   
Liquid LEUKINE
  
Carton of one multiple-use vial; each vial contains 1 mL of preserved 500 mcg/mL liquid LEUKINE
(NDC 58468-0181-1)
Carton of five multiple-use vials; each vial contains 1 mL of preserved 500 mcg/mL liquid LEUKINE.
(NDC 58468-0181-2)
 
STORAGE
 
LEUKINE should be refrigerated at 2-8°C (36-46°F). Do not freeze or shake. Do not use beyond the expiration date printed on the vial
 
REFERENCES
 
1.
Metcalf D. The molecular biology and functions of the granulocyte-macrophage colony-stimulating factors. Blood 1986; 67(2):257-267
 
2.
Park LS, Friend D, Gillis S, Urdal DL. Characterization of the cell surface receptor for human granulocyte/macrophage colony stimulating factor. J Exp Med 1986; 164:251-262.
  
3.
Grabstein KH, Urdal DL, Tushinski RJ, et al. Induction of macrophage tumoricidal activity by granulocyte-macrophage colony-stimulating factors. Science 1986; 232:506-508.
 
4.
Reed SG, Nathan CF, Pihl DL, et al. Recombinant granulocyte/macrophage colony-stimulating factor activates macrophages to inhibit Trypanosoma cruzi and release hydrogen peroxide. J Exp Med 1987; 166:1734-1746.
 
5.
Data on file Bayer HealthCare Pharmaceuticals.
 
6.
Rowe JM, Andersen JW, Mazza JJ, et al. A randomized placebo-controlled phase III study of granulocyte-macrophage colony-stimulating factor in adult patients (>55 to 70 years of age) with acute myelogenous leukemia: a study of the Eastern Cooperative Oncology Group (E1490). Blood 1995; 86(2):457-462.
 
7.
Nemunaitis J, Rabinowe SN, Singer JW, et al. Recombinant human granulocyte-macrophage colony-stimulating factor after autologous bone marrow transplantation for lymphoid malignancy: Pooled results of a randomized, double-blind, placebo controlled trial. NEJM 1991; 324(25):1773-1778.
 
8.
Nemunaitis J, Singer JW, Buckner CD, et al. Use of recombinant human granulocyte-macrophage colony stimulating factor in autologous bone marrow transplantation for lymphoid malignancies. Blood 1988; 72(2):834-836.
 
9.
Nemunaitis J, Singer JW, Buckner CD, et al. Long-term follow-up of patients who received recombinant human granulocyte-macrophage colony stimulating factor after autologous bone marrow transplantation for lymphoid malignancy. BMT 1991; 7:49-52.
 
10.
Goris RJA, Boekhorst TPA, Nuytinck JKS, et al. Multiple organ failure: Generalized auto-destructive inflammation? Arch Surg 1985; 120:1109-1115
 
11.
Bunn P, Crowley J, Kelly K, et al. Chemoradiotherapy with or without granulocyte-macrophage colony-stimulating factor in the treatment of limited-stage small-cell lung cancer: a prospective phase III randomized study of the southwest oncology group. JCO 1995; 13(7):1632-1641.
 
12.
Herrmann F, Schulz G, Lindemann A, et al. Yeast-expressed granulocyte-macrophage colony-stimulating factor in cancer patients: A phase lb clinical study. In Behring Institute Research Communications, Colony Stimulating Factors-CSF. International Symposium, Garmisch-Partenkirchen, West Germany. 1988; 83:107-118.
 
13.
Estey EH, Dixon D, Kantarjian H, et al. Treatment of poor-prognosis, newly diagnosed acute myeloid leukemia with Ara-C and recombinant human granulocyte-macrophage colony-stimulating factor. Blood 1990; 75(9):1766-1769.
 
14.
Vadhan-Raj S, Keating M, LeMaistre A, et al. Effects of recombinant human granulocyte-macrophage colony-stimulating factor in patients with myelodysplastic syndromes. NEJM 1987; 317:1545-1552.
 
15.
Buchner T, Hiddemann W, Koenigsmann M, et al. Recombinant human granulocyte-macrophage colony stimulating factor after chemotherapy in patients with acute myeloid leukemia at higher age or after relapse. Blood 1991; 78(5):1190-1197.
 
16.
Blazar BR, Kersey JH, McGlave PB, et al. In vivo administration of recombinant human granulocyte/macrophage colony-stimulating factor in acute lymphoblastic leukemia patients receiving purged autografts. Blood 1989; 73(3):849-857.
 
© 2009, Genzyme Corporation. All rights reserved. Leukine is a registered trademark licensed to Genzyme Corporation.
 
U.S. Patent Nos. 5,391,485; 5,393,870; and 5,229,496. Licensed under Research Corporation Technologies U.S. Patent No. 5,602,007, and under Novartis Corporation U.S. Patent Nos. 5,942,221; 5,908,763; 5,895,646; 5,891,429; and 5,720,952.
   
Manufactured by:
Distributed by:
Bayer Health Care
Pharmaceuticals, LLC.
Seattle, WA 98101
Genzyme Corporation
US License No. 1791
500 Kendall Street
 
Cambridge, MA02142
 
Phone: 1-888-4RX-LEUKINE
 
6060 (07/09)
Revised July 2009
 
 
6
 

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use MOZOBIL safely and effectively. See full prescribing information for MOZOBIL.

MOZOBIL (plerixafor injection), Solution for Subcutaneous use
Initial U.S. Approval: 2008

INDICATIONS AND USAGE
Mozobil, a hematopoietic stem cell mobilizer, is indicated in combination with granulocyte-colony stimulating factor (G-CSF) to mobilize hematopoietic stem cells to the peripheral blood for collection and subsequent autologous transplantation in patients with non-Hodgkin’s lymphoma and multiple myeloma. (1)

DOSAGE AND ADMINISTRATION
·
Initiate Mozobil treatment after the patient has received G-CSF once daily for 4 days. (2.1)
·
Repeat Mozobil dose up to 4 consecutive days. (2.1)
·
Select dose based on 0.24 mg/kg actual body weight. (2.1)
·
Administer by subcutaneous injection approximately 11 hours prior to initiation of apheresis. (2.1)
·
Renal impairment: If creatinine clearance is ≤ 50 mL/min, decrease dose by one-third to 0.16 mg/kg. (2.3)

DOSAGE FORMS AND STRENGTHS
·
Single-use vial containing 1.2 mL of a 20 mg/mL solution. (3)

CONTRAINDICATIONS
None. (4)

WARNINGS AND PRECAUTIONS
·
Tumor Cell Mobilization in Leukemia Patients: Mozobil may mobilize leukemic cells and should not be used in leukemia patients (5.1)
·
Hematologic Effects: Increased circulating leukocytes and decreased platelet counts have been observed. Monitor blood cell counts and platelet counts during Mozobil use. (5.2)
·
Potential for Tumor Cell Mobilization: Tumor cells may be released from marrow during HSC mobilization with Mozobil and G-CSF. Effect of reinfusion of tumor cells is unknown. (5.3)
·
Potential for Splenic Rupture: Evaluate patients who report left upper abdominal and/or scapular or shoulder pain. (5.4)
·
Pregnancy: May cause fetal harm. Advise women not to become pregnant when taking Mozobil. (5.5, 8.1)

ADVERSE REACTIONS
Most common adverse reactions (≥ 10%): diarrhea, nausea, fatigue, injection site reactions, headache, arthralgia, dizziness, and vomiting. (6)

To report SUSPECTED ADVERSE REACTIONS, contact Genzyme Corporation at 1-877-4MOZOBIL or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

See 17 for PATIENT COUNSELING INFORMATION

Revised: 12/2008

FULL PRESCRIBING INFORMATION: CONTENTS*

1
INDICATIONS AND USAGE
1
2
DOSAGE AND ADMINISTRATION
1
 
2.1
Recommended Dosage and Administration
1
 
2.2
Recommended Concomitant Medications
1
 
2.3
Dosing in Renal Impairment
1
3
DOSAGE FORMS AND STRENGTHS
2
4
CONTRAINDICATIONS
2
5
WARNINGS AND PRECAUTIONS
2
 
5.1
Tumor Cell Mobilization in Leukemia Patients
2
 
5.2
Hematologic Effects
2
 
5.3
Potential for Tumor Cell Mobilization
2
 
5.4
Splenic Enlargement and Potential for Rupture
2
 
5.5
Pregnancy
2
6
ADVERSE REACTIONS
2
 
6.1
Clinical Trial Experience
2
7
DRUG INTERACTIONS
2
8
USE IN SPECIFIC POPULATIONS
2
 
8.1
Pregnancy
2
 
8.3
Nursing Mothers
2
 
8.4
Pediatric Use
3
 
8.5
Geriatric Use
3
 
8.6
Renal Impairment
3
10
OVERDOSAGE
3
11
DESCRIPTION
3
12
CLINICAL PHARMACOLOGY
3
 
12.1
Mechanism of Action
3
 
12.2
Pharmacodynamics
3
 
12.3
Pharmacokinetics
3
13
NONCLINICAL TOXICOLOGY
4
 
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
4
14
CLINICAL STUDIES
4
16
HOW SUPPLIED/STORAGE AND HANDLING
4
17
PATIENT COUNSELING INFORMATION
4
 
*Sections or subsections omitted from the full prescribing information are not listed

1
INDICATIONS AND USAGE
MozobilTM (plerixafor injection) is indicated in combination with granulocytecolony stimulating factor (G-CSF) to mobilize hematopoietic stem cells to the peripheral blood for collection and subsequent autologous transplantation in patients with non-Hodgkin’s lymphoma (NHL) and multiple myeloma (MM).

2
DOSAGE AND ADMINISTRATION
2.1
Recommended Dosage and Administration
Vials should be inspected visually for particulate matter and discoloration prior to administration and should not be used if there is particulate matter or if the solution is discolored.

Begin treatment with Mozobil after the patient has received G-CSF once daily for four days. [see Dosage and Administration (2.2)] Administer Mozobil approximately 11 hours prior to initiation of apheresis for up to 4 consecutive days.

The recommended dose of Mozobil is 0.24 mg/kg body weight by subcutaneous (SC) injection. Use the patient’s actual body weight to calculate the volume of Mozobil to be administered. Each vial delivers 1.2 mL of 20 mg/mL solution, and the volume to be administered to patients should be calculated from the following equation:

0.012 X patient’s actual body weight (in kg) = volume to be administered (in mL)

In clinical studies, Mozobil dose has been calculated based on actual body weight in patients up to 175% of ideal body weight. Mozobil dose and treatment of patients weighing more than 175% of ideal body weight have not been investigated.

Based on increasing exposure with increasing body weight, the plerixafor dose should not exceed 40 mg/day. [see Clinical Pharmacology (12.3)]

2.2
Recommended Concomitant Medications
Administer daily morning doses of G-CSF 10 micrograms/kg for 4 days prior to the first evening dose of Mozobil and on each day prior to apheresis. [see Clinical Studies (14)]

2.3
Dosing in Renal Impairment
In patients with moderate and severe renal impairment (estimated creatinine clearance (CLCR) ≤ 50 mL/min), reduce the dose of Mozobil by one-third to 0.16 mg/kg as shown in Table 1. If CLCR is ≤ 50 mL/min the dose should not exceed 27 mg/day, as the mg/kg-based dosage results in increased plerixafor exposure with increasing body weight. [see Clinical Pharmacology (12.3)] Similar systemic exposure is predicted if the dose is reduced by one-third in patients with moderate and severe renal impairment compared with subjects with normal renal function. [see Clinical Pharmacology (12.3)]

Table 1: Recommended Dosage of Plerixafor in Patients with Renal Impairment

Estimated Creatinine
Clearance (mL/min)
  
Dose
> 50
  
0.24 mg/kg once daily (not to exceed 40 mg/day)
≤ 50
  
0.16 mg/kg once daily (not to exceed 27 mg/day)

The following (Cockroft-Gault) formula may be used to estimate CLCR:

Males:
  
Creatinine clearance (mL/min) = 
weight (kg) X (140 – age in years)
 
72 X serum creatinine (mg/dL)
   
Females:
  
Creatinine clearance (mL/min) = 
0.85 X value calculated for males

There is insufficient information to make dosage recommendations in patients on hemodialysis.

 
1
 

3
DOSAGE FORMS AND STRENGTHS
Single-use vial containing 1.2 mL of a 20 mg/mL solution.

4
CONTRAINDICATIONS
None

5
WARNINGS AND PRECAUTIONS
5.1
Tumor Cell Mobilization in Leukemia Patients
For the purpose of HSC mobilization, Mozobil may cause mobilization of leukemic cells and subsequent contamination of the apheresis product. Therefore, Mozobil is not intended for HSC mobilization and harvest in patients with leukemia.

5.2
Hematologic Effects
Leukocytosis
Administration of Mozobil in conjunction with G-CSF increases circulating leukocytes as well as HSC populations. Monitor white blood cell counts during Mozobil use. Exercise clinical judgment when administering Mozobil to patients with peripheral blood neutrophil counts above 50,000/mcL.

Thrombocytopenia
Thrombocytopenia has been observed in patients receiving Mozobil. Monitor platelet counts in all patients who receive Mozobil and then undergo apheresis.

5.3
Potential for Tumor Cell Mobilization
When Mozobil is used in combination with G-CSF for HSC mobilization‚ tumor cells may be released from the marrow and subsequently collected in the leukapheresis product. The effect of potential reinfusion of tumor cells has not been well-studied.

5.4
Splenic Enlargement and Potential for Rupture
Higher absolute and relative spleen weights associated with extramedullary hematopoiesis were observed following prolonged (2 to 4 weeks) daily plerixafor SC administration in rats at doses approximately 4-fold higher than the recommended human dose based on body surface area. The effect of Mozobil on spleen size in patients was not specifically evaluated in clinical studies. Evaluate individuals receiving Mozobil in combination with G-CSF who report left upper abdominal pain and/or scapular or shoulder pain for splenic integrity.

5.5
Pregnancy
Pregnancy Category D
Mozobil may cause fetal harm when administered to a pregnant woman. Plerixafor was teratogenic in animals. There are no adequate and wellcontrolled studies in pregnant women using Mozobil. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with Mozobil. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. [see Use In Specific Populations (8.1)]

6
ADVERSE REACTIONS
6.1
Clinical Trial Experience
The following serious adverse reactions are discussed elsewhere in the labeling:
·
Potential for tumor cell mobilization in leukemia patients [see Warnings and Precautions (5.1)]
·
Increased circulating leukocytes and decreased platelet counts [see Warnings and Precautions (5.2)]
·
Potential for splenic enlargement [see Warnings and Precautions (5.4)]

The most common adverse reactions (≥ 10%) reported in patients who received Mozobil in conjunction with G-CSF regardless of causality and more frequent with Mozobil than placebo during HSC mobilization and apheresis were diarrhea, nausea, fatigue, injection site reactions, headache, arthralgia, dizziness, and vomiting.

Safety data for Mozobil in combination with G-CSF were obtained from two placebo-controlled studies and 10 uncontrolled studies in 543 patients. Patients were primarily treated with Mozobil at daily doses of 0.24 mg/kg SC. Median exposure to Mozobil in these studies was 2 days (range 1 to 7 days).

In the two randomized studies in patients with NHL and MM, a total of 301 patients were treated in the Mozobil and G-CSF group and 292 patients were treated in the placebo and G-CSF group. Patients received daily morning doses of G-CSF 10 micrograms/kg for 4 days prior to the first dose of Mozobil 0.24 mg/kg SC or placebo and on each morning prior to apheresis. The adverse reactions that occurred in ≥5% of the patients who received Mozobil regardless of causality and were more frequent with Mozobil than placebo during HSC mobilization and apheresis are shown in Table 2.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Table 2: Adverse Reactions in ≥ 5% of Non-Hodgkin’s Lymphoma and Multiple Myeloma Patients Receiving Mozobil and More Frequent than Placebo During HSC Mobilization and Apheresis

   
Percent of Patients (%)
  
   
Mozobil and G-CSF
(n = 301)
    
Placebo and G-CSF
(n = 292)
  
   
All
Gradesa
    
Grade
3
    
Grade
4
    
All
Grades
    
Grade
3
    
Grade
4
  
Gastrointestinal disorders
                                    
Diarrhea
     37    
< 1
       0       17       0       0  
Nausea
     34       1       0       22       0       0  
Vomiting
     10    
< 1
       0       6       0       0  
Flatulence
     7       0       0       3       0       0  
General disorders and administration site conditions
                                                
Injection site reactions
     34       0       0       10       0       0  
Fatigue
     27       0       0       25       0       0  
Musculoskeletal and connective tissue disorders
                                                
Arthralgia
     13       0       0       12       0       0  
Nervous system disorders
                                                
Headache
     22    
< 1
       0       21       1       0  
Dizziness
     11       0       0       6       0       0  
Psychiatric disorders
                                                
Insomnia
     7       0       0       5       0       0  

aGrades based on criteria from the World Health Organization (WHO)

In the randomized studies, 34% of patients with NHL or MM had mild to moderate injection site reactions at the site of subcutaneous administration of Mozobil. These included erythema, hematoma, hemorrhage, induration, inflammation, irritation, pain, paresthesia, pruritus, rash, swelling, and urticaria.

Mild to moderate systemic reactions were observed in less than 1% of patients approximately 30 min after Mozobil administration. Events included one or more of the following: urticaria (n = 2), periorbital swelling (n = 2), dyspnea (n = 1) or hypoxia (n = 1). Symptoms generally responded to treatments (e.g., antihistamines, corticosteroids, hydration or supplemental oxygen) or resolved spontaneously.

Vasovagal reactions, orthostatic hypotension, and/or syncope can occur following subcutaneous injections. In Mozobil oncology and healthy volunteer clinical studies, less than 1% of subjects experienced vasovagal reactions following subcutaneous administration of Mozobil doses ≤ 0.24 mg/kg. The majority of these events occurred within 1 hour of Mozobil administration. Because of the potential for these reactions, appropriate precautions should be taken.

Other adverse reactions that occurred in < 5% of patients but were reported as related to Mozobil during HSC mobilization and apheresis included abdominal pain, hyperhidrosis, abdominal distention, dry mouth, erythema, stomach discomfort, malaise, hypoesthesia oral, constipation, dyspepsia, and musculoskeletal pain.

7
DRUG INTERACTIONS
Based on in vitro data, plerixafor is not a substrate, inhibitor or inducer of human cytochrome P450 isozymes. Plerixafor is not likely to be implicated in in vivo drug-drug interactions involving cytochrome P450s. [see Clinical Pharmacology (12.3)]

8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Pregnancy Category D
Plerixafor was teratogenic in animals. Plerixafor administered to pregnant rats induced embryo-fetal toxicities including fetal death, increased resorptions and post-implantation loss, decreased fetal weights, anophthalmia, shortened digits, cardiac interventricular septal defect, ringed aorta, globular heart, hydrocephaly, dilatation of olfactory ventricles, and retarded skeletal development. Embryofetal toxicities occurred mainly at a dose of 90 mg/m2 (approximately 10 times the recommended human dose of 0.24 mg/kg when compared on a mg/m2 basis or 10 times the AUC in subjects with normal renal function who received a single dose of 0.24 mg/kg).

8.3 Nursing Mothers
It is not known whether plerixafor is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from Mozobil, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

 
2
 

8.4
Pediatric Use
The safety and efficacy of Mozobil in pediatric patients have not been established in controlled clinical studies.

8.5
Geriatric Use
Of the total number of subjects in controlled clinical studies of Mozobil, 24% were 65 and over, while 0.8% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Since plerixafor is mainly excreted by the kidney, no dose modifications are necessary in elderly individuals with normal renal function. In general, care should be taken in dose selection for elderly patients due to the greater frequency of decreased renal function with advanced age. Dosage adjustment in elderly patients with CLCR ≤ 50 mL/min is recommended. [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)]

8.6
Renal Impairment
In patients with moderate and severe renal impairment (CLCR ≤ 50mL/min), reduce the dose of plerixafor by one-third to 0.16 mg/kg. [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)]

10
OVERDOSAGE
Based on limited data at doses above the recommended dose of 0.24 mg/kg SC, the frequency of gastrointestinal disorders, vasovagal reactions, orthostatic hypotension, and/or syncope may be higher.

11
DESCRIPTION
Mozobil (plerixafor injection) is a sterile, preservative-free, clear, colorless to pale yellow, isotonic solution for subcutaneous injection. Each mL of the sterile solution contains 20 mg of plerixafor. Each single-use vial is filled to deliver 1.2 mL of the sterile solution that contains 24 mg of plerixafor and 5.9 mg of sodium chloride in Water for Injection adjusted to a pH of 6.0 to 7.5 with hydrochloric acid and with sodium hydroxide, if required.
 
Plerixafor is a hematopoietic stem cell mobilizer with a chemical name l, 1'- [1,4-phenylenebis (methylene)]-bis-1,4,8,11- tetraazacyclotetradecane. It has the molecular formula C28H54N8. The molecular weight of plerixafor is 502.79 g/mol. The structural formula is provided in Figure 1.

Figure 1: Structural Formula


Plerixafor is a white to off-white crystalline solid. It is hygroscopic. Plerixafor has a typical melting point of 131.5 °C. The partition coefficient of plerixafor between 1-octanol and pH 7 aqueous buffer is < 0.1.

12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
Plerixafor is an inhibitor of the CXCR4 chemokine receptor and blocks binding of its cognate ligand, stromal cell-derived factor-1α (SDF-1α). SDF-1α and CXCR4 are recognized to play a role in the trafficking and homing of human hematopoietic stem cells (HSCs) to the marrow compartment. Once in the marrow, stem cell CXCR4 can act to help anchor these cells to the marrow matrix, either directly via SDF-1α or through the induction of other adhesion molecules. Treatment with plerixafor resulted in leukocytosis and elevations in circulating hematopoietic progenitor cells in mice, dogs and humans. CD34+ cells mobilized by plerixafor were capable of engraftment with long-term repopulating capacity up to one year in canine transplantation models.

12.2
Pharmacodynamics
Data on the fold increase in peripheral blood CD34+ cell count (cells/mcL) by apheresis day were evaluated in two placebo-controlled clinical studies in patients with NHL and MM (Study 1 and Study 2, respectively). The fold increase in CD34+ cell count (cells/mcL) over the 24-hour period starting from the day prior to the first apheresis and ending the next morning just before the first apheresis is summarized in Table 3. During this 24-hour period, a single dose of Mozobil or placebo was administered 10 to 11 hours prior to apheresis.

Table 3: Fold Increase in Peripheral Blood CD34+ Cell Count Following Pretreatment with G-CSF and Administration of Plerixafor

   
Mozobil and G-CSF
    
Placebo and G-CSF
  
Study
  
Median
    
Mean (SD)
    
Median
    
Mean (SD)
  
Study 1
     5.0       6.2 (5.4 )     1.4       1.9 (1.5 )
Study 2
     4.8       6.4 (6.8 )     1.7       2.4 (7.3 )

In pharmacodynamic studies of Mozobil in healthy volunteers, peak mobilization of CD34+ cells was observed between 6 and 9 hours after administration. In pharmacodynamic studies of Mozobil in conjunction with G-CSF in healthy volunteers, a sustained elevation in the peripheral blood CD34+ count was observed from 4 to 18 hours after plerixafor administration with a peak CD34+ count between 10 and 14 hours.

12.3
Pharmacokinetics
The single-dose pharmacokinetics of plerixafor 0.24 mg/kg were evaluated in patients with NHL and MM following pre-treatment with G-CSF (10 micrograms/kg once daily for 4 consecutive days). Plerixafor exhibits linear kinetics between the 0.04 mg/kg to 0.24 mg/kg dose range. The pharmacokinetics of plerixafor were similar across clinical studies in healthy subjects who received plerixafor alone and NHL and MM patients who received plerixafor in combination with G-CSF.

A population pharmacokinetic analysis incorporated plerixafor data from 63 subjects (NHL patients, MM patients, subjects with varying degrees of renal impairment, and healthy subjects) who received a single SC dose (0.04 mg/kg to 0.24 mg/kg) of plerixafor. A two-compartment disposition model with first order absorption and elimination was found to adequately describe the plerixafor concentration-time profile. Significant relationships between clearance and creatinine clearance (CLCR), as well as between central volume of distribution and body weight were observed. The distribution half-life (t1/2α) was estimated to be 0.3 hours and the terminal population half-life (t1/2β) was 5.3 hours in patients with normal renal function.

The population pharmacokinetic analysis showed that the mg/kg-based dosage results in an increased plerixafor exposure (AUC0-24h) with increasing body weight. There is limited experience with the 0.24 mg/kg dose of plerixafor in patients weighing above 160 kg. Therefore the dose should not exceed that of a 160 kg patient (i.e., 40 mg/day if CLCR is > 50 mL/min and 27 mg/day if CLCR is ≤ 50 mL/min). [see Dosage and Administration (2.1, 2.3)]

Absorption
Peak plasma concentrations occurred at approximately 30 - 60 minutes after a SC dose.

Distribution
Plerixafor is bound to human plasma proteins up to 58%. The apparent volume of distribution of plerixafor in humans is 0.3 L/kg demonstrating that plerixafor is largely confined to, but not limited to, the extravascular fluid space.

Metabolism
The metabolism of plerixafor was evaluated with in vitro assays. Plerixafor is not metabolized as shown in assays using human liver microsomes or human primary hepatocytes and does not exhibit inhibitory activity in vitro towards the major drug metabolizing cytochrome P450 enzymes (1A2, 2C9, 2C19, 2D6, and 3A4/5). In in vitro studies with human hepatocytes, plerixafor does not induce CYP1A2, CYP2B6, or CYP3A4 enzymes. These findings suggest that plerixafor has a low potential for involvement in cytochrome P450-dependent drug-drug interactions.

Elimination
The major route of elimination of plerixafor is urinary. Following a 0.24 mg/kg dose in healthy volunteers with normal renal function, approximately 70% of the dose was excreted in the urine as the parent drug during the first 24 hours following administration. In studies with healthy subjects and patients, the terminal half-life in plasma ranges between 3 and 5 hours. The ability of plerixafor to act as a substrate or as an inhibitor of P-glycoprotein has not been investigated.

Renal Impairment
Following a single 0.24 mg/kg SC dose, plerixafor clearance was reduced in subjects with varying degrees of renal impairment and was positively correlated with CLCR. The mean AUC0-24h of plerixafor in subjects with mild (CLCR 51-80 mL/min), moderate (CLCR 31-50 mL/min), and severe (CLCR < 31 mL/min) renal impairment was 7%, 32%, and 39% higher than healthy subjects with normal renal function, respectively. Renal impairment had no effect on Cmax. A population pharmacokinetic analysis indicated an increased exposure (AUC0-24h) in patients with moderate and severe renal impairment compared to patients with CLCR > 50 mL/min. These results support a dose reduction of one-third in patients with moderate to severe renal impairment (CLCR ≤ 50 mL/min) in order to match the exposure in patients with normal renal function. The population pharmacokinetic analysis showed that the mg/kg-based dosage results in an increased plerixafor exposure (AUC0-24h) with increasing body weight; therefore if CLCR is ≤ 50 mL/min the dose should not exceed 27 mg/day. [see Dosage and Administration (2.3)]

 
3
 

Since plerixafor is primarily eliminated by the kidneys, coadministration of plerixafor with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of plerixafor or the coadministered drug. The effects of coadministration of plerixafor with other drugs that are renally eliminated or are known to affect renal function have not been evaluated.

Race
Clinical data show similar plerixafor pharmacokinetics for Caucasians and African-Americans, and the effect of other racial/ethnic groups has not been studied.

Gender
Clinical data show no effect of gender on plerixafor pharmacokinetics.

Age
Clinical data show no effect of age on plerixafor pharmacokinetics.

13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies with plerixafor have not been conducted.
 
Plerixafor was not genotoxic in an in vitro bacterial mutation assay (Ames test in Salmonella), an in vitro chromosomal aberration test using V79 Chinese hamster cells, or an in vivo bone marrow micronucleus test in rats after subcutaneous doses up to 25 mg/kg (150 mg/m2). The effect of plerixafor on human fertility is unknown.
  
The effect of plerixafor on male or female fertility was not studied in designated reproductive toxicology studies. The staging of spermatogenesis measured in a 28-day repeated dose toxicity study in rats revealed no abnormalities considered to be related to plerixafor. No histopathological evidence of toxicity to male or female reproductive organs was observed in 28-day repeated dose toxicity studies.

14
CLINICAL STUDIES
The efficacy and safety of Mozobil in conjunction with G-CSF in non-Hodgkin’s lymphoma (NHL) and multiple myeloma (MM) were evaluated in two placebo-controlled studies (Studies 1 and 2). Patients were randomized to receive either Mozobil 0.24 mg/kg or placebo on each evening prior to apheresis. Patients received daily morning doses of G-CSF 10 micrograms/kg for 4 days prior to the first dose of Mozobil or placebo and on each morning prior to apheresis. Two hundred and ninety-eight (298) NHL patients were included in the primary efficacy analyses for Study 1. The mean age was 55.1 years (range 29-75) and 57.5 years (range 22-75) in the Mozobil and placebo groups, respectively, and 93% of subjects were Caucasian. Three hundred and two (302) MM patients were included in the primary efficacy analyses for Study 2. The mean age was 58.2 years (range 28-75) and 58.5 years (range 28-75) in the Mozobil and placebo groups, respectively, and 81% of subjects were Caucasian.

In Study 1, 59% of NHL patients who were mobilized with Mozobil and G-CSF collected ≥ 5 X 106 CD34+ cells/kg from the peripheral blood in four or fewer apheresis sessions, compared with 20% of patients who were mobilized with placebo and G-CSF (p < 0.001). Other CD34+ cell mobilization outcomes showed similar findings (Table 4).

Table 4: Study 1 Efficacy Results - CD34+ Cell Mobilization in NHL Patients

Efficacy Endpoint
  
Mozobil
and G-CSF
(n = 150)
    
Placebo
and G-CSF
(n = 148)
  
p-valuea
  
Patients achieving ≥ 5 X 106 cells/kg in ≤ 4 apheresis days
     89 (59 )%     29 (20 )%
< 0.001
  
Patients achieving ≥ 2 X 106 cells/kg in ≤ 4 apheresis days
     130 (87 )%     70 (47 )%
< 0.001
  
 
ap-value calculated using Pearson’s Chi-Squared test
 
The median number of days to reach ≥ 5 x 106 CD34+ cells/kg was 3 days for the Mozobil group and not evaluable for the placebo group. Table 5 presents the proportion of patients who achieved ≥ 5 x 106 CD34+ cells/kg by apheresis day.

Table 5: Study 1 Efficacy Results – Proportion of Patients Who Achieved ≥ 5 x 106 CD34+ cells/kg by Apheresis Day in NHL Patients
  
Days
  
Proportiona
in Mozobil
and G-CSF
(n=147b)
    
Proportiona
in Placebo
and G-CSF
(n=142b)
  
1
     27.9 %     4.2 %
2
     49.1 %     14.2 %
3
     57.7 %     21.6 %
4
     65.6 %     24.2 %
  
aPercents determined by Kaplan Meier method
bn includes all patients who received at least one day of apheresis

In Study 2, 72% of MM patients who were mobilized with Mozobil and G-CSF collected ≥ 6 X 106 CD34+ cells/kg from the peripheral blood in two or fewer apheresis sessions, compared with 34% of patients who were mobilized with placebo and G-CSF (p < 0.001). Other CD34+ cell mobilization outcomes showed similar findings (Table 6).

Table 6: Study 2 Efficacy Results – CD34+ Cell Mobilization in Multiple Myeloma Patients

Efficacy Endpoint
  
Mozobil
and G-CSF
(n = 148)
    
Placebo
and G-CSF
(n = 154)
    
p-valuea
  
Patients achieving ≥ 6 X 106 cells/kg in ≤ 2 apheresis days
     106 (72 )%     53 (34 )%  
< 0.001
  
Patients achieving ≥ 6 X 106 cells/kg in ≤ 4 apheresis days
     112 (76 )%     79 (51 )%  
< 0.001
  
Patients achieving ≥ 2 X 106 cells/kg in ≤ 4 apheresis days
     141 (95 )%     136 (88 )%     0.028  
  
ap-value calculated using Pearson’s Chi-Squared test

The median number of days to reach ≥ 6 x 106 CD34+ cells/kg was 1 day for the Mozobil group and 4 days for the placebo group. Table 7 presents the proportion of patients who achieved ≥ 6 x 106CD34+ cells/kg by apheresis day.

Table 7: Study 2 – Proportion of Patients Who Achieved ≥ 6 x 106 CD34+cells/kg by Apheresis Day in MM Patients

Days
  
Proportiona
in Mozobil
and G-CSF
(n=144b)
    
Proportiona
in Placebo
and G-CSF
(n=150b)
  
1
     54.2 %     17.3 %
2
     77.9 %     35.3 %
3
     86.8 %     48.9 %
4
     86.8 %     55.9 %
  
aPercents determined by Kaplan Meier method
bn includes all patients who received at least one day of apheresis

Multiple factors can influence time to engraftment and graft durability following stem cell transplantation. For transplanted patients in the Phase 3 studies, time to neutrophil and platelet engraftment and graft durability were similar across the treatment groups.

16
HOW SUPPLIED/STORAGE AND HANDLING
Each single-use vial is filled to deliver 1.2 mL of 20 mg/mL solution containing 24 mg of plerixafor.

NDC Number: 58468-0140-1
 
·
Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). [see USP Controlled Room temperature]
·
Each vial of Mozobil is intended for single use only. Any unused drug remaining after injection must be discarded.

17
PATIENT COUNSELING INFORMATION
Advise patients of the signs and symptoms of potential systemic reactions such as urticaria, periorbital swelling, dyspnea, or hypoxia during and following Mozobil injection. [see Adverse Reactions (6.1)]

Patients should inform a health care professional immediately if symptoms of vasovagal reactions such as orthostatic hypotension or syncope occur during or shortly after their Mozobil injection. [see Adverse Reactions (6.1)]

If patients experience itching, rash, or reaction at the site of injection, they should notify a health care professional as these symptoms have been treated with over-the-counter medications during clinical trials. [see Adverse Reactions (6.1)]

Inform patients that Mozobil may cause gastrointestinal disorders, including diarrhea, nausea, vomiting, flatulence, and abdominal pain. Patients should be told how to manage specific gastrointestinal disorders and to inform their health care professional if severe events occur following Mozobil injection. [see Adverse Reactions (6.1)]

Advise female patients with reproductive potential to use effective contraceptive methods during Mozobil use. [see Warnings and Precautions (5.5) and Use In Specific Populations (8.1)]

Manufactured by: Patheon UK Ltd., Swindon, UK
Manufactured for: Genzyme Corporation, 500 Kendall Street, Cambridge,
MA 02142 USA
 
©2008 Genzyme Corporation. All rights reserved.
Mozobil is a trademark of Genzyme Corporation.
 
502031
 
4
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Sterile Lyophilized Powder
For Intravenous Use Only
Rx only
 
WARNING
Thymoglobulin® should only be used by physicians experienced in immunosuppressive therapy for the management of renal transplant patients.
 
DESCRIPTION
Thymoglobulin® [Anti-thymocyte Globulin (Rabbit)] is a purified, pasteurized, gamma immune globulin, obtained by immunization of rabbits with human thymocytes. This immunosuppressive product contains cytotoxic antibodies directed against antigens expressed on human T-lymphocytes.

Thymoglobulin is a sterile, freeze-dried product for intravenous administration after reconstitution with Sterile Water for Injection, USP (SWFI).

Each 10 mL vial contains 25 mg anti-thymocyte globulin (rabbit) as well as 50 mg glycine, 50 mg mannitol, and 10 mg sodium chloride.

After reconstitution with 5 mL SWFI, each vial of reconstituted product contains approximately 5 mg/mL of Thymoglobulin, of which >90% is rabbit gamma immune globulin (IgG). The reconstituted solution has a pH of 6.5 - 7.2. Human red blood cells are used in the manufacturing process to deplete cross-reactive antibodies to non-T-cell antigens. The manufacturing process is validated to remove or inactivate potential exogenous viruses. All human red blood cells are from US registered or FDA licensed blood banks. A viral inactivation step (pasteurization, i.e., heat treatment of active ingredient at 60°C/10 hr) is performed for each lot. Each Thymoglobulin lot is released following potency testing (lymphocytotoxicity and E-rosette inhibition assays), and cross-reactive antibody testing (hemagglutination, platelet agglutination, anti-human serum protein antibody, antiglomerular basement membrane antibody, and fibroblast toxicity assays on every fifth lot).

PHARMACOLOGY
Mechanism of Action
The mechanism of action by which polyclonal antilymphocyte preparations suppress immune responses is not fully understood. Possible mechanisms by which Thymoglobulin may induce immunosuppression in vivo include: T-cell clearance from the circulation and modulation of T-cell activation, homing, and cytotoxic activities. Thymoglobulin includes antibodies against T-cell markers such as CD2, CD3, CD4, CD8, CD11a, CD18, CD25, CD44, CD45, HLA-DR, HLA Class I heavy chains, and ß2 micro-globulin. In vitro, Thymoglobulin (concentrations >0.1 mg/mL) mediates T-cell suppressive effects via inhibition of proliferative responses to several mitogens. In patients, T-cell depletion is usually observed within a day from initiating Thymoglobulin therapy. Thymoglobulin has not been shown to be effective for treating antibody (humoral) mediated rejections.

Pharmacokinetics and Immunogenicity
After an intravenous dose of 1.25 to 1.5 mg/kg/day (over 4 hours for 7-11 days) 4-8 hours post-infusion, Thymoglobulin levels were on average 21.5 mcg/mL (10-40 mcg/mL) with a half-life of 2-3 days after the first dose, and 87 mcg/mL (23-170 mcg/mL) after the last dose. During the Thymoglobulin* Phase 3 randomized trial, of the 108 of 163 patients evaluated, anti-rabbit antibodies developed in 68% of the Thymoglobulin-treated patients, and anti-horse antibodies developed in 78% of the Atgam**-treated patients (p=n.s.). No controlled studies have been conducted to study the effect of anti-rabbit antibodies on repeat use of Thymoglobulin. However, monitoring the lymphocyte count to ensure that T-cell depletion is achieved upon retreatment with Thymoglobulin is recommended. Based on data collected from a limited number of patients (Clinical study Phase 3, n=12), T-cell counts are presented in the chart below. These data were collected using flow cytometry (FACSCAN, Becton-Dickinson).
 
Mean T-Cell Counts Following Initiation of Thymoglobulin Therapy
 
 
* Thymoglobulin is a registered trademark of Genzyme Corporation, Cambridge, MA 02142
**Atgam is a registered trademark of Pfizer Inc, New York, NY 10017

 
 
 

Clinical Trials
US Phase 3 Study
A controlled, double-blind, multicenter, randomized clinical trial comparing Thymoglobulin and Atgam was conducted at 28 US transplant centers in renal transplant patients (n=163) with biopsy-proven Banff Grade II (moderate), Grade III (severe), or steroid-resistant Grade I (mild) acute graft rejection. This clinical trial rejected the null hypothesis that Thymoglobulin was more than 20% less effective in reversing acute rejection than Atgam. The overall weighted estimate of the treatment difference (Thymoglobulin – Atgam success rate) was 11.1% with a lower 95% confidence bound of 0.07%. Therefore, Thymoglobulin was at least as effective as Atgam in reversing acute rejection episodes.

In the study, patients were randomized to receive 7 to 14 days of Thymoglobulin (1.5 mg/kg/day) or Atgam (15 mg/kg/day). For the entire study, the two treatment groups were comparable with respect to donor and recipient characteristics. During the trial, the FDA approved new maintenance immunosuppressive agents (tacrolimus and mycophenolate). Off-protocol use of these agents occurred during the second half of the study in some patients without affecting the overall conclusions (Thymoglobulin 22/43, Atgam 20/37; p=0.826). The results, however, are presented for the first and second halves of the study (Table 1). In Table 1, successful treatment is presented as those patients whose serum creatinine levels (14 days from the diagnosis of rejection) returned to baseline and whose graft was functioning on day 30 after the end of therapy.

Table 1. Response to Study Treatment by Rejection Severity and Study Half

Success / n
  
Total
    
First Half
    
Second Half
  
   
Thymoglobulin
    
Atgam
    
Thymoglobulin
    
Atgam
    
Thymoglobulin
    
Atgam
  
Risk Factor:
                                                                        
Baseline
                                                                        
Rejection Severity:
                                                                        
Mild
     9/10       (90.0 )%     5/8       (62.5 )%     5/5       (100 )%     1/3       (33.3 )%     4/5       (80.0 )%     4/5       (80.0 )%
Moderate
     44/58       (75.5 )%     41/58       (70.7 )%     22/26       (84.6 )%     22/32       (68.8 )%     22/32       (68.8 )%     19/26       (73.1 )%
Severe
     11/14       (71.6 )%     8/14       (57.1 )%     6/8       (75.0 )%     3/8       (37.5 )%     5/6       (83.3 )%     5/6       (83.3 )%
Overall
     64/82       (78.0 )%     54/80       (67.5 )%     33/39       (84.6 )%     26/43       (60.5 )%     31/43       (72.1 )%     28/37       (75.7 )%

Weighted estimate of difference
     11.1 %a     19.3 %     –3.2 %
(Thymoglobulin – Atgam)
                        
Lower one-sided 95% confidence bound
     0.07 %     4.6 %     –19.7 %
p Valueb
     0.061
c
     0.008
d
     0.625
d

a. across rejection severity and study half
b. under null hypothesis of equivalence (Cochran-Mantel-Haenszel test)
c. one-sided stratified on rejection severity and study half
d. one-sided stratified on rejection severity

There were no significant differences between the two treatments with respect to (i) day 30 serum creatinine levels relative to baseline, (ii) improvement rate in post-treatment histology, (iii) one-year post-rejection Kaplan-Meier patient survival (Thymoglobulin 93%, n=82 and Atgam 96%, n=80), (iv) day 30 and (v) one-year post-rejection graft survival (Thymoglobulin 83%, n=82; Atgam 75%, n=80).

INDICATIONS AND USAGE
Thymoglobulin is indicated for the treatment of renal transplant acute rejection in conjunction with concomitant immunosuppression.

CONTRAINDICATIONS
Thymoglobulin is contraindicated in patients with history of allergy or anaphylaxis to rabbit proteins or to any product excipients, or who have active acute or chronic infections which contraindicate any additional immunosuppression.

WARNINGS
Thymoglobulin should only be used by physicians experienced in immunosuppressive therapy for the treatment of renal transplant patients. Medical surveillance is required during Thymoglobulin infusion.

Immune-mediated reactions
Serious immune-mediated reactions have been reported with the use of Thymoglobulin and consist of anaphylaxis or severe cytokine release syndrome (CRS).
 
Fatal anaphylaxis has been reported.  If an anaphylactic reaction occurs, the infusion should be terminated immediately. Medical personnel should be available to treat patients who experience anaphylaxis. Emergency treatment such as 0.3 mL to 0.5 mL aqueous epinephrine (1:1000 dilution) subcutaneously and other resuscitative measures including oxygen, intravenous fluids, antihistamines, corticosteroids, pressor amines, and airway management, as clinically indicated, should be provided. Any further administration of Thymoglobulin to a patient who has a history of anaphylaxis to Thymoglobulin is not recommended.

Severe, acute infusion-associated reactions (IARs) are consistent with CRS which is attributed to the release of cytokines by activated monocytes and lymphocytes. Severe acute CRS can cause  serious cardiorespiratory events and/or death (See PRECAUTIONS and ADVERSE REACTIONS: Post-Marketing Experience).

Infection
Thymoglobulin is routinely used in combination with other immunosuppressive agents.  Infections (bacterial, fungal, viral and protozoal), reactivation of infection (particularly cytomegalovirus [CMV]) and sepsis have been reported after Thymoglobulin administration in combination with multiple immunosuppressive agents.  Severe acute infections can be fatal.

 
 
 

PRECAUTIONS
General
Appropriate dosing for Thymoglobulin is different from dosing for other anti-thymocyte globulin (ATG) products, as protein composition and concentrations vary depending on the source of ATG used. Physicians should therefore exercise care to ensure that the dose prescribed is appropriate for the ATG product being administered.

Thymoglobulin should be used under strict medical supervision in a hospital setting, and patients should be carefully monitored during the infusion. The first dose should be infused over a minimum of 6 hours into a high-flow vein. Close compliance with the recommended dosage and infusion time may reduce the incidence and severity of infusion associated reactions (IARs).  Additionally, reducing the infusion rate may minimize many of these IARs. Premedication with corticosteroids, acetaminophen, and/or an antihistamine and/or slowing the infusion rate may reduce reaction incidence and intensity (See DOSAGE AND ADMINISTRATION).

Rapid infusion rates have been reported with case reports consistent with cytokine release syndrome (CRS).  Severe acute CRS can be fatal.

Hematologic Effects
Thrombocytopenia and/or leukopenia (including lymphopenia and neutropenia) have been identified and are reversible following dose adjustments (See DOSAGE AND ADMINISTRATION).

Infection
Infections, reactivation of infection, and sepsis have been reported after Thymoglobulin administration in combination with multiple immunosuppressive agents.  Careful patient monitoring and appropriate anti-infective prophylaxis are recommended.

Malignancy
Use of immunosuppressive agents, including Thymoglobulin, may increase the incidence of malignancies, including lymphoma or post-transplant lymphoproliferative disease (PTLD) (See ADVERSE REACTIONS: Post-Marketing Experience).

Special Considerations for Thymoglobulin Infusion
Reactions at the infusion site can occur and may include pain, swelling, and erythema.

The recommended route of administration for Thymoglobulin is intravenous infusion using a high-flow vein (See DOSAGE AND ADMINISTRATION).

Immunizations
The safety of immunization with attenuated live vaccines following Thymoglobulin therapy has not been studied; therefore, immunization with attenuated live vaccines is not recommended for patients who have recently received Thymoglobulin.

Laboratory Tests
During Thymoglobulin therapy, monitoring the lymphocyte count (i.e., total lymphocyte and/or T-cell subset) may help assess the degree of T-cell depletion (See Pharmacokinetics and Immunogenicity). For safety, WBC and platelet counts should also be monitored (See DOSAGE AND ADMINISTRATION).

Drug Interactions
·
No drug interaction studies have been performed.
·
Because Thymoglobulin is administered to patients receiving a standard immunosuppressive regimen, this may predispose patients to overimmunosuppression. Many transplant centers decrease maintenance immunosuppression therapy during the period of antibody therapy.
·
Thymoglobulin can stimulate the production of antibodies which crossreact with rabbit immune globulins (See Pharmacokinetics and Immunogenicity).

Drug/Laboratory Test Interactions
Thymoglobulin has not been shown to interfere with any routine clinical laboratory tests which do not use immunoglobulins. Thymoglobulin may interfere with rabbit antibody-based immunoassays and with cross-match or panel-reactive antibody cytotoxicity assays.

Carcinogenesis, Mutagenesis, Impairment of Fertility
The carcinogenic and mutagenic potential of Thymoglobulin and its potential to impair fertility have not been studied.

Pregnancy: Pregnancy Category C
Animal reproduction studies have not been conducted with Thymoglobulin. It is also not known whether Thymoglobulin can cause fetal harm or can affect reproduction capacity. Thymoglobulin should be given to a pregnant woman only if clearly needed.

Nursing Mothers
Thymoglobulin has not been studied in nursing women. It is not known whether this drug is excreted in human milk. Because other immunoglobulins are excreted in human milk, breast-feeding should be discontinued during Thymoglobulin therapy.

Pediatric Use
The safety and effectiveness of Thymoglobulin in pediatric patients has not been established in controlled trials. However, the dose, efficacy, and adverse event profile are not thought to be different from adults based on limited European studies and US compassionate use.

 
 
 
 
ADVERSE REACTIONS

Clinical Trials
US Phase 3 Study
Thymoglobulin adverse events are generally manageable or reversible. In the US Phase 3 controlled clinical trial (n=163) comparing the efficacy and safety of Thymoglobulin and Atgam, there were no significant differences in clinically significant adverse events between the two treatment groups (Table 2). Malignancies were reported in 3 patients who received Thymoglobulin and in 3 patients who received Atgam during the one-year follow-up period. These included two post-transplant lymphoproliferative diseases (PTLDs) in the Thymoglobulin group and two PTLDs in the Atgam group.

Table 2. Frequently Reported and Significant Adverse Events*

 
  
Thymoglobulin
n=82
    
Atgam
n=81
    
 
  
   
No. of
    
  
   
No. of
    
  
       
Preferred Term 
 
Patients
    
(%)
    
Patients
    
(%)
    
p Value†
  
                               
Frequently Reported Events
                              
Fever
     52       (63.4 )     51       (63.0 )     1.0  
Chills
     47       (57.3 )     35       (43.2 )     0.086  
Leukopenia
     47       (57.3 )     24       (29.6 )  
<0.001
  
Pain
     38       (46.3 )     35       (43.2 )     0.753  
Headache
     33       (40.2 )     28       (34.6 )     0.518  
Abdominal pain
     31       (37.8 )     22       (27.2 )     0.181  
Diarrhea
     30       (36.6 )     26       (32.1 )     0.622  
Hypertension
     30       (36.6 )     23       (28.4 )     0.316  
Nausea
     30       (36.6 )     23       (28.4 )     0.316  
Thrombocytopenia
     30       (36.6 )     36       (44.4 )     0.341  
Peripheral edema
     28       (34.1 )     28       (34.6 )     1.0  
Dyspnea
     23       (28.0 )     16       (19.8 )     0.271  
Asthenia
     22       (26.8 )     26       (32.1 )     0.495  
Hyperkalemia
     22       (26.8 )     15       (18.5 )     0.262  
Tachycardia
     22       (26.8 )     19       (23.5 )     0.719  
Significant Events§
                                        
Leukopenia
     47       (57.3 )     24       (29.6 )  
<0.001
  
Malaise
     11       (13.4 )     3       (3.7 )     0.047  
Dizziness
     7       (8.5 )     20       (24.7 )     0.006  

*
Treatment Emergent Adverse Events (TEAE) are summarized. Frequently reported adverse events are those reported by more than 25% of patients in a treatment group; significant adverse events are those where the incidence rate differed between treatment groups by a significance level of <0.05.
†
p Value comparing treatment groups using Fisher’s exact test.
§
statistically significant differences in the AEs.

Infections occurring in both treatment groups during the 3-month follow-up are summarized in Table 3. No significant differences were seen between the Thymoglobulin and Atgam groups for all types of infections, and the incidence of cytomegalovirus (CMV) infection was equivalent in both groups. (Viral prophylaxis was by the center’s discretion during antibody treatment, but all centers used gancyclovir infusion during treatment.)

Table 3. Infections

   
Thymoglobulin
    
Atgam
        
   
n=82
    
n=81
        
BODY SYSTEM
  
No. of
          
Total
    
No. of
          
Total
        
Preferred Term
  
Patients
    
(%)
    
Reports
    
Patients
    
(%)
    
Reports
    
p Value†
  
                                           
BODY AS A WHOLE
     30       (36.6 )     36       22       (27.2 )     29       0.240  
Infection
     25       (30.5 )     26       19       (23.5 )     21       0.378  
Other
     14       (17.1 )     15       11       (13.6 )     12       0.665  
CMV
     11       (13.4 )     11       9       (11.1 )     9       0.812  
Sepsis
     10       (12.2 )     10       7       (9.6 )     7       0.610  
Moniliasis
     0       (0.0 )     0       1       (1.2 )     1       0.497  
DIGESTIVE
     5       (6.1 )     5       3       (3.7 )     3       0.720  
Gastrointestinal
                                                        
moniliasis
     4       (4.9 )     4       1       (1.2 )     1       0.367  
Oral moniliasis
     3       (3.7 )     0       2       (2.5 )     1       0.497  
Gastritis
     1       (1.2 )     1       0       (0.0 )     0       1.000  
RESPIRATORY
     0       (0.0 )     0       1       (1.2 )     1       0.497  
Pneumonia
     0       (0.0 )     0       1       (1.2 )     1       0.497  
SKIN
     4       (4.9 )     4       0       (0.0 )     0       0.120  
Herpes simplex
     4       (4.9 )     4       0       (0.0 )     0       0.120  
UROGENITAL
     15       (18.3 )     15       22       (29.2 )     22       0.195  
Urinary tract infection
     15       (18.3 )     15       21       (25.9 )     21       0.262  
Vaginitis
     0       (0.0 )     0       1       (1.2 )     1       0.497  
NOT SPECIFIED
     0       (0.0 )     0       2       (2.5 )     2       0.245  

†
p Value comparing treatment groups using Fisher’s exact test.

 
 
 

Post-marketing Experience
The following adverse reactions have been identified during post approval use of Thymoglobulin. 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-Associated Reactions and Immune System Disorders
IARs may occur following the administration of Thymoglobulin and may occur as soon as the first or second infusion during a single course of Thymoglobulin treatment. Clinical manifestations of Infusion-associated reactions IARs have included some of the following signs and symptoms: fever, chills/rigors, dyspnea, nausea/vomiting, diarrhea, hypotension or hypertension, malaise, rash, and/or headache. IARs with Thymoglobulin are generally manageable with a reduction in infusion rates and/or with medications (See PRECAUTIONS). Serious and fatal anaphylactic reactions have been reported (See WARNINGS). The fatalities occurred in patients who did not receive epinephrine during the event.

IARs consistent with cytokine release syndrome (CRS) have been reported. Severe and potentially life-threatening CRS have also been reported. Post-marketing reports of severe CRS have included cardiorespiratory dysfunction (including hypotension, acute respiratory distress syndrome, pulmonary edema, myocardial infarction, tachycardia, and/or death).

During post-marketing surveillance, reactions such as fever, rash, arthralgia, and/or myalgia, indicating possible serum sickness, have been reported. Serum sickness tends to occur 5 to 15 days after onset of Thymoglobulin therapy. Symptoms are manageable with corticosteroid treatment.

Adverse Events Due to Immunosuppression
Infections, reactivation of infection, and sepsis have been reported after Thymoglobulin administration in combination with multiple immunosuppressive agents (See WARNINGS and PRECAUTIONS). Malignancies including, but not limited to post-transplant lymphoproliferative disorder (PTLD) and other lymphomas as well as solid tumors have been reported (See PRECAUTIONS). These adverse events were reported with use of a combination of multiple immunosuppressive agents.

OVERDOSAGE
Thymoglobulin overdosage may result in leukopenia (including lymphopenia and neutropenia) or thrombocytopenia, which can be managed with dose reduction (See DOSAGE AND ADMINISTRATION).

DOSAGE AND ADMINISTRATION
The recommended dosage of Thymoglobulin for treatment of acute renal graft rejection is 1.5 mg/kg of body weight administered daily for 7 to 14 days. The recommended route of administration is intravenous infusion using a high-flow vein. Thymoglobulin should be infused over a minimum of 6 hours for the first infusion and over at least 4 hours on subsequent days of therapy.

Thymoglobulin should be administered through an in-line 0.22 micrometer filter.

Thymoglobulin is supplied as a 10 mL vial containing lyophilized (solid) Thymoglobulin (25 mg).

Please see Preparation for Administration for vial reconstitution and dilution in infusion solution recommendations. Investigations indicate that Thymoglobulin is less likely to produce side effects when administered at the recommended flow rate. Administration of antiviral prophylactic therapy is recommended. Premedication with corticosteroids, acetaminophen, and/or an antihistamine 1 hour prior to the infusion is recommended and may reduce the incidence and intensity of side effects during the infusion (See PRECAUTIONS: General and ADVERSE REACTIONS: Post-Marketing Experience). Medical personnel should monitor patients for adverse events during and after infusion. Monitoring T-cell counts (absolute and/or subsets) to assess the level of T-cell depletion is recommended. Total white blood cell and platelet counts should be monitored.

Overdosage of Thymoglobulin may result in leukopenia (including lymphopenia and neutropenia) and/or thrombocytopenia. The Thymoglobulin dose should be reduced by one-half if the WBC count is between 2,000 and 3,000 cells/mm3 or if the platelet count is between 50,000 and 75,000 cells/mm3. Stopping Thymoglobulin treatment should be considered if the WBC count falls below 2,000 cells/mm3 or platelets below 50,000 cells/mm3.

Preparation for Administration
Reconstitution
After calculating the number of vials needed, using aseptic technique, reconstitute each vial of Thymoglobulin with 5 mL of Sterile Water for Injection, USP (SWFI). Reconstituted Thymoglobulin is physically and chemically stable for up to 24 hours at room temperature; however, room temperature storage is not recommended. As Thymoglobulin contains no preservatives, reconstituted product should be used immediately.

1. 
Allow Thymoglobulin vials to reach room temperature before reconstituting the lyophilized product.
2. 
Aseptically remove caps to expose rubber stoppers.
3. 
Clean stoppers with germicidal or alcohol swab.
4. 
Aseptically reconstitute each vial of Thymoglobulin lyophilized powder with the 5 mL of SWFI.
5. 
Rotate vial gently until powder is completely dissolved. Each reconstituted vial contains 25 mg or 5 mg/mL of Thymoglobulin.

 
 
 
  
6. 
Inspect solution for particulate matter after reconstitution. Should some particulate matter remain, continue to gently rotate the vial until no particulate matter is visible. If particulate matter persists, discard this vial.

Dilution
1. 
Transfer the contents of the calculated number of Thymoglobulin vials into the bag of infusion solution (saline or dextrose). Recommended volume: per one vial of Thymoglobulin use 50 mL of infusion solution (total volume usually between 50 to 500 mL).
2. 
Mix the solution by inverting the bag gently only once or twice.
 
Infusion
1. 
Follow the manufacturer’s instructions for the infusion administration set. Infuse through a 0.22 micrometer filter into a high-flow vein.
2. 
Set the flow rate to deliver the dose over a minimum of 6 hours for the first dose and over at least 4 hours for subsequent doses.

HOW SUPPLIED
Thymoglobulin is available as sterile, lyophilized powder to be reconstituted with sterile Water for Injection, USP (SWFI). Each package contains a 10 mL vial of freeze-dried Thymoglobulin (25 mg) NDC# 58468-0080-1.

Storage
· 
Store in refrigerator at 2°C to 8°C (36°F to 46°F).
·
 Protect from light. 
· 
Do not freeze.
· 
Do not use after the expiration date indicated on the label.
· 
Reconstituted Thymoglobulin is physically and chemically stable for up to 24 hours at room temperature; however, room temperature storage is not recommended. As Thymoglobulin contains no preservatives, reconstituted product should be used immediately.
· 
Infusion solutions of Thymoglobulin must be used immediately.
·
 Any unused drug remaining after infusion must be discarded. 

REFERENCES
1.   
Bonnefoy-Bérard N, et al. Antibodies against functional leukocyte surface molecules in polyclonal antilymphocyte and antithymocyte globulins. Transplantation (1991)51:669-673.
2.   
Bonnefoy-Bérard N, et al. Inhibition of CD25 (IL-2Rα) expression and Tcell proliferation by polyclonal anti-thymocyte globulins. Immunology (1992)77:61-67.
3.   
Bonnefoy-Bérard N, et al. Antiproliferative effect of antilymphocyte globulins on B cells and B-cell lines. Blood (1992)79:2164-2170.
4.   
Bonnefoy-Bérard N, Revillard J-P. Mechanisms of immunosuppression induced by antilymphocyte globulins and OKT3. J Heart Lung Transplant (1996)15:435-442.
5.   
Bourdage J, et al. Comparative polyclonal antithymocyte globulin and antilymphocyte/antilymphoblast globulin anti-CD antigen analysis by flow cytometry. Transplantation (1995)59:1194-1200.
6.   
Broyer M, et al. Triple therapy including cyclosporine A versus conventional regimen–a randomized prospective study in pediatric kidney transplantation. Transplant Proc (1987)19:3582-3585.
7.   
Clark KR, et al. Administration of ATG according to the absolute T lymphocyte count during therapy for steroid-resistant rejection. Transpl Int (1993)6:18-21.
8.   
Gaber AO, et al. Results of the double-blind, randomized, multicenter, phase III clinical trial of Thymoglobulin versus Atgam in the treatment of acute graft rejection episodes after renal transplantation. Transplantation (1998)66:29-37.
9.   
Guttmann RD, et al. Pharmacokinetics, foreign protein immune response, cytokine release, and lymphocyte subsets in patients receiving Thymoglobuline and immunosuppression. Transplant Proc (1997)29(suppl 7A):24S-26S.
10. 
Ippoliti G, et al. Prophylactic use of rabbit ATG vs horse ALG in hearttrans planted patients under Sandimmun (CyA) therapy: clinical and immunological effects. Clin Transplantation (1989)3:204-208.

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By:
Genzyme Corporation
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©2008 Genzyme Corporation. All rights reserved.
Issued: 09/08
  


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