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
]
- Serious Infections [see
Warnings and Precautions]
- Hyperuricemia (Tumor Lysis) [see
Warnings and Precautions
]
- Systemic Inflammatory Response Syndrome (SIRS) and Capillary Leak Syndrome [see
Warnings and Precautions
]
- Venous Occlusive Disease of the Liver [see Warnings and Precautions
]
- Hepatotoxicity [see Warnings and Precautions
]
- Renal Toxicity [see Warnings and Precautions
]
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).
In total, 115 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 occurring in 10% or more of patients treated 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 reactions 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 Reactions by System Organ Class (N=115 pooled analysis)
|
|
|
|
Worst NCI Common Terminology Criteria Grade
|
|
|
ALL/AML (N=115) |
3 |
4 |
5 |
| System Organ Class
|
Preferred Term
|
N |
% |
N |
% |
N |
% |
N |
% |
| Blood and Lymphatic System Disorders |
Febrile neutropenia |
63 |
54.8 |
59 |
51.3 |
3 |
2.6 |
. |
. |
| 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 |
. |
. |
. |
. |
| Gastrointestinal Disorders |
Abdominal pain |
40 |
34.8 |
8 |
7.0 |
. |
. |
. |
. |
| Abdominal pain upper |
9 |
7.8 |
1 |
0.9 |
. |
. |
. |
. |
| Diarrhea |
64 |
55.7 |
14 |
12.2 |
. |
. |
. |
. |
| Gingival or mouth bleeding |
20 |
17.4 |
8 |
7.0 |
1 |
0.9 |
. |
. |
| 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 and Administration Site Conditions |
Asthenia |
12 |
10.4 |
1 |
0.9 |
1 |
0.9 |
. |
. |
| Chills |
39 |
33.9 |
3 |
2.6 |
. |
. |
. |
. |
| 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 Infestations |
Bacteremia |
10 |
8.7 |
10 |
8.7 |
. |
. |
. |
. |
| 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, including septic shock |
19 |
16.5 |
6 |
5.2 |
4 |
3.5 |
9 |
7.8 |
| 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 infection |
6 |
5.2 |
1 |
0.9 |
. |
. |
. |
. |
| Metabolism and Nutrition Disorders |
Anorexia |
34 |
29.6 |
6 |
5.2 |
8 |
7.0 |
. |
. |
| Musculoskeletal and Connective Tissue Disorders |
Arthralgia |
10 |
8.7 |
3 |
2.6 |
. |
. |
. |
. |
| Back pain |
12 |
10.4 |
3 |
2.6 |
. |
. |
. |
. |
| 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 Disorders |
Headache |
49 |
42.6 |
6 |
5.2 |
. |
. |
. |
. |
| 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 and Mediastinal Disorders |
Dyspnea |
15 |
13.0 |
6 |
5.2 |
2 |
1.7 |
. |
. |
| Epistaxis |
31 |
27.0 |
15 |
13.0 |
. |
. |
. |
. |
| 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 |
. |
. |
| Skin and Subcutaneous Tissue Disorders |
Erythema |
13 |
11.3 |
. |
. |
. |
. |
. |
. |
| Palmar-plantar 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 |
. |
. |
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%) |
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.
- Gastrointestinal disorders: Gastrointestinal hemorrhage including fatalities.
- 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. Other exfoliative conditions have also been reported.
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