Clolar (Clofarabine) - Side Effects and Adverse Reactions

ADVERSE REACTIONS

One hundred thirteen (113) pediatric patients with ALL (67) or AML (46) were exposed to Clolar^®.

Ninety six (96) of the pediatric patients treated in clinical trials received the recommended dose of Clolar^® 52 mg/m² daily x 5.

The most common adverse effects after Clolar^® treatment, regardless of causality, were gastrointestinal tract symptoms, including vomiting, nausea, and diarrhea; hematologic effects, including anemia, leukopenia, thrombocytopenia, neutropenia, and febrile neutropenia; and infection.

Table 2  lists adverse events by System Organ Class regardless of causality, including severe or life-threatening events (NCI CTC grade 3 or grade 4), reported in ≥10% of the 96 patients in the 52 mg/m²/day dose group. More detailed information and follow-up of certain events is given below.

Table 2: Most Commonly Reported (≥10% Overall) Adverse Events by System Organ Class (N=96)

System Organ Class Adverse Event*	52 mg/m2 (N=96)
	Total		Grade 3		Grade 4
	N	%	n	%	n	%
* Patients with more than one occurrence of the same preferred term are counted only once.Grade 4 includes deaths (Grade 5).
Blood and Lymphatic System Disorders
Febrile neutropenia	55	57	51	53	3	3
Neutropenia	10	10	3	3	7	7
Transfusion reaction	10	10	3	3	.	.
Cardiac Disorders
Tachycardia NOS	33	34	6	6	.	.
Gastrointestinal Disorders
Abdominal pain NOS	35	36	7	7	.	.
Constipation	20	21	.	.	.	.
Diarrhea NOS	51	53	10	10	.	.
Gingival bleeding	14	15	7	7	1	1
Nausea	72	75	14	15	1	1
Sore throat NOS	13	14	.	.	.	.
Vomiting NOS	80	83	8	8	1	1
General Disorders and Administration Site Conditions
Edema NOS	19	20	1	1	2	2
Fatigue	35	36	3	3	1	1
Injection site pain	13	14	1	1	.	.
Lethargy	11	11	.	.	.	.
Mucosal inflammation NOS	17	18	3	3	.	.
Pain NOS	18	19	6	6	1	1
Pyrexia	39	41	15	16	.	.
Rigors	36	38	3	3	.	.
Hepato-Biliary Disorders
Hepatomegaly	14	15	8	8	.	.
Jaundice NOS	14	15	2	2	.	.
Infections and Infestations
Bacteremia	10	10	10	10	.	.
Cellulitis	11	11	9	9	.	.
Herpes simplex	11	11	6	6	.	.
Oral candidiasis	12	13	2	2	.	.
Pneumonia NOS	10	10	5	5	2	2
Sepsis NOS	14	15	7	7	7	7
Staphylococcal infection NOS	12	13	10	10	.	.
Investigations
Weight decreased	10	10	1	1	.	.
Metabolism and Nutrition Disorders
Anorexia	30	31	5	5	7	7
Appetite decreased NOS	11	11	.	.	.	.
Musculoskeletal, Connective Tissue and Bone Disorders
Arthralgia	11	11	3	3	.	.
Back pain	12	13	3	3	.	.
Myalgia	13	14	.	.	.	.
Pain in limb	28	29	5	5	.	.
Nervous System Disorders
Dizziness (except vertigo)	15	16	.	.	.	.
Headache NOS	44	46	4	4	.	.
Somnolence	10	10	1	1	.	.
Tremor NEC	10	10	.	.	.	.
Psychiatric Disorders
Anxiety NEC	21	22	2	2	.	.
Depression NEC	11	11	1	1	.	.
Irritability	11	11	1	1	.	.
Renal and Urinary Disorders
Hematuria	16	17	2	2	.	.
Respiratory, Thoracic and Mediastinal Disorders
Cough	18	19	.	.	.	.
Dyspnea NOS	12	13	4	4	2	2
Epistaxis	30	31	14	15	.	.
Pleural effusion	10	10	3	3	2	2
Respiratory distress	13	14	6	6	5	5
Skin and Subcutaneous Tissue Disorders
Contusion	11	11	1	1	.	.
Dermatitis NOS	39	41	7	7	.	.
Dry skin	10	10	1	1	.	.
Erythema NEC	17	18	.	.	.	.
Palmar-plantar erythrodysesthesia syndrome	12	13	4	4	.	.
Petechiae	28	29	7	7	.	.
Pruritus NOS	45	47	1	1	.	.
Vascular Disorders
Flushing	17	18	.	.	.	.
Hypertension NOS	11	11	4	4	.	.
Hypotension NOS	28	29	12	13	7	7

Cardiovascular

The most frequently reported cardiac disorder was tachycardia (34%), which was, however, already present in 27.4% of patients at study entry. Most of the cardiac adverse events were reported in the first 2 cycles. Pericardial effusion was a frequent finding in these patients on post-treatment studies, [19/55 (35%)]. The effusion was almost always minimal to small and in no cases had hemodynamic significance.

Left ventricular systolic dysfunction (LVSD) was also noted. Fifteen out of fifty-five patients [15/55 (27%)] had some evidence of LVSD after study entry. In most cases where subsequent follow-up data were available, the LVSD appeared to be transient. The exact etiology for the LVSD is unclear because of previous therapy or serious concurrent illness.

Hepatic

Hepato-biliary toxicities were frequently observed in pediatric patients during treatment with Clolar^®. Grade 3 or 4 elevated aspartate aminotransferase (AST) occurred in 38% of patients and grade 3 or 4 elevated alanine aminotransferase (ALT) occurred in 44% of patients. Grade 3 or 4 elevated bilirubin occurred in 15% of patients, with 2 cases of grade 4 hyperbilirubinemia resulting in treatment discontinuation.

For patients with follow-up data, elevations in AST and ALT were transient and typically of <2 weeks duration. The majority of AST and ALT elevations occurred within 1 week of Clolar^® administration and returned to baseline or ≤ grade 2 within several days. Although less common, elevations in bilirubin appeared to be more persistent. Where follow-up data are available, the median time to recovery from grade 3 and grade 4 elevations in bilirubin to ≤ grade 2 was 6 days.

Infection

At baseline, 47% of the patients had 1 or more concurrent infections. A total of 85% of patients experienced at least 1 infection after Clolar^® treatment, including fungal, viral and bacterial infections.

Renal

The most prevalent renal toxicity was elevated creatinine. Grade 3 or 4 elevated creatinine occurred in 6% of patients. Nephrotoxic medications, tumor lysis, and tumor lysis with hyperuricemia may contribute to renal toxicity.

Systemic Inflammatory Response Syndrome (SIRS)/Capillary Leak Syndrome

Capillary leak syndrome or SIRS (signs and symptoms of cytokine release, e.g., tachypnea, tachycardia, hypotension, pulmonary edema), occurred in 4 pediatric patients overall (3 ALL, 1 AML). Several patients developed rapid onset of respiratory distress, hypotension, capillary leak (pleural and pericardial effusions), and multi-organ failure. 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.

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 x 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.