Clolar (Clofarabine) - Side Effects and Adverse Reactions

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 x 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)

System Organ Class¹	Preferred Term¹	ALL/AML (N=115)		Worst NCI Common Terminology Criteria Grade¹
				3		4		5
		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 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 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	.	.	.	.
	Oedema	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	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 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	.	.
¹Patients 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, Parainfluenzae 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%)	9/115 (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 Warning 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.

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.

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.