Included as part of the PRECAUTIONS section.
Clolar causes myelosuppression which may be severe and prolonged.
Febrile neutropenia occurred in 55% and non-febrile neutropenia in an
additional 10% of pediatric patients in clinical trials. At initiation of treatment,
most patients in the clinical studies had hematological impairment as a
manifestation of leukemia. Myelosuppression is usually reversible with interruption
of Clolar treatment and appears to be dosedependent. Monitor complete blood
counts [see DOSAGE AND ADMINISTRATION].
Serious and fatal hemorrhage, including cerebral,
gastrointestinal and pulmonary hemorrhage, has occurred. The majority of the cases
were associated with thrombocytopenia. Monitor platelets and coagulation parameters
and treat accordingly [see ADVERSE REACTIONS].
Clolar increases the risk of infection, including severe
and fatal sepsis, and opportunistic infections. At baseline, 48% of the pediatric
patients had one or more concurrent infections. A total of 83% of patients
experienced at least one infection after Clolar treatment, including fungal,
viral and bacterial infections. Monitor patients for signs and symptoms of
infection, discontinue Clolar, and treat promptly.
Hyperuricemia (Tumor Lysis)
Administration of Clolar may result in tumor lysis
syndrome associated with the break-down metabolic products from peripheral
leukemia cell death. Monitor patients undergoing treatment for signs and
symptoms of tumor lysis syndrome and initiate preventive measures including
adequate intravenous fluids and measures to control uric acid.
Systemic Inflammatory Response Syndrome (SIRS) And Capillary
Clolar may cause a cytokine release syndrome (e.g.,
tachypnea, tachycardia, hypotension, pulmonary edema) that may progress to the
systemic inflammatory response syndrome (SIRS) with capillary leak syndrome and
organ impairment which may be fatal. Monitor patients frequently for these
conditions. In clinical trials, SIRS was reported in two patients (2%);
capillary leak syndrome was reported in four 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
may reduce the risk. ÃÂ Immediately discontinue Clolar and provide appropriate supportive
measures. 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. Consider use of diuretics and/or albumin. After the patient is
stabilized and organ function has returned to baseline, re-treatment with
Clolar can be considered with a 25% dose reduction.
Venous Occlusive Disease Of The Liver
Patients who have previously received a hematopoietic stem cell transplant (HSCT) are at higher risk for veno-occlusive disease (VOD)
of the liver 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 a combination study of clofarabine in pediatric
patients with relapsed or refractory acute leukemia. Two cases (2%) of VOD in
the mono-therapy studies were considered related to study drug. Monitor for and
discontinue Clolar if VOD is suspected.
Severe and fatal hepatotoxicity, including hepatitis and
hepatic failure, has occurred with the use of Clolar [see ADVERSE REACTIONS].
In clinical studies, Grade 3-4 liver enzyme elevations were observed in
pediatric patients during treatment with Clolar at the following rates:
elevated aspartate aminotransferase (AST) occurred in 36% of patients; elevated
alanine aminotransferase (ALT) occurred in 44% of patients. AST and ALT elevations
typically occurred within 10 days of Clolar administration and returned to
Grade 2 or less within 15 days. 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 and one patient had multi-organ failure
and died. Eight patients (7%) 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. Monitor hepatic function and for signs and symptoms of
hepatitis and hepatic failure. Discontinue Clolar immediately for Grade 3 or
greater liver enzyme and/or bilirubin elevations [see ADVERSE REACTIONS].
Clolar may cause acute renal failure. In Clolar treated
patients in clinical studies, Grade 3 or 4 elevated creatinine occurred in 8% of
patients and acute renal failure was reported as Grade 3 in three patients (3%)
and Grade 4 in two patients (2%). Patients with infection, sepsis, or tumor
lysis syndrome may be at increased risk of renal toxicity when treated with
Hematuria occurred in 13% of Clolar treated patients
overall. Monitor patients for renal toxicity and interrupt or discontinue Clolar
as necessary [see ADVERSE REACTIONS].
Fatal and serious cases of enterocolitis, including
neutropenic colitis, cecitis, and C. difficile colitis, have occurred during treatment
with clofarabine. This has occurred more frequently within 30 days of
treatment, and in the setting of combination chemotherapy. Enterocolitis may
lead to necrosis, perforation, hemorrhage or sepsis complications. Monitor
patients for signs and symptoms of enterocolitis and treat promptly [see
Serious and fatal cases of Stevens-Johnson syndrome (SJS)
and toxic epidermal necrolysis (TEN), have been reported. Discontinue
Clofarabine for exfoliative or bullous rash, or if SJS or TEN is suspected [see
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].
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Clofarabine has not been tested for carcinogenic
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.
Use In Specific Populations
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
postimplantation 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
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 breastfeeding during treatment with Clolar.
Safety and effectiveness have been established in
pediatric patients 1 to 21 years old with relapsed or refractory acute lymphoblastic
Safety and effectiveness of Clolar has not been
established in geriatric patients aged 65 and older.
Adults With Hematologic Malignancies
Safety and effectiveness have not been established in
Reduce the Clolar starting dose by 50% in patients with
CrCL of 30 to 60 mL/min. There is insufficient information to make a dosage
recommendation in patients with CrCL less than 30 mL/min or in patients on
The pharmacokinetics of clofarabine in patients with renal
impairment and normal renal function were obtained from a population
pharmacokinetic analysis of three pediatric and two adult studies. In patients
with CrCL 60 to less than 90 mL/min (N=47) and CrCL 30 to less than 60 mL/min
(N=30), the average AUC of clofarabine increased by 60% and 140%, respectively,
compared to patients with normal (N=66) renal function (CrCL greater than 90