CLOLAR Solution for injection Ref.[10776] Active ingredients: Clofarabine

5.1 Myelosuppression

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 dose-dependent. Monitor complete blood counts [see Dosage and Administration (2.4)].

5.2 Hemorrhage

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 (6.2)].

5.3 Infections

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.

5.4 Tumor Lysis Syndrome

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.

5.5 Systemic Inflammatory Response Syndrome (SIRS) and Capillary Leak Syndrome

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 multiorgan failure. Close monitoring for this syndrome and early intervention may reduce the risk. 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 syndrome. Consider use of diuretics and/or albumin. After the patient is stabilized and organ function has returned to baseline, retreatment with Clolar can be considered with a 25% dose reduction.

5.6 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 monotherapy studies were considered related to study drug. Monitor for and discontinue Clolar if VOD is suspected.

5.7 Hepatotoxicity

Severe and fatal hepatotoxicity, including hepatitis and hepatic failure, has occurred with the use of Clolar. 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 multiorgan 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 multiorgan 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 Dosage and Administration (2.4)].

5.8 Renal Toxicity

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 Clolar. Hematuria occurred in 13% of Clolar treated patients overall. Monitor patients for renal toxicity and interrupt or discontinue Clolar as necessary [see Dosage and Administration (2.4)].

5.9 Enterocolitis

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.

5.10 Skin Reactions

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 Adverse Reactions (6.2)].

5.11 Embryo-Fetal Toxicity

Based on findings from animal reproductive studies and the drug’s mechanism of action, Clolar can cause fetal harm when administered to a pregnant woman. Intravenous doses of clofarabine in rats and rabbits administered during organogenesis at doses that were below the maximum recommended human dose of 52 mg/m² based on body surface area (mg/m²) caused an increase in resorptions, malformations, and variations. Advise females of reproductive potential of the potential risk to a fetus and to use an effective method of contraception during treatment with Clolar and for at least 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with Clolar and for at least 3 months after the last dose [see Use in Specific Populations (8.1)].

The following clinically significant adverse reactions are discussed in greater detail in other sections of the label:

• Myelosuppression [see Warnings and Precautions (5.1)]
• Hemorrhage [see Warnings and Precautions (5.2)]
• Serious Infections [see Warnings and Precautions (5.3)]
• Hyperuricemia (tumor lysis syndrome) [see Warnings and Precautions (5.4)]
• Systemic Inflammatory Response Syndrome (SIRS) and Capillary Leak Syndrome [see Warnings and Precautions (5.5)]
• Venous Occlusive Disease of the Liver [see Warnings and Precautions (5.6)]
• Hepatotoxicity [see Warnings and Precautions (5.7)]
• Renal Toxicity [see Warnings and Precautions (5.8)]
• Enterocolitis [see Warnings and Precautions (5.9)]
• Skin Reactions [see Warnings and Precautions (5.10)]

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.

Most common adverse reactions (≥25%): vomiting, nausea, diarrhea, febrile neutropenia, pruritus, headache, bacteremia, pyrexia, rash, tachycardia, abdominal pain, chills, fatigue, anorexia, pain in extremity, hypotension, epistaxis, and petechiae.

Table 1 lists adverse reactions by System Organ Class, including severe or life-threatening (NCI CTCAE 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):

The following adverse reactions were reported in <5% 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:

The following adverse reactions have been identified during postapproval 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.

Gastrointestinal disorders: gastrointestinal hemorrhage including fatalities

Metabolism and nutrition disorders: hyponatremia

Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) (including fatal cases)

Risk Summary

In animal reproduction studies, intravenous administration of clofarabine to pregnant rats and rabbits during organogenesis at doses approximately 0.2 to 1-times the maximum recommended human dose of 52 mg/m² based on body surface area (BSA) resulted in embryo-fetal mortality, alterations to growth, and structural abnormalities (see Data). Advise pregnant women of the potential risk to a fetus. There are no available data on Clolar use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Clofarabine should be used during pregnancy only if the potential benefits to the mother outweigh the potential risks, including those to the fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal data

Intravenous administration of clofarabine to pregnant rats during organogenesis (gestation days [GD] 7–17) at doses of 1, 3 or 9 mg/kg/day (equivalent to 6, 18, 54 mg/m²/day) resulted in maternal toxicities at the 9 mg/kg dose, as indicated by reduced body weights and food consumption. Developmental toxicity (i.e., reduced fetal body weights and increased postimplantation loss) and increased incidences of external, soft tissue, and skeletal malformations and variations (including retarded ossification) were observed at 9 mg/kg/day (54 mg/m²; approximately equivalent to the recommended human dose based on BSA). Altered ossification patterns (extra metacarpal or metatarsal ossification) were observed in single fetuses at lower doses of clofarabine (1 and 3 mg/kg/day; 0.1- and 0.3-times the recommended human dose based on BSA).

When clofarabine was administered intravenously to pregnant rabbits during organogenesis (GD 6–18) at doses of 0.1, 0.3, or 1 mg/kg/day (equivalent to 1.2, 3.6, 12 mg/m²/day), developmental toxicity (i.e., reduced fetal body weights and increased postimplantation loss) and increased incidences of external, soft tissue, and skeletal malformations and variations (including retarded ossification) were observed at the 1 mg/kg/day dose (12 mg/m²; 0.2-times the recommended human dose based on BSA). Alterations in ossification patterns (increase in the average numbers of ossified thoracic vertebrae and rib pairs, and reduction in the average number of forepaw metacarpals) and abdominal wall defect were observed at 0.3 mg/kg/day (3.6 mg/m²; 0.1-times the recommended human dose based on BSA).

Risk Summary

There are no data on the presence of clofarabine in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in the breastfed child including genotoxicity, advise patients not to breastfeed during treatment with Clolar, and for at least 2 weeks after the last dose.

Pregnancy Testing

Pregnancy testing is recommended for females of reproductive potential prior to initiating Clolar.

Contraception

Females

Clolar can cause embryo-fetal harm when administered to pregnant women [see Use in Specific Populations (8.1)]. Advise female patients to use effective contraception during treatment with Clolar and for 6 months after the last dose.

Males

Based on genotoxicity findings, advise males with female partners of reproductive potential to use effective contraception during treatment with Clolar and for at least 3 months after the last dose [see Nonclinical Toxicology (13.1)].

Infertility

Females

Based on findings from animal studies, Clolar may impair female fertility [see Nonclinical Toxicology (13.1)]. The reversibility of the effect on fertility is unknown.

Males

Based on findings from animal studies, Clolar may impair male fertility [see Nonclinical Toxicology (13.1)]. The reversibility of the effect on fertility is unknown.

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

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

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 dialysis.

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 mL/min).

8.6 Adults with Hematologic Malignancies

Safety and effectiveness have not been established in adults.