CLOFARABINE: 1,419 Adverse Event Reports & Safety Profile

Clofarabine Injection contains clofarabine, a purine nucleoside metabolic inhibitor. The chemical name of clofarabine is 2-chloro-9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-9H-purin-6-amine. Its molecular formula is C 10 H 11 ClFN 5 O 3 with a molecular weight of

303.68 Daltons. The molecular structure of clofarabine is: Clofarabine Injection (1 mg per mL) is supplied in a 20 mL single-dose vial.

The

20 mL vial contains 20 mg clofarabine formulated in 20 mL unbuffered normal saline (comprised of Water for Injection, USP and Sodium Chloride, USP). The pH range of the solution is 4.5 to 7.5. The solution is sterile, clear and practically colorless, and is preservative-free.

Molecular

Structure of Clofarabine

AND USAGE Clofarabine Injection is indicated for the treatment of pediatric patients 1 to 21 years old with relapsed or refractory acute lymphoblastic leukemia after at least two prior regimens. This indication is based upon response rate. There are no trials verifying an improvement in disease-related symptoms or increased survival with Clofarabine Injection. Clofarabine injection is a nucleoside metabolic inhibitor indicated for the treatment of pediatric patients 1 to 21 years old with relapsed or refractory acute lymphoblastic leukemia after at least two prior regimens. This indication is based upon response rate. There are no trials verifying an improvement in disease-related symptoms or increased survival with Clofarabine Injection. ( 1 )

AND ADMINISTRATION

• Administer the recommended pediatric dose of 52 mg/m 2 as an intravenous infusion over 2 hours daily for 5 consecutive days of a 28-day cycle. Repeat cycles every 2 to 6 weeks. ( 2.1 )
• Provide supportive care, such as intravenous infusion fluids, antihyperuricemic treatment, and alkalinization of urine throughout the 5 days of clofarabine injection administration to reduce the risk of tumor lysis and other adverse reactions. ( 2.1 )
• Discontinue clofarabine injection if hypotension develops during the 5 days of administration. ( 2.1 )
• Reduce the dose in patients with renal impairment. ( 2.2 )
• Use dose modification for toxicity. ( 2.4 )

2.1 Recommended Dosage Administer the recommended pediatric dose of 52 mg/m 2 as an intravenous infusion over 2 hours daily for 5 consecutive days.

• Repeat treatment cycles following recovery or return to baseline organ function, approximately every 2 to 6 weeks. Base dosage on the patient’s body surface area (BSA), calculated using the actual height and weight before the start of each cycle. To prevent drug incompatibilities, do not administer other medications through the same intravenous line. Administer subsequent cycles no sooner than 14 days from the starting day of the previous cycle and provided the patient’s ANC is ≥0.75 × 10 9 /L.
• Provide supportive care, such as intravenous fluids, antihyperuricemic treatment, and alkalinize urine throughout the 5 days of clofarabine injection administration to reduce the effects of tumor lysis and other adverse reactions.
• Discontinue clofarabine injection if hypotension develops during the 5 days of administration.
• Monitor renal and hepatic function during the 5 days of clofarabine injection administration [see Warnings and Precautions (5.7 , 5.8) ] .
• Monitor patients taking medications known to affect blood pressure. Monitor cardiac function during administration of clofarabine injection.

2.2 Recommended Dosage Reduction for Renal Impairment

• Reduce the dose by 50% in patients with creatinine clearance (CrCL) between 30 and 60 mL/min. There is insufficient information to make a dosage recommendation in patients with CrCL less than 30 mL/min [see Use in Specific Populations (8.6) ] .

2.3 Potential Concomitant Medications and Medications to Avoid

• Consider prophylactic antiemetic medications as clofarabine injection is moderately emetogenic.
• Consider the use of prophylactic steroids to mitigate Systemic Inflammatory Response Syndrome (SIRS) or capillary leak syndrome (e.g., hypotension, tachycardia, tachypnea, and pulmonary edema).
• Minimize exposure to drugs with known renal toxicity during the 5 days of clofarabine injection administration since the risk of renal toxicity may be increased.
• Avoid concomitant use of medications known to induce hepatic toxicity.

2.4 Dose Modifications and Reinitiation of Therapy after Adverse Reactions Hematologic Toxicity

• If a patient experiences a Grade 4 neutropenia (ANC <0.5 × 10 9 /L) lasting ≥4 weeks, reduce dose by 25% for the next cycle. Non-hematologic Toxicity
• Withhold clofarabine injection if a patient develops a clinically significant infection, until the infection is controlled, then restart at the full dose.
• Withhold clofarabine injection for a Grade 3 non-infectious non-hematologic toxicity (excluding transient elevations in serum transaminases and/or serum bilirubin and/or nausea/vomiting controlled by antiemetic therapy). Re-institute clofarabine injection administration at a 25% dose reduction when resolution or return to baseline.
• Discontinue clofarabine injection administration for a Grade 4 non-infectious non-hematologic toxicity.
• Discontinue clofarabine injection administration if a patient shows early signs or symptoms of SIRS or capillary leak syndrome (e.g., hypotension, tachycardia, tachypnea, and pulmonary edema) occur and provide appropriate supportive measures.
• Discontinue clofarabine injection administration if Grade 3 or higher increases in creatinine or bilirubin are noted. Re-institute clofarabine injection with a 25% dose reduction, when the patient is stable and organ function has returned to baseline. If hyperuricemia is anticipated (tumor lysis), initiate measures to control uric acid.

2.5 Reconstitution/Preparation Filter Clofarabine Injection through a sterile 0.2 micron syringe filter and then dilute with 5% Dextrose Injection, USP, or 0.9% Sodium Chloride Injection, USP, prior to intravenous infusion to a final concentration between 0.15 mg/mL and 0.4 mg/mL. Use within 24 hours of preparation. Parenteral drug products should be visually inspected for particulate matter and discoloration prior to administration, whenever solution and container permit. Store diluted clofarabine injection at room temperature (15°C to 30°C). Discard unused portion in vial.

None.

• None. ( 4 )

REACTIONS The following 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) [ 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) ] 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. (6) To report SUSPECTED ADVERSE REACTIONS, contact Fosun Pharma USA Inc. at 1-866-611-3762 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 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 Clofarabine Injection 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 Clofarabine Injection 52 mg/m2 daily × 5. The median number of cycles was 2. The median cumulative amount of Clofarabine Injection 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 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)

System Organ

Class¹ Preferred Term¹ ALL/AM (N=115) Worst NCI Common Terminology Criteria Grade¹ 3 4 5 N % N % N % N % Blood and Lymphatic System Disorders Febrile neutropenia 63 55 59 51 3 3 Neutropenia 11 10 3 3 8 7 . .

Cardiac Disorders

Pericardial effusion 9 8 . . 1 1 . .

Tachycardia

40 35 6 5 . . . .

Gastrointestinal Disorders

Abdominal pain 40 35 8 7 . . . . Abdominal pain upper 9 8 1 1 . . . .

Diarrhea

64 56 14 12 . . . . Gingival or mouth bleeding 20 17 8 7 1 1 . .

Nausea

84 73 16 14 1 1 . . Oral mucosal petechiae 6 5 4 4 . . . .

Proctalgia

9 8 2 2 . . . .

Stomatitis

8 7 1 1 . . . .

Vomiting

90 78 9 8 1 1 . .

General

Disorders and Administration Site Conditions Asthenia 12 10 1 1 1 1 . .

Chills

39 34 3 3 . . . .

Fatigue

39 34 3 3 2 2 . .

Irritability

11 10 1 1 . . . . Mucosal inflammation 18 16 2 2 . . . .

Edema

14 12 2 2 . . . .

Pain

17 15 7 6 1 1 . .

Pyrexia

45 39 16 14 . . . .

Hepatobiliary Disorder Jaundice

9 8 2 2 . . . . Infections and Infestations Bacteremia 10 9 10 9 . . . .

Candidiasis

8 7 1 1 . . . . Catheter related infection 14 12 13 11 . . . .

Cellulitis

9 8 7 6 . . . . Clostridium colitis 8 7 6 5 . . . . Herpes simplex 11 10 6 5 . . . . Herpes zoster 8 7 6 5 . . . . Oral candidiasis 13 11 2 2 . . . .

Pneumonia

11 10 6 5 1 1 1 1 ¹ Patients 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.

Table

1: Most Commonly Reported (≥5% Overall)

Adverse

Reactions by System Organ Class (N=115 pooled analysis) (Continued)

System Organ

Class¹ Preferred Term¹ ALL/AML (N=115) Worst NCI Common Terminology Criteria Grade¹ 3 4 5 N % N % N % N % Infections and Infestations (continued) Sepsis, including septic shock 19 17 6 5 4 4 9 8 Staphylococcal bacteremia 7 6 5 4 1 1 . . Staphylococcal sepsis 6 5 5 4 1 1 . . Upper respiratory tract infection 6 5 1 1 . . . . Metabolism and Nutrition Disorders Anorexia 34 30 6 5 8 7 . . Musculoskeletal and Connective Tissue Disorders Arthralgia 10 9 3 3 . . . . Back pain 12 10 3 3 . . . . Bone pain 11 10 3 3 . . . .

Myalgia

16 14 . . . . . . Pain in extremity 34 30 6 5 . . . .

Neoplasms

Benign, Malignant and Unspecified (incl. cysts and polyps) Tumor lysis syndrome 7 6 7 6 . . . .

Nervous System Disorders Headache

49 43 6 5 . . . .

Lethargy

12 10 1 1 . . . .

Somnolence

11 10 1 1 . . . .

Psychiatric Disorders Agitation

6 5 1 1 . . . .

Anxiety

24 21 2 2 . . . . Renal and Urinary Disorders Hematuria 15 13 2 2 . . . . Respiratory, Thoracic and Mediastinal Disorders Dyspnea 15 13 6 5 2 2 . .

Epistaxis

31 27 15 13 . . . . Pleural effusion 14 12 4 4 2 2 . . Respiratory distress 12 10 5 4 4 4 1 1 Tachypnea 10 9 4 4 1 1 . . Skin and Subcutaneous Tissue Disorders Erythema 13 11 . . . . . . Palmar-plantar erythrodysesthesia syndrome 18 16 8 7 . . . .

Petechiae

30 26 7 6 . . . .

Pruritus

49 43 1 1 . . . .

Rash

44 38 8 7 . . . . Rash pruritic 9 8 . . . . . .

Vascular Disorders Flushing

22 19 . . . . . .

Hypertension

15 13 6 5 . . . .

Hypotension

33 29 13 11 9 8 . . ¹ Patients 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, 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 Clofarabine Injection administration at 52 mg/m2 among pediatric patients with ALL and AML (N=115).

Table

2: Incidence of Treatment-Emergent Laboratory Abnormalities after Clofarabine Injection Administration Parameter Any Grade Grade 3 or higher Anemia (N=114) 83% 75% Leukopenia (N=114) 88% 88% Lymphopenia (N=113) 82% 82% Neutropenia (N=113) 64% 64% Thrombocytopenia (N=114) 81% 80% Elevated Creatinine (N=115) 50% 8% Elevated SGOT (N=100) 74% 36% Elevated SGPT (N=113) 81% 43% Elevated Total Bilirubin (N=114) 45% 13%

6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of Clofarabine Injection. 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 Clofarabine Injection. 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).

AND PRECAUTIONS Myelosuppression: May be severe and prolonged. Monitor complete blood counts and platelet counts during Clofarabine Injection therapy. ( 5.1 ) Hemorrhage: Serious and fatal cerebral, gastrointestinal and pulmonary hemorrhage. Monitor platelets and coagulation parameters and treat accordingly. ( 5.2 ) Infections: Severe and fatal sepsis as a result of bone marrow suppression. Monitor for signs and symptoms of infection; discontinue Clofarabine Injection and treat promptly. ( 5.3 )

Tumor

Lysis syndrome: Anticipate, monitor for signs and symptoms and treat promptly. ( 5.4 )

Systemic Inflammatory Response

Syndrome (SIRS) or Capillary Leak Syndrome: Monitor for and discontinue Clofarabine Injection immediately if suspected. ( 5.5 )

Venous Occlusive

Disease of the Liver: Monitor for and discontinue Clofarabine Injection if suspected. ( 5.6 ) Hepatotoxicity: Severe and fatal hepatotoxicity. Monitor liver function, for signs and symptoms of hepatitis and hepatic failure.

Discontinue Clofarabine

Injection immediately for Grade 3 or greater liver enzyme and/or bilirubin elevations. ( 5.7 )

Renal

Toxicity: Increased creatinine and acute renal failure; monitor renal function and interrupt or discontinue Clofarabine Injection. ( 5.8 ) Enterocolitis: Serious and fatal enterocolitis, occurring more frequently within 30 days of treatment and with combination chemotherapy. Monitor patients for signs and symptoms of enterocolitis and treat promptly. ( 5.9 )

Skin

Reactions: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), including fatal cases. Discontinue for exfoliative or bullous rash, or if SJS or TEN is suspected. ( 5.10 ) Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential and males with female partners of reproductive potential of the potential risk to a fetus and to use effective contraception. ( 5.11 )

5.1 Myelosuppression Clofarabine Injection 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 Clofarabine Injection treatment and appears to be dose-dependent. Monitor complete blood counts <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.4 )]</span>.

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 Clofarabine Injection 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 Clofarabine Injection treatment, including fungal, viral and bacterial infections. Monitor patients for signs and symptoms of infection, discontinue Clofarabine Injection, and treat promptly.

5.4 Tumor Lysis Syndrome Administration of Clofarabine Injection 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 Clofarabine Injection 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 Clofarabine Injection and provide appropriate supportive measures. The use of prophylactic steroids (e.g., 100 mg/m 2 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 Clofarabine Injection 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/m 2 ) when used in combination with etoposide (100 mg/m 2 ) and cyclophosphamide (440 mg/m 2 ). 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 Clofarabine Injection if VOD is suspected.

5.7 Hepatotoxicity Severe and fatal hepatotoxicity, including hepatitis and hepatic failure, has occurred with the use of Clofarabine Injection. In clinical studies, Grade 3 to 4 liver enzyme elevations were observed in pediatric patients during treatment with Clofarabine Injection 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 Clofarabine Injection 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 Clofarabine

Injection immediately for Grade 3 or greater liver enzyme and/or bilirubin elevations [see Dosage and Administration ( 2.4 )] .

5.8 Renal Toxicity Clofarabine Injection may cause acute renal failure.

In Clofarabine

Injection 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 Clofarabine Injection. Hematuria occurred in 13% of Clofarabine Injection treated patients overall. Monitor patients for renal toxicity and interrupt or discontinue Clofarabine Injection 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 <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.2 )]</span>.

5.11 Embryo-Fetal Toxicity Based on findings from animal reproductive studies and the drug&apos;s mechanism of action, Clofarabine Injection 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/m 2 based on body surface area (mg/m 2 ) 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 Clofarabine Injection and for 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with Clofarabine Injection and for 3 months after the last dose <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.1 )]</span>.