Clolar

Clofarabine is a cancer medicine that interferes with the growth of cancer cells and slows their growth and spread in the body.

Clofarabine is used to treat acute lymphoblastic leukemia (a type of blood cancer) in children and young adults up to 21 years old.

Clofarabine is usually given after other cancer medicines have been tried without successful treatment.

Clofarabine may also be used for purposes not listed in this medication guide.

A rare but serious side effect of clofarabine is called capillary leak syndrome. Call your doctor right away if you have signs of this condition, which may include: stuffy or runny nose followed by weakness or tired feeling, and sudden swelling in your arms, legs and other parts of the body.

To make sure clofarabine is safe for you, tell your doctor if you have:

• liver disease; or
• kidney disease.

Do not use clofarabine if you are pregnant. It could harm the unborn baby.

Use birth control to prevent pregnancy while you are receiving clofarabine, whether you are a man or a woman. Clofarabine use by either parent may cause birth defects.

It is not known whether clofarabine passes into breast milk or if it could harm a nursing baby. You should not breast-feed while you are receiving clofarabine.

Clofarabine is injected into a vein through an IV. A healthcare provider will give you this injection.

Clofarabine is usually given daily for 5 days in a row during one or more treatment cycles. Your doctor will determine how many treatment cycles you will receive and how often.

You may receive other medications to help prevent certain side effects of clofarabine.

Clofarabine can lower blood cells that help your body fight infections and help your blood to clot. Your blood will need to be tested often. Your kidney or liver function may also need to be tested. Your cancer treatments may be delayed based on the results of these tests.

Since clofarabine is given by a healthcare professional in a medical setting, an overdose is unlikely to occur.

Call your doctor for instructions if you miss an appointment for your clofarabine injection.

Dosage Forms & Strengths

injectable solution

• 1mg/mL (20mg vial)

Refractory or Relapsed Acute Lymphoblastic Leukemia

<21 years: 52 mg/m² IV over 2 hr qDay for 5 consecutive days 

Treatment cycles repeated q2-6wk following recovery or return to baseline organ function

>21 years: Not indicated for this age group

Acute Myelogenous Leukemia (Orphan)

Orphan indication sponsor

• Genzyme Corporation; 4545 Horizon Hill Blvd; San Antonio, TX 78229-2263

Dosage Modifications

Discontinue if hypotension develops during 5 days of treatment

Hepatic impairment: Not studied

Renal impairment

• CrCl 30-60 mL/min: Decrease dose by 50%
• CrCl <30 mL/min: Insufficient data to make recommendation

Monitor

Respiratory status & BP during infusion

Renal & hepatic function during administration

Hematologic status

Dosage Forms & Strengths

injectable solution

• 1mg/mL (20mg vial)

Refractory or Relapsed Acute Lymphoblastic Leukemia

52 mg/m² IV over 2 hr daily for 5 consecutive days 

Treatment cycles repeated q2-6wk following recovery or return to baseline organ function

Dosage Modifications

Discontinue if hypotension develops during 5 days of treatment

Hepatic impairment: Not studied

Renal impairment

• CrCl 30-60 mL/min: Decrease dose by 50%
• CrCl <30 mL/min: Insufficient data to make recommendation

Monitor

Respiratory status & BP during infusion

Renal & hepatic function during administration

Hematologic status

Common side effects include the following:

• nausea
• vomiting
• diarrhea
• febrile neutropenia - a low white blood cell count accompanied by a fever
• headache
• rash
• itching
• fever
• fatigue
• reddening, swelling, numbness and sloughing of skin on the palms and soles of the feet
• anxiety
• flushing
• inflammation of the mucosal membranes (such as in the mouse, nose, and throat)

This is not a complete list of this medication’s side effects. Ask your doctor or pharmacist for more information.

Tell your doctor if you have any side effect that bothers you or that does not go away.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

No Clolar drug interactions have been identified. However, you should tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements. Not all drug interactions are known or reported and new drug interactions are continually being reported.

Tell your doctor if you are breastfeeding or plan to breastfeed.

It is not known if Clolar crosses into human milk. Because many medications can cross into human milk and because of the possibility for serious adverse reactions in nursing infants with use of this medication, a choice should be made whether to stop nursing or stop the use of this medication. It is advisable to avoid breastfeeding while taking Clolar.

Clofarabine is a cancer medicine that interferes with the growth and spread of cancer cells in the body.

Clofarabine is used to treat acute lymphoblastic leukemia (a type of blood cancer) in children and young adults up to 21 years old.

Clofarabine is usually given after other cancer medicines have been tried without successful treatment.

Clofarabine may also be used for purposes not listed in this medication guide.

Acute Lymphocytic Leukemia

Treatment of acute lymphocytic (lymphoblastic) leukemia (ALL) refractory to or relapsed after at least 2 prior therapies in patients 1–21 years of age.1 2 3 4 5 6 7 Designated an orphan drug by FDA for this use.2 3

Current indication based on induction of complete responses; randomized studies showing increased survival or other clinical benefits have not been conducted to date.1

• Advise patients about risk of dehydration secondary to vomiting and diarrhea.1

• Importance of advising patients regarding appropriate measures to avoid dehydration.1

• Advise patients to notify clinician immediately if symptoms of hypotension (e.g., dizziness, lightheadedness, fainting spell) or decreased urine output occurs.1

• Importance of monitoring blood cell counts, renal and hepatic function.1

• Necessity of advising women to use an effective method of contraception and to avoid breast-feeding while receiving clofarabine therapy.1

• Importance of women informing a clinician immediately if they are or plan to become pregnant or plan to breast-feed.1 Advise pregnant women of risk to the fetus.1

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

• Importance of informing patients of other important precautionary information.1 (See Cautions.)

In the U.S.

• Clolar

Available Dosage Forms:

• Solution

Therapeutic Class: Antineoplastic Agent

Pharmacologic Class: Antimetabolite

Chemical Class: Purine Nucleoside Analog

• It is used to treat a type of leukemia.

• Tell all of your health care providers that you take Clolar. This includes your doctors, nurses, pharmacists, and dentists.
• You may have more of a chance of getting an infection. Wash hands often. Stay away from people with infections, colds, or flu. Some infections have been very bad and even deadly.
• You may bleed more easily. Be careful and avoid injury. Use a soft toothbrush and an electric razor.
• Very bad and sometimes deadly bleeding problems have happened with this medicine. Talk with the doctor.
• Patients with cancer who take Clolar may be at a greater risk of getting a bad health problem called tumor lysis syndrome (TLS). Sometimes, this has been deadly. Call your doctor right away if you have a fast heartbeat or a heartbeat that does not feel normal; any passing out; trouble passing urine; muscle weakness or cramps; upset stomach, throwing up, loose stools, or not able to eat; or feel sluggish.
• Very bad and sometimes deadly liver problems have happened with this medicine. Call your doctor right away if you have signs of liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes.
• Very bad and sometimes deadly bowel problems have happened with Clolar. Most of the time, this happened within 30 days of treatment and when more than one chemo drug was used. Talk with the doctor.
• This medicine may cause the release of proteins called cytokines. This may lead to some other health problems and organ problems. Sometimes, these may be deadly. Call your doctor right away if you have a fever, fast heartbeat, fast breathing, shortness of breath, very bad dizziness, or passing out.
• If you have upset stomach, throwing up, loose stools (diarrhea), or are not hungry, talk with your doctor. There may be ways to lower these side effects.
• Have blood work checked as you have been told by the doctor. Talk with the doctor.
• You will need to have heart function tests while taking this medicine. Talk with the doctor.
• If you are a man and have sex with a female who could get pregnant, protect her from pregnancy. Use birth control that you can trust.
• If you are a man and your sex partner is pregnant or gets pregnant at any time while you are being treated, talk with your doctor.
• This medicine may cause harm to the unborn baby if you take it while you are pregnant.
• Use birth control that you can trust to prevent pregnancy while taking Clolar.
• If you are pregnant or you get pregnant while taking this medicine, call your doctor right away.

Use Clolar as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• It is given as an infusion into a vein over a period of time.
• Other drugs may be given before this medicine to help avoid side effects.
• Talk with your doctor before getting any vaccines. Use with Clolar (clofarabine) may either raise the chance of an infection or make the vaccine not work as well.

What do I do if I miss a dose?

• Call your doctor to find out what to do.

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 (2.3)].

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)].

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.

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 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 multi-organ 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. 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.

Hepatotoxicity

Severe and fatal hepatotoxicity, including hepatitis and hepatic failure, has occurred with the use of Clolar [see Adverse Reactions (6.2)]. 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 (6.1)].

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 Adverse Reactions (6.1)].

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 [see Adverse Reactions (6.2)].

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)].

Embryo-fetal Toxicity

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 (8.1)].

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)]

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).

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 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.

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 Clolar administration at 52 mg/m2 among pediatric patients with ALL and AML (N=115).

Postmarketing 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.

• 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).

Pregnancy

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 post-implantation 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 pregnancy.

Nursing Mothers

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.

Pediatric Use

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

Geriatric Use

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 adults.

Renal Impairment

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).

Common side effects of Clolar include: febrile neutropenia, herpes simplex infection, infection, oral candidiasis, pericardial effusion, pleural effusion, pneumonia, respiratory distress, sepsis, staphylococcal infection, abdominal pain, anxiety, arthralgia, back pain, cellulitis, confusion, constipation, cough, depression, dermatitis, diarrhea, dizziness, drowsiness, dyspnea, edema, epistaxis, erythrodysesthesia syndrome, fatigue, fever, gingival hemorrhage, headache, hematuria, hepatomegaly, hypertension, hypotension, jaundice, lethargy, limb pain, mucositis, myalgia, nausea, neutropenia, pain, petechia, pruritus, rigors, sore throat, tachycardia, transfusion reaction, tremor, vomiting, weight loss, anorexia, bacteremia, decreased appetite, erythema, flushing, irritability, pain at injection site, and xeroderma. Other side effects include: increased serum creatinine. See below for a comprehensive list of adverse effects.