cladribine

Cladribine is an anticancer (antineoplastic) and immunosuppressive medication used in the treatment of adults with hairy cell leukemia, a type of blood cancer, and relapsing forms of multiple sclerosis, an autoimmune disorder. Cladribine intravenous solution is infused to treat hairy cell leukemia while the oral tablet formulation is used in the treatment of multiple sclerosis. Cladribine belongs to the antimetabolite class of antineoplastic drugs, which prevent the growth of cancer cells by preventing DNA synthesis and repair.

Hairy cell leukemia is a blood cancer in which lymphocytes, T-cells and B-cells that form part of the immune system, grow and multiply out of control. In multiple sclerosis, the lymphocytes mistakenly attack and damage the protective sheath (myelin) around nerve fibers, affecting communication between nerve cells (neurons), and causing symptoms that include pain, fatigue, vision loss and other neuromuscular problems.

Cladribine is a prodrug that enters into the cell and is converted to its active form that gets incorporated into the DNA, causing breakage of DNA strands, and blocking DNA synthesis and repair. This prevents DNA replication, growth and proliferation of cells, and results in death of lymphocytes and monocytes, another type of white blood cell. Unlike other antimetabolite chemotherapy drugs, cladribine is toxic to both actively dividing and quiescent lymphocytes and monocytes.

Cladribine works selectively on lymphocytes, because lymphocytes have less of deoxynucleotidase enzyme that can break down cladribine, and more of deoxycytidine kinase which converts cladribine to its toxic metabolite that kills lymphocytes. Depletion of lymphocytes limits cancer cell growth and division and also their autoimmune activity.

Uses of cladribine include:

FDA-approved:

• Intravenous infusion: Treatment of active hairy cell leukemia as defined by clinically significant anemia, neutropenia, thrombocytopenia, or disease-related symptoms
• Oral tablet: Treatment of relapsing forms of multiple sclerosis (MS), including relapsing-remitting (RRMS) and active secondary progressive disease in adults who have had inadequate response or are intolerant to other therapies for multiple sclerosis

Off-label uses:

• Cutaneous T-cell lymphoma
• Acute myeloid leukemia (AML)
• Chronic lymphocytic leukemia (CLL)
• Non-Hodgkin lymphoma (NHL)
• Autoimmune hemolytic anemia
• Mycosis fungoides
• Sezary syndrome
• Mantle cell lymphoma
• T-cell large granular lymphocytic leukemia (refractory)
• Waldenstrom macroglobulinemia

Orphan Designations

• Non-Hodgkin Lymphoma
• Acute Myeloid Leukemia
• Chronic Lymphocytic Leukemia

• Do not use IV or oral cladribine in patients with a history of hypersensitivity to cladribine or any component of the formulations.
• Do not use cladribine in patients with the following conditions:
  • Current malignancy
  • Human immunodeficiency virus (HIV) infection
  • Active chronic infections including hepatitis or tuberculosis
• Cladribine can cause fetal harm.
  • Screen women of pregnancy potential, apprise them of the potential hazards to the fetus and do not use in pregnant women.
  • Advise women and men of reproductive potential to use highly effective contraception for the recommended period.
  • Discontinue treatment in women who become pregnant during treatment.
• Advise nursing mothers to stop breastfeeding during and for 10 days after treatment.

Precautions pertaining to intravenous cladribine:

• Cladribine IV injection should be administered under the supervision of a qualified physician experienced in the use of antineoplastic therapy.
• Cladribine IV can be neurotoxic at high doses.
• Cladribine IV can cause bone marrow suppression that can result in severe anemia, neutropenia and thrombocytopenia. Monitor the patient’s blood counts periodically for early detection of potential infection or bleeding.
• Monitor kidney and liver function, especially in patients with pre-existing impairment. High doses can be toxic to the kidneys, especially if administered concurrently with other nephrotoxic drugs.
• Administer allopurinol and IV hydration to patients with high tumor burden to prevent tumor lysis syndrome.
• Do not administer live attenuated vaccines during treatment due to the risk for infections.
• Cladribine may impair fertility.
• Cladribine may cause serious respiratory infections, pneumonia and viral skin infections, including fatal infections (sepsis).
• Cladribine IV formulation contains benzyl alcohol which has been known to cause ‘gasping syndrome,’ a fatal complication in premature babies.

Precautions pertaining to oral cladribine:

• Oral cladribine increases the risk for malignant cancers including malignant melanoma, ovarian cancer and pancreatic adenocarcinoma.
  • In patients with a history of malignancy or prior malignancy, consider benefits and risks before initiating cladribine.
  • Follow standard cancer screening guidelines in patients treated with cladribine.
  • Avoid administration of additional treatment within 2 years after completion of 2 treatment courses.
• Cladribine can cause lymphopenia, and mild to moderate decrease in other blood cells and hemoglobin. Monitor the patient’s complete blood count before, during and following treatment.
• Oral cladribine can increase the risk for fungal, viral and bacterial infections:
  • Screen patients and exclude active tuberculosis (TB) and active hepatitis before initiating treatment, and delay treatment until the infection is controlled.
  • Cladribine may activate latent TB. Monitor for TB prior to the first and second treatment course and treat if infection is present, before initiating cladribine.
  • Cladribine may activate latent hepatitis B or C infection. Screen carriers of hepatitis B or C prior to the first and second treatment course and treat if infection is present, before initiating cladribine.
  • Vaccinate patients who are antibody-negative for varicella zoster virus before initiating cladribine.
  • Administer any live attenuated vaccine at least 4 to 6 weeks before starting cladribine. Avoid administration of live attenuated vaccines during and after treatment until the patient’s white cell counts return to normal.
  • Avoid initiating cladribine in patients receiving immunosuppressive treatment.
  • There have been reports of progressive multifocal leukoencephalopathy (PML) caused by JC virus, which can result in severe disability or death, in patients treated with IV cladribine. PML is an opportunistic viral infection that affects the brain and typically occurs in immunocompromised patients. Monitor patients for neurological symptoms and, withhold oral cladribine and evaluate patients at the first signs of PML.
• In patients who require blood transfusions, use irradiated blood cell components to minimize risk of transfusion-related graft-versus host disease, in consultation with a hematologist.
• Cladribine may cause liver injury. Monitor patients for signs and symptoms, evaluate with the necessary tests, and if liver injury occurs, interrupt or discontinue cladribine permanently, as appropriate.
• Discontinue cladribine if the patient develops hypersensitivity reactions.
• Cladribine has been associated with myocarditis and life-threatening acute cardiac failure during clinical trials, which were resolved in a week. Advise patients to report symptoms of heart failure.

Intravenous:

Common side effects of IV cladribine include:

• Fever (pyrexia)
• Fatigue
• Weakness (asthenia)
• Feeling ill (malaise)
• Administration site reactions including:
  • Redness
  • Pain
  • Hemorrhage
  • Cellulitis
  • Swelling (edema)
• Nausea
• Vomiting
• Diarrhea
• Constipation
• Abdominal pain
• Gas (flatulence)
• Reduced appetite
• Bone marrow depression including:
  • Severely low count of neutrophil immune cells (neutropenia)
  • Neutropenia with fever (febrile neutropenia)
  • Severely low red blood cell count (anemia)
  • Low platelet count (thrombocytopenia)
• Reduced count of white cells that fight infection (CD4 lymphocytes)
• Bacterial infections
• Viral infection
• Fungal infection
• Herpes zoster infection
• Localized infection
• Bacteria in blood (bacteremia)
• Blood poisoning from infection (septicemia)
• Skin reactions including:
  • Rash
  • Redness of skin (erythema)
  • Excessive sweating (hyperhidrosis)
  • Itching (pruritus)
  • Bruising and skin discoloration (ecchymosis)
  • Red or purple spots from bleeding beneath the skin (petechiae)
• Back pain
• Chest pain
• Limb pain
• Muscle pain (myalgia)
• Joint pain (arthralgia)
• Chills
• Muscle weakness (myasthenia)
• Headache
• Dizziness
• Insomnia
• Anxiety
• Cough
• Shortness of breath
• Abnormal breathing sounds
• Crackling sound in lungs (rales)
• Rapid heart rate (tachycardia)
• Vein inflammation (phlebitis)
• Swelling from fluid retention (edema)
• Swelling of extremities (peripheral edema)

Less common side effects of IV cladribine include:

• Opportunistic infections
• Septic shock
• Anemia due to lack of red cell production (aplastic anemia)
• Anemia due to premature destruction of red cells (hemolytic anemia)
• Low count of all types of blood cells (pancytopenia)
• Myelodysplastic syndrome, a type of blood cancer (rare)
• Hypersensitivity reaction
• Tumor lysis syndrome, a condition in which large number of tumor cells die and release their contents into the bloodstream
• Impairment of kidney function
• Kidney failure
• Elevated levels of liver enzymes
• Elevated bilirubin
• Respiratory tract infection
• Pneumonia
• Lung inflammation (pneumonitis)
• Scarring of lung tissue (pulmonary fibrosis)
• Interstitial lung disease
• Confusion
• Depressed level of consciousness
• Severe neurotoxicity (rare) including:
  • Sensory nerve disease (neuropathy)
  • Motor neuropathy including paralysis
• Progressive multifocal leukoencephalopathy (PML), a rare viral brain infection
• Eye membrane inflammation (conjunctivitis)
• Severe skin reactions including:
  • Hives (urticaria)
  • Viral skin infection
  • High levels of eosinophil immune cells (hypereosinophilia)
  • Stevens-Johnson syndrome
  • Toxic epidermal necrolysis

Oral:

Common side effects of oral cladribine include:

• Upper respiratory tract infection
• Headache
• Low levels of lymphocytes (lymphopenia)
• Neutropenia
• Thrombocytopenia
• Decrease in hemoglobin
• Nausea
• Back pain
• Joint pain (arthralgia)
• Joint inflammation (arthritis)
• Insomnia
• Bronchial inflammation (bronchitis)
• High blood pressure (hypertension)
• Fever
• Depression
• Hypersensitivity reactions
• Hair loss (alopecia)
• Neutropenia
• Myelodysplastic syndrome
• Oral herpes simplex infection
• Herpes zoster infection
• Herpes brain infection (herpes meningoencephalitis)
• Seizures
• Stevens-Johnson syndrome
• Toxic epidermal necrolysis

Less common side effects of oral cladribine include:

• Heart muscle inflammation (myocarditis)
• Heart failure
• Liver injury
• Tuberculosis
• Skin rash
• Kidney inflammation from bacterial infection (pyelonephritis)
• Fungal infections including coccidioidomycosis
• Cancers including:
  • Malignant melanoma
  • Ovarian cancer
  • Pancreatic adenocarcinoma

Call your doctor immediately if you experience any of the following symptoms or serious side effects while using this drug:

• Serious heart symptoms include fast or pounding heartbeats, fluttering in your chest, shortness of breath, and sudden dizziness;
• Severe headache, confusion, slurred speech, severe weakness, vomiting, loss of coordination, feeling unsteady;
• Severe nervous system reaction with very stiff muscles, high fever, sweating, confusion, fast or uneven heartbeats, tremors, and feeling like you might pass out; or
• Serious eye symptoms include blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights.

This is not a complete list of all side effects or adverse reactions that may occur from the use of this drug. Call your doctor for medical advice about serious side effects or adverse reactions. You may also report side effects or health problems to the FDA at 1-800-FDA-1088.

Injectable solution (generic formulation)

• 1 mg/mL (10 mL single-use vial)

Tablets

• 10 mg (Mavenclad)

Adult:

Hairy Cell Leukemia

• Cladribine (parenteral only)
• 0.09 mg/kg/day intravenous (IV) continuous infusion for 7 days  

Dosing considerations

• Monitor CBC with differential
• Monitor for signs/symptoms of neurotoxicity and infection; if infection present, treat as appropriate prior to therapy; if not possible, consider alternative therapy if possible

Relapsing Forms of Multiple Sclerosis

Mavenclad only

• Include relapsing-remitting disease and active secondary progressive disease
• Use is generally recommended for patients with inadequate response to, or unable to tolerate, alternate indicated drug
• 2 yearly treatment courses: 1.75 mg/kg/course orally; each course divided into 2 treatment cycles; not to exceed 3.5 mg/kg cumulative dosage
• Oral dose per cycle by weight in each treatment course
  • Below 40 kg: Safety and efficacy not established
  • 40 kg to below 50 kg: 40 mg first cycle; 40 mg second cycle
  • 50 kg to below 60 kg: 50 mg first cycle; 50 mg second cycle
  • 60 kg to below 70 kg: 60 mg first cycle; 60 mg second cycle
  • 70 kg to below 80 kg: 70 mg first cycle; 70 mg second cycle
  • 80 kg to below 90 kg: 80 mg first cycle; 70 mg second cycle
  • 90 kg to below 100 kg: 90 mg first cycle; 80 mg second cycle
  • 100 kg to below 110 kg: 100 mg first cycle; 90 mg second cycle
  • 110 kg and above: 100 mg first cycle; 100 mg second cycle
  • Do not administer more than 2 tablets daily; administer 1-2 tablets/day orally over 4-5 consecutive days

Dosage Modifications

Mavenclad only

• Renal impairment
  • Mild (creatinine clearance [CrCl] 60-89 mL/minute): No dosage adjustment recommended
  • Moderate to severe (CrCl below 60 mL/minute): Not recommended
• Hepatic impairment
  • Mild: No dosage adjustment recommended
  • Moderate to severe (Child-Pugh above 6): Not recommended

Dosing Considerations

Mavenclad only

• Limitations of use: Treatment is not recommended for use in patients with clinically isolated syndrome (CIS) because of its safety profile
• Prior to administration
  • Follow standard cancer screening guidelines because of risk of malignancies
  • Exclude pregnancy in females of reproductive potential
  • Exclude HIV infection
  • Perform tuberculosis screening
  • Screen for hepatitis B and C
  • Evaluate acute infection; consider delaying treatment until any acute infection is fully controlled
  • Vaccination recommended for patients who are antibody-negative for varicella zoster virus
  • Administer all immunizations according to immunization guidelines; administer live-attenuated or live vaccines 4-6 weeks prior to therapy; avoid vaccination with live-attenuated or live vaccines during and after therapy while the patient’s white blood cell counts are not within normal limits
  • Obtain a baseline (within 3 months) magnetic resonance imaging prior to first treatment course because of risk of progressive multifocal leukoencephalopathy (PML); at first sign or symptom suggestive of PML, withhold therapy and perform an appropriate diagnostic evaluation
  • Evaluate for liver injury; obtain serum aminotransferase, alkaline phosphatase, and total bilirubin levels
• Complete blood count
  • Lymphocytes must be within normal limits before initiating first treatment course and at least 800 cells/mcL before initiating second treatment course
  • May delay second treatment course for up to 6 months to allow for recovery of lymphocytes to at least 800 cells per microliter; if recovery takes longer than 6 months, patient should not receive further treatment
  • Obtain CBC with differential including lymphocyte count before initiating first treatment course and before initiating second course
  • Obtain CBC with differential including lymphocyte count 2 and 6 months after start of treatment course; if lymphocyte count at month 2 is below 200 cells/mcL, monitor monthly until month 6 and periodically thereafter and when clinically indicated
  • Hold therapy if lymphocyte count below 200 cells/mcL
  • Administer anti-herpes prophylaxis in patients with lymphocyte counts below 200 cells/mcL

Pediatric:

• Safety and efficacy not established

Overdose

• Overdose of intravenous cladribine can cause irreversible neurologic toxicity, kidney damage and bone marrow suppression resulting in anemia, neutropenia and thrombocytopenia. Oral overdose of cladribine may result in lymphopenia.
• There is no known specific antidote for cladribine overdose. The patient’s blood parameters must be monitored and treated with supportive measures as needed.

Inform your doctor of all medications you are currently taking, who can advise you on any possible drug interactions. Never begin taking, suddenly discontinue, or change the dosage of any medication without your doctor’s recommendation.

• Cladribine has no severe interactions with other drugs.
• Serious interactions of cladribine include:
  • adenovirus types 4 and 7 live, oral
  • axicabtagene ciloleucel
  • brexucabtagene autoleucel
  • ciltacabtagene autoleucel
  • idecabtagene vicleucel
  • lisocabtagene maraleucel
  • palifermin
  • ropeginterferon alfa 2b
  • tisagenlecleucel
  • tofacitinib
• Moderate interactions of cladribine include:
  • acalabrutinib
  • belatacept
  • cholera vaccine
  • dengue vaccine
  • denosumab
  • fingolimod
  • hydroxyurea
  • influenza A (H5N1) vaccine
  • influenza virus vaccine (H5N1), adjuvanted
  • ofatumumab SC
  • siponimod
  • sipuleucel-T
  • trastuzumab
  • trastuzumab deruxtecan
• Minor interactions of cladribine include:
  • maitake
  • taurine
  • vitamin A
  • vitamin E

The drug interactions listed above are not all of the possible interactions or adverse effects. For more information on drug interactions, visit the RxList Drug Interaction Checker.

It is important to always tell your doctor, pharmacist, or health care provider of all prescription and over-the-counter medications you use, as well as the dosage for each, and keep a list of the information. Check with your doctor or health care provider if you have any questions about the medication.

• Cladribine can cause fetal harm and loss of pregnancy. Do not use in pregnant women, or women and men of reproductive potential who do not plan to use effective contraception.
• Women of reproductive potential should be screened for pregnancy and excluded before initiating cladribine. Advise women of pregnancy potential and men with women partners who may become pregnant to use effective contraception during treatment and up to 6 months following the final dose.
• It is not known if cladribine reduces the effectiveness of hormonal contraceptives. Women using hormonal contraceptives should use an additional barrier method of contraception. Women who become pregnant during treatment should stop cladribine.
• There is no information on the presence of cladribine in breastmilk or its effects on milk production or the breastfed infant. Nursing mothers should refrain from breastfeeding during treatment and for 10 days after the last dose of cladribine, because of the potential for serious adverse reactions in the breastfed infant.

• Take cladribine oral tablets exactly as instructed.
• Exercise care to minimize skin contact with the tablets, swallow immediately after removing from the package and wash your hands after handling.
• Follow cancer screening guidelines after treatment with cladribine.
• You will need regular blood and other tests. Follow up with your healthcare provider and do not miss your appointments.
• Report to your treating physician immediately if you develop:
  • Any signs of infection such as aching, painful muscles, headache, generally feeling unwell or loss of appetite
  • Signs of JC virus infection that can affect the brain with symptoms that include progressive weakness on one side of the body, clumsiness of limbs, vision problems, confusion, changes in thinking and memory, and personality changes.
  • Signs of liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice
  • Serious or severe hypersensitivity reactions, including skin reactions
  • Symptoms of heart failure, including shortness of breath, rapid or irregular heartbeat and swelling
• Complete all required live or live-attenuated vaccinations 4 to 6 weeks before treatment. Do not take any live or live-attenuated vaccines during treatment and for several months after. Check with your physician before taking any scheduled vaccinations.
• Store cladribine tablets safely out of reach of children.
• In case of overdose, contact your physician or Poison Control.