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ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Pronunciation
(KLA dri been)
Generic Available (U.S.)
Yes
Index Terms
Brand Names: U.S.
Brand Names: Canada
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Treatment of hairy cell leukemia
Use: Unlabeled
Treatment of acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), non-Hodgkin's lymphomas (mantle cell), Waldenström's macroglobulinemia, refractory Langerhans cell histiocytosis
Pregnancy Risk Factor
D
Pregnancy Considerations
Teratogenic effects and fetal mortality were observed in animal studies. There are no adequate and well-controlled studies in pregnant women. Do not administer during pregnancy. Women of childbearing potential should avoid becoming pregnant during treatment.
Lactation
Excretion in breast milk unknown/not recommended
Breast-Feeding Considerations
Due to the potential for serious adverse reactions in the nursing infant, breast-feeding is not recommended.
Contraindications
Hypersensitivity to cladribine or any component of the formulation
Warnings/Precautions
Boxed warnings:
• Bone marrow suppression: See “Concerns related to adverse effects” below.
• Experienced physician: See “Other warnings/precautions” below.
• Neurotoxicity: See “Concerns related to adverse effects” below.
• Renal toxicity: See “Concerns related to adverse effects” below.
Special handling:
• Hazardous agent: Use appropriate precautions for handling and disposal.
Concerns related to adverse effects:
• Bone marrow suppression: [U.S. Boxed Warning]: Dose-dependent myelosuppression (neutropenia, anemia, and thrombocytopenia) is common and generally reversible. Use with caution in patients with pre-existing hematologic or immunologic abnormalities. Monitor blood counts, especially during the first 4-8 weeks after treatment.
• Fever: Treatment is associated with fever (>100°F), with or without neutropenia, observed more commonly in the first month.
• Infection: Infections (bacterial, viral, and fungal) were reported more commonly in the first month after treatment (generally mild or moderate in severity); the incidence is reduced in the second month. Due to neutropenia and T-cell depletion, risk versus benefit of treatment should be evaluated in patients with active infections.
• Neurotoxicity: [U.S. Boxed Warning]: Serious, delayed (~1-3 months) neurologic toxicity, including irreversible paresis, has been reported, usually with continuous infusions of higher doses (4-9 times the FDA-approved dose); may occur at approved doses (rare); diagnostics with electromyography and nerve conduction studies were consistent with demyelinating disease.
• Renal toxicity: [U.S. Boxed Warning]: Acute nephrotoxicity (eg, acidosis, anuria, increased serum creatinine), possibly requiring dialysis, has been reported with high doses (4-9 times the FDA-approved dose); use caution when administering with other nephrotoxic agents.
• Tumor lysis syndrome: With high tumor burden, tumor lysis syndrome and subsequent hyperuricemia may occur (rare); consider allopurinol and hydrate accordingly.
Disease-related concerns:
• Hepatic impairment: Use with caution in patients with hepatic impairment.
• Renal impairment: Use with caution in patients with renal impairment.
Other warnings/precautions:
• Experienced physician: [U.S. Boxed Warning]: Should be administered under the supervision of an experienced cancer chemotherapy physician.
Adverse Reactions
>10%:
Central nervous system: Fever (69%; ≥100ºF: 67%; ≥104ºF: 11%), fatigue (11% to 45%), headache (7% to 22%)
Dermatologic: Rash (10% to 27%)
Gastrointestinal: Nausea (28%), appetite decreased (17%), vomiting (13%)
Hematologic: Neutropenia (grade 4: 70%; recovery: by week 5); anemia (grade 4: 37%; recovery: by week 8); bone marrow hypocellularity (34%; prolonged), neutropenic fever (47%; severe: 32%), thrombocytopenia (grade 4: 12%; recovery: by day 12), CD4 lymphocytopenia (nadir: 4-6 months)
Local: Injection site reactions (9% to 19%)
Respiratory: Abnormal breath sounds (11%)
Miscellaneous: Infection (month 1: 28% [serious: 6%]; month 2: 6%)
1% to 10%:
Cardiovascular: Edema (6%), tachycardia (6%), thrombosis (2%)
Central nervous system: Dizziness (9%), chills (9%), insomnia (7%), malaise (5% to 7%), pain (6%)
Dermatologic: Purpura (10%), petechiae (8%), pruritus (6%), erythema (6%)
Gastrointestinal: Diarrhea (10%), constipation (9%), abdominal pain (6%)
Local: Phlebitis (2%)
Neuromuscular & skeletal: Weakness (9%), myalgia (7%), arthralgia (5%)
Respiratory: Cough (7% to 10%), abnormal chest sounds (9%), dyspnea (7%), epistaxis (5%)
Miscellaneous: Diaphoresis (9%)
<1%, postmarketing and/or case reports: Aplastic anemia, bilirubin increased, hemolytic anemia, hypereosinophilia, myelodysplastic syndrome, neurologic toxicity, opportunistic infections (cytomegalovirus, fungal infections, herpes virus infections, listeriosis, Pneumocystis jirovecii), pancytopenia (prolonged), paraparesis, pneumonia, polyneuropathy (with high doses), progressive multifocal leukoencephalopathy (PML), pulmonary interstitial infiltrates, quadriplegia (reported at high doses), renal dysfunction (with high doses), Stevens-Johnson syndrome, stroke, toxic epidermal necrolysis, transaminases increased, tuberculosis reactivation, tumor lysis syndrome, urticaria
Metabolism/Transport Effects
None known.
Drug Interactions
BCG: Immunosuppressants may diminish the therapeutic effect of BCG. Risk X: Avoid combination
CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for agranulocytosis may be increased. Risk X: Avoid combination
Coccidioidin Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioidin Skin Test. Risk C: Monitor therapy
Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Risk C: Monitor therapy
Echinacea: May diminish the therapeutic effect of Immunosuppressants. Risk D: Consider therapy modification
Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Risk D: Consider therapy modification
Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Risk X: Avoid combination
Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Risk X: Avoid combination
Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Risk D: Consider therapy modification
Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Risk C: Monitor therapy
Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Risk X: Avoid combination
Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Risk C: Monitor therapy
Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Risk C: Monitor therapy
Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Vaccinial infections may develop. Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Risk X: Avoid combination
Ethanol/Nutrition/Herb Interactions
Ethanol: Avoid ethanol (due to GI irritation).
Storage
Store intact vials under refrigeration 2°C to 8°C (36°F to 46°F). Protect from light. Dilutions for infusion should be used promptly; if not used promptly, both the 24-hour and 7-day infusion may be stored refrigerated for up to 8 hours prior to administration. Stability has been demonstrated for7 days (when diluted with bacteriostatic NS) in a CADD® medication cassette reservoir.
Reconstitution
Use appropriate precautions for handling and disposal. To prepare a 24-hour continuous infusion, dilute in 500 mL NS; to prepare a 7-day continuous infusion, dilute to a total volume of 100 mL in a CADD® medication cassette reservoir, using bacteriostatic NS; the manufacturer recommends filtering with a 0.22 micron filter when preparing 7-day infusions.
Compatibility
Stable in NS; incompatible with D5W.
Y-site administration: Compatible: Aminophylline, bumetanide, buprenorphine, butorphanol, calcium gluconate, carboplatin, chlorpromazine, cimetidine, cisplatin, cyclophosphamide, cytarabine, dexamethasone sodium phosphate, diphenhydramine, dobutamine, dopamine, doxorubicin HCl, droperidol, enalaprilat, etoposide, famotidine, furosemide, gallium nitrate, granisetron, haloperidol lactate, heparin, hydrocortisone sodium succinate, hydromorphone, hydroxyzine HCl, idarubicin, leucovorin calcium, lorazepam, mannitol, meperidine, mesna, methylprednisolone sodium succinate, metoclopramide, mitoxantrone, morphine, nalbuphine, ondansetron, paclitaxel, potassium chloride, prochlorperazine edisylate, promethazine, ranitidine, sodium bicarbonate, teniposide, vincristine.
Mechanism of Action
A purine nucleoside analogue; prodrug which is activated via phosphorylation by deoxycytidine kinase to a 5'-triphosphate derivative. This active form incorporates into DNA to result in the breakage of DNA strand and shutdown of DNA synthesis and repair. This also results in a depletion of nicotinamide adenine dinucleotide and adenosine triphosphate (ATP). Cladribine is cell-cycle nonspecific.
Pharmacodynamics/Kinetics
Distribution: Vd: ~9 L/kg; penetrates CSF (CSF concentrations are ~25% of plasma concentrations)
Protein binding: ~20%
Half-life elimination: After a 2-hour infusion (with normal renal function): 5.4 hours
Excretion: Urine (18%)
Dosage
Children: I.V.:
Acute myeloid leukemia (unlabeled use): 8.9 mg/m2/day continuous infusion for 5 days for 1 or 2 courses (Krance, 2001) or 9 mg/m2/day over 30 minutes for 5 days for 1 course (in combination with cytarabine) (Crews, 2002; Rubnitz, 2009)
Langerhans cell histiocytosis, refractory (unlabeled use): 5 mg/m2/day over 2 hours for 5 days every 21 days for up to 6 cycles (Weitzman, 2009)
Adults: Details concerning dosing in combination regimens should also be consulted.
Hairy cell leukemia: I.V.: 0.09 mg/kg/day continuous infusion for 7 days for 1 cycle or (unlabeled dosing) 0.1 mg/kg/day continuous infusion for 7 days for 1 cycle (Goodman, 2003; Saven, 1998)
Acute myeloid leukemia, induction (unlabeled use): I.V.: CLAG or CLAG-M regimen: 5 mg/m2/day over 2 hours for 5 days; a second induction may be administered if needed (Robak, 2000; Wierzbowska, 2008; Wrzesień-Kuś, 2003)
Chronic lymphocytic leukemia (unlabeled use): I.V.: 0.1 mg/kg/day continuous infusion for 7 days every 4-5 weeks (Saven, 1995) or 0.14 mg/kg/day over 2 hours for 5 days every 28 days for 3-6 cycles (Byrd, 2003)
Mantle cell lymphoma (unlabeled use): I.V.: 5 mg/m2/day over 2 hours for 5 days every 4 weeks for 2-6 cycles (Inwards, 2008; Rummel, 1999) or 5 mg/m2/day over 2 hours for 5 days every 4 weeks for 2-6 cycles (in combination with rituximab) (Inwards, 2008)
Waldenström's macroglobulinemia (unlabeled use):
I.V.: 0.1 mg/kg/day continuous infusion for 7 days every 4 weeks for 2 cycles (Dimopoulos, 1994)
SubQ: 0.1 mg/kg/day for 5 consecutive days every month for 4 cycles (in combination with rituximab) (Laszlo, 2010)
Dosing adjustment in renal impairment: The FDA-approved labeling recommends that caution should be used in patients with renal impairment; however, no specific dosage adjustment guidelines are available due to lack of data. The following guidelines have been used by some clinicians (Aronoff, 2007):
Children:
Clcr 10-50 mL/minute: Administer 50% of dose
Clcr <10 mL/minute: Administer 30% of dose
Hemodialysis: Administer 30% of dose
Continuous renal replacement therapy (CRRT): Administer 50% of dose
Adults:
Clcr 10-50 mL/minute: Administer 75% of dose
Clcr <10 mL/minute: Administer 50% of dose
Continuous ambulatory peritoneal dialysis (CAPD): Administer 50% of dose
Dosing adjustment in hepatic impairment: The FDA-approved labeling recommends that caution should be used in patients with hepatic impairment; however, no specific dosage adjustment guidelines are available due to lack of data.
Dosage: Combination Regimens
Leukemia, acute myeloid:
CLAG (AML Induction)
CLAG-M (AML Induction)
Administration: I.V.
Administer as a continuous infusion; may also be administered over 30 minutes or over 2 hours (unlabeled administration rates) depending on indication and/or protocol.
Administration: Other
May also be administered subcutaneously (unlabeled administration route; Laszlo, 2010)
Monitoring Parameters
CBC with differential (particularly during the first 4-8 weeks post-treatment), renal and hepatic function; monitor for fever
Patient Education
This drug can only be administered by infusion. It is important to maintain adequate nutrition and hydration during therapy. You will be more susceptible to infection during therapy and for up to 1 year following therapy. May cause nausea, vomiting, muscle weakness or pain, or mouth sores. Report immediately rash, unusual excessive fatigue, and/or signs of infection. Report rapid heartbeat or palpitations; unusual bruising or bleeding; persistent GI disturbances; diarrhea or constipation; yellowing of eyes or skin; change in color of urine or stool; swelling, warmth, or pain in extremities; or difficult respirations.
Dental Health: Effects on Dental Treatment
No significant effects or complications reported
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
May cause drowsiness, dizziness, or insomnia
Mental Health: Effects on Psychiatric Treatment
May cause bone marrow suppression; use caution with clozapine and carbamazepine
Nursing: Physical Assessment/Monitoring
Monitor for myelosuppression, cardiac changes, and renal failure regularly during therapy and following therapy (patients should be considered immunosuppressed for up to 1 year after cladribine therapy).
Oncology: Emetic Potential
Very low (<10%)
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Injection, solution [preservative free]: 1 mg/mL (10 mL)
Leustatin®: 1 mg/mL (10 mL)
References
Aronoff GR, Bennett WM, Berns JS, et al, Drug Prescribing in Renal Failure: Dosing Guidelines for Adults and Children, 5th ed. Philadelphia, PA: American College of Physicians; 2007, p 98, 170.
Bernard F, Thomas C, Bertrand Y, et al, “Multi-Centre Pilot Study of 2-Chlorodeoxyadenosine and Cytosine Arabinoside Combined Chemotherapy in Refractory Langerhans Cell Histiocytosis With Haematological Dysfunction,” Eur J Cancer, 2005, 41(17):2682-9.
Byrd JC, Peterson B, Piro L, et al, “A Phase II Study of Cladribine Treatment for Fludarabine Refractory B Cell Chronic Lymphocytic Leukemia: Results From CALGB Study 9211,” Leukemia, 2003, 17(2):323-7.
Crews KR, Gandhi V, Srivastava DK, et al, “Interim Comparison of a Continuous Infusion versus a Short Daily Infusion of Cytarabine Given in Combination With Cladribine for Pediatric Acute Myeloid Leukemia,” J Clin Oncol, 2002, 20(20):4217-24.
Dimopoulos MA, Kantarjian H, Weber D, et al, “Primary Therapy of Waldenström's Macroglobulinemia With 2-Chlorodeoxyadenosine,” J Clin Oncol, 1994, 12(12):2694-8.
Goodman GR, Burian C, Koziol JA., et al, “Extended Follow-Up of Patients With Hairy Cell Leukemia After Treatment With Cladribine,” J Clin Oncol, 2003, 21(5):891-6.
Inwards DJ, Fishkin PA, Hillman DW, et al, “Long-Term Results of the Treatment of Patients With Mantle Cell Lymphoma With Cladribine (2-CDA) Alone (95-80-53) or 2-CDA and Rituximab (N0189) in the North Central Cancer Treatment Group,” Cancer, 2008, 113(1):108-16.
Krance RA, Hurwitz CA, Head DR, et al, “Experience With 2-Chlorodeoxyadenosine in Previously Untreated Children With Newly Diagnosed Acute Myeloid Leukemia and Myelodysplastic Diseases,” J Clin Oncol, 2001, 19(11):2804-11.
Laszlo D, Andreola G, Rigacci L, et al, “Rituximab and Subcutaneous 2-Chloro-2'-Deoxyadenosine Combination Treatment for Patients With Waldenström Macroglobulinemia: Clinical and Biologic Results of a Phase II Multicenter Study,” J Clin Oncol, 2010, 28(13):2233-8.
Robak T, “Cladribine in the Treatment of Chronic Lymphocytic Leukemia,” Leuk Lymphoma, 2001, 40(5-6):551-64.
Robak T, Wrzesień-Kuś A, Lech-Marańda E, et al, “Combination Regimen of Cladribine (2-Chlorodeoxyadenosine), Cytarabine and G-CSF (CLAG) as Induction Therapy for Patients With Relapsed or Refractory Acute Myeloid Leukemia,” Leuk Lymphoma, 2000, 39(1-2):121-9.
Rubnitz JE, Crews KR, Pounds S, et al, “Combination of Cladribine and Cytarabine is Effective for Childhood Acute Myeloid Leukemia: Results of the St Jude AML97 Trial,” Leukemia, 2009, 23(8):1410-6.
Rummel MJ, Chow KU, Jäger E, “Treatment of Mantle Cell Lymphomas With Intermittent Two-Hour Infusion of Cladribine as First-Line Therapy or in First Relapse,” Ann Oncol, 1999, 10(1):115-7.
Saven A, Burian C, Koziol JA, et al, “Long-Term Follow-Up of Patients With Hairy Cell Leukemia After Cladribine Treatment,” Blood, 1998, 92(6):1918-26.
Saven A, Lemon RH, Kosty M, et al, “2-Chlorodeoxyadenosine Activity in Patients With Untreated Chronic Lymphocytic Leukemia,” J Clin Oncol, 1995, 13(3):570-4.
Sigal DS, Miller HJ, Schram ED, et al, “Beyond Hairy Cell: The Activity of Cladribine in Other Hematologic Malignancies,” Blood, 2010, 116(16):2884-96.
Sigal DS, Sharpe R, Burian C, et al, “Very Long-Term Eradication of Minimal Residual Disease in Patients With Hairy Cell Leukemia After a Single Course of Cladribine,” Blood, 2010, 115(10):1893-6.
Stine KC, Saylors RL, Saccente S, et al, “Efficacy of Continuous Infusion 2-CDA (Cladribine) in Pediatric Patients With Langerhans Cell Histiocytosis,” Pediatr Blood Cancer, 2004, 43(1):81-4.
Weitzman S, Braier J, Donadieu J, et al, “2'-Chlorodeoxyadenosine (2-CdA) as Salvage Therapy for Langerhans Cell Histiocytosis (LCH). Results of the LCH-S-98 Protocol of the Histiocyte Society,” Pediatr Blood Cancer, 2009, 53(7):1271-6.
Wierzbowska A, Robak T, Pluta A, et al, “Cladribine Combined With High Doses of Arabinoside Cytosine, Mitoxantrone, and G-CSF (CLAG-M) is a Highly Effective Salvage Regimen in Patients With Refractory and Relapsed Acute Myeloid Leukemia of the Poor Risk: A Final Report of the Polish Adult Leukemia Group,” Eur J Haematol, 2008, 80(2):115-26.
Wrzesień-Kuś A, Robak T, Lech-Marańda E, et al, “A Multicenter, Open, Non-Comparative Phase II Study of the Combination of Cladribine (2-Chlorodeoxyadenosine), Cytarabine, and G-CSF as Induction Therapy in Refractory Acute Myeloid Leukemia – a Report of the Polish Adult Leukemia Group (PALG),” Eur J Haematol, 2003, 71(3):155–62.
International Brand Names
Lexi-Comp.com
Last full review/revision January 2012
Content last modified January 2012
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