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Cladribine

Class: Antineoplastic Agents
VA Class: AN300
Chemical Name: 2-Chloro-2′-deoxyadenosine
Molecular Formula: C10H12ClN5O3
CAS Number: 4291-63-8
Brands: Leustatin

Warning(s)

  • Experience of Supervising Clinician
  • Administer only under supervision of qualified clinicians experienced in therapy with antineoplastic agents.1

  • Myelosuppression
  • Risk of severe bone marrow suppression; 1 generally reversible and dose dependent. 1 (See Hematologic Effects under Cautions.)

  • Neurotoxicity
  • Severe, irreversible neurologic effects (e.g., paraparesis/quadriparesis) reported following administration of high dosages (4–9 times current recommended dosage for hairy cell leukemia).1 33 Neurotoxicity appears to be dose related and occurs rarely at recommended dosages.1 (See Neurotoxicity under Cautions.)

  • Nephrotoxicity
  • Acute, renal toxicity reported following administration of high dosages (4–9 times current recommended dosage for hairy cell leukemia), especially in conjunction with other nephrotoxic drugs.1 33 (See Renal Effects under Cautions.)

Introduction

Antimetabolite antineoplastic agent; synthetic purine nucleoside.1 2 3 4 5 6 7 9

Uses for Cladribine

Hairy Cell Leukemia

Used alone as first-line therapy for active hairy cell leukemia (leukemic reticuloendotheliosis), defined as disease involving clinically important anemia, neutropenia, thrombocytopenia, or other disease-related symptoms.1 30 31

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Considered first-line therapy because of apparent greater efficacy compared with interferon alfa.20 29 30 31 32 41

Chronic Lymphocytic Leukemia (CLL)

Used as an alternative agent for the treatment of chronic lymphocytic leukemia.30

Non-Hodgkin’s Lymphoma

Used as an alternative agent for the treatment of low-grade non-Hodgkin’s lymphoma.30

Cutaneous T-cell Lymphoma

Used as an alternative agent for treatment of cutaneous T-cell lymphoma.30

Cladribine Dosage and Administration

General

  • Consult specialized references for procedures for proper handling and disposal of antineoplastics.1

Administration

Administer by IV infusion.1 9 21 42 45 46

IV Administration

For solution compatibility information, see Compatibility under Stability.

Administer by continuous IV infusion as a single course of therapy over 7 consecutive days or as 7 single daily doses infused IV continuously over 24 hours for a total of 7 consecutive days.1

Handle cautiously; use of latex gloves and protective gowns is recommended during preparation and administration.a If skin or mucosal contact occurs, immediately wash affected area(s) thoroughly.a

Dilution

Cladribine for injection concentrate must be diluted prior to administration.1

Use strict aseptic technique since drug product contains no preservative or bacteriostatic agent.1

Continuous 7-day infusion: Must be diluted in bacteriostatic 0.9% sodium chloride injection containing benzyl alcohol as preservative prior to administration, to provide a total solution volume of 100 mL.1 Pass calculated dose of cladribine for injection concentrate, followed by calculated amount of diluent, through a sterile 0.22-mcm disposable hydrophilic syringe filter and into the infusion reservoir.1

Single daily infusions: Must be diluted in a polyvinyl chloride infusion bag containing 500 mL of 0.9% sodium chloride injection prior to administration.1 Dextrose 5% injection should not be used due to accelerated cladribine degradation.1

Rate of Administration

Infuse IV over 7 consecutive 24-hour periods as a repeated single daily dose or as a continuous 7-day infusion of the total dose.1

Dosage

Deviations from recommended dosage regimen not advised.1 If patient fails to respond to the initial course of therapy, additional courses unlikely to provide any benefit.1

Adults

Hairy Cell Leukemia
IV

Continuous 7-day infusion: 0.63 mg/kg by continuous IV infusion over 7 consecutive days.1

Single daily infusions: 0.09 mg/kg daily by repeated 24-hour IV infusions for 7 consecutive days.1

Special Populations

Hepatic Impairment

No specific dosage recommendations at this time;1 however, use with caution.1 20

Renal Impairment

No specific dosage recommendations at this time;1 however, use with caution.1 20 (See Cautions.)

Geriatric Patients

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.a

Cautions for Cladribine

Contraindications

  • Known hypersensitivity to cladribine or any ingredient in the formulation.1

Warnings/Precautions

Warnings

Hematologic Effects

Risk of severe and usually reversible myelosuppression (e.g., neutropenia, anemia, thrombocytopenia),1 5 22 24 especially at high doses or in patients with preexisting pancytopenia.32 Myelotoxicity may be cumulative with multiple cycles of therapy.20 Caution in patients with preexisting myelosuppression, and if drug administered before, after, or in conjunction with other myelosuppressive agents.1

Myelosuppression occurs frequently during the first month after initiation of therapy; transfusions (i.e., RBC, platelet) may be required.1

Mean platelet count, ANC, and hemoglobin concentration decline during first 2 weeks after initiation of therapy; normalization of mean counts generally occurs by day 12, week 5, and week 8, respectively.1

Monitor hematologic function carefully to detect development of anemia, neutropenia, and thrombocytopenia and for early detection of any potential sequelae (e.g., infection, bleeding).1 (See Adequate Patient Evaluation and Monitoring under Cautions.)

Prolonged depression of CD4+ and T4+ cell counts reported.1 24

Neurotoxicity

Potentially severe and irreversible neurologic effects (e.g., delayed, progressive paraparesis/quadriparesis) consistent with demyelinating disease. Manifestations usually appear 35–84 days after initiation of therapy.1

Neurotoxicity appears to be dose related, usually occurring with dosages higher than those recommended for hairy cell leukemia, in conjunction with cyclophosphamide and total body irradiation.1 33

Dose-related axonal peripheral polyneuropathy reported in patients not receiving cyclophosphamide or total body irradiation.1

Renal Effects

Acute renal insufficiency (e.g., acidosis, anuria, elevated Scr) reported; generally has required dialysis and has been reversible in some cases.1 33

Renal dysfunction appears to be dose related, usually occurring with dosages higher than those recommended for hairy cell leukemia, in conjunction with cyclophosphamide and total body irradiation.1 33 Similar nephrotoxicity not reported in patients receiving currently recommended dosage.1

Infectious Complications

Risk of serious, sometimes fatal, infectious complications (e.g., septicemia, pneumonia), especially during the first month after initiation of therapy.1 21 22 24 25 26

Carefully weigh risks and benefits of therapy in patients with active infections.1

Fever

Potentially severe fever (temperature ≥40°C) occurs commonly during the first month after initiation of therapy;1 5 21 22 24 usually associated with neutropenia.1 Careful monitoring recommended.1 (See Hematologic Effects and also see Adequate Patient Evaluation and Monitoring under Cautions.)

Fever generally related to the release of pyrogens from tumor cells;5 32 <33% of the febrile events associated with documented infection.1 5 21 22 24

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm;1 teratogenicity and embryotoxicity demonstrated in animals.1

Avoid pregnancy during therapy.1 If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.1

General Precautions

Adequate Patient Evaluation and Monitoring

Toxic drug with a low therapeutic index; therapeutic response is not likely to occur without some evidence of toxicity.1 Administer only under constant supervision by clinicians experienced in therapy with cytotoxic agents.1

Perform peripheral blood cell counts, particularly during the first 4–8 weeks after initiation of therapy.1

Perform bone marrow aspiration and biopsy after peripheral blood counts have returned to within normal limits, to confirm response to therapy.1

Evaluate febrile episodes with appropriate laboratory and radiologic studies and initiate anti-infectives as clinically indicated.1

Monitor renal and hepatic function periodically, especially in those with underlying renal or hepatic dysfunction.1

Tumor Lysis Syndrome

Tumor lysis syndrome reported rarely in patients with other hematologic malignancies with large tumor burdens.1 Not reported in patients with hairy cell leukemia receiving empiric therapy with allopurinol.5 22

Specific Populations

Pregnancy

Category D.a

Lactation

Not known whether cladribine is distributed into milk.1 Discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy not established in children.1

Cladribine IV infusion solutions diluted with bacteriostatic sodium chloride injection containing benzyl alcohol should not be used in neonates.1 Benzyl alcohol as a preservative has been associated with toxicity in neonates, although a causal relationship has not been established.1 12 13 14 15 16 17

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.1 Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy.1 (See Geriatric Patients under Dosage and Administration.)

Hepatic Impairment

Use with caution;1 20 monitor hepatic function periodically.1 33 40

Renal Impairment

Use with caution;1 20 monitor renal function periodically.1 33 40

Common Adverse Effects

Neutropenia, fever, infection, fatigue, nausea, rash, headache, injection site reactions.1

Interactions for Cladribine

Myelosuppressive Drugs

Possible increased myelosuppression; use concomitantly with caution.1

Nephrotoxic Drugs

Potential for increased risk of acute nephrotoxicity; monitor renal function periodically.33 40

Cladribine Pharmacokinetics

Distribution

Extent

Distributed into CSF; CSF concentrations are about 25% of concurrent serum concentrations.a

Plasma Protein Binding

Approximately 20%.a

Elimination

Elimination Route

18% of administered dose excreted in urine.a

Half-life

4.2–9.2 hours.a

Stability

Storage

Parenteral

Injection Concentrate

2–8°C; protect from light.a

Following dilution, refrigerate at 2–8°C for no more than 8 hours before administration.a

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution CompatibilityHID

Compatible

Sodium chloride 0.9%

Drug CompatibilityHID
Y-Site Compatibility

Compatible

Aminophylline

Bumetanide

Buprenorphine HCl

Butorphanol tartrate

Calcium gluconate

Carboplatin

Chlorpromazine HCl

Cimetidine HCl

Cisplatin

Cyclophosphamide

Cytarabine

Dexamethasone sodium phosphate

Diphenhydramine HCl

Dobutamine HCl

Dopamine HCl

Doxorubicin HCl

Droperidol

Enalaprilat

Etoposide

Famotidine

Furosemide

Gallium nitrate

Granisetron HCl

Haloperidol lactate

Heparin sodium

Hydrocortisone sodium phosphate

Hydrocortisone sodium succinate

Hydromorphone HCl

Hydroxyzine HCl

Idarubicin HCl

Leucovorin calcium

Lorazepam

Mannitol

Meperidine HCl

Mesna

Methylprednisolone sodium succinate

Metoclopramide HCl

Mitoxantrone HCl

Morphine sulfate

Nalbuphine HCl

Ondansetron HCl

Paclitaxel

Potassium chloride

Prochlorperazine edisylate

Promethazine HCl

Ranitidine HCl

Sodium bicarbonate

Teniposide

Vincristine sulfate

Actions

  • Exact mechanism(s) of antileukemic action not fully elucidated.1 3 6 7 8

    Converted intracellularly by deoxycytidine kinase to cladribine triphosphate which accumulates and incorporates into DNA.1 2 7

    High intracellular concentrations of cladribine triphosphate inhibit ribonucleotide reductase, causing an imbalance in triphosphorylated deoxynucleotide (dNTP) pools and subsequent DNA strand breaks, inhibition of DNA synthesis and repair, nicotinamide adenine dinucleotide (NAD) and ATP depletion, and cell death.1 3 6 8

  • Cytotoxic effects extend to resting and proliferating lymphocytes and monocytes.1 2 4 7 20

Advice to Patients

  • Importance of immediately informing clinician if fever or bleeding occurs.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 women informing clinicians immediately if they are or plan to become pregnant or plan to breast-feed;a necessity for clinicians to advise women to avoid pregnancy during therapy and advise pregnant women of risk to the fetus.1

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

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Cladribine

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection concentrate, for IV infusion only

1 mg/mL*

Cladribine for Injection Concentrate

Abraxis, Bedford

Leustatin (with sodium chloride)

Centocor Ortho Biotech

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions December 1, 2010. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Ortho Biotech. Leustatin (cladribine) injection for intravenous infusion only prescribing information. Raritan, NJ; 2002 Oct.

2. Carson DA, Wasson DB, Taetle R et al. Specific toxicity of 2-chlorodeoxyadenosine toward resting and proliferating human lymphocytes. Blood. 1983; 62:737-43. [PubMed 6136305]

3. Griffig J, Koob R, Blakley RL. Mechanisms of inhibition of DNA synthesis by 2-chlorodeoxyadenosine in human lymphoblastic cells. Cancer Res. 1989; 49:6923-8. [PubMed 2573423]

4. Carson DA, Wasson DB, Beutler E. Antileukemic and immunosuppressive activity of 2-chloro-2′-deoxyadenosine. Proc Natl Acad Sci USA. 1984; 81:2232-6. [PubMed 6585795]

5. Piro LD, Carrera CJ, Carson DA et al. Lasting remissions in hairy-cell leukemia induced by a single infusion of 2-chlorodeoxyadenosine. N Engl J Med. 1990; 322: 1117-21. [IDIS 265561] [PubMed 1969613]

6. Hirota Y, Yoshioka A, Tanaka S et al. Imbalance of deoxyribonucleoside triphosphates, DNA double-strand breaks, and cell death caused by 2-chlorodeoxyadenosine in mouse FM3A cells. Cancer Res. 1989; 49:915-9. [PubMed 2563234]

7. Riscoe MK, Brouns MC, Fitchen JH. Purine metabolism as a target for leukemia chemotherapy. Blood Rev. 1989; 3:162-73. [PubMed 2676034]

8. Seto S, Carrera CJ, Wasson DB et al. Biochemical basis for deoxyadenosine and 2-chlorodeoxyadenosine toxicity to resting human lymphocytes. Adv Exp Med Biol. 1986; 195(Part B):577-82. [PubMed 2876594]

9. Cheson BD, Sorensen JM, Vena DA et al. Treatment of hairy cell leukemia with 2-chlorodeoxyadenosine via the Group C protocol mechanism of the National Cancer Institute: a report of 979 patients. J Clin Oncol. 1998; 16:3007-15. [IDIS 414248] [PubMed 9738569]

10. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97-414), to March 31, 1993. Rockville, MD; 1993 Apr.

11. US Food and Drug Administration. Leustatin approved for hairy cell leukemia. Rockville, MD: 1993 Mar 2. Press release.

12. American Academy of Pediatrics Committee on Fetus and Newborn and Committee on Drugs. Benzyl alcohol: toxic agent in neonatal units. Pediatrics. 1983; 72:356-8. [IDIS 175725] [PubMed 6889041]

13. Anon. Benzyl alcohol may be toxic to newborns. FDA Drug Bull. 1982; 12:10-1. [PubMed 7188569]

14. Anon. Neonatal deaths associated with use of benzyl alcohol—United States. MMWR Morb Mortal Wkly Rep. 1982; 31:290-1. [IDIS 150868] [PubMed 6810084]

15. Gershanik J, Boecler B, Ensley H et al. The gasping syndrome and benzyl alcohol poisoning. N Engl J Med. 1982; 307:1384-8. [IDIS 160823] [PubMed 7133084]

16. Menon PA, Thach BT, Smith CH et al. Benzyl alcohol toxicity in a neonatal intensive care unit: incidence, symptomatology, and mortality. Am J Perinatol. 1984; 1:288-92. [PubMed 6440575]

17. Anderson CW, Ng KJ, Andresen B et al. Benzyl alcohol poisoning in a premature newborn infant. Am J Obstet Gynecol. 1984; 148:344-6. [IDIS 181207] [PubMed 6695984]

18. Saven A, Piro LD. Treatment of hairy cell leukemia. Blood. 1992; 79:1111-20. [IDIS 293082] [PubMed 1371410]

19. Cheson BD. The purine analogs—a therapeutic beauty contest. J Clin Oncol. 1992; 10:352-5. [PubMed 1346799]

20. Bryson HM, Sorkin EM. Cladribine. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in haematological malignancies. Drugs. 1993; 46:872-94. [PubMed 7507037]

21. Saven A, Burian C, Koziol JA et al. Long-term follow-up of patients with hairy cell leukemia after cladribine treatment. Blood. 1998; 92:1918-26. [IDIS 415018] [PubMed 9731048]

22. Tallman MS, Hakimian D, Variakojis D et al. A single cycle of 2-chlorodeoxyadenosine results in complete remission in the majority of patients with hairy cell leukemia. Blood. 1992; 80:2203-9. [IDIS 304962] [PubMed 1358262]

23. Saven A, Piro LD. Complete remissions in hairy cell leukemia with 2-chlorodeoxyadenosine after failure with 2′-deoxycoformycin. Ann Intern Med. 1993; 119:278-83. [IDIS 318583] [PubMed 8101069]

24. Estey EH, Kurzrock R, Kantarjian HM et al. Treatment of hairy cell leukemia with 2-chlorodeoxyadenosine (2-CdA). Blood. 1992; 79:882-7. [IDIS 291938] [PubMed 1346577]

25. Juliusson G, Liliemark J. Rapid recovery from cytopenia in hairy cell leukemia after treatment with 2-chloro-2′-deoxyadenosine (CDA): relation to opportunistic infections. Blood. 1992; 79:888-94. [IDIS 291939] [PubMed 1346578]

26. Jaiyesimi IA, Kantarjian HM, Estey EH. Advances in therapy for hairy cell leukemia: a review. Cancer. 1993; 72:5-16. [IDIS 316257] [PubMed 7685243]

27. Spielberger RT, Golomb HM. Hairy cell leukemia 1992. Leukemia. 1992; 6(Suppl 4):142-6. [PubMed 1279327]

28. Golomb HM, Ratain MJ, Mick R et al. The treatment of hairy cell leukemia: an update. Leukemia. 1992; 6(Suppl 2):24-7. [PubMed 1349662]

29. Baltz JK, Montello MJ. Cladribine for the treatment of hematologic malignancies. Clin Pharm. 1993; 12:805-13. [IDIS 321039] [PubMed 7903917]

30. Anon. Drugs of choice for cancer. Treat Guidel Med Lett. 2003; 1:41-52. [PubMed 15529105]

31. Hairy cell leukemia. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2005 Apr 5.

32. Beutler E. Cladribine (2-chlorodeoxyadenosine). Lancet. 1993; 340:952-6.

33. Beutler E, Piro LD, Saven A et al. 2-Chlorodeoxyadenosine (2-CdA): a potent chemotherapeutic and immunosuppressive nucleoside. Leuk Lymphoma. 1991; 5:1-8.

34. Dann EJ, Gillis S, Polliack A et al. Brief report: tumor lysis syndrome following treatment with 2-chlorodeoxyadenosine for refractory chronic lymphocytic leukemia. N Engl J Med. 1993; 329:1547-8. [IDIS 322265] [PubMed 8105383]

35. Betticher DC, Fey MF, Rabaglio M et al. Cladribine and severe myelotoxicity. Lancet. 1993; 342:1369. [IDIS 322590] [PubMed 7901666]

36. Dimopoulos MA, Kantarjian H, Estey E et al. Treatment of Waldenstrom macroglobulinemia with 2-chlorodeoxyadenosine. Ann Intern Med. 1993; 118:195-8. [IDIS 308703] [PubMed 8093333]

37. Saven A, Carrera CJ, Carson DA et al. 2-Chlorodeoxyadenosine: an active agent in the treatment of cutaneous T cell lymphoma. Blood. 1992; 80:587-92. [IDIS 299980] [PubMed 1353380]

38. Delannoy A, Hanique G, Ferrant A. 2-Chlorodeoxyadenosine for patients with B-cell chronic lymphocytic leukemia resistant to fludarabine. N Engl J Med. 1993; 328:812. [IDIS 310610] [PubMed 8094888]

39. Santana VM, Mirro J Jr, Harwood FC et al. A Phase I trial of 2-chlorodeoxyadenosine in pediatric patients with acute leukemia. J Clin Oncol. 1991; 9:416-22. [PubMed 1671875]

40. Ortho Biotech, Raritan, NJ: personal communication.

41. Saven A, Piro L. Newer purine analogues for the treatment of hairy-cell leukemia. N Engl J Med. 1994; 330:691-7. [IDIS 326313] [PubMed 7906385]

42. Hoffman MA, Janson D, Rose E et al. Treatment of hairy-cell leukemia with cladribine: response, toxicity, and long-term follow-up. J Clin Oncol. 1997; 15:1138-42. [IDIS 383240] [PubMed 9060556]

43. Au WY, Klasa RJ, Gallagher R et al. Second malignancies in patients with hairy cell leukemia in British Columbia: a 20-year experience. Blood. 1998; 92:1160-4. [IDIS 412557] [PubMed 9694703]

44. Kurzrock R, Strom SS, Estey E et al. Second cancer risk in hairy cell leukemia: analysis of 350 patients. J Clin Oncol. 1997; 15:1803-10. [IDIS 387779] [PubMed 9164188]

45. 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; 21:891-6. [IDIS 500957] [PubMed 12610190]

46. Chadha P, Rademaker AW, Mendiratta P et al. Treatment of hairy cell leukemia with 2-chlorodeoxyadenosine (2-CdA): long-term follow-up of the Northwestern University experience. Blood. 2005; 106:241-6. [IDIS 537243] [PubMed 15761021]

47. Juliusson G, Heldal D, Hippe E et al. Subcutaneous injections of 2-chlorodeoxyadenosine for symptomatic hairy cell leukemia. J Clin Oncol. 1995; 13:989-95. [IDIS 344875] [PubMed 7707128]

a. Ortho Biotech. Leustatin (cladribine) injection for intravenous infusion only prescribing information. Raritan, NJ; 2006 Jan.

HID. Trissel LA. Handbook on injectable drugs. 14th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2007:413-7.

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