Cladribine

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

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}

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 S_cr) 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 Compatibility^HID

Drug Compatibility^HID

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.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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