Cladribine (Monograph)

Drug class: Antineoplastic Agents
VA class: AN300
Chemical name: 2-Chloro-2′-deoxyadenosine
Molecular formula: C₁₀H₁₂ClN₅O₃
CAS number: 4291-63-8

Medically reviewed by Drugs.com on Apr 21, 2023. Written by ASHP.

Warning

Administer only under supervision of qualified clinicians experienced in therapy with antineoplastic agents.

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

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

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. (See Renal Effects under Cautions.)

Introduction

Antimetabolite antineoplastic agent; synthetic purine nucleoside.

Uses for Cladribine

Hairy Cell Leukemia

Cladribine injection is 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. Designated an orphan drug by FDA for treatment of hairy cell leukemia.

The American Society of Hematology (ASH) guidelines recommend that in the absence of renal impairment or active infection, first-line therapy of classic hairy cell leukemia should consist of a standard regimen of a purine nucleoside analog (either cladribine or pentostatin).

Chronic Lymphocytic Leukemia (CLL)

Used as an alternative agent for the treatment of chronic lymphocytic leukemia^{† [off-label]}.

Non-Hodgkin’s Lymphoma

Used as an alternative agent for the treatment of low-grade non-Hodgkin’s lymphoma^{† [off-label]}.

Cutaneous T-cell Lymphoma

Used as an alternative agent for treatment of cutaneous T-cell lymphoma^{† [off-label]}.

Cladribine Dosage and Administration

General

Pretreatment Screening

Assess the risks and benefits of cladribine therapy in patients with active infections.

Patient Monitoring

Monitor hematologic parameters, particularly during the first 4–8 weeks after treatment.
After peripheral counts have normalized, perform bone marrow aspiration and biopsy to confirm response to treatment.
Monitor for fever, especially during the first month of therapy.
Monitor renal and hepatic function, especially in patients with underlying kidney or liver dysfunction and in patients receiving other potentially nephrotoxic agents.
Observe patients closely for signs of hematologic and nonhematologic toxicity.

Dispensing and Administration Precautions

Cladribine is a hazardous drug. Use disposable gloves and protective garments when handling and disposing of cladribine.
If the drug comes in contact with the skin or mucous membranes, immediately wash the involved surface with large amounts of water.
Cladribine injection should be administered under the supervision of a qualified physician experienced in the use of antineoplastic therapy.

Administration

Administer by IV infusion. Also has been administered sub-Q^{† [off-label]}.

IV Administration

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.

Dilution

Cladribine injection concentrate must be diluted prior to administration.

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

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. Pass calculated dose of cladribine for injection concentrate, followed by calculated amount of diluent, through a sterile 0.22-µm disposable hydrophilic syringe filter and into the infusion reservoir. Admixtures for the 7-day infusion have demonstrated acceptable chemical and physical stability for at least 7 days in the SIMS Deltec Medication Cassette Reservoir.

Single daily infusions:Dilute calculated dose through a sterile 0.22-µm disposable hydrophilic syringe filter into an infusion bag containing 500 mL of 0.9% sodium chloride injection prior to administration. Do not use dextrose 5% injection due to accelerated cladribine degradation. Repeat daily for a total of 7 consecutive days. Admixtures are chemically and physically stable for at least 24 hours at room temperature under normal room fluorescent light in Baxter Viaflex PVC infusion containers.

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.

Dosage

If patient fails to respond to the initial course of therapy, additional courses unlikely to provide any benefit.

Adults

Hairy Cell Leukemia

IV

Continuous 7-day infusion: single course given by continuous infusion for 7 consecutive days at a dosage of 0.09 mg/kg daily.

Special Populations

Hepatic Impairment

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

Renal Impairment

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

Geriatric Patients

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

Cautions for Cladribine

Contraindications

Known hypersensitivity to cladribine or any ingredient in the formulation.

Warnings/Precautions

Warnings

Hematologic Effects

Risk of severe and usually reversible myelosuppression (e.g., neutropenia, anemia, thrombocytopenia), especially at high doses or in patients with preexisting pancytopenia. (See Boxed Warning.) Myelotoxicity may be cumulative with multiple cycles of therapy. Caution advised in patients with preexisting myelosuppression, and if drug is administered before, after, or in conjunction with other myelosuppressive agents.

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

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.

Monitor hematologic function carefully to detect development of anemia, neutropenia, and thrombocytopenia and for early detection of any potential sequelae (e.g., infection, bleeding).

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

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. (See Boxed Warning.)

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.

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

Renal Effects

Acute renal insufficiency (e.g., acidosis, anuria, elevated S_cr) reported; generally has required dialysis and has been reversible in some cases. (See Boxed Warning.)

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. Similar nephrotoxicity not reported in patients receiving currently recommended dosage.

Other Warnings and Precautions

Infectious Complications

Risk of serious, sometimes fatal, infectious complications (e.g., septicemia, pneumonia), especially during the first month after initiation of therapy.

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

Fever

Potentially severe fever (temperature ≥40°C) occurs commonly during the first month after initiation of therapy; usually associated with neutropenia. Careful monitoring recommended.

Fever generally related to the release of pyrogens from tumor cells; <33% of the febrile events associated with documented infection.

Tumor Lysis Syndrome

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

Vaccinations

Due to the increased risk of infection with immunosuppression with chemotherapy including cladribine, it is recommended not to administer live attenuated vaccines to patients receiving cladribine injection.

Specific Populations

Pregnancy

Can cause fetal harm; teratogenicity and embryotoxicity demonstrated in animals.

Avoid pregnancy during therapy. If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard. (See Females and Males of Reproductive Potential under Cautions.)

Lactation

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

Females and Males of Reproductive Potential

Females of childbearing potential should be advised to avoid becoming pregnant while receiving cladribine. Such females should use highly effective contraception during treatment with the drug.

Following IV administration in cynomolgus monkeys, cladribine has been shown to cause suppression of rapidly generating cells, including testicular cells. The effect of the drug on fertility in humans is not known.

Pediatric Use

Safety and efficacy not established in children.

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

Geriatric Use

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

Hepatic Impairment

Use with caution; monitor hepatic function periodically.

Renal Impairment

Use with caution; monitor renal function periodically.

Common Adverse Effects

The most frequent adverse effects of cladribine include pyrexia (33%), fatigue (31%), nausea (22%), rash (16%), and headache (14%).

Drug Interactions

No known drug interactions.

Immunosuppressive and Myelosuppressive Drugs

Possible increased immunosuppression or myelosuppression; use concomitantly with caution.

Nephrotoxic Drugs

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

Vaccinations

Increased risk of infection with immunosuppression; avoid administration of live attenuated vaccines.

Cladribine Pharmacokinetics

Distribution

Extent

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

Plasma Protein Binding

Approximately 20%.

Elimination

Elimination Route

18% of administered dose excreted in urine.

Half-life

4.2–9.2 hours.

Stability

Storage

Parenteral

Injection Concentrate

2–8°C; protect from light.

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

Actions

Exact mechanism(s) of antileukemic action not fully elucidated.

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

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.
Cytotoxic effects extend to resting and proliferating lymphocytes and monocytes.

Advice to Patients

Advise patients that they are more susceptible to infections while receiving cladribine and to immediately report any signs or symptoms of infection (e.g., fever, chills, constant cough, dysuria) to their healthcare provider.
Advise patients of the risk of lymphopenia and other hematologic toxicity and the need to monitor complete blood cell counts during therapy.
Advise patients of the risk of nephrotoxicity and neurotoxicity and to immediately report signs and symptoms to their healthcare provider.
Advise patients to avoid the use of live attenuated vaccines during treatment with cladribine.
Advise females of reproductive potential of the potential risk to a fetus and to use highly effective contraception during treatment with cladribine.
Advise females to inform their clinician if they are breastfeeding or plan to breastfeed.
Advise patients to inform their healthcare provider about all concomitant medications, including prescription medicine, over the counter drugs, vitamins, and herbal products, as well as any concomitant illnesses.
Advise patients to inform their healthcare provider of other important precautionary information. (See Cautions.)

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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