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Cladribine

Pronunciation

(KLA dri been)

Index Terms

  • 2-CdA
  • 2-Chlorodeoxyadenosine
  • Leustatin

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Solution, Intravenous:

Leustatin: 1 mg/mL (10 mL [DSC])

Generic: 1 mg/mL (10 mL [DSC])

Solution, Intravenous [preservative free]:

Generic: 1 mg/mL (10 mL)

Brand Names: U.S.

  • Leustatin [DSC]

Pharmacologic Category

  • Antineoplastic Agent, Antimetabolite
  • Antineoplastic Agent, Antimetabolite (Purine Analog)

Pharmacology

A purine nucleoside analogue; prodrug which is activated via phosphorylation by deoxycytidine kinase to a 5'-triphosphate derivative (2-CaAMP). 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.

Distribution

Vd: Children 8 months to 18 years: 12.7 ± 8.5 L/kg; penetrates CSF (CSF concentrations are ~18% of plasma concentration) (Kearns, 1994); Adults: ~9 L/kg; penetrates CSF (CSF concentrations are ~25% of plasma concentrations)

Excretion

Urine (18%)

Half-Life Elimination

Children 8 months to 18 years: 19.7 ± 3.4 hours (Kearns, 1994) ; Adults: After a 2-hour infusion (with normal renal function): 5.4 hours

Protein Binding

~20%

Use: Labeled Indications

Treatment of active 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

Contraindications

Hypersensitivity to cladribine or any component of the formulation

Dosage

Children: IV:

Acute myeloid leukemia (off-label 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 (off-label 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: IV: 0.09 mg/kg/day continuous infusion for 7 days for 1 cycle or (off-label dosing) 0.1 mg/kg/day continuous infusion for 7 days for 1 cycle (Goodman, 2003; Saven, 1998)

Acute myeloid leukemia, induction (off-label use): IV: 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 (off-label use): IV: 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 (off-label use): IV: 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 (off-label use):

IV: 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: No dosage adjustment provided in the manufacturer’s labeling (due to inadequate data); use with caution. The following adjustments have been used (Aronoff, 2007):

Children:

CrCl 10-50 mL/minute: Administer 50% of dose

CrCl <10 mL/minute: Administer 30% of dose

Hemodialysis: Administer 30% of dose

Continuous renal replacement therapy (CRRT): Administer 50% of dose

Adults:

CrCl 10-50 mL/minute: Administer 75% of dose

CrCl <10 mL/minute: Administer 50% of dose

Continuous ambulatory peritoneal dialysis (CAPD): Administer 50% of dose

Dosing adjustment in hepatic impairment: No dosage adjustment provided in the manufacturer’s labeling (due to inadequate data); use with caution.

Dosing in obesity: ASCO Guidelines for appropriate chemotherapy dosing in obese adults with cancer: Utilize patient’s actual body weight (full weight) for calculation of body surface area- or weight-based dosing, particularly when the intent of therapy is curative; manage regimen-related toxicities in the same manner as for nonobese patients; if a dose reduction is utilized due to toxicity, consider resumption of full weight-based dosing with subsequent cycles, especially if cause of toxicity (eg, hepatic or renal impairment) is resolved (Griggs, 2012).

Reconstitution

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

A precipitate may develop at low temperatures and may be resolubilized at room temperature or by shaking the solution vigorously. Inadvertent freezing does not affect the solution; if freezing occurs prior to dilution, allow to thaw naturally; do not heat or microwave; do not refreeze.

To prepare a 24-hour continuous infusion: Dilute in 500 mL NS. The manufacturer recommends filtering with a 0.22 micron hydrophilic syringe filter prior to adding to infusion bag.

To prepare a 7-day continuous infusion: Dilute to a total volume of 100 mL in a CADD medication cassette reservoir using bacteriostatic NS. Filter diluent and cladribine with a 0.22 micron hydrophilic filter prior to adding to cassette/reservoir.

Administration

IV: Administer as a continuous infusion. May also be administered over 30 minutes or over 2 hours (off-label administration rates) depending on indication and/or protocol.

SubQ (off-label route): May also be administered SubQ (Laszlo, 2010)

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

Compatibility

Stable in NS; incompatible with D5W.

Storage

Store intact vials refrigerated at 2°C to 8°C (36°F to 46°F). Protect from light. A precipitate may develop at low temperatures and may be resolubilized at room temperature or by shaking the solution vigorously. Inadvertent freezing does not affect the solution; if freezing occurs prior to dilution, allow to thaw naturally prior to reconstitution; do not heat or microwave; do not refreeze.

24-hour continuous infusion: Dilutions for infusion should be used promptly; if not used promptly, the 24-hour infusion may be stored refrigerated for up to 8 hours prior to administration.

7-day continuous infusion: Dilutions for infusion should be used promptly; if not used promptly, the 7-day infusion may be stored refrigerated for up to 8 hours prior to administration. Reconstituted solution is stable for 7 days (when diluted in bacteriostatic NS) in a CADD® medication cassette reservoir. For patients weighing >85 kg, the effectiveness of the preservative in the bacteriostatic diluent may be reduced (due to dilution).

Drug Interactions

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). 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. Consider therapy modification

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Avoid combination

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). 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. Avoid combination

Adverse Reactions

>10%:

Central nervous system: Fever (33% to 69%; ≥100°F: 67%; ≥104°F: 11%), fatigue (11% to 45%), headache (7% to 22%)

Dermatologic: Rash (10% to 27%)

Gastrointestinal: Nausea (22% to 28%), appetite decreased (8% to 17%), vomiting (9% to 13%)

Hematologic: Neutropenia (grade 4: 70%; recovery: by week 5); anemia (1% to 37%; recovery: by week 8); myelosuppression (34%; prolonged), neutropenic fever (8% to 47%; severe: 32%), thrombocytopenia (grade 4: 12%; recovery: by day 12)

Local: Injection site reactions (9% to 19%)

Respiratory: Abnormal breath sounds (4% to 11%)

Miscellaneous: Infection (month 1: 28% [serious: 6%]; month 2: 6%)

1% to 10%:

Cardiovascular: Edema (2% to 6%), tachycardia (2% to 6%), thrombosis (2%)

Central nervous system: Chills (2% to 9%), dizziness (6% to 9%), insomnia (3% to 7%), malaise (5% to 7%), pain (6%), anxiety (1%)

Dermatologic: Purpura (10%), petechiae (2% to 8%), pruritus (2% to 6%), erythema (6%), hyperhidrosis (3%), bruising (1% to 2%)

Gastrointestinal: Diarrhea (7% to 10%), constipation (4% to 9%), abdominal pain (4% to 6%), flatulence (1%)

Local: Phlebitis (2%)

Neuromuscular & skeletal: Weakness (6% to 9%), myalgia (6% to 7%), arthralgia (3% to 5%), muscle weakness (1%)

Respiratory: Cough (7% to 10%), abnormal chest sounds (9%), dyspnea (5% to 7%), epistaxis (5%), rales (1%)

Miscellaneous: Diaphoresis (9%)

<1% (Limited to important or life-threatening): Aplastic anemia, bacteremia, CD4 lymphocytopenia (nadir: 4-6 months), cellulitis, consciousness decreased, conjunctivitis, hemolytic anemia, hypereosinophilia, hypersensitivity, myelodysplastic syndrome, 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, quadriparesis (reported at high doses); renal dysfunction (with high doses), renal failure, septic shock, Stevens-Johnson syndrome, stroke, toxic epidermal necrolysis, tuberculosis reactivation, tumor lysis syndrome

ALERT: U.S. Boxed Warning

Experienced physician:

Cladribine should be administered under the supervision of a qualified health care provider experienced in the use of antineoplastic therapy.

Bone marrow suppression:

Anticipate suppression of bone marrow function. This is usually reversible and appears to be dose dependent.

Neurotoxicity:

Serious neurological toxicity (including irreversible paraparesis and quadriparesis) has been reported in patients who received cladribine by continuous infusion at high doses (4 to 9 times the recommended dose for hairy cell leukemia). Neurologic toxicity appears to demonstrate a dose relationship; however, severe neurological toxicity has been reported rarely following treatment with standard cladribine dosing regimens.

Renal toxicity:

Acute nephrotoxicity has been observed with high doses of cladribine (4 to 9 times the recommended dose for hairy cell leukemia), especially when given concomitantly with other nephrotoxic agents/therapies.

Warnings/Precautions

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 preexisting 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, although serious infections including sepsis have been reported); 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, dose-related neurologic toxicity (including irreversible paraparesis and quadriparesis) has been reported with continuous infusions of higher doses (4-9 times the FDA-approved dose); may also occur at approved doses (rare). Neurotoxicity may be delayed and may present as progressive, irreversible weakness; 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), particularly when administered 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.

Dosage form specific issues:

• Benzyl alcohol and derivatives: Weekly (7-day) infusion preparation recommends further dilution with bacteriostatic normal saline which contains benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC, 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors, 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates. See manufacturer’s labeling.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

Other warnings/precautions:

• Experienced physician: [U.S. Boxed Warning]: Should be administered under the supervision of an experienced cancer chemotherapy physician.

• Vaccines: Administration of live vaccines is not recommended during treatment with cladribine (may increase the risk of infection due to immunosuppression).

Monitoring Parameters

CBC with differential (particularly during the first 4-8 weeks post-treatment), renal and hepatic function; bone marrow biopsy (after CBC has normalized, to confirm treatment response); monitor for fever; monitor for signs/symptoms of neurotoxicity

Pregnancy Risk Factor

D

Pregnancy Considerations

Teratogenic effects and fetal mortality were observed in animal reproduction studies. May cause fetal harm if administered during pregnancy. Women of reproductive potential should use highly effective contraception during treatment.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience dizziness, headache, cough, muscle pain, or lack of appetite. Have patient report immediately to prescriber signs of infection, signs of kidney problems (urinary retention, blood in urine, change in amount of urine passed, weight gain), numbness, tingling, or weakness in arms or legs, tachycardia, arrhythmia, bruising, bleeding, shortness of breath, severe nausea, vomiting, severe diarrhea, dark urine, jaundice, severe skin irritation, loss of strength and energy, severe injection site irritation, or signs of tumor lysis syndrome (fast heartbeat or abnormal heartbeat; any passing out; trouble passing urine; muscle weakness or cramps; nausea, vomiting, diarrhea or lack of appetite; or feel sluggish) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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