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Drug Formulary information is intended for use by healthcare professionals. It is not intended to be medical advice. Some of the information, including information about funding for cancer drugs, does not apply to all patients. Cancer treatment plans are unique to each patient. If you are a patient, please speak with your healthcare team to understand how this information applies to you.

A - Drug Name

cladribine

SYNONYM(S):   2-chloro-2'-deoxyadenosine; CdA, 2-CdA; NSC-105014-F

COMMON TRADE NAME(S):   Leustatin® (generic brand available)

 
B - Mechanism of Action and Pharmacokinetics

Cladribine is structurally related to fludarabine and pentostatin but has a different mechanism of action. It is phosphorylated by deoxycytidine kinase to its corresponding nucleotide CdATP, which accumulates and is incorporated into the DNA of cells such as lymphocytes. High levels of CdATP lead to DNA strand breaks, inhibition of DNA synthesis, and cell death. May be selective for cells with high deoxycytidine kinase. Unlike other antimetabolite drugs, cladribine has cytotoxic effects on resting as well as proliferating lymphocytes and monocytes. It causes cells to accumulate at the G1/S phase junction, suggesting that cytotoxicity is associated with events critical to cell entry into S phase. Cladribine is resistant to deamination by adenosine deaminase.



Absorption
Acid labile
Bioavailability (oral) 37-55%

Distribution

No information found

Cross blood brain barrier? 25% of plasma levels
PPB 20%
Metabolism

Prodrug, activated by intracellular phosphorylation

Active metabolites CdATP
Inactive metabolites Chloroadenine
Elimination

Biphasic

Urine 10-30%, within 24 hours
Half-life 5.4 hours (terminal t½)
 
C - Indications and Status
Health Canada Approvals:

  • Hairy cell leukemia


 
D - Adverse Effects

Emetogenic Potential:  

Minimal

Extravasation Potential:   None

Adverse effects include those with incidences ≥ 5% and those that are less common, but may be severe. Exact incidences are noted where available.

ORGAN SITE SIDE EFFECT* (%) ONSET**
Cardiovascular Tachycardia (≥5%) E
Venous thromboembolism (2%) (thrombosis) E  D
Dermatological Rash (27%) (may be severe) E
Gastrointestinal Abdominal pain (≥5%) E
Anorexia (≥5%) I  E
Constipation (≥5%) E
Diarrhea (≥5%) E
Nausea, vomiting (28%) (mild) I  E
General Edema (≥5%) E
Fatigue (45%) E
Fever (69%) I
Hematological Hemolysis (rare) E
Myelosuppression ± infection, bleeding (70%) (37% severe anemia) E
Hepatobiliary ↑ LFTs (mild; rare) E  D
Hypersensitivity Drug reaction (rare) I
Infection Infection (28%) (including opportunistic) E
Injection site Injection site reaction (19%) I
Metabolic / Endocrine Tumor lysis syndrome (rare) I
Musculoskeletal Musculoskeletal pain (≥5%) E
Neoplastic Secondary malignancy (including MDS; rare) L
Nervous System Dizziness (≥5%) E
Headache (22%) I
Insomnia (≥5%) E
Neurotoxicity (rare for standard dose; 45% with high dose) E  D
Ophthalmic Conjunctivitis E
Renal Nephrotoxicity (with high doses; rare) E
Respiratory Cough, dyspnea (7%) E
Pneumonitis (rare) E


* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare" may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal reports.
Dose-limiting side effects are underlined.

** I = immediate (onset in hours to days)     E = early (days to weeks)
D = delayed (weeks to months)      L = late (months to years)

The most common side effects for cladribine include myelosuppression, fever, fatigue, infection, nausea, vomiting, rash, headache, injection site reaction, cough, dyspnea and abdominal pain.

Patients at risk of tumour lysis syndrome should have appropriate prophylaxis and be monitored closely.

Severe bone marrow suppression has been commonly observed, especially at high doses. This appears to be dose-dependent and is usually reversible. Significant and prolonged lymphopenia has been noted. Cumulative myelotoxicity and prolonged thrombocytopenia can occur after multiple cycles.

Febrile episodes and infections are common. Cladribine can be immunosuppressive, causing a reduction in the number of CD4 (helper) and CD8 (suppressor) T lymphocytes, which can last for years. Cases of  opportunistic infections and secondary malignancies have been reported.

High doses (4 to 9 times the recommended dose x 7-14 days) in conjunction with cyclophosphamide and total body radiation as preparation for bone marrow transplantation have been associated with severe, irreversible neurologic toxicity (paraparesis, quadriparesis, axonal polyneuropathy, demyelination) and/or acute renal impairment (some patients required dialysis). Axonal neuropathy has been reported with high doses of cladribine alone. Neurologic toxicity appears to be dose-related; however, severe neurotoxicity has been reported rarely with standard cladribine dosing regimens (0.09mg/kg/day x 7 days).

Severe rashes, including Steven-Johnson Syndrome and Toxic Epidermal Necrolysis have been reported in patients who were also receiving other medications (e.g. allopurinol, antibiotics).

 
E - Dosing

Refer to protocol by which patient is being treated.  Numerous dosing schedules exist depending on disease, response and concomitant therapy.

Usually given as a continuous infusion.  Patients who respond to their first course of cladribine may be retreated, but non-responsive patients rarely gain benefit from additional courses. 



Adults:

Intravenous: 0.09 mg/kg/day as continuous infusion for 7 days

Dosage with Toxicity:

Toxicity

Cladrabine dose

Myelosuppression

No adjustment required. Consider delay until recovery to baseline counts.

Neurotoxicity

Delay or discontinue, depending on severity

Nephrotoxicity

Delay or discontinue, depending on severity. See dosage with renal impairment table.

 

 



Dosage with Hepatic Impairment:

Exercise caution. No data available.



Dosage with Renal Impairment:

10-30% excretion in urine, thus caution should be exercised.

Suggested reductions:

Creatinine clearance (mL/min)

% dose

≥ 50

100%

10-50

75%

≤ 10

50%

 


Dosage in the elderly:

Use with caution due to possible decreases in hepatic, renal, or cardiac function.



Children:

Safety and efficacy in children have not been established. Fatal dose-limiting toxicity occurred at doses of 10.7mg/m2/day in a Phase I study. Do not use benzyl alcohol-containing diluents in infants or neonates.

 



 
F - Administration Guidelines
  • Continuous infusion; can be given by ambulatory infusion with CADD pump.  Bacteriostatic normal saline (containing benzyl alcohol preservative) should be used as diluent. Drug and diluent should be passed through 0.22 µ hydrophilic syringe filter.
  • May mix in 500 mL Normal Saline and administer over 2 hours each day.
  • Do not mix with dextrose 5% in water (results in increased degradation of cladribine).
  • Do not admix with other drugs.
  • Vials and infusion solution should be protected from light and refrigerated (2-8°C)
  • Refer to the cladrabine product monograph for detailed stability information
 
G - Special Precautions
Contraindications:

  • patients who have a hypersensitivity to this drug or any of its components

Other Warnings/Precautions:

  • Exercise caution in patients with severe bone marrow impairment of any etiology.

  • Patients receiving high doses in a clinical trial (prior to bone marrow transplantation) had severe neurotoxicity

  • Avoid the use of live vaccines due to the increased risk of infection.


Other Drug Properties:

  • Carcinogenicity: Yes

Pregnancy and Lactation:
  • Clastogenicity: Yes
  • Genotoxicity: Yes
  • Fetotoxicity: Yes
  • Embryotoxicity: Yes

    Cladrabine is not recommended for use in pregnancy.  Adequate contraception should be used by both sexes during treatment, and for at least 6 months after the last dose.

  • Excretion into breast milk: Probable

    Breastfeeding is not recommended.

  • Fertility effects: Probable
 
H - Interactions

No significant drug interactions reported. Exercise caution when administered in association with other agents known to cause myelosuppression.

 
I - Recommended Clinical Monitoring
Recommended Clinical Monitoring

Monitor Type Monitor Frequency

CBC

Baseline, at each visit and as clinically indicated, especially during the first 4 to 8 weeks after treatment

Uric acid

Baseline and as clinically indicated, especially when treatment is initiated and in patients at risk of tumour lysis syndrome

Renal and liver function tests

Baseline, at each visit and as clinically indicated, especially with underlying renal or hepatic impairment

Clinical toxicity assessment for fever, infection, bleeding, rash, neurotoxicity, fatigue and GI toxicity

At each visit

Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version



 
K - References

Else M, Dearsden CE, Matutes E, et al.  Long-term follow-up of 233 patients with hairy cell leukaemia, treated initially with pentostatin or cladribine, at a median of 16 years from diagnosis.  BJH 2009; 145; 733–40.

Else M, Osuji N, Francesco F, et al.  The role of rituximab in combination with pentostatin or cladribine for the treatment of recurrent/refractory hairy cell leukemia.  Cancer 2007; 110: 2240-7.

Morton J, Taylor K, Bunce I, et al.  High response rates with short infusional 2-chlorodeoxyadenosine in novo and relapsed low-grade lymphoma.   Australian and New Zealand Lymphoma Study Group. Br J Haematol. 1996 Oct; 95(1): 110-5.

Piro LD, Carrera CJ, Carson DA, et al.  Lasting remissions in hairy-cell leukemia induced by a single infusion of 2-chlorodeoxyadenosine.  NEJM 1990; 322; 1117-21.

Product Monograph:  Cladribine for injection.  Fresenius Kabi Canada Ltd., March 2015.


October 2017 updated adverse effects, administration, precautions and monitoring sections

 
L - Disclaimer

Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.

The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.

The format and content of the drug monographs, regimen monographs, appendices and symptom management information contained in the Formulary will change as they are reviewed and revised on a periodic basis. The date of last revision will be visible on each page of the monograph and regimen. Since standards of usage are constantly evolving, it is advised that the Formulary not be used as the sole source of information. It is strongly recommended that original references or product monograph be consulted prior to using a chemotherapy regimen for the first time.

Some Formulary documents, such as the medication information sheets, regimen information sheets and symptom management information (for patients), are intended for patients. Patients should always consult with their healthcare provider if they have questions regarding any information set out in the Formulary documents.

While care has been taken in the preparation of the information contained in the Formulary, such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability.

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