LEUSTATIN(r)
antimetabolite, cytotoxic
Special pediatric considerations are noted when applicable, otherwise adult provisions apply.
Like fludarabine, cladribine is a synthetic purine nucleoside prodrug that is resistant to deamination by adenosine deaminase which permits intracellular accumulation.1 Cladribine is phosphorylated via deoxycytidine kinase to the active triphosphate derivative (CdATP) which inhibits ribonucleotide reductase.4 In cells such as lymphocytes with high levels of deoxycytidine kinase and low levels of deoxynucleotidase, CdATP also prevents elongation of DNA strands via direct incorporation into DNA as a false nucleotide.1,4 Depletion of adenine dinucleotide and adenosine triphosphate (ATP) also occurs.1,4 Unlike other drugs that affect purine metabolism, cladribine has cytotoxic effects on actively dividing and resting cells.4 Cladribine is an immunosuppressive agent.4
| Oral Absorption | oral solution: 37-55% 5,6 ; investigational | |
| Distribution | extensive 2 | |
| cross blood brain barrier? | yes; ~25% of plasma concentration | |
| volume of distribution (V D ) | 4.52 + 2.82 L/kg | |
| plasma protein binding | 20% | |
| Metabolism | phosphorylated to CdATP | |
| active metabolite(s) | CdATP | |
| inactive metabolite(s) 5 | chloroadenine | |
| Excretion | biphasic | |
| urine 4,6 | 18-44% | |
| feces | no information found | |
| terminal half life | 5.4 h | |
| clearance | 664 ml/h/kg 29.5 + 8.3 L/h/m 2 | |
| Children 7,8 | V D =305-357 L/m 2 ; clearance=39 L/h/m 2 ; longer terminal half life than adults | |
Adapted from standard reference4 unless specified otherwise.
| Primary uses: | Other uses: |
| * Leukemia, hairy cell | Leukemia, chronic lymphocytic 1,6 |
| Leukemia, chronic myelogenous 6 | |
| Lymphoma, cutaneous T-cell 1 | |
| Lymphoma, non-Hodgkin's 1,6 | |
*Health Canada approved indication
Cladribine produces severe myelosuppression; monitor hematologic function regularly especially during the first 4- 8 weeks after therapy.4
High-doses
(4-9 times the recommended dose for hairy cell leukemia) as preparation for BMT, have been associated with:
serious neurotoxicity including irreversible paraparesis and quadriparesis (35-45%)
1,4
acute nephrotoxicity (19-45%)
1,4
severe bone marrow suppression4
Hepatitis B (HBV) reactivation:
All lymphoma patients should be tested for both HBsAg and HBcAb. If either test is positive, such patients should be treated with lamivudine 100 mg/day orally, for the entire duration of chemotherapy and for six months afterwards. Such patients should also be monitored with frequent liver function tests and HBV DNA at least every two months. If the HBV DNA level rises during this monitoring, management should be reviewed
with a hepatologist and consideration given to halting chemotherapy.
9,10
Carcinogenicity: not studied to date4; based on genotoxicity, carcinogenicity cannot be ruled out 4 Mutagenicity: Not mutagenic in Ames test and mammalian in vitro mutation test.4 Cladribine is clastogenic in mammalian in vitro and in vivo chromosome tests.4 Fertility: effect unknown4; in monkeys, cladribine affects testicular cells4 Pregnancy: FDA Pregnancy Category D.6 Although there is no evidence of teratogenicity in humans, teratogenic effects and fetal mortality have been observed in animals6; other drugs that inhibit DNA synthesis have been reported to be teratogenic.4
Breastfeeding 4
is not recommended due to the potential secretion into breast milk.
The table includes adverse events that presented during drug treatment but may not necessarily have a causal relationship with the drug. Because clinical trials are conducted under very specific conditions, the adverse event rates observed may not reflect the rates observed in clinical practice. Adverse events are generally included if they were reported in more than 1% of patients in the product monograph or pivotal trials, and/or determined to be clinically important.9
| ORGAN SITE | SIDE EFFECT |
| Clinically important side effects are in bold, italics At recommended doses, most nonhematologic adverse effects are typically mild to moderate in severity. 1 | |
| blood/bone marrow/ febrile neutropenia | anemia (severe 37%) nadir typically occurs during the first 2 weeks with recovery by week 8; hemolytic anemia and aplastic anemia also reported |
| bone marrow hypocellularity (34%); prolonged hypocellularity (32 months) has been reported | |
| erythroid macrocytosis 1 ; prolonged, reported in patients who received up to 6 courses of cladribine 1 | |
| lymphopenia ; may be significant and prolonged neutropenia (severe 70%); nadir typically occurs during the first 2 weeks with recovery by week 5 febrile neutropenia (47%) 32% with severe neutropenia hypereosinophilia; typically occurs in patients receiving multiple courses of cladribine 1 | |
| myelosuppression; dose-related, most notable during the first month after treatment | |
| thrombocytopenia (12%); nadir typically occurs during the first 2 weeks with recovery by day 12; recovery may be delayed in patients with severe baseline thrombocytopenia 1 | |
| cardiovascular (arrhythmia) | tachycardia ( < 6%) 1,4,6 |
| ORGAN SITE | SIDE EFFECT |
| Clinically important side effects are in bold, italics At recommended doses, most nonhematologic adverse effects are typically mild to moderate in severity. 1 | |
| constitutional symptoms | chills ( < 9%) 1,4,6 |
| fatigue ( < 45%), asthenia ( < 9%) 1,4 | |
| fever (67-69%, severe 11%); during the first month of therapy; less than 1/3 of febrile events are associated with a documented infection | |
| insomnia ( < 7%) 1,4 | |
| diaphoresis ( < 9%) 1,4,6 | |
| dermatology/skin | extravasation hazard: none 11 |
| injection site reaction ( < 19%); including redness ( < 6%), 1,4 swelling, pruritis ( < 6%), 1,4 pain ( < 6%) 4 | |
| phlebitis (2%); likely related to the infusion procedure and/or indwelling catheter rather than the treatment | |
| rash ( < 27%); typically mild | |
| Stevens-Johnson syndrome and toxic epidermal necrolysis (<1%) | |
| urticaria; typically occurs in patients receiving multiple courses of cladribine 1 | |
| gastrointestinal | emetogenic potential: rare 12 |
| anorexia ( < 17%) 1,4 | |
| constipation ( < 9%) 1,4,6 | |
| diarrhea ( < 10%) 1,4,6 | |
| nausea (28%); typically mild and not associated with vomiting | |
| vomiting ( < 13%) 1,4,6 | |
| hemorrhage | epistaxis (>5%) 1,4,6 |
| purpura ( < 10%), 1,4,6 petechiae ( < 8%) 1,4,6 | |
| hepatobiliary/pancreas | elevated bilirubin and transaminases; reversible and typically mild; typically occurs in patients receiving multiple courses of therapy 1 |
| infection | immunosuppression ; prolonged depression of CD4 counts and transient suppression of CD8 counts; CD4 nadir typically occurs during the first 4-6 months with recovery by 40 months; prolonged lymphopenia has occurred |
| infection (28%); during the first month after treatment; including serious infection e.g., septicemia, pneumonia (6%) and those associated with immunosuppression e.g., opportunistic infections: fungal, viral; deaths have occurred | |
| lymphatics | edema ( < 6%) 1,4,6 |
| metabolic/laboratory | hyperuricemia |
| musculoskeletal | myalgia ( < 7%) 1,4,6 ; arthralgia (>5%) 1,4,6 |
| weakness (9%) 6 | |
| neurology | dizziness ( < 9%) 1,4,6 |
| neurotoxicity (severe <1%); with standard-dose neurotoxicity (35-45%) 1,4 ; with high-dose (4-9 times the recommended dose); may be severe and irreversible including peripheral polyneuropathy, paraparesis, and quadriparesis | |
| ORGAN SITE | SIDE EFFECT |
| Clinically important side effects are in bold, italics At recommended doses, most nonhematologic adverse effects are typically mild to moderate in severity. 1 | |
| pain | abdominal pain ( < 6%) 1,4,6 |
| headache ( < 22%) | |
| trunk pain ( < 6%) 1,4 | |
| pulmonary | abnormal breath sounds ( < 11%) 1,4,6 |
| cough ( < 10%) 1,4,6 | |
| dyspnea ( < 7%) 1,4,6 | |
| pulmonary interstitial infiltrates; typically of infectious etiology | |
| renal/genitourinary | renal insufficiency (19-45%) 1,4 ; with high-dose (4-9 times the recommended dose); not reported with standard doses |
| secondary malignancy | myelodysplastic syndrome (0.03%) |
| syndromes | tumour lysis syndrome (<1%) |
| vascular | thrombosis (2%); likely related to the infusion procedure and/or indwelling catheter rather than treatment |
Adapted from standard reference4 unless specified otherwise. Hyperuricemia may result from cell lysis by cytotoxic chemotherapy and may lead to electrolyte disturbances or acute renal failure.13 It is most likely with highly proliferative tumours of massive burden, such as leukemias, high- grade lymphomas, and myeloproliferative diseases. The risk may be increased in patients with preexisting renal dysfunction, especially ureteral obstruction. Suggested prophylactic treatment for high-risk patients14: aggressive hydration: 3 L/m2/24 hr with target urine output > 100 mL/hr if possible, discontinuation of drugs that cause hyperuricemia (e.g., thiazide diuretics) or acidic urine (e.g., salicylates) monitoring of electrolytes, calcium, phosphate, renal function, LDH, and uric acid q6h x 24-48 hours electrolyte replacement as required allopurinol 600 mg po initially, then 300 mg po q6h x 6 doses, then 300 mg po daily x 5-7 days Urine should be alkalinized only if the uric acid level is elevated, using sodium bicarbonate IV or PO titrated to maintain urine pH > 7. Rasburicase (FASTURTEC(r)) is a novel uricolytic agent that catalyzes the oxidation of uric acid to a water-soluble metabolite, removing the need for alkalinization of the urine.15 It may be used for treatment or prophylaxis of hyperuricemia, 0.2 mg/kg IV daily for up to 7 days; however, its place in therapy has not yet been established.
no documented interactions
Injection4
: Janssen-Ortho Inc. supplies cladribine as a preservative-free 10 mg/10 mL solution. Store in the refrigerator, protect from light during storage. Freezing does not affect the solution. If freezing occurs, thaw at room temperature, do not refreeze.
For basic information on the current brand used at the BC Cancer Agency, see Chemotherapy Preparation and Stability Chart in Appendix.
For basic information on the current brand used at the BC Cancer Agency, see Chemotherapy Preparation and Stability Chart in Appendix.
Additional information: 4
must be diluted prior to intravenous administration
Compatibility:
consult detailed reference
| BCCA administration guideline noted in bold , italics | |
| Subcutaneous 2,6,10 | rotate sites on thighs, abdomen, and flank |
| Intramuscular | no information found |
| Direct intravenous 4 | not recommended; must be diluted prior to intravenous administration 4 |
| Intermittent infusion 4,6 | over 1- 2 h |
| Continuous infusion 4 | over 24 h; 7-day infusions have been used |
| Intraperitoneal | no information found |
| Intrapleural | no information found |
| Intrathecal | no information found |
| Intra-arterial | no information found |
| Intravesical | no information found |
Refer to protocol by which patient is being treated. Numerous dosing schedules exist and depend on disease, response, and concomitant therapy. Guidelines for dosing also include consideration of absolute neutrophil count (ANC). Dosage may be reduced, delayed or discontinued in patients with bone marrow depression due to cytotoxic/radiation therapy or with other toxicities.
Adults:
| BCCA usual dose noted in bold, italics | ||
| Cycle Length: | ||
| Intravenous: | n/a 6,10 : | 0.14 mg/kg ( range 0.028-0.14 mg/kg) IV or SC once daily for 5 consecutive days starting on day 1 (total dose 0.7 mg/kg [range 0.14-0.7 mg/kg]) |
| n/a 41,6 : | 0.09-0.1 mg/kg IV over 24 hours for 7 consecutive days starting on day 1 (total dose 0.63-0.7 mg/kg) may be administered as a continuous 7-day infusion | |
| n/a 2,4 : | 3.6 mg/m 2 IV over 24 hours for 7 consecutive days starting on day 1 (total dose 25.2 mg/m 2 ) may be administered as a continuous 7-day infusion | |
BCCA usual dose noted in bold, italics n/a1,6: 3.4 mg/m2 SC once daily for 7 consecutive days starting on day 1 (total dose 23.8 mg/m2)
Concurrent radiation:
no information found
Dosage in myelosuppression:
modify according to protocol by which patient is being treated; if no guidelines
available, refer to Appendix 6 "Dosage Modification for Myelosuppression" Dosage in renal failure: use with caution4; dosage adjustment recommendations exist16, including the following 10:
| Creatinine clearance (mL/min) | Dose |
| >70 | 100% |
| 30-70 | 60% |
| <30 | do not use |
Calculated creatinine clearance = N * x (140 - Age) x weight in kg * For males N=1.23; for females N=1.04
Dosage in hepatic failure: 4
use with caution
Dosage in dialysis: 1
unknown if removed by dialysis
*
Children:
safety and effectiveness have not been established4; has been used1,6-8 *Cladribine IV solutions prepared with bacteriostatic NS, for a 7-day infusion, contain benzyl alcohol and should NOT be used in neonates4
McEvoy GK, editor. AHFS 2007 Drug Information. Bethesda, Maryland: American Society of Health-System Pharmacists, Inc. p. 979-982.
MARTINDALE - The Complete Drug Reference (database on the Internet). Caldribine. Thomson MICROMEDEX(r), 2008. Available at: http://www.micromedex.com/. Accessed 12 Mar 2008.
National Institute for Occupational Safety and Health (NIOSH). Preventing occupational exposures to antineoplastic and other hazardous drugs in healthcare settings. Cincinnati, Ohio: NIOSH - Publications Dissemination; September 2004. p. 31-40.
Janssen-Ortho Inc. LEUSTATIN(r) Product Monograph. Toronto, Ontario; 31 July 2006.
DRUGDEX(r) Evaluations (database on the Internet). Cladribine. Thomson MICROMEDEX(r), 2008. Available at: www.micromedex.com. Accessed 13 Mar 2007.
Rose BD editor. Cladribine. UpToDate 15.3 ed. Waltham, Massachusetts: UpToDate(r); 2008.
Pizzo P, Poplack D. Principles and Practice of Pediatric Oncology. 5th ed. Philadelphia, Pennsylvania: Lippincott Williams & Wilkins; 2006. p. 301.
Rose BD editor. Cladribine: Pediatric Drug Information. UpToDate 15.3 ed. Waltham, Massachusetts: UpToDate(r); 2008.
Joseph Connors MD. Personal communication. BC Cancer Agency Lymphoma Tumour Group; 28 March 2008.
BC Cancer Agency Lymphoma Tumour Group. (LYCDA) BCCA Protocol Summary for Tretament of Hairy Cell Leukemia with Cladribine. Vancouver, British Columbia: BC Cancer Agency; 1 February 2007.
BC Cancer Agency Provincial Systemic Therapy Program. Provincial Systemic Therapy Program Policy III-20: Prevention and Management of Extravasation of Chemotherapy. Vancouver, British Columbia: BC Cancer Agency; 1 December 2007.
BC Cancer Agency. (SCNAUSEA) Guidelines for Prevention and Treatment of Chemotherapy-induced Nausea and Vomiting in Adults. Vancouver, British Columbia: BC Cancer Agency; 1 March 2008.
DeVita VT, Hellman S, Rosenberg SA. Cancer Principles & Practice of Oncology. 6th ed. Philadelphia, Pennsylvania: Lippincott Williams & Wilkins; 2001. p. 2640.
Leukemia/Bone Marrow Transplant Program of British Columbia. Leukemia/BMT Manual. 4th ed. Vancouver, British Columbia: Vancouver Hospital and Health Sciences Centre / BC Cancer Agency; 2003. p. 27.
Sanofi-Synthelabo. Rasburicase product information. Markham, Ontario; 2004.
Aronoff GR, Bennett WM, Berns JS, Brier ME, et al. Drug Prescribing in Renal Failure: Dosing guidelines for adults and children. 5th ed. Philadelphia, Pennsylvania: American College of Physicians; 2007. p. 98.