Leustatin (Cladribine)

LEUSTATIN®

Janssen-Ortho

Cladribine

Antineoplastic – Chemotherapeutic Agent

Warning: Cladribine should be administered under the supervision of a qualified physician experienced in the use of antineoplastic therapy.

Suppression of bone marrow function should be anticipated. This is usually reversible and appears to be dose-dependent. Significant and prolonged lymphopenia has been noted.

Serious neurological toxicity (including irreversible paraparesis and quadriparesis) has been reported in patients who received cladribine injection 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 dose regimens.

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.

Action And Clinical Pharmacology: Cladribine (also commonly known as 2-chloro-2-deoxy-B-D-adenosine) is a synthetic antineoplastic agent. The selective toxicity of cladribine towards certain normal and malignant lymphocyte and monocyte populations is based on the relative activities of deoxycytidine kinase, and deoxynucleotidase. Like some other deoxypurine nucleosides, cladribine crosses the cell membrane by facilitated diffusion. In cells with a high ratio of deoxycytidine kinase to deoxynucleotidase, it is phosphorylated by deoxycytidine kinase to 2-chloro-2-deoxy-B-D-adenosine monophosphate (2-CdAMP). Since cladribine is resistant to deamination by adenosine deaminase and there is little deoxynucleotidase in lymphocytes and monocytes, 2-CdAMP accumulates intracellularly and is subsequently converted into the active triphosphate deoxynucleotide, 2-chloro-2-deoxy-B-D-adenosine triphosphate (2-CdATP). It is postulated that cells with high deoxycytidine kinase and low deoxynucleotidase activities will be selectively killed by cladribine as toxic deoxynucleotides accumulate intracellularly.

Cells containing high concentrations of deoxynucleotides are unable to properly repair single-strand DNA breaks. The broken ends of DNA activate the enzyme poly (ADP-ribose) polymerase resulting in NAD and ATP depletion and disruption of cellular metabolism. There is evidence, also, that 2-CdATP is incorporated into the DNA of dividing cells, resulting in impairment of DNA synthesis. Thus cladribine can be distinguished from other chemotherapeutic agents affecting purine metabolism in that it is cytotoxic to both actively dividing and quiescent lymphocytes and monocytes, inhibiting both DNA synthesis and repair.

Pharmacokinetics: In one study following 7 days of continuous infusion of i.v. cladribine (0.09 mg/kg/day), the mean steady-state serum concentration was estimated to be 5.7 ng/mL with an estimated systemic clearance of 663.5 mL/hr/kg. Accumulation of cladribine over the 7 day treatment period was not noted.

In a second study, following a 2 hour infusion of cladribine (0.12 mg/kg), the mean end-of-infusion plasma cladribine concentration was 48±19 ng/mL. The mean harmonic terminal half-life was 5.4 hours. Mean values for clearance and steady-state volume of distribution were 978±422 mL/hr/kg and 4.52±2.82 L/kg, respectively.

In patients with Hairy Cell Leukemia (HCL) there does not appear to be a relationship between serum concentrations and ultimate clinical outcome.

Cladribine is bound approximately 20% to plasma proteins.

Except for limited understanding of the mechanism of cellular toxicity and route of excretion, no other information is available on the metabolism of cladribine in humans. An average of 18% of the administered dose has been reported to be excreted in urine of patients with solid tumors during a 5-day continuous i.v. infusion of 3.5 to 8.1 mg/mday of cladribine. Other investigators reported an approximately 30% of urinary recovery of cladribine during the first 24 hour post-infusion period during 5-day 2-hour i.v. infusion of 3.5 to 10.5 mg/mday of cladribine in patients with solid tumors and during 5-day 2-hour i.v. infusion of 6 to 12 mg/mday of cladribine in 10 patients with leukemia or lymphoma. The effect of renal and hepatic impairment on the elimination of cladribine has not been investigated in humans.

Indications And Clinical Uses: For the treatment of patients with Hairy Cell Leukemia.

Contra-Indications: In those patients who are hypersensitive to this drug or any of its components.

Manufacturers’ Warnings In Clinical States: General: Cladribine should be administered under the supervision of a qualified physician experienced in the use of antineoplastic therapy.

Suppression of bone marrow function should be anticipated. This is usually reversible and appears to be dose-dependent. Significant and prolonged lymphopenia has been noted.

High doses (4 to 9 times the recommended dose for Hairy Cell Leukemia), in conjunction with cyclophosphamide and total body irradiation as preparation for bone marrow transplantation, have been associated with severe, irreversible, neurologic toxicity (paraparesis/quadriparesis) and/or acute renal insufficiency in 45% of patients treated for 7 to 14 days. In patients with Hairy Cell Leukemia treated with the recommended dose (0.09 mg/kg/day for 7 days), no nephrotoxicity has been reported.

Bone Marrow Suppression: Severe bone marrow suppression, including neutropenia, anemia and thrombocytopenia, have been commonly observed in patients treated with cladribine, especially at high doses. The myelosuppressive effects of cladribine were most notable during the first month following treatment. Forty-four per cent of patients received transfusions with RBCs and 14% received platelets during Month 1. Most patients in the clinical studies had hematologic impairment as a manifestation of active Hairy Cell Leukemia. Consequently care should be taken to distinguish disease-related bone marrow suppression from that which may result following treatment with cladribine. (During the first 2 weeks after treatment initiation, Mean Platelet Count, Absolute Neutrophil Count (ANC) and Hemoglobin concentration declined and subsequently increased with normalization of mean counts by Day 12, Week 5 and Week 8, respectively). Proceed carefully in patients with severe bone marrow impairment of any etiology since further suppression of bone marrow function should be anticipated.

Fever: Fever (T³37.8°C) was associated with the use of cladribine in approximately two-thirds of patients (131/196) in the first month of therapy. Virtually all of these patients were treated empirically with parenteral antibiotics. Overall, 47% (93/196) of all patients had fever in the setting of neutropenia (ANC£1 000´10L), including 62 patients (32%) with severe neutropenia (ANC£500´10L) (see Adverse Effects).

Effects of High Doses: Nephrotoxicity and neurotoxicity were observed in patients undergoing bone marrow transplantation for acute leukemia, who were treated with high doses of cladribine (4 to 9 times the recommended dose). In patients with Hairy Cell Leukemia treated with the recommended treatment regimen (0.09 mg/kg/day for 7 consecutive days), there have been no reports of nephrotoxicities. Deviations from the dosing regimen recommended for Hairy Cell Leukemia are not advised.

Pregnancy: Fetotoxicity: Cladribine is teratogenic in mice and rabbits and consequently has the potential to cause fetal harm when administered to a pregnant woman. A significant increase in variations of fetal growth/development (i.e., increases in cervical ribs, irregularly-shaped exoccipital bones, and variations in sternal ossification) was observed in mice receiving 1.5 mg/kg/day (4.5 mg/m and increased resorptions, reduced litter size and increased fetal malformations were observed when mice received 3 mg/kg/day (9 mg/m. Fetal death and malformations were observed in rabbits that received 3 mg/kg/day (33 mg/m. No fetal effects were seen in mice at 0.5 mg/kg/day (1.5 mg/m or in rabbits at 1 mg/kg/day (11 mg/m.

Although there is no evidence of teratogenicity due to cladribine in humans, other drugs which inhibit DNA synthesis (e.g., methotrexate and aminopterin) have been reported to be teratogenic in humans. Cladribine has been shown to be embryotoxic in mice when given at doses equivalent to the recommended dose. Cladribine should not be given during pregnancy. There are no adequate and well-controlled studies in pregnant women. If cladribine is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing age should be advised to avoid becoming pregnant.

Precautions: General: Cladribine is a potent antineoplastic agent with potentially significant toxic side effects. It should be administered only under the supervision of a physician experienced with the use of cancer chemotherapeutic agents. Patients undergoing therapy should be closely observed for signs of hematologic and non-hematologic toxicity. Careful hematologic monitoring (assessment of peripheral blood counts), particularly during the first 4 to 8 weeks post-treatment, is recommended to detect the development of anemia, neutropenia and thrombocytopenia. Since fever is a frequently observed side effect during the first month on therapy, patients should be kept well hydrated. As with other potent chemotherapeutic agents, monitoring of renal and hepatic function is also recommended, especially in patients with underlying kidney or liver dysfunction (see Warnings, Adverse Effects and Dosage).

Rare cases of tumor lysis syndrome have been reported in patients treated with cladribine with other hematologic malignancies having a high tumor burden.

Cladribine must be diluted in designated i.v. solutions prior to administration (see Dosage).

Children: Safety and effectiveness in children have not been established. In a Phase I study involving patients 1 to 21 years old with relapsed acute leukemia, cladribine was given by continuous i.v. infusion in doses ranging from 3 to 10.7 mg/mday for 5 days (one-half to twice the dose recommended in Hairy Cell Leukemia). In this study, the dose-limiting toxicity was severe myelosuppression with profound neutropenia and thrombocytopenia. At the highest dose (10.7 mg/mday), 3 of 7 patients developed irreversible myelosuppression and fatal systemic bacterial or fungal infections. No unique toxicities were noted in this study (see Warnings and Adverse Effects).

Benzyl Alcohol as a Diluent: Benzyl alcohol is a constituent of the recommended diluent for the 7-day infusion solution. Benzyl alcohol has been reported to be associated with a fatal “Gasping Syndrome” in premature infants (see Dosage).

Impairment of Fertility: When administered i.v. to Cynomolgus monkeys, cladribine has been shown to cause suppression of rapidly generating cells, including testicular cells. The effect on human fertility is unknown.

Pregnancy: See Warnings.

Lactation: It is not known whether this drug is excreted in human milk. Cladribine should not be given to a nursing mother.

Effects on Renal and Hepatic Function: Acute renal insufficiency has developed in some patients receiving high doses of cladribine. In one study following a 1 hour infusion, the recovery of cladribine in the urine over a 24 hour period was between 10 to 30% of the administered dose. There are inadequate data on dosing of patients with renal or hepatic insufficiency. Therefore, caution is advised when administering cladribine to patients with known or suspected renal or hepatic insufficiency (see Warnings).

Drug Interactions: There are no known drug interactions with cladribine. Caution should be exercised if cladribine is administered before, after or in conjunction with other drugs known to cause immunosuppression or myelosuppression (see Warnings).

Laboratory Tests: During and following treatment, the patient’s hematologic profile should be monitored regularly to determine the degree of hematopoietic suppression. In the clinical studies, following reversible declines in all cell counts, the mean Platelet Count reached 100´10L by Day 12, the mean Absolute Neutrophil Count reached 1 500´10L by Week 5 and the mean Hemoglobin reached 12 g/dL by Week 8. After peripheral counts have normalized, bone marrow aspiration and biopsy should be performed to confirm response to treatment with cladribine. Febrile events should be investigated with appropriate laboratory and radiologic studies. Periodic assessment of renal function and hepatic function should be performed as clinically indicated.

Mutagenesis: As expected for compounds in this class, the actions of cladribine yield DNA damage. In mammalian cells in culture, cladribine caused the accumulation of DNA strand breaks. Cladribine was also incorporated into DNA of human lymphoblastic leukemia cells. Cladribine was not mutagenic in vitro and did not induce unscheduled DNA synthesis in primary rat hepatocyte cultures. However, cladribine was clastogenic both in vitro (chromosome abberrations in Chinese hamster ovary cells) and in vivo (mouse bone marrow micronucleus test).

Adverse Reactions: Safety data are based on 196 patients with Hairy Cell Leukemia: the original cohort of 124 patients plus an additional 72 patients enrolled at the same 2 centres after the original enrollment cutoff.

In Month 1 of the clinical trials for Hairy Cell Leukemia, severe neutropenia was noted in 70% of patients, fever in 69%, and infection was documented in 28%. Other adverse experiences reported frequently during the first 14 days after initiating treatment included: fatigue (45%), nausea (28%), rash (27%), headache (22%) and injection site reactions (19%). Most of the non-hematologic adverse experiences were mild to moderate in severity.

Myelosuppression: Myelosuppression was frequently observed during the first month after starting treatment.

Fever and Infection: Fever was a frequently observed side effect during the first month on study. During the first month, 11% of patients experienced severe fever (i.e., ³40°C). Since fever may be accompanied by increased fluid loss, patients should be kept well hydrated during treatment. Since the majority of fevers occurred in neutropenic patients, patients should be closely monitored during the first month of treatment and empiric antibiotics should be initiated as clinically indicated. Although 69% of patients developed fevers, less than one-third of febrile events were associated with documented infection. Given the known myelosuppressive effects of cladribine, practitioners should carefully evaluate the risks and benefits of administering this drug to patients with active infections (see Warnings).

Documented infections were noted in fewer than one-third of febrile episodes. Of the 196 patients studied, 19 were noted to have a documented infection in the month prior to treatment. In the month following treatment, there were 54 episodes of documented infection: 23 (42%) were bacterial, 11 (20%) were viral and 11 (20%) were fungal. Seven of eight documented episodes of herpes zoster occurred during the month following treatment. Fourteen of sixteen episodes of documented fungal infections occurred in the first 2 months following treatment. Virtually all of these patients were treated empirically with antibiotics.

Effects on Lymphocytes: Analysis of lymphocyte subsets indicates that treatment with cladribine is associated with prolonged depression of the CD4 counts and transient suppression of CD8 counts. Prior to treatment, the mean CD4 count was 766/L. The mean CD4 count nadir, which occurred 4 to 6 months following treatment was 272/L. Fifteen months after treatment, mean CD4 counts remained below 500/L. CD8 counts behaved similarly, though increasing counts were observed after 9 months. There were no associated opportunistic infections reported during this time.

Bone Marrow Hypocellularity: Another event of unknown clinical significance includes the observation of prolonged bone marrow hypocellularity. Bone marrow hypocellularity of
Rash: The vast majority of rashes were mild and occurred in patients who were receiving or had recently been treated with other medications (e.g., allopurinol or antibiotics) known to cause rash.

Nausea: Most episodes of nausea were mild, not accompanied by vomiting, and did not require treatment with antiemetics. In patients requiring antiemetics, nausea was easily controlled, most frequently with chlorpromazine.

Adverse reactions reported during the first 2 weeks following treatment initiation (regardless of relationship to drug) by ³5% of patients.

Adverse experiences related to i.v. administration included: Injection site reactions (9%): (i.e., redness, swelling, pain), thrombosis (2%), phlebitis (2%) and a broken catheter (1%). These appear to be related to the infusion procedure and/or indwelling catheter, rather than the medication or the vehicle.

From Day 15 to the last follow-up visit, the only events reported by ³5% of patients were: fatigue (11%), rash (10%), headache (7%), cough (7%) and malaise (5%).

Deaths: Of the 196 patients with Hairy Cell Leukemia entered in the 2 trials, there were 8 deaths following treatment. Of these, 6 were of infectious etiology, including 3 pneumonias, and 2 occurred in the first month following cladribine therapy. Of the 8 deaths, 6 occurred in previously treated patients who were refractory to a-interferon.

The following additional adverse events have been reported since the drug became commercially available. These adverse events have been reported primarily in patients who received multiple courses of cladribine.

Hematologic: bone marrow suppression with prolonged pancytopenia, including some reports of aplastic anemia; hemolytic anemia which was reported in patients with lymphoid malignancies, occuring within the first few weeks following treatment; hypereosinophilia.

Hepatic: reversible, generally mild increases in bilirubin and transaminases.

Nervous System: neurological toxicity, however, severe neurotoxicity has been reported rarely following treatment with standard cladribine dosing regimens.

Respiratory: pulmonary interstitial infiltrates; in most cases, an infectious etiology was identified.

Skin/S.C.: urticaria, hypereosinophilia. In isolated cases Stevens-Johnson and toxic epidermal necrolysis have been reported in patients who were receiving or had recently been treated with other medications (e.g., allopurinol or antibiotics) known to cause these syndromes. Opportunistic infections have occurred in the acute phase of treatment due to the immunosuppression mediated by cladribine.

Effects of High Doses: In a Phase I investigational study using cladribine in high doses (4 to 9 times the recommended dose for Hairy Cell Leukemia) as part of a bone marrow transplant conditioning regimen, which also included high dose cyclophosphamide and total body irradiation, acute nephrotoxicity and delayed onset neurotoxicity were observed. Thirty-one poor-risk patients with drug-resistant acute leukemia in relapse (29 cases) or non-Hodgkins lymphoma (2 cases) received doses of cladribine for 7 to 14 days prior to bone marrow transplantation. During cladribine infusion, 8 patients experienced gastrointestinal symptoms. While the bone marrow was initially cleared of all hematopoietic elements, including tumor cells, leukemia eventually recurred in all treated patients. Within 7 to 13 days after starting treatment with cladribine, 6 patients (19%) developed manifestations of renal dysfunction (i.e., acidosis, anuria, elevated serum creatinine, etc.) and 5 required dialysis. Several of these patients were also being treated with other medications having known nephrotoxic potential. Renal dysfunction was reversible in 2 of these patients. In the 4 patients whose renal function had not recovered at the time of death, autopsies were performed; in 2 of these, evidence of tubular damage was noted. Eleven patients (35%) experienced delayed onset neurologic toxicity. In the majority, this was characterized by progressive irreversible motor weakness (paraparesis/quadriparesis) of the upper and/or lower extremities, first noted 35 to 84 days after starting high dose therapy with cladribine. Non-invasive testing (electromyography and nerve conduction studies) was consistent with demyelinating disease.

Axonal peripheral polyneuropathy was observed in a dose escalation study at the highest dose levels (approximately 4 times the recommended dose for Hairy Cell Leukemia) in patients not receiving cyclophosphamide or total body irradiation. Severe neurological toxicity has been reported rarely following treatment with standard cladribine dosing regimens.

Effect on Renal and Hepatic Function: Acute renal insufficiency has developed in some patients receiving high doses of cladribine. In one study following a 1 hour infusion, the recovery of cladribine in the urine over a 24 hour period was between 10 to 30% of the administered dose. In addition, there are inadequate data on dosing of patients with renal or hepatic insufficiency. Therefore, caution is advised when administering cladribine to patients with known or suspected renal or hepatic insufficiency (see Warnings).

Symptoms And Treatment Of Overdose: Symptoms and Treatment: High doses of cladribine have been associated with: irreversible neurologic toxicity (paraparesis/quadriparesis), acute nephrotoxicity, and severe bone marrow suppression resulting in neutropenia, anemia and thrombocytopenia (see Warnings and Adverse Effects). There is no known specific antidote to overdosage. Treatment of overdosage consists of discontinuation of cladribine, careful observation and appropriate supportive measures. It is not known whether cladribine can be removed from the circulation by any form of dialysis or hemofiltration.

Dosage And Administration: The recommended dose and schedule for Hairy Cell Leukemia is a single course given by continuous infusion for 7 consecutive days at a dose of 0.09 mg/kg/day. Deviations from this dosage regimen are not advised. If the patient does not respond to the initial course of cladribine treatment for hairy-cell leukemia, it is unlikely that he/she will benefit from additinal courses. Physicians should consider delaying or discontinuing the drug if neurotoxicity or renal toxicity occurs (see Warnings).

Specific risk factors predisposing to increased toxicity from cladribine have not been defined. In view of the known toxicities of agents of this class, it would be prudent to proceed carefully in patients with known or suspected renal insufficiency or severe bone marrow impairment of any etiology. Patients should be monitored closely for hematologic or non-hematologic toxicity (see Warnings and Precautions).

Effect on Renal and Hepatic Function: Acute renal insufficiency has developed in some patients receiving high doses of cladribine. In one study following a 1 hour infusion, the recovery of cladribine in the urine over a 24 hour period was between 10 to 30% of the administered dose. In addition, there are inadequate data on dosing of patients with renal or hepatic insufficiency. Therefore, caution is advised when administering cladribine to patients with known or suspected renal or hepatic insufficiency (see Warnings and Adverse Effects).

The potential hazards associated with cytotoxic agents are well established and proper precautions should be taken when handling, preparing, and administering cladribine. The use of disposable gloves and protective garments is recommended. If cladribine comes in contact with the skin or mucous membranes, wash the involved surface immediately with copious amounts of water. Several guidelines on this subject have been published.

Reconstituted Solutions: Cladribine must be diluted with the designated diluent prior to administration. Since the drug product does not contain any antimicrobial preservative or bacteriostatic agent, aseptic technique and proper environmental precautions must be observed in preparation of cladribine solutions.

Preparation of a Single Daily Dose (see Table II): Add the calculated dose (0.09 mg/kg or 0.09 mL/kg) of cladribine to an infusion bag containing 500 mL of 0.9% Sodium Chloride Injection, USP. Infuse continuously over 24 hours. Repeat daily for a total of 7 consecutive days. The use of 5% dextrose as a diluent is not recommended because of increased degradation of cladribine. Admixtures of cladribine are chemically and physically stable for at least 24 hours at room temperature under normal room fluorescent light in Baxter Viaflex PVC infusion containers.

Preparation of a 7-Day Infusion (see Table III): The 7-day infusion solution should only be prepared with Bacteriostatic 0.9% Sodium Chloride Injection, USP (0.9% benzyl alcohol preserved). In order to minimize the risk of microbial contamination, both cladribine and the diluent should be passed through a sterile 0.22 disposable hydrophilic syringe filter as each solution is being introduced into the infusion reservoir. First add the calculated dose of cladribine (7 days´0.09 mg/kg) to the infusion reservoir through the sterile filter. Then add a calculated amount of Bacteriostatic 0.9% Sodium Chloride Injection, USP (0.9% benzyl alcohol preserved) also through the filter to bring the total volume of the solution to 100 mL. After completing solution preparation, clamp off the line, disconnect and discard the filter. Aseptically aspirate air bubbles from the reservoir as necessary using the syringe and a dry second sterile filter or a sterile vent filter assembly. Reclamp the line and discard the syringe and filter assembly. Infuse continuously over 7 days. Solutions prepared with Bacteriostatic Sodium Chloride Injection for individuals weighing more than 85 kg may have reduced preservative effectiveness due to greater dilution of the benzyl alcohol preservative. Admixtures for the 7-day infusion have demonstrated acceptable chemical and physical stability for at least 7 days in SIMS Deltec Inc. Medication Cassettes.

Since limited compatibility data are available, adherence to the recommended diluents and infusion systems is advised. Solutions containing cladribine should not be mixed with other i.v. drugs or additives or infused simultaneously via a common i.v. line, since compatibility testing has not been performed. Preparations containing benzyl alcohol should not be used in neonates (see Warnings).

If the same i.v. line is used for sequential infusion of several different drugs, the line should be flushed with a compatible diluent before and after infusion of cladribine.

Care must be taken to assure the sterility of prepared solutions. Once diluted, solutions of cladribine should be administered promptly or stored in the refrigerator (2 to 8°C) for no more than 8 hours prior to start of administration. Vials of cladribine are for single-use only. Any unused portion should be discarded in an appropriate manner.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. A precipitate may occur during the exposure of cladribine to low temperatures; it may be resolubilized by allowing the solution to warm naturally to room temperature and by shaking vigorously. Do not heat or microwave.

Handling and Diposal: The potential hazards associated with cytotoxic agents are well established and proper precautions should be taken when handling, preparing and administering cladribine. The use of disposable gloves and protective garments is recommended. If cladribine comes in contact with the skin or mucous membranes, wash the involved surface immediately with copious amounts of water. Several guidelines on this subject have been published. Refer to your institution’s guidelines for disposal of cytotoxic waste.

Stability and Storage: When vials and infusion solutions are stored between 2 to 8°C protected from light, unopened vials are stable until the expiration date indicated on the package. Freezing does not adversely affect the solution. If freezing occurs, thaw naturally to room temperature. Do not heat or microwave. Once thawed, the vial is stable until expiry if refrigerated. Do not refreeze. Once diluted, solutions containing cladribine should be administered promptly or stored in the refrigerator (2 to 8°C) for no more than 8 hours prior to administration. Store refrigerated 2 to 8°C. Protect from light during storage.

Availability And Storage: Each mL of sterile, preservative-free, isotonic solution contains: cladribine 1 mg and sodium chloride 9 mg as an inactive ingredient. Phosphoric acid and/or dibasic sodium phosphate may have been added to adjust the pH. pH: 5.5 to 8.0. Single use clear flint glass 20 mL vials of 10 mL (1 mg/mL).

LEUSTATIN® Janssen-Ortho Cladribine Antineoplastic – Chemotherapeutic Agent Warning: Cladribine should be administered under the supervision of a qualified physician experienced in the use of antineoplastic therapy. Suppression of bone marrow function should be anticipated. This is usually reversible and appears to be dose-dependent. Significant and prolonged lymphopenia has been noted. Serious neurological toxicity (including irreversible paraparesis and quadriparesis) has been reported in patients who received cladribine injection 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 dose regimens. 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.

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