CLADRIBINE: 7,521 Adverse Event Reports & Safety Profile

Cladribine tablets contains the nucleoside metabolic inhibitor cladribine, which is a white to off-white crystalline powder with the molecular formula C 10 H 12 ClN 5 O 3 and molecular weight 285.69 g/mol. It differs in structure from the naturally occurring nucleoside, deoxyadenosine, by the substitution of chlorine for hydrogen in the 2-position of the purine ring. The chemical name of cladribine is 2-chloro-2′-deoxy-adenosine. The structural formula is shown below: Cladribine is stable at slightly basic and at neutral pH. The main degradation pathway is hydrolysis and at acidic pH significant decomposition occurs with time. The ionization behavior of the molecule over the pH range 0 to 12 is characterized by a single pKa of approximately 1.21. Cladribine tablets are provided as 10 mg tablet for oral use.

Each

10 mg tablet contains cladribine as an active ingredient and magnesium stearate and sorbitol as inactive ingredients. Cladribine tablets also contain hydroxypropyl betadex.

AND USAGE MAVENCLAD is indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include relapsing-remitting disease and active secondary progressive disease, in adults. Because of its safety profile, use of MAVENCLAD is generally recommended for patients who have had an inadequate response to, or are unable to tolerate, an alternate drug indicated for the treatment of MS [see Warnings and Precautions (5) ]. MAVENCLAD is a purine antimetabolite indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include relapsing-remitting disease and active secondary progressive disease, in adults. Because of its safety profile, use of MAVENCLAD is generally recommended for patients who have had an inadequate response to, or are unable to tolerate, an alternate drug indicated for the treatment of MS . ( 1 , 5 ) Limitations of Use MAVENCLAD is not recommended for use in patients with clinically isolated syndrome (CIS) because of its safety profile . ( 1 , 5 ) Limitations of Use MAVENCLAD is not recommended for use in patients with clinically isolated syndrome (CIS) because of its safety profile [see Warnings and Precautions (5)] .

DOSAGE AND ADMINISTRATION: Usual Dosage The recommended dose and schedule of cladribine injection for active Hairy Cell Leukemia is as a single course given by continuous infusion for seven 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 injection for Hairy Cell Leukemia, it is unlikely that they will benefit from additional 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 injection 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 and non-hematologic toxicity (see WARNINGS and PRECAUTIONS ). Preparation and Administration of Intravenous Solutions Cladribine injection 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 injection solutions . To prepare a single daily dose Cladribine injection should be passed through a sterile 0.22 μ m disposable hydrophilic syringe filter prior to introduction into the infusion bag, prior to each daily infusion. Add the calculated dose (0.09 mg/kg or 0.09 mL/kg) of cladribine injection through the sterile filter 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 seven consecutive days. The use of 5% dextrose as a diluent is not recommended because of increased degradation of cladribine. Admixtures of cladribine injection are chemically and physically stable for at least 24 hours at room temperature under normal room fluorescent light in Baxter Viaflex ® PVC infusion containers. Since limited compatibility data are available, adherence to the recommended diluents and infusion systems is advised. Dose of Cladribine Injection Recommended Diluent Quantity of Diluent 24-hour infusion method 1 (day) x 0.09 mg/kg 0.9% Sodium Chloride Injection, USP 500 mL To prepare a 7-day infusion The seven-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 injection and the diluent should be passed through a sterile 0.22 μ m disposable hydrophilic syringe filter as each solution is being introduced into the infusion reservoir. First add the calculated dose of cladribine injection (7 days x 0.09 mg/kg or mL/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 seven 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 seven-day infusion have demonstrated acceptable chemical and physical stability for at least seven days in the SIMS Deltec MEDICATION CASSETTE™ Reservoir. Dose of Cladribine Injection Recommended Diluent Quantity of Diluent 7-day infusion method (use sterile 0.22 μ m filter when preparing infusion solution 7 (days) x 0.09 mg/kg Bacteriostatic 0.9% Sodium Chloride Injection, USP (0.9% benzyl alcohol) q.s. to 100 mL Since limited compatibility data are available, adherence to the recommended diluents and infusion systems is advised. Solutions containing cladribine injection should not be mixed with other intravenous drugs or additives or infused simultaneously via a common intravenous line, since compatibility testing has not been performed. Preparations containing benzyl alcohol should not be used in neonates (see WARNINGS ). Care must be taken to assure the sterility of prepared solutions. Once diluted, solutions of cladribine injection should be administered promptly or stored in the refrigerator (2° to 8°C) for no more than eight hours prior to start of administration. Vials of cladribine injection are for single-use only. Any unused portion should be discarded in an appropriate manner (see Handling and Disposal ). 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 injection 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.

Chemical

Stability of Vials When stored in refrigerated conditions between 2° to 8°C (36° to 46°F) and protected from light, unopened vials of cladribine injection 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 of cladribine injection is stable until expiry if refrigerated. DO NOT refreeze. Once diluted, solutions containing cladribine injection should be administered promptly or stored in the refrigerator (2° to 8°C) for no more than 8 hours prior to administration. Handling and Disposal The potential hazards associated with cytotoxic agents are well established and proper precautions should be taken when handling, preparing, and administering cladribine injection. The use of disposable gloves and protective garments is recommended. If cladribine injection contacts the skin or mucous membranes, wash the involved surface immediately with copious amounts of water. Several guidelines on this subject have been published. (2-8) There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. Refer to your Institution’s guidelines and all applicable state/local regulations for disposal of cytotoxic waste.

Usual Dosage

The recommended dose and schedule of cladribine injection for active Hairy Cell Leukemia is as a single course given by continuous infusion for seven 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 injection for Hairy Cell Leukemia, it is unlikely that they will benefit from additional 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 injection 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 and non-hematologic toxicity (see WARNINGS and PRECAUTIONS ).

Preparation and Administration of Intravenous Solutions Cladribine injection 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 injection solutions . To prepare a single daily dose Cladribine injection should be passed through a sterile 0.22 μ m disposable hydrophilic syringe filter prior to introduction into the infusion bag, prior to each daily infusion. Add the calculated dose (0.09 mg/kg or 0.09 mL/kg) of cladribine injection through the sterile filter 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 seven consecutive days. The use of 5% dextrose as a diluent is not recommended because of increased degradation of cladribine. Admixtures of cladribine injection are chemically and physically stable for at least 24 hours at room temperature under normal room fluorescent light in Baxter Viaflex ® PVC infusion containers. Since limited compatibility data are available, adherence to the recommended diluents and infusion systems is advised. Dose of Cladribine Injection Recommended Diluent Quantity of Diluent 24-hour infusion method 1 (day) x 0.09 mg/kg 0.9% Sodium Chloride Injection, USP 500 mL To prepare a 7-day infusion The seven-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 injection and the diluent should be passed through a sterile 0.22 μ m disposable hydrophilic syringe filter as each solution is being introduced into the infusion reservoir. First add the calculated dose of cladribine injection (7 days x 0.09 mg/kg or mL/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 seven 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 seven-day infusion have demonstrated acceptable chemical and physical stability for at least seven days in the SIMS Deltec MEDICATION CASSETTE™ Reservoir. Dose of Cladribine Injection Recommended Diluent Quantity of Diluent 7-day infusion method (use sterile 0.22 μ m filter when preparing infusion solution 7 (days) x 0.09 mg/kg Bacteriostatic 0.9% Sodium Chloride Injection, USP (0.9% benzyl alcohol) q.s. to 100 mL Since limited compatibility data are available, adherence to the recommended diluents and infusion systems is advised. Solutions containing cladribine injection should not be mixed with other intravenous drugs or additives or infused simultaneously via a common intravenous line, since compatibility testing has not been performed. Preparations containing benzyl alcohol should not be used in neonates (see WARNINGS ). Care must be taken to assure the sterility of prepared solutions. Once diluted, solutions of cladribine injection should be administered promptly or stored in the refrigerator (2° to 8°C) for no more than eight hours prior to start of administration. Vials of cladribine injection are for single-use only. Any unused portion should be discarded in an appropriate manner (see Handling and Disposal ). 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 injection 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.

Chemical

Stability of Vials When stored in refrigerated conditions between 2° to 8°C (36° to 46°F) and protected from light, unopened vials of cladribine injection 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 of cladribine injection is stable until expiry if refrigerated. DO NOT refreeze. Once diluted, solutions containing cladribine injection should be administered promptly or stored in the refrigerator (2° to 8°C) for no more than 8 hours prior to administration.

Handling and Disposal The potential hazards associated with cytotoxic agents are well established and proper precautions should be taken when handling, preparing, and administering cladribine injection. The use of disposable gloves and protective garments is recommended. If cladribine injection contacts the skin or mucous membranes, wash the involved surface immediately with copious amounts of water. Several guidelines on this subject have been published. (2-8) There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. Refer to your Institution’s guidelines and all applicable state/local regulations for disposal of cytotoxic waste.

Cladribine tablets are contraindicated: in patients with current malignancy [ see Warnings and Precautions (5.1) ] . in pregnant women and in women and men of reproductive potential who do not plan to use effective contraception during cladribine tablets dosing and for 6 months after the last dose in each treatment course. May cause fetal harm [ see Warnings and Precautions (5.2) and Use in Specific Populations (8.1, 8.3 )]. in patients infected with the human immunodeficiency virus (HIV) [ see Warnings and Precautions (5.4) ]. in patients with active chronic infections (e.g., hepatitis or tuberculosis) [ see Warnings and Precautions (5.4) ]. in patients with a history of hypersensitivity to cladribine [ see Warnings and Precautions (5.8) ]. in women intending to breastfeed on a cladribine treatment day and for 10 days after the last dose [ see Use in Specific Populations (8.2) ]. Patients with current malignancy. (4) Pregnant women, and women and men of reproductive potential who do not plan to use effective contraception during cladribine tablets dosing and for 6 months after the last dose in each treatment course. (4, 8.3) HIV infection. (4) Active chronic infections (e.g., hepatitis or tuberculosis). (4) History of hypersensitivity to cladribine. (4, 5.8) Women intending to breastfeed on a cladribine treatment day and for 10 days after the last dose. (4, 8.2)

ADVERSE REACTIONS: Clinical Trials Experience Adverse drug reactions reported by ≥ 1% of cladribine-treated patients with HCL noted in the HCL clinical dataset (studies K90-091 and L91-048, n=576) are shown in the table below.

Adverse Drug

Reactions in ≥ 1% of Patients Treated with Cladribine in HCL Clinical Trials System Organ Class Preferred Term Cladribine (n=576) % Blood and Lymphatic System Disorder (see also sections WARNINGS and PRECAUTIONS )

Anemia

1 Febrile neutropenia 8 Psychiatric Disorders Anxiety 1 Insomnia 3 Nervous System Disorders Dizziness 6 Headache 14 Cardiac Disorders Tachycardia 2 Respiratory, Thoracic and Mediastinal Disorders Breath sounds abnormal 4 Cough 7 Dyspnea* 5 Rales 1 Gastrointestinal Disorders Abdominal pain** 4 Constipation 4 Diarrhea 7 Flatulence 1 Nausea 22 Vomiting 9 Skin and Subcutaneous Tissue Disorders Ecchymosis 2 Hyperhidrosis 3 Petechiae 2 Pruritus 2 Rash*** 16 Musculoskeletal, Connective Tissue, and Bone Disorders Arthralgia 3 Myalgia 6 Pain**** 6 General Disorders and Administration Site Conditions (see also sections WARNINGS and PRECAUTIONS ) Administration site reaction***** 11 Asthenia 6 Chills 2 Decreased appetite 8 Fatigue 31 Malaise 5 Muscular weakness 1 Edema peripheral 2 Pyrexia 33 Injury, Poisoning and Procedural Complications Contusion 1 * Dyspnea includes dyspnea, dyspnea exertional, and wheezing ** Abdominal pain includes abdominal discomfort, abdominal pain, and abdominal pain (lower and upper) *** Rash includes erythema, rash, and rash (macular, macula-papular, papular, pruritic, pustular and erythematous) **** Pain includes pain, back pain, chest pain, arthritis pain, bone pain, and pain in extremity *****Administration site reaction includes administration site reaction, catheter site (cellulitis, erythema, hemorrhage, and pain), and infusion site reaction (erythema, edema, and pain) The following 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 two centers after the original enrollment cutoff.

In Month

1 of the Hairy Cell Leukemia clinical trials, severe neutropenia was noted in 70% of patients, fever in 69%, and infection was documented in 28%. Most non-hematologic adverse experiences were mild to moderate in severity. Myelosuppression was frequently observed during the first month after starting treatment. Neutropenia (ANC < 500 x 10 6 /L) was noted in 70% of patients, compared with 26% in whom it was present initially. Severe anemia (Hemoglobin < 8.5 g/dL) developed in 37% of patients, compared with 10% initially and thrombocytopenia (Platelets < 20 x 10 9 /L) developed in 12% of patients, compared to 4% in whom it was noted initially. During the first month, 54 of 196 patients (28%) exhibited documented evidence of infection. Serious infections (e.g., septicemia, pneumonia) were reported in 6% of all patients; the remainder were mild or moderate. Several deaths were attributable to infection and/or complications related to the underlying disease. During the second month, the overall rate of documented infection was 6%; these infections were mild to moderate and no severe systemic infections were seen. After the third month, the monthly incidence of infection was either less than or equal to that of the months immediately preceding cladribine therapy. During the first month, 11% of patients experienced severe fever (i.e., ≥ 104°F). 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 (7) of 8 documented episodes of herpes zoster occurred during the month following treatment. Fourteen (14) of 16 episodes of documented fungal infections occurred in the first two months following treatment. Virtually all of these patients were treated empirically with antibiotics (see WARNINGS and PRECAUTIONS ). Analysis of lymphocyte subsets indicates that treatment with cladribine is associated with prolonged depression of the CD4 counts. Prior to treatment, the mean CD4 count was 766/ μ L. The mean CD4 count nadir, which occurred four to six months following treatment, was 272/ μ L. Fifteen (15) months after treatment, mean CD4 counts remained below 500/ μ L. CD8 counts behaved similarly, though increasing counts were observed after nine months. The clinical significance of the prolonged CD4 lymphopenia is unclear. Another event of unknown clinical significance includes the observation of prolonged bone marrow hypocellularity. Bone marrow cellularity of < 35% was noted after four months in 42 of 124 patients (34%) treated in the two pivotal trials. This hypocellularity was noted as late as Day 1,010. It is not known whether the hypocellularity is the result of disease related marrow fibrosis or if it is the result of cladribine toxicity. There was no apparent clinical effect on the peripheral blood counts. The vast majority of rashes were mild. 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. When used in other clinical settings the following ADRs were reported: bacteremia, cellulitis, localized infection, pneumonia, anemia, thrombocytopenia (with bleeding or petechiae), phlebitis, purpura, crepitations, localized edema and edema. For a description of adverse reactions associated with use of high doses in non-Hairy Cell Leukemia patients, see WARNINGS .

Postmarketing Experience

The following additional adverse reactions have been reported since the drug became commercially available. These adverse reactions have been reported primarily in patients who received multiple courses of cladribine injection: Infections and infestations: Septic shock. Opportunistic infections have occurred in the acute phase of treatment. Blood and lymphatic system disorders: Bone marrow suppression with prolonged pancytopenia, including some reports of aplastic anemia; hemolytic anemia (including autoimmune hemolytic anemia), which was reported in patients with lymphoid malignancies, occurring within the first few weeks following treatment. Rare cases of myelodysplastic syndrome have been reported. Immune system disorders: Hypersensitivity. Metabolism and nutrition disorders: Tumor lysis syndrome. Psychiatric disorders: Confusion (including disorientation). Hepatobiliary disorders: Reversible, generally mild increases in bilirubin (uncommon) and transaminases.

Nervous

System disorders: Depressed level of consciousness, neurological toxicity (including peripheral sensory neuropathy, motor neuropathy (paralysis), polyneuropathy, paraparesis); however, severe neurotoxicity has been reported rarely following treatment with standard cladribine dosing regimens. Eye disorders: Conjunctivitis. Respiratory, thoracic and mediastinal disorders: Pulmonary interstitial infiltrates (including lung infiltration, interstitial lung disease, pneumonitis and pulmonary fibrosis); in most cases, an infectious etiology was identified. Skin and tissue disorders: Urticaria, hypereosinophilia; Stevens-Johnson. In isolated cases toxic epidermal necrolysis has 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. Renal and urinary disorders: Renal failure (including renal failure acute, renal impairment).

Clinical Trials Experience

Adverse drug reactions reported by ≥ 1% of cladribine-treated patients with HCL noted in the HCL clinical dataset (studies K90-091 and L91-048, n=576) are shown in the table below.

Adverse Drug

Reactions in ≥ 1% of Patients Treated with Cladribine in HCL Clinical Trials System Organ Class Preferred Term Cladribine (n=576) % Blood and Lymphatic System Disorder (see also sections WARNINGS and PRECAUTIONS )

Anemia

1 Febrile neutropenia 8 Psychiatric Disorders Anxiety 1 Insomnia 3 Nervous System Disorders Dizziness 6 Headache 14 Cardiac Disorders Tachycardia 2 Respiratory, Thoracic and Mediastinal Disorders Breath sounds abnormal 4 Cough 7 Dyspnea* 5 Rales 1 Gastrointestinal Disorders Abdominal pain** 4 Constipation 4 Diarrhea 7 Flatulence 1 Nausea 22 Vomiting 9 Skin and Subcutaneous Tissue Disorders Ecchymosis 2 Hyperhidrosis 3 Petechiae 2 Pruritus 2 Rash*** 16 Musculoskeletal, Connective Tissue, and Bone Disorders Arthralgia 3 Myalgia 6 Pain**** 6 General Disorders and Administration Site Conditions (see also sections WARNINGS and PRECAUTIONS ) Administration site reaction***** 11 Asthenia 6 Chills 2 Decreased appetite 8 Fatigue 31 Malaise 5 Muscular weakness 1 Edema peripheral 2 Pyrexia 33 Injury, Poisoning and Procedural Complications Contusion 1 * Dyspnea includes dyspnea, dyspnea exertional, and wheezing ** Abdominal pain includes abdominal discomfort, abdominal pain, and abdominal pain (lower and upper) *** Rash includes erythema, rash, and rash (macular, macula-papular, papular, pruritic, pustular and erythematous) **** Pain includes pain, back pain, chest pain, arthritis pain, bone pain, and pain in extremity *****Administration site reaction includes administration site reaction, catheter site (cellulitis, erythema, hemorrhage, and pain), and infusion site reaction (erythema, edema, and pain) The following 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 two centers after the original enrollment cutoff.

In Month

1 of the Hairy Cell Leukemia clinical trials, severe neutropenia was noted in 70% of patients, fever in 69%, and infection was documented in 28%. Most non-hematologic adverse experiences were mild to moderate in severity. Myelosuppression was frequently observed during the first month after starting treatment. Neutropenia (ANC < 500 x 10 6 /L) was noted in 70% of patients, compared with 26% in whom it was present initially. Severe anemia (Hemoglobin < 8.5 g/dL) developed in 37% of patients, compared with 10% initially and thrombocytopenia (Platelets < 20 x 10 9 /L) developed in 12% of patients, compared to 4% in whom it was noted initially. During the first month, 54 of 196 patients (28%) exhibited documented evidence of infection. Serious infections (e.g., septicemia, pneumonia) were reported in 6% of all patients; the remainder were mild or moderate. Several deaths were attributable to infection and/or complications related to the underlying disease. During the second month, the overall rate of documented infection was 6%; these infections were mild to moderate and no severe systemic infections were seen. After the third month, the monthly incidence of infection was either less than or equal to that of the months immediately preceding cladribine therapy. During the first month, 11% of patients experienced severe fever (i.e., ≥ 104°F). 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 (7) of 8 documented episodes of herpes zoster occurred during the month following treatment. Fourteen (14) of 16 episodes of documented fungal infections occurred in the first two months following treatment. Virtually all of these patients were treated empirically with antibiotics (see WARNINGS and PRECAUTIONS ). Analysis of lymphocyte subsets indicates that treatment with cladribine is associated with prolonged depression of the CD4 counts. Prior to treatment, the mean CD4 count was 766/ μ L. The mean CD4 count nadir, which occurred four to six months following treatment, was 272/ μ L. Fifteen (15) months after treatment, mean CD4 counts remained below 500/ μ L. CD8 counts behaved similarly, though increasing counts were observed after nine months. The clinical significance of the prolonged CD4 lymphopenia is unclear. Another event of unknown clinical significance includes the observation of prolonged bone marrow hypocellularity. Bone marrow cellularity of < 35% was noted after four months in 42 of 124 patients (34%) treated in the two pivotal trials. This hypocellularity was noted as late as Day 1,010. It is not known whether the hypocellularity is the result of disease related marrow fibrosis or if it is the result of cladribine toxicity. There was no apparent clinical effect on the peripheral blood counts. The vast majority of rashes were mild. 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. When used in other clinical settings the following ADRs were reported: bacteremia, cellulitis, localized infection, pneumonia, anemia, thrombocytopenia (with bleeding or petechiae), phlebitis, purpura, crepitations, localized edema and edema. For a description of adverse reactions associated with use of high doses in non-Hairy Cell Leukemia patients, see WARNINGS .

Postmarketing Experience

The following additional adverse reactions have been reported since the drug became commercially available. These adverse reactions have been reported primarily in patients who received multiple courses of cladribine injection: Infections and infestations: Septic shock. Opportunistic infections have occurred in the acute phase of treatment. Blood and lymphatic system disorders: Bone marrow suppression with prolonged pancytopenia, including some reports of aplastic anemia; hemolytic anemia (including autoimmune hemolytic anemia), which was reported in patients with lymphoid malignancies, occurring within the first few weeks following treatment. Rare cases of myelodysplastic syndrome have been reported. Immune system disorders: Hypersensitivity. Metabolism and nutrition disorders: Tumor lysis syndrome. Psychiatric disorders: Confusion (including disorientation). Hepatobiliary disorders: Reversible, generally mild increases in bilirubin (uncommon) and transaminases.

Nervous

System disorders: Depressed level of consciousness, neurological toxicity (including peripheral sensory neuropathy, motor neuropathy (paralysis), polyneuropathy, paraparesis); however, severe neurotoxicity has been reported rarely following treatment with standard cladribine dosing regimens. Eye disorders: Conjunctivitis. Respiratory, thoracic and mediastinal disorders: Pulmonary interstitial infiltrates (including lung infiltration, interstitial lung disease, pneumonitis and pulmonary fibrosis); in most cases, an infectious etiology was identified. Skin and tissue disorders: Urticaria, hypereosinophilia; Stevens-Johnson. In isolated cases toxic epidermal necrolysis has 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. Renal and urinary disorders: Renal failure (including renal failure acute, renal impairment).

AND PRECAUTIONS Lymphopenia: Monitor lymphocyte counts before, during and after treatment. (5.3) Infections: Serious, including life-threatening and fatal infections, have occurred. Screen patients for active and latent infections; delay treatment until infection is fully resolved or controlled. Vaccination of patients seronegative to varicella zoster virus (VZV) is recommended prior to treatment. Vaccination of patients seropositive to VZV with zoster vaccine recombinant, adjuvanted, is recommended prior to or during treatment. Administer anti-herpes prophylaxis in patients with lymphocyte counts less than 200 cells per microliter. Monitor for infections. (5.4) Hematologic toxicity: Monitor complete blood count before, during and after treatment. (5.5) Graft-versus-host-disease with blood transfusion: Irradiation of cellular blood components is recommended. (5.6) Liver injury: Clinically significant liver injury has occurred. Obtain tests prior to treatment. Discontinue if clinically significant injury is suspected. (5.7)

5.1 Malignancies Treatment with cladribine tablets may increase the risk of malignancy. In controlled and extension clinical studies worldwide, malignancies occurred more frequently in cladribine-treated patients [10 events in 3,754 patient-years (0.27 events per 100 patient-years)], compared to placebo patients [3 events in 2,275 patient-years (0.13 events per 100 patient-years)]. Malignancy cases in cladribine patients included metastatic pancreatic carcinoma, malignant melanoma (2 cases), ovarian cancer, compared to malignancy cases in placebo patients, all of which were curable by surgical resection [basal cell carcinoma, cervical carcinoma in situ (2 cases)]. The incidence of malignancies in United States cladribine clinical study patients was higher than the rest of the world [4 events in 189 patient-years (2.21 events per 100 patient-years) compared to 0 events in United States placebo patients]; however, the United States results were based on a limited amount of patient data. After the completion of 2 treatment courses, do not administer additional cladribine treatment during the next 2 years [ see Dosage and Administration (2.2) ]. In clinical studies, patients who received additional cladribine treatment within 2 years after the first 2 treatment courses had an increased incidence of malignancy [7 events in 790 patient-years (0.91 events per 100 patient-years) calculated from the start of cladribine treatment in Year 3]. The risk of malignancy with reinitiating cladribine tablets more than 2 years after the completion of 2 treatment courses has not been studied. Cladribine tablets are contraindicated in patients with current malignancy. In patients with prior malignancy or with increased risk of malignancy, evaluate the benefits and risks of the use of cladribine tablets on an individual patient basis. Follow standard cancer screening guidelines in patients treated with cladribine tablets.

5.2 Risk of Teratogenicity Cladribine tablets may cause fetal harm when administered to pregnant women. Malformations and embryolethality occurred in animals [ see Use in Specific Populations (8.1) ] . Advise women of the potential risk to a fetus during cladribine tablets dosing and for 6 months after the last dose in each treatment course. In females of reproductive potential, pregnancy should be excluded before initiation of each treatment course of cladribine tablets and prevented by the use of effective contraception during cladribine tablets dosing and for at least 6 months after the last dose of each treatment course. Women who become pregnant during treatment with cladribine tablets should discontinue treatment [ see Use in Specific Populations (8.1 , 8.3) ] . Cladribine tablets are contraindicated for use in pregnant women and in women and men of reproductive potential who do not plan to use effective contraception.

5.3 Lymphopenia Cladribine tablets cause a dose-dependent reduction in lymphocyte count. In clinical studies, 87% of cladribine-treated patients experienced lymphopenia. The lowest absolute lymphocyte counts occurred approximately 2 to 3 months after the start of each treatment course and were lower with each additional treatment course. In patients treated with a cumulative dose of cladribine tablets 3.5 mg per kg over 2 courses as monotherapy, 26% and 1% had nadir absolute lymphocyte counts less than 500 and less than 200 cells per microliter, respectively. At the end of the second treatment course, 2% of clinical study patients had lymphocyte counts less than 500 cells per microliter; median time to recovery to at least 800 cells per microliter was approximately 28 weeks. Additive hematological adverse reactions may be expected if cladribine tablets are administered prior to or concomitantly with other drugs that affect the hematological profile [ see Drug Interactions (7.3) ]. The incidence of lymphopenia less than 500 cells per microliter was higher in patients who had used drugs to treat relapsing forms of MS prior to study entry (32.1%), compared to those with no prior use of these drugs (23.8%). Obtain complete blood count (CBC) with differential including lymphocyte count prior to, during, and after treatment with cladribine tablets.

See

Dosage and Administration (2.1, 2.5) and Warnings and Precautions (5.4) for timing of CBC measurements and additional instructions based on the patient’s lymphocyte counts and clinical status (e.g., infections).

5.4 Infections Serious, including life-threatening or fatal, bacterial, viral, parasitic, and fungal infections have been reported in patients receiving cladribine tablets. Cladribine tablets reduces the body&apos;s immune defense, and an increased risk of infections has been observed in patients receiving cladribine tablets. Infections occurred in 49% of cladribine-treated patients compared to 44% of placebo patients in clinical studies; serious or severe infections occurred in 2.4% of cladribine-treated patients and 2% of placebo-treated patients. The most frequent serious infections in cladribine-treated patients included herpes zoster and pyelonephritis ( see Herpes Virus Infections ). Fungal infections were observed, including cases of coccidioidomycosis. In the postmarketing setting, serious infections have been reported, including nocardiosis, varicella zoster, histoplasmosis, cryptococcosis, and toxoplasmosis. The majority of patients with these infections who had an available absolute lymphocyte count at the time of the event had concurrent lymphopenia, consistent with the mechanism of action of cladribine tablets <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.3 )]</span>. HIV infection, active tuberculosis, and active hepatitis must be excluded before initiation of each treatment course of cladribine tablets [ see Contraindications (4) ]. Delay initiation of cladribine tablets in patients with an acute infection until the infection is fully resolved or controlled. Initiation of cladribine tablets in patients currently receiving immunosuppressive or myelosuppressive therapy is not recommended <span class="opacity-50 text-xs">[see Drug Interactions ( 7.1 )]</span> . Concomitant use of cladribine tablets with these therapies could increase the risk of immunosuppression.

Tuberculosis

Three of 1,976 (0.2%) cladribine-treated patients in the clinical program developed tuberculosis. All three cases occurred in regions where tuberculosis is endemic. One case of tuberculosis was fatal, and two cases resolved with treatment. Perform tuberculosis screening prior to initiation of the first and second treatment course of cladribine tablets. Latent tuberculosis infections may be activated with use of cladribine tablets. In patients with tuberculosis infection, delay initiation of cladribine tablets until the infection has been adequately treated.

Hepatitis

One clinical study patient died from fulminant hepatitis B infection. Perform screening for hepatitis B and C prior to initiation of the first and second treatment course of cladribine tablets. Latent hepatitis infections may be activated with use of cladribine tablets. Patients who are carriers of hepatitis B or C virus may be at risk of irreversible liver damage caused by virus reactivation. In patients with hepatitis infection, delay initiation of cladribine tablets until the infection has been adequately treated.

Herpes Virus

Infections In controlled clinical studies, 6% of cladribine-treated patients developed a herpes viral infection compared to 2% of placebo patients. The most frequent types of herpes viral infections were herpes zoster infections (2.0% vs. 0.2%) and oral herpes (2.6% vs. 1.2%). Serious herpes zoster infections occurred in 0.2% of cladribine-treated patients. Vaccination of patients who are seronegative for varicella zoster virus is recommended prior to initiation of cladribine tablets. Administer live-attenuated or live vaccines at least 4 to 6 weeks prior to starting cladribine tablets. Vaccination with zoster vaccine recombinant, adjuvanted is recommended for patients who are seropositive to VZV, either prior to or during cladribine treatment, including when their lymphocyte counts are less than or equal to 500 cells per microliter. The incidence of herpes zoster was higher during the period of absolute lymphocyte count less than 500 cells per microliter, compared to the time when the patients were not experiencing this degree of lymphopenia. Administer anti-herpes prophylaxis in patients with lymphocyte counts less than 200 cells per microliter. Patients with lymphocyte counts below 500 cells per microliter should be monitored for signs and symptoms suggestive of infections, including herpes infections. If such signs and symptoms occur, initiate treatment as clinically indicated. Consider interruption or delay of cladribine tablets until resolution of the infection.

Progressive Multifocal Leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML) is an opportunistic viral infection of the brain caused by the JC virus (JCV) that typically only occurs in patients who are immunocompromised, and that usually leads to death or severe disability. Typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes. No case of PML has been reported in clinical studies of cladribine in patients with multiple sclerosis. In patients treated with parenteral cladribine for oncologic indications, cases of PML have been reported in the postmarketing setting. Obtain a baseline (within 3 months) magnetic resonance imaging (MRI) before initiating the first treatment course of cladribine tablets. At the first sign or symptom suggestive of PML, withhold cladribine tablets and perform an appropriate diagnostic evaluation. MRI findings may be apparent before clinical signs or symptoms.

Vaccinations

Administer all immunizations (except as noted for VZV) according to immunization guidelines prior to starting cladribine tablets. Administer live-attenuated or live vaccines at least 4 to 6 weeks prior to starting cladribine tablets, because of a risk of active vaccine infection (see Herpes Virus Infections) . Avoid vaccination with live-attenuated or live vaccines during and after cladribine treatment while the patient’s white blood cell counts are not within normal limits.

5.5 Hematologic Toxicity In addition to lymphopenia <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.3 )]</span> , decreases in other blood cells and hematological parameters have been reported with cladribine in clinical studies. Mild to moderate decreases in neutrophil counts (cell count between 1,000 cells per microliter and &lt; lower limit of normal (LLN)) were observed in 27% of cladribine-treated patients, compared to 13% of placebo patients whereas severe decreases in neutrophil counts (cell count below 1,000 cells per microliter) were observed in 3.6% of cladribine-treated patients, compared to 2.8% of placebo patients. Decreases in hemoglobin levels, in general mild to moderate (hemoglobin 8 g per dL to &lt; LLN), were observed in 26% of cladribine-treated patients, compared to 19% of placebo patients. Decreases in platelet counts were generally mild (cell count 75,000 cells per microliter to &lt; LLN) and were observed in 11% of cladribine- treated patients, compared to 4% of placebo patients. In clinical studies at dosages similar to or higher than the approved cladribine dosage, serious cases of thrombocytopenia, neutropenia, and pancytopenia (some with documented bone marrow hypoplasia) requiring transfusion and granulocyte-colony stimulating factor treatment have been reported [ see Warnings and Precautions (5.6) for information regarding graft-versus- host disease with blood transfusion ]. Obtain complete blood count (CBC) with differential prior to, during, and after treatment with cladribine tablets [ see Dosage and Administration (2.1, 2.5) ].

5.6 Risk of Graft-Versus-Host Disease With Blood Transfusion Transfusion-associated graft-versus-host disease has been observed rarely after transfusion of nonirradiated blood in patients treated with cladribine for non-MS treatment indications. In patients who require blood transfusion, irradiation of cellular blood components is recommended prior to administration to decrease the risk of transfusion-related graft-versus-host disease. Consultation with a hematologist is advised.

5.7 Liver Injury Cladribine tablets can cause liver injury. In clinical studies, 0.3% of cladribine-treated patients had liver injury (serious or causing treatment discontinuation) considered related to treatment, compared to 0 placebo patients. Onset ranged from a few weeks to several months after initiation of treatment with cladribine. Signs and symptoms of liver injury, including elevation of serum aminotransferases to greater than 20-fold the upper limit of normal, were observed. These abnormalities resolved upon treatment discontinuation. Clinically significant and life-threatening liver injury has been reported in patients treated with cladribine tablets in the postmarketing setting. Patients with pre-existing liver disease and patients taking other hepatotoxic drugs may be at increased risk for developing liver injury when taking cladribine tablets. Most reported cases of liver injury associated with cladribine tablets occurred approximately 30 days after initiation (i.e., course 1, cycle 1) of treatment. Cladribine tablets are not recommended in patients with moderate to severe hepatic impairment (Child-Pugh score greater than 6) <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.7 ), Clinical Pharmacology ( 12.3 )]</span>. Obtain serum aminotransferase, alkaline phosphatase, and total bilirubin levels prior to each treatment cycle and course [ see Dosage and Administration (2.1) ]. If a patient develops clinical signs, including unexplained liver enzyme elevations, or symptoms suggestive of hepatic dysfunction (e.g., unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine), promptly measure serum transaminases and total bilirubin and interrupt or discontinue treatment with cladribine tablets, as appropriate.

5.8 Hypersensitivity In clinical studies, 11% of cladribine-treated patients had hypersensitivity reactions, compared to 7% of placebo patients. Hypersensitivity reactions that were serious and/or led to discontinuation of cladribine tablets (e.g., dermatitis, pruritis) occurred in 0.5% of cladribine-treated patients, compared to 0.1% of placebo patients. One patient had a serious hypersensitivity reaction with rash, mucous membrane ulceration, throat swelling, vertigo, diplopia, and headache after the first dose of cladribine tablets. If a hypersensitivity reaction is suspected, discontinue cladribine therapy. Do not use cladribine tablets in patients with a history of hypersensitivity to cladribine [ see Contraindications (4) ].

5.9 Cardiac Failure In clinical studies, one cladribine-treated patient experienced life-threatening acute cardiac failure with myocarditis, which improved after approximately one week. Cases of cardiac failure have also been reported with parenteral cladribine used for treatment indications other than multiple sclerosis. Instruct patients to seek medical advice if they experience symptoms of cardiac failure (e.g., shortness of breath, rapid or irregular heartbeat, swelling).

PRECAUTIONS: General Cladribine injection 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. Periodic assessment of peripheral blood counts, particularly during the first four to eight weeks posttreatment, is recommended to detect the development of anemia, neutropenia and thrombocytopenia and for early detection of any potential sequelae (e.g., infection or bleeding). 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 and ADVERSE REACTIONS ). Fever was a frequently observed side effect during the first month on study. 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 1/3 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 and ADVERSE REACTIONS ). There are inadequate data on dosing of patients with renal or hepatic insufficiency. Development of acute renal insufficiency in some patients receiving high doses of cladribine has been described. Until more information is available, caution is advised when administering the drug to patients with known or suspected renal or hepatic insufficiency (see WARNINGS ). Rare cases of tumor lysis syndrome have been reported in patients treated with cladribine with other hematologic malignancies having a high tumor burden. Cladribine injection must be diluted in designated intravenous solutions prior to administration (see DOSAGE AND ADMINISTRATION ).

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 x 10 9 /L by Day 12, the mean Absolute Neutrophil Count reached 1,500 x 10 6 /L 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.

Drug Interactions

There are no known drug interactions with cladribine injection. Caution should be exercised if cladribine injection is administered before, after, or in conjunction with other drugs known to cause immunosuppression or myelosuppression (see WARNINGS ). Carcinogenesis No animal carcinogenicity studies have been conducted with cladribine. However, its carcinogenic potential cannot be excluded based on demonstrated genotoxicity of cladribine. 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 (Ames and Chinese hamster ovary cell gene mutation tests) and did not induce unscheduled DNA synthesis in primary rat hepatocyte cultures. However, cladribine was clastogenic both in vitro (chromosome aberrations in Chinese hamster ovary cells) and in vivo (mouse bone marrow micronucleus test). Impairment of Fertility The effect on human fertility is unknown. When administered intravenously to Cynomolgus monkeys, cladribine has been shown to cause suppression of rapidly generating cells, including testicular cells.

Pregnancy Pregnancy

Category D (see WARNINGS ).

Nursing

Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from cladribine, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug for the mother.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established. In a Phase I study involving patients 1 to 21 years old with relapsed acute leukemia, cladribine injection was given by continuous intravenous infusion in doses ranging from 3 to 10.7 mg/m 2 /day for five 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/m 2 /day), three of seven patients developed irreversible myelosuppression and fatal systemic bacterial or fungal infections. No unique toxicities were noted in this study (1) (see WARNINGS and ADVERSE REACTIONS ).

Geriatric Use

Clinical studies of cladribine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in elderly patients.

General

Cladribine injection 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. Periodic assessment of peripheral blood counts, particularly during the first four to eight weeks posttreatment, is recommended to detect the development of anemia, neutropenia and thrombocytopenia and for early detection of any potential sequelae (e.g., infection or bleeding). 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 and ADVERSE REACTIONS ). Fever was a frequently observed side effect during the first month on study. 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 1/3 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 and ADVERSE REACTIONS ). There are inadequate data on dosing of patients with renal or hepatic insufficiency. Development of acute renal insufficiency in some patients receiving high doses of cladribine has been described. Until more information is available, caution is advised when administering the drug to patients with known or suspected renal or hepatic insufficiency (see WARNINGS ). Rare cases of tumor lysis syndrome have been reported in patients treated with cladribine with other hematologic malignancies having a high tumor burden. Cladribine injection must be diluted in designated intravenous solutions prior to administration (see DOSAGE AND ADMINISTRATION ).

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 x 10 9 /L by Day 12, the mean Absolute Neutrophil Count reached 1,500 x 10 6 /L 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.

Drug Interactions

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

Carcinogenesis No animal carcinogenicity studies have been conducted with cladribine. However, its carcinogenic potential cannot be excluded based on demonstrated genotoxicity of cladribine.

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 (Ames and Chinese hamster ovary cell gene mutation tests) and did not induce unscheduled DNA synthesis in primary rat hepatocyte cultures. However, cladribine was clastogenic both in vitro (chromosome aberrations in Chinese hamster ovary cells) and in vivo (mouse bone marrow micronucleus test).

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

Pregnancy Pregnancy

Category D (see WARNINGS ).

Nursing

Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from cladribine, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug for the mother.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established. In a Phase I study involving patients 1 to 21 years old with relapsed acute leukemia, cladribine injection was given by continuous intravenous infusion in doses ranging from 3 to 10.7 mg/m 2 /day for five 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/m 2 /day), three of seven patients developed irreversible myelosuppression and fatal systemic bacterial or fungal infections. No unique toxicities were noted in this study (1) (see WARNINGS and ADVERSE REACTIONS ).

Geriatric Use

Clinical studies of cladribine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in elderly patients.

INTERACTIONS Table 3 Drug Interactions with cladribine tablets

7.1 Immunomodulatory, Immunosuppressive, or Myelosuppressive Drugs Clinical Impact Concomitant use of cladribine with immunomodulatory, immunosuppressive, or myelosuppressive drugs may increase the risk of adverse reactions because of the additive effects on the immune system <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.4 )]</span>. Prevention or Management Concomitant use with myelosuppressive or other immunosuppressive drugs is not recommended. Acute short-term therapy with corticosteroids can be administered. In patients who have previously been treated with immunomodulatory or immunosuppressive drugs, consider potential additive effect, the mode of action, and duration of effect of the other drugs prior to initiation of cladribine.

7.2 Interferon-Beta Clinical Impact Concomitant use of cladribine with interferon-beta did not change the exposure of cladribine to a clinically significant effect; however, lymphopenia risk may be increased [ see Warnings and Precautions (5.3) ]. Prevention or Management Concomitant use is not recommended.

7.3 Hematotoxic Drugs Clinical Impact Concomitant use of cladribine with hematotoxic drugs may increase the risk of adverse reactions because of the additive hematological effects [ see Warnings and Precautions (5.5) ]. Prevention or Management Monitor hematological parameters.

7.4 Antiviral and Antiretroviral Drugs Clinical Impact Compounds that require intracellular phosphorylation to become active (e.g., lamivudine, zalcitabine, ribavirin, stavudine, and zidovudine) could interfere with the intracellular phosphorylation and activity of cladribine. Prevention or Management Avoid concomitant use.

7.5 Potent ENT, CNT and BCRP Transporter Inhibitors Clinical Impact Cladribine is a substrate of breast cancer resistance protein (BCRP), equilibrative nucleoside (ENT1), and concentrative nucleoside (CNT3) transport proteins. The bioavailability, intracellular distribution, and renal elimination of cladribine may be altered by potent ENT1, CNT3, and BCRP transporter inhibitors. Prevention or Management Avoid co-administration of potent ENT1, CNT3, or BCRP transporter inhibitors (e.g., ritonavir, eltrombopag, curcumin, cyclosporine, dilazep, nifedipine, nimodipine, cilostazol, sulindac, dipyridamole, or reserpine) during the 4 to 5 day cladribine treatment cycles. If this is not possible, consider selection of alternative concomitant drugs with no or minimal ENT1, CNT3, or BCRP transporter inhibiting properties. If this is not possible, dose reduction to the minimum mandatory dose of drugs containing these compounds, separation in the timing of administration, and careful patient monitoring is recommended.

7.6 Potent BCRP and P-gp Transporter Inducers Clinical Impact Possible decrease in cladribine exposure if potent BCRP or P-gp transporter inducers are co-administered. Prevention or Management Consider a possible decrease in cladribine efficacy if potent BCRP (e.g., corticosteroids) or P-gp (e.g., rifampicin, St. John&apos;s Wort) transporter inducers are co-administered. Immunosuppressive drugs: Consider overlapping effects on immune system, when used sequentially. Concomitant use not recommended. (7.1) Hematotoxic drugs: Monitor patients for additive effects on the hematological profile. (7.3) Antiviral and antiretroviral drugs: Avoid concomitant use. (7.4) BCRP or ENT/CNT inhibitors: May alter bioavailability of cladribine. Avoid concomitant use. (7.5)