Cladribine is a synthetic purine nucleoside antimetabolite. It belongs to the antimetabolite class of antineoplastics but is most closely related to other purine analogs such as fludarabine, mercaptopurine, pentostatin, and thioguanine. Cladribine is an adenosine deaminase (ADA)-resistant analog of deoxyadenosine, with demonstrated activity in vitro against both lymphoid and myeloid neoplasms. Cladribine is not active against solid tumors. Favorable results have been seen with parenteral cladribine in the treatment of hairy cell leukemia (HCL). Cladribine also may be efficacious in the treatment of acute myelogenous leukemia (AML) in children, chronic lymphocytic leukemia (CLL), Waldenstrom's macroglobulinemia, cutaneous T-cell lymphoma, and non-Hodgkin's lymphoma. A distinguishing feature of cladribine is its activity against both dividing and nondividing cells. In comparison with other agents approved for the treatment of HCL, cladribine's shorter duration of therapy and lower overall cost make it an attractive choice over interferon alfa or pentostatin. Oral cladribine is indicated for the treatment of relapsing forms of multiple sclerosis, including relapsing-remitting disease and active secondary progressive disease. In clinical trials, patients treated with oral cladribine experienced a 58% relative risk reduction in annual relapse rate compared to those treated with placebo (0.14 vs. 0.33, p less than 0.001). Serious, generally dose-dependent and reversible, bone marrow suppression, including anemia, lymphopenia, neutropenia, thrombocytopenia, and pancytopenia have been reported with cladribine therapy. Cladribine may increase the risk of infection due to immunosuppression; serious, including fatal, infections have been reported with cladribine.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Hazardous Drugs Classification
-NIOSH 2016 List: Group 1
-NIOSH (Draft) 2020 List: Table 1
-Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
-Oral Tablets/Capsules: Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure.
-Injectables: Use double chemotherapy gloves and a protective gown. Prepare in a biological safety cabinet or compounding aseptic containment isolator with a closed system drug transfer device. Eye/face and respiratory protection may be needed during preparation and administration.
Emetic Risk
-Minimal
-Administer prn antiemetics as necessary.
Extravasation Risk
-Nonvesicant
Route-Specific Administration
Oral Administration
-Follow applicable special handling and disposal procedures for cytotoxic drugs.
-Separate administration of cladribine and any other oral drugs by at least 3 hours during the 4 or 5-day treatment cycles.
-If a dose is missed, take the missed dose on the following day and extend the number of days in that treatment cycle. If 2 consecutive doses are missed, extend the treatment cycle by 2 days.
Oral Solid Formulations
-Administer using dry hands. Wash hands thoroughly after administration. Avoid prolonged contact with skin.
-If a tablet is left on a surface or a broken or fragmented tablet is released from the blister, wash the area thoroughly with water.
-Take without regard to meals.
-Swallow tablet whole with water immediately after removal from blister. Do not chew.
Injectable Administration
-Visually inspect parenteral products 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 the solution.
-Variation from the given dosage regimen is not recommended. Evidence of neurotoxicity or renal toxicity may necessitate a delay or discontinuation of dosage.
Intravenous Administration
-CAUTION: Observe and exercise usual cautions for handling and preparing solutions of cytotoxic drugs.
-Utilize aseptic technique and proper environmental precautions, as cladribine does not contain any antimicrobial preservative or bacteriostatic agent.
-The concentrate for injection must be diluted before IV infusion. Do not use Dextrose 5% Injection because cladribine degradation is accelerated.
-Do not use solutions containing benzyl alcohol in neonates.
-Do not mix solutions containing cladribine with other intravenous drugs or additives or infuse simultaneously via a common intravenous line, as compatibility testing has not been performed.
Daily IV infusion:
-Add the calculated single daily dose of the concentrate for injection through a sterile 0.22-micrometer disposable hydrophilic syringe filter to a polyvinyl chloride infusion bag containing 500 mL of 0.9% Sodium Chloride Injection. Prepare each solution daily. Discard any unused portion; cladribine vials are for single-use only. Once cladribine solutions are diluted, promptly administer or store at 2 to 8 degrees C for no more than 8 hours before the start of administration.
-Infuse continuously over 24 hours.
-Cladribine admixtures are chemically and physically stable for at least 24 hours at room temperature under normal room fluorescent light in Baxter Viaflex PVC infusion containers.
Seven (7) day IV infusion:
-Calculate the dose for a 7-day period and withdraw from the concentrate for injection. Dilute in bacteriostatic 0.9% Sodium Chloride Injection containing benzyl alcohol as a preservative. To minimize the risk of microbial contamination, first the calculated 7-day dose and then the amount of diluent needed to bring the total volume to 100 mL should be passed through a sterile 0.22-micrometer disposable hydrophilic syringe filter as each solution is being added to the infusion reservoir. 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.
-Discard any unused portion of cladribine injection; vials are for single-use only. Once cladribine solutions are diluted, promptly administer or store at 2 to 8 degrees C for no more than 8 hours before the start of administration.
-Solutions prepared for individuals weighing more than 85 kg may have reduced preservative effectiveness due to greater dilution of the benzyl alcohol. Admixtures for the 7-day infusion have demonstrated acceptable chemical and physical stability for at least 7 days in the SIMS Deltec MEDICATION CASSETTE Reservoir.
-Infuse continuously over 7 days.
Prolonged CD4 count depression has been reported in patients with hairy cell leukemia who received cladribine in clinical studies (n = 196). At 4 to 6 months after therapy, the mean CD4 count fell from 766 cells/microliter (microL) to 272 cells/microL; the mean CD4 count was < 500 cells/microL at 15 months after therapy. CD8 counts also decreased with cladribine therapy; however, these counts were increasing at 9 months after therapy.
Contusions (1%) were reported with cladribine use in pooled results from 2 studies in 576 hairy cell leukemia patients.
Bone marrow suppression including severe neutropenia (defined as an absolute neutrophil count (ANC) less than 500 x 106/L), anemia (defined as a hemoglobin (Hb) concentration less than 8.5 g/dL), and thrombocytopenia (defined as a platelet count less than 20 x 109/L) has been reported with parenteral cladribine use in 70%, 37%, and 12% of patients with hairy cell leukemia (HCL), respectively, in a safety analysis of 196 patients in clinical studies. In pooled results from 2 studies in 576 patients with HCL, anemia occurred in 1% of patients. Prolonged bone marrow hypocellularity (cellularity less than 35% for 4 months) was reported in 42 of 124 HCL patients (34%) in 2 clinical studies; hypocellularity was noted up until day 1,010. Other hematologic adverse events include aplastic anemia, hemolytic anemia (occurring in patients with lymphoid malignancies within the first few weeks after treatment), and myelodysplastic syndrome. Myelosuppression (pancytopenia) occurs particularly with high intravenous cladribine doses and is most severe during the first month after therapy. In clinical studies, blood counts declined in the first 2 weeks after cladribine therapy; on average, normalization occurred by day 12 for platelet counts (mean, 100 x 109/L), by week 5 for ANC (mean, 1,500 x 106/L), and by week 8 for Hb (mean, 12 g/dL). Red blood cell (RBC) and platelet transfusions were required in 44% and 14% of patients, respectively, during the first month of intravenous cladribine therapy. Anemia and thrombocytopenia have been reported with intravenous cladribine use in other clinical settings. Monitor white blood counts periodically, especially during the first 4 to 8 weeks after therapy; also monitor for signs of bleeding. Lymphopenia has been reported in 87% of patients who received oral cladribine during clinical trials. 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 who received a cumulative dose of 3.5 mg/kg over 2 courses, 26% and 1% had nadir absolute lymphocyte counts less than 500 and less than 200 cells/microliter, respectively. Lymphocyte counts less than 500 cells/microliter occurred in 2% of patients at the end of the second treatment course. Median time to recovery to at least 800 cells/microliter was about 28 weeks. Mild to moderate decreases in neutrophil counts (cell count between 1,000 cells/microliter and less than the lower limit of normal) occurred in 27% of patients who received oral cladribine compared to 13% of patients who received placebo. Severe decreases in neutrophils (cell count below 1,000 cells/microliter) were observed in 3.6% of oral cladribine-treated patients compared to 2.8% of patients given placebo. Mild to moderate decreases in hemoglobin concentrations (8 g/dL to less than the lower limit of normal) were observed in 26% of oral cladribine-treated patients compared to 19% of patients given placebo. Mild decreases in platelet counts (cell count 75,000 cells/microliter to less than the lower limit of normal) occurred in 11% of oral cladribine-treated patients compared to 4% of patients given placebo. Serious cases of thrombocytopenia, neutropenia, and pancytopenia (some with documented bone marrow hypoplasia) requiring transfusion and granulocyte-colony stimulating factor treatment have been reported at dosages similar to or higher than the oral dose used for the treatment of multiple sclerosis. Obtain a complete blood count (CBC) with differential including lymphocyte count before each treatment cycle of oral cladribine. Lymphocytes must be within normal limits before initiating the first oral cladribine treatment course and at least 800 cells/microliter before initiating the second treatment course. If necessary, delay the second treatment course for up to 6 months to allow lymphocyte recovery to at least 800 cells/microliter; if recovery takes more than 6 months, do not continue treatment with oral cladribine. Monitor CBC with differential including lymphocyte count at 2 and 6 months after the start of each oral cladribine treatment course; if the lymphocyte count at month 2 is less than 200 cells/microliter, monitor monthly until month 6. Hold treatment with oral cladribine if the lymphocyte count is less than 200 cells/microliter. Transfusion-related graft-versus-host disease (GVHD) has been observed rarely after transfusion of nonirradiated blood in patients treated with cladribine. In patients who require blood transfusion, irradiation of cellular blood components is recommended.
Infection was reported in 28% of patients (bacterial, 42%; viral, 20%; fungal, 20%) within the first month of intravenous cladribine therapy in a safety analysis of 196 hairy cell leukemia (HCL) patients in clinical studies. Serious infections (e.g., septicemia, pneumonia) were reported in 6% of patients. There were 6 deaths attributed to infection, including 3 from pneumonia; 2 deaths occurred within the first month after intravenous cladribine therapy. The overall rate of infection during the second month of cladribine therapy was 6%. Herpes zoster infection (8 episodes) and fungal infections (16 episodes) were also reported, with most cases occurring within the first couple months after therapy. Additionally, bacteremia, cellulitis, localized infection, and pneumonia have occurred with intravenous cladribine use in other clinical settings. Use intravenous cladribine with caution after evaluating the risks vs. benefits of therapy in patients with active infection. Fever (temperature more than 100 degrees F) was reported in 69% of patients within the first month of intravenous cladribine therapy in clinical studies; severe fever (temperature more than 104 degrees F) was reported in 11% of patients. Less than one-third of patients with fever had a documented infection. Neutropenic fever (ANC less than 1,000/mm3) occurred in 47% of patients (severe (ANC less than 500/mm3), 32%). Fever (33%), neutropenic fever (8%), and chills (2%) were reported with intravenous cladribine use in pooled results from 2 studies in 576 HCL patients. In postmarketing surveillance septic shock and opportunistic infections (in the acute phase) were reported in patients who received intravenous cladribine therapy. Perform periodic peripheral blood count monitoring during intravenous cladribine therapy, especially the first 4 to 8 weeks, for early detection of any sequelae, including infection. Closely monitor patients, especially during the first month of therapy, for signs of infection or febrile neutropenia and start empiric antibiotics as clinically indicated. In clinical trials of oral cladribine for multiple sclerosis (MS), infections occurred in 49% of those treated with oral cladribine compared to 44% with placebo. Serious bacterial, viral, parasitic, and fungal infections that were life-threatening or fatal have also been reported with oral cladribine. Serious/severe infections occurred in 2.4% with oral cladribine compared to 2% with placebo during clinical trials. The most frequent serious infections in MS clinical trials included herpes zoster infection and pyelonephritis. Serious fungal infections (including coccidioidomycosis) were observed. Tuberculosis infection occurred in 3 of 1,976 patients, and 1 case was fatal. All cases of tuberculosis occurred in regions where tuberculosis is endemic. A fatal case of fulminant hepatitis B infection occurred in 1 oral cladribine clinical study patient. Additionally, 6% of oral cladribine-treated patients developed a herpes viral infection compared to 2% of patients given placebo. Herpes zoster infection (2% vs. 0.2%) and oral herpes (2.6% vs. 1.2%) were the most frequent types of herpes viral infections. Serious herpes zoster infections occurred in 0.2% of oral cladribine-treated patients. The incidence of herpes zoster was higher during the period of absolute lymphocyte count less than 500 cells/microliter. A fatal case of herpes meningoencephalitis occurred in 1 patient treated with oral cladribine at a higher dosage and longer duration of therapy than the approved regimen and in combination with interferon beta-1a treatment. Fever occurred in 5% of oral cladribine-treated patients compared to 3% of patients given placebo. Upper respiratory infection (38% oral cladribine vs. 32% placebo) and bronchitis (5% oral cladribine vs. 3% placebo) were also reported. Serious infections including nocardiosis, varicella zoster, histoplasmosis, cryptococcosis, and toxoplasmosis have been reported with oral cladribine during postmarketing experience. The majority of patients with these infections who had an absolute lymphocyte count available had concurrent lymphopenia. Exclude HIV infection and active tuberculosis or hepatitis before initiation of each oral cladribine treatment course. Screen patients for tuberculosis and hepatitis B and C before initiation of first and second treatment courses of oral cladribine; latent tuberculosis or hepatitis infections may be activated with cladribine use. Delay initiation of oral cladribine until tuberculosis or hepatitis infection has been adequately treated. Carriers of hepatitis B or C virus may be at risk of irreversible liver damage from virus reactivation. Monitor patients with lymphocyte count less than 500 cells/microliter for signs and symptoms suggestive of infection. Treat infections as clinically indicated. Delay oral cladribine treatment until full resolution or control of an acute infection. Administer anti-herpes infection prophylaxis in oral cladribine-treated patients with lymphocyte count less than 200 cells/microliter. Avoid vaccination with live-attenuated or live virus vaccines during or after oral cladribine treatment while white blood cell counts are not within normal limits.
Gastrointestinal adverse effects, including nausea (22%), vomiting (9%), diarrhea (7%), anorexia (8%), constipation (4%), abdominal pain (4%) and flatulence (1%), were reported with intravenous cladribine use in pooled results from 2 studies in 576 hairy cell leukemia (HCL) patients. In a safety analysis of 196 HCL patients who received intravenous cladribine in clinical studies, most episodes of nausea were mild, were not accompanied by vomiting, and did not require treatment with antiemetics; nausea was well controlled in patients who received antiemetics (primarily chlorpromazine). In clinical trials of oral cladribine, nausea occurred in 10% of cladribine-treated patients compared to 9% of patients given placebo.
Severe neurotoxicity, including irreversible paraparesis, quadriparesis, and axonal peripheral neuropathy (polyneuropathy), occurred in patients who received high-dose cladribine via continuous infusion at doses 4 to 9 times those used to treat hairy cell leukemia (HCL). Severe delayed onset neurological toxicity developed in 11 of 31 poor-risk patients (35%) with resistant leukemia or lymphoma who received high-dose cladribine for 7 to 14 days before a bone marrow transplant in a phase 1 study. Headache (14%) and dizziness (6%) have been reported with intravenous cladribine use in pooled results from 2 studies in 576 HCL patients. Neurologic toxicity may be related to the intravenous cladribine dose; however, severe neurologic toxicity (e.g., peripheral neuropathy, motor neuropathy, paralysis, polyneuropathy, paraparesis) has been reported rarely after standard dose intravenous cladribine in postmarketing surveillance. Depressed consciousness has also occurred. Consider delaying or discontinuing intravenous cladribine in patients who develop neurotoxicity. Seizures occurred in 0.3% of patients treated with oral cladribine during clinical trials; seizures were not reported in patients given placebo. Serious events included generalized tonic-clonic seizures and status epilepticus. It is not known if the seizures were directly related to oral cladribine, multiple sclerosis, or a combination of both. Headache occurred in 25% of oral cladribine-treated patients compared to 19% of patients given patients.
Tumor lysis syndrome (TLS) has been reported rarely after intravenous cladribine treatment in patients with hematologic malignancies having a high tumor burden.
In postmarketing surveillance, conjunctivitis was reported in patients who received intravenous cladribine therapy.
Acute nephrotoxicity occurred in patients who received high-dose cladribine via continuous infusion at doses 4 to 9 times those used to treat hairy cell leukemia; some patients who developed nephrotoxicity also received concomitant nephrotoxic agents/therapies. Renal dysfunction (e.g., acidosis, anuria, elevated serum creatinine) developed in 6 of 31 poor-risk patients (19%) with resistant leukemia or lymphoma who received high-dose cladribine for 7 to 14 days before a bone marrow transplantation in a phase 1 study. Acute renal dysfunction was reversible in 2 of these patients. In postmarketing surveillance, renal failure (unspecified), including acute renal failure and renal impairment, have been reported in patients who received intravenous cladribine therapy. Use cladribine cautiously in patients with known or suspected renal insufficiency; periodic renal function monitoring is recommended, especially in patients with a history of renal dysfunction. Consider delaying or discontinuing intravenous cladribine therapy if nephrotoxicity develops.
In postmarketing surveillance, reversible, mild elevated hepatic enzymes (i.e., increased bilirubin and transaminase concentrations) have been reported in patients with hairy cell leukemia who received intravenous cladribine. Use intravenous cladribine cautiously in patients with known or suspected hepatic insufficiency; periodic hepatic function monitoring is recommended, especially in patients with a history of liver dysfunction. In clinical trials, 0.3% of patients treated with oral cladribine experienced hepatic injury (serious or causing treatment discontinuation) compared to 0% of patients treated with placebo. Onset ranged from a few weeks to months after starting treatment with oral cladribine. Signs and symptoms of liver injury, including hepatic enzyme elevations more than 20-fold the upper limit of normal, have been observed. Abnormalities resolved upon oral cladribine discontinuation. Obtain serum aminotransferases, alkaline phosphatase, and total bilirubin concentrations before each oral cladribine treatment course. If a patient develops clinical signs of liver dysfunction, promptly measure serum transaminases and total bilirubin, and interrupt or discontinue oral cladribine treatment as clinically appropriate.
Fatigue (31%), asthenia (6%), and malaise (5%) were reported with intravenous cladribine use in pooled results from 2 studies in 576 hairy cell leukemia patients.
Respiratory adverse effects, including cough (7%), dyspnea (5%), abnormal breath sounds (4%), and rales (1%), were reported with intravenous cladribine use in pooled results from 2 studies in 576 hairy cell leukemia patients. Dyspnea included wheezing and exertional dyspnea. Additionally, crepitations have occurred with intravenous cladribine use in other clinical settings. In postmarketing surveillance, pulmonary interstitial infiltrates (e.g., interstitial pneumonitis, interstitial lung disease, pneumonitis, pulmonary fibrosis) were reported in patients who received intravenous cladribine therapy; most cases were determined to be infectious.
Myalgia (6%), pain (6%), arthralgia (3%), and muscular weakness (1%) were reported with intravenous cladribine use in pooled results from 2 studies in 576 hairy cell leukemia patients. Pain included back pain, chest pain (unspecified), arthritis pain, bone pain, and extremity pain. Back pain (8%) and arthralgia and arthritis (7%) occurred in patients treated with oral cladribine.
Sinus tachycardia (2%) and peripheral edema (2%) were reported with intravenous cladribine use in pooled results from 2 studies in 576 hairy cell leukemia patients. Additionally, edema and localized edema have occurred with intravenous cladribine use in other clinical settings.
Rash (unspecified) (16%) and administration site reactions (11%) have been reported with intravenous cladribine use in pooled results from 2 studies in 576 hairy cell leukemia patients. Most rashes (e.g., maculopapular rash, and papular, pruritic, pustular, and erythematous rashes) were mild. Administration site reactions included injection site reaction (erythema, edema, pain) and catheter site reaction (cellulitis, erythema, bleeding, pain). Other skin and soft issue adverse events included hyperhidrosis (3%), ecchymosis (2%), petechiae (2%), and pruritus (2%). Purpura, phlebitis, and localized edema have been reported with intravenous cladribine use in other clinical settings. In postmarketing surveillance, hypersensitivity, urticaria, eosinophilia, and Stevens-Johnson syndrome have been reported in patients who received intravenous cladribine therapy; toxic epidermal necrolysis (TEN) was reported rarely in patients also taking other agents known to cause TEN (e.g., allopurinol, antibiotics). In clinical trials, 11% of patients treated with oral cladribine had hypersensitivity adverse reactions compared to 7% of patients given placebo. Hypersensitivity reactions that were serious and/or led to treatment discontinuation (e.g., dermatitis or pruritus) occurred in 0.5% of cladribine-treated patients compared to 0.1% of patients given placebo. A case of serious hypersensitivity with rash, mucous membrane ulceration, throat swelling, vertigo, diplopia, and headache occurred after a first dose of oral cladribine in a single patient. Discontinue oral cladribine if a hypersensitivity reaction is suspected.
Insomnia (3%) and anxiety (1%) were reported with intravenous cladribine use in pooled results from 2 studies in 576 hairy cell leukemia patients. In postmarketing surveillance, confusion including disorientation was reported in patients who received intravenous cladribine therapy. In clinical trials of oral cladribine, insomnia occurred in 6% of patients who received cladribine compared to 4% of patients who received placebo. Depression occurred in 5% of cladribine-treated patients compared to 3% with placebo.
Alopecia occurred in 3% of patients treated with oral cladribine during clinical trials compared to 1% of patients treated with placebo.
Treatment with oral cladribine may increase the risk of new primary malignancy. In controlled and extension clinical trials, malignancies occurred more frequently in oral cladribine-treated patients compared to patients given placebo (0.27 vs. 0.13 events per 100 patient-years). Malignancies reported with oral cladribine include metastatic pancreatic carcinoma, malignant melanoma (2 cases), and ovarian cancer. Basal cell carcinoma and cervical carcinoma in situ (2 cases) occurred in patients given placebo and were curable by surgical resection. Follow standard cancer screening guidelines in patients treated with oral cladribine. After completion of 2 oral cladribine treatment courses, do not administer additional oral cladribine during the next 2 years. In clinical studies, there was an increased risk of malignancy in patients who received additional oral cladribine treatment within 2 years after the first 2 treatment courses. The risk of malignancy with reinitiating oral cladribine treatment more than 2 years after the completion of 2 courses has not been studied.
Cladribine is associated with teratogenesis. Malformations and embryolethality occurred during animal studies. Although there is no evidence of teratogenicity in humans due to cladribine, other inhibitors of DNA synthesis have been reported to be teratogenic in humans. Discontinue oral cladribine if the patient becomes pregnant. If intravenous cladribine is used during pregnancy, or if the patient becomes pregnant during therapy, advise the patient of the potential harm to the fetus.
Progressive multifocal leukoencephalopathy (PML) has been reported in the postmarketing setting with parenteral cladribine for oncologic indications. No cases of PML have been reported in clinical studies of oral cladribine in patients with multiple sclerosis. Instruct patients to notify their healthcare provider immediately if they develop any new or worsening neurologic signs or symptoms of PML. Typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on 1 side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes. At the first sign or symptom suggestive of PML, withhold oral cladribine and perform an appropriate diagnostic evaluation. MRI findings may be apparent before clinical signs or symptoms.
Heart failure occurred in 1 patient treated with oral cladribine during clinical trials. The patient experienced life-threatening acute heart failure with myocarditis, which improved after approximately 1 week. Cases of cardiac failure have also been reported with parenteral cladribine. Instruct patients to seek medical attention if they experience symptoms of heart failure (e.g., shortness of breath, rapid or irregular heartbeat, swelling). Hypertension occurred in 5% of patients treated with oral cladribine compared to 3% of patients given placebo.
Cladribine is contraindicated in patients with a history of hypersensitivity to cladribine or any of its components. Hypersensitivity reactions that are serious or led to treatment discontinuation have been reported.
Intravenous cladribine therapy requires an experienced clinician who is proficient in the use of chemotherapy. Serious bone marrow suppression, including anemia, lymphopenia, neutropenia, thrombocytopenia, and pancytopenia have been reported with cladribine therapy, especially at high doses. Cladribine-induced bone marrow suppression is usually dose-dependent and reversible. The lowest absolute lymphocyte count occurred approximately 2 to 3 months after the start of each oral cladribine treatment course and was lower with each additional treatment course. Obtain a complete blood count (CBC) with differential including lymphocyte count before each treatment cycle of oral cladribine. Lymphocytes must be within normal limits before initiating the first oral cladribine treatment course and at least 800 cells/microliter before initiating the second treatment course. If necessary, delay the second treatment course for up to 6 months to allow lymphocyte recovery to at least 800 cells/microliter; if recovery takes more than 6 months, do not continue treatment with oral cladribine. Monitor CBC with differential including lymphocyte count at 2 and 6 months after the start of each oral cladribine treatment course; if the lymphocyte count at month 2 is less than 200 cells/microliter, monitor monthly until month 6. Hold treatment with oral cladribine if the lymphocyte count is less than 200 cells/microliter. Use intravenous cladribine cautiously in patients with known or suspected severe bone marrow impairment of any etiology. Perform periodic peripheral blood count monitoring during intravenous cladribine therapy, especially the first 4 to 8 weeks. Additive hematological adverse reactions may occur if cladribine is given before or concomitantly with other drugs that affect the hematological profile. In patients who require blood transfusion, irradiation of cellular blood components is recommended before oral cladribine administration to decrease the risk of transfusion-related graft-versus-host disease.
Oral cladribine is not recommended for use in patients with moderate to severe renal impairment or renal failure (creatinine clearance less than 60 mL/minute). Use intravenous cladribine with caution in patients with known or suspected renal impairment. Monitor renal function, especially in patients with underlying renal disease. Acute nephrotoxicity and serious neurotoxicity have been reported with high doses (4 to 9 times the dose for hairy cell leukemia) of intravenous cladribine. Acute nephrotoxicity has been observed at high intravenous cladribine doses especially when given concomitantly with other nephrotoxic agents. Neurologic toxicity, including irreversible paraparesis and quadriparesis, appears to be dose-related; however, severe neurological toxicity has been reported after treatment with standard intravenous cladribine dosing regimens.
Benzyl alcohol is a preservative in the recommended diluent for the 7-day cladribine intravenous infusion solution. Benzyl alcohol has been associated with a fatal 'gasping syndrome' in premature neonates. Do not use preparations containing benzyl alcohol in neonates.
Vaccinate patients who are seropositive to varicella zoster virus (VZV) with zoster vaccine, recombinant at any time prior to or during treatment with oral cladribine, including when their lymphocyte counts are 500 cells/mcL or less. Vaccination of patients who are seronegative for VZV with zoster vaccine is recommended before starting oral cladribine. Administer all other vaccines according to guidelines before starting oral cladribine treatment. Administer live-attenuated or live vaccines at least 4 to 6 weeks before oral cladribine treatment because of a risk of active infection. It is recommended not to administer live attenuated vaccines to patients receiving parenteral cladribine. In general, avoid vaccination during chemotherapy because the antibody response may be suboptimal. Consider patients vaccinated within 14 days before starting immunosuppressive therapy or while receiving immunosuppressive therapy as unimmunized and revaccinate at least 3 months after therapy is discontinued if immune competence has been restored. Passive immunoprophylaxis with immune globulins may be indicated for immunocompromised persons instead of, or in addition to, vaccination. Household or other close contacts of patients with altered immunocompetence may receive all vaccines, with the exception of smallpox vaccine.
Oral cladribine is not recommended for use in patients with moderate to severe hepatic disease (Child-Pugh score more than 6). Hepatic injury has been reported in oral cladribine-treated patients. Signs and symptoms of liver injury, including hepatic enzyme elevations more than 20-fold the upper limit of normal, have been observed with onset from a few weeks to several months after starting oral cladribine treatment. Obtain serum aminotransferases, alkaline phosphatase, and total bilirubin concentrations before each treatment course. If a patient develops clinical signs of liver dysfunction, promptly measure serum transaminases and total bilirubin, and interrupt or discontinue oral cladribine treatment as clinically appropriate. Use intravenous cladribine with caution in patients with known or suspected hepatic insufficiency. Periodically assess hepatic function during intravenous cladribine therapy as clinically indicated.
Oral cladribine is contraindicated in patients with current malignancy. Treatment with oral cladribine may increase the risk of new primary malignancy. In patients with prior malignancy or with increased risk of malignancy, evaluate the benefits and risks of oral cladribine use on an individual basis. Follow standard cancer screening guidelines in patients treated with oral cladribine. After completion of 2 oral cladribine treatment courses, do not administer additional oral cladribine during the next 2 years. In clinical studies, there was an increased risk of malignancy in patients who received additional oral cladribine treatment within 2 years after the first 2 treatment courses. The risk of malignancy with reinitiating oral cladribine treatment more than 2 years after the completion of 2 courses has not been studied.
Obtain a baseline (within 3 months) MRI before initiating the first treatment course of oral cladribine because of the risk of progressive multifocal leukoencephalopathy (PML). Advise patients that PML has occurred with parenteral cladribine. Instruct patients to notify their healthcare provider immediately if they develop any new or worsening neurologic signs or symptoms of PML. At the first sign or symptom suggestive of PML, withhold oral cladribine and perform an appropriate diagnostic evaluation. MRI findings may be apparent before clinical signs or symptoms of PML.
Cladribine may increase the risk of infection due to immunosuppression; serious, including fatal, infections have been reported with cladribine use. Oral cladribine is contraindicated in patients with active chronic infection (e.g., hepatitis or tuberculosis) or human immunodeficiency virus (HIV) infection. Exclude HIV infection and active tuberculosis or hepatitis before initiation of each oral cladribine treatment course. Screen patients for tuberculosis and hepatitis B and C before initiation of first and second treatment courses of oral cladribine; latent tuberculosis or hepatitis infections may be activated with cladribine use. Delay initiation of oral cladribine until tuberculosis or hepatitis infection has been adequately treated. Carriers of hepatitis B or C virus may be at risk of irreversible liver damage from virus reactivation. Initiation of oral cladribine in patients receiving concomitant immunosuppressive or myelosuppressive therapy is not recommended; concomitant use with these therapies could increase the risk of immunosuppression. Monitor patients with lymphocyte count less than 500 cells/microliter for signs and symptoms suggestive of infection. Treat infections as clinically indicated. Delay oral cladribine treatment until full resolution or control of an acute infection. Administer anti-herpes infection prophylaxis in oral cladribine-treated patients with lymphocyte count less than 200 cells/microliter. Perform periodic peripheral blood count monitoring during intravenous cladribine therapy, especially the first 4 to 8 weeks, for early detection of any sequelae, including infection. Given the known myelosuppressive effects, carefully evaluate risks and benefits of administering intravenous cladribine to patients with active infections.
Cladribine can cause fetal harm when administered during pregnancy. Oral cladribine is contraindicated for use during pregnancy. There are no adequate data on the developmental risk associated with oral cladribine use during human pregnancy. If intravenous cladribine is used during pregnancy, or if the patient becomes pregnant during therapy, advise the patient of the potential harm to the fetus. Cladribine is teratogenic in animals. In mice, a significant increase in fetal variations was observed with intravenous cladribine doses of 1.5 mg/kg/day (4.5 mg/m2); additionally, increased resorptions, reduced litter size, and increased fetal malformations occurred with doses of 3 mg/kg/day (9 mg/m2). In rabbits, fetal deaths and malformations occurred with intravenous cladribine doses of 3 mg/kg/day (33 mg/m2). Although there is no evidence of teratogenicity in humans due to cladribine, other inhibitors of DNA synthesis have been reported to be teratogenic in humans. There is a pregnancy safety study that monitors pregnancy and infant outcomes following exposure to oral cladribine. The pregnancy outcomes of patients with multiple sclerosis exposed to cladribine during pregnancy or within 6 months before conception, or pregnancies fathered by individuals with multiple sclerosis with cladribine exposure within 6 months before conception, may be reported by calling EMD Serono's Adverse Event reporting line at 1-800-283-8088 ext. 5563 or by faxing 1-781-681-2961.
Oral cladribine is contraindicated in breast-feeding women intending to breast-feed on a cladribine treatment day and for 10 days after the last dose. Because of the potential for serious adverse effects in breast-feeding infants from cladribine, discontinue breast-feeding or discontinue intravenous cladribine, taking into account the importance of the drug to the mother. There are no data on the presence of cladribine in human milk, the effects on the breast-fed infant, or the effects on milk production.
Cladribine is associated with reproductive risk. Highly effective contraception is recommended during treatment with intravenous cladribine. Oral cladribine is contraindicated in females and males of reproductive potential who do not plan to use effective contraception during treatment and for 6 months after the last dose in each treatment course. Exclude pregnancy with pregnancy testing in those of reproductive potential before the initiation of each treatment course of oral cladribine. Discuss contraception requirements with the patient; contraception requirements apply to both male and female patients. Advise those who can become pregnant to use effective contraception during treatment with oral cladribine and for at least 6 months after the last dose in each treatment course. Advise those who have the ability to father a child to take precautions to prevent pregnancy of their partner during oral cladribine treatment and for at least 6 months after the last dose in each treatment course. Adverse effects on human gametogenesis could be expected. The effect of cladribine on the efficacy of systemic hormonal contraceptives in unknown.
For the treatment of relapsing forms of multiple sclerosis, including relapsing-remitting disease and active secondary progressive disease:
NOTE: Cladribine is not for use in persons with clinically isolated syndrome because of its safety profile.
Oral dosage:
Adults weighing 110 kg or more: 100 mg/first cycle PO divided once daily for 4 to 5 days (Max: 20 mg/day), followed by 100 mg/second cycle PO divided once daily for 4 to 5 days (Max: 20 mg/day) starting 23 to 27 days after the last dose of first cycle. Repeat course once at least 43 weeks after the last dose of second cycle. Max: 1.75 mg/kg/course and 3.5 mg/kg. After administration of 2 treatment courses, do not administer additional cladribine during the next 2 years due to increased risk of malignancy. The safety and efficacy of reinitiating cladribine more than 2 years after completing 2 treatment courses has not been studied.
Adults weighing 100 to 109 kg: 100 mg/first cycle PO divided once daily for 4 to 5 days (Max: 20 mg/day), followed by 90 mg/second cycle PO divided once daily for 4 to 5 days (Max: 20 mg/day) starting 23 to 27 days after the last dose of first cycle. Repeat course once at least 43 weeks after the last dose of second cycle. Max: 1.75 mg/kg/course and 3.5 mg/kg. After administration of 2 treatment courses, do not administer additional cladribine during the next 2 years due to increased risk of malignancy. The safety and efficacy of reinitiating cladribine more than 2 years after completing 2 treatment courses has not been studied.
Adults weighing 90 to 99 kg: 90 mg/first cycle PO divided once daily for 4 to 5 days (Max: 20 mg/day), followed by 80 mg/second cycle PO divided once daily for 4 to 5 days (Max: 20 mg/day) starting 23 to 27 days after the last dose of first cycle. Repeat course once at least 43 weeks after the last dose of second cycle. Max: 1.75 mg/kg/course and 3.5 mg/kg. After administration of 2 treatment courses, do not administer additional cladribine during the next 2 years due to increased risk of malignancy. The safety and efficacy of reinitiating cladribine more than 2 years after completing 2 treatment courses has not been studied.
Adults weighing 80 to 89 kg: 80 mg/first cycle PO divided once daily for 4 to 5 days (Max: 20 mg/day), followed by 70 mg/second cycle PO divided once daily for 4 to 5 days (Max: 20 mg/day) starting 23 to 27 days after the last dose of first cycle. Repeat course once at least 43 weeks after the last dose of second cycle. Max: 1.75 mg/kg/course and 3.5 mg/kg. After administration of 2 treatment courses, do not administer additional cladribine during the next 2 years due to increased risk of malignancy. The safety and efficacy of reinitiating cladribine more than 2 years after completing 2 treatment courses has not been studied.
Adults weighing 70 to 79 kg: 70 mg/first cycle PO divided once daily for 4 to 5 days (Max: 20 mg/day), followed by 70 mg/second cycle PO divided once daily for 4 to 5 days (Max: 20 mg/day) starting 23 to 27 days after the last dose of first cycle. Repeat course once at least 43 weeks after the last dose of second cycle. Max: 1.75 mg/kg/course and 3.5 mg/kg. After administration of 2 treatment courses, do not administer additional cladribine during the next 2 years due to increased risk of malignancy. The safety and efficacy of reinitiating cladribine more than 2 years after completing 2 treatment courses has not been studied.
Adults weighing 60 to 69 kg: 60 mg/first cycle PO divided once daily for 4 to 5 days (Max: 20 mg/day), followed by 60 mg/second cycle PO divided once daily for 4 to 5 days (Max: 20 mg/day) starting 23 to 27 days after the last dose of first cycle. Repeat course once at least 43 weeks after the last dose of second cycle. Max: 1.75 mg/kg/course and 3.5 mg/kg. After administration of 2 treatment courses, do not administer additional cladribine during the next 2 years due to increased risk of malignancy. The safety and efficacy of reinitiating cladribine more than 2 years after completing 2 treatment courses has not been studied.
Adults weighing 50 to 59 kg: 50 mg/first cycle PO divided once daily for 4 to 5 days (Max: 20 mg/day), followed by 50 mg/second cycle PO divided once daily for 4 to 5 days (Max: 20 mg/day) starting 23 to 27 days after the last dose of first cycle. Repeat course once at least 43 weeks after the last dose of second cycle. Max: 1.75 mg/kg/course and 3.5 mg/kg. After administration of 2 treatment courses, do not administer additional cladribine during the next 2 years due to increased risk of malignancy. The safety and efficacy of reinitiating cladribine more than 2 years after completing 2 treatment courses has not been studied.
Adults weighing 40 to 49 kg: 40 mg/first cycle PO divided once daily for 4 to 5 days (Max: 10 mg/day), followed by 40 mg/second cycle PO divided once daily for 4 to 5 days (Max: 10 mg/day) starting 23 to 27 days after the last dose of first cycle. Repeat course once at least 43 weeks after the last dose of second cycle. Max: 1.75 mg/kg/course and 3.5 mg/kg. After administration of 2 treatment courses, do not administer additional cladribine during the next 2 years due to increased risk of malignancy. The safety and efficacy of reinitiating cladribine more than 2 years after completing 2 treatment courses has not been studied.
For the treatment of active hairy-cell leukemia as defined by clinically significant anemia, neutropenia, thrombocytopenia, or disease-related symptoms:
NOTE: Cladribine has been designated an orphan drug by the FDA for this indication.
Intravenous dosage:
Adults: 0.09 mg/kg/day continuous IV infusion for 7 days.
For induction therapy of previously untreated acute myelogenous leukemia (AML)*, in combination with daunorubicin and cytarabine:
NOTE: Cladribine has been designated an orphan drug by the FDA for this indication.
Intravenous dosage:
Adults 60 years or younger: 5 mg/m2/day IV on days 1, 2, 3, 4, 5 in combination with daunorubicin 60 mg/m2/day IV on days 1, 2, 3 and cytarabine 200 mg/m2/day continuous IV infusion on days 1, 2, 3, 4, 5, 6, 7 as induction therapy in adult patients (age range, 16 to 60 years) was evaluated in 2 multicenter, randomized, phase 3 studies. This regimen was repeated in patients who achieved only a partial remission. Two cycles of consolidation therapy were given to patients who achieved a complete remission: 1 cycle of cytarabine 1.5 g/m2/day on days 1, 2, 3 plus mitoxantrone 10 mg/m2/day on days 3, 4, 5 and then 1 cycle of high-dose cytarabine 2 g/m2/dose IV every 12 hours on days 1, 3, and 5. Patients not eligible for hematopoietic stem-cell transplantation received 2 years of maintenance therapy consisting of daunorubicin 45 mg/m2/day IV on day 1 plus cytarabine 100 mg/m2 subcutaneously every 12 hours on days 1, 2, 3, 4, 5, alternating every second month with 6-thioguanine 100 mg/m2/day PO on days 1, 2, 3, 4, 5 plus cytarabine 100 mg/m2 subcutaneously every 12 hours on days 1, 2, 3, 4, 5. In 1 of the studies, cladribine 5 mg/m2 IV on days 1, 3, and 5 was given in combination with the high-dose cytarabine during consolidation and cladribine 5 mg/m2/day IV on days 1, 2, 3 was administered with each of the alternating maintenance therapies during the first 4 months of maintenance.
Adolescents 16 to 17 years: 5 mg/m2/day IV on days 1, 2, 3, 4, 5 in combination with daunorubicin 60 mg/m2/day IV on days 1, 2, 3 and cytarabine 200 mg/m2/day continuous IV infusion on days 1, 2, 3, 4, 5, 6, 7 as induction therapy in adult patients (age range, 16 to 60 years) was evaluated in 2 multicenter, randomized, phase 3 studies. This regimen was repeated in patients who achieved only a partial remission. Two cycles of consolidation therapy were given to patients who achieved a complete remission: 1 cycle of cytarabine 1.5 g/m2/day on days 1, 2, 3 plus mitoxantrone 10 mg/m2/day on days 3, 4, 5 and then 1 cycle of high-dose cytarabine 2 g/m2/dose IV every 12 hours on days 1, 3, and 5. Patients not eligible for hematopoietic stem-cell transplantation received 2 years of maintenance therapy consisting of daunorubicin 45 mg/m2/day IV on day 1 plus cytarabine 100 mg/m2 subcutaneously every 12 hours on days 1, 2, 3, 4, 5, alternating every second month with 6-thioguanine 100 mg/m2/day PO on days 1, 2, 3, 4, 5 plus cytarabine 100 mg/m2 subcutaneously every 12 hours on days 1, 2, 3, 4, 5. In 1 of the studies, cladribine 5 mg/m2 IV on days 1, 3, and 5 was given in combination with the high-dose cytarabine during consolidation and cladribine 5 mg/m2/day IV on days 1, 2, 3 was administered with each of the alternating maintenance therapies during the first 4 months of maintenance.
For the treatment of chronic lymphocytic leukemia (CLL)*:
NOTE: Cladribine has been designated an orphan drug by the FDA for this indication.
-for the first-line treatment of CLL, in combination with cyclophosphamide*:
Intravenous dosage:
Adults: 0.12 mg/kg/day IV on days 1, 2, and 3 repeated every 28 days for up to 6 cycles in combination with cyclophosphamide has been evaluated in 2 randomized, phase 3 trials. In 1 study, cladribine was administered over 30 minutes and the cyclophosphamide dosage was 250 mg/m2/day IV over 30 to 60 minutes on days 1, 2, and 3; therapy was continued for a median of 6 cycles. In another study, cladribine was given over 2 hours, and the cyclophosphamide dosage was 650 mg/m2 IV on day 1 only; therapy was administered for a median of 3 cycles.
-for the first-line treatment of CLL, in combination with cyclophosphamide and mitoxantrone*:
Intravenous dosage:
Adults: 0.12 mg/kg/day IV over 2 hours on days 1, 2, and 3 in combination with cyclophosphamide 650 mg/m2 IV on day 1 and mitoxantrone 10 mg/m2 IV on day 1 repeated every 28 days for up to 6 cycles (median, 3 cycles) has been evaluated in a randomized, phase 3 trial.
-for the first-line treatment of CLL, in combination with prednisone*:
Intravenous dosage:
Adults: 0.12 mg/kg/day IV over 2 hours for 5 days in combination with prednisone 30 mg/m2/day PO for 5 days repeated 28 days for up to 6 cycles has been studied in a randomized trial.
For the first-line treatment of low-grade non-Hodgkin's lymphoma (NHL)*:
NOTE: Cladribine has been designated an orphan drug by the FDA for non-Hodgkin's lymphoma.
Intravenous dosage:
Adults: 0.12 mg/kg/day IV over 2 hours on days 1, 2, 3, 4, and 5 repeated every 28 days for 6 cycles was evaluated in a randomized, 3-arm, phase 3 study.
For the treatment of relapsed or refractory cutaneous T-cell lymphoma (CTCL)*, including mycosis fungoides* and Sezary syndrome*:
Intravenous dosage:
Adults: 0.1 mg/kg/day IV for 5 or 7 days repeated every 28 days for up to 6 cycles (range 1 to 5 cycles) or unacceptable toxicity has been evaluated in a small, nonrandomized, clinical trial; overall response rate was 24%. Due to prolonged myelosuppression in the first 13 patients who received 7 days of continuous intravenous infusion (CIV) cladribine, the duration of therapy was decreased to 5 days in the last 12 patients treated (CIV, n = 9; IV bolus infusion over 2 hours, n = 3).
Maximum Dosage Limits:
-Adults
0.09 mg/kg/day continuous IV for hairy-cell leukemia; 20 mg (2 tablets)/cycle day PO and 1.75 mg/kg PO per course for 2 courses up to cumulative 3.5 mg/kg PO in 2 years for multiple sclerosis.
-Geriatric
0.09 mg/kg/day continuous IV for hairy-cell leukemia; 20 mg (2 tablets)/cycle day PO and 1.75 mg/kg PO per course for 2 courses up to cumulative 3.5 mg/kg PO in 2 years for multiple sclerosis.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
No dosage adjustment for oral cladribine is recommended for patients with mild hepatic impairment. Oral cladribine is not recommended in patients with moderate to severe hepatic impairment (Child-Pugh score more than 6). Use intravenous cladribine with caution in patients with known or suspected hepatic insufficiency.
Patients with Renal Impairment Dosing
No dosage adjustment for oral cladribine is recommended for patients with mild renal impairment (CrCl 60 to 89 mL/minute). Oral cladribine is not recommended in patients with moderate to severe renal impairment (CrCl less than 60 mL/minute). Use intravenous cladribine with caution in patients with known or suspected renal impairment.
*non-FDA-approved indication
Abciximab: (Moderate) Due to the thrombocytopenic effects of purine analogs, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
Acetaminophen; Ibuprofen: (Major) Due to the thrombocytopenic effects of cladribine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Albuterol; Budesonide: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
Alemtuzumab: (Major) Concomitant use of cladribine with alemtuzumab may increase the risk of immunosuppression. Avoid the use of these drugs together.
Alpha interferons: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
Amlodipine; Celecoxib: (Major) Due to the thrombocytopenic effects of cladribine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Anagrelide: (Moderate) Due to the thrombocytopenic effects of purine analogs, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
Aspirin, ASA; Dipyridamole: (Moderate) Due to the thrombocytopenic effects of purine analogs, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
Azelastine; Fluticasone: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
Bacillus Calmette-Guerin Vaccine, BCG: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Basiliximab: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents may result in additive effects. A dosage reduction of the purine analog may be indicated when used in combination with other myelosuppressive chemotherapy.
Beclomethasone: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
Betamethasone: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
Budesonide: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
Budesonide; Formoterol: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
Budesonide; Glycopyrrolate; Formoterol: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
Bupivacaine; Meloxicam: (Major) Due to the thrombocytopenic effects of cladribine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Celecoxib: (Major) Due to the thrombocytopenic effects of cladribine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Celecoxib; Tramadol: (Major) Due to the thrombocytopenic effects of cladribine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Chikungunya Vaccine, Live: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Major) Due to the thrombocytopenic effects of cladribine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Ciclesonide: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
Cilostazol: (Moderate) Due to the thrombocytopenic effects of purine analogs, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
Clopidogrel: (Moderate) Due to the thrombocytopenic effects of purine analogs, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
Clozapine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Corticosteroids: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
Cortisone: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
Cyclosporine: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as immunosuppressives may result in additive effects. A dosage reduction of the antineoplastic may be indicated when used in combination with other myelosuppressive chemotherapy.
Deflazacort: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
Dexamethasone: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
Diclofenac: (Major) Due to the thrombocytopenic effects of cladribine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Diclofenac; Misoprostol: (Major) Due to the thrombocytopenic effects of cladribine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Diflunisal: (Major) Due to the thrombocytopenic effects of cladribine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Digoxin: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa. For the digoxin tablets, there was a significant reduction in the AUC after chemotherapy to 54.4% +/- 35.5% (mean plus/minus SD) of the value before chemotherapy (p = 0.02), whereas for lanoxin capsules there was an insignificant reduction in AUC to 85.1% +/- 42.7% of the value before chemotherapy. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin tablets while they are receiving chemotherapy.
Diphenhydramine; Ibuprofen: (Major) Due to the thrombocytopenic effects of cladribine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Diphenhydramine; Naproxen: (Major) Due to the thrombocytopenic effects of cladribine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Dipyridamole: (Moderate) Due to the thrombocytopenic effects of purine analogs, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
Eptifibatide: (Moderate) Due to the thrombocytopenic effects of purine analogs, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
Etodolac: (Major) Due to the thrombocytopenic effects of cladribine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Febuxostat: (Major) Coadministration of febuxostat and cytotoxic antineoplastic agents has not been studied. After antineoplastic therapy, tumor cell breakdown may greatly increase the rate of purine metabolism to uric acid. Febuxostat inhibits uric acid formation, but does not affect xanthine and hypoxanthine formation. An increased renal load of these two uric acid precursors can occur and result in xanthine nephropathy and calculi.
Fenoprofen: (Major) Due to the thrombocytopenic effects of cladribine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Filgrastim, G-CSF: (Major) Filgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert their toxic effects against rapidly growing cells, filgrastim is contraindicated for use during the 24 hours before or after cytotoxic chemotherapy.
Fludrocortisone: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
Flunisolide: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
Flurbiprofen: (Major) Due to the thrombocytopenic effects of cladribine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Fluticasone: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
Fluticasone; Salmeterol: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
Fluticasone; Umeclidinium; Vilanterol: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
Fluticasone; Vilanterol: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
Formoterol; Mometasone: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
Hydrocodone; Ibuprofen: (Major) Due to the thrombocytopenic effects of cladribine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Hydrocortisone: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
Ibuprofen: (Major) Due to the thrombocytopenic effects of cladribine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Ibuprofen; Famotidine: (Major) Due to the thrombocytopenic effects of cladribine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Ibuprofen; Oxycodone: (Major) Due to the thrombocytopenic effects of cladribine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Ibuprofen; Pseudoephedrine: (Major) Due to the thrombocytopenic effects of cladribine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Indomethacin: (Major) Due to the thrombocytopenic effects of cladribine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Interferon Alfa-2b: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
Interferon Alfa-n3: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
Intranasal Influenza Vaccine: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Ketoprofen: (Major) Due to the thrombocytopenic effects of cladribine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Ketorolac: (Major) Due to the thrombocytopenic effects of cladribine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Live Vaccines: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Measles Virus; Mumps Virus; Rubella Virus; Varicella Virus Vaccine, Live: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Measles/Mumps/Rubella Vaccines, MMR: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Meclofenamate Sodium: (Major) Due to the thrombocytopenic effects of cladribine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Mefenamic Acid: (Major) Due to the thrombocytopenic effects of cladribine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Meloxicam: (Major) Due to the thrombocytopenic effects of cladribine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Methylprednisolone: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
Mometasone: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
Nabumetone: (Major) Due to the thrombocytopenic effects of cladribine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Naproxen: (Major) Due to the thrombocytopenic effects of cladribine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Naproxen; Esomeprazole: (Major) Due to the thrombocytopenic effects of cladribine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Naproxen; Pseudoephedrine: (Major) Due to the thrombocytopenic effects of cladribine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Nonsteroidal antiinflammatory drugs: (Major) Due to the thrombocytopenic effects of cladribine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Ofatumumab: (Moderate) Concomitant use of ofatumumab with cladribine may increase the risk of immunosuppression. Ofatumumab has not been studied in combination with other immunosuppressive or immune modulating therapies used for the treatment of multiple sclerosis, such as cladribine. Consider the duration and mechanism of action of drugs with immunosuppressive effects when switching therapies for multiple sclerosis patients.
Olopatadine; Mometasone: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
Oxaprozin: (Major) Due to the thrombocytopenic effects of cladribine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Ozanimod: (Moderate) Concomitant use of ozanimod with cladribine may increase the risk of immunosuppression. Ozanimod has not been studied in combination with other immunosuppressive or immune modulating therapies used for the treatment of multiple sclerosis.
Pegfilgrastim: (Major) Pegfilgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert their toxic effects against rapidly growing cells, pegfilgrastim should not be given 14 days before or for 24 hours after cytotoxic chemotherapy.
Peginterferon Alfa-2a: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
Peginterferon Alfa-2b: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
Piroxicam: (Major) Due to the thrombocytopenic effects of cladribine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Platelet Inhibitors: (Moderate) Due to the thrombocytopenic effects of purine analogs, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
Prasugrel: (Moderate) Due to the thrombocytopenic effects of purine analogs, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
Prednisolone: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
Prednisone: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
Ropeginterferon alfa-2b: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
Rotavirus Vaccine: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Smallpox and Monkeypox Vaccine, Live, Nonreplicating: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Smallpox Vaccine, Vaccinia Vaccine: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Sulindac: (Major) Due to the thrombocytopenic effects of cladribine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Sumatriptan; Naproxen: (Major) Due to the thrombocytopenic effects of cladribine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Tbo-Filgrastim: (Major) Filgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert their toxic effects against rapidly growing cells, filgrastim is contraindicated for use during the 24 hours before or after cytotoxic chemotherapy.
Ticagrelor: (Moderate) Due to the thrombocytopenic effects of purine analogs, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
Tirofiban: (Moderate) Due to the thrombocytopenic effects of purine analogs, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
Tolmetin: (Major) Due to the thrombocytopenic effects of cladribine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Triamcinolone: (Minor) Concurrent use of purine analogs with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
Typhoid Vaccine: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Varicella-Zoster Virus Vaccine, Live: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Vorapaxar: (Moderate) Due to the thrombocytopenic effects of purine analogs, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
Yellow Fever Vaccine, Live: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Leukemia and Lymphoma
Cladribine is phosphorylated intracellularly by deoxycytidine kinase to produce the active moiety chlorodeoxyadenosine triphosphate. Monophosphate and diphosphate forms also may be detected. Cells rich in deoxycytidine kinase, such as lymphocytes, are sensitive to cladribine. Chlorodeoxyadenosine triphosphate can be incorporated into DNA and interfere with normal DNA function. More important, chlorodeoxyadenosine triphosphate inhibits DNA polymerase, DNA ligase, and ribonucleotide reductase, all of which are enzymes important in DNA maintenance and repair. Strand breaks in DNA begin to accumulate and cause synthesis of poly (ADP-ribose) polymerase. To synthesize this enzyme, nicotinamide adenine dinucleotide (NAD) must be consumed. NAD is necessary for ATP synthesis, and its consumption subsequently impairs ATP synthesis. Without adequate ATP concentrations, the cell dies within 48 hours. Cladribine is resistant to ADA, the enzyme responsible for the deamination of deoxyadenosine. Deoxyadenosine is a byproduct of DNA breakdown. Unlike pentostatin, cladribine does not inhibit ADA. In vitro studies reveal that cladribine affects resting and proliferating lymphocytes. Unlike other antimetabolite antineoplastics, cladribine is not specific for the S-phase but interferes with events that prepare the cell to enter the S-phase. Low concentrations of cladribine inhibit the growth of certain lymphoblastoid cell lines and are lethal to slowly dividing malignant T-cells. Cladribine does not affect solid-tissue cell lines. Normal resting peripheral blood lymphocytes are unaffected. Cell growth inhibition is dose- and time-dependent. Cladribine's proclivity for lymphocytes makes it highly effective as an antileukemic agent. The most dramatic responses have been achieved in treatment of HCL.
Multiple Sclerosis
The mechanism by which cladribine exerts its effects in multiple sclerosis has not been fully elucidated but is thought to involve lymphocyte depletion through cytotoxic effects on B and T lymphocytes through impairment of DNA synthesis.
Cladribine is administered orally and intravenously. The mean apparent volume of distribution is 480 to 490 L after oral administration and 9 L/kg after intravenous administration. Mean steady-state volume of distribution was 4.5 +/- 2.8 L/kg after a 2-hour intravenous infusion. Plasma protein binding is 20% and independent of concentration, in vitro. Cladribine has the potential to cross the blood-brain barrier with a cerebrospinal fluid/plasma concentration ratio of approximately 0.25 in cancer patients. Intracellular concentrations of cladribine and/or its metabolites in human lymphocytes are approximately 30 to 40 times extracellular, in vitro. Cladribine is a prodrug that is phosphorylated to cladribine monophosphate (Cd-AMP) by deoxycytidine kinase in lymphocytes and deoxyguanosine kinase in the mitochondria. Cd-AMP is further phosphorylated to cladribine diphosphate and to 2-chlorodeoxyadenosine triphosphate (Cd-ATP), which is the active moiety. The dephosphorylation and deactivation of Cd-AMP is catalyzed by cytoplasmic 5'-nucleotidase. Extensive whole blood and negligible hepatic enzyme metabolism were observed, in vitro. The intracellular half-lives of Cd-AMP and Cd-ATP are 15 hours and 10 hours, respectively. The estimated terminal half-life of cladribine is approximately 1 day. Median apparent renal clearance of orally administered cladribine is 22.2 L/hour, and non-renal clearance is 23.4 L/hour. Mean clearance was 978 +/- 422 mL/hour/kg after a 2-hour intravenous infusion.
Affected cytochrome P450 isoenzymes and drug transporters: BCRP, P-gp, ENT1, CNT3
Cladribine is a substrate of breast cancer resistance protein (BCRP), P-glycoprotein (P-gp), equilibrative nucleoside transporter 1 (ENT1), and concentrative nucleoside transporter 3 (CNT3). Inhibition of BCRP in the GI tract may increase oral bioavailability and systemic exposure of cladribine. Potent ENT1 or CNT3 inhibition may alter intracellular distribution and renal elimination of cladribine.
-Route-Specific Pharmacokinetics
Oral Route
After the oral administration of cladribine 10 mg, mean Cmax was 22 to 29 ng/mL, and the corresponding mean AUC was 80 to 101 ng x hour/mL. Cmax and AUC increased proportionally across a dose range of 3 to 20 mg, and no accumulation of cladribine was observed in plasma after repeated dosing. The bioavailability of oral cladribine was approximately 40%. Median Tmax was 0.5 hours (range 0.5 to 1.5 hours) after fasted administration. Administration with a high-fat meal decreased the geometric mean Cmax by 29%, and AUC was unchanged; Tmax was prolonged to 1.5 hours (range 1 to 3 hours), which is not expected to be clinically significant. Renal clearance exceeded the glomerular filtration rate, indicating active renal secretion of cladribine. After oral administration of cladribine 10 mg, 28.5% (mean [standard deviation]) of the dose was excreted unchanged via the renal route.
Intravenous Route
Intravenous administration of cladribine yields 100% bioavailability. Rapid increases in plasma cladribine concentrations occur at the end of infusion.
-Special Populations
Hepatic Impairment
The pharmacokinetics of cladribine have not been evaluated in patients with hepatic impairment.
Renal Impairment
Renal clearance after oral cladribine administration was shown to be dependent on creatinine clearance. In a pooled pharmacokinetic analysis of oral cladribine, a decrease in total clearance of 18% was estimated in a typical subject with a CrCl of 65 mL/minute leading to an increase in cladribine exposure by 25%. The effect of renal impairment on the elimination of cladribine after intravenous administration has not been studied in humans.
Geriatric
The pharmacokinetics of cladribine after oral administration have not been evaluated in geriatric patients.
Gender Differences
There were no clinically significant differences in the pharmacokinetics of cladribine after oral administration based on gender.
Other
Age
There were no clinically significant differences in the pharmacokinetics of cladribine after oral administration based on age in the range of 18 to 65 years.