Leustatin

Browse PDR's full list of drug information

Leustatin

Classes

MS Agents
Purine Analogs

Administration

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

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.[64040]

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.[64040]

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.[30468]
 
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.[30468]
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.[30468]

Adverse Reactions
Severe

neutropenia / Delayed / 70.0-70.0
anemia / Delayed / 1.0-37.0
thrombocytopenia / Delayed / 12.0-12.0
fever / Early / 11.0-11.0
infection / Delayed / 6.0-6.0
toxic epidermal necrolysis / Delayed / 0-1.0
heart failure / Delayed / 0-1.0
seizures / Delayed / 0.3-0.3
hemolytic anemia / Delayed / Incidence not known
graft-versus-host disease (GVHD) / Delayed / Incidence not known
aplastic anemia / Delayed / Incidence not known
pancytopenia / Delayed / Incidence not known
tumor lysis syndrome (TLS) / Delayed / Incidence not known
renal failure (unspecified) / Delayed / Incidence not known
nephrotoxicity / Delayed / Incidence not known
anuria / Delayed / Incidence not known
pulmonary fibrosis / Delayed / Incidence not known
Stevens-Johnson syndrome / Delayed / Incidence not known
new primary malignancy / Delayed / Incidence not known
teratogenesis / Delayed / Incidence not known
progressive multifocal leukoencephalopathy / Delayed / Incidence not known

Moderate

lymphopenia / Delayed / 87.0-87.0
constipation / Delayed / 9.0-9.0
dyspnea / Early / 5.0-5.0
depression / Delayed / 5.0-5.0
hypertension / Early / 5.0-5.0
sinus tachycardia / Rapid / 2.0-2.0
peripheral edema / Delayed / 2.0-2.0
bone marrow suppression / Delayed / Incidence not known
hepatitis / Delayed / Incidence not known
neurotoxicity / Early / Incidence not known
peripheral neuropathy / Delayed / Incidence not known
conjunctivitis / Delayed / Incidence not known
elevated hepatic enzymes / Delayed / Incidence not known
wheezing / Rapid / Incidence not known
pneumonitis / Delayed / Incidence not known
chest pain (unspecified) / Early / Incidence not known
bone pain / Delayed / Incidence not known
edema / Delayed / Incidence not known
bleeding / Early / Incidence not known
erythema / Early / Incidence not known
eosinophilia / Delayed / Incidence not known
phlebitis / Rapid / Incidence not known
confusion / Early / Incidence not known

Mild

fatigue / Early / 31.0-31.0
headache / Early / 14.0-25.0
nausea / Early / 10.0-22.0
rash / Early / 16.0-16.0
vomiting / Early / 9.0-9.0
anorexia / Delayed / 8.0-8.0
back pain / Delayed / 8.0-8.0
diarrhea / Early / 7.0-7.0
cough / Delayed / 7.0-7.0
arthralgia / Delayed / 3.0-7.0
dizziness / Early / 6.0-6.0
asthenia / Delayed / 6.0-6.0
myalgia / Early / 6.0-6.0
insomnia / Early / 3.0-6.0
malaise / Early / 5.0-5.0
abdominal pain / Early / 4.0-4.0
hyperhidrosis / Delayed / 3.0-3.0
alopecia / Delayed / 3.0-3.0
chills / Rapid / 2.0-2.0
ecchymosis / Delayed / 2.0-2.0
petechiae / Delayed / 2.0-2.0
pruritus / Rapid / 2.0-2.0
flatulence / Early / 1.0-1.0
weakness / Early / 1.0-1.0
anxiety / Delayed / 1.0-1.0
purpura / Delayed / Incidence not known
urticaria / Rapid / Incidence not known
maculopapular rash / Early / Incidence not known
injection site reaction / Rapid / Incidence not known

Boxed Warning
Bone marrow suppression, requires an experienced clinician

Intravenous cladribine therapy requires an experienced clinician who is proficient in the use of chemotherapy.[30468] 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.[30468] [64040] 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.[64040] 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.[30468] 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.[64040]

Nephrotoxicity, neurotoxicity, renal disease, renal failure, renal impairment

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).[64040] 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.[30468]

New primary malignancy

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.[64040]

Pregnancy

Cladribine can cause fetal harm when administered to a pregnant woman. Oral cladribine is contraindicated in 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.[30468] [64040]

Contraception requirements, pregnancy testing, reproductive risk

Cladribine is associated with reproductive risk. 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 females of reproductive potential before the initiation of each treatment course of oral cladribine. Discuss contraception requirements with the patient. Advise females of reproductive potential to use effective contraception during treatment with oral cladribine and for at least 6 months after the last dose in each treatment course. Instruct women who are using systemic hormonal contraceptives to add a barrier method during oral cladribine dosing and for at least 4 weeks after the last treatment course, as it is not known if cladribine can decrease the effectiveness of hormonal contraceptives. Advise male patients of reproductive potential 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. Highly effective contraception is recommended during treatment with intravenous cladribine.[30468] [64040]

Common Brand Names

Leustatin, MAVENCLAD

Dea Class

Rx

Description

Parenteral and oral, synthetic purine nucleoside antimetabolite
Used for various lymphomas and leukemias and relapsing forms of multiple sclerosis
Associated with serious, generally dose-dependent and reversible, bone marrow suppression and increased risk of infection

Dosage And Indications
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 patients with clinically isolated syndrome because of its safety profile.[64040]
Oral dosage Adults

1.75 mg/kg PO per treatment course divided into 2 cycles and given as divided doses of 1 or 2 tablets PO once daily over 4 or 5 days for each cycle with second cycle starting 23 to 27 days after the last dose of first cycle. Administer a second course at least 43 weeks after the last dose of the first course, second cycle for a cumulative dosage of 3.5 mg/kg. Max: 20 mg (2 tablets)/cycle day. Do not administer additional doses during the next 2 years after 2 treatment courses. The safety and efficacy of reinitiating therapy more than 2 years after completing 2 treatment courses have not been studied.
FIRST CYCLE DOSE BY PATIENT WEIGHT: 40 to less than 50 kg, 40 mg; 50 to less than 60 kg, 50 mg; 60 to less than 70 kg, 60 mg; 70 to less than 80 kg, 70 mg; 80 to less than 90 kg, 80 mg; 90 to less than 100 kg, 90 mg; 100 kg or more, 100 mg. SECOND CYCLE DOSE BY PATIENT WEIGHT: 40 to less than 50 kg, 40 mg; 50 to less than 60 kg, 50 mg; 60 to less than 70 kg, 60 mg; 70 to less than 90 kg, 70 mg; 90 to less than 100 kg, 80 mg; 100 to less than 110 kg, 90 mg; 110 kg or more, 100 mg.[64040]

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.[30468]

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.[51279] [51280] 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.[51280]

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.[51279] [51280] 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.[51280]

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.[43762] [50166] 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.[43762] 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.[50166]

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).

†Indicates off-label use

Dosing Considerations
Hepatic Impairment

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.

Renal Impairment

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.

Drug Interactions

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.
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.
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.
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.
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.
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.
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.
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.
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.
Valdecoxib: (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.
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.
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.

How Supplied

Cladribine/Leustatin Intravenous Inj Sol: 1mg, 1mL
MAVENCLAD Oral Tab: 10mg

Maximum Dosage
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.

Mechanism Of Action

Leukemia and Lymphoma
Cladribine is phosphorylated intracellularly by deoxycytidine kinase to produce the active moiety chlorodeoxyadenosine triphosphate.[23951] 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.[23952] 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.[23953] 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.[64040]

Pharmacokinetics

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.[30468] [64040]
 
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.[64040]

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% [20] (mean [standard deviation]) of the dose was excreted unchanged via the renal route.[64040]

Intravenous Route

Intravenous administration of cladribine yields 100% bioavailability. Rapid increases in plasma cladribine concentrations occur at the end of infusion.[23953]

Pregnancy And Lactation
Pregnancy

Cladribine can cause fetal harm when administered to a pregnant woman. Oral cladribine is contraindicated in 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.[30468] [64040]

Cladribine is associated with reproductive risk. 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 females of reproductive potential before the initiation of each treatment course of oral cladribine. Discuss contraception requirements with the patient. Advise females of reproductive potential to use effective contraception during treatment with oral cladribine and for at least 6 months after the last dose in each treatment course. Instruct women who are using systemic hormonal contraceptives to add a barrier method during oral cladribine dosing and for at least 4 weeks after the last treatment course, as it is not known if cladribine can decrease the effectiveness of hormonal contraceptives. Advise male patients of reproductive potential 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. Highly effective contraception is recommended during treatment with intravenous cladribine.[30468] [64040]