cladribine (Rx)

Brand and Other Names:Leustatin DSC, Mavenclad
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

injectable solution

  • 1mg/mL as 10 mL single-use vial (generic formulation)

tablets

  • 10mg (Mavenclad)
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Hairy Cell Leukemia

Cladribine (parenteral only)

  • 0.09 mg/kg/day IV continuous infusion for 7 days 

Dosing considerations

  • Monitor CBC with differential
  • Monitor for signs/symptoms of neurotoxicity and infection; if infection present, treat as appropriate prior to therapy; if not possible, consider alternative therapy if possible

Multiple Sclerosis

Mavenclad only

  • Indicated for relapsing forms of multiple sclerosis (MS), to include relapsing-remitting disease and active secondary progressive disease; because of its safety profile, use is generally recommended for patients with inadequate response to, or unable to tolerate, alternate indicated drug
  • 2 yearly treatment courses: 1.75 mg/kg/course PO; each course divided into 2 treatment cycles; not to exceed 3.5 mg/kg cumulative dosage (see oral administration)
  • Oral dose per cycle by weight in each treatment course
    • Also see Administration for timing of each treatment course and cycles
    • <40 kg: Safety and efficacy not established
    • 40 kg to <50 kg: 40 mg first cycle; 40 mg second cycle
    • 50 kg to <60 kg: 50 mg first cycle; 50 mg second cycle
    • 60 kg to <70 kg: 60 mg first cycle; 60 mg second cycle
    • 70 kg to <80 kg: 70 mg first cycle; 70 mg second cycle
    • 80 kg to <90 kg: 80 mg first cycle; 70 mg second cycle
    • 90 kg to <100 kg: 90 mg first cycle; 80 mg second cycle
    • 100 kg to <110 kg: 100 mg first cycle; 90 mg second cycle
    • ≥110 kg: 100 mg first cycle; 100 mg second cycle
    • Do not administer >2 tablets daily; administer 1-2 tablets/day PO over 4-5 consecutive days

Dosage Modifications

Mavenclad only

  • Renal impairment
    • Mild (CrCl 60-89 mL/min): No dosage adjustment recommended
    • Moderate to severe (CrCl <60 mL/min): Not recommended
  • Hepatic impairment
    • Mild: No dosage adjustment recommended
    • Moderate to severe (Child-Pugh >6): Not recommended

Dosing Considerations

Mavenclad only

  • Limitations of use: Treatment is not recommended for use in patients with clinically isolated syndrome (CIS) because of its safety profile
  • Prior to administration
    • Follow standard cancer screening guidelines because of risk of malignancies
    • Exclude pregnancy in females of reproductive potential
    • Exclude HIV infection
    • Perform tuberculosis screening
    • Screen for hepatitis B and C
    • Evaluate acute infection; consider delaying treatment until any acute infection is fully controlled
    • Vaccination recommended for patients who are antibody-negative for varicella zoster virus
    • Administer all immunizations according to immunization guidelines; administer live-attenuated or live vaccines 4-6 weeks prior to therapy; avoid vaccination with live-attenuated or live vaccines during and after therapy while the patient’s white blood cell counts are not within normal limits
    • Obtain a baseline (within 3 months) magnetic resonance imaging prior to first treatment course because of risk of progressive multifocal leukoencephalopathy (PML); at first sign or symptom suggestive of PML, withhold therapy and perform an appropriate diagnostic evaluation
    • Evaluate for liver injury; obtain serum aminotransferase, alkaline phosphatase, and total bilirubin levels
  • Complete blood count
    • Lymphocytes must be within normal limits before initiating first treatment course and at least 800 cells/mcL before initiating second treatment course
    • May delay second treatment course for up to 6 months to allow for recovery of lymphocytes to at least 800 cells per microliter; if recovery takes >6 months, patient should not receive further treatment
    • Obtain CBC with differential including lymphocyte count before initiating first treatment course and before initiating second course
    • Obtain CBC with differential including lymphocyte count 2 and 6 months after start of treatment course; if lymphocyte count at month 2 <200 cells/mcL, monitor monthly until month 6 and periodically thereafter and when clinically indicated
    • Hold therapy if lymphocyte count <200 cells/mcL
    • Administer antiherpes prophylaxis in patients with lymphocyte counts <200 cells/mcL

Orphan Designations

Non-Hodgkin Lymphoma

Acute Myeloid Leukemia

Chronic Lymphocytic Leukemia

Orphan sponsor

  • Ortho Biotech Oncology Research & Development, Unit of J & J Pharmaceutical Research & Dev., LLC; 920 Route 202 South, P.O. Box 300; Raritan, NJ 08869-0602

Other Uses

Off-label: Cutaneous T-cell lymphoma, AML, CLL, NHL, autoimmune hemolytic anemia, mycosis fungoides, Sezary syndrome

Safety and efficacy not established

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Interactions

Interaction Checker

and cladribine

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            Adverse Effects

            >10%

            Cladribine (parenteral)

            • Fever (69%)
            • Fatigue (45%)
            • Nausea (28%)
            • Rash (27%)
            • Headache (22%)
            • Appetite decreased (17%)
            • Vomiting (13%)

            Mavenclad

            • Upper respiratory tract infection (38%)
            • Headache (25%)
            • Lymphopenia (24%)
            • Nausea (10%)
            • Hypersensitivity (11%)

            1-10%

            Cladribine (parenteral)

            • Diarrhea (10%)
            • Purpura (10%)
            • Asthenia  (9%)
            • Chills (9%)
            • Constipation (9%)
            • Dizziness (9%)
            • Petechiae (8%)
            • Insomnia (7%)
            • Malaise (7%)
            • Abdominal pain (6%)
            • Edema (6%)
            • Erythema (6%)
            • Pruritus (6%)

            Mavenclad

            • Back pain (8%)
            • Arthralgia and arthritis (7%)
            • Insomnia (6%)
            • Bronchitis (5%)
            • Hypertension (5%)
            • Fever (5%)
            • Depression (5%)
            • Alopecia (3%)

            <1%

            Cladribine (parenteral)

            • Aplastic anemia
            • Cellulitis
            • Eosinophilia
            • Hemolytic anemia
            • Melodysplastic syndrome
            • Fungal infection
            • Pneumonia
            • Pancytopenia

            Mavenclad

            • Seizures
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            Warnings

            Black Box Warnings

            Cladribine (parenteral)

            • The drug should be administered under the supervision of an experienced cancer chemotherapy physician
            • Bone marrow suppression may occur but is usually reversible and appears to be dose dependent  
            • Continuous infusion of high doses of 4 to 9 times the recommended dose for hairy cell leukemia has been associated with serious acute nephrotoxicity and neurological toxicity resulting in irreversible paraparesis and quadriparesis; standard cladribine dosing regimens have also been associated with severe neurological toxicity
            • Acute nephrotoxicity reported with high doses (4-9 times recommended dose for hairy cell leukemia), especially when used concomitantly with nephrotoxic agents

            Mavenclad

            • Malignancies
              • Therapy may increase risk of malignancy
              • Contraindicated in patients with current malignancy
              • Evaluate on an individual patient basis the benefits and risks therapy in patients with prior malignancy or with increased risk of malignancy; follow standard cancer screening guidelines in patients receiving therapy
            • Risk of teratogenicity
              • Contraindicated for use in pregnant women and women and men of reproductive potential who do not plan to use effective contraception because of potential for fetal harm
              • Malformations and embryolethality shown in animals
              • Exclude pregnancy before start of treatment in females of reproductive potential
              • Advise females and males of reproductive potential to use effective contraception during therapy and for 6 months after last dose in each treatment course
              • Stop therapy if patient becomes pregnant

            Contraindications

            Cladribine (parenteral)

            • Hypersensitivity

            Mavenclad

            • Patients with current malignancy
            • Pregnant women and women and men of reproductive potential who do not plan to use effective contraception during therapy and for 6 months after last dose in each treatment course
            • Patients with infected HIV
            • Active chronic infections (eg, hepatitis, tuberculosis)
            • History of hypersensitivity to drug or excipients
            • Women intending to breastfeed on a treatment day and for 10 days after last dose

            Cautions

            Cladribine (parenteral)

            • As with other potent chemotherapeutic agents, monitoring of renal and hepatic function is also recommended, especially in patients with underlying kidney or liver dysfunction
            • Allopurinol and IV hydration recommended for patients with high tumor burden to prevent tumor lysis syndrome
            • May impair fertility; shown to suppress rapidly generating cells, including testicular cells
            • Fever with or without neutropenia is frequently observed during first month of treatment; given known myelosuppressive effects of therapy, practitioners should carefully evaluate risks and benefits of administering this drug to patients with active infections
            • Nephrotoxicity reported with high doses (4-9 times approved dose), especially when coadministered with other nephrotoxic drugs; manufacturer reports no nephrotoxicity at doses approved for hairy cell leukemia
            • Periodic assessment of peripheral blood counts, particularly during first 4-8 weeks post-treatment, recommended to detect development of anemia, neutropenia and thrombocytopenia and for early detection of any potential sequelae (eg, infection or bleeding)

            Mavenclad

            • Treatment may increase risk of malignancies, including metastatic pancreatic carcinoma, malignant melanoma, and ovarian cancer
            • Serious cases of thrombocytopenia, neutropenia, and pancytopenia (some with documented bone marrow hypoplasia) requiring transfusion and granulocyte-colony stimulating factor treatment reported; monitor CBC
            • Advise women of potential risk to a fetus during therapy and for 6 months after last dose in each treatment course
            • Latent tuberculosis infections may be activated with therapy; in patients with tuberculosis infection, delay initiation of treatment until infection adequately treated
            • Patients who are carriers of hepatitis B or C virus may be at risk of irreversible liver damage caused by virus reactivation; in patients with hepatitis infection, delay initiation of therapy until infection adequately treated
            • Incidence of herpes zoster reported to be higher during period of absolute lymphocyte count <500 cells/mcL per microliter; monitor for signs and symptoms suggestive of infections, including herpes infections in patients with lymphocyte counts <500 cells/mcL; if such signs and symptoms occur, initiate treatment as clinically indicated; consider interruption or delay of therapy until there is resolution of infection
            • In patients treated with parenteral cladribine for oncologic indications, cases of PML reported in the postmarketing setting; no cases reported in clinical studies of receiving therapy for MS
            • In patients who require blood transfusion, irradiation of cellular blood components recommended prior to administration to decrease risk of transfusion-related graft versus host disease; consultation with hematologist advised
            • Liver injury may occur; if a patient develops clinical signs, including unexplained liver enzyme elevations or symptoms suggestive of hepatic dysfunction, including unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice, and/or dark urine, promptly measure serum transaminases and total bilirubin and interrupt or discontinue treatment as appropriate
            • Not for use in patients with history of hypersensitivity; discontinue therapy if hypersensitivity reaction suspected
            • Cardiac failure with myocarditis reported with parenteral cladribine for indications other than MS; patients should seek medical advice if they experience symptoms of cardiac failure, including shortness of breath, rapid or irregular heartbeat, or swelling

            Drug interaction overview

            • Therapy causes dose-dependent reduction in lymphocyte count; additive hematological adverse reactions may be expected if therapy administered prior to or concomitantly with other drugs that affect the hematological profile
            • Initiation of therapy in patients currently receiving immunosuppressive or myelosuppressive therapy not recommended; concomitant use may increase risk of myelosuppression; acute short-term therapy with corticosteroids may be administered
            • Do not administer live virus vaccines; risk of infection in setting of immunosuppression
            • Lymphopenia risk may be increased when therapy coadministered with interferon-beta
            • Avoid coadministration of potent ENT1, CNT3, or BCRP transporter inhibitors (eg, ritonavir, eltrombopag, curcumin, cyclosporine, diltiazem, nifedipine, nimodipine, cilostazol, sulindac, dipyridamole, or reserpine) during the 4- to 5-day treatment cycle; the bioavailability, intracellular distribution, and renal elimination of the drug may be altered    
            • Consider a possible decrease in efficacy if potent BCRP (eg, corticosteroids) or P-gp (eg, rifampicin, St. John's wort) transporter inducers are coadministered  
            • Women using systemically acting hormonal contraceptives should add a barrier method during therapy and for at least 4 weeks after last dose in each treatment course
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            Pregnancy & Lactation

            Pregnancy

            Contraindicated in pregnant women and in females and males of reproductive potential who do not plan to use effective contraception; there are no adequate data on the developmental risk associated with therapy in pregnant women

            Reproductive potential

            • Females of reproductive potential should prevent pregnancy by use of effective contraception during therapy and for at least 6 months after last dose in each treatment course; add also a barrier method during therapy and for at least 4 weeks after last dose in each treatment course
            • As cladribine interferes with DNA synthesis, adverse effects on human gametogenesis could be expected; male patients of reproductive potential should take precautions to prevent pregnancy of their partner during therapy and for at least 6 months after last dose in each treatment course

            Animal data

            • Cladribine was embryolethal when administered to pregnant mice and produced malformations in mice and rabbits; the observed developmental effects are consistent with the effects of cladribine on DNA

            Lactation

            Therapy is contraindicated in breastfeeding women because of potential for serious adverse reactions in breastfed infants; advise women not to breastfeed during therapy and for 10 days after last dose 

            There are no data on presence of cladribine in human milk, effects on breastfed infant, or on milk production

            Pregnancy Categories

            A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA:Information not available.

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            Pharmacology

            Mechanism of Action

            Purine analog, impairs DNA repair; cladribine is a prodrug; in the treatment of hairy cell leukemia, the active form incorporates into DNA, resulting in breakage of DNA strand and shutdown of DNA synthesis and repair, which in turn inhibits cell replication

            Cladribine is a prodrug of the active moiety Cd-ATP; mechanism in multiple sclerosis not fully elucidated but is thought to involve cytotoxic effects on B and T lymphocytes through impairment of DNA synthesis, resulting in depletion of lymphocytes

            Pharmacokinetics

            Parenteral

            • Half-Life: 5.4 hr
            • Protein bound: 20%
            • Vd: 4.5 L/kg
            • Clearance: 978 mL/hr/kg
            • Excretion: urine

            Oral

            • Absorption
              • Bioavailability: 40%
              • Peak plasma time: 0.5 hr (0.5-1.5 hr range)
              • Peak plasma concentration: 22-29 ng/mL
              • Mean AUC: 80-101 ng.h/mL
            • Distribution
              • Protein bound: 20%
              • Vd: 480-490 L
            • Metabolism
              • Prodrug is phosphorylated to active moiety Cd-ATP by deoxycytidine kinase and deoxyguanosine kinase in the mitochondria; dephosphorylation and deactivation of Cd-AMP is catalyzed by cytoplasmic 5”-nucleotidase
            • Elimination
              • Half-life: 1 day
              • Renal clearance: 22.2 L/hr
              • Excretion: Urine (28.5%)
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            Administration

            IV Incompatibilities (Cladribine Parenteral)

            Solution: D5W

            Y-site: none reported

            IV Compatibilities (Cladribine Parenteral)

            Y-site (partial list): carboplatin, cisplatin, cyclophosphamide, cytarabine, diphenhydramine, dopamine, etoposide, heparin, lorazepam, metoclopramide, morphine, ondansetron, paclitaxel, KCl, prochlorperazine, promethazine, NaHCO3, teniposide, vincristine

            IV Preparation (Cladribine Parenteral)

            Single-use vials

            Prepare with bacteriostatic NS

            Both cladribine and diluent should be passed through a sterile 0.22 micron hydrophilic filter as they are being introduced into infusion reservoir

            The calculated dose of cladribine (7 days x 0.09 mg/kg) should first be added to the infusion reservoir through a filter, then the bacteriostatic NS should be added to the reservoir to obtain a total volume of 100 mL

            Standard IV 24 hr infusion dilution: 24 hr dose/500 mL NS

            Standard IV 7 day infusion dilution: 7 day dose/QS to 100 mL with bacteriostatic NS

            Do not dilute in D5W

            IV Administration (Cladribine Parenteral)

            Single daily infusion: administer diluted in an infusion bag containing 500 mL of NS and repeated for a total of 7 consecutive days

            7 day infusion: administer via ambulatory infusion pump into central line; use 0.22 micron filter to infuse

            Oral Administration (Mavenclad)

            Administer tablets with water, swallowed whole without chewing; may take with or without food

            Administration of other drugs should be separated by at least 3 hr during 4-5 day of treatment cycle

            First course

            • First cycle: Start anytime
            • Second cycle: Administer 23-27 days after last dose of first course/first cycle

            Second course

            • First cycle: Administer at least 43 weeks after last dose of first course/second cycle
            • Second cycle: Administer 23-27 days after last dose of second course/first cycle
            • Following administration of 2 treatment courses, do not administer additional treatment during next 2 years; it may further increase risk of malignancy
            • Safety and efficacy of reinitiating therapy more than 2 years after completing 2 treatment courses not studied

            Missed dose

            • If a dose missed, do not take double or extra doses
            • If dose not taken on scheduled day, patient must take missed dose on following day and extend number of days in that treatment cycle; if two consecutive doses missed, extend treatment cycle by 2 days

            Cytotoxic handling

            • Drug is cytotoxic; follow applicable special handling and disposal procedures; patients hand must be dry when handling drug; tablet is uncoated and must be swallowed immediately once removed from blister
            • If tablet left on surface, or if broken or fragmented tablet released from blister, area must be washed with water; avoid prolonged contact with skin

            Storage

            Cladribine (parenteral)

            • Store intact vials under refrigeration

            Mavenclad

            • Store in original package in order to protect from moisture
            • Store at controlled room temperature, 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F)
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            Formulary

            FormularyPatient Discounts

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            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
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            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
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            NC NOT COVERED – Drugs that are not covered by the plan.
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