Cladribine


Generic Medicine Info
Indications and Dosage
Intravenous
B cell chronic lymphocytic leukaemia
Adult: 0.12 mg/kg (4.8 mg/m2) daily via continuous infusion over 2 hours on days 1-5 of a 28-day cycle. Response to therapy must be determined every 2 cycles. When a Max response has occurred (defined as lymphocyte reduction of ≥50%), it is recommended to give 2 more treatment cycles then re-evaluate response whether to continue. Max: 6 cycles. Patients who do not respond after 2 cycles must not receive further therapy.

Intravenous
Hairy cell leukaemia
Adult: Single course of 0.09 mg/kg (3.6 mg/m2) daily via continuous infusion for 7 consecutive days. If the patient does not respond to the initial course, they are unlikely to benefit from additional courses. Consider treatment delay or discontinuation if neurotoxicity or renal toxicity occurs.

Oral
Relapsing forms of multiple sclerosis
Adult: Relapsing-remitting disease and active secondary progressive disease: For patients who have an inadequate response, or are intolerant to other therapy: Recommended cumulative dose: 3.5 mg/kg over 2 years; given as 1 treatment course of 1.75 mg/kg per year. A treatment course consists of 2 treatment weeks, one at the beginning of the 1st month and one at the start of the 2nd month of each respective treatment year. Each treatment week consists of 4 or 5 days wherein the patient receives 10 mg or 20 mg (1 or 2 tabs) as a single daily dose, based on individual body weight. Refer to specific product guidelines for detailed dose distribution per treatment week by patient weight in each treatment year and other dosing instructions. Initiate and continue treatment if lymphocyte counts are normal before starting in year 1, and at least 800 cells/mm3 before beginning in year 2. Treatment course interruption, delay or discontinuation may be required according to individual safety or tolerability (refer to detailed product guideline).

Subcutaneous
Hairy cell leukaemia
Adult: Single course of 0.14 mg/kg (5.6 mg/m2) daily via bolus inj for 5 consecutive days. Consider treatment delay or discontinuation if severe toxicity occurs.

Subcutaneous
Waldenstrom's macroglobulinaemia
Adult: 0.10 mg/kg (4 mg/m2) daily via bolus inj for 5 consecutive days. Consider treatment delay or discontinuation if severe toxicity occurs.
Renal Impairment
Oral
Relapsing forms of multiple sclerosis:
Moderate to severe: Contraindicated.

Subcutaneous
Hairy cell leukaemia; Waldenstrom's macroglobulinaemia:
Moderate to severe: Contraindicated.
Hepatic Impairment
Oral
Relapsing forms of multiple sclerosis:
Moderate to severe (Child-Pugh score >6): Not recommended.

Subcutaneous
Hairy cell leukaemia; Waldenstrom's macroglobulinaemia:
Moderate to severe (Child-Pugh score >6): Contraindicated.
Reconstitution
IV: Hairy cell leukaemia (HCL): 24-hour continuous infusion: Dilute the calculated dose (0.09 mg/kg or 0.09 mL/kg) to an infusion bag containing 100-500 mL of 0.9% NaCl inj. Refer to product-specific guidelines for an alternative method (7-day infusion) of preparing the infusion. B-cell CLL: 2-hour continuous infusion: Add the calculated dose (0.12 mg/kg) to an infusion bag containing 100-500 mL 0.9% NaCl inj. Before each daily infusion, all solutions should be filtered through a sterile 0.22 micron hydrophilic filter prior to addition in the respective infusion bag.
Incompatibility
IV: Incompatible with 5% dextrose in water. Should not be mixed with other IV drugs or additives or administered simultaneously via a common IV line.
Contraindications
HIV infection, active chronic infections (e.g. hepatitis, TB), active malignancy, immunocompromised patients, men or women of reproductive potential who do not plan to use effective contraception during dosing and for 6 months after the last dose in each treatment course (oral). Moderate to severe hepatic (Child-Pugh score >6) impairment (SC); moderate to severe renal impairment (oral/SC). Pregnancy and lactation. Co-administration with live or live-attenuated vaccines during treatment. Concomitant immunosuppressive or myelosuppressive therapy (oral/SC).
Special Precautions
Oral: Patient with prior malignancy or increased risk of malignancy. Patient without a history of exposure to varicella-zoster virus (VZV); vaccination is recommended before treatment initiation if VZV antibody-negative, and delay therapy for 4-6 weeks after vaccination. Consider delaying treatment in patients with lymphocyte count <500 cells/mm3 and signs and symptoms of infection (particularly herpes zoster) until full infection resolution. Anti-herpes prophylaxis based on local standard practice may be given if lymphocyte count is <200 cells/mm3. Not indicated for use in patients with clinically isolated syndrome. Administration of any other oral drugs must be separated from oral cladribine by at least 3 hours. Not recommended for moderate to severe hepatic (Child-Pugh score >6) impairment. IV/SC: Patient with high tumour burden, primary haematologic malignancy, severe bone marrow impairment (any aetiology); increased infection risk, manifestation of bone marrow failure or infiltration, myelosuppressive pre-treatment. Administer hyperuricaemia prophylaxis with adequate or increased hydration before starting therapy in patients with high tumour burden. Patient with active/acute infection must be treated before therapy initiation. Not recommended for use in chronic lymphocytic leukaemia (CLL) patients whose disease has progressed during fludarabine treatment. Discontinue treatment if patient is suspected of PML. Cellular blood components or products should be irradiated prior to blood transfusion. Renal and hepatic impairment.
Adverse Reactions
Significant: Increased risk of malignancy, herpes zoster, and lymphopenia (oral); severe bone marrow suppression (e.g. neutropenia, anaemia, thrombocytopenia), prolonged immunosuppression; fever (with or without neutropenia); hepatotoxicity (e.g. serious liver injury); acute nephrotoxicity with high doses (e.g. acidosis, anuria, increased serum creatinine); hypersensitivity reactions. Rarely, serious neurotoxicity including irreversible paraparesis and quadriparesis (high IV doses).
Blood and lymphatic system disorders: Haemolytic anaemia, febrile neutropenia, pancytopenia.
Cardiac disorders: Myocardial ischaemia, tachycardia, heart murmur.
Eye disorders: Conjunctivitis.
Gastrointestinal disorders: Nausea, vomiting, abdominal pain, diarrhoea, flatulence, constipation.
General disorders and administration site conditions: Inj site reaction, fatigue, chills, asthenia, malaise, pain, peripheral oedema, crepitations.
Infections and infestations: Dermatomal herpes zoster, oral herpes (oral); pneumonia, septic shock, bacteraemia, localised infection.
Injury, poisoning and procedural complications: Contusion.
Investigations: Decreased neutrophil count (oral); increased transaminases and bilirubin.
Metabolism and nutrition disorders: Decreased appetite.
Musculoskeletal and connective tissue disorders: Myalgia, arthralgia, muscle weakness, bone pain, arthritis; back pain (oral).
Neoplasms benign, malignant and unspecified: Primary haematological malignancies, secondary malignancies.
Nervous system disorders: Headache, dizziness.
Psychiatric disorders: Insomnia, confusion, anxiety; depression (oral).
Renal and urinary disorders: Renal failure.
Respiratory, thoracic and mediastinal disorders: Abnormal breath or chest sounds, cough, epistaxis, dyspnoea, rales, pulmonary interstitial infiltrates; upper respiratory tract infection, bronchitis (oral).
Skin and subcutaneous tissue disorders: Rash, alopecia, urticaria, pruritus, ecchymosis, hyperhidrosis, petechiae, cellulitis, erythema, localised exanthema.
Vascular disorders: Phlebitis, purpura, hypotension; hypertension (oral).
Potentially Fatal: Severe bacterial, viral, and fungal infections; cardiotoxicity including acute cardiac failure with myocarditis; progressive multifocal leucoencepalopathy (PML); graft-versus-host disease (may occur after transfusion of non-irradiated blood). Rarely, tumour lysis syndrome and subsequent hyperuricaemia (in patients with high tumour burden).
IV/Parenteral/SC: D
Patient Counseling Information
IV/SC: This drug may cause dizziness or drowsiness, if affected, do not drive or operate machinery.
Monitoring Parameters
Before therapy initiation, evaluate pregnancy status in women of reproductive potential. Closely monitor for haematologic (e.g. myelosuppression) and non-haematologic toxicity (e.g. cardiac changes, renal failure) periodically during and after treatment; signs and symptoms of infection, PML or neurotoxicity. Oral: Determine HIV, active or latent TB, active or latent hepatitis B and C, and varicella-zoster antibody status prior to each course of treatment. Perform standard cancer screening guidelines. Monitor CBC including lymphocyte count (before each treatment course, 2 and 6 months after the initiation of each annual course [if 2-month lymphocyte count is <200 cells/mm3, monitor monthly till month 6], then periodically during and after treatment); LFTs (e.g. serum aminotransferase, alkaline phosphatase, total bilirubin levels) before starting each therapy course and as clinically necessary; MRI (at baseline [within 3 months] before the 1st course); signs and symptoms of PML. Closely assess patients with lymphocyte count <500 cells/mm3 for signs and symptoms of infection (particularly herpes zoster). IV/SC: Screen for hepatitis B virus with hepatitis B surface antigen or core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen before or during initiation of therapy. Obtain CBC with differential (specifically during the 1st 4-8 weeks of post-treatment), bone marrow biopsy (after CBC has normalised); renal and hepatic function (periodically and as clinically indicated). Monitor for haemolysis (particularly in patients who are or become Coombs’ positive).
Overdosage
Symptoms: Dose-dependent lymphopenia (oral); nausea, vomiting, diarrhoea, severe bone marrow suppression leading to neutropenia, anaemia and thrombocytopenia, neurotoxicity including irreversible paraparesis/quadriparesis, acute nephrotoxicity, Guillain-Barre and Brown-Sequard syndromes (IV/SC). Management: Supportive treatment. Closely monitor the haematologic parameters.
Drug Interactions
Due to similar intracellular metabolism, cross-resistance may occur with other nucleoside analogues (e.g. fludarabine). Increased risk of lymphopenia with interferon-β. May cause additive haematologic adverse effect when given with or prior to other substances that affect the haematological profile (e.g. carbamazepine). May increase the oral bioavailability and systemic exposure with breast cancer resistance protein (BCRP) inhibitors (e.g. eltrombopag). May alter the bioavailability, intracellular distribution and renal elimination with potent equilibrative nucleoside (ENT1) and concentrative nucleoside (CNT3) transporter inhibitors (e.g. nifedipine, nimodipine, dilazep, cilostazol, reserpine, sulindac). May decrease exposure with potent BCRP inducer (e.g. corticosteroids) or P-glycoprotein transporter inducers (e.g. rifampicin). Cladribine tab contains hydroxypropylbetadex that may form complex with other oral agents (specifically those with low solubility), leading to increased bioavailability of these agents; doses of other oral agents must be separated by at least 3 hours.
Potentially Fatal: Increased risk of infections with concurrent live or live-attenuated vaccines. Additive immunosuppressive and bone marrow suppressive effects with concomitant immunosuppressive or myelosuppressive therapy (e.g. methotrexate, cyclophosphamide, azathioprine, ciclosporin, chronic corticosteroid use).
Food Interaction
May decrease exposure with St. John’s wort.
Action
Description: Cladribine, a purine nucleoside analogue acting as an antimetabolite, is a prodrug that is activated via phosphorylation and converted to cladribine triphosphate or Cd-ATP (active metabolite). Cd-ATP inhibits ribonucleotide reductase; it also incorporates into DNA strands, thereby interfering with DNA synthesis and repair. Its mechanism of action for the treatment of multiple sclerosis has not been fully elucidated; however, it is thought to involve cytotoxic effects on B and T lymphocytes through DNA synthesis impairment, leading to lymphocyte depletion.
Pharmacokinetics:
Absorption: Rapidly absorbed from the gastrointestinal tract. Bioavailability: Approx 40% (oral). Time to peak plasma concentration: Fasting: 0.5 hour (range: 0.5-1.5 hours); With high-fat meal: 1.5 hours (range: 1-3 hours).
Distribution: Extensively distributed; penetrates the CSF. Volume of distribution: 480-490 L or approx 9 L/kg. Plasma protein binding: Approx 20%.
Metabolism: Phosphorylated within cells by deoxycytidine kinase to form cladribine monophosphate (Cd-AMP); undergoes further phosphorylation by nucleoside monophosphate kinase to cladribine diphosphate (Cd-ADP) and by nucleoside diphosphate kinase to the active metabolite, cladribine triphosphate (Cd-ATP). Negligible metabolism in the liver.
Excretion: Via urine (18-28.5%). Terminal elimination half-life: Approx 24 hours (oral); 3-22 hours (IV). Elimination half-life: SC: 2 hours (initial) and 11 hours (terminal).
Chemical Structure

Chemical Structure Image
Cladribine

Source: National Center for Biotechnology Information. PubChem Database. Cladribine, CID=20279, https://pubchem.ncbi.nlm.nih.gov/compound/Cladribine (accessed on Jan. 21, 2020)

Storage
Tab: Store between 15-30°C. Protect from moisture. Solution for SC inj: Store between 2-8°C. Do not freeze. Solution for IV infusion: Store intact vials between 2-8°C. Protect from light. Accidental freezing does not adversely affect the solution; if freezing occurs, allow to thaw naturally at room temperature then refrigerate; do not heat or microwave. Do not refreeze. During low-temperature exposure, a precipitate may form; resolubilise the solution by allowing the vial to warm at room temperature or by shaking vigorously. Do not heat or microwave. Diluted solutions may be stored between 2-8°C for up to 8 hours before administration. This is a cytotoxic drug. Follow applicable procedures for receiving, handling, administration, and disposal.
ATC Classification
L04AA40 - cladribine ; Belongs to the class of selective immunosuppressive agents. Used to induce immunosuppression.
L01BB04 - cladribine ; Belongs to the class of antimetabolites, purine analogues. Used in the treatment of cancer.
References
Anon. Cladribine (Antineoplastic). AHFS Clinical Drug Information [online]. Bethesda, MD. American Society of Health-System Pharmacists, Inc. https://www.ahfscdi.com. Accessed 02/07/2021.

Anon. Cladribine (Immunosuppressive). AHFS Clinical Drug Information [online]. Bethesda, MD. American Society of Health-System Pharmacists, Inc. https://www.ahfscdi.com. Accessed 02/07/2021.

Anon. Cladribine. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 02/07/2021.

Buckingham R (ed). Cladribine. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 02/07/2021.

Cladribine Injection (Fresenius Kabi USA, LLC). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed. Accessed 02/07/2021.

Healthcare Logistics. Mavenclad 10 mg Tablets data sheet 13 April 2021. Medsafe. http://www.medsafe.govt.nz. Accessed 02/07/2021.

Joint Formulary Committee. Cladribine. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 02/07/2021.

Leustat Injection (Janssen-Cilag Limited). MHRA. https://products.mhra.gov.uk. Accessed 02/07/2021.

Litak 2 mg/mL Solution for Injection (Lipomed GmbH). European Medicines Agency [online]. Accessed 12/08/2021.

Mavenclad 10 mg Tablets (Merck Sdn. Bhd.). National Pharmaceutical Regulatory Agency - Ministry of Health Malaysia. https://www.npra.gov.my. Accessed 02/07/2021.

Mavenclad 10 mg Tablets (Merck Serono Limited). MHRA. https://products.mhra.gov.uk. Accessed 02/07/2021.

Mavenclad Tablet (EMD Serono, Inc.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed. Accessed 12/08/2021.

Disclaimer: This information is independently developed by MIMS based on Cladribine from various references and is provided for your reference only. Therapeutic uses, prescribing information and product availability may vary between countries. Please refer to MIMS Product Monographs for specific and locally approved prescribing information. Although great effort has been made to ensure content accuracy, MIMS shall not be held responsible or liable for any claims or damages arising from the use or misuse of the information contained herein, its contents or omissions, or otherwise. Copyright © 2021 MIMS. All rights reserved. Powered by MIMS.com
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