Cladribine (Immunomodulatory Agent) (Monograph)

Brand name: Mavenclad
Drug class: Antimetabolites

Medically reviewed by Drugs.com on Sep 10, 2024. Written by ASHP.

Warning

May increase risk of malignancy.
Contraindicated in patients with current malignancy; individualize use in patients with prior or increased risk of malignancy based on an assessment of risks versus benefits.

Risk of fetal harm; contraindicated in pregnant women and in females and males of reproductive potential who do not plan to use effective contraception.

Introduction

Purine nucleoside antimetabolite with immunomodulatory and disease-modifying activity in multiple sclerosis (MS).

Uses for Cladribine (Immunomodulatory Agent)

Multiple Sclerosis (MS)

Used orally for treatment of relapsing forms of MS in adults, including relapsing-remitting disease and active secondary progressive disease.

Because of substantial risks associated with the drug (e.g., malignancy, teratogenicity), generally reserved for patients with inadequate response to, or unable to tolerate, an alternative MS therapy.

Not indicated for use in patients with clinically isolated syndrome.

Cladribine is one of several disease-modifying therapies used in the management of relapsing forms of MS. Although not curative, these therapies have all been shown to modify several measures of disease activity, including relapse rates, new or enhancing MRI lesions, and disability progression.

The American Academy of Neurology (AAN) recommends that disease-modifying therapy be offered to patients with relapsing forms of MS who have had recent relapses and/or MRI activity. Clinicians should consider the adverse effects, tolerability, method of administration, safety, efficacy, and cost of the drugs in addition to patient preferences when selecting an appropriate therapy.

Cladribine (Immunomodulatory Agent) Dosage and Administration

General

Pretreatment Screening

Screen patients for malignancies according to standard cancer screening guidelines prior to initiation of each treatment course.
Screen patients for HIV, tuberculosis, hepatitis B virus, and hepatitis C virus, and evaluate for active infections prior to initiation of each treatment course. Consider delay in therapy in patients with acute infections until fully controlled.
Exclude pregnancy in females of childbearing potential prior to initiation of each treatment course.
Perform a baseline (within 3 months) MRI of the brain prior to the first treatment course.
Complete any necessary immunizations prior to initiating therapy. Administer live or live attenuated vaccines at least 4–6 weeks before the start of therapy. Administer varicella zoster virus (VZV) vaccination in patients who are seronegative for the virus. Administer zoster vaccine recombinant (adjuvanted) in patients who are seropositive to VZV, either prior to or during cladribine treatment.
Perform CBC with differential, including lymphocyte count, prior to initiation of each treatment course.
Perform liver function tests, including serum transaminase, alkaline phosphatase, and total bilirubin concentrations, prior to initiation of each treatment cycle and course.

Patient Monitoring

Monitor CBC with differential, including lymphocyte count, prior to initiation of each treatment course, at 2 and 6 months after the start of each treatment course, periodically thereafter, and when clinically indicated. If the lymphocyte count is less than 200/mm³ at 2 months, increase the frequency of monitoring to a monthly basis until 6 months. Lymphocytes must be within normal limits before initiating the first treatment course and at least 800/mm³ before initiating the second treatment course. Withhold treatment if the lymphocyte count is less than 200/mm³ and administer herpes prophylaxis. Patients may be administered zoster vaccine recombinant (adjuvanted) if their lymphocyte count is less than 500/mm³.
Monitor for signs or symptoms suggestive of hepatic dysfunction (e.g., unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, jaundice, dark urine); if any manifestations occur, assess serum aminotransferase and total bilirubin concentrations promptly and interrupt or discontinue cladribine therapy as appropriate.

Dispensing and Administration

Cladribine is a hazardous drug. Consult specialized references for procedures for proper handling and disposal.
Handle tablets with dry hands; avoid prolonged contact with the skin and wash hands thoroughly after handling the tablets. If a tablet comes in contact with a surface, or if a broken or fragmented tablet is released from the blister packaging, thoroughly wash the area with water.

Administration

Oral Administration

Administer orally once daily without regard to food. Swallow tablets whole with water; do not chew.

Separate administration of other oral drugs by ≥3 hours during the 4–5 day dosing cycle.

Dosage

Adults

Multiple Sclerosis

Oral

Cumulative dosage of 3.5 mg/kg, administered over 2 yearly treatment courses (1.75 mg/kg per year). Administer second treatment course at least 43 weeks after the last dose of the first treatment course.

Each treatment course consists of two 4–5 day dosing cycles. In each dosing cycle, administer 1–2 tablets (10 or 20 mg of cladribine) over 4 or 5 consecutive days (depending on body weight) for a total dose of 1.75 mg/kg; do not administer more than 2 tablets a day. (See Table 1 for doses and number of tablets for each cycle based on body weight.)

Timing of administration in first treatment course: Administer first dosing cycle at any time and administer second cycle 23–27 days after the last dose of the first cycle.

Timing of administration in second treatment course: Administer first dosing cycle at least 43 weeks after the last dose of the first treatment course and administer second cycle 23–27 days after the last dose of the first cycle in the second treatment course.

Not studied in patients weighing <40 kg.

Table 1. Dose of Oral Cladribine per Treatment Cycle.1
Body Weight (kg)	First Cycle Dose (Number of 10-mg tablets)	Second Cycle Dose (Number of 10-mg tablets)
40 to <50	40 mg (4 tablets)	40 mg (4 tablets)
50 to <60	50 mg (5 tablets)	50 mg (5 tablets)
60 to <70	60 mg (6 tablets)	60 mg (6 tablets)
70 to <80	70 mg (7 tablets)	70 mg (7 tablets)
80 to <90	80 mg (8 tablets)	70 mg (7 tablets)
90 to <100	90 mg (9 tablets)	80 mg (8 tablets)
100 to <110	100 mg (10 tablets)	90 mg (9 tablets)
110 or greater	100 mg (10 tablets)	100 mg (10 tablets)

If a dose is missed, administer the missed dose as soon as it is remembered on the same day; if the day has already passed, take missed dose the following day and extend the number of days in treatment cycle. If 2 consecutive doses are missed, extend treatment cycle by 2 days. Do not administer additional or double doses to make up for a missed dose.

The risks of cladribine therapy increase beyond 2 courses of treatment and have not been studied beyond 4 courses of treatment. Do not administer additional doses during the 2 years following completion of initial 2-year treatment course; additional exposure to the drug during this time period may increase the risk of malignancy. Safety and efficacy of reinitiation of therapy more than 2 years after completion of 2 treatment courses not evaluated.

Special Populations

Hepatic Impairment

Dosage adjustment not necessary in patients with mild hepatic impairment. Not recommended in patients with moderate to severe hepatic impairment (Child-Pugh score greater than 6).

Renal Impairment

Dosage adjustment not necessary in patients with mild renal impairment (Cl_cr 60–89 mL/minute). Not recommended in patients with moderate to severe renal impairment (Cl_cr <60 mL/minute).

Geriatric Patients

The manufacturer makes no specific dosage recommendations for geriatric patients.

Cautions for Cladribine (Immunomodulatory Agent)

Contraindications

Current malignancy.
Women who are pregnant and women and men of reproductive potential who do not plan to use effective contraception during cladribine treatment and for 6 months after the last dose in each treatment course.
Women intending to breast-feed during cladribine treatment and for 10 days after the last dose.
HIV infection or active chronic infections (e.g., hepatitis, tuberculosis).
History of hypersensitivity to cladribine.

Warnings/Precautions

Warnings

Malignancies

In clinical studies, malignancies reported more frequently with drug than placebo; reported malignancies included metastatic pancreatic carcinoma, malignant melanoma, and ovarian cancer. (See Boxed Warning.)

Additional cladribine treatment within 2 years after the first 2 treatment courses may increase incidence of malignancy. Do not administer additional cladribine during this time period. Risk of malignancy in patients who are retreated with cladribine more than 2 years after completion of 2 treatment courses not known.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm. (See Boxed Warning.) Embryolethality and teratogenicity observed in animals. Exclude pregnancy in women of childbearing potential prior to each treatment course. Women and men of reproductive potential must use effective contraception during therapy and for 6 months after the last dose in each treatment course. Discontinue therapy if a patient becomes pregnant.

Other Warnings and Precautions

Lymphopenia

Causes a dose-dependent reduction in lymphocyte count. Lowest absolute lymphocyte counts occur approximately 2–3 months after the start of each treatment course and are further reduced with each additional treatment course. Nadir absolute lymphocyte counts <500/mm³ reported in clinical studies; although less common, lymphocyte counts <200/mm³ also have occurred. Median time to recovery to ≥800/mm³ was approximately 28 weeks.

Reduced lymphocyte counts may increase the risk of immunosuppression and infections. Monitor patients with lymphocyte counts <500/mm³ for infections. Administer zoster vaccine recombinant (adjuvanted) if lymphocyte count ≤500/mm³. If lymphocyte count <200/mm³, withhold therapy and initiate herpes prophylaxis.

Obtain CBC with differential, including lymphocyte count, prior to, during, and after each treatment course.

Lymphocyte counts must be within normal limits before initiating the first treatment course and ≥800/mm³ before initiating the second treatment course. May delay second treatment course for up to 6 months to allow for recovery of lymphocytes to ≥800/mm³; if recovery takes more than 6 months, discontinue cladribine therapy.

Infectious Complications

May increase the risk of infections, including serious, life-threatening, or fatal bacterial, viral, parasitic, and fungal infections. In clinical studies, 2 fatalities occurred from infectious complications (one from tuberculosis and the other from fulminant HBV infection).

Most frequently reported types of herpes viral infections were herpes zoster and oral herpes; higher risk observed when absolute lymphocyte count <500/mm³. Monitor patients with absolute lymphocyte count <500/mm³ for infections, including herpes virus infections. Administer zoster vaccine recombinant (adjuvanted) if lymphocyte count ≤ 500/mm³. If any signs and symptoms occur, initiate appropriate treatment as clinically indicated. Consider delaying or interrupting therapy until resolution of the infection.

Withhold therapy and administer anti-herpes prophylaxis in patients with lymphocyte count <200/mm³.

Although not reported with oral cladribine, progressive multifocal leukoencephalopathy (PML), an opportunistic infection of the brain caused by the JC virus, reported in patients receiving the parenteral formulation of the drug for oncologic indications. Immunocompromised patients are at increased risk of PML. At the first sign or symptom suggestive of PML, withhold cladribine therapy and perform an appropriate diagnostic evaluation. MRI signs of PML may be apparent before clinical manifestations develop. Obtain baseline MRI within 3 months of initiating first treatment course.

Exclude HIV infection, active tuberculosis, and active hepatitis (HBV and HCV) before initiation of each treatment course. Consider delaying start of therapy in patients with acute infection until the infection is fully resolved or controlled.

Test patients for antibodies to VZV before initiating cladribine and vaccinate patients who are seronegative. Administer the vaccine at least 4–6 weeks prior to starting cladribine. In patients who are seropositive to VZV, administer zoster vaccine recombinant (adjuvanted) either prior to or during cladribine treatment.

Do not initiate cladribine in patients receiving other immunomodulatory, immunosuppressive, or myelosuppressive agents; increased risk of immunosuppression may occur.

Hematologic Toxicity

Other adverse hematologic effects, including mild to moderate decreases in neutrophil counts, hemoglobin concentrations, and platelet counts, reported.

Serious cases of thrombocytopenia, neutropenia, and pancytopenia (including documented bone marrow hypoplasia) reported with dosages similar to or higher than recommended for MS; transfusion and treatment with granulocyte-colony stimulating factor (G-CSF) were required.

Obtain CBC with differential, including lymphocyte count, prior to, during, and after treatment.

Graft-Versus-Host Disease Associated with Blood Transfusion

Transfusion-associated graft-versus-host disease observed rarely following transfusion of nonirradiated blood in patients treated with cladribine for indications other than MS. If blood transfusion is required, irradiation of cellular blood components is recommended prior to administration to decrease this risk. Consultation with a hematologist is advised.

Liver Injury

Serious treatment-related liver injury reported. Onset ranged from a few weeks to several months after initiation of cladribine treatment. In one case, elevated serum aminotransferase concentrations were >20 times the ULN. These abnormalities resolved upon treatment discontinuance. Risk of liver injury may be increased in patients with pre-existing liver disease and those administered other hepatotoxic drugs concurrently. Majority of events occurred approximately 30 days after initiation (i.e., course 1, cycle 1) of treatment. Not recommended in patients with moderate to severe hepatic impairment.

Perform liver function tests (serum aminotransferase, alkaline phosphatase, and total bilirubin concentrations) prior to each treatment cycle and course of cladribine. If clinical signs or symptoms suggestive of hepatic dysfunction (e.g., unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, jaundice, dark urine) occur, assess serum aminotransferase and total bilirubin concentrations promptly and interrupt or discontinue cladribine as appropriate.

Hypersensitivity Reactions

Hypersensitivity reactions (e.g., dermatitis, pruritus) reported. A case of serious hypersensitivity with rash, mucous membrane ulceration, throat swelling, vertigo, diplopia, and headache was reported following administration of the first dose of cladribine.

If a hypersensitivity reaction is suspected, discontinue drug and initiate appropriate therapy.

Heart Failure

Life-threatening acute cardiac failure with myocarditis reported in one patient with MS in clinical studies; the condition improved after approximately 1 week. Cases of cardiac failure also reported with parenteral cladribine for indications other than MS.

Specific Populations

Pregnancy

May cause fetal harm. Exclude pregnancy prior to initiation of therapy. Discontinue drug if patient becomes pregnant during therapy.

A pregnancy safety study is monitoring pregnancy and infant outcomes following exposure to cladribine. Report pregnancies of women with MS exposed to oral cladribine during pregnancy or within 6 months before conception as well as pregnancies fathered by men with MS who had taken oral cladribine within 6 months before conception by calling EMD Serono’s Adverse Event reporting line at 1-800-283-8088 ext. 5563 or by faxing 1-781- 681-2961.

Lactation

Not known whether cladribine or its metabolites are distributed into milk; effects on milk production or breast-fed infant also not known. Breast-feeding not advised during cladribine treatment and for 10 days after the last dose of the drug.

Females and Males of Reproductive Potential

Females of childbearing potential must use effective contraception during cladribine treatment and for 6 months after the last dose in each treatment course.

Male patients with partners of childbearing potential should take precautions to prevent pregnancy of their partner by using effective contraception during cladribine treatment and for at least 6 months after the last dose in each treatment course.

Not known whether cladribine reduces the effectiveness of systemic hormonal contraceptives; females using such hormonal contraceptives should add a barrier method during cladribine treatment and for ≥4 weeks after the last dose in each treatment course.

Pediatric Use

Safety and efficacy not established in patients <18 years of age. Use not recommended in pediatric patients because of risk of malignancies.

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults. Use with caution because of possible age-related decreases in hepatic and/or renal function and concomitant disease and other drug therapy.

Hepatic Impairment

Formal pharmacokinetic studies not conducted to date. Not recommended in patients with moderate to severe hepatic impairment (Child-Pugh score >6).

Dosage adjustment not necessary in patients with mild hepatic impairment.

Renal Impairment

Formal pharmacokinetic studies not conducted to date; however, renal impairment expected to decrease clearance. Not recommended in patients with moderate to severe renal impairment (Cl_cr <60 mL/minute).

Patients with mild renal impairment (Cl_cr 60–89 mL/minute) were included in clinical studies in patients with MS.

Common Adverse Effects

Adverse effects (>20%) include upper respiratory tract infection, headache, lymphopenia.

Drug Interactions

Drugs Affecting or Affected by Hepatic Microsomal Enzymes

Not a substrate of CYP isoenzymes; not expected to inhibit nor induce major CYP isoenzymes to a clinically important extent.

Pharmacokinetic interactions with drugs affecting or metabolized by CYP isoenzymes not expected.

Drugs Affecting Transporter Systems

Substrate of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and equilibrative nucleoside (ENT1) and concentrative nucleoside (CNT3) transport proteins.

Potent ENT1, CNT3, or BCRP inhibitors: Possible alteration of bioavailability, intracellular distribution, and/or renal elimination of cladribine. Avoid concomitant use during the 4–5 day cladribine dosing cycle; consider an alternative drug with minimal or no ENT1, CNT3, or BCRP inhibiting potential. If this is not possible, reduce dosage of these drugs to minimum effective dosage, separate administration times, and carefully monitor patient.

Potent BCRP (e.g., corticosteroids) or P-gp (e.g., rifampin, St. John's wort) inducers: Possible decreased systemic exposure and efficacy of cladribine.

Drugs Affected by Hydroxypropyl Betadex-related Complex Formation

Hydroxypropyl betadex, an excipient in the formulation of cladribine tablets, can form complexes with active ingredients of other concomitantly administered drugs. Bioavailability of other concomitantly administered drugs (particularly drugs with low solubility) may be increased, which may increase risk or severity of adverse reactions.

Separate administration of cladribine tablets and other oral drugs by at least 3 hours during the 4–5 day dosing cycle.

Drugs Associated with Hematologic Toxicity

Additive hematologic effects may occur if used concomitantly with other drugs that can affect hematologic profile (e.g., carbamazepine). Monitor hematologic parameters.

Immunomodulatory, Immunosuppressive, or Myelosuppressive Agents

Additive immunosuppressive effects may occur. Concomitant use not recommended. Consider overlapping effects on immune system when used sequentially in patients previously treated with immunomodulatory or immunosuppressive drugs; consider duration and mechanism of the previous drug when initiating cladribine therapy.

Specific Drugs

Drug	Interaction	Comments
Antiviral or antiretroviral drugs that require activation by intracellular phosphorylation (e.g., lamivudine, ribavirin, stavudine, zidovudine)	Potential competition with cladribine for intracellular phosphorylation	Avoid concomitant use
Cilostazol	Bioavailability, intracellular distribution, and/or renal elimination of cladribine may be affected via potent inhibition of ENT1, CNT3, and/or BCRP	Avoid concomitant use during the 4- to 5-day cladribine dosing cycle Consider an alternative drug with minimal or no ENT1, CNT3, or BCRP inhibiting properties; if this is not possible, reduce dosage of these drugs to minimum effective dosage, separate timing of administration, and carefully monitor patient
Corticosteroids, systemic	Corticosteroids (potent inducers of BCRP) may decrease systemic exposure and efficacy of cladribine No clinically important effects on absolute lymphocyte count	Short-term therapy with corticosteroids may be administered during cladribine therapy
Curcumin	Bioavailability, intracellular distribution, and/or renal elimination of cladribine may be affected via potent inhibition of ENT1, CNT3, and/or BCRP	Avoid concomitant use during the 4- to 5-day cladribine dosing cycle Consider an alternative drug with minimal or no ENT1, CNT3, or BCRP inhibiting properties; if this is not possible, reduce dosage of these drugs to minimum effective dosage, separate timing of administration, and carefully monitor patient
Cyclosporine	Bioavailability, intracellular distribution, and/or renal elimination of cladribine may be affected via potent inhibition of ENT1, CNT3, and/or BCRP	Avoid concomitant use during the 4- to 5-day cladribine dosing cycle Consider an alternative drug with minimal or no ENT1, CNT3, or BCRP inhibiting properties; if this is not possible, reduce dosage of these drugs to minimum effective dosage, separate timing of administration, and carefully monitor patient
Dipyridamole	Bioavailability, intracellular distribution, and/or renal elimination of cladribine may be affected via potent inhibition of ENT1, CNT3, and/or BCRP	Avoid concomitant use during the 4- to 5-day cladribine dosing cycle Consider an alternative drug with minimal or no ENT1, CNT3, or BCRP inhibiting properties; if this is not possible, reduce dosage of these drugs to minimum effective dosage, separate timing of administration, and carefully monitor patient
Eltrombopag	Bioavailability, intracellular distribution, and/or renal elimination of cladribine may be affected via potent inhibition of ENT1, CNT3, and/or BCRP	Avoid concomitant use during the 4- to 5-day cladribine dosing cycle Consider an alternative drug with minimal or no ENT1, CNT3, or BCRP inhibiting properties; if this is not possible, reduce dosage of these drugs to minimum effective dosage, separate timing of administration, and carefully monitor patient
Furosemide	Complex formation between furosemide and hydroxypropyl betadex (excipient in cladribine tablets) observed Possible increased bioavailability of furosemide	Separate administration of the drugs by at least 3 hours during the 4- to 5-day cladribine dosing cycle
Gabapentin	Complex formation between gabapentin and hydroxypropyl betadex (excipient in cladribine tablets) observed Possible increased bioavailability of gabapentin	Separate administration of the drugs by at least 3 hours during the 4–5 day cladribine dosing cycle
Hormonal contraceptives	Not known whether cladribine may reduce the effectiveness of systemic hormonal contraceptives	In women of childbearing potential, use an additional barrier method of contraception during cladribine treatment and for ≥4 weeks after the last dose in each treatment course
Ibuprofen	Complex formation between ibuprofen and hydroxypropyl betadex (excipient in cladribine tablets) observed Possible increased bioavailability of ibuprofen	Separate administration of the drugs by at least 3 hours during the 4–5 day cladribine dosing cycle
Interferon beta	Possible additive immune system effects No clinically important effects on cladribine pharmacokinetics; however, concomitant use may increase risk of lymphopenia	Concomitant use not recommended In patients who previously received interferon beta, consider duration of effect and mechanism when initiating cladribine therapy
Nifedipine	Bioavailability, intracellular distribution, and/or renal elimination of cladribine may be affected via potent inhibition of ENT1, CNT3, and/or BCRP	Avoid concomitant use during the 4- to 5-day cladribine dosing cycle Consider an alternative drug with minimal or no ENT1, CNT3, or BCRP inhibiting properties; if this is not possible, reduce dosage of these drugs to minimum effective dosage, separate timing of administration, and carefully monitor patient
Nimodipine	Bioavailability, intracellular distribution, and/or renal elimination of cladribine may be affected via potent inhibition of ENT1, CNT3, and/or BCRP	Avoid concomitant use during the 4- to 5-day cladribine dosing cycle Consider an alternative drug with minimal or no ENT1, CNT3, or BCRP inhibiting properties; if this is not possible, reduce dosage of these drugs to minimum effective dosage, separate timing of administration, and carefully monitor patient
Pantoprazole	No clinically important effects on cladribine pharmacokinetics
Rifampin	Rifampin (potent inducer of P-gp) may decrease systemic exposure and efficacy of cladribine
Ritonavir	Bioavailability, intracellular distribution, and/or renal elimination of cladribine may be affected via potent inhibition of ENT1, CNT3, and/or BCRP	Avoid concomitant use during the 4- to 5-day cladribine dosing cycle Consider an alternative drug with minimal or no ENT1, CNT3, or BCRP inhibiting properties; if this is not possible, reduce dosage of these drugs to minimum effective dosage, separate timing of administration, and carefully monitor patient
St. John's wort	St. John's wort (potent inducer of P-gp) may decrease systemic exposure and efficacy of cladribine
Sulindac	Bioavailability, intracellular distribution, and/or renal elimination of cladribine may be affected via potent inhibition of ENT1, CNT3, and/or BCRP	Avoid concomitant use during the 4- to 5-day cladribine dosing cycle Consider an alternative drug with minimal or no ENT1, CNT3, or BCRP inhibiting properties; if this is not possible, reduce dosage of these drugs to minimum effective dosage, separate timing of administration, and carefully monitor patient
Vaccines (live or live attenuated)	Possible risk of active vaccine infection	Administer at least 4–6 weeks prior to starting cladribine; avoid vaccination during and after cladribine therapy while the patient's WBC count is not within normal limits

Cladribine (Immunomodulatory Agent) Pharmacokinetics

Absorption

Bioavailability

Oral bioavailability is approximately 40%.

Peak plasma concentrations occur approximately 0.5 hours (range: 0.5–1.5 hours) following oral administration in the fasted state.

Cladribine concentrations increase proportionally over oral dosage range of 3–20 mg.

Accumulation not observed with repeated dosing.

Food

High fat meal delayed time to peak concentration by 1 hour and decreased peak concentrations by 29%; no effect on AUC.

Distribution

Extent

Extensively distributed into tissues; intracellular concentrations in lymphocytes are approximately 30–40 times those of extracellular concentrations in vitro.

May cross blood-brain barrier; in patients with cancer, CSF concentrations are about 25% of plasma concentrations.

Plasma Protein Binding

20%; independent of concentration.

Elimination

Metabolism

Prodrug that is phosphorylated to its active 2-chlorodeoxyadenosine triphosphate (CdATP) metabolite in lymphocytes.

Metabolism in whole blood not fully characterized. Negligible hepatic enzyme metabolism observed in vitro.

Elimination Route

28.5% excreted unchanged in urine.

Renal clearance exceeds glomerular filtration rate, indicating active renal secretion.

Half-life

Terminal half-life: Approximately 1 day.

Intracellular half-life of phosphorylated metabolites cladribine monophosphate (CdAMP) and CdATP: 15 and 10 hours, respectively.

Special Populations

Reduced clearance expected in patients with renal impairment.

Stability

Storage

Oral

Tablets

20–25°C (may be exposed to 15–30°C); store in original package to protect from moisture.

Actions

Purine nucleoside antimetabolite.
Although exact mechanism in MS not fully elucidated, depletion of B and T lymphocytes is thought to result in the drug's immunomodulatory effects.
Undergoes intracellular phosphorylation by deoxycytidine kinase to the active CdATP moiety.
Preferential accumulation of cytotoxic CdATP in lymphocytes causes DNA strand breaks, inhibition of DNA synthesis and repair, and cell death via apoptosis or other mechanisms. Cytotoxic effects occur in both dividing and resting lymphocytes. Cells of the innate immune system and those produced by the bone marrow are less impacted.
Causes dose-dependent reduction in lymphocyte count.

Advice to Patients

Advise patients of the risk of malignancies and to follow standard cancer screening guidelines.
Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider of a known or suspected pregnancy. Advise females of childbearing potential to use effective contraception during cladribine treatment and for at least 6 months after the last dose in each treatment course. Cladribine may decrease the effectiveness of systemic hormonal contraceptives, so an additional barrier method should be used during treatment and for at least 4 weeks after the last dose in each treatment course. Advise male patients who have partners of childbearing potential to use effective contraception while receiving the drug and for 6 months after the last dose in each treatment course.
Advise patients that there is a pregnancy safety study that is monitoring pregnancy outcomes in women exposed to cladribine during pregnancy or within 6 months before conception, as well as pregnancies fathered by men exposed to cladribine within 6 months before conception; such exposure can be reported to EMD Serono's Adverse Event reporting line at 1-800-283-8088 ext. 5563 or 1-781-681-2961 (fax).
Advise females to avoid breast-feeding during cladribine treatment and for 10 days after the last dose of the drug.
Advise patients of the risk of lymphopenia and other hematologic toxicities. Advise patients of the need for laboratory monitoring of complete blood cell counts.
Advise patients of the risk of infections, including reactivation of latent infections. Instruct them to immediately contact their clinician if they develop any signs or symptoms of infection (e.g., fever, aching painful muscles, headache, generally feeling unwell, anorexia) during therapy or after a course of treatment.
Advise patients that progressive multifocal leukoencephalopathy (PML) has occurred in cancer patients treated with parenteral cladribine and that the condition usually leads to death or severe disability over weeks or months. Instruct patients to inform their clinician if they develop any symptoms suggestive of PML (e.g., progressive weakness on one side of body; clumsiness of limbs; vision disturbance; changes in thinking, memory, or orientation leading to confusion and personality changes).
Advise patients that some vaccines containing live virus (live attenuated vaccines) should be avoided during and after treatment with cladribine therapy. Advise patients to complete any live or live-attenuated vaccinations at least 4 to 6 weeks prior to initiation of cladribine. Instruct patients to contact their healthcare provider prior to receiving any vaccinations.
Advise patients of the risk of liver injury. Instruct patients to contact their clinician if they experience unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine during cladribine therapy.
Advise patients to seek immediate medical attention if they experience a serious hypersensitivity reaction, including skin reactions.
Advise patients of the risk of cardiac failure. Instruct patients to seek medical advice if they experience symptoms of cardiac failure (e.g., shortness of breath, rapid or irregular heartbeat, swelling).
Advise patients to use care when handling cladribine tablets and to limit direct skin contact. Hands must be dry when handling the tablets and washed thoroughly afterwards. Instruct patients to keep the tablets in the original packaging until just prior to each scheduled dose and to consult their pharmacist on the proper disposal of unused tablets.
Advise patients to inform their healthcare provider about existing or contemplated concomitant therapy, including prescription and OTC drugs (e.g., other immunomodulatory, immunosuppressive, or myelosuppressive agents) and dietary or herbal supplements, as well as any concomitant illnesses (e.g., malignancy, infections).
Advise patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Cladribine is available only through designated specialty pharmacies. Clinicians may contact the manufacturer at 877-447-3243 or consult the Mavenclad website ([Web]) for additional information.