section name header

Introduction ⬇

AHFS Class:

Generic Name(s):

Cladribine, a purine nucleoside antimetabolite, has immunomodulatory and disease-modifying activity in multiple sclerosis (MS);1,2,6

Uses ⬆ ⬇

[Section Outline]

Multiple Sclerosis !!navigator!!

Cladribine is used orally in adults for the treatment of relapsing forms of multiple sclerosis (MS), including relapsing-remitting disease and active secondary progressive disease.1 Because of the substantial risks associated with the drug (e.g., malignancy, teratogenicity), cladribine generally is reserved for patients who have had an inadequate response to, or are unable to tolerate, an alternative MS therapy.1,2 Because of its safety profile, cladribine is not indicated for use in patients with clinically isolated syndrome.1

Clinical Experience

Efficacy and safety of oral cladribine for the management of MS have been established in a multicenter, randomized, double-blind, placebo-controlled study (Cladribine Tablets Treating Multiple Sclerosis Orally [CLARITY]).1,2 In this study, patients with relapsing forms of MS who had at least 1 relapse within the previous 12 months and an Expanded Disability Status Scale (EDSS) score of 0-5.5 at baseline were randomized to receive cladribine (cumulative oral dosage of 3.5 or 5.25 mg/kg administered as 2 treatment courses) or placebo over 96 weeks.1,2 The median age of patients in this study was 39 years, median disease duration prior to enrollment was 8.7 years, and median EDSS score at baseline was 3.1

At 96 weeks, the annualized relapse rate (primary outcome measure) was substantially lower in patients receiving cladribine in a cumulative dosage of 3.5 mg/kg compared with those receiving placebo (0.14 versus 0.33; relative reduction of 58%).1,2 Secondary MRI endpoints demonstrated substantially fewer active gadolinium-enhancing lesions and active T2-weighted lesions in cladribine-treated patients compared with those receiving placebo.1,2 The higher cumulative cladribine dosage of 5.25 mg/kg did not provide additional clinical benefit over the 3.5-mg/kg dosage and was associated with a higher incidence of grade 3 or higher lymphopenia.1

In a 2-year extension study, patients who had previously received placebo during the CLARITY study were initiated on cladribine (cumulative oral dose of 3.5 mg/kg), while those who had received cladribine were rerandomized to receive additional cladribine treatment (cumulative oral dose of 3.5 mg/kg) or placebo over 96 weeks.3 In patients who had previously received placebo, treatment with cladribine 3.5 mg/kg reduced the annualized relapse rate to a similar degree as observed in the CLARITY study.3 In patients who switched from cladribine to placebo, no evidence of disease exacerbation or rebound was observed, indicating that treatment with the drug for 2 years produces a durable clinical response.3 However, in patients who continued to receive cladribine, no incremental benefit was derived from additional treatment beyond the first 2 courses of therapy received in the CLARITY study.3

Clinical Perspective

Cladribine is one of several disease-modifying therapies used in the management of relapsing forms of multiple sclerosis.76,77,78 Although not curative, these therapies have all been shown to modify several measures of disease activity, including relapse rates, new or enhancing magnetic resonance imaging (MRI) lesions, and disability progression.76,78 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; these experts state that the benefits versus risks (e.g., adverse effects or burden of taking a long-term medication) of treatment in patients who have had no relapses in 2 or more years and who do not have active MRI lesions are not known.76 Because CNS damage occurs early and continues throughout the course of MS, other clinicians recommend that disease-modifying therapy be initiated as soon as possible following diagnosis and continued indefinitely unless there is a clear lack of benefit, adverse effects are intolerable, the patient is unable to adhere to the recommended treatment regimen, or a more appropriate treatment becomes available.77 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 disease-modifying therapy.76,77

Direct comparison studies with oral cladribine and other drugs used for the treatment of MS are not available; indirect comparisons via network meta-analysis identified greater efficacy with oral cladribine compared with other disease-modifying oral drugs (dimethyl fumarate, fingolimod, and teriflunomide) in outcomes related to disease activity.14

Dosage and Administration ⬆ ⬇

[Section Outline]

General !!navigator!!

Pretreatment Screening

Patient Monitoring

Dispensing and Administration

Administration !!navigator!!

Cladribine tablets are administered orally without regard to food.1 Swallow the tablets whole with water, and do not chew.1

Administration of cladribine tablets and other oral drugs should be separated by at least 3 hours during the 4-5 day treatment cycle.1

Follow proper procedures for handling and disposal of antineoplastic drugs when administering cladribine tablets.1 Because the tablets are not coated, they must be swallowed immediately once removed from their packaging.1

Store cladribine tablets at 20-25°C, with excursions permitted to 15-30°C.1 Store in the original package and protect from moisture.1

Dosage !!navigator!!

The recommended cumulative dosage of cladribine for the treatment of relapsing forms of MS in adults is 3.5 mg/kg, administered over 2 yearly treatment courses (1.75 mg/kg per year).1 Each treatment course consists of two 4-5 day dosing cycles.1,9 In each dosing cycle, 1-2 tablets (10 or 20 mg of cladribine) should be administered once daily over 4 or 5 consecutive days (depending on the patient's body weight) for a total dose of 1.75 mg/kg; no more than 2 tablets (20 mg) should be administered in one day.1 (See Table 1 for doses and number of tablets for each cycle based on body weight.) Cladribine has not been evaluated in patients weighing less than 40 kg.1

In the first treatment course, the first dosing cycle may be administered at any time, but the second cycle should be administered 23-27 days after the last dose of the first cycle.1

In the second treatment course, the first dosing cycle should be administered at least 43 weeks after the last dose of the first treatment course and the second cycle should be administered 23-27 days after the last dose of the first cycle in the second treatment course.1

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 less than 50

40 mg (4 tablets)

40 mg (4 tablets)

50 to less than 60

50 mg (5 tablets)

50 mg (5 tablets)

60 to less than 70

60 mg (6 tablets)

60 mg (6 tablets)

70 to less than 80

70 mg (7 tablets)

70 mg (7 tablets)

80 to less than 90

80 mg (8 tablets)

70 mg (7 tablets)

90 to less than 100

90 mg (9 tablets)

80 mg (8 tablets)

100 to less than 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, take the missed dose as soon as it is remembered on the same day; if the day has already passed, the missed dose should be taken the following day and the number of days in the treatment cycle should be extended.1 If 2 consecutive doses are missed, extend the treatment cycle by 2 days.1 Do not take additional or double doses to make up for a missed dose.1

The risks of cladribine therapy increase beyond 2 courses of treatment and have not been studied beyond 4 courses of treatment.4 Cladribine should not be administered during the 2 years following the initial 2-year treatment course since additional exposure to the drug during this time period may increase the risk of malignancy.1,9 Safety and efficacy of reinitiation of cladribine therapy more than 2 years after completion of 2 treatment courses have not been evaluated.1

Special Populations !!navigator!!

Hepatic Impairment

No dosage adjustment is necessary in patients with mild hepatic impairment.1 Use of cladribine is not recommended in patients with moderate to severe hepatic impairment (Child-Pugh score greater than 6).1

Renal Impairment

No dosage adjustment is necessary in patients with mild renal impairment (creatinine clearance 60-89 mL/minute).1 Use of cladribine is not recommended in patients with moderate to severe renal impairment (creatinine clearance less than 60 mL/minute).1

Geriatric Patients

The manufacturer makes no specific dosage recommendations for geriatric patients.1

Cautions ⬆ ⬇

[Section Outline]

Contraindications !!navigator!!

Warnings/Precautions !!navigator!!

Warnings

Malignancies

A boxed warning about the risk of malignancy is included in the prescribing information for cladribine.1 Cladribine may increase the risk of malignancies.1 In clinical studies performed worldwide with oral cladribine, malignancies were reported at a rate of 0.27 events per 100 patient-years in patients receiving the drug compared with 0.13 events per 100 patient-years in those receiving placebo.1 Some malignancies reported in cladribine-treated patients (e.g., metastatic pancreatic carcinoma, malignant melanoma, ovarian cancer) were more severe than those reported in placebo recipients (e.g., basal cell carcinoma, cervical carcinoma in situ), but were all curable by surgical resection.1,4

In clinical studies, patients who received additional cladribine treatment in the 2 years following the first 2 courses of therapy had an increased incidence of malignancy.1 Therefore, cladribine should not be administered during this time period.1 The risk of malignancy in patients who are retreated with cladribine more than 2 years after completion of 2 treatment courses is not known.1

Cladribine is contraindicated in patients with current malignancy.1 Use of cladribine in patients with prior malignancy or with increased risk of malignancy should be individualized based on an assessment of the potential risks versus benefits.1 Standard cancer screening guidelines should be followed in patients treated with cladribine.1

Fetal/Neonatal Morbidity and Mortality

A boxed warning about the risk of fetal/neonatal morbidity and mortality is included in the prescribing information for cladribine.1 Cladribine may cause fetal harm when administered to pregnant women.1 Embryolethality and teratogenicity have been observed in animals.1

Other Warnings and Precautions

Lymphopenia

Cladribine can cause a dose-dependent reduction in lymphocyte count.1 In controlled studies evaluating oral cladribine as monotherapy in patients with MS, 87% of patients who received the drug (cumulative dose of 3.5 mg/kg administered over 2 treatment courses) developed lymphopenia; 26% had nadir absolute lymphocyte counts less than 500/mm3 and 1% had nadir counts less than 200/mm3.1,4 The lowest absolute lymphocyte counts occurred approximately 2-3 months after the start of each treatment course and were further reduced with each additional treatment course.1 At the end of the second treatment course, 2% of patients had lymphocyte counts less than 500/mm3; the median time to recovery of lymphocyte counts to at least 800/mm3 was approximately 28 weeks.1

Reduced lymphocyte counts may result in an immunocompromised state and potentially increase the risk of infections.1 Patients with lymphocyte counts below 500/mm3 should be monitored for infections, including herpes infections, and administered zoster vaccine recombinant (adjuvanted) if lymphocyte ≤500/mm3.1 Cladribine therapy should be withheld in patients with a lymphocyte count less than 200/mm3 and herpes prophylaxis should be administered.1

Additive hematologic toxicity may occur if cladribine is administered prior to or concomitantly with other drugs that affect the hematologic profile.1 In clinical studies, patients who had previously received disease-modifying drugs to treat relapsing forms of MS were more likely to have decreased lymphocyte counts to below 500/mm3 than those with no prior use of these drugs (32.1 versus 23.8%, respectively).1

A complete blood count (CBC) with differential, including lymphocyte count, should be obtained prior to, during, and after each treatment course of cladribine.1 Lymphocyte counts must be within normal limits before initiating the first treatment course and at least 800/mm3 before initiating the second treatment course.1 The second treatment course may be delayed for up to 6 months to allow lymphocytes to recover to at least 800/mm3; if recovery takes more than 6 months, the patient should not receive further cladribine treatment.1

Infectious Complications

Cladribine may increase the risk of infections, including serious, life-threatening, or fatal bacterial, viral, parasitic, and fungal infections.1 In controlled studies in patients with MS, infections occurred in 49% of cladribine-treated patients compared with 44% of placebo recipients.1 Serious or severe infections were reported in 2.4% of patients treated with cladribine compared with 2% of placebo recipients.1 Serious infections reported most frequently in cladribine-treated patients included herpes zoster and pyelonephritis; fungal infections also were reported, including cases of coccidioidomycosis.1 Serious infections reported in the postmarketing setting include nocardiosis, varicella zoster, histoplasmosis, cryptococcosis, and toxoplasmosis.1 Most patients with these infections and an available absolute lymphocyte count demonstrated concomitant lymphopenia.1

HIV infection, active tuberculosis, and active hepatitis must be excluded before initiation of each treatment course of cladribine.1 In patients with an acute infection, a delay in cladribine therapy should be considered until the infection is fully resolved or controlled.1 Because of the additive risk of immunosuppression, initiation of cladribine in patients receiving other immunomodulatory, immunosuppressive, or myelosuppressive agents is not recommended.1

In clinical studies in MS patients, tuberculosis occurred in 3 patients (0.2%) receiving cladribine.1 All 3 cases occurred in regions where tuberculosis is endemic.1 While 2 of the patients recovered with treatment, one patient had a fatal outcome.1 Activation of latent tuberculosis infections also can occur with cladribine therapy.1 Patients should be screened for tuberculosis prior to initiation of the first and second treatment course of cladribine therapy.1

A case of fatal fulminant hepatitis B virus (HBV) infection occurred in controlled studies in patients with MS.1 Activation of latent HBV or hepatitis C virus (HCV) infections also can occur with cladribine therapy, which can result in irreversible liver damage.1 Patients should be screened for HBV and HCV infection prior to initiation of the first and second treatment course of cladribine.1 In patients with active hepatitis, initiation of cladribine therapy should be delayed until the infection has been adequately treated.1

Herpes virus infections were reported in 6% of MS patients receiving oral cladribine in controlled studies compared with 2% of placebo recipients.1 The most frequent types of herpes viral infections were herpes zoster and oral herpes.1 Serious herpes zoster infections occurred in 0.2% of cladribine-treated patients.1 The incidence of herpes zoster infection was higher when the absolute lymphocyte count was less than 500/mm3.1

Patients with lymphocyte counts below 500/mm3 should be monitored for infections, including herpes virus infections.1 Vaccination with zoster vaccine recombinant (adjuvanted) is recommended when lymphocytecounts are less than or equal to 500/mm3.1 If any signs and symptoms of infection occur, appropriate treatment should be initiated as clinically indicated.1 Consideration should be given to interrupting or delaying cladribine therapy until resolution of the infection.1 Prophylaxis against herpes virus should be administered in patients with lymphocyte counts less than 200/mm3.1 In patients who are seronegative for varicella zoster virus (VZV), vaccination against VZV is recommended prior to initiation of cladribine therapy.1 In patients who are seropositive to VZV, vaccination with zoster vaccine recombinant, adjuvanted is recommended either prior to or during cladribine treatment.1

Although not reported in premarketing studies with oral cladribine in patients with MS, progressive multifocal leukoencephalopathy (PML), an opportunistic infection of the brain caused by the JC virus, has been reported in patients receiving the parenteral formulation of the drug for oncologic indications.1 Patients who are immunocompromised are at increased risk of PML.1 Symptoms typically associated with PML are diverse, progress over a period of days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, vision disturbances, and changes in thinking, memory, orientation, or personality.1 At the first sign or symptom suggestive of PML, cladribine therapy should be withheld and an appropriate diagnostic evaluation should be performed.1 MRI signs of PML may be apparent before clinical manifestations develop.1 The manufacturer recommends that a baseline MRI of the brain be obtained within 3 months of initiating the first treatment course of cladribine.1

Hematologic Toxicity

In addition to lymphopenia, decreases in other blood cells and hematologic parameters have been reported with cladribine.1

In clinical studies in patients with MS, mild to moderate decreases in neutrophil counts (i.e., neutrophil count below the lower limit of normal [LLN] but not less than 1000/mm3) occurred in 27% of cladribine-treated patients compared with 13% of placebo recipients.1 Severe decreases in neutrophil counts (neutrophil count below 1000/mm3) occurred in 3.6% of cladribine-treated patients compared with 2.8% of placebo recipients.1

Decreases in hemoglobin concentrations were observed in 26% of cladribine-treated patients compared with 19% of placebo recipients and generally were mild to moderate (hemoglobin concentrations below the LLN but not less than 8 g/dL).1

Decreases in platelet counts were observed in 11% of cladribine-treated patients compared with 4% of placebo recipients and generally were mild (platelet count below the LLN but not less than 75,000/mm3).1

Serious cases of thrombocytopenia, neutropenia, and pancytopenia (some with documented bone marrow hypoplasia) requiring transfusion and treatment with granulocyte colony-stimulating factor (G-CSF) have been reported in clinical trials using oral cladribine dosages similar to or higher than those recommended for MS.1

A CBC with differential, including lymphocyte count, should be obtained prior to, during, and after treatment with cladribine.1

Graft-Versus-Host Disease Associated with Blood Transfusion

Transfusion-associated graft-versus-host disease has been observed rarely following transfusion of nonirradiated blood in patients treated with cladribine for indications other than MS.1 If a cladribine-treated patient requires blood transfusion, irradiation of cellular blood components is recommended prior to administration to decrease the risk of transfusion-related graft-versus-host disease.1 Consultation with a hematologist is advised.1

Liver Injury

Treatment-related liver injury that was serious and/or led to discontinuance of therapy occurred in 0.3% of MS patients receiving oral cladribine in clinical studies compared with no patients receiving placebo.1 Onset of liver injury ranged from a few weeks to several months after initiation of cladribine treatment.1 In one case, elevated serum aminotransferase concentrations to greater than 20 times the upper limit of normal were reported.1,4 These abnormalities resolved upon treatment discontinuance.1

In the postmarketing setting, clinically significant and life-threatening liver injury was reported with cladribine therapy.1 Risk of liver injury may be increased in patients with pre-existing liver disease and those concurrently administered other hepatotoxic drugs.1 The majority of cladribine-associated liver injury events occurred approximately 30 days after initiation (i.e., course 1, cycle 1) of treatment.1 Cladribine is not recommended in patients with moderate to severe hepatic impairment.1

Liver function tests (serum aminotransferase, alkaline phosphatase, and total bilirubin concentrations) should be performed prior to each treatment cycle and course of cladribine.1 If clinical signs or symptoms suggestive of hepatic dysfunction (e.g., unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, jaundice, dark urine) occur, serum aminotransferase and total bilirubin concentrations should be assessed promptly and cladribine therapy should be interrupted or discontinued as appropriate.1

Hypersensitivity Reactions

Hypersensitivity reactions occurred in 11% of MS patients receiving oral cladribine compared with 7% of placebo recipients in clinical studies.1 Hypersensitivity reactions (e.g., dermatitis, pruritus) were serious and/or led to discontinuance of therapy in 0.5% of cladribine-treated patients, compared with 0.1% of placebo recipients.1 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.1

Cladribine should be discontinued if a hypersensitivity reaction is suspected.1

Heart Failure

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

Specific Populations

Pregnancy

Cladribine is contraindicated in pregnant females.1 There are no adequate data regarding use of cladribine in pregnant females; however, embryolethality and teratogenicity have been demonstrated in animals.1 The observed developmental effects in animals are consistent with the mechanism of action of cladribine.1

Pregnancy should be excluded prior to initiation of cladribine therapy.1 Cladribine should be discontinued if a patient becomes pregnant during therapy.1

A pregnancy safety study is monitoring pregnancy and infant outcomes following exposure to cladribine.1 Physicians and patients are encouraged to 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 1-781-681-2961.1

Lactation

It is not known whether cladribine or its metabolites are distributed into human milk.1 Because of the potential for serious adverse reactions to cladribine in nursing infants, cladribine is contraindicated in women who are breast-feeding.1 Breast-feeding is not advised during cladribine treatment and for 10 days after the last dose of the drug.1 The effects of the drug on nursing infants or on milk production are not known.1

Females and Males of Reproductive Potential

Females of childbearing potential must use effective contraception during cladribine treatment and for at least 6 months after the last dose in each treatment course.1 Because it is not known whether cladribine reduces the effectiveness of systemic hormonal contraceptives, females using systemically acting hormonal contraceptives should add a barrier method during cladribine treatment and for at least 4 weeks after the last dose in each treatment course.1

Because cladribine may cause adverse effects on human gametogenesis, male patients with partners of childbearing potential should take precautions to prevent pregnancy in their partner; such male patients should use effective contraception during cladribine treatment and for at least 6 months after the last dose in each treatment course.1

Cladribine is contraindicated in females and males 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.1

Pediatric Use

Safety and efficacy of cladribine have not been established in pediatric patients younger than 18 years of age.1 Use of the drug is not recommended in pediatric patients because of the risk of malignancies.1

Geriatric Use

Clinical studies of cladribine did not include sufficient numbers of patients 65 years of age or older to determine whether they respond differently than younger patients.1 Other clinical experience has not identified differences in response between geriatric patients and younger adults.1 Cladribine should be used with caution in geriatric patients, reflecting the greater frequency of decreased hepatic, renal, and cardiac function and of concomitant disease and other drug therapy.1

Hepatic Impairment

Formal pharmacokinetic studies of cladribine have not been conducted in patients with hepatic impairment.1 The manufacturer states that dosage adjustment is not necessary in patients with mild hepatic impairment.1

Cladribine is not recommended in patients with moderate to severe hepatic impairment (Child-Pugh score greater than 6).1

Renal Impairment

Formal pharmacokinetic studies of cladribine have not been conducted in patients with renal impairment; however, clearance of cladribine is expected to decrease in patients with renal impairment.1 Patients with mild renal impairment (creatinine clearance 60-89 mL/minute) were included in clinical studies in patients with MS; dosage adjustment is not necessary in these patients.1

Cladribine is not recommended in patients with moderate to severe renal impairment (creatinine clearance below 60 mL/minute).1

Common Adverse Effects !!navigator!!

Adverse effects occurring in >20% of patients receiving oral cladribine for the treatment of MS and with an incidence greater than with placebo include upper respiratory tract infection,1 headache,1 and lymphopenia.1

Drug Interactions ⬆ ⬇

[Section Outline]

Drugs Affecting or Affected by Hepatic Microsomal Enzymes !!navigator!!

Cladribine is not a substrate of cytochrome P-450 (CYP) isoenzymes;1,6 CYP inhibitors and inducers are not expected to have a clinically important effect on the pharmacokinetics of cladribine.6

Cladribine is not expected to inhibit CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4 nor induce CYP 1A2, 2B6, or 3A4 to a clinically important extent.1

Drugs Affecting Transporter Systems !!navigator!!

Cladribine is a substrate of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), equilibrative nucleoside (ENT1), and concentrative nucleoside (CNT3) transport proteins.1 The bioavailability, intracellular distribution, and renal elimination of cladribine may be affected by potent inhibitors of ENT1, CNT3, or BCRP.1,6 Systemic exposure of cladribine may be decreased by potent inducers of BCRP or P-gp.1

Potent ENT, CNT, or BCRP Inhibitors

Inhibition of BCRP in the GI tract may result in increased oral bioavailability and systemic exposure of cladribine.1,6 Intracellular distribution and renal elimination of cladribine may be altered by potent ENT1 or CNT3 transporter inhibitors.1,6

Concomitant use of cladribine and potent inhibitors of ENT1, CNT3, or BCRP (e.g., ritonavir, eltrombopag, curcumin, cyclosporine, nifedipine, nimodipine, cilostazol, sulindac, dipyridamole) may increase exposure to cladribine and should be avoided during the 4-5 day cladribine dosing cycle.1 Selection of an alternative drug with minimal or no ENT1, CNT3, or BCRP inhibiting properties should be considered.1 If this is not possible, the lowest effective dosage of the ENT1, CNT3, or BCRP inhibitor should be used, the administration times of the drugs should be separated, and the patient should be carefully monitored.1

Potent BCRP or P-gp Inducers

Concomitant use of cladribine and potent inducers of BCRP (e.g., corticosteroids) or P-gp (e.g., rifampin, St. John's wort) may decrease systemic exposure and efficacy of cladribine.1

Drugs Affected by Hydroxypropyl Betadex-related Complex Formation !!navigator!!

Cladribine tablets contain the excipient hydroxypropyl betadex, which can form complexes with other concomitantly administered drugs.1 The bioavailability of concomitantly administered drugs, particularly drugs with low solubility, may be increased, which may increase the risk or severity of adverse reactions.1 Complex formation between hydroxypropyl betadex and concomitantly administered ibuprofen, furosemide, and gabapentin has been observed.1

Oral administration of cladribine tablets and other drugs should be separated by at least 3 hours during the 4-5 day dosing cycle.1,4

Drugs Associated with Hematologic Toxicity !!navigator!!

Additive hematologic effects may occur if cladribine is used concomitantly with other drugs that can affect the hematologic profile.1 Hematologic parameters should be monitored.1

Antiviral and Antiretroviral Drugs !!navigator!!

Because of potential competition for intracellular phosphorylation, concomitant use of cladribine and other drugs that require activation via intracellular phosphorylation (e.g., lamivudine, ribavirin, stavudine, zidovudine) should be avoided.1

Hormonal Contraceptives !!navigator!!

It is not known whether cladribine may reduce the effectiveness of systemic hormonal contraceptives.1 Therefore, an additional barrier method of contraception should be used during cladribine treatment and for at least 4 weeks after the last dose in each treatment course in women of childbearing potential.1

Immunomodulatory, Immunosuppressive, or Myelosuppressive Drugs !!navigator!!

Additive immunosuppressive effects may occur with concomitant use of cladribine and other immunomodulatory, immunosuppressive, or myelosuppressive drugs.1 Concomitant use with these drugs is not recommended.1 When evaluating the potential for additive effects in patients previously treated with immunomodulatory or immunosuppressive drugs, the mechanisms of action and durations of effect of these drugs should be considered prior to initiation of cladribine therapy.1

Concomitant use of cladribine and corticosteroids did not result in clinically important effects on absolute lymphocyte count;6 the manufacturer therefore states that acute, short-term treatment with corticosteroids may be administered during cladribine therapy.1

Interferon Beta

Interferon beta did not have any clinically important effects on the pharmacokinetics of cladribine; however, concomitant use is not recommended because of the potential for increased risk of lymphopenia.1

Pantoprazole !!navigator!!

Pantoprazole did not have any clinically important effects on the pharmacokinetics of cladribine.1

Vaccines !!navigator!!

Because of a risk of active vaccine infection, live or live attenuated vaccines should be administered at least 4-6 weeks prior to starting cladribine.1 Vaccination with live or live attenuated vaccines should be avoided during and after cladribine treatment while the patient's white blood cell counts are not within normal limits.1

Other Information ⬆ ⬇

Description

Cladribine is a purine nucleoside antimetabolite that has immunomodulatory and disease-modifying activity in multiple sclerosis (MS).1,2,6 Although the exact mechanism of action of cladribine in patients with MS has not been fully elucidated, the drug's immunomodulatory effects are thought to result from depletion of B and T lymphocytes.1,5,6,9 Cladribine is a prodrug that undergoes intracellular phosphorylation to produce the active 2-chlorodeoxyadenosine triphosphate (CdATP) metabolite.1,5,6 The drug is first phosphorylated by deoxycytidine kinase (and also by deoxyguanosine kinase in the mitochondria) in lymphocytes to cladribine monophosphate (CdAMP), which is further phosphorylated to cladribine diphosphate (CdADP) and CdATP.1,5,6 The dephosphorylation and deactivation of CdAMP is catalyzed by cytoplasmic 5'-nucleotidase (5'-NTase).1,6 Because lymphocytes have relatively high levels of deoxycytidine kinase and low levels of 5'-NTase, the active CdATP moiety preferentially accumulates in lymphocytes and causes DNA strand breaks, resulting in inhibition of DNA synthesis and repair and cell death; cladribine is cytotoxic in both dividing and resting lymphocytes.2,5,6 Cells of the innate immune system and those produced by the bone marrow are less impacted by cladribine since these cells have lower deoxycytidine kinase to 5'-NTase ratios than lymphocytes.5

Cladribine causes a dose-dependent reduction in lymphocyte count.1,7 The 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.1 The median time to recovery from lymphocyte counts less than 500/mm3 to at least 800/mm3 is approximately 28 weeks.1

Peak concentrations and area under the concentration-time curve (AUC) of cladribine are dose proportional over the dose range of 3-20 mg.1,6 Following oral administration of cladribine in the fasted state, peak concentrations occur in 0.5 hours (range 0.5-1.5 hours).1,6 Administration with a high fat meal delays time to peak concentration by 1 hour and decreases peak concentrations by 29%, but does not affect the AUC.1,6 No plasma accumulation of cladribine is observed after repeated dosing.1,6 The oral bioavailability of cladribine is approximately 40%.1,6 Cladribine is 20% bound to plasma proteins (independent of concentration) and is extensively distributed into tissues; intracellular concentrations in human lymphocytes are approximately 30-40 times those of extracellular concentrations.1,5 The drug can cross the blood-brain barrier; in patients with cancer, CSF concentrations are about 25% of plasma concentrations.1 Cladribine is a prodrug that is phosphorylated to its active metabolite in lymphocytes.1 The metabolism of cladribine in whole blood has not been fully characterized; however, extensive whole blood and negligible hepatic enzyme metabolism have been observed in vitro.1,6 Following administration of a 10-mg oral dose in patients with MS, 28.5% of the dose was excreted unchanged in urine.1 Renal clearance of cladribine exceeds the glomerular filtration rate, indicating active renal secretion.1,6 The estimated terminal half-life of cladribine is approximately 1 day.1 The intracellular half-life of the phosphorylated metabolites Cd-AMP and Cd-ATP is 15 and 10 hours, respectively.1,6

Advice to Patients

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.8 Clinicians may contact the manufacturer at 877-447-3243 or consult the Mavenclad® website ([Web]) for additional information.8

Cladribine

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

10 mg

Mavenclad®

EMD Serono

Copyright ⬆ ⬇

AHFS® Drug Information. © Copyright, 1959-2024, Selected Revisions September 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.

References ⬆

1. EMD Serono, Inc. Mavenclad® (cladribine) tablets prescribing information. Rockland, MA; 2024 May.

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