Cladribine (oral) Monograph for Professionals - Drugs.com

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# Cladribine (oral)

Brand name: Mavenclad
Drug class: Immunosuppressive Agents
Chemical name: (2R,3S,5R)-5-(6-amino-2-chloropurin-9-yl)-2-(hydroxymethyl)oxolan-3-ol
Molecular formula: C10H12ClN5O3
CAS number: 123318-82-1

Medically reviewed by Drugs.com on Feb 21, 2022. Written by ASHP.

### Warning

Malignancies

- May increase risk of malignancy. (See Malignancies under Cautions.)

- 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.

Teratogenicity

- Risk of fetal harm; contraindicated in pregnant women and in women and men of reproductive potential who do not plan to use effective contraception. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

## Introduction

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

## Uses for Cladribine (oral)

### Multiple Sclerosis (MS)

Used orally for treatment of relapsing forms of MS, 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. (See Boxed Warning and also see Cautions.)

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 magnetic resonance imaging (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 (oral) Dosage and Administration

### General

- Screen for malignancies according to standard cancer screening guidelines prior to each cladribine treatment course. (See Malignancies under Cautions.)

- Screen for HIV, tuberculosis, HBV, and HCV, and evaluate for active infections prior to each treatment course; in patients with active infections, consider delaying therapy until the infection is fully controlled.

- Exclude pregnancy in women of childbearing potential prior to each treatment course. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

- Complete any necessary immunizations prior to initiating therapy. Vaccination against varicella zoster virus (VZV) is recommended in antibody-negative patients. Administer live or live attenuated vaccines at least 4–6 weeks prior to initiation of therapy.

- Perform baseline (within 3 months) MRI of the brain prior to initiating therapy. (See Infectious Complications under Cautions.)

- Perform CBC with differential, including lymphocyte count, prior to each treatment course, at 2 and 6 months after the start of each treatment course, periodically thereafter, and when clinically indicated. If lymphocyte count <200/mm3 at 2 months, increase monitoring frequency to monthly until 6 months. Lymphocytes must be within normal limits prior to initiating the first treatment course and ≥800/mm3 before initiating the second treatment course.

- Withhold treatment and administer herpes virus prophylaxis in patients with lymphocyte count <200/mm3. (See Infectious Complications under Cautions.)

- Perform liver function tests, including serum aminotransferase, alkaline phosphatase, and total bilirubin concentrations, prior to initiation of each treatment course.

#### Restricted Distribution

- Obtain cladribine only through specialty pharmacies.

- Contact the manufacturer at 877-447-3243 or consult the Mavenclad website ([Web]) for additional information.

### 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. (See Drugs Affected by Hydroxypropyl Betadex-related Complex Formation under Interactions.)

Observe usual precautions for handling and disposal of cytotoxic drugs. Tablets are not coated and must be swallowed immediately once removed from their packaging. Handle tablets with dry hands; avoid prolonged contact with the skin and wash hands thoroughly after handling. Any surface or area that comes in contact with a tablet or a fragment of the tablet must be thoroughly washed with water.

Administer orally as 2 treatment courses separated by at least 43 weeks. Each treatment course consists of 2 treatment cycles separated by 23–27 days. In each treatment cycle, the drug is administered as 1 or 2 tablets once daily over 4–5 consecutive days to obtain the required dose. (See Dosage under Dosage and Administration.)

### 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. (See Hepatic Impairment under Cautions.)

#### Renal Impairment

Dosage adjustment not necessary in patients with mild renal impairment (Clcr 60–89 mL/minute).

Detailed Cladribine dosage information

## Cautions for Cladribine (oral)

### 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. (See Contraindications under Cautions.)

#### 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. If lymphocyte count <200/mm3, withhold therapy and initiate herpes prophylaxis. (See Infectious Complications under Cautions.)

Obtain CBC with differential, including lymphocyte count, prior to, during, and after each treatment course. (See General under Dosage and Administration.)

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.

##### Other Hematologic Effects

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. (See General under Dosage and Administration.)

##### Infectious Complications

May increase the risk of infections, including life-threatening opportunistic infections and reactivation of latent infections (e.g., herpes virus infections, hepatitis, pyelonephritis, tuberculosis, coccidioidomycosis). 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. 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 (see Advice to Patients), 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 controlled.

Test patients for antibodies to VZV before initiating cladribine and vaccinate patients who are antibody negative. Administer the vaccine at least 4–6 weeks prior to starting cladribine.

Do not initiate cladribine in patients receiving other immunomodulatory, immunosuppressive, or myelosuppressive agents; increased risk of immunosuppression may occur. (See Immunomodulatory, Immunosuppressive, or Myelosuppressive Agents under Interactions.)

##### 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.

Perform liver function tests (serum aminotransferase, alkaline phosphatase, and total bilirubin concentrations) prior to the first and second treatment courses 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. (See Contraindications under Cautions.)

##### 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. (See Advice to Patients.)

#### Specific Populations

##### Pregnancy

May cause fetal harm. Exclude pregnancy prior to initiation of therapy. Discontinue drug if patient becomes pregnant during therapy. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

##### Lactation

Not known whether distributed into milk; effects on milk production or breast-fed infant also not known. Consider known benefits of breast-feeding along with mother's clinical need for cladribine and any potential adverse effects of the drug or disease on the infant.

##### Women and Men of Reproductive Potential

Women of childbearing potential must use effective contraception during cladribine treatment and for 6 months after the last dose in each treatment course. (See Contraindications under Cautions.)

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; women using such hormonal contraceptives should add a barrier method during cladribine treatment and for ≥4 weeks after the last dose in each treatment course. (See Specific Drugs under Interactions.)

##### 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 (Clcr <60 mL/minute).

Patients with mild renal impairment (Clcr 60–89 mL/minute) were included in clinical studies in patients with MS. (See Renal Impairment under Dosage and Administration.)

### Common Adverse Effects

Upper respiratory tract infection, headache, lymphopenia, nausea.

## Interactions for Cladribine (oral)

### 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. (See Infectious Complications under Cautions.)

### 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 (see Actions) | 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
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 drug interactions (more detail)

## Cladribine (oral) 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

- Importance of advising patients to read the manufacturer's patient information (medication guide).

- Importance of advising 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. Advise 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. (See Administration under Dosage and Administration.)

- Risk of malignancies. Importance of advising patients to follow standard cancer screening guidelines.

- Risk of fetal harm. Importance of advising women of childbearing potential to use effective contraception during cladribine treatment and for at least 6 months after the last dose in each treatment course. Advise patients that cladribine may decrease the effectiveness of systemic hormonal contraceptives and that an additional barrier method should be used during treatment and for at least 4 weeks after the last dose in each treatment course. Importance of also advising 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. Importance of patients immediately informing their clinician if pregnancy occurs.

- Importance of advising women to avoid breast-feeding during cladribine treatment and for 10 days after the last dose of the drug.

- Risk of lymphopenia and other hematologic toxicity. Importance of advising patients of the need for monitoring CBCs. (See Lymphopenia and also see Other Hematologic Effects under Cautions.)

- Risk of infections, including reactivation of latent infections; importance of advising patients 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.

- Importance of informing patients that 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. Importance of advising 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). (See Infectious Complications under Cautions.)

- Risk of liver injury. Importance of advising patients to contact their clinician if they experience unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine during cladribine therapy.

- Importance of instructing patients to seek immediate medical attention if they experience a serious or hypersensitivity reaction, including skin reactions.

- Risk of cardiac failure. Importance of advising patients to seek medical advice if they experience symptoms of cardiac failure (e.g., shortness of breath, rapid or irregular heartbeat, swelling).

- Importance of patients informing clinicians of 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).

- Importance of informing patients of other important precautionary information. (See Cautions.)

## 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.

Distribution of cladribine is restricted. (See Restricted Distribution under Dosage and Administration.)

Cladribine
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer
--- | --- | --- | --- | ---
Oral | Tablets | 10 mg | Mavenclad | EMD Serono

AHFS DI Essentials™. © Copyright 2023, Selected Revisions March 2, 2020. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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