MAVENCLAD

Cladribine is a purine analogue or a chlorinated derivative of adenine 6 that causes apoptosis of B and T lymphocytes.

Cladribine was first approved in the United States in 1993 2 initially as a treatment for a number of hematological malignancies; currently, it is approved for the treatment of hairy cell leukemia.

In in Europe and in in the United States, cladribine was also approved for the treatment multiple sclerosis.

Intravenous cladribine is indicated for the treatment of active Hairy Cell Leukemia as defined by clinically significant anemia, neutropenia, thrombocytopenia or disease-related symptoms.

Oral cladribine is indicated for the treatment of relapsing forms of multiple sclerosis (MS), including relapsing-remitting disease and active secondary progressive disease, in adults.

Because of its safety profile, the use of cladribine is generally recommended for patients who have had an inadequate response to, or are unable to tolerate, an alternate drug indicated for the treatment of MS. 7,

Cladribine is an antineoplastic agent with cytotoxic effects on actively dividing and quiescent B and T lymphocytes and monocytes. 7, 8 It produces a dose-dependent reduction in lymphocyte count.

Because cladribine is resistant to deamination by adenosine deaminase (ADA), a purine-degrading enzyme, it is reported to have a prolonged intracellular residence time. 1, 4 Following oral administration, the lowest absolute lymphocyte counts occurred approximately 2-3 months after the start of each treatment cycle and were lower with each additional treatment cycle.

At the end of

Year 2, 2% of patients continued to have absolute lymphocyte counts less than 500 cells per microliter.

The median time to recovery from lymphocyte counts less than 500 cells per microliter to at least 800 cells per microliter was approximately 28 weeks.

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Oral bioavailability is approximately 40%.

Following the oral administration of 10 mg cladribine, the mean maximum concentration (C max ) was in the range of 22-29 ng/ mL, and the corresponding mean AUC was in the range of 80-101 ng x h/mL.

The C max and

AUC of cladribine increased proportionally across a dose range from 3-20 mg.

Under fasted conditions, the median time to maximum concentration (T max ) was 0.5 h (range 0.5-1.5 hours).

A high-fat meal decreased

C max by 29% and delayed T max to 1.5 hours (range one to three hours), but this difference is not expected to be clinically significant.

Following a cladribine injection given by continuous infusion over seven days, the mean steady-state serum concentration was estimated to be 5.7 ng/mL.

In general, the apparent volume of distribution of cladribine is approximately 9 L/kg, indicating an extensive distribution in body tissues.

In patients with hematologic malignancies who received a two-hour infusion of cladribine injection at a dose of 0.12 mg/kg, the mean steady-state volume of distribution was 4.5 ± 2.8 L/kg.

Following oral administration, the mean apparent volume of distribution ranges from 480-490 L.

Cladribine penetrates into cerebrospinal fluid.

One report indicates that concentrations are approximately 25% of those in plasma.

A cerebrospinal fluid:plasma concentration ratio of approximately 0.25 was observed in cancer patients.

Cladribine is a prodrug that is phosphorylated to cladribine monophosphate (Cd-AMP, 2-chlorodeoxyadenosine monophosphate) by deoxycytidine kinase and mitochondrial deoxyguanosine kinase in lymphocytes.

Cd-AMP is further phosphorylated to cladribine diphosphate (Cd-ADP, 2-chlorodeoxyadenosine diphosphate) and the active moiety Cd-ATP.

The dephosphorylation and deactivation of

Cd-AMP is catalyzed by cytoplasmic 5'-nucleotidase (5'-NTase).

The metabolism of cladribine in whole blood has not been fully characterized; however, extensive whole blood and negligible hepatic enzyme metabolism was observed, in vitro.

Hover over products below to view reaction partners Cladribine Cladribine 5'-monophosphate Cladribine diphosphate Cladribine triphosphate.

An average of 18% of the administered dose has been reported to be excreted in the urine of patients with solid tumours during a five-day continuous intravenous infusion of 3.5-8.1 mg/m 2 /day of cladribine injection.

Following oral administration of 10 mg cladribine in patients with MS, about 28.5% of the dose was excreted unchanged via the renal route.

Renal clearance exceeded the glomerular filtration rate, indicating active renal secretion of cladribine.

Cladribine plasma concentration after intravenous administration declines multi-exponentially with an average half-life of 6.7 +/.

Following oral administration, the terminal half-life is approximately one day.

The intracellular half-life is 15 hours for Cd-AMP and 10 hours for Cd-ATP.

In patients with hematologic malignancies who received a two-hour infusion of cladribine injection at a dose of 0.12 mg/kg, the mean clearance was 978 ± 422 mL/h/kg.

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LD is 150 mg/kg in mice.

High doses of cladribine have been associated with irreversible neurologic toxicity (paraparesis/quadriparesis), acute nephrotoxicity, and severe bone marrow suppression resulting in neutropenia, anemia, and thrombocytopenia.

Lymphopenia may also occur, which is known to be dose-dependent.

There is no known antidote to cladribine overdosage; thus, treatment of overdosage consists of drug discontinuation, careful observation, and appropriate supportive measures.

Although it is not known whether cladribine can be removed from the circulation by dialysis or hemofiltration, because of its rapid and extensive intracellular and tissue distribution, hemodialysis is unlikely to eliminate cladribine to a significant extent.

Cladribine tablets are contraindicated: in patients with current malignancy. in pregnant women and in women and men of reproductive potential who do not plan to use effective contraception during cladribine tablets dosing and for 6 months after the last dose in each treatment course.

May cause fetal harm. in patients infected with the human immunodeficiency virus (HIV) . in patients with active chronic infections (e.g., hepatitis or tuberculosis) . in patients with a history of hypersensitivity to cladribine. in women intending to breastfeed on a cladribine treatment day and for 10 days after the last dose.

Patients with current malignancy.

Pregnant women, and women and men of reproductive potential who do not plan to use effective contraception during cladribine tablets dosing and for 6 months after the last dose in each treatment course.

HIV infection.

Active chronic infections (e.g., hepatitis or tuberculosis).

History of hypersensitivity to cladribine.

Women intending to breastfeed on a cladribine treatment day and for 10 days after the last dose.

Assessments are required prior to starting each cladribine treatment course.

Cumulative dosage of 3.5 mg/kg administered orally and divided into 2 treatment courses (1.75 mg/kg per treatment course).

Each treatment course is divided into 2 treatment cycles.

Cladribine tablets are a cytotoxic drug.

Separate administration from any other oral drug by at least 3 hours. 2.1 Assessments Prior to Starting Each Cladribine Treatment Course Cancer Screening Follow standard cancer screening guidelines because of the risk of malignancies.

Exclude pregnancy prior to treatment with cladribine tablets in females of reproductive potential.

Count (CBC) Obtain a CBC with differential including lymphocyte count.

Lymphocytes must be: within normal limits before initiating the first treatment course at least 800 cells per microliter before initiating the second treatment course If necessary, delay the second treatment course for up to 6 months to allow for recovery of lymphocytes to at least 800 cells per microliter.

If this recovery takes more than 6 months, the patient should not receive further treatment with cladribine tablets.

Infections Exclude HIV infection.

Perform tuberculosis screening.

Screen for hepatitis B and C

Evaluate for acute infection.

Consider a delay in cladribine treatment until any acute infection is fully controlled.

Vaccination of patients who are seronegative for VZV is recommended prior to initiation of cladribine tablets.

Vaccination of patients who are seropositive to VZV is recommended with zoster vaccine recombinant, adjuvanted.

Patients may be administered zoster vaccine recombinant, adjuvanted at any time prior to or during the year 1 or year 2 course of cladribine treatment.

These patients may also be administered the vaccine if their lymphocyte counts are ≤ 500 cells per microliter.

Administer all immunizations (except as noted for VZV) according to immunization guidelines prior to starting cladribine tablets.

Administer live-attenuated or live vaccines at least to 6 weeks prior to starting cladribine tablets.

Obtain a baseline (within 3 months) magnetic resonance imaging prior to the first treatment course because of the risk of progressive multifocal leukoencephalopathy (PML).

Obtain serum aminotransferase, alkaline phosphatase, and total bilirubin levels prior to each treatment cycle and course. 2.2 Recommended Dosage The recommended cumulative dosage of cladribine tablets is 3.5 mg per kg body weight administered orally and divided into 2 yearly treatment courses (1.75 mg per kg per treatment course) .

Each treatment course is divided into 2 treatment cycles: Administration of First Treatment Course First Course/First Cycle: start any time.

Course/Second Cycle: administer to 27 days after the last dose of First Course/First Cycle.

Administration of Second Treatment Course Second

Course/First Cycle: administer at least 43 weeks after the last dose of First Course/Second Cycle.

Course/Second Cycle: administer to 27 days after the last dose of Second Course/First Cycle.

Table 1 Dose of Cladribine tablets per Cycle by Patient Weight in Each Treatment Course Weight Range Dose in mg (Number of 10 mg Tablets) per Cycle kg First Cycle Second Cycle 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 and above 100 mg (10 tablets) 100 mg (10 tablets) The use of cladribine tablets in patients weighing less than 40 kg has not been investigated.

Administer the cycle dosage as 1 or 2 tablets once daily over 4 or 5 consecutive days.

Do not administer more than 2 tablets daily.

Following the administration of 2 treatment courses, do not administer additional cladribine treatment during the next 2 years.

Treatment during these 2 years may further increase the risk of malignancy.

The safety and efficacy of reinitiating cladribine tablets more than 2 years after completing 2 treatment courses has not been studied. 2.3 Missed Dose If a dose is missed, patients should not take double or extra doses.

If a dose is not taken on the scheduled day, then the patient must take the missed dose on the following day and extend the number of days in that treatment cycle.

If two consecutive doses are missed, the treatment cycle is extended by 2 days. 2.4 Administration Cladribine tablets are taken orally, with water, and swallowed whole without chewing.

Cladribine tablets can be taken with or without food.

Separate administration of cladribine tablets and any other oral drugs by at least 3 hours during the to 5 day cladribine treatment cycles.

Follow applicable special handling and disposal procedures.

Cladribine tablets are an uncoated tablet and must be swallowed immediately once removed from the blister.

If a tablet is left on a surface, or if a broken or fragmented tablet is released from the blister, the area must be thoroughly washed with water.

The patient’s hands must be dry when handling the tablets and washed thoroughly afterwards.

Avoid prolonged contact with skin. 2.5 Laboratory Testing and Monitoring to Assess Safety Cancer Screening Follow standard cancer screening guidelines in patients treated with cladribine tablets.

Obtain complete blood count (CBC) with differential including lymphocyte count: before initiating the first treatment course of cladribine tablets before initiating the second treatment course of cladribine tablets and 6 months after start of treatment in each treatment course; if the lymphocyte count at month is below 200 cells per microliter, monitor monthly until month 6.

See Warnings and

Precautions for instructions based on the patient’s lymphocyte counts and clinical status (e.g., infections).

Hold cladribine tablets therapy if the lymphocyte count is below 200 cells per microliter periodically thereafter and when clinically indicated 2.6 Recommended Concomitant Medication Herpes Prophylaxis Administer anti-herpes prophylaxis in patients with lymphocyte counts less than 200 cells per microliter.

Cladribine tablets, 10 mg, are white to off white, round, biconvex tablets debossed with “10” on one side and plain on the other side.

Each tablet is packaged in a child-resistant day pack containing one or two tablets in a blister card.

Dispense one box for each treatment cycle with a Medication Guide.

NDC 60505-4791-4 NDC 60505-4791-5 NDC 60505-4791-6 NDC 60505-4791-7 NDC 60505-4791-8 NDC 60505-4791-9 NDC 60505-4791-1 Box of 4 tablets: Four day packs each containing one tablet.

Box of 5 tablets: Five day packs each containing one tablet.

Box of 6 tablets: One day pack containing two tablets.

Four day packs each containing one tablet.

Box of 7 tablets: Two day packs each containing two tablets.

Three day packs each containing one tablet.

Box of 8 tablets: Three day packs each containing two tablets.

Two day packs each containing one tablet.

Box of 9 tablets: Four day packs each containing two tablets.

One day pack containing one tablet.

Box of 10 tablets: Five day packs each containing two tablets. 16.2 Storage and Handling Store at controlled room temperature, 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) .

Store in original package in order to protect from moisture.

Cladribine tablets are a cytotoxic drug.

Follow applicable special handling and disposal procedures.

Cladribine tablets are contraindicated in pregnant women and in females and males of reproductive potential who do not plan to use effective contraception.

There are no adequate data on the developmental risk associated with use of cladribine in pregnant women.

Cladribine was embryolethal when administered to pregnant mice and produced malformations in mice and rabbits.

The observed developmental effects are consistent with the effects of cladribine on DNA.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

The background risk of major birth defects and miscarriage for the indicated population is unknown.

When cladribine was administered intravenously (0, 0.5, 1.5, or 3 mg/kg/day) to pregnant mice during the period of organogenesis, fetal growth retardation and malformations (including exencephaly and cleft palate) and embryofetal death were observed at the highest dose tested.

An increase in skeletal variations was observed at all but the lowest dose tested.

There was no evidence of maternal toxicity.

When cladribine was administered intravenously (0, 0.3, 1, and 3 mg/kg/day) to pregnant rabbits during the period of organogenesis, fetal growth retardation and a high incidence of craniofacial and limb malformations were observed at the highest dose tested, in the absence of maternal toxicity.

When cladribine was administered intravenously (0, 0.5, 1.5, or 3 mg/kg/day) to mice throughout pregnancy and lactation, skeletal anomalies and embryolethality were observed at all but the lowest dose tested.

The safety and effectiveness in pediatric patients (below 18 years of age) have not been established.

Use of cladribine is not recommended in pediatric patients because of the risk of malignancies.

Clinical studies with cladribine did not include sufficient numbers of patients aged and over to determine whether they respond differently from younger patients.

Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

Caution is recommended when cladribine is used in elderly patients, taking into account the potential greater frequency of decreased hepatic, renal, or cardiac function, concomitant diseases, and other drug therapy.