Mavenclad

— THERAPEUTIC CATEGORIES —
  • Multiple sclerosis
PAGE CONTENTS
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  • Generic Name & Formulations
  • Indications
  • Dosage and Administration
  • Contraindications
  • Boxed Warnings
  • Warnings/Precautions
  • Pharmacokinetics
  • Interactions
  • Adverse Reactions
  • Clinical Trials
  • Note
  • Patient Counseling

    • Mavenclad Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Cladribine 10mg; tabs.

    Pharmacological Class

    Chlorinated purine nucleoside analog.

    How Supplied

    Tabs—4, 5, 6, 7, 8, 9, 10

    How Supplied

    Mavenclad tablets, 10 mg, are uncoated, white, round, biconvex, and engraved with a "C" on one side and “10” on the other side. Each tablet is packaged in a child-resistant day pack containing one or two tablets in a blister card. 

    Presentations

    • 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. 

    Storage

    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) [see USP Controlled Room Temperature]. Store in original package in order to protect from moisture. 

    Follow applicable special handling and disposal procedures.

    Manufacturer

    EMD Serono, Inc.

    Generic Availability

    NO

    Mavenclad Indications

    Indications

    Relapsing forms of multiple sclerosis (MS), including relapsing-remitting disease and active secondary progressive disease.

    Limitations of Use

    Not for use in clinically isolated syndrome (CIS).

    Mavenclad Dosage and Administration

    Prior to Treatment Evaluations

    Assessments prior to starting each Mavenclad treatment course

    • Cancer screening: Follow standard cancer screening guidelines because of the risk of malignancies.

    • Pregnancy: Exclude status prior to treatment in females of reproductive potential.

    • Complete blood count (CBC): Obtain CBC with differential including lymphocyte count. Lymphocytes must be: within normal limits before initiating the first treatment course, and at least 800 cells per microliter before initiating the second treatment course.

      • If needed, 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 Mavenclad.

    • Infections:

      • Exclude HIV infection.

      • Perform tuberculosis screening.

      • Screen for hepatitis B and C. 

      • Evaluate for acute infection. Consider a delay in Mavenclad treatment until any acute infection is fully controlled.

      • Vaccinate patients who are seronegative for VZV is recommended prior to initiating Mavenclad.

      • Vaccinate patients who are seropositive to VZV is recommended with zoster vaccine recombinant, adjuvanted. May administer zoster vaccine recombinant, adjuvanted at any time prior to or during the year 1 or year 2 course of Mavenclad treatment. May also administer the vaccine if lymphocyte counts ≤ 500 cells per microliter.

      • Give all immunizations (except as noted for VZV) according to guidelines prior to starting treatment, and at least 4 to 6 weeks prior to starting treatment for live-attenuated or live vaccines.

      • Obtain baseline MRI within 3 months prior to the first treatment course due to the risk of PML.

    • Liver Injury:

      • Obtain serum aminotransferase, alkaline phosphatase, and total bilirubin levels.

    Adult

    See full labeling. Give 3.5mg/kg cumulative dose divided into 2 yearly treatment courses (1.75mg/kg per treatment course). ≥18yrs: Swallow whole. Each cycle: give 1–2 tabs once daily over 4–5 consecutive days. First course/first cycle: start at any time; first course/second cycle: give 23–27 days after the last dose of first course/first cycle. Second course/first cycle: give ≥43 weeks after the last dose of first course/second cycle; second course/second cycle: give 23–27 days after the last dose of second course/first cycle. 40–<50kg: 4 tabs per cycle; 50–<60kg: 5 tabs per cycle; 60–<70kg: 6 tabs per cycle; 70–<80kg: 7 tabs per cycle; 80–<90kg: 8 tabs in first cycle, then 7 tabs in second cycle; 90–<100kg: 9 tabs in first cycle, then 8 tabs in second cycle; 100–<110kg: 10 tabs in first cycle, then 9 tabs in second cycle; ≥110kg: 10 tabs per cycle. Give herpes prophylaxis if lymphocycte counts <200cells/mcL. Additional treatment after completion of 2 treatment courses: not recommended for next 2 years.

    Adult

    • Give anti-herpes prophylaxis if lymphocyte counts <200 cells per microliter.

    • Give 3.5 mg/kg cumulative dose divided into 2 yearly treatment courses (1.75 mg/kg per treatment course). Swallow whole. Each cycle: give 1–2 tabs once daily over 4–5 consecutive days. 

    • Administration of First Treatment Course

      • First Course/First Cycle: start any time. 

      • First Course/Second Cycle: administer 23 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. 

      • Second Course/Second Cycle: administer 23 to 27 days after the last dose of Second Course/First Cycle.  

    • Dose of Mavenclad per cycle by patient weight in each treatment course:

      • 40–<50 kg: 4 tabs per cycle; 

      • 50–<60 kg: 5 tabs per cycle; 

      • 60–<70 kg: 6 tabs per cycle; 

      • 70–<80 kg: 7 tabs per cycle; 

      • 80–<90 kg: 8 tabs in first cycle, then 7 tabs in second cycle; 

      • 90–<100 kg: 9 tabs in first cycle, then 8 tabs in second cycle; 

      • 100–<110 kg: 10 tabs in first cycle, then 9 tabs in second cycle; 

      • ≥110 kg: 10 tabs per cycle. 

    • Additional treatment after completion of 2 treatment courses: not recommended for next 2 years. Increased risk of malignancy during these 2 years if Mavenclad is used. Safety and efficacy of reinitiating Mavenclad more than 2 years after completing 2 treatment courses has not been studied.

    • Missed Dose: Do not take double or extra doses if a dose is missed. If a dose is not taken on the scheduled day, take the missed dose on the following day and extend the number of days in that treatment cycle. If 2 consecutive doses are missed, extend the treatment cycle by 2 days.

    Children

    <18yrs: not recommended.

    Mavenclad Contraindications

    Contraindications

    Current malignancy. Pregnancy. Men and women of reproductive potential (without plans to use effective contraception during and for 6 months after last dose in each course). Nursing mothers (who plan to breastfeed on treatment day and for 10 days after last dose). HIV infection. Active chronic infections (eg, hepatitis, TB).

    Mavenclad Boxed Warnings

    Boxed Warning

    Malignancies. Risk of teratogenicity.

    Boxed Warning

    Malignancies 

    • Increased risk of malignancy. Contraindicated in patients with current malignancy.

    • Evaluate benefits and risks on an individual basis of patients with prior or increased risk of malignancy. Follow standard cancer screening guidelines.

    Risk of Teratogenicity

    • Contraindicated for use in pregnant women and in women and men of reproductive potential who do not plan to use effective contraception because of the risk of fetal harm.

    • Exclude pregnancy before initiating treatment in females of reproductive potential.

    • Advise females and males of reproductive potential to use effective contraception during and for 6 months after the last dose. Discontinue if patient becomes pregnant.

    Mavenclad Warnings/Precautions

    Warnings/Precautions

    Perform cancer screening according to guidelines prior to each course. Prior malignancy or increased risk of malignancy: evaluate benefits/risks. Risk of lymphopenia and hematologic toxicity; obtain CBC with differential (include lymphocyte counts) prior to, during, and after treatment. Exclude HIV infection prior to initiation. Screen for TB, hepatitis prior to first and second courses. Evaluate for acute infection; consider delaying start until fully controlled. Test for antibodies to varicella zoster virus; if negative, give vaccination prior to initiating cladribine; see full labeling. If lymphocyte counts <500cells/mcL: monitor for infections (eg, herpes) and treat. Administer all immunizations (except as noted for VZV) according to immunization guidelines prior to starting cladribine. Obtain baseline MRI (within 3 months) prior to first course due to risk of progressive multifocal leukoencephalopathy (PML); withhold and evaluate if signs/symptoms occur. Graft-versus-host disease with blood transfusion: irradiation of cellular blood component is recommended. Obtain serum AST/ALT, total bilirubin prior to first and second course. Interrupt or discontinue treatment if hepatic dysfunction is suspected. Cardiac failure. Moderate to severe renal or hepatic impairment: not recommended. Elderly. Risk of teratogenicity. Advise females and males (w. female partners) of reproductive potential to use effective contraception during and for ≥6 months after the last dose in each treatment course. Pregnancy: exclude status before initiation; discontinue if occurs during treatment. Nursing mothers: not recommended (during and for 10 days after the last dose).

    Warnings/Precautions

    Malignancies

    • Increased risk of malignancy. Contraindicated in patients with current malignancy.

    • Evaluate benefits and risks on an individual basis of patients with prior or increased risk of malignancy. Follow standard cancer screening guidelines.

    Risk of Teratogenicity

    • Contraindicated for use in pregnant women and in women and men of reproductive potential who do not plan to use effective contraception because of the risk of fetal harm.

    • Exclude pregnancy before initiating treatment in females of reproductive potential.

    • Advise females and males of reproductive potential to use effective contraception during and for 6 months after the last dose. Discontinue if patient becomes pregnant.

    Lymphopenia

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

    Infections

    • Exclude HIV infection, active tuberculosis, and active hepatitis before initiation of each treatment course of Mavenclad.

    • Consider a delay in initiation of Mavenclad in patients with an acute infection until infection is fully controlled.

    • Initiating Mavenclad in patients taking immunosuppressive or myelosuppressive therapy: not recommended. Concomitant use with these therapies may increase the risk of immunosuppression.

    • Tuberculosis:

      • Prior to initiation of the first and second treatment course, perform tuberculosis screening. Latent TB infections may be activated with the use of Mavenclad.

      • Delay initiating Mavenclad in patients with TB infection until the infection has been adequately treated.

    • Hepatitis:

      • Screen for hepatitis B and C prior to initiating the first and second treatment course of Mavenclad. Latent hepatitis infections may be activated.

      • Carriers of hepatitis B or C may be at risk of irreversible liver damage.

      • Delay initiating Mavenclad in patients with hepatitis until the infection has been adequately treated.

    • Herpes Virus Infections:

      • Prior to initiation, vaccinating patients who are seronegative for VZV is recommended. Give live-attenuated or live vaccines at least 4 to 6 weeks prior to initiating.

      • Vaccinating patients who are seropositive to VZV is recommended with zoster vaccine recombinant, adjuvanted, either prior to or during Mavenclad treatment, including if lymphocyte counts ≤500 cells per microliter.

      • Give anti-herpes prophylaxis in patients with lymphocyte counts <200 cells per microliter.

      • Monitor for signs/symptoms suggestive of infections, including herpes infections, in patients with lymphocyte counts <500 cells per microliter. Initiate treatment as clinically indicated if signs and symptoms occur. Consider interrupting or delaying Mavenclad until infection resolves.

    • Progressive Multifocal Leukoencephalopathy (PML):

      • Obtain a baseline (within 3 months) MRI before initiating the first treatment course. Withhold and perform an appropriate diagnostic evaluation at the first sign or symptom suggestive of PML.

    • Vaccinations:

      • Give all immunizations (except as noted for VZV) according to immunization guidelines prior to starting Mavenclad.

      • Administer live-attenuated or live vaccines at least 4 to 6 weeks prior to starting Mavenclad, because of a risk of active vaccine infection (see Herpes Virus Infections). 

      • Avoid vaccination with live-attenuated or live vaccines during and after Mavenclad treatment while the patient’s white blood cell counts are not within normal limits.

    Hematologic Toxicity 

    • Obtain CBC with differential prior to, during, and after treatment with Mavenclad.

    Graft-Versus-Host Disease With Blood Transfusion

    • In patients who require blood transfusion, irradiation of cellular blood components is recommended prior to administration to decrease the risk of transfusion-related graft-versus-host disease. Consultation with a hematologist is advised.

    Liver Injury 

    • Obtain serum aminotransferase, alkaline phosphatase, and total bilirubin levels prior to the first and second treatment course.

    • If a patient develops clinical signs, including unexplained liver enzyme elevations or symptoms suggestive of hepatic dysfunction, promptly measure serum transaminases and total bilirubin and interrupt or discontinue treatment with Mavenclad, as appropriate. 

    Hypersensitivity

    • Discontinue Mavenclad therapy if a hypersensitivity reaction is suspected.

    Cardiac Failure

    • Seek medical advice if symptoms of cardiac failure occur (e.g., shortness of breath, rapid or irregular heartbeat, swelling). 

    Pregnancy Considerations

    Risk Summary

    • Contraindicated in pregnant women and in females and males of reproductive potential who do not plan to use effective contraception.

    Nursing Mother Considerations

    Risk Summary

    • Contraindicated in breastfeeding women because of the potential for serious adverse reactions in breastfed infants.

    • Do not breastfeed during Mavenclad treatment and for 10 days after the last dose.

    Pediatric Considerations

    • Safety and effectiveness in patients <18 years of age have not been established.

    • Not recommended to use in pediatric patients due to the risk of malignancies.

    Geriatric Considerations

    • Use caution in elderly patients due to the potential greater frequency of decreased hepatic, renal, or cardiac function, concomitant diseases, and other drug therapy.

    Renal Impairment Considerations

    • Not recommended to use in patients with moderate to severe renal impairment (CrCL <60mL/min).

    Hepatic Impairment Considerations

    • Not recommended to use in patients with moderate to severe hepatic impairment (Child-Pugh score >6).

    Other Considerations for Specific Populations

    Females and Males of Reproductive Potential 

    • Pregnancy Testing: Exclude pregnancy status before the initiation of each treatment course.

    • Contraception: Advise females and males (w. female partners) of reproductive potential to use effective contraception during and for ≥6 months after the last dose in each treatment course.

    Mavenclad Pharmacokinetics

    Absorption

    The bioavailability of cladribine was approximately 40%. Following fasted administration of cladribine, the median time to maximum concentration (Tmax) was 0.5 h (range 0.5 to 1.5 hours).

    Distribution

    • Cladribine mean apparent volume of distribution ranges from 480 to 490 liters. 

    • The plasma protein binding of cladribine is 20% and is independent of concentration, in vitro. 

    • Intracellular concentrations of cladribine and/or its metabolites in human lymphocytes were approximately 30 to 40 times extracellular, in vitro. 

    • Cladribine has the potential to penetrate the blood brain barrier. A cerebrospinal fluid/plasma concentration ratio of approximately 0.25 was observed in cancer patients. 

    Metabolism

    Cladribine is a prodrug that is phosphorylated to Cd-AMP by deoxycytidine kinase (and also by deoxyguanosine kinase in the mitochondria) in lymphocytes. 

    Elimination

    Renal. Half-life: ~1 day. 

    Elimination

    • Terminal half-life is approximately 1 day. 

    • The intracellular half-life of the cladribine phosphorylated metabolites cladribine monophosphate (Cd-AMP) is 15 hours and CdATP is 10 hours.

    • Cladribine estimated median apparent renal clearance is 22.2 liter per hour and non-renal clearance is 23.4 liter per hour. 

    •  

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

    Mavenclad Interactions

    Interactions

    Concomitant myleosuppressive or other immunosuppressive therapy: not recommended. Give live-attenuated or live vaccines ≥4–6 weeks prior to treatment; avoid during and after treatment. Concomitant interferon-beta may increase lymphopenia risk: not recommended. Additive effects with hematotoxic drugs: monitor. Avoid concomitant drugs that require intracellular phosphorylation (eg, lamivudine, zalcitabine, ribavirin, stavudine, zidovudine). Avoid potent ENT1, CNT3, or BCRP transporter inhibitors (eg, ritonavir, eltrombopag, curcumin, cyclosporine, dilazep, nifedipine, nimodipine, cilostazol, sulindac, dipyridamole, reserpine) during the 4–5 day treatment cycles; if unavoidable, consider alternatives or reduce dose. May be antagonized by potent BCRP (eg, corticosteroids) or P-gp (eg, rifampicin, St John's wort) transporter inducers. Separate dosing with other oral drugs by ≥3hrs during the 4–5 day treatment cycles. Use additional barrier method with systemic hormonal contraceptives during and for ≥4 weeks after the last dose in each treatment course.

    Mavenclad Adverse Reactions

    Adverse Reactions

    Upper respiratory tract infection, headache, lymphopenia, nausea, back pain, arthralgia/arthritis, insomnia, bronchitis, hypertension, fever, depression; liver injury, hypersensitivity (discontinue if occurs).

    Mavenclad Clinical Trials

    Clinical Trials

    • The efficacy of Mavenclad  was evaluated in a 96-week randomized, double-blind, placebo-controlled clinical study (Study 1; NCT00213135) in 1326 patients with relapsing forms of MS who had at least 1 relapse in the previous 12 months. Patients were randomly assigned to receive either placebo (n=437) or a cumulative oral dosage of Mavenclad 3.5 mg/kg (n=433) or 5.25 mg/kg (n=456) for 96 weeks in 2 treatment courses.

    • The primary endpoint was the annulaized relapse rate (ARR). Additional outcome measures included the proportion of patients with confirmed disability progression, the time to first qualifying relapse, the mean number of MRI T1 Gadolinium-enhancing (Gd+) lesions, and new or enlarging MRI T2 hyperintense lesions. 

    • Results showed that treatment with Mavenclad 3.5 mg/kg achieved the following clinical outcomes at week 96 compared with placebo, respectively:

      • ARR: 0.14 vs 0.33 (P <.001); relative reduction, 58%

      • Proportion of patients without relapse: 81% vs 63% (nominal P <.05)

      • Time to 3-month confirmed EDSS progression, Hazard Ratio: 0.67 (nominal P <.05)

      • Proportion of patients with a 3-month EDSS progression: 13% vs 19%

      • Median number of active T1 Gd+ lesions: 0 vs 0.33 (P <.001)

      • Median number of active T2 lesions: 0 vs 0.67 (P <.001)

    Mavenclad Note

    Not Applicable

    Mavenclad Patient Counseling

    Patient Counseling

    Malignancies

    • May increase the risk of malignancies. Follow standard cancer screening guidelines.

    Risk of teratogenicity

    • May cause fetal harm. Discuss with women of childbearing age whether they are pregnant, might be pregnant, or are trying to become pregnant.

    • Advise females or partners of male patients to use effective contraception during and at least 6 months after the last dose in each treatment course.

    • Advise females using systemically acting hormonal contraceptives to add a barrier method during Mavenclad dosing and for at least 4 weeks after the last dose in each treatment course.

    Lactation

    • Do not breastfeed on treatment day and for 10 days after the last dose.

    Lymphopenia and Other Hematologic Toxicity

    • May decrease lymphocyte counts and may also decrease counts of other blood cells.

    • Obtain blood test before starting a treatment course, 2 and 6 months after starting, periodically thereafter, and as clinically needed.

    Infections

    • May increase the risk of infections including PML. PML is characterized by a progression of deficits and can lead to death or severe disability.

    • Notify health care provider if fever or other signs of infections occur.

    • Avoid live vaccinations during and after treatment. Advise patients to complete any live or live-attenuated vaccinations at least 4 to 6 weeks prior to initiation of Mavenclad. 

    Liver Injury 

    • May cause liver injury. Promptly report any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice.

    • Obtain a blood test prior to each treatment course and as clinically indicated.

    Hypersensitivity

    • Seek immediate medical attention if they experience any symptoms of serious or severe hypersensitivity reactions, including skin reactions.

    Cardiac Failure

    • May cause cardiac failure. Seek medical advice if they experience symptoms of cardiac failure (e.g., shortness of breath, rapid or irregular heartbeat, swelling). 

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