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Consider MAVENCLAD

MAVENCLAD is approved to treat relapsing-remitting and active secondary progressive multiple sclerosis.

Indication

MAVENCLAD is indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include relapsing-remitting disease and active secondary progressive disease, in adults. Because of its safety profile, use of MAVENCLAD 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.

Limitations of Use: MAVENCLAD is not recommended for use in patients with clinically isolated syndrome (CIS) because of its safety profile.

MAVENCLAD was studied in a Phase III pivotal trial: CLARITY1,2

CLARITY was a Phase III, multicenter, randomized, double-blind trial of MAVENCLAD versus placebo in patients with relapsing-remitting multiple sclerosis (MS). Patients were eligible if they met certain criteria, including at least 1 MS relapse within the past 12 months, EDSS scores ≤5.5, and <2 prior DMT failures. Out of 1,326 patients, 1,184 patients completed the study at 2 years (96 weeks).2 Endpoints at 2 years included:

Primary endpoint2: Annualized relapse rate

Key secondary endpoints2: Proportion of relapse-free patients; time to 3-month confirmed disability progression; mean number of active T1-Gd+ and active T2 lesions.

DMT: disease-modifying therapy; EDSS: Expanded Disability Status Scale.


Proven efficacy

In the CLARITY trial, MAVENCLAD demonstrated efficacy1:

58% of MAVENCLAD® patients experienced relative reduction in ARR at 2 years
33% of MAVENCLAD® patients experienced a reduction in risk of three month confirmed EDSS progression

*Nominal P value.


MAVENCLAD® showed zero reduction in median number of active t1-Gd+ lesions compared to a placebo

MAVENCLAD® showed zero reduction in median number of active T2 lesions compared to a placebo

Significant reduction in mean number of active T1-Gd+ and T2 lesions2

The mean number of T1-Gd+ lesions were reduced by 86% with MAVENCLAD®

Relative reduction in mean number of active T1-Gd+ lesions

MAVENCLAD 0.12 (n=433) vs 0.91 placebo (n=437); P<0.0012

73% relative reduction in the mean number of active T2 lesions with MAVENCLAD®

Relative reduction in mean number of active T2 lesions

MAVENCLAD 0.38 (n=433) vs 1.43 placebo (n=437); P<0.0012

ARR: annualized relapse rate; CI: confidence interval; EDSS: Expanded Disability Status Scale; HR: hazard ratio; T1-Gd+: T1 gadolinium-enhanced.


Efficacy in active SPMS: post hoc subgroup analyses of CLARITY

One proposed definition for active secondary progressive MS (SPMS) is that relapsing MS patients with an EDSS score of ≥3.5 can serve as a proxy of active SPMS.3-6 Approximately 40% of patients from CLARITY met this criterion (n=335/870; placebo and MAVENCLAD 3.5 mg/kg).7

In this baseline EDSS ≥3.5 patient subgroup, MAVENCLAD demonstrated:

57% of MAVENCLAD® patients experienced a relative reduction in ARR

Well-characterized safety and tolerability profile

In the clinical trial program of cladribine in MS:

  • 1,976 patients received cladribine for a total of 9,509 patient-years
  • The mean time on study including follow-up was ≈4.8 years
  • ≈24% of cladribine-treated patients had ≈8 years of time on study including follow-up.1†

In the pivotal trial, 3.5% of patients receiving MAVENCLAD discontinued treatment due to adverse reactions vs 2.1% of patients receiving placebo.2 92% of patients treated with MAVENCLAD completed the full 96 weeks of the study vs 87% of patients receiving placebo.1

Includes data from studies of oral and parenteral forms of cladribine.

 

In up to 8 years of safety-registry follow-up, no cases of progressive multifocal leukoencephalopathy (PML) have been reported in MS.1‡

In patients treated with parenteral cladribine for oncologic indications, cases of PML have been reported in the postmarketing setting.1

Through March 29, 2019.

Adverse reactions ≥5% for MAVENCLAD and higher than placebo in CLARITY1
Chart showing MAVENCLAD® adverse reactions

Lymphopenia1

 

In clinical studies, 87% of MAVENCLAD patients experienced lymphopenia. The lowest absolute lymphocyte counts occurred approximately 2 to 3 months after the start of each treatment course and were lower with each additional treatment course. The median time to recovery to at least 800 cells per microliter was approximately 28 weeks. 

Percentages of patients and their lymphocyte counts

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 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 MAVENCLAD. 

Malignancy1

 

In controlled and extension clinical studies worldwide, malignancies occurred more frequently with MAVENCLAD (10 events in 3,754 patient-years) compared with placebo (3 events in 2,275 patient-years).

The incidence of malignancies in MAVENCLAD clinical study patients in the United States was higher than the rest of the world (4 events in 189 patient-years [2.21 events per 100 patient-years] compared to 0 events in United States placebo patients). However, the United States results were based on a limited amount of patient data.

After the completion of 2 treatment courses, do not administer additional MAVENCLAD treatment during the next 2 years. Treatment during these 2 years may further increase the risk of malignancy. MAVENCLAD is contraindicated in patients with current malignancy. In patients with prior malignancy or with increased risk of malignancy, evaluate the benefits and risks of the use of MAVENCLAD on an individual patient basis. Follow standard cancer screening guidelines in patients treated with MAVENCLAD.

Malignancy rates compared to placebo1
Bar graph showing unique events of malignancy in MAVENCLAD® patients compared to those taking placebo

Teratogenicity1

 

In females of reproductive potential, pregnancy should be excluded before initiation of each treatment course of MAVENCLAD and prevented by the use of effective contraception during MAVENCLAD dosing and for at least 6 months after the last dose of each treatment course. Women who become pregnant during treatment with MAVENCLAD should discontinue treatment.

MAVENCLAD may cause fetal harm when administered to pregnant women. Malformations and embryolethality occurred in animals. MAVENCLAD is contraindicated for use in pregnant women and in women and men of reproductive potential who do not plan to use effective contraception.

Infections1

 

MAVENCLAD can reduce the body's immune defense and may increase the likelihood of infections.

  • Infections occurred in 49% of patients on MAVENCLAD compared to 44% on placebo. The most frequent serious infections in MAVENCLAD patients included herpes zoster and pyelonephritis
  • HIV infection, active tuberculosis, and active hepatitis must be excluded before initiating MAVENCLAD
  • Patients should also be screened for latent infections, particularly tuberculosis and hepatitis B and C, before treatment initiation in both treatment years 
  • Three of 1,976 (0.2%) cladribine-treated patients in the clinical program developed tuberculosis. All 3 cases occurred in regions where tuberculosis is endemic. One case of tuberculosis was fatal, and 2 cases resolved with treatment
  • 6% of patients on MAVENCLAD developed a herpes viral infection compared to 2% on placebo
  • Patients who are antibody-negative to varicella zoster virus should be vaccinated prior to treatment. Administer live-attenuated or live vaccines at least 4 to 6 weeks prior to starting MAVENCLAD

FDA approves MAVENCLAD

View Press Release

IMPORTANT SAFETY INFORMATION

WARNING: MALIGNANCIES and RISK OF TERATOGENICITY

  • Treatment with MAVENCLAD may increase the risk of malignancy. MAVENCLAD is contraindicated in patients with current malignancy. In patients with prior malignancy or with increased risk of malignancy, evaluate the benefits and risks of the use of MAVENCLAD on an individual patient basis. Follow standard cancer screening guidelines in patients treated with MAVENCLAD
  • MAVENCLAD is 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 potential for fetal harm. Malformations and embryolethality occurred in animals. Exclude pregnancy before the start of treatment with MAVENCLAD in females of reproductive potential. Advise females and males of reproductive potential to use effective contraception during MAVENCLAD dosing and for 6 months after the last dose in each treatment course. Stop MAVENCLAD if the patient becomes pregnant

 

CONTRAINDICATIONS

  • Patients with current malignancy.
  • Pregnant women, and women and men of reproductive potential who do not plan to use effective contraception during and for 6 months after the last dose in each treatment course. May cause fetal harm.
  • Patients with human immunodeficiency virus (HIV).
  • Patients with active chronic infections (e.g., hepatitis or tuberculosis).
  • Patients with a history of hypersensitivity to cladribine.
  • Women intending to breastfeed while taking MAVENCLAD tablets and for 10 days after the last dose.

 

WARNINGS AND PRECAUTIONS

  • Malignancies: Treatment with MAVENCLAD may increase the risk of malignancy. After the completion of 2 treatment courses, do not administer additional MAVENCLAD treatment during the next 2 years. The risk of malignancy with reinitiating MAVENCLAD more than 2 years after the completion of 2 treatment courses has not been studied. Follow standard cancer screening guidelines in patients treated with MAVENCLAD.
  • Risk of Teratogenicity: MAVENCLAD may cause fetal harm when administered to pregnant women. In females of reproductive potential, exclude pregnancy before initiation of each treatment course of MAVENCLAD and prevent by the use of effective contraception during MAVENCLAD dosing and for at least 6 months after the last dose of each treatment course. Women who become pregnant during treatment with MAVENCLAD should discontinue treatment.
  • Lymphopenia: MAVENCLAD causes a dose-dependent reduction in lymphocyte count. In clinical studies, 87% of MAVENCLAD-treated patients experienced lymphopenia. The lowest absolute lymphocyte counts occurred approximately 2 to 3 months after the start of each treatment course and were lower with each additional treatment course. Concomitant use of MAVENCLAD with hematotoxic drugs may increase the risk of adverse reactions because of the additive hematological effects. Monitor lymphocyte counts before and during treatment, periodically thereafter, and when clinically indicated.
  • Infections: MAVENCLAD can reduce the body's immune defense and may increase the likelihood of infections. Infections occurred in 49% of MAVENCLAD-treated patients compared to 44% of patients treated with placebo in clinical studies. The most frequent serious infections included herpes zoster and pyelonephritis. Single fatal cases of tuberculosis and fulminant hepatitis B were reported in the clinical program. Administer live-attenuated or live vaccines at least 4 to 6 weeks prior to starting MAVENCLAD. Screen patients for latent infections; consider delaying treatment until infection is fully controlled. Vaccinate patients antibody-negative to varicella zoster virus prior to treatment. Administer anti-herpes prophylaxis in patients with lymphocyte counts less than 200 cells per microliter. Monitor for infections. In patients treated with parenteral cladribine for oncologic indications, cases of progressive multifocal leukoencephalopathy (PML) have been reported. No case of PML has been reported in clinical studies of cladribine in patients with MS.
  • Hematologic Toxicity: In addition to lymphopenia, decreases in other blood cells and hematological parameters have been reported with MAVENCLAD in clinical studies. In general, mild to moderate decreases in neutrophil counts, hemoglobin levels, and platelet counts were observed. Severe decreases in neutrophil counts were observed in 3.6% of MAVENCLAD-treated patients, compared to 2.8% of placebo patients. Obtain complete blood count (CBC) with differential including lymphocyte count before and during treatment, periodically thereafter, and when clinically indicated.
  • Risk of Graft-versus-Host Disease With Blood Transfusions: Transfusion-associated graft-versus-host disease has been observed rarely after transfusion of nonirradiated blood in patients treated with cladribine for non-MS treatment indications.
  • Liver Injury: In clinical studies, 0.3% of MAVENCLAD-treated patients had liver injury (serious or causing treatment discontinuation) compared to 0 placebo patients. Obtain serum aminotransferase, alkaline phosphatase, and total bilirubin levels prior to treatment. Discontinue if clinically significant injury is suspected.
  • Hypersensitivity: In clinical studies, 11% of MAVENCLAD-treated patients had hypersensitivity reactions, compared to 7% of placebo patients. Hypersensitivity reactions that were serious and/or led to discontinuation of MAVENCLAD, occurred in 0.5% of MAVENCLAD-treated patients, compared to 0.1% of placebo patients. If a hypersensitivity reaction is suspected, discontinue MAVENCLAD therapy. Do not use MAVENCLAD in patients with a history of hypersensitivity to cladribine.
  • Cardiac Failure: In clinical studies, one MAVENCLAD-treated patient experienced life-threatening acute cardiac failure with myocarditis, which improved after approximately one week. Cases of cardiac failure have also been reported with parenteral cladribine used for treatment indications other than multiple sclerosis.

 

Adverse Reactions: The most common adverse reactions with an incidence of >20% for MAVENCLAD are upper respiratory tract infection, headache, and lymphopenia.

 

Drug Interactions/Concomitant Medication: Concomitant use of MAVENCLAD with immunosuppressive or myelosuppressive drugs and some immunomodulatory drugs (e.g., interferon beta) is not recommended and may increase the risk of adverse reactions. Acute short-term therapy with corticosteroids can be administered.


Avoid concomitant use of certain antiviral and antiretroviral drugs. Avoid concomitant use of BCRP or ENT/CNT inhibitors as they may alter bioavailability of MAVENCLAD.

 

Use in Specific Populations: Studies have not been performed in pediatric or elderly patients, pregnant or breastfeeding women. Use in patients with moderate to severe renal or hepatic impairment is not recommended.

 

Please see the full Prescribing Information, including boxed WARNING for additional information.

INDICATION

MAVENCLAD® (cladribine) tablets is indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include relapsing-remitting disease and active secondary progressive disease, in adults. Because of its safety profile, use of MAVENCLAD 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.

Limitations of Use: MAVENCLAD is not recommended for use in patients with clinically isolated syndrome (CIS) because of its safety profile.

IMPORTANT SAFETY INFORMATION

WARNING: MALIGNANCIES and RISK OF TERATOGENICITY

  • Treatment with MAVENCLAD may increase the risk of malignancy. MAVENCLAD is contraindicated in patients with current malignancy. In patients with prior malignancy or with increased risk of malignancy, evaluate the benefits and risks of the use of MAVENCLAD on an individual patient basis. Follow standard cancer screening guidelines in patients treated with MAVENCLAD
  • MAVENCLAD is 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 potential for fetal harm. Malformations and embryolethality occurred in animals. Exclude pregnancy before the start of treatment with MAVENCLAD in females of reproductive potential. Advise females and males of reproductive potential to use effective contraception during MAVENCLAD dosing and for 6 months after the last dose in each treatment course. Stop MAVENCLAD if the patient becomes pregnant

 

CONTRAINDICATIONS

  • Patients with current malignancy.
  • Pregnant women, and women and men of reproductive potential who do not plan to use effective contraception during and for 6 months after the last dose in each treatment course. May cause fetal harm.
  • Patients with human immunodeficiency virus (HIV).
  • Patients with active chronic infections (e.g., hepatitis or tuberculosis).
  • Patients with a history of hypersensitivity to cladribine.
  • Women intending to breastfeed while taking MAVENCLAD tablets and for 10 days after the last dose.

 

WARNINGS AND PRECAUTIONS

  • Malignancies: Treatment with MAVENCLAD may increase the risk of malignancy. After the completion of 2 treatment courses, do not administer additional MAVENCLAD treatment during the next 2 years. The risk of malignancy with reinitiating MAVENCLAD more than 2 years after the completion of 2 treatment courses has not been studied. Follow standard cancer screening guidelines in patients treated with MAVENCLAD.
  • Risk of Teratogenicity: MAVENCLAD may cause fetal harm when administered to pregnant women. In females of reproductive potential, exclude pregnancy before initiation of each treatment course of MAVENCLAD and prevent by the use of effective contraception during MAVENCLAD dosing and for at least 6 months after the last dose of each treatment course. Women who become pregnant during treatment with MAVENCLAD should discontinue treatment.
  • Lymphopenia: MAVENCLAD causes a dose-dependent reduction in lymphocyte count. In clinical studies, 87% of MAVENCLAD-treated patients experienced lymphopenia. The lowest absolute lymphocyte counts occurred approximately 2 to 3 months after the start of each treatment course and were lower with each additional treatment course. Concomitant use of MAVENCLAD with hematotoxic drugs may increase the risk of adverse reactions because of the additive hematological effects. Monitor lymphocyte counts before and during treatment, periodically thereafter, and when clinically indicated.
  • Infections: MAVENCLAD can reduce the body's immune defense and may increase the likelihood of infections. Infections occurred in 49% of MAVENCLAD-treated patients compared to 44% of patients treated with placebo in clinical studies. The most frequent serious infections included herpes zoster and pyelonephritis. Single fatal cases of tuberculosis and fulminant hepatitis B were reported in the clinical program. Administer live-attenuated or live vaccines at least 4 to 6 weeks prior to starting MAVENCLAD. Screen patients for latent infections; consider delaying treatment until infection is fully controlled. Vaccinate patients antibody-negative to varicella zoster virus prior to treatment. Administer anti-herpes prophylaxis in patients with lymphocyte counts less than 200 cells per microliter. Monitor for infections. In patients treated with parenteral cladribine for oncologic indications, cases of progressive multifocal leukoencephalopathy (PML) have been reported. No case of PML has been reported in clinical studies of cladribine in patients with MS.
  • Hematologic Toxicity: In addition to lymphopenia, decreases in other blood cells and hematological parameters have been reported with MAVENCLAD in clinical studies. In general, mild to moderate decreases in neutrophil counts, hemoglobin levels, and platelet counts were observed. Severe decreases in neutrophil counts were observed in 3.6% of MAVENCLAD-treated patients, compared to 2.8% of placebo patients. Obtain complete blood count (CBC) with differential including lymphocyte count before and during treatment, periodically thereafter, and when clinically indicated.
  • Risk of Graft-versus-Host Disease With Blood Transfusions: Transfusion-associated graft-versus-host disease has been observed rarely after transfusion of nonirradiated blood in patients treated with cladribine for non-MS treatment indications.
  • Liver Injury: In clinical studies, 0.3% of MAVENCLAD-treated patients had liver injury (serious or causing treatment discontinuation) compared to 0 placebo patients. Obtain serum aminotransferase, alkaline phosphatase, and total bilirubin levels prior to treatment. Discontinue if clinically significant injury is suspected.
  • Hypersensitivity: In clinical studies, 11% of MAVENCLAD-treated patients had hypersensitivity reactions, compared to 7% of placebo patients. Hypersensitivity reactions that were serious and/or led to discontinuation of MAVENCLAD, occurred in 0.5% of MAVENCLAD-treated patients, compared to 0.1% of placebo patients. If a hypersensitivity reaction is suspected, discontinue MAVENCLAD therapy. Do not use MAVENCLAD in patients with a history of hypersensitivity to cladribine.
  • Cardiac Failure: In clinical studies, one MAVENCLAD-treated patient experienced life-threatening acute cardiac failure with myocarditis, which improved after approximately one week. Cases of cardiac failure have also been reported with parenteral cladribine used for treatment indications other than multiple sclerosis.

 

Adverse Reactions: The most common adverse reactions with an incidence of >20% for MAVENCLAD are upper respiratory tract infection, headache, and lymphopenia.

 

Drug Interactions/Concomitant Medication: Concomitant use of MAVENCLAD with immunosuppressive or myelosuppressive drugs and some immunomodulatory drugs (e.g., interferon beta) is not recommended and may increase the risk of adverse reactions. Acute short-term therapy with corticosteroids can be administered.


Avoid concomitant use of certain antiviral and antiretroviral drugs. Avoid concomitant use of BCRP or ENT/CNT inhibitors as they may alter bioavailability of MAVENCLAD.

 

Use in Specific Populations: Studies have not been performed in pediatric or elderly patients, pregnant or breastfeeding women. Use in patients with moderate to severe renal or hepatic impairment is not recommended.

 

Please see the full Prescribing Information, including boxed WARNING for additional information.

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