-------------------------------CONTRAINDICATIONS------------------------------
` Patients with current malignancy. (4)
` Pregnant women, and women and men of reproductive potential who do
`not plan to use effective contraception during MAVENCLA D dosing and
`for 6 months after the last dose in each treatment course. (4, 8.3)
` HIV infection. (4)
` Active chronic infections (e.g., hepatitis or tuberculosis). (4)
` History of hypersensitivity to cladribine. (4, 5.8)
` Women intending to breastfeed on a MAVENCLAD treatment day and for
`10 days after the last dose. (4, 8.2)
`
`
` -----------------------WARNINGS AND PRECAUTIONS ------------------------
` Lymphopenia: Monitor lymphocyte counts before, during and after
`treatment. (5.3)
` Infections: 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. (5.4)
` Hematologic toxicity: Monitor complete blood count before, during and
`after treatment. (5.5)
` Graft-versus-host-disease with blood transfusion: Irradiation of cellular
`blood components is recommended. (5.6)
` Liver injury: Obtain tests prior to treatment. Discontinue if clinically
`significant injury is suspected. (5.7)
`
`
`
`------------------------------ADVERS E REACTIONS-------------------------------
`Most common adverse reactions (incidence > 20%) are upper respiratory tract
`infection, headache, and lymphopenia. (6.1)
`
`To report SUSPECTED ADVERS E REACTIONS, contact EMD Serono
`at 1-800-283-8088 ext. 5563 or FDA at 1-800-FDA-1088 or
`www.fda.gov/ me dwatch.
`
`-------------------------------DRUG INTERACTIONS------------------------------
` Immunosuppressive drugs: Consider overlapping effects on immune
`system, when used sequentially. Concomitant use not recommended. (7.1)
` Hematotoxic drugs: Monitor patients for additive effects on the
`hematological profile. (7.3)
` Antiviral and antiretroviral drugs: Avoid concomitant use. (7.4)
` BCRP or ENT/CNT inhibitors: May alter bioavailability of cladribine.
`Avoid concomitant use. (7.5)
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`Guide.
`
`
`
`
`
`
`
`
`
`
`Revised: 3/2019
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`MAVENCLAD safely and effectively. See full prescribing information for
`MAVENCLAD.
`
`MAVENCLAD® (cladribine) tablets, for oral use
`Initial U S. Approval: 1993
`
`WARNING: MALIGNANCIES and RISK OF TERATOGENICITY
`See full prescribing information for complete boxed warning.
`
`
` Malignancies
`MAVENCLAD may increase the risk of malignancy. MAVENCLAD
`is contraindicate d in patients with current malignancy; evaluate the
`benefits and risks on an individual basis for patients with prior or
`increased risk of malignancy. (5.1)
`
` 
`
`
`Risk of Teratogenicity
`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 risk of fetal harm. (5.2)
`
`
`----------------------------INDICATIONS AND USAGE---------------------------
`MAVENCLAD is a purine antimetabolite 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 [see Warnings and Precautions (5)] .
`(1)
`
`Limitations of Use
`MAVENCLAD is not recommended for use in patients with clinically isolated
`syndrome (CIS) because of its safety profile [see Warnings and Precautions
`(5)]. (1)
`----------------------DOSAGE AND ADMINIS TRATION-----------------------
` Assessments are required prior to starting each MAVENCLAD treatment
`course. (2.1)
` 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. (2 2)
` MAVENCLAD is a cytotoxic drug. (2.4)
` Separate administration from any other oral drug by at least 3 hours. (2.4)
`
`
`---------------------DOSAGE FORMS AND STRENGTHS ----------------------
`Tablets: 10 mg (3)
`
`
`________________________________________________________________________________________________________ _______________________________
`
`
`
`
`
`
`1
`
`Biogen Exhibit 2145
`Mylan v. Biogen
`IPR 2018-01403
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`

`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`WARNING: MALIGNANCIES and RISK OF TERATOGENICITY
`1
`INDICATIONS AND USAGE
`2 DOSAGE AND ADMINISTRATION
`2 1 Assessments Prior to Starting Each MAVENCLAD Treatment
`Course
`2 2 Recommended Dosage
`2 3 Missed Dose
`2.4 Administration
`2 5 Laboratory Testing and Monitoring to Assess Safety
`2.6 Recommended Concomitant Medication
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5 1 Malignancies
`5 2 Risk of Teratogenicity
`5 3 Lymphopenia
`5.4
`Infections
`5 5 Hematologic Toxicity
`5.6 Risk of Graft-Versus-Host Disease With Blood Transfusions
`5.7 Liver Injury
`5.8 Hypersensitivity
`5 9 Cardiac Failure
`6 ADVERS E REACTIONS
`6 1 Clinical Trials Experience
`7 DRUG INTERACTIONS
`7 1
`Immunomodulatory, Immunosuppressive, or Myelosuppressive
`Drugs
`Interferon-Beta
`7 2
`7 3 Hematotoxic Drugs
`7.4 Antiviral and Antiretroviral Drugs
`7 5 Potent ENT, CNT, and BCRP Transporter Inhibitors
`7.6 Potent BCRP and P-gp Transporter Inducers
`7.7 Hormonal Contraceptives
`_____________________________________________________________________________________________________________________________ __________
`
` USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.2 Lactation
`8.3 Females and Males of Reproductive Potential
`8.4 Pediatric Use
`8.5 Geriatric Use
`8.6 Patients with Renal Impairment
`8.7 Patients with Hepatic Impairment
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12 1 Mechanism of Action
`12 2 Pharmacodynamics
`12 3 Pharmacokinetics
`12.6 Hydroxypropyl Betadex-Related Complex Formation
`13 NONCLINICAL TOXICOLOGY
`13 1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`15 REFERENCES
`16 HOW SUPPLIED/STORAGE AND HANDLING
`16 1 How Supplied
`16 2 Storage and Handling
`17 PATIENT COUNSELING INFORMATION
`
`*Sections or subsections omitted from the full prescribing information are not
`listed.
`
`
`
`
` 8
`
`2
`
`Page 2 of 28
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`

`
`
`FULL PRESCRIBING INFORMATION
`
`
`WARNING: MALIGNANCIES AND RISK OF TERATOGENICITY
`
` 
`
`
`Malignancies
`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 [see Contraindications (4) and Warnings and
`Precautions (5.1)].
`
` 
`
`
`Risk of Teratogenicity
`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 [see Contraindications (4),
`Warnings and Precautions (5.2), and Use in Specific Populations (8.1, 8.3)].
`
`
`INDICATIONS AND USAGE
`
` 1
`
`
`
`
`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 [see Warnings and Precautions (5)].
`
`Limitations of Use
`
`MAVENCLAD is not recommended for use in patients with clinically isolated syndrome (CIS)
`because of its safety profile [see Warnings and Precautions (5)].
`
`
`DOSAGE AND ADMINISTRATION
`
`
`
` 2
`
`Assessments Prior to Starting Each MAVENCLAD Treatment Course
`
`
`2.1
`
`Cancer Screening
`
`Follow standard cancer screening guidelines because of the risk of malignancies [see Boxed
`Warning and Warnings and Precautions (5.1)].
`
`
`3
`
`Page 3 of 28
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`

`

`
`
`Pregnancy
`
`Exclude pregnancy prior to treatment with MAVENCLAD in females of reproductive potential
`[see Contraindications (4), Warnings and Precautions (5.2), and Use in Specific Populations
`(8.1, 8.3)].
`
`Complete Blood Count (CBC)
`
`Obtain a CBC with differential including lymphocyte count [see Dosage and Administration
`(2.5) and Warnings and Precautions (5.3)]. 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 MAVENCLAD.
`
`Infections [see Warnings and Precautions (5.4)]
`
`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.
`
`Vaccination of patients who are antibody-negative for varicella zoster virus is
`recommended prior to initiation of MAVENCLAD.
`
`Administer all immunizations according to immunization guidelines prior to starting
`MAVENCLAD. Administer live-attenuated or live vaccines at least 4 to 6 weeks prior to
`starting MAVENCLAD.
`
`Obtain a baseline (within 3 months) magnetic resonance imaging prior to the first
`treatment course because of the risk of progressive multifocal leukoencephalopathy
`(PML).
`
` 
`
`
`
` 
`
`
`
` 
`
`
`
` 
`
`
`
` 
`
`
`
` 
`
`
`
` 
`
`
`
`
`Liver Injury
`
`Obtain serum aminotransferase, alkaline phosphatase, and total bilirubin levels [see Warnings
`and Precautions (5.7)].
`
`
`4
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`

`

`5
`
`
`
`Recommended Dosage
`
`2.2
`
`The recommended cumulative dosage of MAVENCLAD 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) (see Table 1). Each treatment course is divided into 2 treatment cycles:
`
`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.
`
` 
`
`
`
` 
`
`
`
`
`Table 1
`
`Dose of MAVENCLAD per Cycle by Patient Weight in Each Treatment
`Course
`
`Weight Range
`
`Dose in mg (Number of 10 mg Tablets) per Cycle
`
`kg
`
`First Cycle
`
`40* to less than 50
`
`40 mg (4 tablets)
`
`50 to less than 60
`
`50 mg (5 tablets)
`
`60 to less than 70
`
`70 to less than 80
`
`80 to less than 90
`
`60 mg (6 tablets)
`
`70 mg (7 tablets)
`
`80 mg (8 tablets)
`
`90 to less than 100
`
`90 mg (9 tablets)
`
`Second Cycle
`
`40 mg (4 tablets)
`
`50 mg (5 tablets)
`
`60 mg (6 tablets)
`
`70 mg (7 tablets)
`
`70 mg (7 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 MAVENCLAD 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 [see How
`Supplied/Storage and Handling (16.1)]. Do not administer more than 2 tablets daily.
`
`
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`

`
`
`Administration
`
`Following the administration 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 [see Warnings and Precautions (5.1)]. The safety and efficacy of
`reinitiating MAVENCLAD 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
`
`MAVENCLAD tablets are taken orally, with water, and swallowed whole without chewing.
`MAVENCLAD can be taken with or without food.
`
`Separate administration of MAVENCLAD and any other oral drugs by at least 3 hours during
`the 4 to 5 day MAVENCLAD treatment cycles [see Clinical Pharmacology (12.6)].
`
`MAVENCLAD is a cytotoxic drug. Follow applicable special handling and disposal procedures
`[see References (15)]. MAVENCLAD is 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
`
`Cancer Screening
`
`Follow standard cancer screening guidelines in patients treated with MAVENCLAD [see
`Dosage and Administration (2.1) and Warnings and Precautions (5.1)].
`
`
`Laboratory Testing and Monitoring to Assess Safety
`
`6
`
`Page 6 of 28
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`

`

`
`
`Complete Blood Count
`
`Obtain complete blood count (CBC) with differential including lymphocyte count:
`
`before initiating the first treatment course of MAVENCLAD
`
`before initiating the second treatment course of MAVENCLAD
`
`2 and 6 months after start of treatment in each treatment course; if the lymphocyte count
`at month 2 is below 200 cells per microliter, monitor monthly until month 6. See
`Warnings and Precautions (5.3, 5.4) for instructions based on the patient’s lymphocyte
`counts and clinical status (e.g., infections). Hold MAVENCLAD therapy if the
`lymphocyte count is below 200 cells per microliter
`periodically thereafter and when clinically indicated [see Warnings and Precautions
`(5.5)]
`
`
`
`Recommended Concomitant Medication
`
`
`2.6
`
`Herpes Prophylaxis
`
`Administer anti-herpes prophylaxis in patients with lymphocyte counts less than 200 cells per
`microliter [see Warnings and Precautions (5.4)].
`
`
`DOSAGE FORMS AND STRENGTHS
`
` 3
`
`
`
`
`MAVENCLAD is available as 10 mg tablets. The tablets are uncoated, white, round, biconvex,
`and engraved with a “C” on one side and “10” on the other side.
`
`
`CONTRAINDICATIONS
`
` 4
`
`
`
`
`MAVENCLAD is contraindicated:
`
`in patients with current malignancy [see Warnings and Precautions (5.1)].
`
`in pregnant women and in women and men of reproductive potential who do not plan to
`use effective contraception during MAVENCLAD dosing and for 6 months after the last
`dose in each treatment course. May cause fetal harm [see Warnings and Precautions
`(5.2) and Use in Specific Populations (8.1, 8.3)].
`
`in patients infected with the human immunodeficiency virus (HIV) [see Warnings and
`Precautions (5.4)].
`
`in patients with active chronic infections (e.g., hepatitis or tuberculosis) [see Warnings
`and Precautions (5.4)].
`
`in patients with a history of hypersensitivity to cladribine [see Warnings and Precautions
`(5.8)].
`
` 
`
`
`
` 
`
`
`
` 
`
`
`
` 
`
`
`
` 
`
`
`
`7
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`Page 7 of 28
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`

`

`in women intending to breastfeed on a MAVENCLAD treatment day and for 10 days
`after the last dose [see Use in Specific Populations (8.2)].
`
`WARNINGS AND PRECAUTIONS
`
`
`
` 
`
`
`
`
`
` 5
`
`
`
`
`5.1 Malignancies
`
`Treatment with MAVENCLAD may increase the risk of malignancy. In controlled and extension
`clinical studies worldwide, malignancies occurred more frequently in MAVENCLAD-treated
`patients [10 events in 3,754 patient-years (0.27 events per 100 patient-years)], compared to
`placebo patients [3 events in 2,275 patient-years (0.13 events per 100 patient-years)].
`Malignancy cases in MAVENCLAD patients included metastatic pancreatic carcinoma,
`malignant melanoma (2 cases), ovarian cancer, compared to malignancy cases in placebo
`patients, all of which were curable by surgical resection [basal cell carcinoma, cervical
`carcinoma in situ (2 cases)]. The incidence of malignancies in United States MAVENCLAD
`clinical study patients 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 [see Dosage and Administration (2.2)]. In clinical studies,
`patients who received additional MAVENCLAD treatment within 2 years after the first
`2 treatment courses had an increased incidence of malignancy [7 events in 790 patient-years
`(0.91 events per 100 patient-years) calculated from the start of cladribine treatment in Year 3].
`The risk of malignancy with reinitiating MAVENCLAD more than 2 years after the completion
`of 2 treatment courses has not been studied.
`
`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.
`
`5.2
`
`MAVENCLAD may cause fetal harm when administered to pregnant women. Malformations
`and embryolethality occurred in animals [see Use in Specific Populations (8.1)]. Advise women
`of the potential risk to a fetus during MAVENCLAD dosing and for 6 months after the last dose
`in each treatment course.
`
`
`Risk of Teratogenicity
`
`8
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`Page 8 of 28
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`

`

`
`
`Lymphopenia
`
`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 [see Use in Specific Populations (8.1, 8.3)]. MAVENCLAD is contraindicated for use
`in pregnant women and in women and men of reproductive potential who do not plan to use
`effective contraception.
`
`5.3
`
`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. In patients treated with a cumulative dose of
`MAVENCLAD 3.5 mg per kg over 2 courses as monotherapy, 26% and 1% had nadir absolute
`lymphocyte counts less than 500 and less than 200 cells per microliter, respectively. At the end
`of the second treatment course, 2% of clinical study patients had lymphocyte counts less than
`500 cells per microliter; median time to recovery to at least 800 cells per microliter was
`approximately 28 weeks.
`
`Additive hematological adverse reactions may be expected if MAVENCLAD is administered
`prior to or concomitantly with other drugs that affect the hematological profile [see Drug
`Interactions (7.3)]. The incidence of lymphopenia less than 500 cells per microliter was higher in
`patients who had used drugs to treat relapsing forms of MS prior to study entry (32.1%),
`compared to those with no prior use of these drugs (23.8%).
`
`Obtain complete blood count (CBC) with differential including lymphocyte count prior to,
`during, and after treatment with MAVENCLAD. See Dosage and Administration (2.1, 2.5) and
`Warnings and Precautions (5.4) for timing of CBC measurements and additional instructions
`based on the patient’s lymphocyte counts and clinical status (e.g., infections).
`
`5.4
`
`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
`placebo patients in clinical studies. The most frequent serious infections in MAVENCLAD-
`treated patients included herpes zoster and pyelonephritis (see Herpes Virus Infections). Fungal
`infections were observed, including cases of coccidioidomycosis.
`
`HIV infection, active tuberculosis, and active hepatitis must be excluded before initiation of each
`treatment course of MAVENCLAD [see Contraindications (4)].
`
`Consider a delay in initiation of MAVENCLAD in patients with an acute infection until the
`infection is fully controlled.
`
`
`Infections
`
`9
`
`Page 9 of 28
`
`

`

`
`
`Initiation of MAVENCLAD in patients currently receiving immunosuppressive or
`myelosuppressive therapy is not recommended [see Drug Interactions (7.1)]. Concomitant use
`of MAVENCLAD with these therapies could increase the risk of immunosuppression.
`
`Tuberculosis
`
`Three of 1,976 (0.2%) cladribine-treated patients in the clinical program developed tuberculosis.
`All three cases occurred in regions where tuberculosis is endemic. One case of tuberculosis was
`fatal, and two cases resolved with treatment.
`
`Perform tuberculosis screening prior to initiation of the first and second treatment course of
`MAVENCLAD. Latent tuberculosis infections may be activated with use of MAVENCLAD. In
`patients with tuberculosis infection, delay initiation of MAVENCLAD until the infection has
`been adequately treated.
`
`Hepatitis
`
`One clinical study patient died from fulminant hepatitis B infection. Perform screening for
`hepatitis B and C prior to initiation of the first and second treatment course of MAVENCLAD.
`Latent hepatitis infections may be activated with use of MAVENCLAD. Patients who are
`carriers of hepatitis B or C virus may be at risk of irreversible liver damage caused by virus
`reactivation. In patients with hepatitis infection, delay initiation of MAVENCLAD until the
`infection has been adequately treated.
`
`Herpes Virus Infections
`
`In controlled clinical studies, 6% of MAVENCLAD-treated patients developed a herpes viral
`infection compared to 2% of placebo patients. The most frequent types of herpes viral infections
`were herpes zoster infections (2.0% vs. 0.2%) and oral herpes (2.6% vs. 1.2%). Serious herpes
`zoster infections occurred in 0.2% of MAVENCLAD-treated patients.
`
`Vaccination of patients who are antibody-negative for varicella zoster virus is recommended
`prior to initiation of MAVENCLAD. Administer live-attenuated or live vaccines at least 4 to
`6 weeks prior to starting MAVENCLAD.
`
`The incidence of herpes zoster was higher during the period of absolute lymphocyte count less
`than 500 cells per microliter, compared to the time when the patients were not experiencing this
`degree of lymphopenia. Administer anti-herpes prophylaxis in patients with lymphocyte counts
`less than 200 cells per microliter.
`
`Patients with lymphocyte counts below 500 cells per microliter should be monitored for signs
`and symptoms suggestive of infections, including herpes infections. If such signs and symptoms
`occur, initiate treatment as clinically indicated. Consider interruption or delay of MAVENCLAD
`until resolution of the infection.
`
`
`10
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`

`
`
`Progressive Multifocal Leukoencephalopathy
`
`Progressive multifocal leukoencephalopathy (PML) is an opportunistic viral infection of the
`brain caused by the JC virus (JCV) that typically only occurs in patients who are
`immunocompromised, and that usually leads to death or severe disability. Typical symptoms
`associated with PML are diverse, progress over days to weeks, and include progressive weakness
`on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking,
`memory, and orientation leading to confusion and personality changes.
`
`No case of PML has been reported in clinical studies of cladribine in patients with multiple
`sclerosis. In patients treated with parenteral cladribine for oncologic indications, cases of PML
`have been reported in the postmarketing setting.
`
`Obtain a baseline (within 3 months) magnetic resonance imaging (MRI) before initiating the first
`treatment course of MAVENCLAD. At the first sign or symptom suggestive of PML, withhold
`MAVENCLAD and perform an appropriate diagnostic evaluation. MRI findings may be
`apparent before clinical signs or symptoms.
`
`Vaccinations
`
`Administer all immunizations 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.
`
`5.5 Hematologic Toxicity
`
`In addition to lymphopenia [see Warnings and Precautions (5.3)], decreases in other blood cells
`and hematological parameters have been reported with MAVENCLAD in clinical studies. Mild
`to moderate decreases in neutrophil counts (cell count between 1,000 cells per microliter and
`< lower limit of normal (LLN)) were observed in 27% of MAVENCLAD-treated patients,
`compared to 13% of placebo patients whereas severe decreases in neutrophil counts (cell count
`below 1,000 cells per microliter) were observed in 3.6% of MAVENCLAD-treated patients,
`compared to 2.8% of placebo patients. Decreases in hemoglobin levels, in general mild to
`moderate (hemoglobin 8.0 g per dL to < LLN), were observed in 26% of MAVENCLAD-treated
`patients, compared to 19% of placebo patients. Decreases in platelet counts were generally mild
`(cell count 75,000 cells per microliter to < LLN) and were observed in 11% of MAVENCLAD-
`treated patients, compared to 4% of placebo patients.
`
`In clinical studies at dosages similar to or higher than the approved MAVENCLAD dosage,
`serious cases of thrombocytopenia, neutropenia, and pancytopenia (some with documented bone
`marrow hypoplasia) requiring transfusion and granulocyte-colony stimulating factor treatment
`have been reported [see Warnings and Precautions (5.6) for information regarding graft-versus-
`host disease with blood transfusion].
`
`
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`

`
`
`Liver Injury
`
`Obtain complete blood count (CBC) with differential prior to, during, and after treatment with
`MAVENCLAD [see Dosage and Administration (2.1, 2.5)].
`
`5.6 Graft-Versus-Host Disease With Blood Transfusion
`
`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.
`
`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.
`
`5.7
`
`In clinical studies, 0.3% of MAVENCLAD-treated patients had liver injury (serious or causing
`treatment discontinuation) considered related to treatment, compared to 0 placebo patients. Onset
`has ranged from a few weeks to several months after initiation of treatment with MAVENCLAD.
`Signs and symptoms of liver injury, including elevation of serum aminotransferases to greater
`than 20-fold the upper limit of normal, have been observed. These abnormalities resolved upon
`treatment discontinuation.
`
`Obtain serum aminotransferase, alkaline phosphatase, and total bilirubin levels prior to the first
`and second treatment course [see Dosage and Administration (2.1)]. If a patient develops clinical
`signs, including unexplained liver enzyme elevations or symptoms suggestive of hepatic
`dysfunction (e.g., unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice
`and/or dark urine), promptly measure serum transaminases and total bilirubin and interrupt or
`discontinue treatment with MAVENCLAD, as appropriate.
`
`5.8 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 (e.g., dermatitis, pruritis) occurred in 0.5% of
`MAVENCLAD-treated patients, compared to 0.1% of placebo patients. One patient had a
`serious hypersensitivity reaction with rash, mucous membrane ulceration, throat swelling,
`vertigo, diplopia, and headache after the first dose of MAVENCLAD.
`
`If a hypersensitivity reaction is suspected, discontinue MAVENCLAD therapy. Do not use
`MAVENCLAD in patients with a history of hypersensitivity to cladribine [see Contraindications
`(4)].
`
`
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`
`
`Cardiac Failure
`
`5.9
`
`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.
`
`Instruct patients to seek medical advice if they experience symptoms of cardiac failure (e.g.,
`shortness of breath, rapid or irregular heartbeat, swelling).
`
`
`ADVERSE REACTIONS
`
` 6
`
`
`
`
`The following serious adverse reactions and potential risks are discussed, or discussed in greater
`detail, in other sections of the labeling:
`
`Malignancies [see Warnings and Precautions (5.1)]
`Risk of Teratogenicity [see Warnings and Precautions (5.2)]
`Lymphopenia [see Warnings and Precautions (5.3)]
`Infections [see Warnings and Precautions (5.4)]
`Hematologic Toxicity [see Warnings and Precautions (5.5)]
`Graft-Versus-Host Disease With Blood Transfusion [see Warnings and Precautions
`(5.6)]
`Liver Injury [see Warnings and Precautions (5.7)]
`Hypersensitivity [see Warnings and Precautions (5.8)]
`Cardiac Failure [see Warnings and Precautions (5.9)]
`
` 
`
`
`
`
`
`
`
`
`Clinical Trials Experience
`
`
`
`
`
`6.1
`
`Because clinical studies are conducted under widely varying conditions, adverse reaction rates
`observed in the clinical trials of a drug cannot be directly compared to rates in the clinical s tudies
`of another drug and may not reflect the rates observed in practice.
`
`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 approximately 4.8 years,
`and approximately 24% of cladribine-treated patients had approximately 8 years of time on study
`including follow-up. Of these, 923 patients aged 18 to 66 years received MAVENCLAD as
`monotherapy at a cumulative dose of 3.5 mg per kg.
`
`Table 2 shows adverse reactions in Study 1 [see Clinical Studies (14)] with an incidence of at
`least 5% for MAVENCLAD and higher than placebo. The most common (> 20%) adverse
`reactions reported in Study 1 are upper respiratory tract infection, headache, and lymphopenia.
`
`
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`
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`

`
`
`Table 2
`
`
`
`Adverse Reactions in Study 1 with an Incidence of at Least 5% for
`MAVENCLAD and Higher than Placebo
`MAVENCLAD
`(N=440)
`%
`
`Placebo
`(N=435)
`%
`
`Upper respiratory tract infection
`
`Headache
`
`Lymphopenia
`
`Nausea
`
`Back pain
`
`Arthralgia and arthritis
`
`Insomnia
`
`Bronchitis
`
`Hypertension
`
`Fever
`
`Depression
`
`38
`
`25
`
`24
`
`10
`
`8
`
`7
`
`6
`
`5
`
`5
`
`5
`
`5
`
`32
`
`19
`
`2
`
`9
`
`6
`
`5
`
`4
`
`3
`
`3
`
`3
`
`3
`
`
`Hypersensitivity
`In clinical studies, 11% of MAVENCLAD patients had hypersensitivity adverse reactions,
`compared to 7% of placebo patients [see Warnings and Precautions (5.8)].
`
`Alopecia
`Alopecia occurred in 3% of MAVENCLAD-treated patients compared to 1% of placebo patients.
`
`Myelodysplastic Syndrome
`Cases of myelodysplastic syndrome have been reported in patients that had received parenteral