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 contraindicated 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)
`
`
`
` ----------------------------RECENT MAJOR CHANGES--------------------------
`
`
`Dosage and Administration (2.1)
`
`
`9/2022
`
`9/2022
`Warnings and Precautions (5.4)
`
`
`
`----------------------------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 ADMINISTRATION-----------------------
`
`• 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)
`
`
`
`
`-------------------------------CONTRAINDICATIONS------------------------------
`
`• Patients with current malignancy. (4)
`
`
`
`• Pregnant women, and 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. (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. Vaccination of patients
`
`
`seronegative to varicella zoster virus (VZV) is recommended prior to
`
`
`treatment. Vaccination of patients seropositive to VZV with zoster vaccine
`
`
`
`recombinant, adjuvanted, is recommended prior to or during 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)
`
`
`
`
`
`
`------------------------------ADVERSE REACTIONS-------------------------------
`
`Most common adverse reactions (incidence > 20%) are upper respiratory tract
`
`
`
`
`
`infection, headache, and lymphopenia. (6.1)
`
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact EMD Serono
`
`
`at 1-800-283-8088 ext. 5563 or FDA at 1-800-FDA-1088 or
`
`
`www.fda.gov/medwatch.
`
`
`-------------------------------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: 9/2022
`
`
`
`
`_______________________________________________________________________________________________________________________________________
`
`
`
`
`
`
`Reference ID: 5047594
`
`1
`
`Petitioner TWi Pharms., Inc.
`EX1011, Page 1 of 31
`
`

`

`
`
`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 ADVERSE REACTIONS
`
`
`6.1 Clinical Trials Experience
`
`
`7 DRUG INTERACTIONS
`
`
`
`Immunomodulatory, Immunosuppressive, or Myelosuppressive
`7.1
`
`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
`
`
`
`
`
`8 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.
`
`
`
`
` _______________________________________________________________________________________________________________________________________
`
`Reference ID: 5047594
`
`2
`
`
`
`Petitioner TWi Pharms., Inc.
`EX1011, Page 2 of 31
`
`

`

`
`
`
`
` 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)].
`
`
`
`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)].
`
`
`2
`
`2.1
`
`
`Cancer Screening
`
`
`Follow standard cancer screening guidelines because of the risk of malignancies [see Boxed
`
`
`Warning and Warnings and Precautions (5.1)].
`
`
`
`
`INDICATIONS AND USAGE
`
`
`DOSAGE AND ADMINISTRATION
`
`
`
`
`
`Assessments Prior to Starting Each MAVENCLAD Treatment Course
`
`Reference ID: 5047594
`
`3
`
`Petitioner TWi Pharms., Inc.
`EX1011, Page 3 of 31
`
`

`

`
`
`
`
`
`Exclude HIV infection.
`
`
`Perform tuberculosis screening.
`
`
`Screen for hepatitis B and C.
`
` 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)]
`
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`Evaluate for acute infection. Consider a delay in MAVENCLAD treatment until any
`
`
`acute infection is fully controlled.
`
`
`
`
`
`
`Vaccination of patients who are seronegative for VZV is recommended prior to initiation
`
`of MAVENCLAD.
`
`
`
`
`
`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 MAVENCLAD
`
`
`
`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 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).
`
`
`
`•
`
`
`•
`
`
`
`•
`
`
`
`•
`
`
`
`Reference ID: 5047594
`
`4
`
`Petitioner TWi Pharms., Inc.
`EX1011, Page 4 of 31
`
`

`

`
`
`
`
`
`Recommended Dosage
`
`
`First Course/First Cycle: start any time.
`
` Liver Injury
`
`
`Obtain serum aminotransferase, alkaline phosphatase, and total bilirubin levels [see Warnings
`
`and Precautions (5.7)].
`
`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/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
`
`
`Dose in mg (Number of 10 mg Tablets) per Cycle
`Weight Range
` kg
` Second Cycle
`
` First Cycle
`
`
`
`
`
` 40 mg (4 tablets)
`
`
`
` 40 mg (4 tablets)
`
` 40* to less than 50
`
`
` 50 mg (5 tablets)
`
`
`
` 50 mg (5 tablets)
`
` 50 to less than 60
`
`
`
` 60 mg (6 tablets)
`
`
`
` 60 mg (6 tablets)
`
`
`
` 60 to less than 70
`
`
` 70 mg (7 tablets)
`
`
`
` 70 mg (7 tablets)
`
`
`
` 70 to less than 80
`
`
` 70 mg (7 tablets)
`
`
`
` 80 mg (8 tablets)
`
`
`
` 80 to less than 90
`
`
` 80 mg (8 tablets)
`
`
`
` 90 mg (9 tablets)
`
`
`
` 90 to less than 100
`
`
` 90 mg (9 tablets)
`
`
`
`
` 100 mg (10 tablets)
`
` 100 to less than 110
`
`
`
` 100 mg (10 tablets)
`
`
` 100 mg (10 tablets)
`
` 110 and above
`
`
` *The use of MAVENCLAD in patients weighing less than 40 kg has not been investigated.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 5047594
`
`5
`
`Petitioner TWi Pharms., Inc.
`EX1011, Page 5 of 31
`
`

`

`
`
`
`
`
`Administration
`
` 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.
`
`
`
`
`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
`
`Reference ID: 5047594
`
`6
`
`Petitioner TWi Pharms., Inc.
`EX1011, Page 6 of 31
`
`

`

`
`
`
`
`
`•
`
` 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
`
`
`DOSAGE FORMS AND STRENGTHS
`
`
`CONTRAINDICATIONS
`
`
`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)].
`
`
`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.
`
`
`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)].
`
`
`
`•
`
`
`
`•
`
`
`
`•
`
`Reference ID: 5047594
`
`7
`
`Petitioner TWi Pharms., Inc.
`EX1011, Page 7 of 31
`
`

`

`
`
`
`
`•
`
`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
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`
`
`Reference ID: 5047594
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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
`
`
`Reference ID: 5047594
`
`
`
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`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 seronegative 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. Vaccination with zoster vaccine recombinant, adjuvanted is
`
`
`recommended for patients who are seropositive to VZV, either prior to or during MAVENCLAD
`
`
`treatment, including when their lymphocyte counts are less than or equal to 500 cells per
`
`microliter.
`
`
`
`
`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.
`
`
`Reference ID: 5047594
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` 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.
`
`
`
`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 (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.
`
`
`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.
`
`
`Reference ID: 5047594
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`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].
`
`
`
`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 patie