`

`nomenaan marian nmin nina neem” PM TRA TN BICA TRONS @ nme annm nen een te ear
`s Patients with current malignancy. (4)
`* Pregnant women, and women andimen of reproductive potential whe 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)
`ASVinfection.
`
`Active chronic urfections (e.g., hepatitis or tuberculosis}. (4)
`History of hypersensitivity to clhadribine. G, 3.8)
`Women intending to breastteedon aMAVENCLAD treatment day and for
`10 days after the last dose. (4, 8.2
`
`e¢¢©@
`
`«
`
`wntWARNINGS AND PRECAUTIONS -—--—-—--———---—-—-
`
`
`2 Lymphopenia: Monitor lymphocyte counts before, during and afte
`treatment.
`
`Infections: Screen pationts for latent infections, consider delaying
`treatment untilinfection is fully controlled. Vaccinate patients antibody-
`
`negativeto varicella zoster virus prior to treatment. Administer anti-herpes
`prophylamis in patients with lWinphocyte counts less than 200 cells per
`microbter. Monitor for infections. G4)
`Hematologic toxicity: Measure complete blood countannually if chnicaliy
`*®
`
`indicated after treatment. (8.5)
`2 Graft-versus-host-disease with blood transfusion: inadiation ofcellular
`blood components is reconmended. 6.
`e Lyver injury: CJbtain tests* prior teto treatment. Discontinue if clinically
`
`nennnnnnnnnnnernnnnmnnnnenAPYERS Bo REACTIO NG ~~ nnn nnn een ee neee
`Mostcommon adverseteactions {
`ce > 20%) are upperrespiratory tract
`
`tifection, headache, and lymphopenia. (6.1)
`
`To report SUSPECTED ADVERSE REACTIONS, contact EMD Serono
`at 1-$00-293-8088 ext, 5563 or EDA at 1-800-PDA-1088 or
`woefdacov/ me dwatch.
`
`wenntennnenn nnn tnwnneamwnnnn ASRECS INTERAC THB NG --~2- n-neee ence an ee etn ae
`
`« Tmmunosuppressive dnigs: Consider overlapping effects
`
`on immune
`system, when used Sequential. Concomitant use wotiecommended. (7)
`* Hematotoxc drugs: Monitorpatients for additive effects onthe
`
`hematological profile.
`(7.3)
`» Antiviral and antiretroviral drugs. Avoid concomitant use, (74)
`* BCRP ot ENT/CNT imbibitors: Mayalter bioavailability of cladribine.
`Avon concomitant use. (3
`
` See iT fer PA’ ON aud Medication
`
`
`Guide.
`
`Reviseck 3/2019
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed te use
`MAVENCLA® safely and effectively. See full prescribing information for
`MAVENCLAD,
`
`MAVENCLAD® (cladribine) tablets, fer oral use
`lnitial US. Approval: 1993
`
`effective contraception because of the risk of fetal harm, (3.2
`
`
`WARNING: MALIGNANCIES and RISK OF TERATOGENICITY
`See full prescribing informationfor complete boxed warning.
`
`Moaliznancies
`6
`MAVENCLAD may increase the risk of malignancy. MAVENCLAB
`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. (8.3)
`
`Risk of Teratogemicity
`8
`MAVENCLAD is contraindicated for use in pregnant women and in
`women and men af reproductive potential who do not plana to BSE
`
`
`INDICATIONS AND USAGE—
`
`
`
`MAVENCLAD is a purine antimetabolie indicated for the treatment of
`relapsing forms of nuikiple sclerosis MS), to inchide selapsing-remitting
`disease and active secondary progressivedisease, in adults. Because ofits
`safety profile, useof MAVENCLAD is generally recommended for patients
`who have had an inadequate response to, or are unable to tolerate, an alternate
`dsug indicated for the treatment of MS /see Warnings and Precautions (3)].
`
` is notrecommended for use in patients with clinically isolated
`syndrome (CIS} becauseofits safety profile fsee Warnings ond Precautions
`(ELD
`
`seeeeeccnnene anenensenBOSAGE AND ADMINIS TRATION.
`° Assesstents are required prior to starting each MAVENCLAD treatment
`
`course. GD
`@ Cunailatwe dosage of3.3 mg/kg administered oxally and divided into
`2 treatment courses (1.75 mp/ke pertreatinent course). Fach treatment
`
`courseis divided into 2 treatment cycles.
`2
`e MAVENCLAD is acytotonic drag.
`(2.4
`
`se Separate administration from anyother omal drug byatleast 3 hours. (2.43
`
`-DOSAGE FORMS ANE STRENGTHS—---—----ene
`710 meBG
`
`
`Reference ID: 4410993
`
`

`

`FULL PRES CRIBIN
`
`~s
`
`INFORMATION:
`
`co
`
`VTEN TS *
`
`
`
`tieACY
`
`
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`
`4
`
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`*Secti
`listed.
`
`ns or subsections
`
`a
`
`mitted
`d from the full pres
`
`cribbing
`
`formation are 1
`
`ot
`
`
`
`Reference ID
`
`4410993
`
`
`
`
`
`
`
`

`

`FULL PRESCRIBING INFORMATION
`
`WARNING: MALIGNANCIES AND RISK OF TERATOGENICITY
`
`daring MAYENCLADposing and for6 months afterthelast dose jin each treatment
`
`Malignancies
`&
`Treatment with MAVENCLAD may increase the risk of malignancy. MAVENCLAD is
`contraindicated im 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 anindividualemfbasis. Follow standard cancer screeningguidelines
`
`ran£
`eyes saree
`SALEEM
`
`Risk of Teratogenicity
`&
`MAVENCLADBis 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. Exclade
`pregnancy before the start of treatment with MAVENCLAD in females of reproductive
`potential, Advise females and males of repreductive potential to use effective contraception
`
`i
`
`INDICATIONS AND USAGE
`
`MAVENCLAD is indicated for the treatment of relapsing forrns of multiple sclerosis (MS), to
`inchide 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 fre
`
`Limitations of Use
`
`MAVENCLADis not recommended for use in patients with clinically isolated syndrome (CIS)
`because of its safety profile /yce
`
`2
`
`DOSAGE AND ADMINISTRATION
`
`2.4
`
`Assessments Prior to Starting Each MAVENCLAD Treatment Course
`
`Cancer Screening
`
`Follow standard cancer screening guidelines because ofthe risk ofmalignancies /s
`
`
`
`
`Reference ID: 4410993
`
`2
`
`

`

`Pregnancy
`
`Exclude pregnancy priorto treatment withMAVENCLAD in females ofreproductive potential
`
`2) and Use |
`
`the first treatment course
`within normal limits before initiating>
`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 allowfor recovery of
`lymphocytes to at least 800 cells per microliter. If tins recovery takes more than 6 months,
`patient should not receive further treatment with MAVENCLAD.
`
`the
`
`Infections fs
`
`®
`
`8
`
`8
`
`®
`
`8
`
`®
`
`&
`
`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 imrnumzations according to immunization guidelines priorto starting
`MAVENCLAD, Administer live-attenuated or live vaccinesatleast 4 to 6 weeks prior to
`staring MAVENCLAD.
`
`Obtain a baseline (within 3 months} magnetic resonance imaging prior to the first
`treatment course because of the risk of progressive multifocal leakoencephalopathy
`(PML).
`
`Liver Injury
`
`Obtain serum aminotransferase, alkaline phosphatase, and total bilirubin levels fsee
`Op
`
`
`
`
`Reference ID: 4410993
`
`

`

`2.2
`
`Recommended Dosage
`
`The recommended cumulative dosage of MAVENCLADis 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 treatrnent 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 ofFirst
`Course/Second Cycle
`
`Second Course/Second Cycle: administer 23 to 27 days after the last dose of Second
`Course/First Cycle.
`
`Tahle I
`
`Bose of MAVENCLAD per Cycle by Patient Weight in Each Treatment
`Course
`
`Dose in mg (Number of 10 mg Tablets) per Cycle
`
`100 mg (10 tablets}
`
`ke
`
`40* to less than SO
`
`30 to less than 60
`
`60 to less than 70
`
`70 to less than 80
`
`80 to less than 90
`
`90 to less than 100
`
`First Cycle
`
`40 mg (4tablets)
`
`50 mg (5 tablets)
`
`60 mg (6 tablets)
`
`70 mg (7 tablets)
`
`80 mg (8 tablets}
`
`50 me (9 tablets}
`
`2 (10 tablets)
`
`2 (10 tablets)
`
`Second Cycle
`
`40 meg (4 tablets)
`
`50 mg (5 tablets)
`
`60 mg (6 tablets)
`
`70 mg (7 tablets)
`
`70 mg (7 tablets)
`
`80 mg (3 tablets}
`
`90 mg (9 tablets}
`
`Reference ID: 4410993
`
`

`

`Following the administration of 2 treatment courses, do not administer additional
`
`MAVENCLAD treatment during the next 2 years. Treatment during these 2 years mayfarther
`
`increase the risk of malignancy fsee
`y
`7. The safety and efficacy of
`remmtiating MAVENCLAD more than 2 yearss 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.
`
`lf 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 pvo consecutive doses
`are missed, the treatment cycle is extended by 2 days.
`
`2.4
`
`Aciasans (ratio n
`
`MAVENCLAD tablets are taken orally, with water, and swallowed whole without chewing.
`MAVENCLAD canbe taken with or without food.
`
`Separate admunistration of MAVENCLAD and anyother oral drugs by atleast 3 hours during
`the 4 to 5 day MAVENCLAD treatment cycles /se
`
`MAVENCLAD isa cytotoxic drug. Follow applicable special handling and disposal procedures
`
`is
`é
`Vif,MAVENCLAD is an uncoated tablet and must be swallowed immediately
`once removved fromthe blister. If a tablet is left on a surface, orifa 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°
`
`Laboratery Testing and Monitoring to Assess Safety
`
`and #
`
`
`
`Reference ID: 4410993
`
`

`

`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
`8
`2 and 6 months after start oftreatment in each treatment course: ifthe lymphocyte count
` See
`at month 2 is below 200 cells per:microliter, monitor monthly until month 6. :
`‘S.3,
`3.4) for instructions based on the patient’s lymphocyte
`
`counts and clinical status lewg,_ infections). Hold MAVENCLAD therapyifthe
`lymphocyte count is below 200 cells per microliter
`periodicallythereafter and when clinically indicated fse
`
`SF]
`
`
`®
`
`2.6
`
`Recommended Concomitant Medication
`
`Herpes Prophylaxis
`
`Administer anti-herpes prophylaxis in patients with lymphocyte counts less than 200 cells per
`rnicroliter fs
`
`3
`
`DOSAGE FORMS AND STRENGTHS
`
`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 otherside.
`
`4
`
`CONTRAINDICATIONS
`
`MAVENCLAD is contraindicated:
`
`@
`
`&
`
`s
`
`®
`
`@
`
`in patients with current malignancy /
`
`
`
`in pregnant women and in women and men of reproductive potential who do not planto
`use effective contraception during MAVENCLAD dosing and for 6 months after the last
`dose |imeach treatment course. Maycause fetal harm fsee}
`Ave
`
`RS}.
`
`
`
`
`in patients with active chronic infections (e.g, hepatitis or tuberculosis) /se
`
`
`
`
`in patients with a history of hypersensitivity to cladribine /sec
`2 OY
`cs i
`
`
`Reference ID: 4410993
`
`ny;é
`
`

`

`&
`
`Pe
`
`if, women intending to breastfeed on aMAVENCLAD treatment day and for 10 days
`j
`after the Last dose /
`
`WARNINGS AND PRECAUTIONS
`
`cnof
`
`Malignancies
`
`In controlled and extension
`Treatment with MAVENCLAB may increase the risk of malignancy.
`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
`placebopatients [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
`clintcal 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 treatrnent courses, do not administer additionalMAVENCLAD
`treatment during the next 2 years fsee
`Dow
`if. Tn chimeal 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 fromthe 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.
`
`In patients with prior
`MAVENCLAD ts contraindicated in patients with current malignancy.
`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.
`
`3.2
`
`isk of Teratogenicity
`
`MAVENCLAD maycause fetal harm when admintstered to pregnant women. Malformations
`
`and embryolethality occurred in animals fsee Use
`i:]. Advise women
`ofthe potential msk to a fetus during MAVENCLAD dosing and for 6 months after the last dose
`
`in each treatment course.
`
`Reference ID: 4410993
`
`

`

`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 ireatment with MAVENCLAD should discontinue
`
`treatment fee
`&.33},. MAVENCLAD is contraindicated for use
`in pregnant women and in women and men of reproductive potential who do not plan to use
`effective contraception.
`
`3.3
`
`Lyniphopenia
`
`MAVENCLAD causes a dose-dependent reduction in lymphocyte count. In clinical studies, 87%
`of MAVENCLAD-ireated 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 ceils per microliter, respectively. At the end
`of the second treatment course, 2%ofclinical study patients had lymphocyte counts less than
`500cells per microliter, median time io recoveryto at least 800 cells per microliter was
`approximately 28 weeks.
`
`Additive hematological adverse reactions may be expected ifMAVENCLAD ts administered
`pu or to or concomtantly with other drugs that affect the hematological profile /se:
`;
`
`
`s¢?. 33}. The incidence of lymphopenia less than S00 cells per microliter was higher in
`pati ents who had used drugs to treat relapsing forms ofMS priorto study entry (32.1%),
`compared to those with no prior use of these drugs (23.8%).
`
`te count prorto,
`Obtain complete blood count (CBC) with differential including lymphooyt
`during, and after treatment with MAVENCLAD.
`
`4} for timing of CBC measurements and additional instructions
`
`based on the patient’s lymphocyte counts and clinical status (e.g., infections).
`
`5.4
`
`Infections
`
`MAVENCLAD can reduce the body's immune defense and may increase the likelihood of
`infections. Infections occurred in 49%ofMAVENCLAD-treated patients compared to 44%of
`placebo patients in clinical studies. The most frequent serious infections in MAVENCLAD-
`Ss}. Fungal
`
`treated patients included herpes zoster and pyelonephritis (see
`infections were observed, including cases of coccidioidomycasis.
`
`HIVinfection, active tuberculosis, and active hepatitis mustt be excluded beforeinitiation of each
`£4)
`treatment course of MAVENCLAD fse
`as
`
`Consider a delay in inthation of MAVENCLAD in patients with an acute infection until the
`infection is fully controlled.
`
`Reference ID: 4410993
`
`

`

`intiation of MAVENCLAD in patients currently receiving immunosuppressive of
`jf. Concomitant use
`
`rmyelosuppressive therapy is not recommended /se
`of MAVENCLAD with these therapies could increase the risk of immunosuppression.
`
`Tuberculosis
`
`Three of 1,976 (0.2%) cladribine-treated patients in the climcal program developed tuberculosis.
`AU 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 maybe activated with use of MAVENCLAD.
`patients with tuberculosis infection, delay initiation of MAVENCLAD until the infection has
`been adequatelytreated.
`
`In
`
`Hepatitis
`
`One clinical study patient died frorn fulminant hepatitis B infection. Perform screening for
`hepatitis B and C prior to imitiation of the first and second treatment course of MAVENCLAD.
`Latent hepatitis infections may be activated with use of MAVENCLAD. Patients whoare
`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 adequatelytreated.
`
`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-attennated 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 lymphopena. Administer anti-herpes prophylaxis in patients with lymphocyte counts
`fess than 200 cells per microliter.
`
`Patients with lymphocyte counts below S00 cells per microliter should be momtored for signs
`and symptoms suggestive of infections, including herpes infections. Hf such signs and symptoms
`occur, inihate treatment as climcally indicated. Consider interruption or delay of MAVENCLAD
`until resolution of the infection.
`
`Reference ID: 4410993
`
`

`

`Progressive Mulifocal Leukoencephalopathy
`
`
`
`
`Progressive multifocal leukcencephalopathy (PML) is an opportunistic viral infection of the
`brain caused by the IC virusICY) that typically only occurs in patients who are
`immunocompromised, and that usually leads to death or severe disability. Typical symptoms
`associated with PMLare 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 (MRD) 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 (ee
`|
`1S}
`Avoid vaccination with live-attenuated or live vaccines during and after MAVENCLAD
`treatment while the patient’s winte blood cell counts are not within normal limits.
`
`5.3
`
`Hematologic Toxicity
`
`
`33], decreasesin other blood cells
`in addition to lyraphopenia {see
`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
`<fowerlimit of normal CLLN)}) were observed in 27% of MAVENCLAD-treated patients,
`compared to 13%of placebopatients whereas severe decreases in neutrophil counts (cell count
`below 1,000 ceils 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 mid
`(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 climcal studies at dosages similar to or higher than the approved MAVENCLAD dasage,
`serious cases of thrombocytopenia, neutropenia, and pancytopenia (some with documented bone
`
`marrow hypoplasia) requiring transfusion and granulocyte-colony stimulating factor treatment
`
`
`have been reported fsee } 8 i for information regarding grafi-versus-
`
`
`
`host disease with blood transfusion/.
`
`Reference ID: 4410993
`
`il
`
`

`

`Obtain complete blood count (CBC} with differential prior to, during, and after treatment with
`
`MAVENCLAD fee
`23h.
`
`5.6
`
`Gratt-Versus-Hast Discase With Hiood Transfusion
`
`Transfusion-associated grafi-versus-host disease has been observed rarely after transfusion of
`noniiradiated blood in patients treated with cladribine for non-MS treatment indications.
`
`In patients who require blood transfusion, irradtation of cellular blood components ts
`recommended prior to adnunistration to decrease the risk of transtusior-related gratt-versus-host
`disease. Consultation with a hematologist is advised.
`
`5.7
`
`Liver Euury
`
`In clinical studies, 0.3% of MAVENCLAD-treated patients had liver impury (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 arminotransferases 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 secondtreatment course /se
`7. Ta 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 /sce
`
`
`Reference ID: 4410993
`
`

`

`§,9
`
`Cardiac Failure
`
`In clinical studies, one MAVENCLAD-treated patient experienced life-threatening acute cardiac
`failure with myocarditis, which improved afer 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 ifthey experience symptoms of cardiac failure (e.g.,
`shortness of breath, rapid or irregular heartbeat, swelling).
`
`6
`
`ADVERSE REACTIONS
`
`The following serious adverse reactions and potential risks are discussed, or discussed in greater
`detail, in other sections of the labeling:
`
`
`Malignancies fx:
`Risk of Teratogenicity
`
`Lymphopenta /see
`
`Infections /se
`
`
`
`
`Liver Injury fs«
`Hypersensitivity {se
`
`Cardiac Failure /sec
`
`
`®
`@
`&
`®
`
`2 8 8
`
`®
`&
`
`6.1
`
`Chinical Trials Experience
`
`Because clinical studies are conducted under widely varying conditions, adverse reaction rates
`observed in the clinical irials of a drug camnot be directly compared to rates in the clinical studies
`of another drug and may not reflect the rates observed in practice.
`
`In the clinical trial program of cladribine in MS, 1,976 patients recetved cladribine for a total of
`9,509 patient years. The mean me 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 ata cumulative dose of 3.5 mg per kg.
`
` Table 2 shows adversereactions in Study 1 /se
`with an incidenceofat
`least 5%forMAVENCLAD and higher than alacebo. The most common (> 20%) adverse
`reactions reported in Study | are upper respiratorytract infection, headache, and lymphopenia.
`
`Reference ID: 4410993
`
`

`

`Table 2
`
`Adverse Reactions in Study 1 with an Incidence of at Least 3%for
`MAVERCLAD and Higher than Placebo
`
`
`
`MAVENCLAD
`Placebo
`
`
`
`(N=440}
`(N=435}
`
` Upper respiratory tract infection
`
`
`Headache
`
`aynhopeniaa
`
`
`fBackpaie
`
`
`
`
`Arthralgia and arthritisPoUT
`wo}BpA
`
`
`nsomia
`
`
`eeee
`
`
`Hypenensioe
`feeDepression
`
`
`
`
`m
`
`3
`
`fypersensitivity
`
`In clinical studies, 11% ofMAVENCLAD patients had Hypersensitivity adverse reactions,
`af
`compared to 7%of placebo patients /se:
`
`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
`cladribineat a higher dosage than that approved forMAVENCLAD. These cases occurred
`several years afler treatment.
`
`Herpes Meningoencephalitis
`Fatal herpes meningoencephalitis occurred inone MAVENCLAD-treated patient, at a higher
`dosage and longer duration of therapy than the approved MAVENCLAD dosage and in
`combination with interferon beta-1a treatment.
`
`Stevens-Johnson syndrome (SIS) and toxic epidermal necroiysis (TEN)
`SIS and TEN are identified risks of parenteral cladribine for the treatment of oncologic
`indications.
`
`Seizures
`In clinical studies, serious events of seizure occurred in 0.3%of MAVENCLAD-treated patients
`compared to 0 placebo patients. Serious events included generalized tonic-clonic seizures and
`status epilepticus. tis unknown whether these events wererelated to the effects of multiple
`sclerosis alone, to MAVENCLAD, or to a combination of both.
`
`Reference ID: 4410993
`
`14
`
`

`

`7
`
`DRUG INTERACTIONS
`
`Table 3
`
`Drug Interactions with MAVENCLAD
`
`Inununo modulatory, TImmanosuppressive, or Myelosuppressive Drugs
`74
`Clinical Impact
`Concomitant use of MAVENCLAD with immunomodulatory,
`iramunosuppressive, or myelosuppressive drugs may increase
`the risk of adverse reactions because of the additive effects on
`the immune system /y
`}
`Concomitant use with niyelosuppressive or other
`immunosuppressive drugs is not recommended. Acute short-
`term therapy with corticosteroids can be administered.
`
`Prevention or Management
`
`7.2
`
`lEnterferon-Beta
`
`Clinicallmpact
`
`Prevention or Management
`7.3
` Hematotoxic Drugs
`Clinical Impact
`
`In patients who have previously been treated with
`immunomodulatory orimmunosuppressive drugs, consider
`potential additive effect, the mode of action, and duration of
`effect of the other drugs prior to initiation of MAVENCLAD.
`
`Concomitant use of MAVENCLAD with interferon-beta did
`not change the exposure of cladribine to a clinically
`significant effect, however, lymphopenia risk may be
`increasedfsee
`§
`34
`Concomitant use is not recommended.
`
`Concomitant use of MAVENCLAD with hematotoxic drugs
`may increase the risk of adverse reactions because of the
`additive hematological effecis fse
`
` Compounds that require intracellular phosphorylation to
`
`Monitor hematological parameters.
`Prevention or Management
`7.4
`Antiviral and Antiretroviral Drugs
`Clinical impact
`
`Prevention orManagement
`
`become active (e.g, lamivudine, zalcitabine, ribavirin,
`stavudine, and zidovudine) could interfere with the
`intracellular phosphorylation and activity of cladribine.
`Avoid concomitant use.
`
`Reference ID: 4410993
`
`iS
`
`

`

`Potent ENT, CNT and BCRP Transporter Inhibiters
`7.8
`Clinical Tmpact
`Cladribine is a substrate of breast cancer resistance protein
`(BCRP), equilibrative nucleoside CENT I), and concentrative
`nucleoside (CNT3) transport proteins. The bioavailability,
`intracellular distribution, and renal elimination of cladribine
`may be altered by patent ENT1I, CNT3, and BCRP transporter
`inhibitors.
`
`Prevention or Management
`
`course,
`
`Avoid co-admimstration of potent ENT1, CNT3, or BCRP
`transporter inhibitors (e.g, ritonavir, eltrombopag, curcumin,
`cyclosporine, dilazep, nifedipine, nimodipine, cilostazol,
`sulindac, dipyridamole, or reserpine} during the 4 to S day
`MAVENCLADBtreatment cycles. If this is not possible,
`consider selection of alternative concomitant drugs with no or
`minimal ENT, CNYT3, or BCRP transporter inhibiting
`properties. If tis is not possible, dose reduction to the
`minimum rnandatory dose of drugs containing these
`compounds, separation in the timing of administration, and
`careful patient monitoring is recommended.
`Potent BCRP and P-gp Transporter Inducers
`7.6
`Clinicalimpact
`Possible decreasein cladribine exposure if potent BCRP or
`P-gp transporter inducers are co-administered.
`Consider a possible decrease in cladribine efficacy if potent
`BCRP(e.g, corticosteroids} or P-gp (e.g, rifarnpicin, St.
`Jobn's Wort) transporter inducers are co-administered.
`Hormonal Contraceptives
`7.7
`Clinical Impact
`tis currently unknown whether MAVENCLAD mayreduce
`the effectiveness of systemically aching hormonal
`contraceptives.
`Women using systemically acting hormonal contraceptives
`should add a barrier method during MAVENCLAD dosing
`and for at least 4 weeks after the last dose in each treatment
`
`Prevention or Management
`
`Prevention orManagement
`
`Reference ID: 4410993
`
`16
`
`

`

`8
`
`USE EN SPECIFIC POPULATIONS
`
`8.1
`
`Pregnancy
`
`Risk Summary
`
`MAVENCLAD is contraindicated in pregnant women and in females and males of reproductive
`potential who do not plan to use effective contraception. There are no adequate data on the
`developmental risk associated with use of MAVENCLADin pregnant women. Cladribine was
`embryolethal when administered to pregnant mice and produced malformations in nuce and
`Axia}. The observed devel opmental effects are consistent with the effects of
`
`
`cladribine on DNA fseg
`
`In the US. general population, the estimated background risk of major birth defects and
`muscarriage in climcally recognized pregnancies is 2% to 4%and 15%to 20%, respectively. The
`background risk of major birth defects and miscarriage for the indicated population is unknown.
`
`Data
`
`Animal Data
`When cladribine was administered intravenously (0,0.5, 1.5, or 3 mg/kg/day} to pregnant mice
`during the period of organogenesis, fetal growth retardation and malformations Ginchuding
`exencephaly and cleft palate) and ernbryofetal death were observed at t