GILENYA Patient Services Liaison — Giienya
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`The GILENYA Patient Services Liaison
`A dedicated GILENYA Patient Servicss Liaison supports you.
`your staff, and your patiants.“
`The liaison-a keycumpnnarit Dime GILENYASupport Team—is tna
`primary con-n far you and your pltIeMS. The main goal ofInt program
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`is to gut your patienu Started on EILEMVA m submitting the GILENYA SRF
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`GlLENVA©Home
`Til: baselina assessments and/or FDOtorGiLENYA tan now he conducted in the amnion nipltisnrs' own
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`‘ Just submit an SRF and we air: [all omit rest
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`LilLtfl’fn tLh Arress Program: LaratoNe‘t
`CardioNet is available to assist with ECG interpretation and communications during each first-
`dose observation with GiLENt‘A lfyouroffica requires support CardioNet tan provide an ECG
`monitor and train your staff, CardioNEI technicians prepare the ECG report and send It to a
`Harvard cardiologist to he avanead. Each reportis made available through CardinNer's Web
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`INDICATION AND IMPORTANT SAFETY INFORMATION
`Indication
`GILENYA is a sphingosirie 1-phosphata reooptor modulator indicated tor the treatment of relapsing forms oi multiple sclerosis
`(MS). to include ciinically isolated syndrome. relaosino-romittinu disease. and active saoondary oroursssiva disease. in patients
`- Patients who in tho last 6 months experienced myocardial infarction. unstable angina stroke, TIA, decompensated heart tailors
`(HF) requiring hospitalization or Class III/IV HF
`. History or presence of Mobitz Type II second-degree or third-degree ain‘ousntriaular (AV) block or sick sinus syndrome. unless
`patient has a lunctioning pacemaker
`v Bassiins OTC interval 2500 msoc
`~ Cardiac armythrnias requiring treatment with Class Ia or Class III anti-arrhyinrriit: drugs
`- Patisnls who have had a hyparsensilivdy rsaction to fingolin-iod or any of the excipisnis in GILENYA. Ohsowad reactions inctude
`rash. urticaria. and angioedama upon treatment initiation
`Bradyarrhyfltmia and Atrioventricular (AV) Black: Mormor patients during GILENYA initiation because of a risk of
`bradyanhytnrnia and AV block. Prior to dosing and at the end of the observation parioo‘, obtain an electrocardiogram (ECG) in ali
`patients (10 years at age and older); Monitor all patients tor 6 hours attarihs first dose for signs and symptoms of braoyoardia
`with houriy pulse and blood pressure (BP) measurement.
`Continue monitoring until the abnormality resolves it any of the [allowing is present alter 6 hours; (1) The heart rate (HR) 6 hours
`- Patients who in the last 6 months expenenceo myocardial infarction, unstable angina. stroke. TIA, dommpsnsalsd heart failure
`(HF) requiring hospitalization or Class Ill/IV HF
`~ History or presence of Mooitz Type Ii secondrdegree or third-degree atrioventrioular (AV) block or sick sinus syndrome, unless
`patient has a functioning pacemaker
`- Baseline DTc interval 2500 msoc
`- Cardiac arrhythmias requiring treatment with Class Ia or Class III anti-arrhythmic drugs
`- Patients who have had a hypotsonsitivity reaction to fingoiimod or any of the exoipiertts in GILENYA. Observed reactions include
`rash. udicaria, and angiosdema upon treatment initiation
`
`'on because oi as risk or
`Bradyarrhythmia and AtrinventricuiarlAV) Block: Monitor patients during GILENYA in'
`'
`ri an electrocardiogram (ECGI in all
`hradyarrhy‘thmia and AV block. Prior to dosing and at the and o! the observation period, obi
`with nouriy pulse and blood pressure (BP) measurement.
`patients (10 years oi age and older) Monitor all patients lot 6 hours after the first dose for signs and symptoms of bradycardia
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`DEPOSITION
`EXHIBIT
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`Biogen Exhibit 2215
`Mylan v. Biogen
`IPR 2018-01403
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`GILENYA Patient Services Liaison - Gilenya
`
`Continue monitoring until the abnormality resoives if any of the followrng Is present after 6 hours (1] The heart rate (HR) 5 hours
`Begin continuoas ECG monitoring in patients With symptomatic bradycardra until resotutlon lf pharmacological intervention is
`required. continue ECG monitoringovernighl In a medical ‘acil ly‘ and repeat fi-hourmomloring alter the second dose Some
`patients may experience a second decrEES-e in HR within 24 hours aflerthe firstdose
`Patients with preexisting rschemic heartdisease, history at Ml or cardiac arrest. CHF, cerebrovascuier disease, uncontrolled
`hypertension. history of symptomatic bradycardra o' recurrent syncope, severe unt'ealed sleep apnea, AV block. srnoalrial heart
`biock, or or concomrtant drugs that slow hR or AV conduction shouid be evaluated by a physician and, 'f treated wrth GILENYA
`monitored overnight wrth continuous ECG in a medical facility after first dose due to higher risk at symptomatic bradycardia or
`heart block Patients With or at risk for OT prolongation oron concomitant GET—prolonging drugs With a known risk of torsades de
`poimes should also bemonilored overnight wrth continuous ECG
`Repeat first-dose monitoring if GlLENYA is interrupted at day Within first? wears or >7 days during weeks 3 and 4. or >14 days
`after the first month at treatment because effects on HR and AV conduction may occur upon rernr’tiatrorr F‘rst-dose monitoring rs
`also recommended when the dose is increased in pediatric patients swrtching from D 25 mg to 0 5 mg,
`Infections: GlLENYA may increase risk or infections. Life threatening and fatal infections have occurred in association with
`GILENYA. Arecent CBC should be available before initiating GlLENYA Consider suspending GILENYA it a patient develops a
`serious infection. Monitor for signs and symptoms of intaction during treatment and up to 2 months after discontinuation. Do not
`start GILENVA in patients with active acute or chronic infections until infection is resolved. Two patients receiving a higher than
`recommended dose of GILENYA {1 25 mg) in conjunction with high-dose corticosteroid thempy died of herpelic infections. In the
`postmarkeling setting with GILENVA. serious infections, some fatal. have been reported with opportunistic pathogens. including
`viruses (3g. John Cunningham virus [JCV]. herpes simplex viruses 1 and 2. varicella zostsr Virus [VA/'1). fungi tog, cryptocoocr),
`bacteria (cg. atypical mycobacieria). and Kaposi's sarcoma. Patients with signs and symptoms consistent with any of these
`infections should undergo prompt diagnostic evaluation and treatment, Concomitant use with antineoplaslic. immunosuppressive.
`or immune-modulating therapies are expected to increase the risk of additive immunosuppression When switching to GILENYA
`from these types of therapies. consider their duration of effect and mode of action to avoid this fish.
`Before initiating GILENYA, patients should be tested for antibodies to VZV. VZV vaccination of antibody-negative patients is
`recommended prior to starting treatment. GILENYA initiation should be postponed for 1 month after vaccination. It is
`recommended that pediatric patients. if possible. complete all immunizations in accordance with current immunization guidelines
`prior to initiating GlLENYA.
`Progressive Multifocal Leukoencephaioparhy (PML): Cases of PML occurred in patients with M5 who received GILfiNYA in
`the postmarksling setting. PML is an opportunistic viral infection of the brain caused by the JC Virus [JCW that typically only
`occurs in patients who are immunocompromised. and usually leads to severe disability or death. PML has occurred in patients
`who had not been treated previously with natalizumab. which has a known association with PML. and who were not taking
`concomitant immunosuppressive or immunomodulatory medications.
`Typical symptoms associated with PML are diverse. progress over days to weeks. and include progressive weakness on one side
`of the body. oiumsiness of limbs. visual disturbances. and changes in thinking. memory. and orientation. leading to confusion and
`personality changes.
`
`MRI findings may be apparent before clinical signs or symptoms. PML. diagnosed based on MRI findings and detection of JCV
`DNA in the cerebrospinal fluid in the absence of clinical signs or symptoms specific to PML. has been reported in patients treated
`with MS medications associated with PML, including GILENYA. Titer-lore. monitoring with MRI for signs that may be consistent
`with PML may be useful. Any suspicious findings should lead to further investigation to allow for an early diagnosis of PML. Lower
`PML-related morbidity and mortality have been reported following discontinuation of another MS medication associated with PML
`in patients with PML who were initially asymptomatic compared to patients with PML who had characteristic clinical signs and
`symptoms at diagnosis, It is not known whether these differences are due to early detection and discontinuation of MS treatment
`or differences in disease in these patients.
`Atthe first sign or symptom suggestive of PML. withhold GlLENYAand pedorrn an appropriate diagnostic evaluation.
`Macular Edema: Fingolimod increases the risk of macular edema. with or without visual symptoms. Perform an exam at the
`fundus. including the macula. before stoning GILENYA. and 3 to 4 months atlerinitiation Monitor visual acuity at baseline, during
`routine patient evaluations. and It a patient reports visual disturbances while on GILENYA. Patients with diabetes mollltus or
`history of uvsilis are at increased risk and should have regular ophthalmologic evalualions.
`Liver Injury: Clinically significant liver injury has occurred in patients treated with GlLENYA in the postmarketing setting. Signs
`and symptoms ofliver injury, inciudrng markedly elevated serum hepatic enzymes and elevated total bilirubin. have occurred as
`early as 10 days after the first dose and also have been reported after prolonged use. Cases ofacute liver iailure requiring liver
`transplant have been reported.
`Elevation of liver enzymes (ALT. AST. and GGT) 3- and 5-fold the upper timil of normal and greater has occurred with GlLENYA.
`The majority occurred within 6 to 9 months and relumod to normal within 2 months after discontinuing GILENYA. Recurrence of
`liver transaminase elevations occurred with rechailenge in some patients.
`Prior to starting treatment with GILENYA (within 6 months). obtain serum lransaminases (ALT and AST} and iota! bilirubin levels.
`and periodically until 2 months after GILENYA discontinuation, Patients should be monitored for signs and symptoms of any
`hepatic injury. Treatment with GILENYA should be interrupted if the patient is found to have an ALT greaterthan 3 times the
`reference range with serum total bilirubin greater than 2 times the reference range. Patients with severe hepatic impairment
`should be closely monitored, as their risk ofadverse reactions is greater.
`Posterior Reversible Encephalopathy Syndrome (PRES): Rare cases of PRES have been reported with GILENYA. Symptoms
`reported include sudden onset of severe headache. altered mental status. Visual disturbances. and seizure. Symptoms of PRES
`are usually reversible but may evolve into ischemic stroke or cerebrai hemorrhage. Delay in diagnosis and treatment may lead to
`pennanenl neurological sequelao. lf PRES is suspected. GILENYA should be discontinued
`Respiratory Effects: Dose—dependent reductions in forced expiratory volume over 1 second (FEVt) and diffusion lung capacity
`for carbon monoxide (DLCO) were observed in GILENV‘A patients as early as 1 month after initiation. Changes in FEV1 appear to
`be reversible afterdisconlinuing GILENYA: however. there is insufficient information to determine reversibility of DLCO. Obtain
`spirometry and DLCO when clinically indicated.
`Fetal Risk: GiLENYA may cause fetal harm. Woman of childbearing potential should use effective centraception during and tor 2
`months after stopping GlLENYA. A registry for women who become pregnant durrng GILENYA treatment is available. Contact the
`GILENYA Pregnancy Registry by calling 17877759377237, sending an e-mail to gpr@quintiles.ccm, or visiting
`gilsnyagregnancypegistiyopm.
`Severe Increase in Disability After Stopping GILENYA: Severe increase in disability accompanied by multiple new tesions on
`MRI has beln reported following discontinuation of GILENVA in the postmarketing setting, Most of those reported cases did not
`return to the functional status they had before stopping GILENVA, The increase in disability generaliy occurred Within 12 weeks
`aner stopping GILENYA. but was reported up to 24 weeks after GILENYA discontinuation.
`The possibility of severe increase in disability should be considered in patients who discontinue GILENVA. including those who
`are pregnant or planning for pregnancy.
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`GILENYA Patient Services Liaison - Gilonya
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`Monitor patients for development ol severe increase in disability followrng discontinuation of GILENYA and begin appropriate
`treatment as needed.
`
`Increased Blood Pressure (BF): Monitor BP during treatment with GILENVA. An average increase of 3 mm Hg in systoiic and 2
`mm Hg in diastolic EIP was observed in clinical Irlais versus placebo.
`Malignancies: The risk of basat cell carcinoma (ECG) and melanoma is increased in patients treated with GILENYA Melanoma
`and Market cell carcinoma have been reported with GILENYA in the postmarketing setting. Monitor and evaluate suspicious skin
`lesions.
`Cases of lymphoma. including both T-cell arid B—ceil types and CNS lymphoma, have occurred in patients receiving GILENYA,
`The reporting rate oI non-Hodgkin lymphoma with GILENYA is greater than that expected in the general population. Cutaneous
`T-cetl lymphoma (including myoosis fungoides) has also been reported in the postmarketing setting.
`Immune System Effects Following Discontinuation: Fingolimod remains in the blood and has pharmacodynamrc effects,
`including decreased lymphocyte counts for up to 2 months lotlowing the last dose. Lymphocyte counts generally return to normal
`range within 1 to 2 months of stopping therapy. initiating other drugs during this period warrants the same considerations needed
`lor concomitant administration.
`Hypersensitivity Reactions: Hypersensitivity reactions including rash. urticaria, and angioedema have been reported With
`GILENYA.
`
`Drug Interactions: Closely monitor patients receiving systemic ketucunazole. The use of live attenuated vaccines should be
`avoided during. and tor 2 months after stopping GILENVA.
`Common Adverse Reactions: The most common adverse reactions with GILENYA 0.5 mg (incidence 210% and >placebo)
`were headache. livertransamiriase elevations, diarrhea, nausea. cough. influenza. sinusiu‘s, abdominal pain. back pain. and pain
`in extremity.
`Seizure: Cases of seizures. including status epilepticus. have been reported with the use of GILENYA in cliniral trials and in the
`postmarkeling setting in adults. In adult clinical trials. the rate oi seizures was 0.9% in GlLENYA-treated patients and 0.3% in
`placebo-treated patients.
`Pediatric Patients 10 Years of Age and Older: In the pediatric study. the salety profile in pediatnc patients receivrng GILENYA
`0.25 mg or 0.5 mg daily was similar to that seen in adult patients. Cases of seizures were reported in 5.6% of GILENYA-Ireated
`patients and 0.9% of interferon beta-1a-treated patients.
`Please click here tor lull Prescn
`g ntormalion Ior GILENYA.
`
`References: 1. Giienya [prescribing information] East Hanover. NJ Novartrs Pharmaceuticals Corp: August 2019. 2. Kappos
`L. Radue Erw. O‘Connor P. e1 at; for FREEDDMS Study Group A placebo-controlied tnal of oral fingolrmod in retaperng
`multiple scierosrs NEngl J Med 2010,36261'381401 3. Cohen JA BarkhofF, Comi G. et al‘. for TRANSFORMS Study
`Group Oral fingolimod or Intramuscular rnterteron for relapsing multiple sclerOSis, NErrg'l JMed. 2010,362(5):4027415
`4. Data on file Summary oi Clinical Efficacy in Multiple Sclerosn; Novartrs Pharmaceuticals Corp, East Hanover. NJ.
`November 2009 5. Kurtztte JF Rating neurologic impairment in multiple sclerosrs an expanded disability scale (EDSS)
`Neurology 1983;33(11)‘1444.1452 6. Data on file CSR 2302 Novanis Pharmaceuticals Corp: East Hanover. NJ Juty 2008
`7. Data on file, CSR 2381 Nevertis Phan'naoeulrcals Corp; East Hanover, NJ July 2009 8. Ge Y Multiple scleroSis the role
`at MR imagingAJNR Am J Neuroradr'ol. 2066.27t6)‘1155-1176. 9. Herqu SL, Goodrn D3. Multiple sclerDSis and other
`demyelrnating diseases In Fouci AS, Braunweid E. Kasper DL, etal, eds Hamison’s Pnncrpfes of Internal Medicine 17th ed
`New York. NY' The McGraw-Hill Companies. Inc: 2008 2611-2621 10. Data on file Brreling document Novanrs
`Pharmaceuticals Corp, East Hanover, NJ May 2010 11‘ Data on file. GILENYA exposure May 2019 cutott. Novanrs
`Pharmaceuticals Corp. June 2019. 12. Date on file. Hub SRF and Sales Table. Novertis Pharmaceuticals Corp. 04 2017.
`13. Data on file CSR 2309 Novartrs Pharmaceuticals Corp, East Hanover. NJ. July 2009 1-1. Chun J. Harlung H-F‘,
`Mechanism of action of oral fingolimod (W720) in multiple scierosrs Clin Neuropharmacot 2010;33r2):91.101 15. Takabe
`K Paugn SW. Milstien 5, Spregel S "Insrde out' signaling 01 sphrngosrne-1-pnosphate' therapeutic targets. Fhannacol Rev
`2008;60[2]'181-195 16. Data on file GILENYA exposure August 2018 cutoff Novartrs Pharmaceuticals Corp, September
`2013 17. DaMarco JP, O‘Connor P, Cohen JA. et al First-dose effects of fingolimod pooled safety data from three phase 3
`studies MurlRel'aIDrsord 2014,3(5)’629-638 18. Degeute JP, van as Home P, Lintcowski F', et al Quantitative analysrs of
`the ZtLhOUI blood pressure and head rate patterns in young men, HWEFTEJ’ISIOH. 1991;18tztz199-210 15. Zdanowrcz MM,
`Lynch LM Teaching the pharmacology ofentianhythmic dmgs AmJ Pharm Educ 2011.75t7):139 20. Ganusov W, De
`Boer RJ Do most lymphocytes in humans reside in the gut? Trends immune! 200?,28(12)'514-518 21‘ Zheng ZO,
`Notemans DQ, Sedgewrck G, et al Kinetics of CD4+ T cell repopuietton of Iymphord tissues after treatment at HIV—1 rnteclmn
`Proc Nethcao‘ Scr U SA. 1998.95t3):1154—1159. 22. Haynes BF. Soderberg KA, Faucr AS, Introduction to the immune
`syslem in Fauoi AS, ed Hamsori’s Rtieumatology. 2nd edition. New York, NV The McGraw—Hill Companies: 2010'2—43,
`23. Aubagro [prescribing intonnatron]. Cambridge, MA: Genzyme Corp, November 2016
`
`8&9
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