Instructions for Healthcare Providers
`
`oansTsc-us-ozvsvv
`
`@Tecfidera.
`(dimethylfumarate]9"“.....7"i1‘&."u‘t'3'D
`
`To prescribe TECFIDERA. please follow these steps:
`
`0 After discussing TECFIDERA with your patient. have your patient read the Patient Consent Information
`and. if interested. sign the indicated areas on the accompanying Start Form.
`
`Biogen takes your patient's confidentiality very seriously. While patients are not required to sign the Start Form in
`
`order to receive TECFIDERA, signing both lines will expedite their enrollment in Biogen support services, such as
`
`the QuickStart Program and $0 Copay Program [call 1—800—456—2255 for eligibility guidelines]. In addition, with both
`
`signatures, Biogen will have access to your patient's prescription status should you or your patient need assistance.
`
`9 Complete the rest of the Start Form.
`Copy both sides of the patient's medical insurance card and pharmacy benefit card, if available. In some cases, the medical
`
`and pharmacy cards may be the same.
`
`0 Give your patient the Instructions for Patients and Patient Consent Information pages.
`
`Then, fax the Start Form to 1-855-474-3067. Prescriptions are only valid when received via fax.
`
`Your patient will be contacted by a pharmacy in the TECFIDERA Pharmacy Network to arrange for delivery
`
`of the prescription.
`
`Please be sure to fill out all of the sections of the Start Form. Incomplete areas may delay the start of treatment.
`
`If you have any questions or want to learn more about TECFIDERA. please call 1-800-456-2255
`or visit TECFIDERAHCRcom.
`
`225 Binney 5‘79“
`
`”Biogen'
`(Effigy, MA02142
`Tecfiderafgoge 1 0f 23
`
`For Important Safety Information. please see page 2 and accompanying
`full Prescribing Information and Patient Informatio ,
`
`—Blogen Exlublt 2123
`©2018 Biogen.All rights reserved.
`Mylan V. Biogen
`[PR 2018-01403
`
`_
`
`,
`
`Page 1 of 4
`
`

`

`Instructions for Patients
`
`(9Tecfidera.
`[dimethylfumaratelm
`
`03/18 TEC-US-0298 v7
`
`How do I get started?
`
`What happens next?
`
`0 Read the Patient Consent Information and sign
`as indicated in the shaded area of the Start Form.
`
`° You can expect to receive several important phone cells.
`
`These calls will come from a Biogen support coordinator
`
`This will enable you to enroll in Biogen support services,
`
`and a TECFIDERA pharmacy.
`
`such as the QuickStart Program and $0 Copay Program
`
`— You'll see 919-993—7000, a 1-800 number, or
`
`[call 1—800—456-2255 for eligibility guidelines).
`
`9 Be sure to include your email address in the
`space provided.
`
`By giving us your email address, you can stay
`
`up-to-date on the latest news about TECFIDERA.
`
`9 Your doctor fills out the rest of the Start Form.
`You're done. Your doctor will fax us the Start Form.
`
`"unknown" on your caller ID. Please be sure to
`
`answer when you see these calls. They are intended
`
`to help you in getting started on TECFIDERA as
`
`smoothly and quickly as possible.
`
`° Your prescription can be shipped directly to your home.
`
`If you have any questions or want to learn more
`
`about TECFIDERA, please call 1-800-456-2255 or
`visit TECFIDERA.com.
`
`Indication
`
`Tecfidera® ldimethyl fumarate] is a prescription medicine used
`
`to treat people with relapsing forms of multiple sclerosis.
`
`Important Safety Information
`Do not use TECFIDERA if you have had an allergic
`
`reaction [such as welts, hives, swelling of the face, lips,
`
`mouth or tongue, or difficulty breathing] to TECFIDERA
`
`or any of its ingredients.
`
`Before taking and while you take TECFIDERA, tell your
`
`-
`
`-
`
`-
`-
`
`-
`
`severe tiredness
`
`loss of appetite
`
`pain on the right side of your stomach
`dark or brown [tea color] urine
`
`yellowing of your skin or the white part of your eyes
`
`The most common side effects of TECFIDERA include
`
`flushing and stomach problems. These can happen especially
`
`at the start of treatment and may decrease over time. Taking
`
`TECFIDERA with food may help reduce flushing. Call your
`
`doctor if these symptoms bother you or do not go away. Ask
`
`your doctor if taking aspirin before taking TECFIDERA may
`
`doctor about any low white blood cell counts or infections
`
`reduce flushing.
`
`or any other medical conditions.
`
`What are the possible side effects of TECFIDERA?
`
`TECFIDERA may cause serious side effects including:
`
`Allergic reactions
`
`PML, which is a rare brain infection that usually leads
`
`to death or severe disability.
`
`Decreases in your white blood cell count. Your doctor
`
`°
`
`°
`
`0
`
`°
`
`These are not all the possible side effects of TECFIDERA.
`
`Call your doctor for medical advice about side effects.
`
`You may report side effects to FDA at 1-800- FDA-1088.
`
`For more information go to dailymed.nlm.nih.gov.
`
`Tell your doctor if you are pregnant or plan to become
`
`pregnant, or breastfeeding or plan to breastfeed. It is not
`
`known if TECFIDERA will harm your unborn baby or if it
`
`passes into your breast milk. Also tell your doctor if you
`
`should check your white blood cell count before you take
`
`are taking prescription or over-the-counter medicines,
`
`TECFIDERA and from time to time during treatment
`
`Liver problems. Your doctor should do blood tests
`
`to check your liver function before you start taking
`
`vitamins, or herbal supplements. If you take too much
`
`TECFIDERA, call your doctor or go to the nearest hospital
`
`emergency room right away.
`
`TECFIDERA and during treatment if needed. Tell your
`
`For additional Important Safety Information, please
`
`doctor right away if you get any symptoms of a liver
`
`problem during treatment, including:
`
`see accompanying full Prescribing Information and
`
`Patient Information. This is not intended to replace
`
`discussions with your doctor.
`
`Page 2 of 23
`
`Page 2 of 4
`
`

`

`PATIENT CONSENT INFORMATION
`
`©Efifirfiflrflr§llfi§$fi
`
`Please read the following. If you agree, sign and date the corresponding section on the following page.
`
`03/19 TEC'US'0298 V7
`
`I. Authorization to Share Health Information
`
`By signing this Authorization, I authorize my healthcare provider, my health insurance company, and my pharmacy
`providers [“Healthcare Entities] to disclose to Biogen, and companies working with Biogen (collectively, "Biogen"],
`health information relating to my medical condition, treatment, and insurance coverage for Biogen to provide me with
`[i] support services [and related information and materials] related to any of Biogen's products, including but not
`limited to, online support, financial assistance services, compliance and persistency and other therapy support
`services, lii] conduct data analytics, market research and other internal business activities, and [iii] information about
`Biogen's products, services, and programs and othertopics of interest for marketing, educational or other purposes.
`Once my health information has been disclosed to Biogen, I understand that federal privacy laws no longer protect the
`information. However, Biogen agrees to protect my health information by using and disclosing it only for purposes
`authorized in this Authorization or as required by law or regulations. I understand that my pharmacy provider may
`receive remuneration from Biogen in exchange for the health information and/or for any therapy support services
`provided to me.
`
`I understand that I may refuse to sign this Authorization. I further understand that my treatment [including with a
`Biogen product], payment fortreatment, insurance enrollment or eligibility for insurance benefits are not conditioned
`upon my agreement to sign this Authorization; but if I do not sign it or later cancel it, I will not be able to receive
`Biogen's therapy support services.
`
`I may cancel this Authorization at any time by mailing a letterto: Biogen, 5000 Davis Drive, PO Box 13919, Research
`Triangle Park, NC, 27709 orvisiting biogen.com[grivacz. Canceling this Authorization will end my consent to further
`disclosure of my health information to Biogen by my Healthcare Entities after they are notified of my cancellation, but
`will not affect previous disclosures by them pursuant to this Authorization. Canceling this authorization will not affect
`my ability to receive treatment, payment for treatment, or my eligibility for health insurance.
`
`This Authorization expires ten [10] years, or such shorter timeframe required by applicable law, from the day I sign it as
`indicated by the date next to my signature unless otherwise canceled earlier as set forth above.
`
`Please sign in the space in Secu'on 0 on the following page to authorize your consent.
`
`ll. Patient Services and Marketing/Other Communications Authorization
`Patient Services
`
`I authorize Biogen, and companies working with Biogen, to provide me with support services related to any of Biogen's
`products, including but not limited to: online support, financial assistance services, compliance and persistency and
`other therapy support services, as well as any information or materials related to such services. I agree and authorize
`that any nurse providing such support services is not employed by my healthcare professional. I authorize Biogen, and
`companies working with Biogen, to contact me to provide such services and information by mail, email, fax, telephone
`call, text message [including calls and text messages made with an automatic telephone dialing system or a prerecorded
`voice], and other mutually agreed upon means. I also authorize Biogen, and companies working with Biogen, to use
`my health information in connection with the services, including, without limitation, sharing such information with my
`healthcare provider, insurance provider, or pharmacy. I also authorize the disclosure of my health information to specific
`individuals that I have designated.
`
`Marketing/Other Communications
`I further authorize Biogen, and companies working with Biogen, to contact me by mail, email, fax, telephone call, and
`text message for marketing purposes or otherwise provide me with information about Biogen's products, services, and
`programs or other topics of interest, conduct market research or otherwise ask me about my experience with or thoughts
`about such topics. I understand and agree that any information that I provide may be used by Biogen to help develop new
`products, services, and programs. Note that Biogen will not sell or transferyour personal data to any unrelated third party
`for marketing purposes without your express permission. I understand that I may revoke this authorization and choose
`not to receive services or information from Biogen by mailing a letterto the address above orvisiting biogencom/Qrivacy.
`
`Please sign in the space in Section 9 on the following page to authorize your consent.
`
`III. Opt-in for Automated Marketing Calls and Text Messages
`I also consent to receive autodialed and prerecorded marketing calls and text messages from Biogen, and companies
`working with Biogen, at the telephone numberls] that I provide. I understand that my consent is not required as a
`condition of purchasing or receiving any goods or services from Biogen. I understand that I may revoke this
`authorization and choose not to receive automated marketing calls and text messages from Biogen by mailing a
`letter to the address above orvisiting biogen.com[grivacy.
`
`Please check the box in Section 0 on the following page to authorize your consent.
`
`For Impofiagégqu myrmation, please see page 2 and
`
`accompanying full Prescribin Information and Patient Information.
`
`Page 3 0f 4
`
`

`

`Phone: 1-800-456-2255 START FORM
`Fa": 1'855'1‘74'3067
`Patient Information
`E] Male E] Female
`
`I. Authorization to Share Health Information
`I have read and understand theAutha-infionfoSha'eHealthlrformatim and agree to the terms.
`
`9 Tecfidera.
`[dimethylmmarateimfi
`
`03/18 TEC-US-0298 v7
`
`
`
`Signature of patient or patient representative
`
`Date
`
`If signed by patient representative. please explain authority to act on behalf of the patient:
`
`I]. Patient Services and Marketing/Other Communications Authorization
`I have read and understand the Patient Services andMarketing/Othr Cornmunicafions
`Authorizao‘on and agree to the terms.
`
`1 Date
`Signature of patient or patient representative
`In addition, I authorize the disclosure of my health information to the following
`designated individuallsl [optional]:
`
`Designated individual (print name]
`
`Designated individual email
`
`Relationship
`
`Phone
`
`III. Marketing Opt-in
`E] I have read and understand Opt-In to Receive Marketing Communications and
`hereby agree to receive information from Biogen [optional].
`
`First name
`
`Address
`
`City
`
`Date of birth
`
`Email address
`
`Home phone
`
`Cell phone
`
`Last name
`
`State
`
`Zip
`
`E] Preferred number
`E] OK to leave message
`
`E] Preferred number
`E] 0K to leave message
`
`Best time to reach me: E] Morning E] Afternoon E] Evening
`
`Patient preferred language
`
`THE FOLLOWING INFORMATION SHOULD BE FILLED OUT BY YOUR HEALTHCARE PROVIDER
`
`El Samples were provided to patient for 120 mg dose
`Prescription for TECFIDERA
`Month 1
`I] Titration Starter Pack Rx forTECFIDERA:
`120mg P0 BID
`x7 days
`#14 capsules
`2L0mg PO BID
`x23 days
`if“ capsules
`No refills
`Months 2-13
`Maintenance Rx forTECFIDERA:
`3 refills
`#180 capsules
`I] 2“ng PO BID
`x90 days
`11 refills
`#60 capsules
`E] 2L0mg PO BID
`x30 days
`See below or attached for Healthcare Provider Instructions:
`
`Statement of Medical Necessity
`Primary diagnosis: I00 10: 835
`
`Current or most recent therapy
`
`Other therapy [not including TECFIDERA samples]
`
`Height: inches/cm Weight: lbs/kg
`
`Allergies
`
`Prescriber Information
`
`Dates/Duration
`
`D No prior disease-
`”WWW "‘“Pies
`
`QuickStart Program (Optional. at noccstto patient; for commercially insured patients only‘]
`E] Yes, I authorize Bio
`n to provide up to 3 months of TECFIDERA to
`patient at no cost [one
`titration starter
`and ongoin Maintenance Rx, as needed] until
`e patient's presa'hition
`ctuerage is secured. lauthorize
`entofonward this prescriptionto the OuidtStart Program
`designated pharmacy to di
`nse ECFIDERA directly to the above-named patient Patient
`signatures are needed for
`and (BI above to etpedite enrollment in the DuickStart Program.
`‘Pltieru hatred “Irony! Mediid. MediumVA, DoD. TRICARE'. and other governmental haunt“
`are MT elig‘ble for tII's prey-em.
`DuickStart Rx for TECFIDERA:
`Titration Rx
`120mg P0 BID
`240mg PO BID
`Maintenance Rx
`2L0mg P0 BID
`
`x15 days
`
`#28 capsules
`
`1O refills
`
`x7 days
`x7 days
`
`#15 capsules
`#16 capsules
`
`First name
`
`Address
`
`City
`
`Phone
`
`NPI #
`
`Last name
`
`State
`
`Fax
`
`Tax ID #
`
`Zip
`
`Clinical/Hospital affiliation
`
`Office contact name
`
`Besttime to contact: El Morning El Afternoon
`
`
`* Medical Benefit Information
`Pharmacy Benefit Information
`
`Attach copies of both sides of patient's pharmacy benefit carols].
`
`I:I Check if no coverage E] Check if patient has secondary insurance
`Primary insurance
`Polio] ff
`
`Group 4!
`Patient preferred specialty pharmacy
`
`
`
`Policyholder first name
`
`Polio/holder last name
`
`Prescriber Authorization‘
`I authorize Biogen as my designated agent and on behalf of my patient to I1] fonrvard the above statement of medical necessity and furnish any information on this form to the insurer
`of the above-named patient and [2] forward the above prescription, by fax or other mode of delivery, to the pharmacy chosen by the above-named patient. I certify that the rationale
`for prescribing TECFIDERA therapy is for a primary diagnosis of ICD-ID: 635, and I will be supervising the patient's treatment accordingly.
`
`
`
`
`
`Date
`
`
`
`Prescriber signature [Substitution Permitted] Signature stamps not acceptable:
`
`
` Insurance company phone
`
`
`'In New Yor , please attach copies of all prescriptions on Official New York State Prescription forms Prescriber signature (Dispense as written] Signature stamps not acceptable:
`
`Dat*Pa e 4 of 23
`
`Page 4 of 4
`
`

`

` ___________________
`CONTRAINDICATIONS
`Known hypersensitivity to dimethyl fumarate or any of the excipients of
`TECFIDERA. (4)
`
`
` ___________________
`
`
` _______________
` _______________
`WARNINGS AND PRECAUTIONS
`
`• Anaphylaxis and angioedema: Discontinue and do not restart TECFIDERA
`if these occur. (5.1)
`• Progressive multifocal leukoencephalopathy (PML): Withhold
`TECFIDERA at the first sign or symptom suggestive of PML. (5.2)
`• Lymphopenia: Obtain a CBC including lymphocyte count before initiating
`TECFIDERA, after 6 months, and every 6 to 12 months thereafter.
`Consider interruption of TECFIDERA if lymphocyte counts <0 5 x 109/L
`persist for more than six months. (5.3)
`• Liver injury: Obtain serum aminotransferase, alkaline phosphatase, and
`total bilirubin levels before initiating TECFIDERA and during treatment,
`as clinically indicated. Discontinue TECFIDERA if clinically significant
`liver injury induced by TECFIDERA is suspected. (5.4)
`
`
`
` ___________________
`
`ADVERSE REACTIONS
`Most common adverse reactions (incidence ≥10% and ≥2% placebo) were
`flushing, abdominal pain, diarrhea, and nausea. (6.1)
`
`To report SUSPECTED ADVERSE REACTIONS, contact Biogen at 1-
`800-456-2255 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`
` ___________________
`
`
` ______________
`
` _______________
`USE IN SPECIFIC POPULATIONS
`
`Pregnancy: Based on animal data, may cause fetal harm. (8.1)
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`approved patient labeling
`
`Revised: 12/2017
`
`8.4
`
`8.5
`
`Pediatric Use
`
`Geriatric Use
`
`10 OVERDOSE
`
`11 DESCRIPTION
`
`12 CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`
`12.2
`
`Pharmacodynamics
`
`12.3
`
`Pharmacokinetics
`
`13 NONCLINICAL TOXICOLOGY
`
`13.1
`
`Carcinogenesis, Mutagenesis, Impairment of
`Fertility
`
`13.2 Animal Toxicology and/or Pharmacology
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`TECFIDERA safely and effectively. See full prescribing information for
`TECFIDERA.
`
`TECFIDERA® (dimethyl fumarate) delayed-release capsules, for oral use
`Initial U.S. Approval: 2013
`
` _________________
`
` _________________
`RECENT MAJOR CHANGES
`Dosage and Administration, Blood Tests Prior to
`Initiation of Therapy (2.2)
`Warnings and Precautions, PML (5.2)
`Warnings and Precautions, Liver Injury (5.4)
`
`
`1/2017
`12/2017
`1/2017
`
`
`
` __________________
` _________________
`
`INDICATIONS AND USAGE
`TECFIDERA is indicated for the treatment of patients with relapsing forms of
`multiple sclerosis (1)
`
` _______________
` ______________
`DOSAGE AND ADMINISTRATION
`• Starting dose: 120 mg twice a day, orally, for 7 days (2.1)
`• Maintenance dose after 7 days: 240 mg twice a day, orally (2.1)
`• Swallow TECFIDERA capsules whole and intact. Do not crush, chew, or
`sprinkle capsule contents on food (2.1)
`• Take TECFIDERA with or without food (2.1)
`
`
`
` ______________
` _____________
`DOSAGE FORMS AND STRENGTHS
`Delayed-release capsules: 120 mg and 240 mg (3)
`
`
`
`
`
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`INDICATIONS AND USAGE
`
`DOSAGE AND ADMINISTRATION
`
`2.1
`
`2.2
`
`Dosing Information
`
`Blood Tests Prior to Initiation of Therapy
`
`DOSAGE FORMS AND STRENGTHS
`
`CONTRAINDICATIONS
`
` 1
`
`
`
`2
`
`3
`
`4
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1
`
`5.2
`
`5.3
`
`5.4
`
`5.5
`
`Anaphylaxis and Angioedema
`
`Progressive Multifocal Leukoencephalopathy
`
`Lymphopenia
`
`Liver Injury
`
`Flushing
`
`6
`
`ADVERSE REACTIONS
`
`14 CLINICAL STUDIES
`
`6.1
`
`6.2
`
`Clinical Trials Experience
`
`Post Marketing Experience
`
`8
`
`USE IN SPECIFIC POPULATIONS
`
`8.1
`
`8.2
`
`Pregnancy
`
`Lactation
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`17 PATIENT COUNSELING INFORMATION
`
`*Sections or subsections omitted from the full prescribing information are not
`listed.
`
`
`
`
`
`
`1
`
`
`
`
`
`Page 5 of 23
`
`

`

`
`
`FULL PRESCRIBING INFORMATION
`
`1
`
`INDICATIONS AND USAGE
`
`TECFIDERA is indicated for the treatment of patients with relapsing forms of multiple sclerosis.
`
`2
`
`DOSAGE AND ADMINISTRATION
`
`2.1
`
`Dosing Information
`
`The starting dose for TECFIDERA is 120 mg twice a day orally. After 7 days, the dose should
`be increased to the maintenance dose of 240 mg twice a day orally. Temporary dose reductions
`to 120 mg twice a day may be considered for individuals who do not tolerate the maintenance
`dose. Within 4 weeks, the recommended dose of 240 mg twice a day should be resumed.
`Discontinuation of TECFIDERA should be considered for patients unable to tolerate return to
`the maintenance dose. The incidence of flushing may be reduced by administration of
`TECFIDERA with food. Alternatively, administration of non-enteric coated aspirin (up to a dose
`of 325 mg) 30 minutes prior to TECFIDERA dosing may reduce the incidence or severity of
`flushing [see Clinical Pharmacology (12.3)].
`
`
`
`TECFIDERA should be swallowed whole and intact. TECFIDERA should not be crushed or
`chewed and the capsule contents should not be sprinkled on food. TECFIDERA can be taken
`with or without food.
`
`2.2
`
`Blood Tests Prior to Initiation of Therapy
`
`Obtain a complete blood cell count (CBC) including lymphocyte count before initiation of
`therapy [see Warnings and Precautions (5.3)].
`
`Obtain serum aminotransferase, alkaline phosphatase, and total bilirubin levels prior to treatment
`with TECFIDERA [see Warnings and Precautions (5.4)].
`
`3
`
`DOSAGE FORMS AND STRENGTHS
`
`TECFIDERA is available as hard gelatin delayed-release capsules containing 120 mg or 240 mg
`of dimethyl fumarate. The 120 mg capsules have a green cap and white body, printed with “BG-
`12 120 mg” in black ink on the body. The 240 mg capsules have a green cap and a green body,
`printed with “BG-12 240 mg” in black ink on the body.
`
`4
`
`CONTRAINDICATIONS
`
`TECFIDERA is contraindicated in patients with known hypersensitivity to dimethyl fumarate or
`to any of the excipients of TECFIDERA. Reactions have included anaphylaxis and angioedema
`[see Warnings and Precautions (5.1)].
`
`
`
`
`
`
`
`
`
`Page 6 of 23
`
`

`

`
`
`5
`
`WARNINGS AND PRECAUTIONS
`
`5.1
`
`Anaphylaxis and Angioedema
`
`TECFIDERA can cause anaphylaxis and angioedema after the first dose or at any time during
`treatment. Signs and symptoms have included difficulty breathing, urticaria, and swelling of the
`throat and tongue. Patients should be instructed to discontinue TECFIDERA and seek immediate
`medical care should they experience signs and symptoms of anaphylaxis or angioedema.
`
`Progressive Multifocal Leukoencephalopathy
`5.2
`Progressive multifocal leukoencephalopathy (PML) has occurred in patients with MS treated
`with TECFIDERA. 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. A fatal case of PML occurred in a patient who received
`TECFIDERA for 4 years while enrolled in a clinical trial. During the clinical trial, the patient
`experienced prolonged lymphopenia (lymphocyte counts predominantly <0.5x109/L for 3.5
`years) while taking TECFIDERA [see Warnings and Precautions (5.3)]. The patient had no
`other identified systemic medical conditions resulting in compromised immune system function
`and had not previously been treated with natalizumab, which has a known association with PML.
`The patient was also not taking any immunosuppressive or immunomodulatory medications
`concomitantly.
`
`PML has also occurred in the postmarketing setting in the presence of lymphopenia (<0.8x109/L)
`persisting for more than 6 months. While the role of lymphopenia in these cases is uncertain, the
`majority of cases occurred in patients with lymphocyte counts <0.5x 109/L.
`
`At the first sign or symptom suggestive of PML, withhold TECFIDERA and perform an
`appropriate diagnostic evaluation. 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.
`
`MRI findings may be apparent before clinical signs or symptoms. Cases of PML, diagnosed
`based on MRI findings and the detection of JCV DNA in the cerebrospinal fluid in the absence
`of clinical signs or symptoms specific to PML, have been reported in patients treated with other
`MS medications associated with PML. Many of these patients subsequently became
`symptomatic with PML. Therefore, monitoring with MRI for signs that may be consistent with
`PML may be useful, and any suspicious findings should lead to further investigation to allow for
`an early diagnosis of PML, if present. Lower PML-related mortality and morbidity 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 due to differences
`in disease in these patients.
`
`
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`5.3
`
`Lymphopenia
`
`TECFIDERA may decrease lymphocyte counts. In the MS placebo controlled trials, mean
`lymphocyte counts decreased by approximately 30% during the first year of treatment with
`TECFIDERA and then remained stable. Four weeks after stopping TECFIDERA, mean
`lymphocyte counts increased but did not return to baseline. Six percent (6%) of TECFIDERA
`patients and <1% of placebo patients experienced lymphocyte counts <0.5x109/L (lower limit of
`normal 0.91x109/L). The incidence of infections (60% vs 58%) and serious infections (2% vs
`2%) was similar in patients treated with TECFIDERA or placebo, respectively. There was no
`increased incidence of serious infections observed in patients with lymphocyte counts
`<0.8x109/L or <0.5x109/L in controlled trials, although one patient in an extension study
`developed PML in the setting of prolonged lymphopenia (lymphocyte counts predominantly
`<0.5x109/L for 3.5 years) [see Warnings and Precautions (5.2)].
`
`In controlled and uncontrolled clinical trials, 2% of patients experienced lymphocyte counts <0.5
`x 109/L for at least six months, and in this group the majority of lymphocyte counts remained
`<0.5x109/L with continued therapy. TECFIDERA has not been studied in patients with pre-
`existing low lymphocyte counts.
`
`Obtain a CBC, including lymphocyte count, before initiating treatment with TECFIDERA, 6
`months after starting treatment, and then every 6 to 12 months thereafter, and as clinically
`indicated. Consider interruption of TECFIDERA in patients with lymphocyte counts less than
`0.5 x 109/L persisting for more than six months. Given the potential for delayed recovery of
`lymphocyte counts, continue to obtain lymphocyte counts until their recovery if TECFIDERA is
`discontinued or interrupted due to lymphopenia. Consider withholding treatment from patients
`with serious infections until resolution. Decisions about whether or not to restart TECFIDERA
`should be individualized based on clinical circumstances.
`
`5.4
`
`Liver Injury
`
`Clinically significant cases of liver injury have been reported in patients treated with
`TECFIDERA in the postmarketing setting. The onset has ranged from a few days to several
`months after initiation of treatment with TECFIDERA. Signs and symptoms of liver injury,
`including elevation of serum aminotransferases to greater than 5-fold the upper limit of normal
`and elevation of total bilirubin to greater than 2-fold the upper limit of normal have been
`observed. These abnormalities resolved upon treatment discontinuation. Some cases required
`hospitalization. None of the reported cases resulted in liver failure, liver transplant, or death.
`However, the combination of new serum aminotransferase elevations with increased levels of
`bilirubin caused by drug-induced hepatocellular injury is an important predictor of serious liver
`injury that may lead to acute liver failure, liver transplant, or death in some patients.
`
`Elevations of hepatic transaminases (most no greater than 3 times the upper limit of normal)
`were observed during controlled trials [see Adverse Reactions (6.1)].
`
`Obtain serum aminotransferase, alkaline phosphatase (ALP), and total bilirubin levels prior to
`treatment with TECFIDERA and during treatment, as clinically indicated. Discontinue
`TECFIDERA if clinically significant liver injury induced by TECFIDERA is suspected.
`
`
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`
`5.5
`
`Flushing
`
`TECFIDERA may cause flushing (e.g., warmth, redness, itching, and/or burning sensation). In
`clinical trials, 40% of TECFIDERA treated patients experienced flushing. Flushing symptoms
`generally began soon after initiating TECFIDERA and usually improved or resolved over time.
`In the majority of patients who experienced flushing, it was mild or moderate in severity. Three
`percent (3%) of patients discontinued TECFIDERA for flushing and <1% had serious flushing
`symptoms that were not life-threatening but led to hospitalization. Administration of
`TECFIDERA with food may reduce the incidence of flushing. Alternatively, administration of
`non-enteric coated aspirin (up to a dose of 325 mg) 30 minutes prior to TECFIDERA dosing may
`reduce the incidence or severity of flushing [see Dosing and Administration (2.1) and Clinical
`Pharmacology (12.3)].
`
`6
`
`ADVERSE REACTIONS
`
`The following important adverse reactions are described elsewhere in labeling:
`
`• Anaphylaxis and Angioedema [see Warnings and Precautions (5.1)].
`
`• Progressive multifocal leukoencephalopathy [see Warnings and Precautions (5.2)].
`
`• Lymphopenia [see Warnings and Precautions (5.3)].
`
`• Liver Injury [see Warnings and Precautions (5.4)].
`
`• Flushing [see Warnings and Precautions (5.5)].
`
`6.1
`
`Clinical Trials Experience
`
`Because clinical trials are conducted under widely varying conditions, adverse reaction rates
`observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of
`another drug and may not reflect the rates observed in clinical practice.
`
`The most common adverse reactions (incidence ≥10% and ≥2% more than placebo) for
`TECFIDERA were flushing, abdominal pain, diarrhea, and nausea.
`
`Adverse Reactions in Placebo-Controlled Trials
`
`In the two well-controlled studies demonstrating effectiveness, 1529 patients received
`TECFIDERA with an overall exposure of 2244 person-years [see Clinical Studies (14)].
`
`The adverse reactions presented in the table below are based on safety information from 769
`patients treated with TECFIDERA 240 mg twice a day and 771 placebo-treated patients.
`
`Table 1:
`
`Adverse Reactions in Study 1 and 2 reported for TECFIDERA 240 mg BID
`at ≥ 2% higher incidence than placebo
`
`
`
`
`Flushing
`Abdominal pain
`Diarrhea
`Nausea
`
`
`
`
`TECFIDERA
`N=769
`%
`
`Placebo
`N=771
`%
`
`
`
`
`
`6
`10
`11
`9
`
`40
`18
`14
`12
`
`
`
`
`
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`Page 9 of 23
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`

`Vomiting
`Pruritus
`Rash
`Albumin urine present
`Erythema
`Dyspepsia
`Aspartate aminotransferase increased
`Lymphopenia
`
`9
`8
`8
`6
`5
`5
`4
`2
`
`Gastrointestinal
`
`5
`4
`3
`4
`1
`3
`2
`<1
`
`TECFIDERA caused GI events (e.g., nausea, vomiting, diarrhea, abdominal pain, and
`dyspepsia). The incidence of GI events was higher early in the course of treatment (primarily in
`month 1) and usually decreased over time in patients treated with TECFIDERA compared with
`placebo. Four percent (4%) of patients treated with TECFIDERA and less than 1% of placebo
`patients discontinued due to gastrointestinal events. The incidence of serious GI events was 1%
`in patients treated with TECFIDERA.
`
`Hepatic Transaminases
`
`An increased incidence of elevations of hepatic transaminases in patients treated with
`TECFIDERA was seen primarily during the first six months of treatment, and most patients with
`elevations had levels < 3 times the upper limit of normal (ULN) during controlled trials.
`Elevations of alanine aminotransferase and aspartate aminotransferase to ≥ 3 times the ULN
`occurred in a small number of patients treated with both TECFIDERA and placebo and were
`balanced between groups. There were no elevations in transaminases ≥ 3 times the ULN with
`concomitant elevations in total bilirubin > 2 times the ULN. Discontinuations due to elevated
`hepatic transaminases were < 1% and were similar in patients treated with TECFIDERA or
`placebo.
`
`Eosinophilia
`
`A transient increase in mean eosinophil counts was seen during the first 2 months of therapy.
`
`Adverse Reactions in Placebo-Controlled and Uncontrolled Studies
`
`In placebo-controlled and uncontrolled clinical studies, a total of 2513 patients have received
`TECFIDERA and been followed for periods up to 4 years with an overall exposure of 4603
`person-years. Approximately 1162 patients have received more than 2 years of treatment with
`TECFIDERA. The adverse reaction profile of TECFIDERA in the uncontrolled cl