Tolerability Management | Tecfidera® (dimethyl fumarate)
`
`https://www.tecfiderahcp.com/en_us/home/tolerability-and-safety/tolerabi...
`
`Important Safety Information
`TECFIDERA Warnings and Precautions include: Anaphylaxis and Angioedema, Progressive Multifocal
`Leukoencephalopathy, Lymphopenia, Liver Injury, and Flushing.
`
`EXPAND
`
`TOLERABILITY MANAGEMENT
`PROVEN STRATEGIES TO NAVIGATE MOST COMMON SIDE
`EFFECTS
`
`Empower your patients from the start by setting expectations of flushing and GI symptoms
`
`Taking TECFIDERA with breakfast and dinner may help
`with flushing and GI events
`1,2
`A high-fat, high-calorie meal did not affect overall
`exposure to TECFIDERA and reduced the incidence of
`flushing by approximately 25%
`1
`In a study of 233 RMS patients, participants took DMF for
`up to 12 weeks and recorded information regarding GI
`events. The GI events were self-reported by participants
`using an eDiary with 2 questionnaires designed to obtain
`detailed information about the incidence, severity,
`duration, onset, and management of GI symptoms
`2
`
`Taking non-enteric coated aspirin (up to 325 mg) half an
`hour before taking TECFIDERA may reduce the
`frequency and severity of flushing
`1
`
`1 of 4
`
`4/8/2019, 6:04 PM
`
`Biogen Exhibit 2193
`Mylan v. Biogen
`IPR 2018-01403
`
`Page 1 of 4
`
`

`

`Tolerability Management | Tecfidera® (dimethyl fumarate)
`
`https://www.tecfiderahcp.com/en_us/home/tolerability-and-safety/tolerabi...
`
`Temporary dose reductions to 120 mg twice daily may
`help in managing flushing for individuals who cannot
`tolerate the maintenance dose
`1
`Within 4 weeks, resume the recommended dose of 240
`mg twice a day
`1
`7-day samples of 120 mg TECFIDERA are available
`through the TECFIDERA Sample Program to provide
`temporary dose reductions
`
`If the maintenance dose still proves to be a challenge,
`discontinuation of TECFIDERA should be considered
`1
`
`Remind your patients that Biogen Support Coordinators
`are available to assist with any questions or concerns
`Patients can call 1-800-456-2255, Monday through Friday
`from 8:30 AM until 8 PM ET
`
`Indication
`®
`Tecfidera (dimethyl fumarate) is indicated for the treatment of patients with relapsing forms of multiple
`sclerosis.
`Important Safety Information
`TECFIDERA is contraindicated in patients with known hypersensitivity to dimethyl fumarate or any of
`the excipients of TECFIDERA. TECFIDERA can cause anaphylaxis and angioedema after the first dose
`or at any time during treatment. Patients experiencing signs and symptoms of anaphylaxis and
`angioedema (which have included difficulty breathing, urticaria, and swelling of the throat and tongue)
`should discontinue TECFIDERA and seek immediate medical care.
`
`Progressive multifocal leukoencephalopathy (PML) has occurred in patients with MS treated with
`
`2 of 4
`
`4/8/2019, 6:04 PM
`
`Page 2 of 4
`
`

`

`Tolerability Management | Tecfidera® (dimethyl fumarate)
`
`https://www.tecfiderahcp.com/en_us/home/tolerability-and-safety/tolerabi...
`
`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 in a clinical trial.
`PML has also occurred in the postmarketing setting in the presence of lymphopenia (<0.8x10 /L)
`9
`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 <0.5x10 /L. The symptoms associated
`9
`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. At the first sign or symptom suggestive of
`PML, withhold TECFIDERA and perform an appropriate diagnostic evaluation. MRI findings may be
`apparent before clinical signs or symptoms.
`
`TECFIDERA may decrease lymphocyte counts; in clinical trials there was a mean decrease of ~30% in
`lymphocyte counts during the first year which then remained stable. Four weeks after stopping
`TECFIDERA, mean lymphocyte counts increased but not to baseline. Six percent of TECFIDERA
`patients and <1% of placebo patients had lymphocyte counts <0.5x10 /L. TECFIDERA has not been
`9
`studied in patients with pre-existing low lymphocyte counts.
`
`There was no increased incidence of serious infections observed in patients with lymphocyte counts
`<0.8x10 /L or 0.5x10 /L in controlled trials, although one patient in an extension study developed PML
`9
`9
`in the setting of prolonged lymphopenia (lymphocyte counts predominantly <0.5x10 /L for 3.5 years). In
`9
`controlled and uncontrolled clinical trials, 2% of patients experienced lymphocyte counts <0.5x10 /L for
`9
`at least six months. In these patients, the majority of lymphocyte counts remained <0.5x10 /L with
`9
`continued therapy. A complete blood count including lymphocyte count should be obtained before
`initiating treatment, 6 months after starting, every 6 to 12 months thereafter and as clinically indicated.
`Consider treatment interruption if lymphocyte counts <0.5x10 /L persist for more than six months and
`9
`follow lymphocyte counts until lymphopenia is resolved. Consider withholding treatment in patients with
`serious infections until resolved. Decisions about whether or not to restart TECFIDERA should be
`based on clinical circumstances.
`
`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. 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.
`
`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.
`
`TECFIDERA may cause flushing (e.g. warmth, redness, itching, and/or burning sensation). 40% of
`patients taking TECFIDERA reported flushing, which was mostly mild to moderate in severity. Three
`percent of patients discontinued TECFIDERA for flushing and <1% had serious flushing events that led
`to hospitalization. Taking TECFIDERA with food may reduce flushing. Alternatively, administration of
`non-enteric coated aspirin prior to dosing may reduce the incidence or severity of flushing.
`
`3 of 4
`
`4/8/2019, 6:04 PM
`
`Page 3 of 4
`
`

`

`Tolerability Management | Tecfidera® (dimethyl fumarate)
`
`https://www.tecfiderahcp.com/en_us/home/tolerability-and-safety/tolerabi...
`
`TECFIDERA may cause gastrointestinal (GI) events (e.g., nausea, vomiting, diarrhea, abdominal pain,
`and dyspepsia). Four percent of TECFIDERA patients and <1% of placebo patients discontinued due to
`GI events. The incidence of serious GI events was 1%. The most common adverse reactions
`associated with TECFIDERA versus placebo are flushing (40% vs 6%) and GI events: abdominal pain
`(18% vs 10%), diarrhea (14% vs 11%), nausea (12% vs 9%).
`
`A transient increase in mean eosinophil counts was seen during the first two months.
`
`TECFIDERA should be used during pregnancy only if the potential benefit justifies the potential risk to
`the fetus. Encourage patients who become pregnant while taking TECFIDERA to enroll in the
`TECFIDERA pregnancy registry by calling 1-866-810-1462 or visiting
`www.TECFIDERApregnancyregistry.com.
`
`Please see full Prescribing Information and Patient Information for additional Important Safety
`Information.
`
`References: 1. TECFIDERA Prescribing Information, Biogen, Cambridge, MA. 2. Fox E, Vasquez A, Grainger W, et al. Int J MS Care. 2016;18(1):9-18.
`
`© 2019 Biogen. All Rights Reserved. 02/19
`
`4 of 4
`
`4/8/2019, 6:04 PM
`
`Page 4 of 4
`
`