Safety & Monitoring | Tecfidera® (dimethyl fumarate)
`tecfiderahcp.com/en us/home/to erab ty-and-safety/safety.htm
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`DEMONSTRATED SAFETY PROFILE
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`Contraindication
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`TECFIDERA is contraindicated in patients with known hypersensitivity to dimethyl fumarate or to
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`any of the excipients of TECFIDERA. Reactions have included anaphylaxis and angioedema
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`Warnings and Precautions
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`Warning
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`Can occur after the first dose or anytime during treatment with TECFIDERA
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`Signs and symptoms
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`Include difficulty breathing, urticaria, and swelling of the throat and tongue
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`Guidance
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`Discontinue TECFIDERA and seek immediate medical care
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`Warning
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`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
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`Details
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`A fatal case of PML occurred in a patient who received TECFIDERA for 4 years while
`enrolled in a clinical trial
`Patient experienced prolonged lymphopenia (lymphocyte counts predominantly
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`<0.5x10 /L for 3.5 years) while taking TECFIDERA
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`PML has also occurred in the postmarketing setting in the presence of lymphopenia
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`Biogen Exhibit 2195
`Mylan v. Biogen
`IPR 2018-01403
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`(<0.8x10 /L)
`persisting for more than 6 months
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`While the role of lymphopenia in these cases is uncertain, the majority of cases occurred
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`in patients with lymphocyte counts <0.5x10 /L
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`Signs and symptoms
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`Diverse and progress over days to weeks
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`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
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`MRI findings may be apparent before clinical signs or symptoms
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`Guidance
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`At the first sign or symptom suggestive of PML, withhold TECFIDERA and perform an
`appropriate diagnostic evaluation
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`For additional information, please see full Prescribing Information.
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`Warning
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`TECFIDERA may decrease lymphocyte counts
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`Details
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`During the first year in clinical trials, mean lymphocyte counts decreased by approximately
`30% 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
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`lymphocyte counts <0.5x10 /L (lower limit of normal 0.91x10 /L)
`In controlled and uncontrolled clinical trials, 2% of patients experienced lymphocyte
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`counts <0.5x10 /L for at least six months, and in this group, the majority of lymphocyte
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`counts remained <0.5x10 /L with continued therapy
`TECFIDERA has not been studied in patients with pre-existing low lymphocyte counts
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`Guidance
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`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
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`Consider interruption of TECFIDERA in patients with lymphocyte counts <0.5x10 /L
`persisting for more than six months
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`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
`Restart TECFIDERA based on individual and clinical circumstances
`Please see Infections below for additional details
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`Warning
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`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
`None of the reported cases resulted in liver failure, liver transplant, or death. Some cases
`required hospitalization
`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
`
`Signs and symptoms
`
`Include elevation of serum aminotransferases to greater than 5-fold the upper limit of
`normal (ULN) and elevation of total bilirubin to greater than 2-fold the ULN
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`Guidance
`
`Obtain serum aminotransferase, alkaline phosphatase, 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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`Warning
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`May occur during treatment with TECFIDERA. In clinical trials, 40% experienced flushing
`3% of patients discontinued TECFIDERA because of flushing and <1% had serious flushing
`symptoms that were not life-threatening but led to hospitalization
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`Signs and symptoms
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`Generally began soon after initiating treatment and usually improved or resolved over
`time
`Include warmth, redness, itching, and/or burning sensation
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`Guidance
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`Taking TECFIDERA with food may help with flushing
`A high-fat, high-calorie meal did not affect overall exposure to TECFIDERA*
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`Alternatively, taking non-enteric coated aspirin (up to a dose of 325 mg) 30 minutes prior
`to TECFIDERA dosing may reduce the incidence and severity of flushing
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`Advise patients to contact their healthcare provider if they experience persistent and/or
`severe flushing
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`ROUTINE MONITORING FOR YOUR PATIENTS
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`TECFIDERA MAY DECREASE LYMPHOCYTE COUNTS
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`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
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`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 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
`9
`(<0.8x10 /L) persisting for more than 6 months. While the role of lymphopenia in these cases is
`9
`uncertain, the majority of cases occurred in patients with lymphocyte counts <0.5x10 /L. The
`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. 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
`9
`TECFIDERA patients and <1% of placebo patients had lymphocyte counts <0.5x10 /L. TECFIDERA
`has not been studied in patients with pre-existing low lymphocyte counts.
`
`There was no increased incidence of serious infections observed in patients with lymphocyte
`9
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`counts <0.8x10 /L or ≤0.5x10 /L in controlled trials, although one patient in an extension study
`developed PML in the setting of prolonged lymphopenia (lymphocyte counts predominantly
`9
`<0.5x10 /L for 3.5 years). In controlled and uncontrolled clinical trials, 2% of patients
`9
`experienced lymphocyte counts <0.5x10 /L for at least six months. In these patients, the
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`majority of lymphocyte counts remained <0.5x10 /L with 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
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`interruption if lymphocyte counts <0.5x10 /L persist for more than six months and 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
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`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.
`
`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%).
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`A transient increase in mean eosinophil counts was seen during the first two months.
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`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.
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`i n In m i noi in Please see full ePrescribing Information and n Patient Information for additional
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`Important Safety Information.
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`*A high-fat, high-calorie meal did not affect the overall exposure to MMF, a TECFIDERA
`metabolite, but decreased the maximal plasma concentration and increased the time until this
`concentration was reached. A high-fat, high-calorie meal reduced the incidence of flushing by
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`approximately 25%.
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`References: 1. TECFIDERA Prescribing Information, Biogen, Cambridge, MA. 2. Biogen, Data on
`file.
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