bafiertam

Important safety information

Anaphylaxis and Angioedema: Discontinue and do not restart BAFIERTAM if these occur. ( 5.1 ) Progressive Multifocal Leukoencephalopathy (PML): Withhold BAFIERTAM at the first sign or symptom suggestive of PML. ( 5.2 ) Herpes Zoster and Other Serious Opportunistic Infections: Consider withholding BAFIERTAM in cases of serious infection until the infection has resolved. ( 5.3 ) Lymphopenia: Obtain a CBC including lymphocyte count before initiating BAFIERTAM, after 6 months, and every 6 to 12 months thereafter. Consider interruption of BAFIERTAM if lymphocyte counts <0.5 x 10 9 /L persist for more than six months. ( 5.4 ) Liver Injury: Obtain serum aminotransferase, alkaline phosphatase, and total bilirubin levels before initiating BAFIERTAM and during treatment, as clinically indicated. Discontinue BAFIERTAM if clinically significant liver injury induced by BAFIERTAM is suspected. ( 5.5 ) 5.1 Anaphylaxis and Angioedema BAFIERTAM can cause anaphylaxis and angioedema after the first dose or at any time during treatment. Signs and symptoms in patients taking dimethyl fumarate (the prodrug of BAFIERTAM) have included difficulty breathing, urticaria, and swelling of the throat and tongue. Patients should be instructed to discontinue BAFIERTAM and seek immediate medical care should they experience signs and symptoms of anaphylaxis or angioedema. 5.2 Progressive Multifocal Leukoencephalopathy Progressive multifocal leukoencephalopathy (PML) has occurred in patients with MS treated with dimethyl fumarate (the prodrug of BAFIERTAM). 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 dimethyl fumarate for 4 years while enrolled in a clinical trial. During the clinical trial, the patient experienced prolonged lymphopenia (lymphocyte counts predominantly <0.5x10 9 /L for 3.5 years) while taking dimethyl fumarate [see Warnings and Precautions ( 5.4 )] . 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 patients taking dimethyl fumarate in the postmarketing setting in the presence of lymphopenia (<0.9x10 9 /L). While the role of lymphopenia in these cases is uncertain, the PML cases have occurred predominantly in patients with lymphocyte counts <0.8x10 9 /L persisting for more than 6 months. At the first sign or symptom suggestive of PML, withhold BAFIERTAM 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. Magnetic resonance imaging (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. 5.3 Herpes Zoster and Other Serious Opportunistic Infections Serious cases of herpes zoster have occurred with dimethyl fumarate (the prodrug of BAFIERTAM), including disseminated herpes zoster, herpes zoster ophthalmicus, herpes zoster meningoencephalitis, and herpes zoster meningomyelitis. These events may occur at any time during treatment. Monitor patients on BAFIERTAM for signs and symptoms of herpes zoster. If herpes zoster occurs, appropriate treatment for herpes zoster should be administered. Other serious opportunistic infections have occurred with dimethyl fumarate, including cases of serious viral (herpes simplex virus, West Nile virus, cytomegalovirus), fungal (Candida and Aspergillus), and bacterial (Nocardia, Listeria monocytogenes, Mycobacterium tuberculosis) infections. These infections have been reported in patients with reduced absolute lymphocyte counts (ALC) as well as in patients with normal ALC. These infections have affected the brain, meninges, spinal cord, gastrointestinal tract, lungs, skin, eye, and ear. Patients with symptoms and signs consistent with any of these infections should undergo prompt diagnostic evaluation and receive appropriate treatment. Consider withholding BAFIERTAM treatment in patients with herpes zoster or other serious infections until the infection has resolved [see Adverse Reactions ( 6.2 )]. 5.4 Lymphopenia BAFIERTAM may decrease lymphocyte counts. In the MS placebo-controlled trials with dimethyl fumarate (the prodrug of BAFIERTAM), mean lymphocyte counts decreased by approximately 30% during the first year of treatment with dimethyl fumarate and then remained stable. Four weeks after stopping dimethyl fumarate, mean lymphocyte counts increased, but did not return to baseline. Six percent (6%) of dimethyl fumarate patients and <1% of placebo patients experienced lymphocyte counts <0.5x10 9 /L (lower limit of normal 0.91x10 9 /L). The incidence of infections (60% vs 58%) and serious infections (2% vs 2%) was similar in patients treated with dimethyl fumarate or placebo, respectively. There was no increased incidence of serious infections observed in patients with lymphocyte counts <0.8x10 9 /L or ≤0.5x10 9 /L in controlled trials, although one patient in an extension study developed PML in the setting of prolonged lymphopenia (lymphocyte counts predominantly <0.5x10 9 /L for 3.5 years) [see Warnings and Precautions ( 5.2 )] . In controlled and uncontrolled clinical trials with dimethyl fumarate, 2% of patients experienced prolonged, severe lymphopenia (defined as lymphocyte counts <0.5x10 9 /L for at least six months); in this group of patients, the majority of lymphocyte counts remained <0.5x10 9 /L with continued therapy. In these patients with prolonged, severe lymphopenia, the median time for lymphocyte counts to return to normal after discontinuing dimethyl fumarate was 96.0 weeks. In these controlled and uncontrolled clinical studies, among patients who did not experience prolonged, severe lymphopenia during treatment, the median times for lymphocyte counts to return to normal after discontinuing dimethyl fumarate were as follows: 4.3 weeks in patients with mild lymphopenia (lymphocyte count ≥0.8x10 9 /L) at discontinuation, 10.0 weeks in patients with moderate lymphopenia (lymphocyte count 0.5 to <0.8x10 9 /L) at discontinuation, and 16.7 weeks in patients with severe lymphopenia (lymphocyte count <0.5x10 9 /L) at discontinuation. Neither BAFIERTAM nor dimethyl fumarate have been studied in patients with preexisting low lymphocyte counts. Obtain a CBC, including lymphocyte count, before initiating treatment with BAFIERTAM, 6 months after starting treatment, and then every 6 to 12 months thereafter, and as clinically indicated. Consider interruption of BAFIERTAM in patients with lymphocyte counts less than 0.5x10 9 /L…