Bafiertam Drug Information

is indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults. BAFIERTAM is indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.

Blood Tests

Prior to Initiation of BAFIERTAM Obtain the following prior to treatment with BAFIERTAM: A complete blood cell count (CBC), including lymphocyte count . Serum aminotransferase, alkaline phosphatase, and total bilirubin levels .

Dosing Information

The starting dosage for BAFIERTAM is 95 mg twice a day orally for 7 days. After 7 days, the dosage should be increased to the maintenance dosage of 190 mg (administered as two 95 mg capsules) twice a day orally. Temporary dosage reductions to 95 mg twice a day may be considered for individuals who do not tolerate the maintenance dosage.

Within 4 weeks, the recommended dosage of 190 mg twice a day should be resumed. Discontinuation of BAFIERTAM should be considered for patients unable to tolerate return to the maintenance dosage. Administration of non-enteric coated aspirin (up to a dose of 325 mg) 30 minutes prior to BAFIERTAM dosing may reduce the incidence or severity of flushing .

Administration Instructions Swallow

BAFIERTAM capsules whole and intact. Do not crush, chew, or mix the contents with food. BAFIERTAM can be taken with or without food.

Blood Tests to Assess Safety After Initiation of

BAFIERTAM Obtain a complete blood cell count (CBC), including lymphocyte count, 6 months after initiation of BAFIERTAM and then every 6 to 12 months thereafter, as clinically indicated . Obtain serum aminotransferase, alkaline phosphatase, and total bilirubin levels during treatment with BAFIERTAM, as clinically indicated .

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the 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 practice. The data described in the following sections were obtained using dimethyl fumarate delayed-release capsules (the prodrug of BAFIERTAM). Adverse Reactions in Placebo-Controlled Trials with Dimethyl Fumarate In the two well-controlled studies demonstrating effectiveness, 1529 patients received dimethyl fumarate with an overall exposure of 2244 person-years. The adverse reactions presented in Table 1 below are based on safety information from 769 patients treated with dimethyl fumarate 240 mg twice a day and 771 placebo-treated patients.

The most common adverse reactions (incidence ≥10% and ≥2% more than placebo) for dimethyl fumarate were flushing, abdominal pain, diarrhea, and nausea. Table 1: Adverse Reactions in Study 1 and 2 Reported for Dimethyl Fumarate at ≥ 2% Higher Incidence than Placebo Adverse Reaction Dimethyl Fumarate 240 mg Twice Daily N=769 % Placebo N=771 % Flushing 40 6 Abdominal pain 18 10 Diarrhea 14 11 Nausea 12 9 Vomiting 9 5 Pruritus 8 4 Rash 8 3 Albumin urine present 6 4 Erythema 5 1 Dyspepsia 5 3 Aspartate aminotransferase increased 4 2 Lymphopenia 2 <1 Gastrointestinal Dimethyl fumarate caused GI events (e.g., nausea, vomiting, diarrhea, abdominal pain, and dyspepsia). In clinical trials, the incidence of GI events was higher early in the course of treatment (primarily during the first month) and usually decreased over time in patients treated with dimethyl fumarate compared with placebo. Four percent (4%) of patients treated with dimethyl fumarate and less than 1% of patients on placebo discontinued due to gastrointestinal events.

The incidence of serious GI events was 1% in clinical trial patients treated with dimethyl fumarate; these events, none of which were fatal, included vomiting (0.3%) and abdominal pain (0.3%). Hepatic Transaminases An increased incidence of elevations of hepatic transaminases in patients treated with dimethyl fumarate in clinical trials 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). Elevations of alanine aminotransferase and aspartate aminotransferase to ≥ 3 times the ULN occurred in a small number of patients treated with both dimethyl fumarate and in patients on placebo, and were balanced between the 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 dimethyl fumarate or placebo. Eosinophilia A transient increase in mean eosinophil counts was seen during the first 2 months of therapy with dimethyl fumarate.

Adverse Reactions in Studies with BAFIERTAM (Monomethyl Fumarate) In clinical studies, a total of 178 healthy subjects have received single doses of BAFIERTAM. The adverse reaction profile of BAFIERTAM was consistent with the experience in the placebo-controlled clinical trials with dimethyl fumarate. Taking BAFIERTAM without food may reduce the incidence of GI events.

Postmarketing Experience

The following adverse reactions have been identified during post approval use of dimethyl fumarate (the prodrug of BAFIERTAM). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Gastrointestinal Disorders: Acute pancreatitis; Gastrointestinal perforation, ulceration, obstruction, and hemorrhage Hepatobiliary Disorders: Liver function abnormalities (elevations in transaminases ≥ 3 times ULN with concomitant elevations in total bilirubin > 2 times ULN) Infections and Infestations: Herpes zoster infection and other serious opportunistic infections Respiratory, Thoracic, and Mediastinal Disorders: Rhinorrhea Skin and Subcutaneous: Alopecia

Concomitant Dimethyl Fumarate or Diroximel Fumarates Both dimethyl fumarate and diroximel fumarate

are metabolized to monomethyl fumarate. Therefore, BAFIERTAM is contraindicated in patients currently taking dimethyl fumarate or diroximel fumarate. BAFIERTAM may be initiated the day following discontinuation of either of these drugs.

Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to BAFIERTAM during pregnancy. Pregnant women exposed to BAFIERTAM and healthcare providers are encouraged to contact Banner Life Sciences at 1-866-MMF-95MG (1-866-663-9564). Risk Summary There are no adequate data on the developmental risk associated with the use of BAFIERTAM in pregnant women. Available data from a pregnancy registry for dimethyl fumarate (the prodrug of BAFIERTAM), observational studies, and pharmacovigilance with dimethyl fumarate use in pregnant women have not indicated an increased risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes.

Most of the reported exposures to dimethyl fumarate occurred during the first trimester of pregnancy ( see Data ). In animals, adverse effects on offspring survival, growth, sexual maturation, and neurobehavioral function were observed when dimethyl fumarate (DMF) was administered during pregnancy and lactation at clinically relevant doses ( see Data ). The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data Human Data In a prospective observational pregnancy registry for dimethyl fumarate (2013-2022), the rate of major birth defects among 362 live births and stillbirths from women who were exposed to dimethyl fumarate during pregnancy was 3.6% (95% CI: 1.9-6.1). No specific pattern of major birth defects was identified. Important potential study limitations include exposure misclassification, no adjustment for confounders, and lack of an internal comparator cohort. Animal data In rats administered DMF orally (0, 25, 100, and 250 mg/kg/day) throughout organogenesis, embryofetal toxicity (reduced fetal body weight and delayed ossification) were observed at the highest dose tested.

This dose also produced evidence of maternal toxicity (reduced body weight). Plasma exposure (AUC) for monomethyl fumarate (MMF), the major circulating metabolite, at the no-effect dose is approximately three times that in humans at the recommended human dose (RHD) of MMF (380 mg/day). In rabbits administered DMF orally (0, 25, 75, and 150 mg/kg/day) throughout organogenesis, embryolethality and decreased maternal body weight were observed at the highest dose tested. The plasma AUC for MMF at the no-effect dose is approximately 5 times that in humans at the RHD of MMF. Oral administration of DMF (0, 25, 100, and 250 mg/kg/day) to rats throughout organogenesis and lactation resulted in increased lethality, persistent reductions in body weight, delayed sexual maturation (male and female pups), and reduced testicular weight at the highest dose tested. Neurobehavioral impairment was observed at all doses.

A no-effect dose for developmental toxicity was not identified. The lowest dose tested was associated with plasma AUC for MMF lower than that in humans at the RHD of MMF.

Pediatric Use Safety and effectiveness in pediatric patients have not been established. Juvenile Animal Toxicity Data Oral administration of monomethyl fumarate (MMF) (0, 40, 100, or 250 mg/kg/day) to juvenile rats from postnatal day 28 to 70 resulted in reduced body weight and bone growth, delayed sexual maturation in females, and renal tubular (exfoliated cells or degeneration) and gastrointestinal (nonglandular stomach hyperkeratosis or hyperplasia) effects at all but the lowest dose tested. No adverse effects were observed on neurobehavioral development.

is contraindicated in patients: with known hypersensitivity to monomethyl fumarate, dimethyl fumarate, diroximel fumarate, or to any of the excipients of BAFIERTAM. Reactions may include anaphylaxis or angioedema. taking dimethyl fumarate or diroximel fumarate. Known hypersensitivity to monomethyl fumarate, dimethyl fumarate, diroximel fumarate, or any of the excipients of BAFIERTAM Co-administration with dimethyl fumarate or diroximel fumarate