Ropeginterferon alfa-2b

BESREMi is an interferon alfa-2b indicated for: • The treatment of adults with essential thrombocythemia. • The treatment of adults with polycythemia vera.

Interferon alfa belongs to the class of type I interferons, which exhibit their cellular effects in polycythemia vera and essential thrombocythemia in the bone marrow by binding to a transmembrane receptor termed interferon alfa receptor (IFNAR). Binding to IFNAR initiates a downstream signaling cascade through the activation of kinases, in particular Janus kinase 1 (JAK1) and tyrosine kinase 2 (TYK2) and activator of transcription (STAT) proteins. Nuclear translocation of STAT proteins controls distinct gene-expression programs and exhibits various cellular effects. The actions involved in the therapeutic effects of interferon alfa in polycythemia vera and essential thrombocythemia are not fully elucidated.

Essential thrombocythemia: • The recommended dose of BESREMi is: a starting dose of 250 mcg by subcutaneous injection, at 2 weeks, increase the dose to 350 mcg by subcutaneous injection, at 4 weeks, increase to the maintenance dosage of 500 mcg by subcutaneous injection every 2 weeks. Maintain an every 2‑week schedule throughout treatment unless dose modification is required for safety or tolerability. Consider dose re-escalation in case of prior dose reduction, recovery, and lack of hematologic response. Polycythemia vera: • The recommended dose of BESREMi is: a starting dosage of 100 mcg by subcutaneous injection every 2 weeks (50 mcg if receiving hydroxyurea). Increase the dose by 50 mcg every 2 weeks (up to a maximum of 500 mcg) until hematological parameters are stabilized. Interrupt or discontinue dosing if certain adverse reactions occur.

BESREMi is contraindicated in patients with: • Existence of, or history of severe psychiatric disorders, particularly severe depression, suicidal ideation, or suicide attempt. • Hypersensitivity to interferons including interferon alfa-2b or any of the inactive ingredients of BESREMi. • Moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment. • History or presence of active serious or untreated autoimmune disease. • Immunosuppressed transplant recipients. BESREMi is contraindicated in patients with: • Existence of, or history of severe psychiatric disorders, particularly severe depression, suicidal ideation or suicide attempt.

Boxed warning (risk of serious disorders): Risk of Serious Disorders: Interferon alfa products may cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Patients should be monitored closely with periodic clinical and laboratory evaluations. Therapy should be withdrawn in patients with persistently severe or worsening signs or symptoms of these conditions. • Depression and Suicide: Monitor for symptoms and need for treatment. • Endocrine Toxicity: Discontinue if endocrine disorders occur that cannot be medically managed. • Cardiovascular Toxicity: Avoid use in patients with severe or unstable cardiovascular disease. Monitor patients with history of cardiovascular disorders more frequently.

The following clinically significant adverse reactions are described elsewhere in the labeling. • Depression and Suicide • Endocrine Toxicity • Cardiovascular Toxicity • Hematologic and Hemorrhagic Disorders • Hypersensitivity Reactions • Pancreatitis • Colitis • Pulmonary Toxicity • Ophthalmologic Toxicity • Hyperlipidemia • Hepatotoxicity • Renal Toxicity • Dental and Periodontal Toxicity • Dermatologic Toxicity • Driving and Operating Machinery • Embryo-Fetal Toxicity • Essential thrombocythemia: The most common adverse reactions reported in >20% of patients were transaminase elevations, anemia, pyrexia, beta 2 microglobulin urine increased, bacterial infection, pruritus, and weight decreased. • Polycythemia vera: The most common adverse reactions reported in >40% of patients were influenza-like illness, arthralgia, fatigue, pruritus, nasopharyngitis, and musculoskeletal pain.

• Monitor patients taking CYP450 substrates with a narrow therapeutic index for adverse reactions to inform the need for dose adjustment of the concomitant drug. • Avoid use with myelosuppressive agents and monitor patients receiving the combination for effects of excessive myelosuppression. • Avoid use with narcotics, hypnotics or sedatives. Monitor patients receiving the combination for excessive central nervous system toxicity

Store in the refrigerator between 36°F to 46°F (2°C to 8°C) in the original carton to protect from light. DO NOT FREEZE.