Ropeginterferon alfa-2b

12.1 Mechanism of Action Interferon alfa belongs to the class of type I interferons, which exhibit their cellular effects in polycythemia vera 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 are not fully elucidated.

1 INDICATIONS AND USAGE BESREMi is indicated for the treatment of adults with polycythemia vera. BESREMi is an interferon alfa-2b indicated for the treatment of adults with polycythemia vera ( 1 )

2 DOSAGE AND ADMINISTRATION 2.1 Pre-Treatment Testing Obtain a pregnancy test in females of reproductive potential prior to initiating treatment with BESREMi [see Use in Specific Populations (8.3)]. 2.2 Recommended Dosage Patients Not Already on Hydroxyurea: The recommended BESREMi starting dosage for patients not on hydroxyurea is 100 mcg by subcutaneous injection every two weeks. Increase the dose by 50 mcg every two weeks (up to a maximum of 500 mcg), until the hematological parameters are stabilized (hematocrit less than 45%, platelets less than 400 x 109/L, and leukocytes less than 10 x 109/L). Patients Transitioning from Hydroxyurea: When transitioning to BESREMi from hydroxyurea, start BESREMi at 50 mcg by subcutaneous injection every two weeks in combination with hydroxyurea. Gradually taper off the hydroxyurea by reducing the total biweekly dose by 20-40% every two weeks during Weeks 3-12. Increase the dose of BESREMi by 50 mcg every two weeks (up to a maximum of 500 mcg), until the hematological parameters are stabilized (hematocrit less than 45%, platelets less than 400 x 109/L, and leukocytes less than 10 x 109/L). Discontinue hydroxyurea by Week 13. Maintain the two-week dosing interval of BESREMi at which hematological stability is achieved for at least 1 year. After achievement of hematological stability for at least 1 year on a stable dose of BESREMi, the dosing interval may be expanded to every 4 weeks. Monitor patients closely especially during the titration phase. Perform complete blood counts (CBC) regularly, every 2 weeks during the titration phase and every 3-6 months during the maintenance phase (after the patient’s optimal dose is established). Monitor CBC more frequently if clinically indicated. Phlebotomy as rescue treatment to normalize blood hyperviscosity may be necessary during the titration phase [see Clinical Pharmacology (12.2)]. 2.3 Dose Modifications Monitor CBC every 2 weeks during the titration phase and dose modification phase. Phlebotomy as rescue treatment to normalize blood hyperviscosity may be necessary [see Clinical Pharmacology (12.2)]. If dose interruption occurs, resume dosing at previously attained levels. If drug-related toxicities arise, reduce the dose to the next lower level or interrupt in accordance with the table below (Table 1). If there is insufficient efficacy at the decreased dose following dose modification, a dose increase attempt to the next higher dose level should be considered after recovery to grade 1 toxicity. Table 1 Dose Modifications for BESREMi Adverse Reactions Adverse Reaction a Severity Dosage Modification Liver enzyme elevation with concomitant bilirubin elevation, or other evidence of hepatic decompensation Any increase above baseline Interrupt treatment until recovery, restart at dose 50 mcg lower than the interrupted dose. If the interrupted dose is 50 mcg, refrain from treatment until recovery. Consider permanent discontinuation if toxicity persists after four dose- modifications. Liver enzyme elevation >5 x the upper limit of normal (ULN) but ≤20 x ULN Decrease dose by 50 mcg; if toxicity does not improve, continue decreasing at biweekly intervals until alanine aminotransferase (ALT) and aspartate aminotransferase (AST) recover < 3 x ULN if baseline was normal; 3 x baseline if baseline was abnormal, and gamma-glutamyltransferase (GGT) recovers to < 2.5 x ULN if baseline was normal; 2.5 x baseline if baseline was abnormal. If the interrupted dose is 50 mcg, refrain from treatment until recovery. >20 x ULN Interrupt treatment until ALT and AST recover to < 3 x ULN if baseline was normal; 1.5 x baseline if baseline was abnormal, and gamma-glutamyltransferase (GGT) recovers to < 2.5 x ULN if baseline was normal; 2 x baseline if baseline was abnormal. Consider permanent discontinuation if toxicity persists after four dose-modifications. Cytopenia Anemia: Hemoglobin (Hgb) < 8 g/dL Thrombocytopenia: platelet count < 50,000/mm3 but ≥25,000/mm3 Leukopenia: white blood cell count (WBC) <2000/mm3 but ≥1,000/mm3 Decrease dose by 50 mcg; if toxicity does not improve, continue decreasing at biweekly intervals until recovery of Hgb >10.0 g/dL, platelets >75,000/mm3, and WBC >3,000/mm3 If the interrupted dose is 50 mcg, refrain from treatment until recovery. Anemia: Hemoglobin levels are life threatening, or urgent intervention needed Thrombocytopenia: platelet count <25,000/mm3 Leukopenia: WBC <1000/mm3 Interrupt treatment until recovery of Hgb >10.0 g/dL, platelets >75,000/mm3, and WBC >3,000/mm3. Consider permanent discontinuation if toxicity persists after four dose-modifications. Depression Mild, without suicidal ideation Moderate, without suicidal ideation Severe, or any severity with suicidal ideation Consider psychiatric consultation if persistent (>8 weeks). Consider dose reduction and psychiatric consultation. Discontinue therapy, recommend psychiatric consultation. a National Cancer Institute Common Terminology Criteria for Adverse E

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling. Depression and Suicide [see Warnings and Precautions (5.1)] Endocrine Toxicity [see Warnings and Precautions (5.2)] Cardiovascular Toxicity [see Warnings and Precautions (5.3)] Decreased Peripheral Blood Counts [see Warnings and Precautions (5.4)] Hypersensitivity Reactions [see Warnings and Precautions (5.5)] Pancreatitis [see Warnings and Precautions (5.6)] Colitis [see Warnings and Precautions (5.7)] Pulmonary Toxicity [see Warnings and Precautions (5.8)] Ophthalmologic Toxicity [see Warnings and Precautions (5.9)] Hyperlipidemia [see Warnings and Precautions (5.10)] Hepatotoxicity [see Warnings and Precautions (5.11)] Renal Toxicity [see Warnings and Precautions (5.12)] Dental and Periodontal Toxicity [see Warnings and Precautions (5.13)] Dermatologic Toxicity [see Warnings and Precautions (5.14)] Driving and Operating Machinery [see Warnings and Precautions (5.15)] 6.1 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 pooled safety population described in the Warnings and Precautions section reflects exposure to BESREMi as monotherapy for the treatment of polycythemia vera dosed every two to four weeks in 178 patients in two open-label trials [PEGINVERA, PROUD/CONTINUATION PV]. The mean age at baseline was 58.6 years (range 30-85 years), 88 (49.4%) women, 90 (50.6%) men, 177 (99%) Caucasian and 1 (1%) Asian. Among 178 patients who received BESREMi, 80% were exposed for 12 months or longer. The mean dose of BESREMi was 334 mcg SD ± 121 during the treatment period. In this pooled safety population, the most common adverse reactions greater than 10%, were liver enzyme elevations (20%), leukopenia (20%), thrombocytopenia (19%), arthralgia (13%), fatigue (12%), myalgia (11%), and influenza-like illness (11%). The safety findings described below reflect exposure to BESREMi as monotherapy for the treatment of polycythemia vera in 51 patients in the PEGINVERA study [see Clinical Studies (14) ]. Among the 51 patients receiving BESREMi, 71% were exposed for 12 months or longer, 63% were exposed for three years or longer, and 53% were exposed for greater than five years. Serious adverse reactions were reported in 16% of patients in the PEGINVERA study. The most common serious adverse reactions observed during the study (> 4%) included urinary tract infection (8%), transient ischemic attack (6%) and depression (4%). Adverse reactions requiring permanent discontinuation in >2% of patients who received BESREMi included depression (8%) arthralgia (4%), fatigue (4%), and general physical health deterioration (4%) In the PEGINVERA study, patients were not pre-screened for depression or anxiety disorders. The most common adverse reactions reported in ≥10% of patients in the PEGINVERA study are listed in Table 2. Table 2 Adverse Reactions in > 10% of Subjects with Polycythemia Vera in the PEGINVERA Study Over 7.5 Years. Adverse Reactions* BESREMi N=51 % Influenza-like illness a 59 Arthralgia 47 Fatigue b 47 Pruritis 45 Nasopharyngitis c 43 Musculoskeletal pain d 41 Headache e 39 Diarrhea 33 Hyperhidrosis f 29 Nausea 28 Upper respiratory tract infection g 27 Local administration site reactions 26 Dizziness 22 Abdominal pain h 20 Depression 20 Sleep disorder i 20 Leukopenia 18 Decreased appetite 18 Alopecia 16 Edema j 16 Hypertension k 16 Muscle spasms 16 Neutropenia 16 Rash l 16 Transaminase elevations m 16 Urinary tract infection 16 Thrombocytopenia 12 Vertigo 12 *Adverse Reactions defined as all treatment emergent adverse events Grouped Term Definitions a Includes pyrexia, chills, and influenza-like illness. b Includes asthenia, malaise, and fatigue. c Includes pharyngitis and nasopharyngitis. d Includes musculoskeletal pain, back pain, pain in extremity, bone pain, flank pain, and spinal pain. e Includes headache, migraine, and head pain. f Includes night sweats and hyperhidrosis. g Includes upper respiratory tract infection, rhinitis, bronchitis, and respiratory tract infection. h Includes abdominal pain upper, abdominal pain lower, and abdominal pain. i Includes insomnia, sleep disorder, and abnormal dreams. j Includes peripheral edema and generalized edema. k Includes hypertension and hypertensive crisis. l Includes rash, maculopapular rash, and pruritic rash. m Includes transaminase increase, hepatic enzyme increase, GGT increase, AST increase, and ALT increase. Cardiovascular System : Atrial fibrillation The most common adverse reactions reported in > 40% of patients were influenza-like illness, arthralgia, fatigue, pruritus, nasopharyngitis, and musculoskeletal pain ( 6 ). To report SUSPECTED ADVERSE REACTIONS, contact PharmaEssentia at 1-800-999-2449 or FDA

7 DRUG INTERACTIONS 7.1 Drugs Metabolized by Cytochrome P450 Certain proinflammatory cytokines, including interferons, can suppress CYP450 enzymes resulting in increased exposures of some CYP substrates [see Clinical Pharmacology (12.3)] . Therefore, patients on BESREMi who are receiving concomitant drugs that are CYP450 substrates with a narrow therapeutic index should be monitored to inform the need for dosage modification for these concomitant drugs. 7.2 Myelosuppressive Agents Concomitant use of BESREMi and myelosuppressive agents can produce additive myelosuppression. Avoid use and monitor patients receiving the combination for effects of excessive myelosuppression [see Warnings and Precautions (5.4)] . 7.3 Narcotics, Hypnotics or Sedatives Concomitant use of BESREMi and narcotics, hypnotics or sedatives can produce additive neuropsychiatric side effects. Avoid use and monitor patients receiving the combination for effects of excessive CNS toxicity [see Warnings and Precautions (5.1)] . Monitor patients taking CYP450 substrates with a narrow therapeutic index for adverse reactions to inform the need for dose adjustment of the concomitant drug ( 7.1 ) Avoid use with myelosuppressive agents and monitor patients receiving the combination for effects of excessive myelosuppression ( 7.2 ) Avoid use with narcotics, hypnotics or sedatives. Monitor patients receiving the combination for excessive central nervous system toxicity ( 7.3 ) 7.1 Drugs Metabolized by Cytochrome P450 Certain proinflammatory cytokines, including interferons, can suppress CYP450 enzymes resulting in increased exposures of some CYP substrates [see Clinical Pharmacology (12.3) ] . Therefore, patients on BESREMi who are receiving concomitant drugs that are CYP450 substrates with a narrow therapeutic index should be monitored to inform the need for dosage modification for these concomitant drugs. 7.2 Myelosuppressive Agents Concomitant use of BESREMi and myelosuppressive agents can produce additive myelosuppression. Avoid use and monitor patients receiving the combination for effects of excessive myelosuppression [see Warnings and Precautions (5.4) ] . 7.3 Narcotics, Hypnotics or Sedatives Concomitant use of BESREMi and narcotics, hypnotics or sedatives can produce additive neuropsychiatric side effects. Avoid use and monitor patients receiving the combination for effects of excessive CNS toxicity [see Warnings and Precautions (5.1) ] .