BESREMi

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: …

5 WARNINGS AND PRECAUTIONS 5.1 Depression and Suicide Life-threatening or fatal neuropsychiatric reactions have occurred in patients receiving interferon alfa products, including BESREMi. These reactions may occur in patients with and without previous psychiatric illness. Serious neuropsychiatric reactions have been observed in 3% of patients treated with BESREMi during the clinical development program. Among the 178 patients in the clinical development program of BESREMi, 17 cases of depression, depressive symptoms, depressed mood, and listlessness occurred. Of these seventeen cases, 3.4% of the patients recovered with temporary drug interruption and 2.8% stopped BESREMi treatment. Other central nervous system effects, including suicidal ideation, attempted suicide, aggression, bipolar disorder, mania and confusion have been observed with other interferon alfa products. BESREMi is contraindicated in patients with a history of severe psychiatric disorders, particularly severe depression, suicidal ideation, or suicide attempt [see Contraindications (4) ]. Closely monitor patients for any symptoms of psychiatric disorders and consider psychiatric consultation and treatment if such symptoms emerge. If psychiatric symptoms worsen, it is recommended to discontinue BESREMi therapy. 5.2 Endocrine Toxicity Endocrine toxicity has occurred in patients receiving interferon alfa products, including BESREMi. These toxicities may include worsening hypothyroidism and hyperthyroidism. Autoimmune thyroiditis and hyperglycemia, including new onset type 1 diabetes, have been reported in patients receiving interferon alfa-2b products. Eight cases of hyperthyroidism (4.5%), seven cases of hypothyroidism (3.9%) and five cases (2.8%) of autoimmune thyroiditis/thyroiditis occurred in the development program of BESREMi. Do not use BESREMi in patients with active serious or untreated endocrine disorders associated with autoimmune disease [ Contraindications (4) ]. Evaluate thyroid function in patients who develop symptoms suggestive of thyroid disease during BESREMi therapy. Discontinue BESREMi in patients who develop endocrine disorders that cannot be adequately managed during treatment with BESREMi. 5.3 Cardiovascular Toxicity Cardiovascular toxicity has occurred in patients receiving interferon alfa products, including BESREMi. Toxicities may include cardiomyopathy, myocardial infarction, atrial fibrillation and coronary artery ischemia [see Adverse Reactions (6.1) ]. Patients with a history of cardiovascular disorders should be closely monitored for cardiovascular toxicity during BESREMi therapy. Avoid use of BESREMi in patients with severe or unstable cardiovascular disease, (e.g., uncontrolled hypertension, congestive heart failure (≥ NYHA class 2), serious cardiac arrhythmia, significant coronary artery stenosis, unstable angina) or recent stroke or myocardial infarction. 5.4 Decreased Peripheral Blood Counts Decreased peripheral blood counts have occurred in patients receiving interferon alfa products, including BESREMi. These toxicities may include thrombocytopenia (increasing the risk of bleeding), anemia, and leukopenia (increasing the risk of infection). Thrombocytopenia of grade 3 (platelet counts <50,000 – 25,000/mm3) or greater occurred in 2% of BESREMi-treated patients. Anemia of grade 3 (Hgb < 8 g/dL) or greater occurred in 1% of BESREMi-treated patients. Leukopenia of grade 3 (WBC counts <2,000 – 1,000/mm3) or greater occurred in 2% of BESREMi-treated patients. Infection occurred in 48% of BESREMi treated patients, while serious infections occurred in 8% of BESREMi treated patients. Monitor complete blood counts at baseline, during titration and every 3-6 months during the maintenance phase. Monitor patients for signs and symptoms of infection or bleeding. 5.5 Hypersensitivity Reactions Hypersensitivity reactions have occurred in patients receiving interferon alfa products, including BESREMi. BESREMi is contraindicated in patients wit…

4 CONTRAINDICATIONS 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 History of transplantation and receiving immunosuppressant agents. Existence of, or history of severe psychiatric disorders, particularly severe depression, suicidal ideation or suicide attempt ( 4 ) Hypersensitivity to interferon or to any component of BESREMi ( 4 ) Hepatic impairment (Child-Pugh B or C) ( 4 ) History or presence of active serious or untreated autoimmune disease ( 4 ) Immunosuppressed transplant recipients ( 4 )

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) ] .

8.1 Pregnancy Risk Summary Available human data with BESREMi use in pregnant women are insufficient to identify a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Animal studies assessing reproductive toxicity of BESREMi have not been conducted. Based on mechanism of action and the role of interferon alfa in pregnancy and fetal development, BESREMi may cause fetal harm and should be assumed to have abortifacient potential when administered to a pregnant woman. There are adverse effects on maternal and fetal outcomes associated with polycythemia vera in pregnancy (see Clinical Considerations ) . Advise pregnant women of the potential risk to a fetus. The estimated 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 is 2-4% and 15-20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo-Fetal Risk Untreated polycythemia vera during pregnancy is associated with adverse maternal outcomes such as thrombosis and hemorrhage. Adverse pregnancy outcomes associated with polycythemia vera include increased risk for miscarriage.

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 nasophar…