Ropeginterferon Alfa-2b

BESREMi is an interferon alfa-2b indicated for:

• The treatment of adults with essential thrombocythemia. ( 1.1 )
• The treatment of adults with polycythemia vera. ( 1.2 )

1.1 Essential Thrombocythemia BESREMi is indicated for the treatment of adults with essential thrombocythemia.

1.2 Polycythemia Vera BESREMi is indicated for the treatment of adults with polycythemia vera.

BESREMi is a clear and colorless to slightly yellowish solution available as:

• Prefilled Syringe Injection: 500 mcg/mL in a single-dose prefilled syringe
• Prefilled Pen Injector Injection: 500 mcg/0.5 mL in a single-dose prefilled pen injector
• Injection: 500 mcg/mL solution in a single-dose prefilled syringe ( 3 )
• Injection: 500 mcg/0.5 mL solution in a single-dose prefilled pen injector ( 3 )

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 ( 4 )
• Hypersensitivity to interferons or to any of the inactive ingredients in 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 )

• Depression and Suicide: Monitor for symptoms and need for treatment. ( 5.1 )
• Endocrine Toxicity: Discontinue if endocrine disorders occur that cannot be medically managed. ( 5.2 )
• Cardiovascular Toxicity: Avoid use in patients with severe or unstable cardiovascular disease. Monitor patients with history of cardiovascular disorders more frequently. ( 5.3 )
• Hematologic and Hemorrhagic Disorders: Perform blood counts at baseline, every 2 weeks during titration, and at least every 3-6 months during maintenance treatment. ( 5.4 )
• Hypersensitivity Reactions: Stop treatment and immediately manage reaction. ( 5.5 )
• Pancreatitis: Consider discontinuation if confirmed pancreatitis. ( 5.6 )
• Colitis: Discontinue if signs or symptoms of colitis. ( 5.7 )
• Pulmonary Toxicity: Discontinue if pulmonary infiltrates or pulmonary function impairment. ( 5.8 )
• Ophthalmologic Toxicity: Monitor for ocular toxicity. Promptly evaluate eye symptoms and discontinue if new or worsening eye disorders. ( 5.9 )
• Hyperlipidemia: Monitor serum triglycerides before BESREMi treatment and intermittently during therapy and manage when elevated. ( 5.10 )
• Hepatotoxicity: Monitor liver enzymes and hepatic function at baseline and during treatment. Reduce dose or discontinue depending on severity. ( 5.11 )
• Renal Toxicity: Monitor serum creatinine at baseline and during therapy. Discontinue if severe renal impairment develops. ( 5.12 )
• Dental and Periodontal Toxicity: Advise on good oral hygiene and regular dental examinations. ( 5.13 )
• Dermatologic Toxicity: Consider discontinuing if clinically significant dermatologic toxicity. ( 5.14 )
• Driving and Operating Machinery: Advise patients to avoid driving or using machinery if they experience dizziness, somnolence, or hallucination. ( 5.15 )
• Embryo-Fetal Toxicity: Can cause fetal harm. ( 5.16 )

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. Psychiatric reactions have been observed in 10% of BESREMi-treated patients with essential thrombocythemia including depression, adjustment disorder with depressed mood, and depressed mood. Serious neuropsychiatric reactions have been observed in 3% of BESREMi-treated patients with polycythemia vera, including depression, depressive symptoms, depressed mood, and listlessness. Of these 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. Endocrine toxicities included hyperthyroidism (1.1%), hypothyroidism (1.1%), autoimmune thyroiditis (0.5%), and thyroiditis (0.5%) in BESREMi-treated patients with essential thrombocythemia. Endocrine toxicities included hyperthyroidism (4.5%), hypothyroidism (3.9%), and autoimmune thyroiditis/thyroiditis (2.8%) in BESREMi-treated patients with polycythemia vera. Do not use BESREMi in patients with active serious or untreated endocrine disorders associated with autoimmune disease [see 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, coronary artery ischemia, and acute coronary syndrome [see Adverse Reactions ( 6.1 )] . Three thrombotic events of transient ischemic attack (grade 2, 1 patient), pulmonary embolism (grade 3, 1 patient), and peripheral vein thrombosis (grade 2, 1 patient) occurred in the essential thrombocythemia Phase 3 SURPASS ET study. Patients with a history of cardiovascular disorders and/or thrombotic events should be closely monitored for cardiovascular toxicity and/or thrombotic events 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 Hematologic and Hemorrhagic Disorders 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). In BESREMi-treated patients with essential thrombocythemia, anemia of grade 3 or greater occurred in 1% of patients. Leukopenia of grade 3 or greater occurred in 2% of patients. Infection occurred in 45% of patients, while serious infections occurred in 4% of patients. Essential thrombocythemia-related hemorrhagic cases occurred in 6% of patients and included gingival bleeding, tongue hemorrhage, epistaxis, purpura, and retinal hemorrhage. In BESREMi-treated patients with polycythemia vera, thrombocytopenia of grade 3 (platelet counts <50,000 – 25,000/mm 3 ) or greater occurred in 2% of patients. Anemia of grade 3 (Hgb <8 g/dL) or greater occurred in 1% of patients. Leukopenia of grade 3 (WBC counts <2,000 – 1,000/mm 3 ) or greater occurred in 2% of patients. Infection occurred in 48% of patients, while serious infections occurred in 8% of 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 with hypersensitivity reactions to interferon products or any of the inactive ingredients in BESREMi [see Contraindications ( 4 )] . Toxicities may include serious, acute hypersensitivity reactions (e.g., urticaria, angioedema, bronchoconstriction, anaphylaxis, drug eruption). If such reactions occur, discontinue BESREMi and institute appropriate medical therapy immediately. Transient rashes may not necessitate interruption of treatment.

5.6 Pancreatitis Pancreatitis has occurred in patients receiving interferon alfa products, including BESREMi. Pancreatitis was reported in 2.2% of patients receiving BESREMi for polycythemia vera. Symptoms may include nausea, vomiting, upper abdominal pain, bloating, and fever. Patients may experience elevated lipase, amylase, white blood cell count, or altered renal/hepatic function. Interrupt BESREMi treatment in patients with possible pancreatitis and evaluate promptly. Consider discontinuation of BESREMi in patients with confirmed pancreatitis. […]

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 )]
• Hematologic and Hemorrhagic Disorders [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 )]
• Embryo-Fetal Toxicity [see Warnings and Precautions ( 5.16 )]
• 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. ( 6 )
• Polycythemia vera: 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 at 1-800-FDA-1088 or www.fda.gov/medwatch .

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. Essential Thrombocythemia The pooled safety population described in the Warnings and Precautions section reflects exposure to BESREMi as monotherapy for the treatment of essential thrombocythemia dosed every 2 weeks in 182 patients in an open-label trial [P1101 ET, SURPASS ET] and a single-arm trial [A22-301, EXCEED ET]. The mean age was 56 years (range: 21 to 84 years). There were 104 (57%) women, 78 (43%) men, and 93 (51%) Asian, 76 (42%) Caucasian, 5 (2.7%) Black or African American, 5 (2.7%) Other, and 3 (1.6%) Hispanic patients were included in the studies. Among 182 patients who received BESREMi, 70 (39%) patients were exposed for >56 weeks (>14 months). The mean (SD) dose of BESREMi was 394.9 (98.4) mcg during the treatment period. In this pooled safety population, the most common adverse reactions in ≥10% of BESREMi-treated patients were aspartate aminotransferase increased (44%), alanine aminotransferase increased (43%), fatigue (31%), anemia (24%), white blood cell count decreased (23%), neutrophil count decreased (22%), pruritus (17%), gamma-glutamyltransferase increased (16%), alopecia (16%), headache (15%), diarrhea (13%), nausea (13%), beta 2 microglobulin urine increased (12%), influenza like illness (11%), and myalgia (11%). The safety findings described below reflect exposure to BESREMi as monotherapy for the treatment of essential thrombocythemia in 91 patients in the SURPASS ET study [see Clinical Studies ( 14 )] . Among the 91 patients receiving BESREMi, 55% were exposed for 9 to 13 months and 36% were exposed for more than 13 months. Serious adverse reactions were reported in 2.2% of patients treated with BESREMi in the SURPASS ET study and included vascular headache and drug eruption. Adverse reactions requiring permanent discontinuation of patients treated with BESREMi occurred in 1.1% patient each and included aspartate aminotransferase increased, alanine aminotransferase increased, gamma-glutamyltransferase increased, pneumonitis, pulmonary hypertension, thyroiditis, dry eye, and erythema. The most common adverse reactions reported in ≥10% of patients in the SURPASS ET study are listed in Table 4 . Table 4 Adverse Reactions in ≥10% of Patients with Essential Thrombocythemia in the SURPASS ET Study Over 13 Months. * Adverse Reactions defined as all treatment-emergent adverse events 1 Transaminase elevations include: Alanine aminotransferase increased, Aspartate aminotransferase increased, Hepatic function abnormal, and Liver function test increased 2 Grouped related terms 3 Rash includes: Rash, Rash maculo-papular, and Rash pruritic Term BESREMi N=91 Anagrelide N=80 All Grade n (%) Grade ≥3 n (%) All Grade n (%) Grade ≥3 n (%) Transaminase elevations 1 49 (54) 3 (3) 11 (14) 0 Anemia 25 (28) 0 24 (30) 3 (4) Pyrexia 24 (26) 0 7 (9) 0 Beta 2 microglobulin urine increased 23 (25) 0 3 (4) 0 Bacterial infection 2 22 (24) 5 (5) 18 (23) 2 (3) Pruritus 20 (22) 1 (1.1) 15 (19) 0 Weight decreased 19 (21) 1 (1) 5 (6) 0 Leukopenia 2 17 (19) 1 (1) 2 (3) 1 (1) Fatigue 16 (18) 0 10 (13) 0 Hemorrhage 2 15 (17) 0 30 (38) 3 (4) Alopecia 14 (15) 0 1 (1) 0 Headache 14 (15) 0 25 (31) 0 Diarrhea 13 (14) 0 19 (24) 0 Gamma-glutamyl transferase increased 12 (13) 0 9 (11) 0 Nasopharyngitis 2 12 (13) 0 14 (18) 0 Abdominal pain 2 11 (12) 0 11 (14) 0 Neutrophil count decreased 11 (12) 1 (1) 0 0 Arthralgia 10 (11) 0 7 (9) 0 Cough 10 (11) 0 5 (6) 0 Rash 3 10 (11) 0 4 (5) 0 Dizziness 10 (11) 0 16 (20) 1 (1) Malaise 10 (11) 0 3 (4) 0 Myalgia 10 (11) 0 7 (9) 0 Back pain 2 10 (11) 0 5 (6) 0 Polycythemia Vera 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-PV/CONTINUATION-PV]. The mean age at baseline was 58.6 years (range 30-85 years), 88 (49%) women, 90 (51%) 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 5 . Table 5 Adverse Reactions in >10% of Patients with Polycythemia Vera in the PEGINVERA Study Over

7.5 Years. *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. […]

• 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 )] .

• Pregnancy: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception. ( 8.1 , 8.3 )
• Lactation: Breastfeeding not recommended. ( 8.2 )
• Renal Impairment: Avoid use in patients with eGFR <30 mL/min. ( 8.6 )

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. An abortifacient effect was reported in cynomolgus monkeys receiving ropeginterferon alfa-2b ( see Data ). Based on mechanism of action and the role of interferon alfa in pregnancy and fetal development, BESREMi can 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. Data Animal Data In an embryo-fetal development study, pregnant cynomolgus monkeys received subcutaneous injection of ropeginterferon alfa-2b twice weekly during the period of organogenesis (Gestation Days 20-48). Maternal toxicity, characterized by a significant decline in food consumption and transient body weight loss, occurred at all dose levels and ropeginterferon alfa-2b was abortifacient and caused embryonic death at exposures 275-times (C max ) and 64-times (AUC) the human exposure at the maximum recommended human dose of 500 mcg. There were no effects on fetal developmental parameters or abnormalities in the surviving fetuses (GD 100) where the ropeginterferon alfa-2b exposures achieved in pregnant cynomolgus monkeys during the first trimester were 961-times (C max ) and 224-times (AUC) the human exposure at the maximum recommended human dose of 500 mcg. 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.

8.2 Lactation There are no data on the presence of BESREMi in human or animal milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in breastfed children from BESREMi, advise women not to breastfeed during treatment and for 8 weeks after the final dose.

8.3 Females and Males of Reproductive Potential BESREMi can cause embryo-fetal harm when administered to a pregnant woman [see Use in Specific Populations ( 8.1 )] . Pregnancy Testing Pregnancy testing prior to BESREMi treatment is recommended for females of reproductive potential. Contraception Females Advise female patients of reproductive potential to use effective contraception during treatment with BESREMi and for at least 8 weeks after the final dose. Infertility Females Based on its mechanism of action, BESREMi can cause disruption of the menstrual cycle [see Clinical Pharmacology ( 12.1 )] . No animal fertility studies have been conducted with BESREMi.

8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use Of the total number of BESREMi-treated patients in the essential thrombocythemia studies, 65 (36%) were 65 years of age and older, while 15 (8%) were 75 years of age and older [see Clinical Studies ( 14 )] . Of the total number of BESREMi-treated patients in the polycythemia studies, 17 (33%) were 65 years of age and older, while 5 (10%) were 75 years of age and older. Clinical studies of BESREMi did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

8.6 Renal Impairment No dose adjustment is necessary in patients with estimated glomerular filtration rate (eGFR) ≥30 mL/min [see Clinical Pharmacology ( 12.3 )]. Avoid use of BESREMi in patients with eGFR <30 mL/min [see Warnings and Precautions ( 5.12 )].

8.7 Hepatic Impairment BESREMi is contraindicated in patients with hepatic impairment (Child-Pugh B or C) [see Contraindications ( 4 )] . Increased liver enzyme levels have been observed in patients treated with BESREMi. When the increase in liver enzyme levels is progressive and persistent, reduce the dose of BESREMi. If the increase in liver enzymes is progressive and clinically significant despite dose-reduction, or if there is evidence of hepatic impairment (Child-Pugh B or C), discontinue BESREMi [see Dosage and Administration ( 2.3 ) and Warnings and Precautions ( 5.11 )] .

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.