BESREMi

1 INDICATIONS AND USAGE 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.

2 DOSAGE AND ADMINISTRATION 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. ( 2.2 , 2.3 , 5 ) 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 ( 2.1 ). Interrupt or discontinue dosing if certain adverse reactions occur. Dose re-increase to be considered in case of prior dose reduction, recovery, and lack of hematologic response. ( 2.2 , 2.3 , 5 ) 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 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 (platelets less than 400 × 10 9 /L and leukocytes less than 10 × 10 9 /L). • Monitor complete blood counts every 2 weeks during titration and every 3 to 6 months during maintenance. Polycythemia Vera: 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 (hematologic response: hematocrit less than 45%, platelets less than 400 × 10 9 /L, and leukocytes less than 10 × 10 9 /L). • Consider dose re-escalation in case of prior dose reduction, recovery, and lack of hematologic response. 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 × 10 9 /L, and leukocytes less than 10 × 10 9 /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 Essential Thrombocythemia: 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 tables below ( Table 1 and Table 2 ). Table 1 Dose Modifications for BESREMi Adverse Reactions in Patients with Essential Thrombocythemia 1 National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. 2 If toxicity or neutropenia occurs at the lowest recommended dose (100 mcg), withhold treatment until resolution to baseline or Grade ≤1, then resume at the same dose level at the discretion of the treating healthcare provider. Severity 1 Recommended Dosage Modification 2 Grade 3 or 4 toxicity (except neutropenia) Interrupt treatment until recovery to Grade ≤1. Re-escalate the dose to the previous dose level if recovered to Grade ≤1, and if patient is a non-responder (hematological parameters). Grade 3 or 4 neutropenia (ANC <0.5 × 10⁹/L) Interrupt treatment until ANC >0.5 × 10⁹/L. Re-escalate the dose to the previous dose level if recovered to Grade ≤1, and if patient is a non-responder (hematological parameters). Grade 2 toxicity (except neutropenia) Reduce to the next lower dose level (see Table 2 ). Treatment interruption may be considered until recovery to Grade ≤1. Re-escalate the dose to the previous dose level if recovered to Grade ≤1, and if patient is a non-responder (hematological parameters). Grade 2 neutropenia (ANC <0.75 × 10⁹/L but ≥0.5 × 10⁹/L) Reduce to the next lower dose level (see Table 2 ). Treatment interruption is not required. Continued monitoring of the patient is advised; re-escalation to the previous dose level may be considered. Re-escalate the dose to the previous dose level if recovered to Grade ≤1, and if patient is a non-responder (hematological parameters). Table 2 Dose Reduction Sequence for BESREMi Adverse Reactions in Patients with Essential Thrombocythemia Dose Level Dosage Maintenance dose 500 mcg every 2 weeks First dose reduction 350 mcg every 2 weeks Second dose reduction 250 mcg every 2 weeks Third dose reduction 200 mcg every 2 weeks Fourth dose reduction 150 mcg every 2 weeks Fifth dose reduction 100 mcg every 2 weeks Polycythemia Vera: 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 3 ). 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 3 Dose Modifications for BESREMi Adverse Reactions in Patients with Polycythemia Vera a National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 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 reductions. Liver enzyme elevation >5 × the upper limit of normal (ULN) but ≤20 × ULN Decrease dose by 50 mcg; if toxicity does not improve, continue decreasing by 50 mcg at biweekly intervals until alanine aminotransferase (ALT) and aspartate aminotransferase (AST) recover <3 × ULN if baseline was normal; 3 × baseline if baseline was abnormal, and gamma-glutamyltransferase (GGT) recovers to <2.5 × ULN if baseline was normal; 2.5 × baseline if baseline was abnormal. If the interrupted dose is 50 mcg, refrain from treatment until recovery. >20 × ULN Interrupt treatment until ALT and AST recover to <3 × ULN if baseline was normal; 1.5 × baseline if baseline was abnormal, and gamma-glutamyltransferase (GGT) recovers to <2.5 × ULN if baseline was normal; 2 × baseline if baseline was abnormal. Continued monitoring of the patient is advised; re-escalation to the previous dose level may be considered. Re-escalate the dose to the previous dose level if recovered to Grade ≤1, and if patient is a non-responder (hematological parameters). Consider permanent discontinuation if toxicity persists after four dose reductions. Cytopenia Anemia: Hemoglobin (Hgb) <8 g/dL Thrombocytopenia: platelet count <50,000/mm 3 but ≥25,000/mm 3 Leukopenia: white blood cell count (WBC) <2,000/mm 3 but ≥1,000/mm 3 Decrease dose by 50 mcg; if toxicity does not improve, continue decreasing by 50 mcg at bi-weekly intervals until recovery of Hgb >10.0 g/dL, platelets >75,000/mm 3 , and WBC >3,000/mm 3 . If the interrupted dose is 50 mcg, refrain from treatment until recovery. Continued monitoring of the patient is advised; re-escalation to the previous dose level may be considered. Re-escalate the dose to the previous dose level if recovered to Grade ≤1, and if patient is a non-responder (hematological parameters). Anemia: Hemoglobin levels are life threatening, or urgent intervention needed Thrombocytopenia: platelet count <25,000/mm 3 Leukopenia: WBC <1,000/mm 3 Interrupt treatment until recovery of Hgb >10.0 g/dL, platelets >75,000/mm 3 , and WBC >3,000/mm 3 . Re-escalate the dose to the previous dose level if recovered to Grade ≤1, and if patient is a non-responder (hematological parameters). Consider permanent discontinuation if toxicity persists after four dose reductions. Depression Mild, without suicidal ideation Consider psychiatric consultation if persistent (>8 weeks). Moderate, without suicidal ideation Consider dose reduction to 50 mcg and psychiatric consultation is recommended. Severe, or any severity with suicidal ideation Discontinue therapy, recommend psychiatric consultation. 2.4 Preparation and Administration Read the INSTRUCTIONS FOR USE before administering the single-dose BESREMi prefilled syringe or prefilled pen injector. BESREMi is for subcutaneous injection only and may be administered by either a healthcare professional, a patient or a caregiver. Before a decision is made to allow BESREMi to be administered by a patient or caregiver, ensure that the patient is an appropriate candidate for self-administration or administration by a caregiver. Proper training on storage, preparation and administration technique should be provided. If a patient or caregiver is not an appropriate candidate for any reason, then BESREMi should be administered by a healthcare professional. Before each injection, remove the carton that contains the BESREMi prefilled syringe or prefilled pen injector from the refrigerator. Keep the prefilled syringe or prefilled pen injector in the carton and lay it flat on a clean work surface for 15-30 minutes to allow the prefilled syringe or prefilled pen injector to reach room temperature [59˚F to 77˚F (15˚C to 25˚C)]. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit (do not use if the solution in the syringe or pen injector is cloudy, discolored, contains particulate matter or if the syringe or pen injector shows any sign of damage). Prefilled Syringe Preparation • Remove the prefilled syringe cap by unscrewing it counterclockwise. • Attach the covered needle to the prefilled syringe by firmly pushing it onto the collar of the syringe and then screwing (turn clockwise) it on until it feels securely attached. • Choose one of the following injection sites: Lower stomach (abdomen) area, at least 2 inches away from the belly button, or top of thighs. Rotate (change) the injection site for each injection. Do not inject into skin that is irritated, red, bruised, infected, or scarred; clean the chosen injection site with an alcohol swab and let air dry. • Uncap needle and move air bubbles to top. Pull the pink needle shield back and hold the syringe from the syringe body. Remove the clear needle cap by pulling it straight off. Throw away the needle cap into the trash. Hold the prefilled syringe with the needle pointing up. Tap on the body of the prefilled syringe to move any air bubbles to the top. Set Injection Dose • The dose markings on the prefilled syringe are in 50 mcg increments. • Depending on the prescribed dose, the amount of dose in the syringe may need to be adjusted by discarding some of the medication. • Hold the prefilled syringe at eye level with the needle pointing straight up over a paper towel, sink, or trash can. Check that you can see the dose lines and number markings on the prefilled syringe. • Pinch the end of the plunger and slowly push up to remove liquid medicine until the top edge of the gray stopper lines up with the marking for the prescribed dose. Inject BESREMi • Pinch the chosen injection site. While pinching the skin, insert needle at a 45- to 90-degree angle into the pinched skin, then release the pinched skin. • Inject BESREMi by slowly pressing on the plunger all the way until it stops. After all the liquid medicine is injected, remove the needle from the skin. Dispose of Used Prefilled Syringe • Carefully push the pink needle shield over the needle until it snaps into place and covers the needle. Do not recap the needle using the needle cap; only use the pink needle shield to cover the needle. • Throw away the used prefilled syringe with the needle still attached, into an FDA-cleared sharps disposal container. Prefilled Pen Injector Preparation • The prefilled pen injector delivers BESREMi in 50 mcg increments. • Remove the prefilled pen injector cap by pulling it straight off. • Choose one of the following injection sites: Lower stomach (abdomen) area, at least 2 inches away from the belly button, or top of thighs. Rotate (change) the injection site for each injection. Do not inject into skin that is irritated, red, bruised, infected, or scarred; clean the chosen injection site with an alcohol swab and let air dry. • Clean the rubber stopper on the tip of the prefilled pen injector with an alcohol swab. Peel off the protective seal from the needle. Attach the capped needle by pushing it straight onto the prefilled pen injector until you feel or hear it snap into place. Turn or rotate the needle until it “clicks” into place. The needle is attached when it no longer turns or rotates freely. • Remove the needle cover by pulling off the needle cover and throw it away. Remove Air/Flow Check • Turn the dose selector knob until the drop symbol is centered in the dose window. Hold the prefilled pen injector with the needle pointing up and press the injection button all the way in until it stops and the dose window returns to “0”. Repeat these steps 3 more times for a total of 4 cycles. • Look for liquid medicine at the tip of the needle. If you do not see liquid at the tip of the needle, repeat these steps up to 3 more times for a total of 7 cycles or until you see liquid medicine at the tip of the needle. Inject BESREMi • Set your dose by turning the dose selector clockwise until the prescribed dose is centered in the dose window. Check the number in the dose window to make sure you have dialed the correct prescribed dose before giving the injection. • If you accidentally dial past the prescribed dose, dial the dose selector back to the correct dose. • Hold the prefilled pen injector straight (90 degrees) over the cleaned injection site. • Push the prefilled pen injector down to fully insert the needle without touching the injection button. • Press and hold the injection button all the way until it stops. The number in the dose window will go back to “0”. • Keep holding the injection button down after the dose window returns to “0” and count to 5 to make sure the full dose is delivered. • Note: There may still be liquid remaining in the prefilled pen injector after the injection. This is normal. • Remove the needle from the skin by lifting straight up. Dispose of Used Prefilled Pen Injector • Do not recap the needle or attempt to remove it. Throw away the used prefilled pen injector with the needle still attached into a sharps disposal container.

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. • 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 )

5 WARNINGS AND PRECAUTIONS • 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. 5.7 Colitis Serious and, in very rare cases potentially life-threatening ulcerative or hemorrhagic/ischemic colitis have occurred in patients receiving interferon alfa products, some cases occurring as early as 12 weeks after start of treatment. Symptoms may include abdominal pain, bloody diarrhea, and fever. Discontinue BESREMi in patients who develop these signs or symptoms. Colitis may resolve within 1 to 3 weeks of stopping treatment. 5.8 Pulmonary Toxicity Pulmonary toxicity has occurred in patients receiving interferon alfa products, including BESREMi. Pulmonary toxicity may manifest as dyspnea, pulmonary infiltrates, pneumonia, bronchiolitis obliterans, interstitial pneumonitis, pulmonary hypertension, pleural effusion, and sarcoidosis. Some events have resulted in respiratory failure or death. Discontinue BESREMi in patients who develop pulmonary infiltrates or pulmonary function impairment. 5.9 Ophthalmologic Toxicity Ophthalmologic toxicity has occurred in patients receiving interferon alfa products, including BESREMi. These toxicities may include severe eye disorders such as retinopathy, retinal hemorrhage, retinal exudates, retinal detachment and retinal artery or vein occlusion which may result in blindness. During BESREMi therapy in patients with essential thrombocythemia, 23% of patients were identified with eye disorders. Eye disorders in ≥5% of patients included vision blurred (8%) and dry eye (7%). During BESREMi therapy in patients with polycythemia vera, 23% of patients were identified with an eye disorder. Eyes disorders ≥5% included cataract (6%) and dry eye (5%). Advise patients to have eye examinations before and during BESREMi therapy, specifically in those patients with a retinopathy-associated disease such as diabetes mellitus or hypertension. Evaluate eye symptoms promptly. Discontinue BESREMi in patients who develop new or worsening eye disorders. 5.10 Hyperlipidemia Hyperlipidemia has occurred in patients treated with interferon alfa products, including BESREMi. Hypertriglyceridemia occurred in 9% of patients, hyperlipidemia occurred in 2% of patients, and dyslipidemia occurred in 0.5% of patients receiving BESREMi for essential thrombocythemia. Hyperlipidemia, hypertriglyceridemia, or dyslipidemia occurred in 3% of patients receiving BESREMi for polycythemia vera. Elevated triglycerides may result in pancreatitis [see Warnings and Precautions ( 5.6 )] . Monitor serum triglycerides before BESREMi treatment and intermittently during therapy and manage when elevated. Consider discontinuation of BESREMi in patients with persistently, markedly elevated triglycerides. 5.11 Hepatotoxicity Hepatotoxicity has occurred in patients receiving interferon alfa products, including BESREMi. These toxicities may include increases in serum ALT, AST, GGT, and bilirubin. BESREMi is contraindicated in patients with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment [see Contraindications ( 4 )] . Increases in serum ALT ≥3 × the upper limit of normal (ULN), AST ≥3 × the ULN, GGT ≥3 × ULN, and bilirubin >2 × ULN have been observed in patients treated with BESREMi. In BESREMi-treated patients with essential thrombocythemia, 4% of patients experienced Grade ≥3 liver enzyme elevations including alanine aminotransferase increased in 2.7% of patients, aspartate aminotransferase increased in 1.1% of patients, and blood bilirubin increased in 0.5% of patients. There were 20% of patients with alanine aminotransferase levels ≥3 × ULN and 9% of patients with aspartate aminotransferase levels ≥3 × ULN. A single Grade 4 adverse reaction of hepatitis was reported in an open-label single arm study of BESREMi in patients with essential thrombocythemia, with a time to recovery of 11 days. In BESREMi-treated patients with polycythemia vera, 36 patients (20%) experienced liver enzyme elevations, 33 of whom had elevations of 1.25-5 × ULN. Patients were able to resume BESREMi upon resolution of liver enzyme elevations. Liver enzyme elevations have also been reported in patients after long-term BESREMi therapy. Monitor liver enzymes and hepatic function at baseline and during BESREMi treatment. For dose modifications see Table 1 for patients with essential thrombocythemia and see Table 3 for patients with polycythemia vera [see Dosage and Administration ( 2.3 )] . Discontinue BESREMi in patients who develop evidence of hepatic decompensation (characterized by jaundice, ascites, hepatic encephalopathy, hepatorenal syndrome or variceal hemorrhage) during treatment [see Use in Specific Populations ( 8.7 )] . 5.12 Renal Toxicity Renal toxicity has occurred in patients receiving interferon alfa products, including BESREMi. During BESREMi therapy in patients with polycythemia vera, <1% of patients were reported to develop renal impairment and <1% of patients were reported to have toxic nephropathy. Monitor serum creatinine at baseline and during therapy. Avoid use of BESREMi in patients with eGFR <30 mL/min. Discontinue BESREMi if severe renal impairment develops during treatment [see Use in Specific Populations ( 8.6 )]. 5.13 Dental and Periodontal Toxicity Dental and periodontal toxicities may occur in patients receiving interferon alfa products, including BESREMi. These toxicities may include dental and periodontal disorders, which may lead to loss of teeth. In addition, dry mouth could have a damaging effect on teeth and oral mucous membranes during long-term treatment with BESREMi. Patients should have good oral hygiene and regular dental examinations. 5.14 Dermatologic Toxicity Dermatologic toxicity has occurred in patients receiving interferon alfa products, including BESREMi. These toxicities have included skin rash, pruritus, alopecia, erythema, psoriasis, xeroderma, dermatitis acneiform, hyperkeratosis, and hyperhidrosis. Consider discontinuation of BESREMi if clinically significant dermatologic toxicity occurs. 5.15 Driving and Operating Machinery BESREMi may impact the ability to drive and use machinery. Patients should not drive or use heavy machinery until they know how BESREMi affects their abilities. Patients who experience dizziness, somnolence or hallucination during BESREMi therapy should avoid driving or using machinery. 5.16 Embryo-Fetal Toxicity Based on the mechanism of action, BESREMi can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations ( 8.1 ) and Clinical Pharmacology ( 12.1 )] . Obtain a pregnancy test in females of reproductive potential prior to initiating treatment with BESREMi. Advise females of reproductive potential to use an effective method of contraception during treatment with BESREMi and for at least 8 weeks after the final dose [see Dosage and Administration ( 2.2 ) and Use in Specific Populations ( 8.1 , 8.3 )].

7 DRUG INTERACTIONS • 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 )] .

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 )] • 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. 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. Clinically relevant adverse reactions in <10% of patients include: Cardiovascular System: Atrial fibrillation Adverse Reactions* BESREMi N=51 % Influenza-like illness a 59 Arthralgia 47 Fatigue b 47 Pruritus 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

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.