HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. 16.1How Supplied. BESREMi (ropeginterferon alfa-2b-njft) injection is sterile, preservative-free, clear and colorless to slightly yellowish solution for subcutaneous administration in single-dose prefilled syringe. Each carton contains one 500 mcg/mL prefilled syringe with 30 gauge, 1/2 inch safety hypodermic needle (NDC 73536-500-01).. 16.2Storage and Handling. Store in refrigerator at 36 to 46 (2 to C) in the original carton to protect from light.Do not freeze.

GERIATRIC USE SECTION.

8.5 Geriatric Use. 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. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other therapy.

HEPATIC IMPAIRMENT SUBSECTION.

8.7 Hepatic Impairment. BESREMi is contraindicated in patients with hepatic impairment (Child-Pugh 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 or C), discontinue BESREMi [see Dosage and Administration (2.2) and Warnings and Precautions (5.11)].

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. 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. 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)] Embryo-Fetal Toxicity [see Warnings and Precautions (5.16)] Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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%) 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 Adverse Reactions in 10% of Subjects with Polycythemia Vera in the PEGINVERA Study Over 7.5 Years.Adverse ReactionsAdverse Reactions defined as all treatment emergent adverse events BESREMi N=51 %Grouped Term DefinitionsInfluenza-like illness Includes pyrexia, chills, and influenza-like illness. 59Arthralgia47Fatigue Includes asthenia, malaise, and fatigue. 47Pruritis45Nasopharyngitis Includes pharyngitis and nasopharyngitis. 43Musculoskeletal pain Includes musculoskeletal pain, back pain, pain in extremity, bone pain, flank pain, and spinal pain. 41Headache Includes headache, migraine, and head pain. 39Diarrhea33Hyperhidrosis Includes night sweats and hyperhidrosis. 29Nausea28Upper respiratory tract infection Includes upper respiratory tract infection, rhinitis, bronchitis, and respiratory tract infection. 27Local administration site reactions26Dizziness22Abdominal pain Includes abdominal pain upper, abdominal pain lower, and abdominal pain. 20Depression20Sleep disorder Includes insomnia, sleep disorder, and abnormal dreams. 20Leukopenia18Decreased appetite18Alopecia16Edema Includes peripheral edema and generalized edema. 16Hypertension Includes hypertension and hypertensive crisis. 16Muscle spasms16Neutropenia16Rash Includes rash, maculopapular rash, and pruritic rash. 16Transaminase elevations Includes transaminase increase, hepatic enzyme increase, GGT increase, AST increase, and ALT increase. 16Urinary tract infection16Thrombocytopenia12Vertigo12Clinically relevant adverse reactions in 10% of patients include:Cardiovascular System: Atrial fibrillation. 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)] Embryo-Fetal Toxicity [see Warnings and Precautions (5.16)] 6.2 Immunogenicity. As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other interferon alfa-2b products may be misleading.The incidence of binding antibodies to ropeginterferon alfa-2b-njft was 1.4% (2/146) and they were observed as early as weeks post-dosing. Among the patients who tested positive for binding antibodies, none developed neutralizing antibodies.

BOXED WARNING SECTION.

WARNING: RISK OF SERIOUS DISORDERS. Risk of Serious Disorders: Interferon alfa products may cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Patients should be monitored closely with periodic clinical and laboratory evaluations. Therapy should be withdrawn in patients with persistently severe or worsening signs or symptoms of these conditions. In many, but not all cases, these disorders resolve after stopping therapy [see Warnings and Precautions (5.1, 5,2, 5.3, 5.4) and Adverse Reactions (6.1) ].. WARNING: RISK OF SERIOUS DISORDERSSee full prescribing information for complete boxed warning.Risk of Serious Disorders: Interferon alfa products may cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Monitor closely and withdraw therapy with persistently severe or worsening signs or symptoms of the above disorders.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Ropeginterferon alfa-2b-njft has not been tested for its carcinogenic potential. Neither ropeginterferon alfa-2b-njft nor its components, interferon or methoxypolyethylene glycol, caused damage to DNA when tested in the standard battery of mutagenesis assays. Ropeginterferon alfa-2b-njft effects on fertility have not been assessed [see Use in Specific Populations (8.1, 8.2, 8.3)].

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Interferon alfa belongs to the class of type interferons, which exhibit their cellular effects in polycythemia vera in the bone marrow by binding to transmembrane receptor termed interferon alfa receptor (IFNAR). Binding to IFNAR initiates downstream signaling cascade through the activation of kinases, in particular Janus kinase (JAK1) and tyrosine kinase (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.. 12.2 Pharmacodynamics. The efficacy of ropeginterferon alfa-2b-njft is dependent on the stabilization of hematological parameters (hematocrit <45%, platelets <400 109/L and leukocytes <10 109/L). Pharmacokinetic-pharmacodynamic analyses have demonstrated that the reduction in the individual hematological parameters is dependent on ropeginterferon alfa-2b-njft concentrations. Complete hematological response (CHR, defined as patient achieving hematocrit <45% without phlebotomy [at least months since last phlebotomy], platelets <=400 109/L and leukocytes <=10 109/L) increased with increasing ropeginterferon alfa-2b-njft concentration over time. Based on the exposure-response (E-R) analyses using data from the PEGINVERA study, the predicted probability of CHR (95% Prediction Intervals) was 22% (11% 34%) before treatment, 50% (38% 62%) at week 20 (end of titration), 64% (47% 78%) at week 52, and 70% (55% 88%) at week 104. The E-R analyses show that the maximum probability of CHR is reached after years of continuous treatment.. 12.3 Pharmacokinetics. In patients with polycythemia vera, the estimated steady state Cmax, Cmin and area under the curve (AUC) after two-week dosing interval of BESREMi over dose range of 100 mcg to 500 mcg ranged from 4.4 31 ng/mL, 1.4 12 ng/mL, and 1011 7809 ngxh/mL, respectively. The estimated steady state Cmax occurs between to days.. AbsorptionThe estimated geometric mean (CV%) of the absorption rate constant of BESREMi is 0.12 day-1 (27%) in patients with polycythemia vera.. DistributionThe estimated geometric mean (CV%) of apparent volume of distribution of BESREMi is 4.8 (21%) in patients with polycythemia vera.. EliminationBESREMi undergoes receptor independent degradation/excretion and receptor binding and subsequent degradation of the drug-receptor complex. The half-life and clearance of BESREMi is approximately days and 1.7-2.5 L/h in patients with polycythemia vera over dose range of 100 mcg to 500 mcg, respectively.. Specific PopulationsNo clinically significant differences in the pharmacokinetics of BESREMi were observed based on age, sex, body surface area, and JAK2V617F mutation.. Drug Interactions. Clinical StudiesNo clinical studies evaluating the drug interaction potential of BESREMi have been conducted.. In Vitro StudiesIn vitro studies indicate that BESREMi exhibited time-dependent inhibitory potential on CYP2A6. BESREMi did not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 in human liver microsomes. BESREMi is not expected to induce CYP enzymes. However, interferon may influence CYP450 through modulating transcription factors and altering protein expression and/or structure. As this mechanism requires more time to exert effect, it cannot be evaluated by in vitro assays.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. The efficacy and safety of BESREMi were evaluated in the PEGINVERA study, prospective, multicenter, single-arm trial of 7.5 years duration. The study included 51 adults with polycythemia vera. The mean age at baseline was 56 years (range 35-82 years) with 20 (39%) women and 31 (61%) men. All patients had the JAK2V617F mutation with 16% of subjects being newly diagnosed; 84% had known disease with median duration of 2.2 years. One-third (33%) of patients were undergoing treatment with hydroxyurea (HU) upon study entry. At baseline, the mean +- SD hematocrit, platelets, and leukocytes were 45% +- 4.0%, 457 x109/L +- 187 x109/L and 11.8 109/L +- 5.2 109/L, respectively. Median spleen size was 13.2 cm with 16 (31%) having splenomegaly (defined as longitudinal diameter of >12 cm for women and >13 cm for men). Eleven patients (22%) had prior history of major cardiovascular event including pulmonary embolism (6), stroke (2), myocardial infarction (2) and portal vein thrombosis (1).In stage I, the maximum tolerated dose, defined as the highest administered dose without dose-limiting toxicities was determined to be 540 mcg. In stage II, an intra-patient dose escalation began at 150 mcg, or 100 mcg if titrating from hydroxyurea, or at the highest dose achieved in those patients enrolled during stage I. Titration with BESREMi occurred every two-weeks at doses of 225 mcg, 300 mcg, 400 mcg and 450 mcg with dose escalation stopping when hematological parameters were stabilized. For patients transitioning from hydroxyurea, the hydroxyurea dose was tapered off over the first 12 weeks of treatment to avoid toxicity. After at least one year on therapy and at median time of 21.5 months, 28 eligible patients in the PEGINVERA study increased the dosing interval to once every weeks. Because of formulation changes, the recommended starting dose, titration amounts, and maximum dose of BESREMi differ slightly from those used in the trial [see Dosage and Administration (2)].The median duration of treatment exposure was 61 months and 53% of patients completed at least 60 months of treatment. Thirty-six patients completed one year of treatment with eleven patients discontinuing after one year of treatment mainly due to treatment emergent adverse events. The mean dose of BESREMi was 237 mcg (+- 110) during the treatment period.The efficacy of BESREMi was evaluated in the PEGINVERA study by assessing complete hematological response (CHR) defined as hematocrit <45% and no phlebotomy in the preceding months, platelets <=400 109/L and leukocytes <=10 109/L, normal spleen size (longitudinal diameter <= 12 cm for females and <= 13 cm for males) assessed by ultrasound and absence of thromboembolic events.The CHR in the treated population during the treatment period was 61% (31/51) (95% CI: 46, 74). The median duration of response was 14.3 months (95% CI: 5.5, 30.1).Among the patients in the treated population who achieved CHR, the median time to response was 7.8 months of treatment with BESREMi. It required 1.2 years of treatment with BESREMi for 50% of patients (hydroxyurea-naive) to achieve CHR and 1.4 years for 50% of patients with prior hydroxyurea use to achieve CHR.A hematological response based only on hematocrit, platelets, and leukocytes was achieved among 80% of patients treated with BESREMi (41/51) (95% CI: 67, 90). The median duration of this response was 20.8 months (95% CI: 13.0, 43.8).

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience. 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)] Embryo-Fetal Toxicity [see Warnings and Precautions (5.16)] Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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%) 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 Adverse Reactions in 10% of Subjects with Polycythemia Vera in the PEGINVERA Study Over 7.5 Years.Adverse ReactionsAdverse Reactions defined as all treatment emergent adverse events BESREMi N=51 %Grouped Term DefinitionsInfluenza-like illness Includes pyrexia, chills, and influenza-like illness. 59Arthralgia47Fatigue Includes asthenia, malaise, and fatigue. 47Pruritis45Nasopharyngitis Includes pharyngitis and nasopharyngitis. 43Musculoskeletal pain Includes musculoskeletal pain, back pain, pain in extremity, bone pain, flank pain, and spinal pain. 41Headache Includes headache, migraine, and head pain. 39Diarrhea33Hyperhidrosis Includes night sweats and hyperhidrosis. 29Nausea28Upper respiratory tract infection Includes upper respiratory tract infection, rhinitis, bronchitis, and respiratory tract infection. 27Local administration site reactions26Dizziness22Abdominal pain Includes abdominal pain upper, abdominal pain lower, and abdominal pain. 20Depression20Sleep disorder Includes insomnia, sleep disorder, and abnormal dreams. 20Leukopenia18Decreased appetite18Alopecia16Edema Includes peripheral edema and generalized edema. 16Hypertension Includes hypertension and hypertensive crisis. 16Muscle spasms16Neutropenia16Rash Includes rash, maculopapular rash, and pruritic rash. 16Transaminase elevations Includes transaminase increase, hepatic enzyme increase, GGT increase, AST increase, and ALT increase. 16Urinary tract infection16Thrombocytopenia12Vertigo12Clinically relevant adverse reactions in 10% of patients include:Cardiovascular System: Atrial fibrillation. 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)] Embryo-Fetal Toxicity [see Warnings and Precautions (5.16)].

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. BESREMi is contraindicated in patients with:Existence of, or history of severe psychiatric disorders, particularly severe depression, suicidal ideation, or suicide attemptHypersensitivity to interferons including interferon alfa-2b or any of the inactive ingredients of BESREMiModerate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairmentHistory or presence of active serious or untreated autoimmune diseaseImmunosuppressed transplant recipients. 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. 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 or C) (4)History or presence of active serious or untreated autoimmune disease (4)Immunosuppressed transplant recipients (4). 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 or C) (4). History or presence of active serious or untreated autoimmune disease (4). Immunosuppressed transplant recipients (4).

DESCRIPTION SECTION.

11 DESCRIPTION. Ropeginterferon alfa-2b-njft, an interferon alfa-2b, is an N-terminal monopegylated covalent conjugate of proline interferon alfa-2b, produced in Escherichia coli cells by recombinant DNA technology, with methoxy polyethylene glycol (mPEG) moiety. Ropeginterferon alfa-2b-njft has an approximate molecular weight of 60 kDa and the approximate molecular weight of the PEG portion of the molecule is 40 kDa.BESREMi (ropeginterferon alfa-2b-njft) injection is sterile, preservative-free, clear and colorless to slightly yellowish solution for subcutaneous use supplied in single dose prefilled syringe.Each prefilled syringe delivers mL of solution containing 500 mcg of ropeginterferon alfa-2b-njft and benzyl alcohol (10 mg), glacial acetic acid (0.05 mg), polysorbate 80 (0.05 mg), sodium acetate (1.58 mg), sodium chloride (8 mg), and Water for Injection, USP. The pH is approximately 6.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Recommended starting dose: 100 mcg by subcutaneous injection every weeks (50 mcg if receiving hydroxyurea).Increase the dose by 50 mcg every weeks (up to maximum of 500 mcg) until hematological parameters are stabilized (2.1)Interrupt or discontinue dosing if certain adverse reactions occur (2.3, 5). Recommended starting dose: 100 mcg by subcutaneous injection every weeks (50 mcg if receiving hydroxyurea).. Increase the dose by 50 mcg every weeks (up to maximum of 500 mcg) until hematological parameters are stabilized (2.1). Interrupt or discontinue dosing if certain adverse reactions occur (2.3, 5). 2.1Pre-Treatment Testing. Pregnancy testing is recommended prior to BESREMi treatment in females of reproductive potential [see Use in Specific Populations (8.3)].. 2.2Recommended 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 maximum of 500 mcg), until the hematological parameters are stabilized (hematocrit less than 45%, platelets less than 400 109/L, and leukocytes less than 10 109/L).. 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 maximum of 500 mcg), until the hematological parameters are stabilized (hematocrit less than 45%, platelets less than 400 109/L, and leukocytes less than 10 109/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 maximum of 500 mcg), until the hematological parameters are stabilized (hematocrit less than 45%, platelets less than 400 109/L, and leukocytes less than 10 109/L).Discontinue hydroxyurea by Week 13.Maintain the two week dosing interval of BESREMi at which hematological stability is achieved for at least year. After achievement of hematological stability for at least year on stable dose of BESREMi, the dosing interval may be expanded to every weeks.Monitor patients closely especially during the titration phase. Perform complete blood counts (CBC) regularly, every weeks during the titration phase and every 3-6 months during the maintenance phase (after the patients 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)].. 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 maximum of 500 mcg), until the hematological parameters are stabilized (hematocrit less than 45%, platelets less than 400 109/L, and leukocytes less than 10 109/L).. Discontinue hydroxyurea by Week 13.. 2.3Dose Modifications. Monitor CBC every 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, dose increase attempt to the next higher dose level should be considered after recovery to grade toxicity.Table Dose Modifications for BESREMi Adverse ReactionsAdverse ReactionNational Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 SeverityDosage ModificationLiver enzyme elevation with concomitant bilirubin elevation, or other evidence of hepatic decompensationAny increase above baselineInterrupt 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 the upper limit of normal (ULN) but <=20 ULNDecrease dose by 50 mcg; if toxicity does not improve, continue decreasing at biweekly intervals until alanine aminotransferase (ALT) and aspartate aminotransferase (AST) recover 3 ULN if baseline was normal; x 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; x baseline if baseline was abnormal. Consider permanent discontinuation if toxicity persists after four dose-modifications.CytopeniaAnemia: Hemoglobin (Hgb) 8 g/dLDecrease 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 Thrombocytopenia: platelet count 50,000/mm3 but >=25,000/mm3 Leukopenia: white blood cell count (WBC) <2000/mm3 but >=1,000/mm3 If the interrupted dose is 50 mcg, refrain from treatment until recovery.Anemia: Hemoglobin levels are life threatening, or urgent intervention neededInterrupt treatment until recovery of Hgb >10.0 g/dL, platelets >75,000/mm3, and WBC >3,000/mm3. Thrombocytopenia: platelet count <25,000/mm3 Consider permanent discontinuation if toxicity persists after four dose-modifications.Leukopenia: WBC <1000/mm3 DepressionMild, without suicidal ideationConsider psychiatric consultation if persistent (>8 weeks).Moderate, without suicidal ideationConsider dose reduction and psychiatric consultation.Severe, or any severity with suicidal ideationDiscontinue therapy, recommend psychiatric consultation.. 2.4Preparation and Administration. Read the INSTRUCTIONS FOR USE before administering the single-dose BESREMi prefilled syringe. BESREMi is for subcutaneous injection only and may be administered by either healthcare professional, patient or caregiver. Before decision is made to allow BESREMi to be administered by patient or caregiver, ensure that the patient is an appropriate candidate for self-administration or administration by caregiver. Proper training on storage, preparation and administration technique should be provided. If patient or caregiver is not an appropriate candidate for any reason, then BESREMi should be administered by healthcare professional.Before each injection, remove the carton that contains the BESREMi prefilled syringe from the refrigerator. Keep the prefilled syringe in the carton and lay it flat on clean work surface for 15-30 minutes to allow the prefilled syringe to reach room temperature [59 to 77 (15 to 25 C)].Before injection, visually inspect BESREMi in the prefilled syringe for particulate matter and discoloration before administration (do not use if the solution in the syringe is cloudy, discolored, contains particulate matter or if the syringe shows any sign of damage).. Syringe PreparationRemove 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 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.. 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 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 DoseDepending 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 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.. 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 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 BESREMiPinch the chosen injection site. While pinching the skin, insert needle at 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.. Pinch the chosen injection site. While pinching the skin, insert needle at 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 SyringeCarefully 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.. 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.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Injection: 500 mcg/mL clear and colorless to slightly yellowish solution in single-dose prefilled syringe.. Injection: 500 mcg/mL solution in single-dose prefilled syringe (3). Injection: 500 mcg/mL solution in single-dose prefilled syringe (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Monitor patients taking CYP450 substrates with 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). Monitor patients taking CYP450 substrates with 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). 7.1Drugs 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 narrow therapeutic index should be monitored to inform the need for dosage modification for these concomitant drugs.. 7.2Myelosuppressive 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)].

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3 Females and Males of Reproductive Potential. BESREMi may cause embryo-fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)].. Pregnancy TestingPregnancy testing prior to BESREMi treatment is recommended for females of reproductive potential.. Contraception. FemalesAdvise female patients of reproductive potential to use effective contraception during treatment with BESREMi and for at least weeks after the final dose.. Infertility. FemalesBased 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.

IMMUNOGENICITY.

6.2 Immunogenicity. As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other interferon alfa-2b products may be misleading.The incidence of binding antibodies to ropeginterferon alfa-2b-njft was 1.4% (2/146) and they were observed as early as weeks post-dosing. Among the patients who tested positive for binding antibodies, none developed neutralizing antibodies.

INDICATIONS & USAGE SECTION.

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).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).. Depression and SuicideInform patients, their caregivers, and family members that suicidal ideation and behavior, as well as new onset or worsening depression have been reported in patients treated with BESREMi. Advise them to be aware of any unusual changes in mood or behavior, new onset or worsening of depression, or the emergence of suicidal thoughts or behavior. Instruct patients, caregivers, and family members to report signs or symptoms of depression to their healthcare provider right away, but to discontinue BESREMi immediately and seek immediate medical attention if suicidal ideation or attempts occur [see Warnings and Precautions (5.1)].. Endocrine ToxicityAdvise patients to report any signs or symptoms of diabetes or thyroid dysfunction [see Warnings and Precautions (5.2)].. Cardiovascular ToxicityAdvise patients to report signs or symptoms of cardiovascular toxicity to their healthcare provider [see Warnings and Precautions (5.3)]. Decreased Peripheral Blood CountsAdvise patients to seek prompt medical attention if they experience weakness/fatigue, fever, easy bruising, or frequent nose bleeds [see Warnings and Precautions (5.4)]. HypersensitivityAdvise patients to seek immediate medical attention if they experience any symptoms of serious hypersensitivity reactions [see Warnings and Precautions (5.5) and Drug Interactions (7)]. PancreatitisAdvise patients to report signs or symptoms of pancreatitis [see Warnings and Precautions (5.6)].. ColitisAdvise patients to report signs or symptoms of colitis [see Warnings and Precautions (5.7)].. Pulmonary ToxicityAdvise patients to report signs or symptoms of pulmonary toxicity [see Warnings and Precautions (5.8)].. Ophthalmologic ToxicityAdvise patients to report visual changes and to have eye examinations before and during treatment [see Warnings and Precautions (5.9)].. Hyperlipidemia Advise patients that BESREMi may increase blood triglycerides and that they will need blood testing to monitor for this toxicity [see Warnings and Precautions (5.10)].. HepatotoxicityAdvise patients to report signs or symptoms of hepatic toxicity to their healthcare provider [see Warnings and Precautions (5.11) and Use in Specific Populations (8.7)].. Renal ToxicityAdvise patients to report signs or symptoms of kidney disease [see Warnings and Precautions (5.12) and Use in Specific Populations (8.6)].. Dental and Periodontal ToxicityAdvise patients to maintain good oral hygiene and to have regular dental examinations [see Warnings and Precautions (5.13)].. Dermatologic ToxicityAdvise patients to seek medical attention if significant pruritus, alopecia, rash and/or other dermatological toxicities occur [see Warnings and Precautions (5.14)].. Hazardous Occupations/Operating MachineryAdvise patients to refrain from engaging in operating heavy or potentially dangerous machinery until they know how BESREMi will affect their abilities. Advise patients who experience dizziness, somnolence and hallucinations not to drive or use heavy machinery [see Warnings and Precautions (5.15)].. Pregnancy and ContraceptionAdvise women about the need to use an effective method of contraception while taking BESREMi and for at least weeks after the final dose [see Use in Specific Populations (8.1, 8.3)].. LactationAdvise women not to breastfeed during treatment and for weeks after the final dose [see Use in Specific Populations (8.2)].. Instruction on Injection TechniqueInstruct patients on proper storage, preparation and administration techniques for BESREMi. Instruct patients who are self-administering to inject the prescribed dose of BESREMi [see Dosage and Administration (2.4)].

INSTRUCTIONS FOR USE SECTION.

INSTRUCTIONS FOR USE BESREMi [bez-reh-me] (ropeginterferon alfa-2b-njft) injection, for subcutaneous use Single-dose prefilled syringeThis Instructions for Use has been approved by the U.S. Food and Drug Administration.Issued: November 2021This Instructions for Use contains information on how to prepare and inject BESREMi under your skin (subcutaneous injection) using the single-dose prefilled syringe.Guide to Prefilled syringe and Needle Parts (Figure A)Storing BESREMiStore the BESREMi carton in the refrigerator between 36F to 46F (2C to 8C) (Figure B).Keep your BESREMi prefilled syringes in their original carton (Figure B) while stored.Do not freeze the prefilled syringes.Do not use prefilled syringe that has been frozen or left in direct sunlight.Keep BESREMi prefilled syringes, needles, and all medicines out of the reach of children. Important information you need to know before injecting BESREMiRead this Instructions for Use before using your single-dose BESREMi prefilled syringe for the first time and each time you get new prescription. There may be new information. This leaflet does not take the place of talking with your healthcare provider about your medical condition or your treatment. Ask your healthcare provider about the right way to prepare and give your BESREMi injection.Your healthcare provider will tell you the prescribed dose that you should take and the right amount of BESREMi to measure in the prefilled syringe for your dose. Each time you inject, be sure that you know the prescribed dose of BESREMi to inject. Your dose may change over time.BESREMi is for subcutaneous (under the skin) injection only.BESREMi is for one-time use only. Do not reuse your prefilled syringe or needle.Do not use prefilled syringe or needle that is damaged or broken. Contact your healthcare provider for replacement prefilled syringe or additional needles.Inject BESREMi into the top of the thighs or lower stomach-area just under the skin. Do not inject BESREMi into any other area of the body.Throw away (dispose of) the BESREMi prefilled syringe with needle attached right away after use, even if there is medicine left in the prefilled syringe. See Step 10 in the section Dispose of used prefilled syringes and needles. Gather and check supplies1.Prepare BESREMi Prefilled Syringe1.1.Take the BESREMi carton out of the refrigerator (Figure E). 1.2.Check the expiration date (EXP) on the top panel of the carton to make sure it has not passed (Figure F). Do not use the prefilled syringe if the expiration date has passed. 1.3.Let carton containing the BESREMi prefilled syringe sit on clean work surface for 15 to 30 minutes to allow it to come to room temperature (Figure G). Do not warm the prefilled syringe any other way.2.Gather supplies for injection2.1.After allowing the prefilled syringe to come to room temperature for 15 to 30 minutes inside the carton, gather the following additional supplies. Alcohol Swab (Figure H). FDA-cleared Sharps Disposal Container (Figure I) paper towel, sink, or trash can to minimize mess during dose adjustment (Figure J). Optional Items: Gauze or Cotton Ball and Small Adhesive Bandage (Figure K). 3.Wash hands and remove syringe from tray3.1.Wash your hands with soap and water, then dry your hands (Figure L). 3.2.Open the carton and remove the clear plastic tray that holds the BESREMi prefilled syringe and needle package (Figure M). 3.3.Remove the needle package and BESREMi prefilled syringe from the plastic tray. Hold the prefilled syringe by the middle of the syringe body during removal (Figure N). 4.Check the liquid medicine in the BESREMi prefilled syringe4.1.Check the liquid medicine in the prefilled syringe (Figure O). The liquid should be clear and colorless to slightly yellow, and should not have particles. Do not use the prefilled syringe if the liquid is cloudy, discolored, or contains particles. Contact your healthcare provider or pharmacist.4.2.Check the syringe to see if it is damaged or broken (Figure O). Do not use if it shows any signs of damage or breakage. Contact your healthcare provider or pharmacist. Prepare syringe for injection5.Attach the needle to the BESREMi prefilled syringe5.1.Carefully open the needle package, remove the needle, and set it aside (Figure P). Throw away the packaging into household trash. 5.2.Hold the prefilled syringe as shown. Remove the prefilled syringe cap by unscrewing it counter-clockwise (Figure Q). Throw away the syringe cap into household trash. Do not allow the tip of the prefilled syringe to touch anything. 5.3.Attach the needle to the prefilled syringe by firmly pushing it into the collar of the syringe and then screwing (turn clock-wise) it on until it feels securely attached (Figure R). The needle should now be assembled to the prefilled syringe (Figure S). 6.Choose and clean injection site6.1.Choose one of the following injection sites (Figure T):Lower stomach (abdomen) area, at least inches away from the belly button,Top of thighs. Do not inject into skin that is irritated, red, bruised, infected, or scarred.BESREMi is for subcutaneous (under the skin) injection only.Rotate (change) the injection site for each injection. 6.2.Clean the chosen injection site with an alcohol swab and let it air dry (Figure U). Do not blow on or touch the injection site after it has been cleaned. 7.Uncap needle and move air bubbles to top7.1.Pull the pink needle shield back (Figure V). Note: The pink needle shield will be used after the injection to cover the needle and protect you from needle-stick injuries. 7.2.Hold the syringe from the syringe body. Remove the clear needle cap by pulling it straight off (Figure W). Throw away the needle cap into household trash. Do not recap needle. 7.3.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 (Figure X). 8.Set your dose8.1.Check your prescription to identify your prescribed dose (Figure Y). Depending on your prescribed dose, you may have to adjust the dose in the syringe by getting rid of (discarding) some medicine from the prefilled syringe before you inject the medicine. 8.2.To set your dose follow the steps below:1.Hold the prefilled syringe at eye level with the needle pointing straight up over paper towel, sink, or trash can.2.Check that you can see the dose lines and number markings on the prefilled syringe.3.Pinch the end of the plunger as shown (Figure Z).4.Slowly push up on the plunger to remove liquid medicine until the top edge of the gray stopper lines up with the marking for your prescribed dose (Figure Z). Keep holding straight up as you set the dose. Important: If you accidentally remove too much liquid medicine, do not inject. Contact your healthcare provider or pharmacist.Inject BESREMi9.Give Injection9.1.Pinch the chosen injection site (Figure AA). 9.2.While pinching the skin, insert the needle at 45 to 90 degree angle into the pinched skin (Figure AB). Then release the pinched skin. 9.3.Inject the medicine by slowly pressing down on the plunger all the way until it stops (Figure AC). 9.4.After all the liquid medicine is injected, remove the needle from the skin (Figure AD). 9.5Cover needle Carefully push the pink needle shield over the needle until it snaps into place and covers the needle (Figure AE). This helps prevent needle-stick injuries. Do not recap the needle using the needle cap. Only use the pink needle shield to cover the needle.Do not reuse the prefilled syringe and needle.Disposing of used prefilled syringes and needles10.Dispose of used prefilled syringes and needles.Put your used prefilled syringes and needles in FDA-cleared sharps disposal container right away after use (Figure AF). Do not throw away (dispose of) loose prefilled syringes and needles in the household trash. If you do not have FDA-cleared sharps disposal container, you may use household container that is:made of heavy-duty plastic,can be closed with tight-fitting, puncture-resistant lid without sharps being able to come out,upright and stable during use,leak-resistant, andproperly labeled to warn of hazardous waste inside the container. When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDAs website at: http://www.fda.gov/safesharpsdisposal.Do not dispose of your sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container.Always keep the sharps disposal container out of the reach of children.11Check injection site.11.1If there is small amount of blood or liquid at the injection site, press gauze or cotton ball over the injection site until the bleeding stops (Figure AG).11.2Do not rub the injection site. If needed, you may apply small adhesive bandage.Additional information.For additional information about BESREMi and video demonstration on how to use BESREMi, go to: www.BESREMi.comManufactured by: PharmaEssentia Corporation 2F-5 No. YuanQu Street Nangang Dist. Taipei, Taiwan U.S. License number: 2155Distributed by: PharmaEssentia Corporation 35 Corporate Drive, Suite 325, Burlington, MA 01803, USABESREMi is trademark/registered trademark of PharmaEssentia Copyright 2021 PharmaEssentia. Keep your BESREMi prefilled syringes in their original carton (Figure B) while stored.. Do not freeze the prefilled syringes.. Do not use prefilled syringe that has been frozen or left in direct sunlight.. Keep BESREMi prefilled syringes, needles, and all medicines out of the reach of children. Your healthcare provider will tell you the prescribed dose that you should take and the right amount of BESREMi to measure in the prefilled syringe for your dose. Each time you inject, be sure that you know the prescribed dose of BESREMi to inject. Your dose may change over time.. BESREMi is for subcutaneous (under the skin) injection only.. BESREMi is for one-time use only. Do not reuse your prefilled syringe or needle.. Do not use prefilled syringe or needle that is damaged or broken. Contact your healthcare provider for replacement prefilled syringe or additional needles.. Inject BESREMi into the top of the thighs or lower stomach-area just under the skin. Do not inject BESREMi into any other area of the body.. Throw away (dispose of) the BESREMi prefilled syringe with needle attached right away after use, even if there is medicine left in the prefilled syringe. See Step 10 in the section Dispose of used prefilled syringes and needles. Lower stomach (abdomen) area, at least inches away from the belly button,. Top of thighs. Do not inject into skin that is irritated, red, bruised, infected, or scarred.BESREMi is for subcutaneous (under the skin) injection only.Rotate (change) the injection site for each injection. 1.Hold the prefilled syringe at eye level with the needle pointing straight up over paper towel, sink, or trash can.. 2.Check that you can see the dose lines and number markings on the prefilled syringe.. 3.Pinch the end of the plunger as shown (Figure Z).. 4.Slowly push up on the plunger to remove liquid medicine until the top edge of the gray stopper lines up with the marking for your prescribed dose (Figure Z). Keep holding straight up as you set the dose. Important: If you accidentally remove too much liquid medicine, do not inject. Contact your healthcare provider or pharmacist.. Put your used prefilled syringes and needles in FDA-cleared sharps disposal container right away after use (Figure AF). Do not throw away (dispose of) loose prefilled syringes and needles in the household trash. If you do not have FDA-cleared sharps disposal container, you may use household container that is:made of heavy-duty plastic,can be closed with tight-fitting, puncture-resistant lid without sharps being able to come out,upright and stable during use,leak-resistant, andproperly labeled to warn of hazardous waste inside the container. made of heavy-duty plastic,. can be closed with tight-fitting, puncture-resistant lid without sharps being able to come out,. upright and stable during use,. leak-resistant, and. properly labeled to warn of hazardous waste inside the container.. When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDAs website at: http://www.fda.gov/safesharpsdisposal.. Do not dispose of your sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container.. Always keep the sharps disposal container out of the reach of children.. Figure A. Figure B. Figure & D. Figure E. Figure F. Figure G. Figure H. Figure I. Figure J. Figure K. Figure L. Figure M. Figure N. Figure O. Figure P. Figure Q. Figure R. Figure S. Figure T. Figure U. Figure V. Figure W. Figure X. Figure Y. Figure Z. Figure AA. Figure AB. Figure AC. Figure AD. Figure AE. Figure AF. Figure AG.

LACTATION SECTION.

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 weeks after the final dose.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Interferon alfa belongs to the class of type interferons, which exhibit their cellular effects in polycythemia vera in the bone marrow by binding to transmembrane receptor termed interferon alfa receptor (IFNAR). Binding to IFNAR initiates downstream signaling cascade through the activation of kinases, in particular Janus kinase (JAK1) and tyrosine kinase (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.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Ropeginterferon alfa-2b-njft has not been tested for its carcinogenic potential. Neither ropeginterferon alfa-2b-njft nor its components, interferon or methoxypolyethylene glycol, caused damage to DNA when tested in the standard battery of mutagenesis assays. Ropeginterferon alfa-2b-njft effects on fertility have not been assessed [see Use in Specific Populations (8.1, 8.2, 8.3)].

OVERDOSAGE SECTION.

10 OVERDOSAGE. Overdosage of BESREMi may result in influenza-like symptoms or other adverse reactions. There is no antidote to BESREMi overdosage. In case of an overdose, frequently monitor signs and symptoms for adverse reactions.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 500 mcg/mL Syringe Label. BESREMi(R) (ropeginterferon alfa-2b-njft) INJECTION500 mcg/mL For Subcutaneous UseLOT: EXP:Rx Only PharmaEssentia Corp.. PRINCIPAL DISPLAY PANEL 500 mcg/mL Syringe Label.

PEDIATRIC USE SECTION.

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

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. The efficacy of ropeginterferon alfa-2b-njft is dependent on the stabilization of hematological parameters (hematocrit <45%, platelets <400 109/L and leukocytes <10 109/L). Pharmacokinetic-pharmacodynamic analyses have demonstrated that the reduction in the individual hematological parameters is dependent on ropeginterferon alfa-2b-njft concentrations. Complete hematological response (CHR, defined as patient achieving hematocrit <45% without phlebotomy [at least months since last phlebotomy], platelets <=400 109/L and leukocytes <=10 109/L) increased with increasing ropeginterferon alfa-2b-njft concentration over time. Based on the exposure-response (E-R) analyses using data from the PEGINVERA study, the predicted probability of CHR (95% Prediction Intervals) was 22% (11% 34%) before treatment, 50% (38% 62%) at week 20 (end of titration), 64% (47% 78%) at week 52, and 70% (55% 88%) at week 104. The E-R analyses show that the maximum probability of CHR is reached after years of continuous treatment.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. In patients with polycythemia vera, the estimated steady state Cmax, Cmin and area under the curve (AUC) after two-week dosing interval of BESREMi over dose range of 100 mcg to 500 mcg ranged from 4.4 31 ng/mL, 1.4 12 ng/mL, and 1011 7809 ngxh/mL, respectively. The estimated steady state Cmax occurs between to days.. AbsorptionThe estimated geometric mean (CV%) of the absorption rate constant of BESREMi is 0.12 day-1 (27%) in patients with polycythemia vera.. DistributionThe estimated geometric mean (CV%) of apparent volume of distribution of BESREMi is 4.8 (21%) in patients with polycythemia vera.. EliminationBESREMi undergoes receptor independent degradation/excretion and receptor binding and subsequent degradation of the drug-receptor complex. The half-life and clearance of BESREMi is approximately days and 1.7-2.5 L/h in patients with polycythemia vera over dose range of 100 mcg to 500 mcg, respectively.. Specific PopulationsNo clinically significant differences in the pharmacokinetics of BESREMi were observed based on age, sex, body surface area, and JAK2V617F mutation.. Drug Interactions. Clinical StudiesNo clinical studies evaluating the drug interaction potential of BESREMi have been conducted.. In Vitro StudiesIn vitro studies indicate that BESREMi exhibited time-dependent inhibitory potential on CYP2A6. BESREMi did not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 in human liver microsomes. BESREMi is not expected to induce CYP enzymes. However, interferon may influence CYP450 through modulating transcription factors and altering protein expression and/or structure. As this mechanism requires more time to exert effect, it cannot be evaluated by in vitro assays.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryAvailable human data with BESREMi use in pregnant women are insufficient to identify 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 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 fetus.The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have 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 RiskUntreated 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.

RENAL IMPAIRMENT SUBSECTION.

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)].

SPL MEDGUIDE SECTION.

Medication Guide BESREMi(R) (bez-reh-me) ropeginterferon alfa-2b-njft injection, for subcutaneous useThis Medication Guide has been approved by the U.S. Food and Drug Administration. Issued: 11/2021 What is the most important information should know about BESREMiBESREMi can cause serious side effects that:may cause death, ormay worsen certain serious diseases that you may already haveTell your healthcare provider right away if you have any of the symptoms listed below during treatment with BESREMi. If symptoms get worse, or become severe and continue, your healthcare provider may tell you to stop taking BESREMi permanently. These symptoms may go away in some people after they stop taking BESREMi. Mental health problems, including suicide. BESREMi may cause you to develop mood or behavior problems that may get worse during treatment with BESREMi or after your last dose, including:irritability (getting upset easily)restlessness and agitationconfusiondepression (feeling low, feeling bad about yourself or feeling hopeless)unusually grand ideasacting aggressiveacting impulsivelythoughts of hurting yourself or others, or thoughts of suicideIf you develop any of these symptoms, stop using BESREMi right away. You, your caregiver, or family member should call your healthcare provider right away. Your healthcare provider should carefully monitor you during treatment with BESREMi.New or worsening autoimmune problems. BESREMi may cause autoimmune problems (a condition where the bodys immune cells attack other cells or organs in the body), including thyroid problems, increased blood sugar (hyperglycemia), and type diabetes. In some people who already have an autoimmune problem, it may get worse during your treatment with BESREMi. Tell your healthcare provider if you have any of the following symptoms: tiredness, urinating often, or if you are very thirsty.Heart problems. BESREMI may cause heart problems, including problems with your heart muscle (cardiomyopathy), heart attack, abnormal heart rhythm (atrial fibrillation), and decreased blood flow to your heart. You should not use BESREMi if you: have high blood pressure that is not controlled, congestive heart failure, serious abnormal heart rhythm, narrowing of the arteries to your heart, certain types of chest pain (angina), or recent stroke or heart attack.If you have heart problem before you start using BESREMi, your healthcare provider should monitor you closely during treatment with BESREMi.Call your healthcare provider right away if you get any of the symptoms listed above during treatment with BESREMi. Before and during treatment with BESREMi you will need to see your healthcare provider regularly and have blood tests to monitor your polycythemia vera, and to check for side effects. BESREMi can cause serious side effects. Some of these side effects may cause death. Tell your healthcare provider right away if you have any of the symptoms listed above during treatment with BESREMi. For more information about side effects, see What are the possible side effects of BESREMi What is BESREMiBESREMi is prescription medicine that is used to treat adults with polycythemia vera. It is not known if BESREMi is safe and effective in children.Who should not use BESREMiDo not use BESREMi if you:have or had severe mental health problems, especially severe depression, thoughts of suicide, or attempted suicidehave or had serious or untreated autoimmune diseasehave had serious allergic reaction to another interferon product or to any of the ingredients in BESREMi. Symptoms of serious allergic reaction to alpha-interferon may include itching, swelling of your face, tongue, throat, trouble breathing, feeling dizzy or faint, and chest pain. See the end of this Medication Guide for complete list of ingredients in BESREMi. Ask your healthcare provider if you are not sure.have certain types of liver problemshave received transplant and take immunosuppressive medicinesTalk to your healthcare provider before taking BESREMi if you have any of these conditions.Before using BESREMi, tell your healthcare provider about all of your medical conditions, including if you:are being treated for mental illness or had treatment in the past for any mental illness, including depression and have had thoughts of hurting yourself or others.have type diabeteshave or ever had any problems with your heart, including heart attack or high blood pressurehave or ever had bleeding problems or blood clothave or ever had low blood cell countshave condition that suppresses your immune system, such as certain cancershave hepatitis infectionhave HIV infectionhave kidney problemshave liver problemsare pregnant or plan to become pregnant. BESREMi may harm your unborn baby and may cause loss of your pregnancy (miscarriage).Before you start using BESREMi your healthcare provider should do pregnancy test.You should use effective birth control during treatment and for at least weeks after your final dose of BESREMi. Talk to your healthcare provider about birth control choices for you during treatment with BESREMi.BESREMi can affect your menstrual cycles and may cause your menstrual periods to stop.Tell your healthcare provider if you become pregnant during treatment with BESREMi. are breastfeeding or plan to breastfeed. It is not known if BESREMi passes into your breast milk. You should not breastfeed during treatment and for weeks after your final dose of BESREMi.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.BESREMi and certain other medicines may affect each other and cause side effects. Know the medicines you take. Keep list of your medicines and show it to your healthcare provider and pharmacist when you get new medicine.How should use BESREMiSee the Instructions for Use that comes with BESREMi for detailed instructions on how to prepare and inject dose of BESREMi.Use BESREMi exactly as your healthcare provider tells you to. Your healthcare provider will tell you how much BESREMi to inject and when to inject it. Do not inject more than your prescribed dose.BESREMi is given as an injection under your skin (subcutaneous injection). Your healthcare provider should show you how to prepare and measure your dose of BESREMi, and how to inject yourself before you use BESREMi for the first time.You should not inject BESREMi until your healthcare provider has shown you how to use BESREMi the right way. Your healthcare provider will prescribe the amount of BESREMi that is right for you.Do not inject more than dose of BESREMi every weeks without talking to your healthcare provider. Do not re-use the single-dose prefilled syringe.Your healthcare provider should do blood tests before you start BESREMi, and regularly during treatment to monitor your polycythemia vera, and to check you for side effects.What should avoid during treatment with BESREMiBESREMi may cause neurologic symptoms including dizziness, sleepiness, and hallucinations. Avoid driving or using machinery if you develop any of these neurologic symptoms during treatment with BESREMi.What are the possible side effects of BESREMiBESREMi can cause serious side effects including:See What is the most important information should know about BESREMiDecreased blood cell counts. Decreased blood cell counts are common with BESREMi and can sometimes also be severe, especially decreased platelets or white blood cells. Your red blood cells may also be decreased. Your healthcare provider should check your blood cell counts before you start and during treatment with BESREMi. If your blood cell counts are low you can develop anemia, infections or have problems with bleeding or bruising.Call your healthcare provider right away if you develop any of the following symptoms:weakness and tirednessbruising easilyyou have nose bleeds oftenfeverchillsburning and painful urinationurinating oftencoughing up yellow or pink mucus (phlegm)Serious allergic reactions and skin reactions. BESREMi can cause serious, sudden allergic reactions.Get medical help right away if you get any of the following symptoms:skin rash or hivesitching swelling of your face, eyes, lips tongue, or throattrouble breathingchest painfeeling faintEye problems. BESREMi can cause severe eye problems with your retinas that can lead to vision loss or blindness. You should have an eye exam before and during treatment with BESREMi if you have diabetes or high blood pressure and also have retinal problems. Your healthcare provider may stop BESREMi if you develop new or worse eye problems during treatment with BESREMi.Liver problems. BESREMi can cause increases in liver enzymes and liver damage. Your healthcare provider should do blood tests to monitor your liver enzymes and liver function before you start and during treatment with BESREMi.Kidney problems. Your healthcare provider will do blood tests to check your kidney function before starting and during treatment with BESREMi. Tell your healthcare provider right away if you develop any symptoms of kidney problem, including: changes in the amount or color of your urineblood in your urineswelling in your anklesloss of appetiteYour healthcare provider may stop BESREMi if you develop severe kidney problems.Tooth and gum (periodontal) problems. BESREMi can cause tooth and gum problems which can lead to tooth loss. BESREMi can also cause problems with dry mouth that can damage your teeth and the lining of the mouth during long-term treatment with BESREMi. It is important for you to brush your teeth well, two times each day and have regular dental examinations during treatment with BESREMI.Skin problems. BESREMi can cause skin problems. Signs and symptoms of skin problem with BESREMi include:itchinghair lossrashrednesspsoriasisacnethickening of the skinexcessive sweatingCall your healthcare provider if you develop rash that is bothersome or covers large skin area.The most common side effects of BESREMi include:flu like symptoms including: tiredness, weakness, fever, chills, muscle aches, and joint painitchingsore throat.These are not all of the possible side effects of BESREMi.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store BESREMiStore BESREMi in the refrigerator between 36 to 46 (2 to C).Keep BESREMi away from heat.Do not freeze BESREMi.Keep the BESREMi pre-filled syringe in the outer carton to protect it from light.Keep BESREMi and all medicines out of the reach of children.General information about the safe and effective use in BESREMiMedicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use BESREMi for condition for which it has not been prescribed. Do not give BESREMi to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about BESREMi that is written for health professionals.What are the ingredients in BESREMiActive ingredient: ropeginterferon alfa-2b-njftInactive ingredients: benzyl alcohol, glacial acetic acid, polysorbate 80, sodium acetate, sodium chloride, Water for Injection.Manufactured by: PharmaEssentia Corporation 2F-5 No. YuanQu Street Nangang Dist. Taipei, Taiwan U.S. License number: 2155 Distributed by: PharmaEssentia USA Corporation, 35 Corporate Dr, Suite 325, Burlington, MA 01803, USA BESREMi is trademark/registered trademark of PharmaEssentia Copyright 2021 PharmaEssentia For more information, go to www.BESREMi.com or call 1-800-999-2449. may cause death, or. may worsen certain serious diseases that you may already have. irritability (getting upset easily). restlessness and agitation. confusion. depression (feeling low, feeling bad about yourself or feeling hopeless). unusually grand ideas. acting aggressive. acting impulsively. thoughts of hurting yourself or others, or thoughts of suicide. have or had severe mental health problems, especially severe depression, thoughts of suicide, or attempted suicide. have or had serious or untreated autoimmune disease. have had serious allergic reaction to another interferon product or to any of the ingredients in BESREMi. Symptoms of serious allergic reaction to alpha-interferon may include itching, swelling of your face, tongue, throat, trouble breathing, feeling dizzy or faint, and chest pain. See the end of this Medication Guide for complete list of ingredients in BESREMi. Ask your healthcare provider if you are not sure.. have certain types of liver problems. have received transplant and take immunosuppressive medicines. are being treated for mental illness or had treatment in the past for any mental illness, including depression and have had thoughts of hurting yourself or others.. have type diabetes. have or ever had any problems with your heart, including heart attack or high blood pressure. have or ever had bleeding problems or blood clot. have or ever had low blood cell counts. have condition that suppresses your immune system, such as certain cancers. have hepatitis infection. have HIV infection. have kidney problems. have liver problems. are pregnant or plan to become pregnant. BESREMi may harm your unborn baby and may cause loss of your pregnancy (miscarriage).Before you start using BESREMi your healthcare provider should do pregnancy test.You should use effective birth control during treatment and for at least weeks after your final dose of BESREMi. Talk to your healthcare provider about birth control choices for you during treatment with BESREMi.BESREMi can affect your menstrual cycles and may cause your menstrual periods to stop.Tell your healthcare provider if you become pregnant during treatment with BESREMi. Before you start using BESREMi your healthcare provider should do pregnancy test.. You should use effective birth control during treatment and for at least weeks after your final dose of BESREMi. Talk to your healthcare provider about birth control choices for you during treatment with BESREMi.. BESREMi can affect your menstrual cycles and may cause your menstrual periods to stop.. Tell your healthcare provider if you become pregnant during treatment with BESREMi.. are breastfeeding or plan to breastfeed. It is not known if BESREMi passes into your breast milk. You should not breastfeed during treatment and for weeks after your final dose of BESREMi.. See the Instructions for Use that comes with BESREMi for detailed instructions on how to prepare and inject dose of BESREMi.. Use BESREMi exactly as your healthcare provider tells you to. Your healthcare provider will tell you how much BESREMi to inject and when to inject it. Do not inject more than your prescribed dose.. BESREMi is given as an injection under your skin (subcutaneous injection). Your healthcare provider should show you how to prepare and measure your dose of BESREMi, and how to inject yourself before you use BESREMi for the first time.. You should not inject BESREMi until your healthcare provider has shown you how to use BESREMi the right way. Your healthcare provider will prescribe the amount of BESREMi that is right for you.. Do not inject more than dose of BESREMi every weeks without talking to your healthcare provider. Do not re-use the single-dose prefilled syringe.. Your healthcare provider should do blood tests before you start BESREMi, and regularly during treatment to monitor your polycythemia vera, and to check you for side effects.. BESREMi may cause neurologic symptoms including dizziness, sleepiness, and hallucinations. Avoid driving or using machinery if you develop any of these neurologic symptoms during treatment with BESREMi.. See What is the most important information should know about BESREMi. Decreased blood cell counts. Decreased blood cell counts are common with BESREMi and can sometimes also be severe, especially decreased platelets or white blood cells. Your red blood cells may also be decreased. Your healthcare provider should check your blood cell counts before you start and during treatment with BESREMi. If your blood cell counts are low you can develop anemia, infections or have problems with bleeding or bruising.. weakness and tiredness. bruising easily. you have nose bleeds often. fever. chills. burning and painful urination. urinating often. coughing up yellow or pink mucus (phlegm). Serious allergic reactions and skin reactions. BESREMi can cause serious, sudden allergic reactions.. skin rash or hives. itching swelling of your face, eyes, lips tongue, or throat. trouble breathing. chest pain. feeling faint. Eye problems. BESREMi can cause severe eye problems with your retinas that can lead to vision loss or blindness. You should have an eye exam before and during treatment with BESREMi if you have diabetes or high blood pressure and also have retinal problems. Your healthcare provider may stop BESREMi if you develop new or worse eye problems during treatment with BESREMi.. Liver problems. BESREMi can cause increases in liver enzymes and liver damage. Your healthcare provider should do blood tests to monitor your liver enzymes and liver function before you start and during treatment with BESREMi.. Kidney problems. Your healthcare provider will do blood tests to check your kidney function before starting and during treatment with BESREMi. Tell your healthcare provider right away if you develop any symptoms of kidney problem, including: changes in the amount or color of your urine. blood in your urine. swelling in your ankles. loss of appetite. Tooth and gum (periodontal) problems. BESREMi can cause tooth and gum problems which can lead to tooth loss. BESREMi can also cause problems with dry mouth that can damage your teeth and the lining of the mouth during long-term treatment with BESREMi. It is important for you to brush your teeth well, two times each day and have regular dental examinations during treatment with BESREMI.. Skin problems. BESREMi can cause skin problems. Signs and symptoms of skin problem with BESREMi include:. itching. hair loss. rash. redness. psoriasis. acne. thickening of the skin. excessive sweating. flu like symptoms including: tiredness, weakness, fever, chills, muscle aches, and joint pain. itching. sore throat.. Store BESREMi in the refrigerator between 36 to 46 (2 to C).. Keep BESREMi away from heat.. Do not freeze BESREMi.. Keep the BESREMi pre-filled syringe in the outer carton to protect it from light.

SPL UNCLASSIFIED SECTION.

2.1Pre-Treatment Testing. Pregnancy testing is recommended prior to BESREMi treatment in females of reproductive potential [see Use in Specific Populations (8.3)].

STORAGE AND HANDLING SECTION.

16.2Storage and Handling. Store in refrigerator at 36 to 46 (2 to C) in the original carton to protect from light.Do not freeze.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Pregnancy: Can cause fetal harm. Advise females of reproductive potential of the potential risk to fetus and to use effective contraception. (8.1, 8.3)Lactation: Advise women not to breastfeed during treatment and for weeks after the final dose. (8.2)Avoid use in patients with eGFR <30 mL/min. (8.6). Pregnancy: Can cause fetal harm. Advise females of reproductive potential of the potential risk to fetus and to use effective contraception. (8.1, 8.3). Lactation: Advise women not to breastfeed during treatment and for weeks after the final dose. (8.2). Avoid use in patients with eGFR <30 mL/min. (8.6). 8.1 Pregnancy. Risk SummaryAvailable human data with BESREMi use in pregnant women are insufficient to identify 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 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 fetus.The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have 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 RiskUntreated 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 weeks after the final dose. 8.3 Females and Males of Reproductive Potential. BESREMi may cause embryo-fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)].. Pregnancy TestingPregnancy testing prior to BESREMi treatment is recommended for females of reproductive potential.. Contraception. FemalesAdvise female patients of reproductive potential to use effective contraception during treatment with BESREMi and for at least weeks after the final dose.. Infertility. FemalesBased 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. 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. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other therapy.. 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 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 or C), discontinue BESREMi [see Dosage and Administration (2.2) and Warnings and Precautions (5.11)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Patients exhibiting the following events should be closely monitored and may require dose reduction or discontinuation of therapy:Depression and Suicide: Monitor closely 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, acute or unstable cardiovascular disease. Monitor patients with history of cardiovascular disorders more frequently. (5.3)Decreased Peripheral Blood Counts: Perform blood counts at baseline, every 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: Advise patients to have eye examinations before and during treatment. Evaluate eye symptoms promptly 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 patients on good oral hygiene and to have 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). Depression and Suicide: Monitor closely 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, acute or unstable cardiovascular disease. Monitor patients with history of cardiovascular disorders more frequently. (5.3). Decreased Peripheral Blood Counts: Perform blood counts at baseline, every 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: Advise patients to have eye examinations before and during treatment. Evaluate eye symptoms promptly 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 patients on good oral hygiene and to have 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). 5.1Depression 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 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.. 5.2Endocrine 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 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.. 5.3Cardiovascular 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 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.. 5.4Decreased 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 (platelet counts <50,000 25,000/mm3) or greater occurred in 2% of BESREMi-treated patients. Anemia of grade (Hgb 8 g/dL) or greater occurred in 1% of BESREMi-treated patients. Leukopenia of grade (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.. 5.5Hypersensitivity 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). If such reactions occur, discontinue BESREMi and institute appropriate medical therapy immediately. Transient rashes may not necessitate interruption of treatment.. 5.6Pancreatitis. Pancreatitis has occurred in patients receiving interferon alfa products, including BESREMi. Pancreatitis was reported in 2.2% of patients receiving BESREMi. 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.. 5.7Colitis. Fatal and serious 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 to weeks of stopping treatment.. 5.8Pulmonary 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, and sarcoidosis. Some events have resulted in respiratory failure or death. Discontinue BESREMi in patients who develop pulmonary infiltrates or pulmonary function impairment.. 5.9Ophthalmologic 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, 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 retinopathy-associated disease such as diabetes mellitus or hypertension. Evaluate eye symptoms promptly. Discontinue BESREMi in patients who develop new or worsening eye disorders.. 5.10Hyperlipidemia. Hyperlipidemia has occurred in patients treated with interferon alfa products, including BESREMi. Hyperlipidemia, hypertriglyceridemia, or dyslipidemia occurred in 3% of patients receiving BESREMi. 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.. 5.11Hepatotoxicity 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 times the upper limit of normal (ULN), AST >=3 times the ULN, GGT >=3 times the ULN, and bilirubin >2 times the ULN have been observed in patients treated with BESREMi.In the clinical development program of BESREMi, 36 patients (20%) experienced liver enzyme elevations, 33 of whom had elevations of 1.25-5x 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. Reduce BESREMi dosage by 50 mcg for increased AST/ALT/GGT then monitor AST/ALT/GGT weekly until the values return to baseline or grade (ALT and AST 3 ULN if baseline was normal; 1.5 3 baseline if baseline was abnormal, and GGT 2.5 ULN if baseline was normal; - 2.5 baseline if baseline was abnormal) [see Dosage and Administration (2.3)]. If toxicity does not improve, continue decreasing the BESREMi dose at biweekly intervals until recovery to grade 1. Hold if AST/ALT/GGT 20 ULN and consider permanent discontinuation if increased liver enzyme levels persist after four dose-reductions. 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)].. 5.12Renal Toxicity Renal toxicity has occurred in patients receiving interferon alfa products, including BESREMi. During BESREMi therapy, <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)].. 5.13Dental 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 damaging effect on teeth and oral mucous membranes during long-term treatment with BESREMi. Patients should have good oral hygiene and regular dental examinations.. 5.14Dermatologic 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.. 5.15Driving 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.. 5.16Embryo-Fetal Toxicity. Based on the mechanism of action, BESREMi can cause fetal harm when administered to pregnant woman [see Clinical Pharmacology (12.1) and Use in Specific Populations (8.1)]. Pregnancy testing is recommended in females of reproductive potential prior to treatment with BESREMi. Advise females of reproductive potential to use an effective method of contraception during treatment with BESREMi and for at least weeks after the final dose [see Dosage and Administration (2.1) and Use in Specific Populations (8.1, 8.3)].