uce 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) ] .

airment ( 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 ) 5.1 depression and suicide life-threatening or fatal neuropsychiatric reactions have occurred in patients receiving interferon alfa products, including besremi. these reactions may occur in patients with and without previous psychiatric illness. serious neuropsychiatric reactions have been observed in 3% of patients treated with besremi during the clinical development program. among the 178 patients in the clinical development program of besremi, 17 cases of depression, depressive symptoms, depressed mood, and listlessness occurred. of these seventeen cases, 3.4% of the patients recovered with temporary drug interruption and 2.8% stopped besremi treatment. other central nervous system effects, including suicidal ideation, attempted suicide, aggression, bipolar disorder, mania and confusion have been observed with other interferon alfa products. besremi is contraindicated in patients with a history of severe psychiatric disorders, particularly severe depression, suicidal ideation, or suicide attempt [see contraindications (4) ] . closely monitor patients for any symptoms of psychiatric disorders and consider psychiatric consultation and treatment if such symptoms emerge. if psychiatric symptoms worsen, it is recommended to discontinue besremi therapy. 5.2 endocrine toxicity endocrine toxicity has occurred in patients receiving interferon alfa products, including besremi. these toxicities may include worsening hypothyroidism and hyperthyroidism. autoimmune thyroiditis and hyperglycemia, including new onset type 1 diabetes, have been reported in patients receiving interferon alfa-2b products. eight cases of hyperthyroidism (4.5%), seven cases of hypothyroidism (3.9%) and five cases (2.8%) of autoimmune thyroiditis/thyroiditis occurred in the development program of besremi. do not use besremi in patients with active serious or untreated endocrine disorders associated with autoimmune disease [contraindications (4)] . evaluate thyroid function in patients who develop symptoms suggestive of thyroid disease during besremi therapy. discontinue besremi in patients who develop endocrine disorders that cannot be adequately managed during treatment with besremi. 5.3 cardiovascular toxicity cardiovascular toxicity has occurred in patients receiving interferon alfa products, including besremi. toxicities may include cardiomyopathy, myocardial infarction, atrial fibrillation and coronary artery ischemia [see adverse reactions (6.1) ] . patients with a history of cardiovascular disorders should be closely monitored for cardiovascular toxicity during besremi therapy. avoid use of besremi in patients with severe or unstable cardiovascular disease, (e.g., uncontrolled hypertension, congestive heart failure (≥ nyha class 2), serious cardiac arrhythmia, significant coronary artery stenosis, unstable angina) or recent stroke or myocardial infarction. 5.4 decreased peripheral blood counts decreased peripheral blood counts have occurred in patients receiving interferon alfa products, including besremi. these toxicities may include thrombocytopenia (increasing the risk of bleeding), anemia, and leukopenia (increasing the risk of infection). thrombocytopenia of grade 3 (platelet counts <50,000 – 25,000/mm 3 ) or greater occurred in 2% of besremi-treated patients. anemia of grade 3 (hgb < 8 g/dl) or greater occurred in 1% of besremi-treated patients. leukopenia of grade 3 (wbc counts <2,000 – 1,000/mm 3 ) or greater occurred in 2% of besremi-treated patients. infection occurred in 48% of besremi treated patients, while serious infections occurred in 8% of besremi treated patients. monitor complete blood counts at baseline, during titration and every 3-6 months during the maintenance phase. monitor patients for signs and symptoms of infection or bleeding. 5.5 hypersensitivity reactions hypersensitivity reactions have occurred in patients receiving interferon alfa products, including besremi. besremi is contraindicated in patients 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. 5.6 pancreatitis 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. 5.7 colitis 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 1 to 3 weeks of stopping treatment. 5.8 pulmonary toxicity pulmonary toxicity has occurred in patients receiving interferon alfa products, including besremi. pulmonary toxicity may manifest as dyspnea, pulmonary infiltrates, pneumonia, bronchiolitis obliterans, interstitial pneumonitis, pulmonary hypertension, and sarcoidosis. some events have resulted in respiratory failure or death. discontinue besremi in patients who develop pulmonary infiltrates or pulmonary function impairment. 5.9 ophthalmologic toxicity ophthalmologic toxicity has occurred in patients receiving interferon alfa products, including besremi. these toxicities may include severe eye disorders such as retinopathy, retinal hemorrhage, retinal exudates, retinal detachment and retinal artery or vein occlusion which may result in blindness. during besremi therapy, 23% of patients were identified with an eye disorder. eyes disorders ≥5% included cataract (6%) and dry eye (5%). advise patients to have eye examinations before and during besremi therapy, specifically in those patients with a retinopathy-associated disease such as diabetes mellitus or hypertension. evaluate eye symptoms promptly. discontinue besremi in patients who develop new or worsening eye disorders. 5.10 hyperlipidemia hyperlipidemia has occurred in patients treated with interferon alfa products, including besremi. 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. 5.11 hepatotoxicity hepatotoxicity has occurred in patients receiving interferon alfa products, including besremi. these toxicities may include increases in serum alt, ast, ggt and bilirubin. besremi is contraindicated in patients with moderate (child-pugh b) or severe (child-pugh c) hepatic impairment [see contraindications (4) ] . increases in serum alt ≥3 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 1.25-5× uln. patients were able to resume besremi upon resolution of liver enzyme elevations. liver enzyme elevations have also been reported in patients after long-term besremi therapy. monitor liver enzymes and hepatic function at baseline and during besremi treatment. 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 1 (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 - 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) ] . 5.12 renal 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) ] . 5.13 dental and periodontal toxicity dental and periodontal toxicities may occur in patients receiving interferon alfa products, including besremi. these toxicities may include dental and periodontal disorders, which may lead to loss of teeth. in addition, dry mouth could have a damaging effect on teeth and oral mucous membranes during long-term treatment with besremi. patients should have good oral hygiene and regular dental examinations. 5.14 dermatologic toxicity dermatologic toxicity has occurred in patients receiving interferon alfa products, including besremi. these toxicities have included skin rash, pruritus, alopecia, erythema, psoriasis, xeroderma, dermatitis acneiform, hyperkeratosis, and hyperhidrosis. consider discontinuation of besremi if clinically significant dermatologic toxicity occurs. 5.15 driving and operating machinery besremi may impact the ability to drive and use machinery. patients should not drive or use heavy machinery until they know how besremi affects their abilities. patients who experience dizziness, somnolence or hallucination during besremi therapy should avoid driving or using machinery. 5.16 embryo-fetal toxicity based on the mechanism of action, besremi can cause fetal harm when administered to a pregnant woman [see 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 8 weeks after the final dose [see dosage and administration (2.1) and use in specific populations (8.1 , 8.3) ] .

rom hydroxyurea, start besremi at 50 mcg by subcutaneous injection every two weeks in combination with hydroxyurea. gradually taper off the hydroxyurea by reducing the total biweekly dose by 20-40% every two weeks during weeks 3-12. increase the dose of besremi by 50 mcg every two weeks (up to a maximum of 500 mcg), until the hematological parameters are stabilized (hematocrit less than 45%, platelets less than 400 × 10 9 /l, and leukocytes less than 10 × 10 9 /l). discontinue hydroxyurea by week 13. maintain the two week dosing interval of besremi at which hematological stability is achieved for at least 1 year. after achievement of hematological stability for at least 1 year on a stable dose of besremi, the dosing interval may be expanded to every 4 weeks. monitor patients closely especially during the titration phase. perform complete blood counts (cbc) regularly, every 2 weeks during the titration phase and every 3-6 months during the maintenance phase (after the patient's optimal dose is established). monitor cbc more frequently if clinically indicated. phlebotomy as rescue treatment to normalize blood hyperviscosity may be necessary during the titration phase [see clinical pharmacology (12.2) ] . 2.3 dose modifications monitor cbc every 2 weeks during the titration phase and dose modification phase. phlebotomy as rescue treatment to normalize blood hyperviscosity may be necessary [see clinical pharmacology (12.2) ] . if dose interruption occurs, resume dosing at previously attained levels. if drug-related toxicities arise, reduce the dose to the next lower level or interrupt in accordance with the table below (table 1). if there is insufficient efficacy at the decreased dose following dose modification, a dose increase attempt to the next higher dose level should be considered after recovery to grade 1 toxicity. table 1 dose modifications for besremi adverse reactions adverse reaction national cancer institute common terminology criteria for adverse events (ctcae), version 3.0 severity dosage modification liver enzyme elevation with concomitant bilirubin elevation, or other evidence of hepatic decompensation any increase above baseline interrupt treatment until recovery, restart at dose 50 mcg lower than the interrupted dose. if the interrupted dose is 50 mcg, refrain from treatment until recovery. consider permanent discontinuation if toxicity persists after four dose-modifications. liver enzyme elevation >5 × the upper limit of normal (uln) but ≤20 × uln decrease dose by 50 mcg; if toxicity does not improve, continue decreasing at biweekly intervals until alanine aminotransferase (alt) and aspartate aminotransferase (ast) recover < 3 × uln if baseline was normal; 3 × baseline if baseline was abnormal, and gamma-glutamyltransferase (ggt) recovers to < 2.5 × uln if baseline was normal; 2.5 × baseline if baseline was abnormal. if the interrupted dose is 50 mcg, refrain from treatment until recovery. >20 × uln interrupt treatment until alt and ast recover to < 3 × uln if baseline was normal; 1.5 × baseline if baseline was abnormal, and gamma-glutamyltransferase (ggt) recovers to < 2.5 × uln if baseline was normal; 2 × baseline if baseline was abnormal. consider permanent discontinuation if toxicity persists after four dose-modifications. cytopenia anemia: hemoglobin (hgb) < 8 g/dl decrease dose by 50 mcg; if toxicity does not improve, continue decreasing at biweekly intervals until recovery of hgb >10.0 g/dl, platelets >75,000/mm 3 , and wbc >3,000/mm 3 thrombocytopenia: platelet count < 50,000/mm 3 but ≥25,000/mm 3 leukopenia: white blood cell count (wbc) <2000/mm 3 but ≥1,000/mm 3 if the interrupted dose is 50 mcg, refrain from treatment until recovery. anemia: hemoglobin levels are life threatening, or urgent intervention needed interrupt treatment until recovery of hgb >10.0 g/dl, platelets >75,000/mm 3 , and wbc >3,000/mm 3 . thrombocytopenia: platelet count <25,000/mm 3 consider permanent discontinuation if toxicity persists after four dose-modifications. leukopenia: wbc <1000/mm 3 depression mild, without suicidal ideation consider psychiatric consultation if persistent (>8 weeks). moderate, without suicidal ideation consider dose reduction and psychiatric consultation. severe, or any severity with suicidal ideation discontinue therapy, recommend psychiatric consultation. 2.4 preparation and administration read the instructions for use before administering the single-dose besremi prefilled syringe. besremi is for subcutaneous injection only and may be administered by either a healthcare professional, a patient or a caregiver. before a decision is made to allow besremi to be administered by a patient or caregiver, ensure that the patient is an appropriate candidate for self-administration or administration by a caregiver. proper training on storage, preparation and administration technique should be provided. if a patient or caregiver is not an appropriate candidate for any reason, then besremi should be administered by a healthcare professional. before each injection, remove the carton that contains the besremi prefilled syringe from the refrigerator. keep the prefilled syringe in the carton and lay it flat on a clean work surface for 15-30 minutes to allow the prefilled syringe to reach room temperature [59 ˚f to 77 ˚f (15 ˚c 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 preparation remove the prefilled syringe cap by unscrewing it counterclockwise. attach the covered needle to the prefilled syringe by firmly pushing it onto the collar of the syringe and then screwing (turn clockwise) it on until it feels securely attached. choose one of the following injection sites: lower stomach (abdomen) area, at least 2 inches away from the belly button, or top of thighs. rotate (change) the injection site for each injection. do not inject into skin that is irritated, red, bruised, infected, or scarred; clean the chosen injection site with an alcohol swab and let air dry. uncap needle and move air bubbles to top. pull the pink needle shield back and hold the syringe from the syringe body. remove the clear needle cap by pulling it straight off. throw away the needle cap into the trash. hold the prefilled syringe with the needle pointing up. tap on the body of the prefilled syringe to move any air bubbles to the top. set injection dose depending on the prescribed dose, the amount of dose in the syringe may need to be adjusted by discarding some of the medication. hold the prefilled syringe at eye level with the needle pointing straight up over a paper towel, sink, or trash can. check that you can see the dose lines and number markings on the prefilled syringe. pinch the end of the plunger and slowly push up to remove liquid medicine until the top edge of the gray stopper lines up with the marking for the prescribed dose. inject besremi pinch the chosen injection site. while pinching the skin, insert needle at a 45- to 90-degree angle into the pinched skin, then release the pinched skin. inject besremi by slowly pressing on the plunger all the way until it stops. after all the liquid medicine is injected, remove the needle from the skin. dispose of used syringe carefully push the pink needle shield over the needle until it snaps into place and covers the needle. do not recap the needle using the needle cap; only use the pink needle shield to cover the needle. throw away the used prefilled syringe with the needle still attached, into an fda-cleared sharps disposal container.

ee 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 a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. the pooled safety population described in the warnings and precautions section reflects exposure to besremi as monotherapy for the treatment of polycythemia vera dosed every two to four weeks in 178 patients in two open-label trials [ peginvera, proud/continuation pv ]. the mean age at baseline was 58.6 years (range 30-85 years), 88 (49.4%) women, 90 (50.6%) men, 177 (99%) caucasian and 1 (1%) asian. among 178 patients who received besremi, 80% were exposed for 12 months or longer. the mean dose of besremi was 334 mcg sd ± 121 during the treatment period. in this pooled safety population, the most common adverse reactions greater than 10%, were liver enzyme elevations (20%), leukopenia (20%), thrombocytopenia (19%), arthralgia (13%), fatigue (12%), myalgia (11%), and influenza-like illness (11%). the safety findings described below reflect exposure to besremi as monotherapy for the treatment of polycythemia vera in 51 patients in the peginvera study [see clinical studies (14) ] . among the 51 patients receiving besremi, 71% were exposed for 12 months or longer, 63% were exposed for three years or longer, and 53% were exposed for greater than five years. serious adverse reactions were reported in 16% of patients in the peginvera study. the most common serious adverse reactions observed during the study (≥ 4%) included urinary tract infection (8%), transient ischemic attack (6%) and depression (4%). adverse reactions requiring permanent discontinuation in >2% of patients who received besremi included depression (8%), arthralgia (4%), fatigue (4%), and general physical health deterioration (4%) in the peginvera study, patients were not pre-screened for depression or anxiety disorders. the most common adverse reactions reported in ≥10% of patients in the peginvera study are listed in table 2. table 2 adverse reactions in > 10% of subjects with polycythemia vera in the peginvera study over 7.5 years. adverse reactions adverse reactions defined as all treatment emergent adverse events besremi n=51 % grouped term definitions influenza-like illness includes pyrexia, chills, and influenza-like illness. 59 arthralgia 47 fatigue includes asthenia, malaise, and fatigue. 47 pruritis 45 nasopharyngitis includes pharyngitis and nasopharyngitis. 43 musculoskeletal pain includes musculoskeletal pain, back pain, pain in extremity, bone pain, flank pain, and spinal pain. 41 headache includes headache, migraine, and head pain. 39 diarrhea 33 hyperhidrosis includes night sweats and hyperhidrosis. 29 nausea 28 upper respiratory tract infection includes upper respiratory tract infection, rhinitis, bronchitis, and respiratory tract infection. 27 local administration site reactions 26 dizziness 22 abdominal pain includes abdominal pain upper, abdominal pain lower, and abdominal pain. 20 depression 20 sleep disorder includes insomnia, sleep disorder, and abnormal dreams. 20 leukopenia 18 decreased appetite 18 alopecia 16 edema includes peripheral edema and generalized edema. 16 hypertension includes hypertension and hypertensive crisis. 16 muscle spasms 16 neutropenia 16 rash includes rash, maculopapular rash, and pruritic rash. 16 transaminase elevations includes transaminase increase, hepatic enzyme increase, ggt increase, ast increase, and alt increase. 16 urinary tract infection 16 thrombocytopenia 12 vertigo 12 clinically relevant adverse reactions in < 10% of patients include: cardiovascular system: atrial fibrillation 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 8 weeks post-dosing. among the patients who tested positive for binding antibodies, none developed neutralizing antibodies.

uce 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) ] .

pregnant women of the potential risk to a fetus. the estimated background risk of major birth defects and miscarriage for the indicated population is unknown. all pregnancies have a background risk of birth defect, loss, or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage is 2-4% and 15-20%, respectively. clinical considerations disease-associated maternal and/or embryo-fetal risk untreated polycythemia vera during pregnancy is associated with adverse maternal outcomes such as thrombosis and hemorrhage. adverse pregnancy outcomes associated with polycythemia vera include increased risk for miscarriage. 8.2 lactation there are no data on the presence of besremi in human or animal milk, the effects on the breastfed child, or the effects on milk production. because of the potential for serious adverse reactions in breastfed children from besremi, advise women not to breastfeed during treatment and for 8 weeks after the final dose. 8.3 females and males of reproductive potential besremi may cause embryo-fetal harm when administered to a pregnant woman [see use in specific populations (8.1) ] . pregnancy testing pregnancy testing prior to besremi treatment is recommended for females of reproductive potential. contraception females advise female patients of reproductive potential to use effective contraception during treatment with besremi and for at least 8 weeks after the final dose. infertility females based on its mechanism of action, besremi can cause disruption of the menstrual cycle [see clinical pharmacology (12.1) ] . no animal fertility studies have been conducted with besremi. 8.4 pediatric use safety and effectiveness in pediatric patients have not been established. 8.5 geriatric use 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 b or c) [see contraindications (4) ] . increased liver enzyme levels have been observed in patients treated with besremi. when the increase in liver enzyme levels is progressive and persistent, reduce the dose of besremi. if the increase in liver enzymes is progressive and clinically significant despite dose-reduction, or if there is evidence of hepatic impairment (child-pugh b or c), discontinue besremi [see dosage and administration (2.2) and warnings and precautions (5.11) ] .

iage is 2-4% and 15-20%, respectively. clinical considerations disease-associated maternal and/or embryo-fetal risk untreated polycythemia vera during pregnancy is associated with adverse maternal outcomes such as thrombosis and hemorrhage. adverse pregnancy outcomes associated with polycythemia vera include increased risk for miscarriage.

e individual hematological parameters is dependent on ropeginterferon alfa-2b-njft concentrations. complete hematological response (chr, defined as a patient achieving hematocrit <45% without phlebotomy [at least 2 months since last phlebotomy], platelets ≤400 × 10 9 /l and leukocytes ≤10 × 10 9 /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 2 years of continuous treatment. 12.3 pharmacokinetics in patients with polycythemia vera, the estimated steady state c max , c min and area under the curve (auc) after a two-week dosing interval of besremi over a dose range of 100 mcg to 500 mcg ranged from 4.4 – 31 ng/ml, 1.4 – 12 ng/ml, and 1011 – 7809 ng×h/ml, respectively. the estimated steady state c max occurs between 2 to 5 days. absorption the estimated geometric mean (cv%) of the absorption rate constant of besremi is 0.12 day -1 (27%) in patients with polycythemia vera. distribution the estimated geometric mean (cv%) of apparent volume of distribution of besremi is 4.8 l (21%) in patients with polycythemia vera. elimination besremi 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 7 days and 1.7-2.5 l/h in patients with polycythemia vera over a dose range of 100 mcg to 500 mcg, respectively. specific populations no clinically significant differences in the pharmacokinetics of besremi were observed based on age, sex, body surface area, and jak2v617f mutation. drug interactions clinical studies no clinical studies evaluating the drug interaction potential of besremi have been conducted. in vitro studies in 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.

lations no clinically significant differences in the pharmacokinetics of besremi were observed based on age, sex, body surface area, and jak2v617f mutation. drug interactions clinical studies no clinical studies evaluating the drug interaction potential of besremi have been conducted. in vitro studies in 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.

dial 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 a median time of 21.5 months, 28 eligible patients in the peginvera study increased the dosing interval to once every 4 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 2 months, platelets ≤400 × 10 9 /l and leukocytes ≤10 × 10 9 /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 a 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-naïve) to achieve a chr and 1.4 years for 50% of patients with prior hydroxyurea use to achieve a 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).

mptoms of cardiovascular toxicity to their healthcare provider [see warnings and precautions (5.3) ]. decreased peripheral blood counts advise patients to seek prompt medical attention if they experience weakness/fatigue, fever, easy bruising, or frequent nose bleeds [see warnings and precautions (5.4) ]. hypersensitivity advise 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) ]. pancreatitis advise patients to report signs or symptoms of pancreatitis [see warnings and precautions (5.6) ] . colitis advise patients to report signs or symptoms of colitis [see warnings and precautions (5.7) ] . pulmonary toxicity advise patients to report signs or symptoms of pulmonary toxicity [see warnings and precautions (5.8) ] . ophthalmologic toxicity advise 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) ] . hepatotoxicity advise 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 toxicity advise 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 toxicity advise patients to maintain good oral hygiene and to have regular dental examinations [see warnings and precautions (5.13) ] . dermatologic toxicity advise 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 machinery advise 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 contraception advise women about the need to use an effective method of contraception while taking besremi and for at least 8 weeks after the final dose [see use in specific populations (8.1 , 8.3) ] . lactation advise women not to breastfeed during treatment and for 8 weeks after the final dose [see use in specific populations (8.2) ] . instruction on injection technique instruct 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) ] .