Besremi Drug Information
Generic name: ROPEGINTERFERON ALFA-2B
Interferon alfa-2b [EPC]
Uses of Besremi
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
Dosage & Administration of Besremi
| Adverse Reaction a | Severity | |
|---|---|---|
| Liver enzyme elevation withconcomitant bilirubin elevation, orother evidence of hepaticdecompensation | Any increase above baseline | |
| Liver enzyme elevation | >5 x the upper limit of normal (ULN) but ≤20 x ULN | |
| >20 x ULN | Interrupt treatment until ALT and AST recover to < 3 x ULN if baseline was normal; 1.5 x baseline if baseline was abnormal, and gamma-glutamyltransferase (GGT) recovers to < 2.5 x ULN if baseline was normal; 2 x baseline if baseline was abnormal. Consider permanent discontinuation if toxicity persists after four dose-modifications. | |
| Cytopenia | Anemia: Hemoglobin (Hgb) < 8 g/dL | |
| Anemia: Hemoglobin levels are life threatening, or urgent intervention needed | Interrupt treatment until recovery of Hgb >10.0 g/dL, platelets >75,000/mm3, and WBC >3,000/mm3. | |
| Depression | Mild, without suicidal ideation |
Side Effects of Besremi
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The pooled safety population described in the Warnings and Precautions section reflects exposure to BESREMi as monotherapy for the treatment of polycythemia vera dosed every two to four weeks in 178 patients in two open-label trials. 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.
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
Years. Adverse Reactions*
BESREMi N=51 % Influenza-like illness a 59 Arthralgia 47 Fatigue b 47 Pruritis 45 Nasopharyngitis c 43 Musculoskeletal pain d 41 Headache e 39 Diarrhea 33 Hyperhidrosis f 29 Nausea 28 Upper respiratory tract infection g 27 Local administration site reactions 26 Dizziness 22 Abdominal pain h 20 Depression 20 Sleep disorder i 20 Leukopenia 18 Decreased appetite 18 Alopecia 16 Edema j 16 Hypertension k 16 Muscle spasms 16 Neutropenia 16 Rash l 16 Transaminase elevations m 16 Urinary tract infection 16 Thrombocytopenia 12 Vertigo 12 *Adverse Reactions defined as all treatment emergent adverse events Grouped Term Definitions a Includes pyrexia, chills, and influenza-like illness. b Includes asthenia, malaise, and fatigue. c Includes pharyngitis and nasopharyngitis. d Includes musculoskeletal pain, back pain, pain in extremity, bone pain, flank pain, and spinal pain. e Includes headache, migraine, and head pain. f Includes night sweats and hyperhidrosis. g Includes upper respiratory tract infection, rhinitis, bronchitis, and respiratory tract infection. h Includes abdominal pain upper, abdominal pain lower, and abdominal pain. i Includes insomnia, sleep disorder, and abnormal dreams. j Includes peripheral edema and generalized edema. k Includes hypertension and hypertensive crisis. l Includes rash, maculopapular rash, and pruritic rash. m Includes transaminase increase, hepatic enzyme increase, GGT increase, AST increase, and ALT increase. Cardiovascular System : Atrial fibrillation The most common adverse reactions reported in > 40% of patients were influenza-like illness, arthralgia, fatigue, pruritus, nasopharyngitis, and musculoskeletal pain. To report SUSPECTED ADVERSE REACTIONS, contact PharmaEssentia at 1-800-999-2449 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Clinical Trials Experience
The following clinically significant adverse reactions are described elsewhere in the labeling. Depression and Suicide Endocrine Toxicity Cardiovascular Toxicity Decreased Peripheral Blood Counts Hypersensitivity Reactions Pancreatitis Colitis Pulmonary Toxicity Ophthalmologic Toxicity Hyperlipidemia Hepatotoxicity Renal Toxicity Dental and Periodontal Toxicity Dermatologic Toxicity Driving and Operating Machinery Embryo-Fetal Toxicity 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.
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 . 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
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
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.
Warnings & Cautions for Besremi
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. 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.
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. 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.
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. 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.
Decreased Peripheral Blood Counts Decreased peripheral blood counts have occurred in patients
receiving interferon alfa products, including BESREMi. These toxicities may include thrombocytopenia (increasing the risk of bleeding), anemia, and leukopenia (increasing the risk of infection). Thrombocytopenia of grade 3 (platelet counts <50,000 – 25,000/mm3) or greater occurred in 2% of BESREMi-treated patients. Anemia of grade 3 (Hgb < 8 g/dL) or greater occurred in 1% of BESREMi-treated patients.
Leukopenia of grade 3 (WBC counts <2,000 – 1,000/mm3) or greater occurred in 2% of BESREMi-treated patients. Infection occurred in 48% of BESREMi treated patients, while serious infections occurred in 8% of BESREMi treated patients. Monitor complete blood counts at baseline, during titration and every 3-6 months during the maintenance phase.
Monitor patients for signs and symptoms of infection or bleeding.
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. 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.
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.
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.
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.
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. 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.
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 1 (ALT and AST < 3 x ULN if baseline was normal; 1.5 - 3 x baseline if baseline was abnormal, and GGT < 2.5 x ULN if baseline was normal; 2 - 2.5 x baseline if baseline was abnormal). If toxicity does not improve, continue decreasing the BESREMi dose at biweekly intervals until recovery to grade 1. Hold if AST/ALT/GGT > 20 x 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. 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. 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. Obtain a pregnancy test in females of reproductive potential prior to initiating treatment with BESREMi.
Advise females of reproductive potential to use an effective method of contraception during treatment with BESREMi and for at least 8 weeks after the final dose. 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. Endocrine Toxicity: Discontinue if endocrine disorders occur that cannot be medically managed.
Cardiovascular Toxicity: Avoid use in patients with severe, acute or unstable cardiovascular disease. Monitor patients with history of cardiovascular disorders more frequently. Decreased Peripheral Blood Counts: Perform blood counts at baseline, every 2 weeks during titration, and at least every 3-6 months during maintenance treatment.
Hypersensitivity Reactions: Stop treatment and immediately manage reaction. Pancreatitis: Consider discontinuation if confirmed pancreatitis Colitis: Discontinue if signs or symptoms of colitis Pulmonary Toxicity: Discontinue if pulmonary infiltrates or pulmonary function impairment Ophthalmologic Toxicity: Advise patients to have eye examinations before and during treatment. Evaluate eye symptoms promptly and discontinue if new or worsening eye disorders.
Hyperlipidemia: Monitor serum triglycerides before BESREMi treatment and intermittently during therapy and manage when elevated. Hepatotoxicity: Monitor liver enzymes and hepatic function at baseline and during treatment. Reduce dose or discontinue depending on severity.
Renal Toxicity: Monitor serum creatinine at baseline and during therapy. Discontinue if severe renal impairment develops. Dental and Periodontal Toxicity: Advise patients on good oral hygiene and to have regular dental examinations.
Dermatologic Toxicity: Consider discontinuing if clinically significant dermatologic toxicity. Driving and Operating Machinery: Advise patients to avoid driving or using machinery if they experience dizziness, somnolence, or hallucination.
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 . 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.
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 . 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.
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 . 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.
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.
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 . 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.
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.
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.
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.
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 . 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 . 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). 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 . 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 . 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 . 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 .
Drug Interactions with Besremi
Drugs Metabolized by Cytochrome P450 Certain proinflammatory cytokines, including interferons, can suppress
CYP450 enzymes resulting in increased exposures of some CYP substrates . Therefore, patients on BESREMi who are receiving concomitant drugs that are CYP450 substrates with a narrow therapeutic index should be monitored to inform the need for dosage modification for these concomitant drugs.
Myelosuppressive Agents
Concomitant use of BESREMi and myelosuppressive agents can produce additive myelosuppression. Avoid use and monitor patients receiving the combination for effects of excessive myelosuppression .
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 . Monitor patients taking CYP450 substrates with a narrow therapeutic index for adverse reactions to inform the need for dose adjustment of the concomitant drug Avoid use with myelosuppressive agents and monitor patients receiving the combination for effects of excessive myelosuppression Avoid use with narcotics, hypnotics or sedatives. Monitor patients receiving the combination for excessive central nervous system toxicity
Drugs Metabolized by Cytochrome P450 Certain proinflammatory cytokines, including interferons, can suppress
CYP450 enzymes resulting in increased exposures of some CYP substrates . Therefore, patients on BESREMi who are receiving concomitant drugs that are CYP450 substrates with a narrow therapeutic index should be monitored to inform the need for dosage modification for these concomitant drugs.
Myelosuppressive Agents
Concomitant use of BESREMi and myelosuppressive agents can produce additive myelosuppression. Avoid use and monitor patients receiving the combination for effects of excessive myelosuppression .
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 .
Pregnancy Safety for Besremi
Pregnancy Risk Summary Available human data with BESREMi use in pregnant women are insufficient to identify a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Animal studies assessing reproductive toxicity of BESREMi have not been conducted. Based on mechanism of action and the role of interferon alfa in pregnancy and fetal development, BESREMi may cause fetal harm and should be assumed to have abortifacient potential when administered to a pregnant woman.
There are adverse effects on maternal and fetal outcomes associated with polycythemia vera in pregnancy (see Clinical Considerations ). Advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage is 2-4% and 15-20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo-Fetal Risk Untreated polycythemia vera during pregnancy is associated with adverse maternal outcomes such as thrombosis and hemorrhage. Adverse pregnancy outcomes associated with polycythemia vera include increased risk for miscarriage.
Pediatric Use of Besremi
Pediatric Use Safety and effectiveness in pediatric patients have not been established.
Contraindications for Besremi
BESREMi is contraindicated in patients with: Existence of, or history of severe psychiatric disorders, particularly severe depression, suicidal ideation, or suicide attempt Hypersensitivity to interferons including interferon alfa-2b or any of the inactive ingredients of BESREMi Moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment History or presence of active serious or untreated autoimmune disease History of transplantation and receiving immunosuppressant agents. Existence of, or history of severe psychiatric disorders, particularly severe depression, suicidal ideation or suicide attempt Hypersensitivity to interferon or to any component of BESREMi Hepatic impairment (Child-Pugh B or C) History or presence of active serious or untreated autoimmune disease Immunosuppressed transplant recipients
Overdosage Information for Besremi
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.
Clinical Studies of Besremi
The efficacy and safety of BESREMi were evaluated in the PEGINVERA study, a 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 a 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 ×10 9 /L ± 187 ×10 9 /L and 11.8 × 10 9 /L ± 5.2 × 10 9 /L, respectively.
Median spleen size was 13.2 cm with 16 (31%) having splenomegaly (defined as a longitudinal diameter of >12 cm for women and >13 cm for men). Eleven patients (22%) had a prior history of a major cardiovascular event including pulmonary embolism, stroke, myocardial infarction and portal vein thrombosis. 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 . 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).
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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