Besremi

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

• Recommended starting dose: 100 mcg by subcutaneous injection every 2 weeks (50 mcg if receiving hydroxyurea).
• Increase the dose by 50 mcg every 2 weeks (up to a maximum of 500 mcg) until hematological parameters are stabilized (
  
  
  
  2.1 Pre-Treatment Testing

  Pregnancy testing is recommended prior to BESREMi treatment in females of reproductive potential

  [see Use in Specific Populations (8.3)]

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  )
  
  
• Interrupt or discontinue dosing if certain adverse reactions occur (
  
  
  
  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 ReactionNational 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/mm3, and WBC >3,000/mm3
  	Thrombocytopenia: platelet count < 50,000/mm3but ≥25,000/mm3
  	Leukopenia: white blood cell count (WBC) <2000/mm3but ≥1,000/mm3
  		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/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
  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.
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  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.
  • 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.

  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/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.

  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)]

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Injection: 500 mcg/mL clear and colorless to slightly yellowish solution in a single-dose prefilled syringe.

• Pregnancy: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception. (
  
  
  
  8.1 Pregnancy

  Risk Summary

  Available human data with BESREMi use in pregnant women are insufficient to identify a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. 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.
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  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.
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• Lactation: Advise women not to breastfeed during treatment and for 8 weeks after the final dose. (
  
  
  
  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.
  )
  
  
• Avoid use in patients with eGFR <30 mL/min. (
  
  
  
  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)].
  )