Ropeginterferon Alfa-2b (Monograph)

Brand name: Besremi
Drug class: Antineoplastic Agents
Molecular formula: C16-H29-N3-O6(C2-H4-O)n-(C2-H4-O)n
CAS number: 1335098-50-4

Medically reviewed by Drugs.com on Nov 28, 2022. Written by ASHP.

Warning

Interferon alfa products may cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Monitor patients closely with periodic clinical and laboratory evaluations. Withdraw therapy in patients with persistently severe or worsening signs or symptoms of these conditions. In many, but not all cases, these disorders resolve after stopping therapy.

Introduction

Ropeginterferon alfa-2b-njft consists of interferon alfa-2b (recombinant DNA origin) covalently bound to monomethoxy polyethylene glycol (mPEG).

Uses for Ropeginterferon Alfa-2b

Polycythemia Vera

Treatment of adults with polycythemia vera (designated an orphan drug by FDA for this use).

Polycythemia vera is a myeloproliferative neoplasm characterized by uncontrolled malignant proliferation of hematopoietic cells resulting in erythrocytosis, leukocytosis, and thrombocytosis. In high-risk patients, cytoreductive therapy is recommended in addition to phlebotomy and aspirin.

Compared to other pegylated interferon alfa products, ropeginterferon alfa-2b consists of a single positional isomer, resulting in an extended elimination half-life and less frequent dosing (every other week or monthly during maintenance therapy).

Ropeginterferon Alfa-2b Dosage and Administration

General

Pretreatment Screening

Pregnancy testing is recommended in females of reproductive potential prior to initiation of therapy.
Perform liver function tests prior to initiation of treatment.
Monitor serum triglycerides prior to initiation of treatment.
Obtain baseline serum creatinine prior to initiation of treatment.
Perform baseline CBC.
Advise patients to have an eye examination prior to treatment, especially in those with a retinopathy-associated disease such as diabetes or hypertension.

Patient Monitoring

Closely monitor patients for any symptoms of psychiatric disorders. Consider psychiatric consultation and treatment if symptoms emerge.
Monitor patients with a history of cardiovascular disorders for cardiovascular toxicity during treatment.
Monitor CBCs every 2 weeks during the dosage titration phase and every 3–6 months during the maintenance phase. More frequent monitoring may be necessary if clinically indicated.
Advise patients to have periodic eye examinations.
Monitor liver function tests periodically during treatment.
Monitor serum triglycerides intermittently during therapy.
Monitor serum creatinine periodically during treatment.

Administration

Sub-Q Administration

Administer by sub-Q injection every 2 weeks. Commercially available as a 500-mcg/mL solution in a single-dose prefilled syringe.

Several peginterferon alfa subtypes (alfa-2a, alfa-2b), dosage forms, and strengths are commercially available. Verify that correct preparation is used.

May be self-administered if the clinician determines that the patient and/or their caregiver is competent to prepare and safely administer the drug after appropriate training is provided.

Before each injection, remove syringe from refrigerator storage for 15–30 minutes to allow the syringe to reach room temperature.

Visually inspect the solution for particulate matter and discoloration before administration. The solution should be clear and colorless to slightly yellowish; do not use the drug if the solution is cloudy, discolored, or contains particulate matter, or if the syringe shows any sign of damage.

Depending on the prescribed dose, the amount of solution in the syringe may need to be adjusted by discarding some of the drug.

To administer the sub-Q injection, pinch the skin; insert needle at a 45- to 90-degree angle into the pinched skin, then release the skin. After all of the drug is injected, remove the needle from the skin.

Dosage

Adults

Polycythemia Vera

Sub-Q

Patients not already receiving hydroxyurea: recommended initial dosage is 100 mcg every 2 weeks. Increase dosage by 50 mcg every 2 weeks (up to a maximum of 500 mcg) until hematologic parameters are stabilized (hematocrit <45%, platelet counts <400,000/mm³, and leukocytes <10,000/mm³).

Patients transitioning from hydroxyurea: initiate ropeginterferon alfa-2b-njft at a dosage of 50 mcg every 2 weeks in combination with hydroxyurea. Gradually taper dosage of hydroxyurea by reducing the total biweekly dosage by 20–40% every 2 weeks during weeks 3–12. Increase the dosage of ropeginterferon alfa-2b-njft by 50 mcg every 2 weeks (up to a maximum of 500 mcg) until hematologic parameters are stabilized (hematocrit <45%, platelets <400,000/mm³, and leukocytes <10,000/mm³). Discontinue hydroxyurea by week 13.

Maintain the 2-week dosing interval at which hematological stability is achieved for at least 1 year. After achievement of hematological stability for at least 1 year on a stable dosage of the drug, the dosing interval may be increased to every 4 weeks.

Dosage Modification for Toxicity

If drug-related toxicities occur, reduce dose of ropeginterferon alfa-2b-njft to the next lower dose level or interrupt therapy in accordance with Table 1. If there is insufficient efficacy at the decreased dose following dose modification, consider attempting a dose increase to the next higher dose level after recovery to grade 1 toxicity.

Table 1. Recommended Dosage Modification of Ropeginterferon alfa-2b-njft for Adverse Reactions1
Adverse Reaction	Severity	Dosage Modification
Liver enzyme elevation with concomitant bilirubin elevation, or other evidence of hepatic decompensation	Any increase above baseline	Interrupt treatment until recovery, then restart at a 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 times the upper limit of normal (ULN) but ≤20 times ULN	Decrease dose by 50 mcg; if toxicity does not improve, continue decreasing at biweekly intervals until ALT and AST recover to <3 times the ULN if baseline was normal or to 3 times baseline if baseline was abnormal, and gamma-glutamyltransferase (GGT) recovers to <2.5 times the ULN if baseline was normal, or to 2.5 times baseline if baseline was abnormal. If the interrupted dose is 50 mcg, refrain from treatment until recovery.
	>20 times the ULN	Interrupt treatment until ALT and AST recover to <3 times the ULN if baseline was normal, or to 1.5 times baseline if baseline was abnormal, and GGT recovers to <2.5 times the ULN if baseline was normal, or to 2 times baseline if baseline was abnormal. Consider permanent discontinuation if toxicity persists after four dose modifications.
Cytopenia	Anemia: hemoglobin (Hgb) <8 g/dL Thrombocytopenia: platelet count <50,000/mm³ but ≥25,000/mm³ Leukopenia: white blood cell count (WBC) <2000/mm³ but ≥1,000/mm³	Decrease dose by 50 mcg; if toxicity does not improve, continue decreasing at biweekly intervals until recovery of Hgb >10 g/dL, platelets >75,000/mm³, and WBC >3,000/mm³ If the interrupted dose is 50 mcg, refrain from treatment until recovery.
	Anemia: Hemoglobin levels are life threatening, or urgent intervention needed Thrombocytopenia: platelet count <25,000/mm³ Leukopenia: WBC <1000/mm³	Interrupt treatment until recovery of Hgb >10 g/dL, platelets >75,000/mm³, and WBC >3,000/mm³ Consider permanent discontinuation if toxicity persists after four dose modifications.
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

Prescribing Limits

Adults

Polycythemia Vera

Sub-Q

Maximum dose of 500 mcg.

Special Populations

Hepatic Impairment

Contraindicated in patients with moderate (Child-Pugh class B) or severe (Child-Pugh class C) hepatic impairment.

Renal Impairment

No dosage adjustment necessary in patients with mild to moderate renal impairment (eGFR ≥30 mL/minute).

Avoid use in patients with eGFR <30 mL/minute.

Geriatric Patients

In general, dosage selection should be cautious, usually starting at the low end of the dosing range.

Cautions for Ropeginterferon Alfa-2b

Contraindications

Current or prior history of severe psychiatric disorders, particularly severe depression, suicidal ideation, or suicide attempt.
Known hypersensitivity to interferons or any component of the preparation.
Moderate or severe hepatic impairment (Child-Pugh class B or C).
History or presence of active serious or untreated autoimmune disease.
Immunosuppressed transplant recipients.

Warnings/Precautions

Warnings

Risk of Serious Disorders

Interferon alfa products may cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. (See Boxed Warning.)

Other Warnings and Precautions

Depression and Suicide

Life-threatening or fatal neuropsychiatric reactions reported. May occur in patients with and without previous psychiatric illness.

Other CNS effects, including suicidal ideation, attempted suicide, aggression, bipolar disorder, mania, and confusion, observed with other interferon alfa products.

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; consider psychiatric consultation and treatment if such symptoms emerge. If psychiatric symptoms worsen, discontinuance of ropeginterferon alfa-2b therapy is recommended.

Endocrine Toxicity

Endocrine toxicities, including hypothyroidism, hyperthyroidism, autoimmune thyroiditis, and hyperglycemia reported.

Do not use 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 therapy.

Discontinue therapy in patients who develop endocrine disorders that cannot be adequately managed.

Cardiovascular Toxicity

Cardiovascular toxicities (e.g., cardiomyopathy, MI, atrial fibrillation, coronary artery ischemia) reported.

Monitor patients with a history of cardiovascular disorders closely for cardiovascular toxicity during therapy.

Avoid use 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 MI.

Decreased Peripheral Blood Counts

Decreased peripheral blood counts, including thrombocytopenia, anemia, and leukopenia reported. Infections occurred in almost 50% of patients receiving the drug.

Monitor CBCs at baseline, during dosage titration, and then every 3–6 months during the maintenance phase. Monitor patients for signs and symptoms of infection or bleeding.

Hypersensitivity Reactions

Hypersensitivity reactions, including urticaria, angioedema, bronchoconstriction, and anaphylaxis reported. If such reactions occur, discontinue drug and institute appropriate medical therapy immediately. Transient rashes may not necessitate interruption of treatment.

Pancreatitis

Pancreatitis reported; symptoms may include nausea, vomiting, upper abdominal pain, bloating, and fever. Patients may also experience elevated lipase, amylase, WBC count, or altered renal/hepatic function.

Interrupt treatment in patients with possible pancreatitis and evaluate promptly. Consider discontinuation of the drug in patients with confirmed pancreatitis.

Colitis

Fatal and serious ulcerative or hemorrhagic/ischemic colitis reported, some cases occurring as early as 12 weeks after initiating therapy. Symptoms may include abdominal pain, bloody diarrhea, and fever.

Discontinue therapy in patients who develop signs or symptoms. Colitis may resolve within 1 to 3 weeks of stopping treatment.

Pulmonary Toxicity

Pulmonary toxicity reported; may manifest as dyspnea, pulmonary infiltrates, pneumonia, bronchiolitis obliterans, interstitial pneumonitis, pulmonary hypertension, and sarcoidosis. Some cases have resulted in respiratory failure or death.

Discontinue therapy in patients who develop pulmonary infiltrates or pulmonary function impairment.

Ophthalmologic Toxicity

Ophthalmologic toxicities, including retinopathy, retinal hemorrhage, retinal exudates, retinal detachment, and retinal artery or vein occlusion reported.

Advise patients to have eye examinations before and during therapy, especially in those patients with a retinopathy-associated disease such as diabetes mellitus or hypertension.

If any eye symptoms occur during treatment, evaluate the patient promptly. Discontinue drug in patients who develop new or worsening eye disorders.

Hyperlipidemia

Hyperlipidemia, hypertriglyceridemia, and dyslipidemia reported.

Monitor serum triglycerides prior to initiating therapy and intermittently during treatment; manage any abnormalities.

Consider discontinuation of the drug in patients with persistently, markedly elevated triglycerides.

Hepatotoxicity

Hepatotoxicity, including increases in serum ALT, AST, γ-glutamyltransferase (GGT), and bilirubin reported. Contraindicated in patients with moderate (Child-Pugh class B) or severe (Child-Pugh class C) hepatic impairment.

Monitor liver enzymes and hepatic function at baseline and during treatment. Reduce dose of ropeginterferon alfa-2b-njft by 50 mcg in patients with increased AST/ALT/GGT, then monitor these liver enzymes weekly until values return to baseline or grade 1 (ALT and AST <3 times the ULN if baseline values were normal; ALT and AST 1.5–3 times baseline if baseline values were abnormal and GGT <2.5 times the ULN if baseline values were normal; or GGT 2–2.5 times baseline values if baseline values were abnormal).

If toxicity does not improve, continue decreasing the ropeginterferon alfa-2b-njft dose at biweekly intervals until recovery to grade 1.

Withhold therapy if AST/ALT/GGT >20 times the ULN and consider permanent discontinuation if increased liver enzyme levels persist after four dose reductions.

Discontinue drug in patients who develop evidence of hepatic decompensation (characterized by jaundice, ascites, hepatic encephalopathy, hepatorenal syndrome, or variceal hemorrhage).

Renal Toxicity

Renal impairment and toxic nephropathy reported.

Monitor serum creatinine at baseline and during therapy. Avoid use in patients with eGFR <30 mL/minute. Discontinue therapy if severe renal impairment develops during treatment.

Dental and Periodontal Toxicities

Dental and periodontal toxicities may occur. The drug may have a damaging effect on teeth and oral mucous membranes during long-term treatment.

Patients should have good oral hygiene and regular dental examinations.

Dermatologic Toxicity

Dermatologic toxicity, including skin rash, pruritus, alopecia, erythema, psoriasis, xeroderma, dermatitis acneiform, hyperkeratosis, and hyperhidrosis reported.

Consider discontinuation of the drug if clinically significant dermatologic toxicity occurs.

Effects on Driving and Operating Machinery

Ropeginterferon alfa-2b may impact the ability to drive and use machinery. Patients should not drive or use heavy machinery until they know how the drug affects their abilities. Patients who experience dizziness, somnolence, or hallucination during therapy should avoid driving or using machinery.

Fetal/Neonatal Morbidity and Mortality

Based on its mechanism of action, may cause fetal harm. (See Females and Males of Reproductive Potential under Cautions.)

Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity with ropeginterferon alfa-2b-njft. Binding antibodies to ropeginterferon alfa-2b-njft were detected; however, none of the patients who tested positive for such antibodies developed neutralizing antibodies.

Specific Populations

Pregnancy

Insufficient data to identify a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Animal reproductive studies not conducted.

Based on its mechanism of action and the role of interferon alfa in pregnancy and fetal development, ropeginterferon alfa-2b may cause fetal harm and should be assumed to have abortifacient potential when administered to a pregnant woman.

Advise pregnant women of the potential risk to a fetus.

Adverse maternal and fetal outcomes such as thrombosis and hemorrhage, including a risk of miscarriage, have been associated with polycythemia vera in pregnant women.

Lactation

Not known whether ropeginterferon alfa-2b-njft distributes into milk or if the drug has any effects on the breast-fed child or on milk production. Breastfeeding is not recommended during ropeginterferon alfa-2b-njft treatment and for 8 weeks after the final dose.

Females and Males of Reproductive Potential

Pregnancy testing prior to treatment is recommended in females of reproductive potential. Such females should use effective contraception during treatment and for at least 8 weeks after the final dose.

Based on its mechanism of action, ropeginterferon alfa-2b-njft can cause disruption of the menstrual cycle.

Pediatric Use

Safety and effectiveness not established in pediatric patients.

Geriatric Use

Insufficient experience in patients ≥ 65 years of age to determine whether they respond differently from younger patients. In general, dosage selection in geriatric patients should be cautious.

Hepatic Impairment

Contraindicated in patients with moderate to severe hepatic impairment (Child-Pugh class B or C).

Increased liver enzyme levels observed. If progressive and persistent liver enzyme elevations occur, reduce dosage. If persistent or clinically significant elevations in liver enzymes occur or if there is evidence of hepatic impairment (Child-Pugh class B or C), discontinue the drug.

Renal Impairment

No dosage adjustment is necessary in patients with eGFR ≥30 mL/minute. Avoid use in patients with eGFR <30 mL/minute

Common Adverse Effects

Common adverse reactions (>40%): influenza-like illness, arthralgia, fatigue, pruritus, nasopharyngitis, musculoskeletal pain.

Drug Interactions

No clinical studies evaluating drug interaction potential of ropeginterferon alfa-2b conducted.

In vitro studies indicate that the drug can inhibit CYP2A6, but does not appear to inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4. Not expected to induce CYP enzymes.

Drugs Metabolized by Hepatic Microsomal Enzymes

Certain proinflammatory cytokines, including interferons, can suppress CYP isoenzymes, resulting in increased exposures of some CYP substrates.

Monitor patients taking CYP substrates with a narrow therapeutic index for adverse reactions; adjust dosage of the concomitant CYP substrate drug as necessary when used with ropeginterferon alfa-2b.

Myelosuppressive Agents

Additive myelosuppression can occur.

Avoid concomitant use; if concomitant use is necessary, monitor patients for effects of excessive myelosuppression.

Narcotics, Hypnotics, or Sedatives

Additive neuropsychiatric effects can occur.

Avoid concomitant use. If concomitant use is necessary, monitor patients for excessive CNS toxicity.

Ropeginterferon Alfa-2b Pharmacokinetics

Absorption

Bioavailability

Absolute bioavailability not known.

Following sub-Q administration, AUC and plasma concentrations increase in a greater than dose proportional manner over the dose range of 24 to 270 mcg.

Elimination

Metabolism

There is evidence that pegylated proteins are susceptible to hydrolysis with the release of interferon and PEG moieties.

Elimination Route

Eliminated via receptor independent degradation/excretion and receptor binding followed by subsequent degradation of the drug-receptor complex.

The PEG moiety may undergo uptake by macrophages and Kupffer cells by pinocytosis; however, biliary excretion only plays a minor role in the clearance of PEG, whereas urinary clearance predominates.

Half-life

Approximately 7 days.

Special Populations

No clinically important differences in pharmacokinetics observed based on age, sex, body surface area, and JAK2V617F mutation.

Stability

Storage

Parenteral

Injection

Store in a refrigerator at 2–8°C in the original carton to protect from light. Do not freeze.

Actions

A recombinant DNA-derived human interferon alfa-2b covalently bound to monomethoxy polyethylene glycol (mPEG).
Therapeutic effects in polycythemia vera not fully exhibited, but the drug is a member of the type I class of interferons, which exhibit cellular effects in the bone marrow by binding to the interferon alfa transmembrane receptor (IFNAR).
Upon binding to IFNAR, initiates a downstream signaling cascade through the activation of kinases, affecting distinct gene-expression and exhibiting various cellular effects.

Advice to Patients

Advise patients to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).
Inform patients, their caregivers, and family members that suicidal ideation and behavior, as well as new onset or worsening depression have been reported in patients treated with ropeginterferon alfa-2b-njft. Advise them to be aware of any unusual changes in mood or behavior, new onset or worsening of depression, or the emergence of suicidal thoughts or behavior. Instruct patients, caregivers, and family members to report signs or symptoms of depression to their healthcare provider right away, but to discontinue ropeginterferon alfa-2b-njft immediately and seek immediate medical attention if suicidal ideation or attempts occur.
Advise patients to report any signs or symptoms of diabetes or thyroid dysfunction.
Advise patients to report signs or symptoms of cardiovascular toxicity to their healthcare provider.
Advise patients to seek prompt medical attention if they experience weakness/fatigue, fever, easy bruising, or frequent nose bleeds.
Advise patients to seek immediate medical attention if they experience any symptoms of serious hypersensitivity reactions.
Advise patients to report signs or symptoms of pancreatitis.
Advise patients to report signs or symptoms of colitis.
Advise patients to report signs or symptoms of pulmonary toxicity.
Advise patients to report visual changes and to have eye examinations before and during treatment.
Advise patients that ropeginterferon alfa-2b-njft may increase blood triglycerides; importance of blood testing to monitor for this toxicity.
Advise patients to report signs or symptoms of hepatic toxicity to their healthcare provider.
Advise patients to report signs or symptoms of kidney disease.
Advise patients to maintain good oral hygiene and to have regular dental examinations.
Advise patients to seek medical attention if significant pruritus, alopecia, rash, and/or other dermatological toxicities occur.
Advise patients to refrain from engaging in operating heavy or potentially dangerous machinery until they know how ropeginterferon alfa-2b-njft will affect their abilities. Advise patients who experience dizziness, somnolence, and hallucinations not to drive or use heavy machinery.
Advise women about the need to use an effective method of contraception while taking ropeginterferon alfa-2b-njft and for at least 8 weeks after the final dose.
Advise women not to breast-feed during treatment and for 8 weeks after the final dose.
Instruct patients on proper storage, preparation, and administration techniques for ropeginterferon alfa-2b-njft. Instruct patients who are self-administering to inject the prescribed dose of ropeginterferon alfa-2b-njft.
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.
Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Ropeginterferon alfa-2b-njft is available only from designated specialty pharmacies. Contact the manufacturer for additional information.