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Peginterferon Alfa-2b and Ribavirin

Pronunciation

(peg in ter FEER on AL fa too bee & rye ba VYE rin)

Index Terms

  • Ribavirin and Peginterferon Alfa-2b

Pharmacologic Category

  • Antihepaciviral, Nucleoside (Anti-HCV)
  • Interferon

Pharmacology

Peginterferon Alfa-2b: Alpha interferons are a family of proteins, produced by nucleated cells that have antiviral, antiproliferative, and immune-regulating activity. There are 16 known subtypes of alpha interferons. Interferons interact with cells through high affinity cell surface receptors. Following activation, multiple effects can be detected including induction of gene transcription. Inhibits cellular growth, alters the state of cellular differentiation, interferes with oncogene expression, alters cell surface antigen expression, increases phagocytic activity of macrophages, and augments cytotoxicity of lymphocytes for target cells.

Ribavirin: Inhibits replication of RNA and DNA viruses; inhibits influenza virus RNA polymerase activity and inhibits the initiation and elongation of RNA fragments resulting in inhibition of viral protein synthesis.

Use: Labeled Indications

Note: Not approved in the US

Combination therapy for the treatment of chronic hepatitis C in patients with compensated liver disease, including treatment-naive patients and those who have failed prior treatment with pegylated or nonpegylated interferon alpha and ribavirin combination therapy

Contraindications

Hypersensitivity to polyethylene glycol (PEG), interferons, ribavirin, or any component of the formulation; autoimmune hepatitis or history of autoimmune disease; decompensated liver disease; history of or pre-existing severe psychiatric disorder; uncontrolled thyroid dysfunction; epilepsy; severe renal dysfunction (CrCl <50 mL/minute); males with a pregnant female partner; pregnancy

Dosing: Adult

Note: Canadian Consensus Guidelines recommend peginterferon plus ribavirin as treatment of choice for chronic hepatitis C (HCV) (Sherman, 2007). American Association for the Study of Liver Diseases (AASLD) practice guidelines also recommend the use of boceprevir or telaprevir in combination with peginterferon plus ribavirin for chronic HCV patients with genotype 1 (Ghany, 2011). Administration of acetaminophen 30 minutes prior to therapy may help reduce fever and headache associated with peginterferon.

Chronic hepatitis C:

Pegetron® peginterferon alfa-2b component: SubQ: 1.5 mcg/kg/week

and

Pegetron® ribavirin component: Oral:

HCV genotype 1 (treatment-naive):

≤65 kg: 800 mg/day (two 200 mg capsules in the morning and two 200 mg capsules in the evening)

66-80 kg: 1000 mg/day (two 200 mg capsules in the morning and three 200 mg capsules in the evening)

81-105 kg: 1200 mg/day (three 200 mg capsules in the morning and three 200 mg capsules in the evening)

>105 kg: 1400 mg/day (three 200 mg capsules in the morning and four 200 mg capsules in the evening)

HCV nongenotype 1 (treatment-naive):

≤65 kg: 800 mg/day (two 200 mg capsules in the morning and two 200 mg capsules in the evening)

66-85 kg: 1000 mg/day (two 200 mg capsules in the morning and three 200 mg capsules in the evening)

>85 kg: 1200 mg/day (three 200 mg capsules in the morning and three 200 mg capsules in the evening)

Re-treatment (relapser or nonresponder): Any HCV genotype:

≤65 kg: 800 mg/day (two 200 mg capsules in the morning and two 200 mg capsules in the evening)

66-85 kg: 1000 mg/day (two 200 mg capsules in the morning and three 200 mg capsules in the evening)

86-105 kg: 1200 mg/day (three 200 mg capsules in the morning and three 200 mg capsules in the evening)

>105 kg: 1400 mg/day (three 200 mg capsules in the morning and four 200 mg capsules in the evening)

Treatment duration: Canadian consensus guidelines (Sherman, 2007):

HCV genotype 1: Treatment recommended for 48 weeks or may consider extended therapy up to 72 weeks in slow responders; may reduce treatment to 24 weeks in patients achieving RVR at 4 weeks and without poor response predictors (eg, high viral load, advanced fibrosis, elderly); discontinue therapy in patients failing to achieve EVR at 12 weeks or with detectable HCV RNA at 24 weeks; re-treatment for 48 weeks is required in patients who relapse after discontinuing abbreviated therapy (24 weeks).

HCV genotypes 2,3: Treatment recommended for 24 weeks; may consider abbreviated therapy (12 or 16 weeks) in patients with weight-based ribavirin dosing and RVR; if relapse occurs following abbreviated therapy, re-treat for 24 weeks

HCV genotype 4,5, and 6: Treatment recommended for 48 weeks; discontinue therapy in patients failing to achieve EVR at 12 weeks or with detectable HCV RNA at 24 weeks

Relapsing or nonresponding patients (regardless of genotype): Peginterferon/ribavirin therapy may be considered in patients that have relapsed or were nonresponsive to prior interferon monotherapy or interferon/ribavirin combination therapy; discontinue therapy if EVR not achieved after 12 weeks.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

CrCl ≥50 mL/minute: No dosage adjustment provided in manufacturer’s labeling; however, use caution and monitor closely for signs/symptoms of toxicity.

CrCl <50 mL/minute: Use is contraindicated

Serum creatinine >2 mg/dL: Permanently discontinue therapy in any patient.

Dosing: Hepatic Impairment

Mild or moderate impairment (Child-Pugh class A or B): No dosage adjustment provided in manufacturer’s labeling; however, limited data shows Cmax increases with increasing severity of hepatic impairment.

Severe impairment (Child-Pugh class C): Avoid use.

Indirect bilirubin >5 mg/dL:

HCV genotype 1 (treatment-naive): Continue current peginterferon alfa-2b dose; decrease ribavirin dose by 200 mg/day if receiving ≤1200 mg/day or by 400 mg/day if receiving 1400 mg/day (first reduction), and by an additional 200 mg/day (second reduction) if necessary.

HCV nongenotype 1 (treatment-naive): Continue current peginterferon alfa-2b dose; decrease ribavirin dose to 600 mg/day.

Relapser or nonresponder (any HCV genotype): Continue current peginterferon alfa-2b dose; decrease ribavirin dose by 200 mg/day if receiving ≤1000 mg/day or by 400 mg/day if receiving ≥1200 mg/day (first reduction), and by an additional 200 mg/day (second reduction) if necessary.

Direct bilirubin >2.5 times ULN or indirect bilirubin >4 mg/dL (for >4 weeks): Permanently discontinue both peginterferon alfa-2b and ribavirin in any patient.

AST/ALT 2 times baseline and >10 times ULN: Permanently discontinue both peginterferon alfa-2b and ribavirin in any patient.

Dosing: Adjustment for Toxicity

Note: Recommendations (per manufacturer labeling - also refer to dosing in renal and hepatic impairment):

Hemoglobin:

HCV genotype 1 (treatment-naive):

Hemoglobin <10 g/dL: Continue current peginterferon alfa-2b dose; decrease ribavirin dose by 200 mg/day if receiving ≤1200 mg/day or by 400 mg/day if receiving 1400 mg/day (first reduction), and by an additional 200 mg/day (second reduction) if necessary.

Hemoglobin decrease ≥2 g/dL in any 4-week period and stable cardiac disease: Decrease peginterferon alfa-2b dose in increments of 0.5 mcg/kg/week; decrease ribavirin dose by 200 mg/day if receiving ≤1200 mg/day or by 400 mg/day if receiving 1400 mg/day (first reduction), and by an additional 200 mg/day (second reduction) if necessary.

Hemoglobin <8.5 g/dL or <12 g/dL after ribavirin dose is decreased for 4 weeks and stable cardiac disease: Permanently discontinue both peginterferon alfa-2b and ribavirin

HCV nongenotype 1 (treatment-naive):

Hemoglobin <10 g/dL: Continue current peginterferon alfa-2b dose; decrease ribavirin dose to 600 mg/day

Hemoglobin decrease ≥2 g/dL in any 4-week period and stable cardiac disease: Decrease peginterferon alfa-2b dose by one-half; decrease ribavirin dose to 600 mg/day

Hemoglobin <8.5 g/dL or <12 g/dL after ribavirin dose is decreased for 4 weeks and stable cardiac disease: Permanently discontinue both peginterferon alfa-2b and ribavirin

Relapser or nonresponder (any HCV genotype):

Hemoglobin <10 g/dL: Continue current peginterferon alfa-2b dose; decrease ribavirin dose by 200 mg/day if receiving ≤1000 mg/day or by 400 mg/day if receiving ≥1200 mg/day (first reduction), and by an additional 200 mg/day (second reduction) if necessary.

Hemoglobin decrease ≥2 g/dL in any 4-week period and stable cardiac disease: Decrease peginterferon alfa-2b dose in increments of 0.5 mcg/kg/week; decrease ribavirin dose by 200 mg/day if receiving ≤1000 mg/day or by 400 mg/day if receiving ≥1200 mg/day (first reduction), and by an additional 200 mg/day (second reduction) if necessary.

Hemoglobin <8.5 g/dL or <12 g/dL after ribavirin dose is decreased for 4 weeks and stable cardiac disease: Permanently discontinue both peginterferon alfa-2b and ribavirin.

White blood cells:

HCV genotype 1 (treatment-naive) or relapser/nonresponder (any HCV genotype): WBC <1.5 x 109/L: Decrease peginterferon alfa-2b dose in increments of 0.5 mcg/kg/week.

HCV nongenotype 1 (treatment-naive): WBC <1.5 x 109/L: Decrease peginterferon alfa2b-dose by one-half.

Any patient with WBC <1.0 x 109/L: Permanently discontinue peginterferon alfa-2b and ribavirin.

Neutrophils:

HCV genotype 1 (treatment-naive) or relapser/nonresponder (any HCV genotype): Neutrophils <0.75 x 109/L: Decrease peginterferon alfa-2b dose in increments of 0.5 mcg/kg/week.

HCV nongenotype 1 (treatment-naive): Neutrophils <0.75 x 109/L: Decrease peginterferon alfa-2b dose by one-half.

Any patient with neutrophils <0.5 x 109/L: Permanently discontinue peginterferon alfa-2b and ribavirin.

Platelets:

HCV genotype 1 (treatment-naive) or relapser/nonresponder (any HCV genotype):

Platelet count <50 x 109/L: Decrease peginterferon alfa-2b dose in increments of 0.5 mcg/kg/week.

Platelet count <25 x 109/L: Permanently discontinue peginterferon alfa-2b and ribavirin.

HCV nongenotype 1 (treatment-naive):

Platelet count <80 x 109/L: Decrease peginterferon alfa-2b dose by one-half.

Platelet count <50 x 109/L: Permanently discontinue peginterferon alfa-2b and ribavirin.

Reconstitution

Peginterferon alfa-2b injection:

Vials: Peginterferon alfa-2b powder for injection should be reconstituted with 0.7 mL of SWFI (sterile water for injection) (provided). Roll gentle to form solution; do not shake. Vials are calibrated to provide appropriate dose in a volume of 0.5 mL of resulting solution.

Redipen®: Reconstitute with SWFI (provided). Allow solution to form. Gently turn upside down twice; do not shake. Pen provides appropriate dose in a volume of 0.5 mL of resulting solution.

Hazardous agent (ribavirin); use appropriate precautions for handling and disposal (NIOSH 2014 [group 3]).

Administration

See individual agents.

Hazardous agent (ribavirin); use appropriate precautions for handling and disposal (NIOSH 2014 [group 3]).

Dietary Considerations

Take oral formulation without regard to meals, but always in a consistent manner with respect to food intake (ie, always take with food or always take on an empty stomach).

Storage

Pegetron® capsule/peginterferon alfa-2b injection combination package: Store under refrigeration between 2°C and 8°C (36°F and 46°F).

When the package is separated:

Pegetron® capsules: Store under refrigeration between 2°C and 8°C (36°F and 46°F) or at room temperature between 15°C to 30°C (59°F to 86°F).

Peginterferon alfa-2b injection:

Vials: Store vial/carton under refrigeration between 2°C and 8°C (36°F and 46°F). Use within 3 hours of reconstitution.

Redipen®: Store under refrigeration between 2°C and 8°C (36°F and 46°F). Immediate use after reconstitution is recommended; however, may be stored up to 24 hours under refrigeration between 2°C and 8°C (36°F and 46°F).

Drug Interactions

Aldesleukin: Interferons (Alfa) may enhance the adverse/toxic effect of Aldesleukin. In particular, risks of myocardial and renal toxicity may be increased by this combination. Consider therapy modification

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

CYP1A2 Substrates: Peginterferon Alfa-2b may increase the serum concentration of CYP1A2 Substrates. Monitor therapy

CYP2D6 Substrates: Peginterferon Alfa-2b may decrease the serum concentration of CYP2D6 Substrates. Peginterferon Alfa-2b may increase the serum concentration of CYP2D6 Substrates. Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

FLUoxetine: Peginterferon Alfa-2b may decrease the serum concentration of FLUoxetine. Monitor therapy

Methadone: Interferons (Alfa) may increase the serum concentration of Methadone. Monitor therapy

Pegloticase: May diminish the therapeutic effect of Peginterferon Alfa-2b. Monitor therapy

Ribavirin (Oral Inhalation): Interferons (Alfa) may enhance the adverse/toxic effect of Ribavirin (Oral Inhalation). Hemolytic anemia has been observed. Monitor therapy

Ribavirin (Systemic): Interferons (Alfa) may enhance the adverse/toxic effect of Ribavirin (Systemic). Hemolytic anemia has been observed. Monitor therapy

Telbivudine: Peginterferon Alfa-2b may enhance the adverse/toxic effect of Telbivudine. Specifically, the risk for peripheral neuropathy may be increased. Avoid combination

TiZANidine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of TiZANidine. Management: Avoid these combinations when possible. If combined use cannot be avoided, initiate tizanidine at an adult dose of 2 mg and increase in 2-4 mg increments based on patient response. Monitor for increased effects of tizanidine, including adverse reactions. Consider therapy modification

Zidovudine: Interferons may enhance the adverse/toxic effect of Zidovudine. Interferons may decrease the metabolism of Zidovudine. Monitor therapy

Adverse Reactions

>10%:

Central nervous system: Fatigue (32% to 65%), headache (39% to 62%), rigors (43% to 48%), fever (32% to 46%), insomnia (21% to 40%), chills (22% to 39%), irritability (17% to 35%), depression (12% to 34%), dizziness (10% to 21%), impaired concentration (5% to 19%), anxiety (8% to 16%), pain (4% to 13%), emotional lability (1% to 11%)

Dermatologic: Alopecia (17% to 45%), pruritus (13% to 29%), dry skin (8% to 26%), rash (9% to 24%)

Gastrointestinal: Nausea (24% to 43%), anorexia (9% to 35%), weight loss (7% to 30%), diarrhea (12% to 22%), appetite decreased (8% to 18%), vomiting (8% to 16%), abdominal pain (3% to 15%), right upper quadrant pain (7% to 12%), xerostomia (5% to 12%)

Hematologic: Anemia (16% to 34%), hemolytic anemia (<1% to 28%), neutropenia (2% to 26%; grade 4: <1% to 7%)

Local: Injection site reaction (5% to 59%), injection site inflammation (20% to 27%), injection site erythema (10% to 18%)

Neuromuscular & skeletal: Myalgia (26% to 56%), arthralgia (16% to 34%), weakness (4% to 28%), musculoskeletal pain (<1% to 21%)

Respiratory: Dyspnea (10% to 27%), cough (14% to 19%), pharyngitis (11% to 16%)

Miscellaneous: Flu-like syndrome (2% to 27%), viral infection (10% to 15%), diaphoresis (7% to 11%)

1% to 10%:

Cardiovascular: Chest pain (2% to 10%), tachycardia (<1% to 10%), flushing (1% to 5%), hyper/hypotension (1% to 5%), syncope (1% to 5%), palpitation (<1% to 5%), peripheral edema (≤1%)

Central nervous system: Agitation (1% to 10%), nervousness (<1% to 10%), apathy (2% to 5%), malaise (2% to 5%), vertigo (2% to 5%), aggression (1% to 5%), migraine (1% to 5%), hyper/hypoesthesia (1% to 5%), tremor (1% to 5%), confusion (<1% to 5%), somnolence (<1% to 5%), memory impairment (2% to 4%), amnesia (2% to 3%), lethargy (≤1% to 3%), anger (2%), crying (1% to 2%), restlessness (1% to 2%), sleep disturbances (≤1% to 2%); Note: Life-threatening psychiatric events (suicidal ideation, suicide attempt, suicide [completed], psychosis including hallucinations and aggressive behavior) have been reported in up to 1.2% of patients.

Dermatologic: Erythema (2% to 5%), hair texture abnormal (2% to 5%), photosensitivity (2% to 5%), eczema (1% to 5%), rash (erythematous and maculopapular; <1% to 5%), hyperhidrosis (2% to 3%), dermatitis (2%), cellulitis (≤1%), cheilitis (≤1%), psoriasis (≤1%), scaling (≤1%)

Endocrine & metabolic: Menorrhagia (5% to 10%), menstrual disorder (5% to 10%), thyroid abnormalities (hyper-/hypothyroidism; 1% to 10%), amenorrhea (2% to 5%), lacrimal gland disorder (2% to 5%), libido decreased (1% to 5%), hyperuricemia (1% to 2%), TSH increased (1%), dehydration (≤1%)

Gastrointestinal: Dyspepsia (4% to 10%), constipation (3% to 10%), taste perversion (3% to 10%), flatulence (2% to 5%), glossitis (2% to 5%), loose stools (2% to 5%), stomatitis (including aphthous and ulcerative; 1% to 5%), bleeding gums (<1% to 5%), GERD (1% to 2%), herpes labialis (1% to 2%), mouth ulcerations (1% to 2%), abdominal distension (1%), burning mouth (1%), gastritis (1%), stomach discomfort (1%), serum amylase increased (≤1%)

Genitourinary: Prostatitis (2% to 5%), erectile dysfunction (1%), polyuria (1%)

Hematologic: Leukopenia (2% to 10%; grades 3 and 4: <1% to 7%), thrombocytopenia (<1% to 7%), lymphopenia (1%)

Hepatic: Hyperbilirubinemia (1% to 2%)

Local: Injection site pain (1% to 5%), injection site rash (1% to 4%), injection site pruritus (1% to 3%)

Neuromuscular & skeletal: Paresthesia (2% to 10%), back pain (5% to 6%), hypertonia (2% to 5%), muscle spasms (2% to 5%), limb pain (3% to 4%), bone pain (1%), neck pain (≤1%)

Ocular: Vision blurred (2% to 10%), conjunctivitis (2% to 5%), eye pain (<1% to 5%), dry eyes (2% to 3%), photophobia (≤1%), retinal exudates (≤1%), visual disturbances (≤1%)

Otic: Hearing impaired/loss (2% to 5%), otitis media (2% to 5%), tinnitus (1% to 5%)

Respiratory: Rhinitis (8% to 10%), nonproductive cough (5% to 10%), exertional dyspnea (4% to 5%), respiratory disorder (2% to 5%), bronchitis (1% to 5%), nasal congestion (1% to 5%), sinusitis (1% to 5%), rhinorrhea (<1% to 5%), pharyngolaryngeal pain (2% to 4%), epistaxis (2%), upper respiratory tract infection (<1% to 2%), postnasal drip (1%), nasal dryness (≤1%)

Miscellaneous: Fungal infection (2% to 5%), herpes simplex (2% to 5%), thirst (2% to 5%), lymphadenopathy (<1% to 5%), night sweats (1% to 2%), sensitivity to temperature extremes (≤1%)

<1% (Limited to important or life-threatening; reported with other interferon preparations and/or ribavirin): Anaphylaxis, angioedema, aplastic anemia, arrhythmia, arthritis (including rheumatoid), bacterial infection (including sepsis), bipolar disorder, cardiac ischemia, cardiomyopathy, cerebrovascular hemorrhage, cerebrovascular ischemia, colitis (ischemic, ulcerative), coma, diabetes mellitus, diabetic ketoacidosis, DVT, encephalopathy, erythema multiforme, facial palsy, hepatotoxic reactions, homicidal ideation, hypersensitivity reactions, injection site necrosis, lower respiratory tract infection, macular edema, MI, myositis, nephrotic syndrome, optic neuritis, pancreatitis, papilledema, parosmia, pericarditis, peripheral neuropathy, pneumonia, pneumonitis, pulmonary infiltrates, pure red cell aplasia, rectal bleeding, renal failure, renal insufficiency, restless leg syndrome, retinal hemorrhages, retinal artery or vein obstruction, retinopathy, rhabdomyolysis, sarcoidosis (including exacerbation), seizures, Stevens-Johnson syndrome, toxic epidermal necrolysis

Use of alfa interferons has been associated with rare cases of autoimmune diseases including vasculitis, systemic lupus erythematosus, thrombocytopenic purpura (idiopathic and thrombotic), and Vogt-Koyanagi-Harada syndrome; altered lipid metabolism (including hypercholesterolemia and hyperlipemia), and pulmonary hypertension

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: Anemia and severe cytopenias have has been observed in patients receiving the interferon/ribavirin combination. Rarely, aplastic anemia has been observed with peginterferon alfa-2b therapy. Use peginterferon alfa-2b with caution in patients with low peripheral blood counts or myelosuppression, including concurrent use of myelosuppressive therapy. Reduce dose with decreased neutrophil, platelet count, or hemoglobin and discontinue therapy if significant decreases in neutrophil (<0.5 x 109/L), platelet counts (<25 x 109/L), or hemoglobin <8.5 g/dL.

• Cerebrovascular events: Cerebrovascular events (ischemic and hemorrhagic) have been observed in patients receiving peginterferon alfa-2b, including patients without risk factors.

• CNS effects: High-dose peginterferon alfa-2b has been associated with significant obtundation and coma, including cases of encephalopathy (usually elderly patients), and rarely seizures. May cause CNS depression (somnolence, fatigue), which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).

• Colitis: Serious cases of ischemic and ulcerative colitis have been observed within 12 weeks of initiation of peginterferon alfa-2b therapy; discontinue therapy in suspected/confirmed colitis; upon discontinuation of therapy, resolution of colitis is usually observed within 1-3 weeks.

• Dehydration: Maintain adequate hydration; hypotension associated with dehydration has been observed with use alfa interferons (including peginterferon alfa-2b); fluid replacement may be required.

• Dental/periodontal disorders: Have been reported with ribavirin and interferon therapy; patients should be instructed to brush teeth twice daily and have regular dental exams.

• Dermatologic reactions: Interferon therapy is associated with immune-mediated reactions including erythema multiforme, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN).

• Hemolytic anemia: Hemolytic anemia is a significant toxicity, usually occurring within 1-4 weeks, and may worsen underlying cardiac disease; use caution and assess cardiac disease before initiation; avoid use in patients with history of significant or unstable cardiac disease. Patients with renal dysfunction and/or those >50 years of age should be carefully assessed for development of anemia. If any deterioration in cardiovascular status occurs, discontinue therapy.

• Hypersensitivity: Rare cases of acute hypersensitivity (eg, anaphylaxis, angioedema, bronchoconstriction) have been observed with alfa-interferon therapy. Discontinue therapy immediately with signs of hypersensitivity and treat appropriately. Transient skin reactions may not warrant treatment interruption in the absence of more severe reactions.

• Hypertriglyceridemia: New onset or aggravation of existing hypertriglyceridemia (sometimes severe) has been observed with use of peginterferon alfa-2b; monitor lipids with therapy.

• Ocular effects: Ophthalmologic disorders (including retinal hemorrhages, cotton wool spots, and retinal artery or vein obstruction) have occurred rarely in patients using peginterferon alfa-2b. Ophthalmic examinations are recommended prior to therapy for all patients and periodically during therapy for patients at risk for retinopathy (eg, diabetes mellitus or hypertension). Patients presenting with ocular symptoms (eg, loss of visual acuity or vision field) at any time during therapy should receive a prompt ophthalmic examination. Consider discontinuation of therapy with new or worsening ophthalmologic disorders.

• Otic effects: Hearing impairment and/or loss have been observed with use of peginterferon alfa-2b.

• Pancreatitis: Has been reported with use; interrupt therapy for signs/symptoms of pancreatitis. Discontinue therapy in suspected/confirmed pancreatitis.

Disease-related concerns:

• Autoimmune disease: [Canadian Boxed Warning]: Alpha interferons cause or aggravate fatal or life-threatening autoimmune disorders. Patients predisposed to developing autoimmune disorders may be at greater risk (use is contraindicated in patients with history of autoimmune disease). Monitor patients closely. Discontinue therapy for persistently severe or worsening symptoms. Symptom resolution generally occurs upon discontinuation of therapy in most cases, but not all cases.

• Cardiovascular disease: Use peginterferon alfa-2b with caution in patients with ischemic or thromboembolic cardiac disease, heart failure, hypertension or arrhythmias; avoid use in patients with severe cardiac disease within previous 6 months; discontinuation of therapy may be indicated with worsening cardiovascular status. Rarely, cardiomyopathy has been reported in patients without prior history of cardiac disease; cardiomyopathy may be reversible following discontinuation.

• Endocrine disorders: Use peginterferon alfa-2b with caution in patients with endocrine disorders; hyper/hypothyroid have been observed (infrequently) with use of peginterferon alfa-2b; changes may or may not reverse with therapy discontinuation; obtain thyroid stimulating hormone (TSH) levels if symptomatic; avoid initiating therapy or discontinue existing therapy with uncontrolled TSH levels; diabetes mellitus and hyperglycemia have been observed with use; monitor glucose; dosage adjustments of antidiabetic therapy may be necessary.

• Epilepsy: Use is contraindicated in patients with epilepsy. Rarely, high-dose peginterferon alfa-2b has been associated with seizures.

• Gout: Use of ribavirin may be associated with increased uric acid levels (due to hemolysis); monitor for signs/symptoms of gout (particularly in predisposed patients).

• Hemoglobinopathies: Avoid use in patients with hemoglobinopathies (eg, sickle-cell anemia, thalassemia).

• Hepatic impairment: Use in decompensated hepatic disease is contraindicated; use with caution in patients with mild-to-moderate hepatic impairment; discontinue treatment with worsening hepatic function or signs/symptoms of hepatic failure.

• Infectious disorders: [Canadian Boxed Warning]: Alpha interferons cause or aggravate fatal or life-threatening infectious disorders. Monitor patients closely. Discontinue therapy for persistently severe or worsening symptoms. Symptom resolution generally occurs upon discontinuation of therapy in most cases, but not all cases. Investigate the etiology of any persistent fever during therapy.

• Ischemic disorders: [Canadian Boxed Warning]: Alpha interferons cause or aggravate fatal or life-threatening ischemic disorders. Monitor patients closely. Discontinue therapy for persistently severe or worsening symptoms. Symptom resolution generally occurs upon discontinuation of therapy in most cases, but not all cases.

• Neuropsychiatric disorders: [Canadian Boxed Warning]: Life-threatening or fatal psychiatric adverse events (psychosis, aggressive behavior, severe depression, suicidal behavior/ideation and suicide) have been reported in patients with and without previous psychiatric symptoms. Additional CNS adverse effects (confusion, mental status changes) have also been reported. Use with extreme caution in patients with a history of pre-existing psychiatric disorders who report a history of severe depression. Use in patients with pre-existing or a history of severe psychiatric disorders is contraindicated. Onset of psychiatric or CNS adverse effects (including clinical depression) warrants careful neuropsychiatric monitoring during and for 6 months following discontinuation of therapy. Discontinue use with worsening or persistent symptoms.

• Psoriasis: Exacerbation of disease has been observed with use of peginterferon alfa-2b. Use only if potential benefit outweighs risk.

• Renal impairment: Evaluate renal function prior to initiating therapy and monitor closely during therapy; use peginterferon alfa-2b with caution in patients with renal impairment; use is contraindicated if CrCl <50 mL/minute; use in moderate renal impairment is not recommended; monitor for signs/symptoms of toxicity (dosage adjustment required if toxicity occurs); discontinue therapy if serum creatinine >2 mg/dL.

• Respiratory disease: Avoid use in patients with chronic obstructive pulmonary disease (COPD); use caution in other pulmonary disease. Pulmonary effects (eg, pneumonitis, pulmonary infiltrates, pulmonary hypertension ), sometimes fatal, have been reported. Symptomatic patients should receive a chest x-ray; if pulmonary abnormalities are present, monitor patient closely. Discontinuation of therapy may be necessary. Concomitant use of the herbal product Shosaikoto has been associated with increased reports of pulmonary symptoms.

• Sarcoidosis: Exacerbation of disease has been observed with use of peginterferon alfa-2b. Use only if potential benefit outweighs risk.

Concurrent drug therapy issues:

• Medications causing lactic acidosis: Use with caution in patient receiving medications which may cause lactic acidosis (eg, nucleoside analogues).

Special populations:

• Debilitated patients: Avoid use in patients with severe debilitating medical conditions.

• Elderly: Use with caution in elderly patients; encephalopathy may be increased in the elderly as well as a higher frequency of anemia in older adults >50 years of age and/or those with renal impairment <50 mL/minute; monitor closely for anemia, particularly in the initial 4 weeks of therapy; evaluate renal function before initiating and during therapy.

• Pregnancy: Use during pregnancy is contraindicated; avoid pregnancy in female patients and female partners of male patients during ribavirin therapy by using two effective forms of contraception; continue contraceptive measures for at least 6 months after completion of therapy. If patient or female partner becomes pregnant during treatment, she should be counseled about potential risks of exposure. Manufacturer recommends reporting pregnancies to (800) 463-5442. Negative pregnancy test is required before initiation and monthly thereafter.

Dosage form specific issues:

• Product variability: Due to differences in dosage, patients should not change brands of interferons.

Special handling:

• Hazardous agent: Ribavirin is a hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 3]).

Other warnings/precautions:

• Appropriate use: Safety and efficacy have not been established in patients who have received organ transplants, have been coinfected with HIV or hepatitis B. Ribavirin monotherapy is not effective and must be used in combination with interferon.

Monitoring Parameters

CBC (pretreatment, at weeks 2 and 4 [or more frequently if indicated], and routinely during therapy) , renal and liver function tests (pretreatment and routinely during therapy), lipids, TSH, and electrolytes; glucose (diabetic or symptomatic patients); uric acid (patients predisposed to gout); ECG (at baseline and during therapy) in patients with pre-existing cardiac disease; pretreatment and monthly pregnancy test for women of childbearing age; dental exams; neuropsychiatric monitoring during and for 6 months after discontinuing therapy (patients developing psychiatric or CNS problems); vision and hearing evaluations

Serum HCV RNA levels (pretreatment, 4-,12-, and 24 weeks after therapy initiation, 24 weeks after completion of therapy)

Pregnancy Considerations

Use during pregnancy is contraindicated. Abortifacient and/or teratogenic effects have been reported in animal studies with interferons and ribavirin. Women of childbearing potential should not be treated unless two reliable forms of contraception are used. In addition, male patients and their female partners must also use two reliable forms of contraception. Pregnancy must be avoided during treatment and for 6 months following therapy.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience flu-like symptoms, nausea, vomiting, diarrhea, abdominal pain, back pain, dry mouth, lack of appetite, weight loss, muscle pain, joint pain, hair thinning, skin irritation, dry skin, insomnia, loss of strength and energy, or injection site irritation. Have patient report immediately to prescriber signs of infection, signs of hemolytic anemia (severe loss of strength and energy, dark urine, or jaundice), signs of bowel problems (black, tarry, or bloody stools; fever; mucus in stools; vomiting; vomiting blood; severe abdominal pain; constipation; or diarrhea), signs pancreatitis (severe abdominal pain, severe back pain, severe nausea, or vomiting), signs of depression (suicidal ideation, anxiety, emotional instability, or illogical thinking), signs of high blood sugar (confusion, feeling sleepy, more thirst, hunger, passing urine more often, flushing, fast breathing, or breath that smells like fruit), signs of low blood sugar (dizziness, headache, fatigue, feeling weak, shaking, a fast heartbeat, confusion, hunger, or sweating), signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), signs of a severe pulmonary disorder (lung or breathing problems like trouble breathing, shortness of breath, or a cough that is new or worse), signs of thyroid problems (change in weight without trying, feeling nervous and excitable, feeling restless, feeling very weak, hair thinning, low mood (depression), neck swelling, not able to focus, not able to handle heat or cold, period (menstrual) changes, shakiness, or sweating), signs of severe cerebrovascular disease (change in strength on one side is greater than the other, trouble speaking or thinking, change in balance, or change in eyesight), vision changes, thoughts of homicide, hallucinations, psychosis, relapse of drug addiction, angina, tachycardia, arrhythmia, shortness of breath, excessive weight gain, swelling of arms or legs, severe dizziness, passing out, difficulty focusing, memory impairment, decreased libido, burning or numbness feeling, hearing impairment, painful urination, or signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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