Peginterferon Alfa-2b and Ribavirin

• Ribavirin and Peginterferon Alfa-2b

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.

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

Guideline recommendations: Peginterferon and ribavirin combination therapy (without the addition of another HCV antiviral agent) is not recommended in HCV treatment guidelines (treatment-naive or treatment-experienced). Current AASLD/IDSA recommendations do not specify a particular peginterferon (eg, 2a or 2b); however, guideline recommendations are based on clinical trials that used peginterferon alfa-2a (AASLD/IDSA 2015). Recommended regimen depends on HCV genotype and whether patient is treatment-naive or treatment-experienced. Hepatitis C treatment guidelines are constantly changing with the advent of new treatment therapies and information; consult current clinical practice guidelines for the most recent treatment recommendations.

Mild or moderate impairment (Child-Pugh class A or B): There are no dosage adjustments provided in the 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.

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.

>10%:

Central nervous system: Fatigue (32% to 65%), headache (39% to 62%), rigors (43% to 48%), insomnia (21% to 40%), chills (22% to 39%), irritability (17% to 35%), depression (12% to 34%), dizziness (10% to 21%), lack of concentration (5% to 19%), anxiety (8% to 16%), pain (4% to 13%), right upper quadrant pain (7% to 12%), emotional lability (1% to 11%)

Dermatologic: Alopecia (17% to 45%), pruritus (13% to 29%), xeroderma (8% to 26%), skin rash (9% to 24%), diaphoresis (7% to 11%)

Endocrine & metabolic: Weight loss (7% to 30%)

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

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

Infection: Viral infection (10% to 15%)

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

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

Respiratory: Dyspnea (10% to 27%), flu-like symptoms (2% to 27%), cough (14% to 19%), pharyngitis (11% to 16%)

Miscellaneous: Fever (32% to 46%)

1% to 10%:

Cardiovascular: Tachycardia (≤10%), chest pain (2% to 10%), hypertension (≤5%), hypotension (≤5%), palpitations (≤5%), flushing (1% to 5%), syncope (1% to 5%), peripheral edema (≤1%)

Central nervous system: Nervousness (≤10%), paresthesia (2% to 10%), agitation (1% to 10%), confusion (≤5%), drowsiness (≤5%), hyperesthesia (≤5%), hypoesthesia (≤5%), apathy (2% to 5%), hypertonia (2% to 5%), malaise (2% to 5%), vertigo (2% to 5%), aggressive behavior (1% to 5%), migraine (1% to 5%), tremor (1% to 5%), memory impairment (2% to 4%), lethargy (≤3%), amnesia (2% to 3%), outbursts of anger (2%), disturbed sleep (≤2%), crying (1% to 2%), restlessness (1% to 2%), intolerance to temperature (≤1%), suicidal ideation (≤1%), psychosis (≤1%; including hallucinations)

Dermatologic: Erythematous maculopapular rash (≤5%), erythema (2% to 5%), hair disease (abnormal hair texture: 2% to 5%), skin photosensitivity (2% to 5%), eczema (1% to 5%), rash at injection site (1% to 4%), hyperhidrosis (2% to 3%), injection site pruritus (1% to 3%), dermatitis (2%), night sweats (1% to 2%), cellulitis (≤1%), cheilitis (≤1%), psoriasis (≤1%), desquamation (≤1%)

Endocrine & metabolic: Hyperthyroidism (≤10%), hypothyroidism (≤10%), hypermenorrhea (5% to 10%), menstrual disease (5% to 10%), amenorrhea (2% to 5%), increased thirst (2% to 5%), decreased libido (1% to 5%), hyperuricemia (1% to 2%), increased thyroid stimulating hormone level (1%), dehydration (≤1%), increased amylase (≤1%)

Gastrointestinal: Dyspepsia (4% to 10%), constipation (3% to 10%), dysgeusia (3% to 10%), gingival hemorrhage (≤5%), flatulence (2% to 5%), glossitis (2% to 5%), loose stools (2% to 5%), stomatitis (1% to 5%; including aphthous and ulcerative), gastroesophageal reflux disease (1% to 2%), oral mucosa ulcer (1% to 2%), abdominal distention (1%), burning sensation of mouth (1%), gastritis (1%), stomach discomfort (1%)

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

Hematologic & oncologic: Leukopenia (2% to 10%; grades 3/4: ≤7%), thrombocytopenia (≤7%), lymphadenopathy (≤5%), lymphocytopenia (1%)

Hepatic: Hyperbilirubinemia (1% to 2%)

Infection: Fungal infection (2% to 5%), herpes simplex infection (2% to 5%)

Local: Pain at injection site (1% to 5%)

Neuromuscular & skeletal: Back pain (5% to 6%), muscle spasm (2% to 5%), limb pain (3% to 4%), ostealgia (1%), neck pain (≤1%)

Ophthalmic: Blurred vision (2% to 10%), eye pain (≤5%), conjunctivitis (2% to 5%), lacrimal dysfunction (2% to 5%), xerophthalmia (2% to 3%), photophobia (≤1%), retinal exudates (≤1%), visual disturbance (≤1%)

Otic: Auditory impairment (2% to 5%), otitis media (2% to 5%), tinnitus (1% to 5%)

Renal: Polyuria (1%)

Respiratory: Rhinitis (8% to 10%), nonproductive cough (5% to 10%), rhinorrhea (≤5%), dyspnea on exertion (4% to 5%), respiratory tract disease (2% to 5%), bronchitis (1% to 5%), nasal congestion (1% to 5%), sinusitis (1% to 5%), pharyngolaryngeal pain (2% to 4%), epistaxis (2%), upper respiratory tract infection (≤2%), post nasal drip (1%), dry nose (≤1%)