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Peginterferon Alfa-2a and Ribavirin

Pronunciation

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

Index Terms

  • Ribavirin and Peginterferon Alfa-2a

Pharmacologic Category

  • Antihepaciviral, Nucleoside (Anti-HCV)
  • Interferon

Pharmacology

Peginterferon Alfa-2a: 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

Hepatitis C: Combination therapy for the treatment of chronic hepatitis C (HCV) in patients without cirrhosis and patients with compensated cirrhosis; includes patients coinfected with stable HIV disease

Contraindications

Hypersensitivity to alfa interferons, ribavirin, E. coli-derived products, polyethylene glycol (PEG), or any component of the formulation; decompensated cirrhosis; autoimmune hepatitis or history of autoimmune disease; HCV-HIV coinfection with cirrhosis and baseline Child-Pugh score ≥6 (unless score is induced by drugs known to cause indirect hyperbilirubinemia and patient is without evidence of clinical hepatic decompensation); hemoglobinopathies; history of or pre-existing severe psychiatric disorder; uncontrolled thyroid dysfunction; neonates and infants (due to benzyl alcohol component); males with a pregnant female partner; pregnancy; breast-feeding

Dosing: Adult

Chronic hepatitis C (HCV) monoinfection:

Genotypes 1,4:

<75 kg: Peginterferon alfa-2a (SubQ): 180 mcg once weekly and ribavirin (oral) 1000 mg daily (divided into 2 doses) for 48 weeks

≥75 kg: Peginterferon alfa-2a (SubQ): 180 mcg once weekly and ribavirin (oral) 1200 mg daily (divided into 2 doses) for 48 weeks

Genotypes 2,3: Peginterferon alfa-2a (SubQ): 180 mcg once weekly and ribavirin (oral) 800 mg daily (divided into 2 doses) for 24 weeks

HIV-HCV coinfection: HCV genotypes 1,2,3,4: Peginterferon alfa-2a (SubQ): 180 mcg once weekly and ribavirin (oral) 800 mg daily (divided into 2 doses) for 48 weeks

Treatment duration (Canadian Consensus Guidelines [Meyers, 2012]):

HCV genotype 1:

Treatment-naive:

Without cirrhosis:

Receiving concomitant telaprevir: If undetectable HCV RNA at weeks 4 and 12 discontinue telaprevir after week 12 and continue peginterferon alfa-2a/ribavirin for 12 weeks (total of 24 weeks); if HCV RNA detectable at weeks 4 or 12 discontinue telaprevir at week 12 and continue peginterferon alfa-2a/ribavirin for 36 weeks (total: 48 weeks).

Receiving concomitant boceprevir (initiated after 4 weeks of peginterferon alfa-2a/ribavirin therapy): If undetectable HCV RNA at weeks 8 through 24 continue triple therapy for total of 28 weeks; if HCV RNA detectable at week 8 continue triple therapy through week 28 then discontinue boceprevir and continue peginterferon alfa-2a/ribavirin for 20 weeks (total: 48 weeks).

With cirrhosis (compensated):

Receiving concomitant telaprevir: Discontinue telaprevir after week 12 and continue peginterferon alfa-2a/ribavirin for 36 weeks (total: 48 weeks)

Receiving concomitant boceprevir (initiated after 4 weeks of peginterferon alfa-2a/ribavirin therapy): Peginterferon alfa-2a/ribavirin for 4 weeks then initiate triple therapy for 44 weeks (total: 48 weeks)

Patients with <1 log10 decrease in HCV RNA after 4 weeks of peginterferon alfa-2a/ribavirin: Triple therapy with boceprevir should be continued for 44 weeks (total: 48 weeks)

Previously-treated patients (relapsers, partial responders, null responders):

Without cirrhosis:

Receiving concomitant telaprevir: Relapsers achieving undetectable HCV RNA at weeks 4 and 12, may discontinue telaprevir after week 12 and continue peginterferon alfa-2a/ribavirin for 12 weeks (total 24 weeks). Relapsers with HCV RNA detectable at weeks 4 and/or 12 and previous partial responders or null responders should discontinue telaprevir after week 12 and continue peginterferon alfa-2a/ribavirin for 36 weeks (total: 48 weeks)

Receiving concomitant boceprevir (initiated after 4 weeks of peginterferon alfa-2a/ribavirin therapy): Relapsers and partial responders achieving undetectable HCV RNA at weeks 8 through 24, may discontinue therapy at 36 week. Relapsers with HCV RNA detectable at week 8 and undetectable at week 24 discontinue boceprevir at 36 weeks and continue peginterferon alfa-2a/ribavirin through week 48. Prior null responders should receive triple therapy for 44 weeks (total therapy: 48 weeks)

With cirrhosis (compensated): Peginterferon alfa-2a/ribavirin are recommended for 48 weeks as part of triple therapy with either boceprevir (weeks 5 to 48) or telaprevir (first 12 weeks)

HCV genotypes 2,3:

Treatment-naive: Treatment recommended for 24 weeks; discontinue therapy in patients failing to achieve early virological response (EVR) at 12 weeks. Full treatment course should be used in patients with cofactors that reduce the likelihood of success (eg, advanced fibrosis, black race, metabolic syndrome/insulin resistance, obesity) even if rapid virological response (RVR) is achieved. May consider abbreviated therapy (12 or 16 weeks) in patients without these cofactors who achieve a RVR with weight-based ribavirin dosing. If relapse occurs following abbreviated therapy, consider re-treatment for 24 weeks.

Genotype 3 patients who do not achieve an RVR but have an EVR may be considered for extended treatment (36 to 48 weeks) especially if the patient has cofactors that reduce the likelihood of success (eg, advanced fibrosis, black race, metabolic syndrome/insulin resistance, obesity).

Treatment of relapser patients: May consider re-treatment for 48 weeks in patients with ≥stage 2 fibrosis who have failed a previous 24-week course of therapy

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. Patients with genotype 4 who have low baseline viral loads <800,000 units/mL and mild fibrosis (METAVIR score ≤F2) may be treated for 36 weeks.

Treatment futility Discontinue all treatment if HCV RNA ≥1000 units/mL at weeks 4 or 12 or detectable at week 24 (with concomitant telaprevir) or if HCV RNA ≥100 units/mL at week 12 or detectable at week 24 (with concomitant boceprevir)

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

Peginterferon alfa-2a: SubQ:

CrCl >20 mL/minute: No dosage adjustment necessary. Monitor closely as dose reduction may be warranted with onset of adverse events.

End-stage renal disease requiring hemodialysis: Reduce initial dosage to 135 mcg once weekly

Ribavirin: Oral: Serum creatinine >2 mg/dL (SI: 177 micromole/L) or CrCl <50 mL/minute. Use is not recommended

Dosing: Hepatic Impairment

Avoid use in decompensated hepatic disease (eg, Child-Pugh class B or C). Use is contraindicated in HCV-HIV coinfected patients with cirrhosis and baseline Child-Pugh score ≥6 (unless score is induced by drugs known to cause indirect hyperbilirubinemia and without evidence of clinical hepatic decompensation).

Peginterferon alfa-2a: SubQ: Reduce dose to 90 mcg/once weekly in the presence of progressive ALT increases greater than baseline. Therapy discontinuation may be necessary for persistently marked ALT elevations despite dose reduction and/or with accompanying elevated bilirubin or with evidence of hepatic decompensation.

Dosing: Adjustment for Toxicity

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

Adverse events/toxicity: For moderate-to-severe adverse reactions (clinical and/or laboratory): Reduce peginterferon alfa-2a dose to 90 to 135 mcg once weekly.

Depression:

Mild depression: No dosage adjustment required; monitor closely.

Moderate depression: Decrease peginterferon alfa-2a dose to 90 to 135 mcg once weekly; monitor closely.

Severe depression: Discontinue combination therapy; obtain immediate psychiatric consultation.

Hemoglobin (patients without cardiac disease):

Hemoglobin <10 g/dL: Decrease ribavirin dose to 600 mg daily

Hemoglobin <8.5 g/dL: Discontinue ribavirin; upon resolution of decreased hemoglobin, may reinitiate ribavirin therapy at 600 mg daily with subsequent increase to 800 mg daily as tolerated; higher doses are not recommended.

Hemoglobin (patients with stable cardiac disease):

Hemoglobin decrease >2 g/dL in any 4-week period: Permanently decrease ribavirin dose to 600 mg daily.

Hemoglobin <12 g/dL after ribavirin dose is decreased for 4 weeks: Discontinue ribavirin; upon resolution of decreased hemoglobin, may reinitiate ribavirin therapy at 600 mg daily with subsequent increase to 800 mg daily as tolerated; higher doses are not recommended.

Neutrophils:

Neutrophils <0.75 x 109/L: Decrease peginterferon alfa-2a dose to 135 mcg weekly.

Neutrophils <0.5 x 109/L: Interrupt peginterferon alfa-2a therapy; may reinitiate therapy at 90 mcg weekly when ANC >1 x 109/L.

Platelets:

Platelet count <50 x 109/L: Decrease peginterferon alfa-2a dose to 90 mcg weekly.

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

Administration

See individual agents.

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

Dietary Considerations

Take ribavirin with food.

Storage

Pegasys RBV combination package: Store under refrigeration between 2°C and 8°C (36°F and 46°F); do not freeze. Protect from light. Do not shake. When the package is separated:

Copegus tablets: Store under refrigeration or below 30°C (86°F).

Pegasys prefilled syringes/vials: Store under refrigeration between 2°C and 8°C (36°F and 46°F); do not freeze. Protect from light. Do not shake.

Adverse Reactions

Adverse reactions as reported with use of the combination product. Also see individual agents.

>10%:

Central nervous system: Fatigue (40% to 49%), headache (35% to 48%), insomnia (19% to 32%), rigors (16% to 30%), irritability (15% to 28%), depression (17% to 22%), dizziness (7% to 15%)

Dermatologic: Alopecia (10% to 25%), pruritus (4% to 25%), dermatitis (1% to 16%), xeroderma (4% to 13%)

Endocrine & metabolic: Weight loss (2% to 16%)

Gastrointestinal: Nausea (24% to 29%), anorexia (20% to 27%), diarrhea (14% to 16%)

Hematologic & oncologic: Hemolytic anemia (≤14%), neutropenia (3% to 11%)

Local: Injection site reaction (10% to 28%)

Neuromuscular & skeletal: Myalgia (32% to 42%), weakness (≥1% to 26%), arthralgia (16% to 22%)

Respiratory: Cough (3% to 13%), dyspnea (3% to 13%)

Miscellaneous: Fever (37% to 41%)

1% to 10%:

Cardiovascular: Chest pain (≥1% to ≤5%), flushing (≥1% to ≤5%), hypertension (≥1% to ≤5%), palpitations (≥1% to ≤5%), peripheral edema (≥1% to ≤5%), syncope (≥1% to ≤5%), tachycardia (≥1% to ≤5%)

Central nervous system: Pain (6% to 10%), lack of concentration (2% to 10%), anxiety (8%), mood changes (<1% to 8%), malaise (3% to 6%), emotional disturbance (<1% to 5%), aggressive behavior (≥1% to ≤5%), confusion (≥1% to ≤5%), drowsiness (≥1% to ≤5%), drug abuse (≥1% to ≤5%), hyperesthesia (≥1% to ≤5%), hypoesthesia (≥1% to ≤5%), lethargy (≥1% to ≤5%), migraine (≥1% to ≤5%), myasthenia (≥1% to ≤5%), nightmares (≥1% to ≤5%), paresthesia (≥1% to ≤5%), suicidal ideation (≥1% to ≤5%), vertigo (≥1% to ≤5%), memory impairment (1% to 5%), nervousness (1% to 3%), apathy (HIV-HCV coinfection: ≥1% to ≤3%), emotional lability (HIV-HCV coinfection: ≥1% to ≤3%)

Dermatologic: Skin rash (5% to 9%), diaphoresis (2% to 5%), dermatological reaction (≥1% to ≤5%), eczema (≥1% to ≤5%), night sweats (≥1% to ≤5%), psoriasis (≥1% to ≤5%), skin photosensitivity (≥1% to ≤5%), urticaria (≥1% to ≤5%), cheilitis (HIV-HCV coinfection: ≥1% to ≤3%)

Endocrine & metabolic: Decreased libido (2% to 5%), dehydration (≥1% to ≤5%), hot flash (≥1% to ≤5%), hyperthyroidism (≥1% to ≤5%), increased thirst (≥1% to ≤5%), hypothyroidism (<1% to 4%), lactic acidosis (HIV-HCV coinfection: ≥1% to ≤3%), lipodystrophy (HIV-HCV coinfection: ≥1% to ≤3%)

Gastrointestinal: Abdominal pain (7% to 10%), nausea and vomiting (7% to 8%), xerostomia (5% to 8%), decreased appetite (≤7%), dyspepsia (2% to 6%), constipation (≥1% to ≤5%), dental bleeding (≥1% to ≤5%), dysgeusia (≥1% to ≤5%), dysphagia (≥1% to ≤5%), flatulence (≥1% to ≤5%), glossitis (≥1% to ≤5%), oral candidiasis (≥1% to ≤5%), oral mucosa ulcer (≥1% to ≤5%), sore throat (≥1% to ≤5%), stomatitis (≥1% to ≤5%)

Genitourinary: Impotence (≥1% to ≤5%), urine discoloration (HIV-HCV coinfection: ≥1% to ≤3%)

Hematologic & oncologic: Thrombocytopenia (≥1% to 8%), lymphadenopathy (≥1% to ≤5%)

Infection: Herpes virus infection (≥1% to ≤5%), influenza (HIV-HCV coinfection: ≥1% to ≤3%)

Neuromuscular & skeletal: Back pain (3% to 5%), arthritis (≥1% to ≤5%), muscle cramps (≥1% to ≤5%), musculoskeletal pain (≥1% to ≤5%), neck pain (≥1% to ≤5%), ostealgia (≥1% to ≤5%), tremor (≥1% to ≤5%)

Ophthalmic: Blurred vision (≥1% to ≤5%), eye pain (≥1% to ≤5%), uveitis (≥1% to ≤5%), xerophthalmia (≥1% to ≤5%)

Otic: Otalgia (≥1% to ≤5%), tinnitus (≥1% to ≤5%)

Respiratory: Bronchitis (≥1% to ≤5%), epistaxis (≥1% to ≤5%), flu-like symptoms (≥1% to ≤5%), nasal congestion (≥1% to ≤5%), nasopharyngitis (≥1% to ≤5%), pharyngolaryngeal pain (≥1% to ≤5%), rhinitis (≥1% to ≤5%), sinus congestion (≥1% to ≤5%), upper respiratory tract infection (≥1% to ≤5%), dyspnea on exertion (3% to 4%), pneumonia (HIV-HCV coinfection: ≥1% to ≤3%)

<1% (Limited to important or life-threatening; reported with other interferon preparations and/or ribavirin): Abdominal distention, acute psychosis, anaphylaxis, angioedema, aplastic anemia (rare), atrial fibrillation, bacterial infection (including sepsis), Bell's palsy, brain disease, bronchoconstriction, cardiac arrhythmia, cardiomyopathy, cerebral hemorrhage, cerebral ischemia, cerebrovascular hemorrhage, cholangitis, coma, congestive heart failure, corneal ulcer, deafness (rare), decreased platelet count, decreased white blood cell count, dental disorders, diabetes mellitus, endocarditis, erythema multiforme, fungal infection, gastrointestinal hemorrhage, gout, hallucination, hepatic insufficiency, hepatitis, hepatotoxicity, homicidal ideation, hyperglycemia, hypersensitivity reaction, hypertriglyceridemia, hypoglycemia, increased serum ALT, increased uric acid, interstitial nephritis, interstitial pneumonitis, ischemic colitis, ischemic heart disease, leukopenia, liver steatosis, macular edema, malignant neoplasm (hepatic), myocardial infarction, myositis, nephrotic syndrome, obtundation, optic neuritis, otitis externa, pancreatitis, pancytopenia, panic attack, papilledema, peptic ulcer, pericarditis, periodontal disease, peripheral neuropathy, pneumonitis, psychiatric signs and symptoms, pulmonary embolism, pulmonary infiltrates, pure red cell aplasia, renal failure, renal insufficiency, retinal blood vessel occlusion, retinal cotton-wool spot, retinal detachment, retinal hemorrhage, rhabdomyolysis, sarcoidosis (including exacerbation), seizure, skin infection, Stevens-Johnson syndrome, suicidal tendencies, thrombotic thrombocytopenic purpura, thyroid dysfunction, thyroiditis, tissue necrosis at injection site, toxic epidermal necrolysis, ulcerative colitis, viral infection

Use of alfa interferons has been associated with rare cases of autoimmune disease, including immune thrombocytopenia (ITP), thyroiditis, rheumatoid arthritis, systemic lupus erythematosus, vasculitis, and Vogt-Koyanagi-Harada syndrome

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: May cause bone marrow suppression, and rarely pancytopenia. Monitor blood counts closely. Use with caution if baseline ANC <1.5 x 109/L, platelets <90 x 109/L, or hemoglobin <10g/dL. Temporarily suspend or discontinue therapy for ANC <0.5 x 109/L or platelets <25 x 109/L. Dosage reduction required if ANC <0.75 x 109/L or platelets <50 x 109/L. Hemolytic anemia is a significant toxicity, usually occurring within 1-2 weeks. Suspend or discontinue ribavirin therapy for any deterioration in hemoglobin levels. Anemia may worsen underlying cardiac disease. Assess cardiac disease before initiation; avoid use of ribavirin in patients with history of significant or unstable cardiac disease. If any deterioration in cardiovascular status occurs, suspend or discontinue ribavirin therapy. Patients with renal dysfunction should be carefully assessed for development of anemia. Use caution with concomitant use of other myelosuppressive agents.

• CNS effects: 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/hemorrhagic colitis (some fatal) have been observed within 12 weeks of initiating alfa interferon therapy; ulcerative colitis has been reported with use as well; discontinue therapy in suspected/confirmed colitis; upon discontinuation of therapy, resolution of colitis is usually observed within 1 to 3 weeks.

• Dehydration: Maintain adequate hydration; hypotension associated with dehydration has been observed with use alfa interferons.

• Flu-like symptoms: Interferon therapy is commonly associated with flu-like symptoms, including fever; however, rule out other causes/infection with persistent fever.

• Hypersensitivity: Acute hypersensitivity (eg, anaphylaxis, angioedema, bronchoconstriction, urticaria) has been rarely observed with alfa-interferon therapy. Stevens-Johnson syndrome (SJS), erythema multiforme and toxic epidermal necrolysis (TEN) have been reported very rarely. Discontinue therapy immediately with signs of hypersensitivity and treat appropriately. Presence of transient rashes may not warrant treatment interruption in the absence of more severe reactions.

• Hypertriglyceridemia: Elevated triglyceride levels have been associated with alfa interferon therapy; monitor lipids with therapy.

• Ocular effects: May aggravate or induce vision loss/reduction, macular edema, and optic neuritis. Retinal detachment or hemorrhages, cotton wool spots, and retinal artery or vein obstruction have occurred rarely in patients using peginterferon alfa-2a. Prior to start of therapy, visual exams are recommended for all patients and periodically during therapy for patients with pre-existing ophthalmologic disorders (eg, diabetic or hypertensive retinopathy). Prompt ophthalmic evaluation is necessary if patient experiences loss of visual acuity or visual field. Discontinue therapy with new or worsening ophthalmologic disorders.

• Otic effects: Very rare cases of deafness have been reported with use.

• Pancreatitis: Pancreatitis has been reported (including fatalities). Suspend therapy for symptoms/signs suggestive of pancreatitis. Discontinue therapy with confirmed pancreatitis.

Disease-related concerns:

• Autoimmune disease: [Canadian Boxed Warning]: Alfa interferons (including peginterferon alfa-2a) may aggravate or cause life-threatening autoimmune disorders. Monitor patients closely and discontinue use for persistently severe or worsening symptoms. Resolution occurs in many but not all cases after discontinuation. Use is contraindicated in patients with a history of autoimmune disease; exacerbation of myositis, thyroiditis, immune thrombocytopenia (ITP), rheumatoid arthritis, interstitial nephritis, systemic lupus erythematosus, and psoriasis has been reported with interferon therapy; consider therapy discontinuation with appearance of psoriatic lesions and sarcoidosis.

• Cardiovascular disease: Use peginterferon alfa-2a with caution in patients with cardiac disease; MI, angina, arrhythmias, heart failure, and hypertension have been associated with interferons (including peginterferon). ECG prior to initiation and during therapy is recommended. Avoid use of ribavirin in patients with unstable or severe cardiac disease within previous 6 months; anemia associated with ribavirin may worsen underlying cardiac disease. Suspend or discontinue use with worsening cardiovascular status.

• Dental disorders: Dental and periodontal disorders have been reported; xerostomia associated with therapy may also lead to detrimental effects on teeth (including loss) and oral mucous membranes. Advise patients to follow good oral hygiene (eg, brush teeth twice daily) and have regular dental exams.

• Endocrine disorders: Use with caution in patients with endocrine disorders (eg, thyroid, diabetes); hyper-/hypothyroid, diabetes mellitus and/or loss of glucose control have been observed with use of peginterferon alfa-2a. Avoid initiating therapy or discontinue existing therapy in patients whose endocrine disorder is uncontrolled. Monitor TSH and glucose; dosage adjustments of antidiabetic therapy may be necessary.

• Hepatic impairment: Use in decompensated hepatic disease or in (HIV/HCV) coinfection with cirrhosis and baseline Child-Pugh score ≥6 is contraindicated (unless score is induced by drugs known to cause indirect hyperbilirubinemia and without evidence of clinical hepatic decompensation). Use with caution in HIV/HCV coinfected patients or with mild to moderate hepatic impairment; monitor closely for hepatic decompensation. Discontinue treatment immediately with worsening hepatic function or signs/symptoms of hepatic failure. Elevated ALT may occur during therapy, including patients with a virological response; discontinue for progressive elevations in ALT despite dose reduction or if accompanied by increased bilirubin.

• Hepatitis B: Safety and efficacy have not been established in patients with hepatitis B virus infection.

• Infectious disorders: [Canadian Boxed Warning]: Alfa interferons (including peginterferon alfa-2a) may aggravate or cause fatal or life-threatening infectious disorders. Monitor patients closely and discontinue use for persistently severe or worsening symptoms. Resolution occurs in many but not all cases after discontinuation. Investigate the etiology of any persistent fever during therapy.

• Ischemic disorders: [Canadian Boxed Warning]: Alfa interferons (including peginterferon alfa-2a) may aggravate or cause life-threatening ischemic disorders. Monitor patients closely and discontinue use for persistently severe or worsening symptoms. Resolution occurs in many but not all cases after discontinuation. Cerebrovascular events (ischemic and hemorrhagic) have been observed in patients receiving alfa interferon therapy, including younger patients (ie, <45 years of age) and those without risk factors.

• Neuropsychiatric disorders: [Canadian Boxed Warning]: Alfa interferons (including peginterferon alfa-2a) may aggravate or cause fatal or life-threatening neuropsychiatric disorders. Monitor patients closely and discontinue use for persistently severe or worsening symptoms. Resolution occurs in many but not all cases after discontinuation. Use in patients with pre-existing or history of severe psychiatric disorders is contraindicated. Use with extreme caution in patients with preexisting depression; monitor all patients for evidence of depressive symptoms. Severe psychiatric adverse events (confusion, depression, suicidal behavior/ideation, aggression, mental status changes) may occur in patients with and without previous psychiatric symptoms; if severe symptoms persist, psychiatric consult should be obtained. Patients receiving alfa interferons and with a history of substance use/abuse are at increased risk of developing psychiatric disorders or experiencing exacerbation of an existing disorder; initiate therapy carefully and monitor closely during therapy and after therapy discontinuation. Early intervention for re-emergence of development of neuropsychiatric disorders and substance use is recommended.

• Renal impairment: Evaluate renal function prior to initiating therapy; use with caution in patients with renal impairment and only if considered essential. Avoid use if serum creatinine >2 mg/dL (SI: 177 micromole/L) or CrCl <50 mL/minute; monitor for signs/symptoms of toxicity (therapy discontinuation may be required if toxicity occurs).

• Respiratory disease: Avoid use in patients with chronic obstructive pulmonary disease (COPD); use caution in other pulmonary disease; dyspnea, pneumonia, pneumonitis, and pulmonary infiltrates have been reported with use. Obtain chest x-ray with onset of fever, dyspnea, cough, or other symptoms; discontinue treatment with persistent/unexplained pulmonary function impairment or pulmonary infiltrates.

Special populations:

• Elderly: Use with caution in elderly patients; evaluate renal function before initiating therapy.

• Organ transplant recipients: Safety and efficacy have not been established in organ transplant patients. Liver and renal graft rejection has been reported in patients receiving interferons with or without concomitant ribavirin.

• Pediatric: In combination therapy with alfa interferons, ribavirin may cause a reduction in growth velocity in pediatric patients for the length of treatment. Delay in weight and height increases have been noted in children treated with combination therapy. In clinical studies, decreases were noted in weight and height for age z-scores and normative growth curve percentiles. Following treatment, rebound growth and weight gain occurred in most patients; however, a small percentage did not. Long-term data indicate that combination therapy may inhibit growth resulting in reduced adult height. Use in patients <18 years is not recommended.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

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 failed other alfa interferon therapy. Ribavirin monotherapy is not effective and must be used in combination therapy.

Monitoring Parameters

Obtain pretreatment CBC, liver function tests, renal function, lipids, TSH, and electrolytes, then monitor CBC routinely throughout therapy at 2- and 4 weeks (more frequently if indicated) and other tests every 4 weeks (more frequently if indicated). Pretreatment and monthly pregnancy test (up to 6 months following therapy discontinuation) for women of childbearing age. Baseline chest x-ray, ECG, weight; patients with pre-existing cardiac abnormalities should have an ECG before and during treatment; glucose (diabetic or symptomatic patients), I & O; dental exams; neuropsychiatric monitoring; vision (pretreatment and periodic during therapy).

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

In addition, the following baseline values were used as entrance criteria in clinical trials:

Platelet count ≥90 x 109/L (as low as 75 x 109/L in patients with cirrhosis or transition to cirrhosis)

ANC ≥1.5 x 109/L

Serum creatinine <1.5 times ULN

TSH and T4 within normal limits or adequately controlled

CD4+ cell count ≥200 cells/microL or CD4+ cell count ≥100 cells/microL, but <200 cells/microL and HIV-1 RNA <5000 copies/mL in CHC-HIV coinfected patients

Pregnancy Considerations

Use during pregnancy is contraindicated. Abortifacient and teratogenic effects have been reported in women receiving interferons. Negative pregnancy test is required before initiation and monthly thereafter. Avoid pregnancy in female patients and female partners of male patients during therapy by using two effective forms of contraception; continue contraceptive measures for at least 6 months after completion of therapy. If female patients or female partners of male patients become pregnant during treatment, she should be counseled about potential risks of exposure.

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 of 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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