AHFS Class:

• Interferons 8:18.20

Generic Name(s):

• Interferon Alfa-2a

• Interferon Alfa-2b

Interferon alfa is a family of proteins and glycoproteins with antiviral, antineoplastic, and immunomodulating activities.2 Interferon alfa is available as interferon alfa-2b2 and interferon alfa-n3.3 Interferon alfa also is available covalently bound to monomethoxy polyethylene glycol (PEG) (i.e., peginterferon alfa).20,48,49 For information on peginterferon alfa, see Peginterferon Alfa 8:18.20 and Peginterferon Alfa 10:00.

Interferon alfa is used in the treatment of certain viral infections, including hepatitis B virus (HBV),2,97 hepatitis C virus (HCV),2 hepatitis D virus (HDV)†,6,97,99,101 and human papillomavirus (HPV) infections.2,3

For information on use of interferon alfa in the treatment of various neoplastic diseases, see Interferon Alfa 10:00.

Chronic Hepatitis B Virus Infection

Interferon alfa-2b (Intron^® A) is used for treatment of chronic HBV infection in adults and children 1 year of age and older with compensated liver disease.2,14,16,25,27,97

The goal of antiviral therapy in patients with chronic HBV infection is to achieve sustained suppression of HBV replication and remission of liver disease.97 The long-term goal of therapy is to prevent cirrhosis, hepatic failure, and hepatocellular carcinoma.97,110 Currently available therapies for chronic HBV infection (e.g., interferon alfa, peginterferon alfa, adefovir, entecavir, lamivudine, telbivudine, tenofovir) do not eradicate HBV and may have only limited long-term efficacy.97 Decisions on the appropriate time to initiate therapy and which drug to use should take into consideration the patient's age, severity of liver disease, likelihood of response, safety and efficacy of the drug, potential for selection of resistant HBV strains, potential for adverse reactions, costs, patient's pregnancy potential, and patient and provider preferences.97

The American Association for the Study of Liver Diseases (AASLD) states that, unless contraindicated or ineffective, the drugs of choice for initial treatment of chronic HBV infection in patients with compensated liver disease are peginterferon alfa, entecavir, or tenofovir.97 Although efficacy of nonconjugated interferon alfa and peginterferon alfa are considered similar for treatment of chronic HBV infection, the dosing schedule for peginterferon alfa may be more convenient and is generally preferred instead of interferon alfa.97

The AASLD states that treatment of HBV infection is indicated if the risk of liver-related morbidity and mortality in the near future (5-10 years) and the likelihood of achieving sustained HBV suppression during continued treatment are high.97 Treatment also is indicated if the risk of liver-related morbidity and mortality in the foreseeable future (10-20 years) and the likelihood of achieving sustained HBV suppression after a defined course of therapy are high.97 These experts state that treatment is not indicated if both the risk of liver-related morbidity or mortality in the next 20 years and the likelihood of achieving sustained HBV suppression after a defined course of treatment are low.97

Clinical Experience

HBeAg-positive and HBeAg-negative Adults

In several randomized, controlled trials in patients with hepatitis B e antigen (HBeAg)-negative chronic HBV infection, the end-of-treatment response after 6-12 months of nonconjugated interferon alfa therapy ranged from 38-90%, but approximately 50% of responders relapsed in the months or years following discontinuance of therapy.97 The sustained response rate in HBeAg-negative patients is only 15-30%;97 extending the duration of interferon alfa therapy to 24 months may increase the sustained response rate in such patients.97 In patients with HBeAg-positive chronic HBV infection, high pretreatment ALT concentrations (more than twice the upper limit of normal) and lower levels of serum HBV DNA are the most important predictors of response to nonconjugated interferon alfa.97

Pediatric Patients

Efficacy of nonconjugated interferon alfa in children with HBV infection is similar to that reported in adults; however, most children (especially those who acquired HBV perinatally) have normal ALT concentrations and interferon alfa therapy clears HBeAg in less than 10% of these children.97 In randomized controlled clinical studies, 23-26% of children who received interferon alfa therapy cleared serum HBV DNA and HBeAg compared with 11% of untreated children.12,27,105 In addition, up to 10% of those receiving interferon alfa cleared HBsAg compared with up to 1% of those who were untreated.27 In a long-term follow-up study conducted in Italy, most children were found to have a durable loss of HBeAg and improvement in serum ALT concentrations.12 However, spontaneous loss of HBeAg also occurred naturally in untreated children and, after 5 years, there was no substantial difference in loss of HBeAg or HBsAg between children treated with interferon alfa and those who were untreated.12 Attempts to improve response to interferon alfa (e.g., increasing the dose or duration of therapy, repeating treatment regimens, pretreatment with a short course of prednisone) have been ineffective.12 Pretreatment factors that correlate with a higher likelihood of response in children are similar to those reported in adults and include high baseline serum ALT concentrations, low serum HBV DNA levels, and female gender.12

HIV-infected Individuals

Interferon alfa has been less effective for treatment of chronic HBV infection in HIV-infected patients than in patients not infected with HIV.12,97,109,106 In limited studies in adults with chronic HBV infection who received interferon alfa, HBeAg seroconversion occurred in less than 10% of those who had HIV coinfection, whereas about 31% of those not infected with HIV responded.12,109 Patients coinfected with HBV and HIV who have relatively high CD4⁺ counts are the most likely to respond to interferon alfa therapy.97,109

HIV-infected patients coinfected with HBV often have higher HBV viral loads and are more likely to have detectable HBeAg, lower rates of HBeAg seroconversion, and an increased risk for and more rapid progression to cirrhosis, end-stage liver disease, and/or hepatocellular carcinoma compared with individuals not infected with HIV.97,190 Decisions to initiate HBV treatment in patients coinfected with HIV and HBV and the most appropriate drugs for HBV treatment in such patients depend on various factors, including the possible effects on replication of both HIV and HBV and whether the patient is currently receiving antiretroviral therapy.97,190 Specialized references should be consulted for specific information regarding the evaluation and management of chronic HBV infection in HIV-infected patients.97,190

Chronic Hepatitis C Virus Infection

Interferon alfa-2b (Intron^® A) has been used alone or in conjunction with oral ribavirin for treatment of chronic HCV infection in adults with compensated liver disease.2

Safety and efficacy of interferon alfa-2b (Intron^® A) have been established for use alone or in conjunction with oral ribavirin for treatment of chronic HCV infection in adults and children 3 years of age or older with compensated liver disease who have not previously received interferon alfa therapy (treatment-naive) and for treatment of chronic HCV infection in adults with compensated liver disease who relapsed following prior interferon alfa therapy.2 However, use of nonconjugated interferon alfa alone or in conjunction with oral ribavirin in patients with chronic HCV infection is associated with lower response rates than peginterferon alfa in conjunction with oral ribavirin.36,37,38,39,349

Peginterferon alfa (not interferon alfa) is recommended when an interferon is used for treatment of chronic HCV infection.119 For information on use of peginterferon alfa for treatment of chronic HCV infection, see Uses: Chronic Hepatitis C Virus Infection, in Peginterferon Alfa 8:18.20..

Because treatment of chronic HCV is complex and rapidly evolving, it is recommended that treatment be directed by clinicians who are familiar with the disease and that a specialist be consulted to obtain the most up-to-date information.119 Information from the American Association for the Study of Liver Diseases (AASLD), Infectious Diseases Society of America (IDSA), and International Antiviral Society-USA (IAS-USA) regarding diagnosis and management of HCV infection, including recommendations for initial treatment, is available at [Web].119

Clinical Experience

In randomized clinical studies in patients receiving nonconjugated interferon alfa monotherapy, the SVR rate was approximately 6-20%.36,37 Higher response rates (31-46%) were reported when nonconjugated interferon alfa was used in conjunction with oral ribavirin in adults and children with chronic HCV infection.35,36,37,111,349 The response rate depends on the patient's HCV genotype.35,36,37,38 Following 48 weeks of concomitant nonconjugated interferon alfa and oral ribavirin therapy, SVR was reported in approximately 30% of patients with HCV genotype 1 infection (the most prevalent genotype of HCV in the US) and approximately 70% of those with genotype 2 or 3 infections.35,36,37 In a study in children receiving interferon alfa-2b and oral ribavirin, the response rate was 84% in those with HCV genotype 2/3 and 36% in those with HCV genotype 1.111 SVR may be more likely to occur in HCV patients with genotype 1 infections who receive 48 weeks, rather than 24 weeks, of concomitant therapy.349

Chronic Hepatitis D Virus Infection

Interferon alfa (alfa-2a [not commercially available in the US], alfa-2b) has been used with some limited success for treatment of chronicHDV infection† in adults and children coinfected with HBV.6,97,99,100,101,102,130,140,141 Although a 1-year regimen of interferon alfa may suppress viral activity in some patients, sustained response is not obtained and relapse generally occurs after the drug is discontinued.6,101,101,140,141

HDV infection only occurs in individuals infected with HBV since HDV depends on HBV for production of envelope proteins.97 HDV infection can be acquired as a coinfection with HBV, resulting in a more severe acute hepatitis with a higher mortality rate than acute HBV infection alone.97,140 HDV infection also can occur as a superinfection in HBV carriers and manifests as severe acute hepatitis in previously asymptomatic HBV carriers or as an exacerbation of underlying chronic HBV infection.97,140 HDV superinfection in HBV carriers almost always results in chronic infection with both viruses and is associated with a high risk of cirrhosis, hepatic decompensation, and hepatocellular carcinoma.97

Clinical Experience

In a randomized, placebo-controlled study in adults, 50% of patients with chronic HDV infection who received nonconjugated interferon alfa-2a (no longer commercially available in the US) in a dosage of 9 million units 3 times weekly for 48 weeks had an initial virologic response to therapy, but this response was sustained in only 21% of patients 6 months following discontinuance of the drug.6 Effects of the drug appear to be dose related since lower interferon alfa dosage (3-5 million units 3 times weekly) in adults generally has been no more effective than placebo.6,97,99,100,102 Data from long-term follow-up (2-14 years) of a limited number of adults who received high-dose interferon alfa-2a indicate that some patients had sustained biochemical responses, decreased HDV replication leading to clearance of HDV RNA, and improvements in liver histology with respect to activity grade and fibrosis stage.102

In a study in children with chronic HDV infection, interferon alfa-2b therapy given for 12 or 24 months resulted in a complete biochemical response (normalization of serum ALT concentrations) in 39 or 54%, respectively, and a virologic response in some patients; however, the benefits were transient and the longer treatment regimen did not appear to provide any greater therapeutic benefit in terms of biochemical and virologic responses.101

Human Papillomavirus Infections

External Genital and Perianal Warts

Interferon alfa-2b (Intron^® A) and interferon alfa-n3 (Alferon^® N) are used intralesionally in adults for treatment of external genital and perianal exophytic warts (condylomata acuminata) caused by HPV.2,3,17 Although interferon alfa has been administered systemically (IM or subcutaneously at a distant site) in the past for treatment of genital and perianal HPV warts, results of controlled studies indicate that systemic interferon alfa generally is no more effective than placebo for treatment of these HPV infections.9,19

The CDC states that intralesional interferon alfa is considered an alternative option for treatment of external genital warts because it is associated with a higher frequency of adverse effects, including rare severe systemic adverse effects, and/or has less efficacy data compared with other options.17 No currently available option for treatment of external genital and perianal warts has been shown to eradicate HPV infectivity.17

For further information on treatment of external genital and perianal HPV warts, including CDC guidelines, see Uses: External Genital and Perianal Warts, in Podofilox 84:92.

Recurrent Respiratory Papillomatosis

Interferon alfa (alfa-n3, alfa-n1 [no longer commercially available in the US]) has been used as an adjunct to surgery in the treatment of recurrent respiratory papillomatosis† (recurrent laryngeal papillomas, juvenile laryngeal papillomatosis).29,31,32,46

West Nile Virus Infection

Interferon alfa (alfa-2b, alfa-n3) has been investigated for treatment of serious West Nile virus (WNV) infection†.92,93,94,196,201 Although innate interferons appear to play a role in host responses against WNV and initial in vitro studies indicated that interferon alfa had some activity against WNV,68,70,194,197,201 subsequent in vitro and animal studies suggested that interferon alfa treatment is unlikely to inhibit WNV replication following establishment of an infection.194,195,200,201

WNV is a mosquito-borne flavivirus and a human, equine, and avian neuropathogen.68,69,73,199,201 WNV is classified in the same virus antigen complex as Japanese encephalitis, St. Louis encephalitis, Murray Valley encephalitis, and Kunjin virus.68,73,201 Although WNV infection usually is transmitted to humans by the bite of infected mosquitoes,68,69,73,199,201 WNV also has been transmitted in transplanted organs (e.g., heart, liver, lung, kidney) and blood products (e.g., whole blood, packed red blood cells, fresh frozen plasma)69,73,81,85,86,87,108,201 and transferred from mother to child during pregnancy or through breast milk.73,80,201

Although WNV infections were first identified in North America in 1999, WNV is now been reported throughout the US and has become the leading cause of domestically acquired arbovirus (i.e., arthropod-borne virus) disease in the US.68,69,73,199,201 Most WNV infections are asymptomatic or involve a nonspecific febrile illness (West Nile fever); approximately 1 in 150 infections results in severe neurologic disease (meningitis, encephalitis, acute flaccid paralysis).68,69,73,74,75,76,199,201 Individuals 50 years of age or older (especially those 70 years of age or older) and immunocompromised individuals are most likely to develop severe WNV neuroinvasive disease.68,69,73,74,75,76,199,201

Despite initial case reports suggesting that interferon alfa provided some clinical benefits in a few patients with WNV neuroinvasive disease,92,93,94,196,201 efficacy has not been proven in controlled clinical trials.68,201 To date, no specific drug treatment has been identified that has proven efficacy in patients with WNV infection.68,73,198,201 Treatment of serious WNV infection is mainly supportive and usually involves hospitalization, IV fluids, respiratory support, and prevention of secondary infections.68,73,198 Prevention involves personal protective measures to decrease the possibility of mosquito bites (e.g., using appropriate insect repellents and wearing long-sleeved shirts and long pants when outdoors) and community mosquito abatement programs.68,73,199,201 Several vaccines to prevent WNV are being investigated.68,69,73,201

Reconstitution and Administration

For treatment of chronic hepatitis B virus (HBV) infection and treatment of chronic hepatitis C virus (HCV) infection, interferon alfa-2b (Intron^® A) is administered by IM or subcutaneous injection.2

For treatment of external genital and perianal warts (condylomata acuminata) caused by human papillomavirus (HPV), interferon alfa-2b (Intron^® A)2 and interferon alfa-n3 (Alferon^® N)3 are administered by intralesional injection.

Interferon alfa-2b may be self-administered if the clinician determines that the patient and/or their caregiver are competent to reconstitute and safely administered the drug after appropriate training and with medical follow-up as necessary.2 Patients and/or their caregivers who administer interferon alfa in a home setting should be cautioned against reuse of syringes and needles, supplied with a puncture-resistant container for the safe disposal of such equipment after use, and instructed on the proper disposal of full disposal containers.2

Interferon alfa-2b is available in various strengths in single-dose vials containing a powder for injection that requires reconstitution prior to injection and in multiple-dose vials containing solution for injection.2 Not all dosage forms and strengths are appropriate for all indications.2

Interferon alfa solutions should be inspected visually for discoloration and particulate matter prior to administration whenever solution and container permit.2,3

Patients should be well hydrated during interferon alfa therapy, especially during the initial stages of treatment.2

Some adverse effects associated with interferon alfa therapy (e.g., flu-like syndrome) may be prevented or ameliorated by administering the drug in the evening or at bedtime.2 In addition, acetaminophen or other nonopiate analgesics may be administered at the time of interferon alfa injection to reduce the incidence of adverse effects.2

IM Injection

Interferon Alfa-2b (Intron® A)

For IM injection for treatment of chronic HBV infection in adults, a single-dose vial of interferon alfa-2b powder for injection labeled as containing 10 million units should be reconstituted with the sterile water for injection diluent provided by the manufacturer according to the manufacturer's directions.2 The single-dose vials do not contain a preservative and should be discarded after reconstitution and withdrawal of a single dose.2 Alternatively, a multiple-dose vial of interferon alfa-2b solution for injection containing 10 million units/mL may be used.2

For IM injection for treatment of chronic HCV infection, a multiple-dose vial of interferon alfa-2b solution for injection containing 6 million units/mL should be used.2

Subcutaneous Injection

Subcutaneous injections should be made into the anterolateral thigh, upper arm, or abdomen (avoiding the navel).115 Subcutaneous injections should not be made into an area where the skin is irritated, red, bruised, infected, or has scars, stretch marks, or lumps.115

Interferon Alfa-2b (Intron® A)

For subcutaneous administration, a single-dose vial containing interferon alfa-2b powder for injection should be reconstituted with the sterile water for injection diluent provided by the manufacturer according to the manufacturer's directions.2 The single-dose vials do not contain a preservative and should be discarded after reconstitution and withdrawal of a single dose.2

For subcutaneous injection for treatment of chronic HBV infection in adults or pediatric patients, a single-dose vial of interferon alfa-2b powder for injection labeled as containing 10 million units or a multiple-dose vial of solution for injection containing 10 million units/mL may be used.2

For subcutaneous injection for treatment of chronic HCV infection in adults, a multiple-dose vial of solution for injection containing 6 million units/mL of interferon alfa-2b may be used.2

Intralesional Injection

For intralesional injection of interferon alfa-2b (Intron^® A) or interferon alfa-n3 (Alferon^® N), a tuberculin or similar syringe and a 25- to 30-gauge short (e.g., 0.25- to 0.5-inch) needle should be used.2,3 During injection, the needle should be directed at the center of the base of the wart,2,3 at an angle nearly parallel to the plane of the skin (approximating that used in the Mantoux method for administration of tuberculin).2 Maintaining the needle at this angle will deliver interferon alfa to the dermal core of the lesion, infiltrating the lesion and causing the formation of a small wheal.2 Subcutaneous injection should be avoided since this is below the base of the lesion.2 To avoid subcutaneous injection, the injection should not be made too deeply beneath the lesion.2 However, if the injection is made too superficially, leakage of interferon alfa may occur and the drug will infiltrate the keratinized layer only and not the dermal core of the lesion.2

Interferon Alfa-2b (Intron® A)

For intralesional injection for treatment of external genital and perianal warts (condylomata acuminata), single-dose vials of interferon alfa-2b powder for injection labeled as containing 10 million units of the drug should be reconstituted by adding 1 mL of the sterile water for injection diluent provided by the manufacturer and gently agitating the vial; the resultant solution contains 10 million units/mL.2 The single-dose vials do not contain a preservative and should be discarded after reconstitution and withdrawal of a single dose.2 Alternatively, for intralesional injection for treatment of external genital and perianal warts, multiple-dose vials containing 10 million units/mL can be used.2

The manufacturer states that vials of the powder for injection labeled as containing 18 or 50 million units of interferon alfa-2b and multiple-dose vials of solution for injection labeled as containing 6 million units/mL should not be used to prepare doses for intralesional injection.2

Interferon Alfa-n3 (Alferon® N)

For intralesional injection for treatment of external genital and perianal warts, interferon alfa-n3 injection is administered undiluted.3 Vials of the injection should be stored at 2-8°C and should not be shaken prior to administration.3

Dosage

Because there are differences in the potencies and differences in recommended dosages and routes of administration among the various commercially available interferon alfa preparations, the interferon alfa preparation selected for the patient should be used throughout the treatment regimen.2,3 Patients should be cautioned not to change brands or alter dosage of interferon alfa without consulting their clinician.2,3

Chronic Hepatitis B Virus Infection

Interferon Alfa-2b (Intron® A)

For treatment of chronic HBV infection in adults, the recommended IM or subcutaneous dosage of nonconjugated interferon alfa-2b is 30-35 million units per week (given as 5 million units once daily or as 10 million units 3 times weekly) for a duration of 16 weeks.2

For treatment of chronic HBV infection in children 1 year of age or older, the recommended subcutaneous dosage of nonconjugated interferon alfa-2b is 3 million units/m² given 3 times weekly for the first week of therapy, then 6 million units/m² given 3 times weekly (maximum of 10 million units 3 times weekly) for a total duration of 16-24 weeks.2

If nonconjugated interferon alfa is used for treatment of chronic HBV infection, the American Association for the Study of Liver Diseases (AASLD) recommends a treatment duration of 16-24 weeks in those who are hepatitis B e antigen (HBeAg)-positive and a duration of at least 12 months in those who are HBeAg-negative.97 However, some evidence suggests that a duration of 24 months may increase the rate of sustained response in HBeAg-negative patients.97

Dosage Modification for Toxicity (Interferon Alfa-2b [Intron® A])

If severe adverse reactions or laboratory abnormalities develop during interferon alfa-2b therapy in patients with chronic HBV infection, the manufacturer states that dosage should be reduced by 50% or the drug discontinued, if appropriate, until the adverse reactions abate; if intolerance persists after dosage reduction, the drug should be discontinued.2

Dosage of interferon alfa-2b should be reduced by 50% in patients with leukocyte counts less than 1500/mm³, granulocyte counts less than 750/mm³, or platelet counts less than 50,000/mm³.2 The drug should be permanently discontinued in patients with leukocyte counts less than 1000/mm³, granulocyte counts less than 500/mm³, or platelet counts less than 25,000/mm³.2 Therapy has been resumed at up to 100% of the initial dosage when leukocyte, granulocyte, and/or platelet counts returned to normal or baseline values.2

Chronic Hepatitis C Virus Infection

Concomitant Interferon Alfa-2b (Intron® A) and Oral Ribavirin

If interferon alfa-2b is used for initial treatment of chronic HCV infection in adults or children 3 years of age or older with compensated liver disease who are treatment-naive (have not previously received interferon alfa therapy) or for treatment of chronic HCV infection in adults with compensated liver disease who have relapsed following prior interferon alfa therapy, the manufacturer recommends a dosage of 3 million units given 3 times weekly by IM or subcutaneous injection in conjunction with oral ribavirin.2

The manufacturer of interferon alfa-2b recommends a total treatment duration of 18-24 months if the regimen is tolerated and serum ALT concentrations are normalized at 16 weeks,2 but recommends that discontinuance of treatment be considered if ALT concentrations have not normalized or if high plasma HCV RNA levels persist after 16 weeks of treatment.2 Manufacturers of oral ribavirin state that concomitant interferon alfa-2b and oral ribavirin therapy should be continued for 24-48 weeks in treatment-naive patients, but discontinuance of treatment should be considered in patients who have not achieved HCV RNA levels below the limits of detection at 24 weeks.349,403 If concomitant therapy is used in patients who relapsed after prior nonconjugated interferon monotherapy, these manufacturers recommend a treatment duration of 24 weeks.349,403

Interferon Alfa-2b (Intron® A) Monotherapy

If interferon alfa-2b is used alone for treatment of chronic HCV infection in adults with compensated liver disease, the manufacturer recommends a dosage of 3 million units given 3 times weekly by IM or subcutaneous injection.2

The manufacturer of interferon alfa-2b recommends a total treatment duration of 18-24 months if the drug is tolerated and serum ALT concentrations are normalized at 16 weeks,2 but recommends that discontinuance of treatment be considered if ALT concentrations have not normalized or if high plasma HCV RNA levels persist at 16 weeks.2

Dosage Modification for Toxicity (Interferon Alfa-2b [Intron® A])

If serious adverse effects or laboratory abnormalities occur in patients with chronic HCV infection receiving interferon alfa-2b and concomitant oral ribavirin, dosage of one or both drugs should be modified or therapy discontinued until the adverse effects resolve or decrease in severity.349 Dosage of interferon alfa-2b should be decreased by 50%.2 If the reduced dosage is not tolerated, the drug should be discontinued.2

In patients receiving interferon alfa-2b monotherapy who do not tolerate the usual dosage of the drug, dosage should be reduced by 50% or the drug temporarily withheld until adverse effects resolve.2 If the reduced dosage is not tolerated, the drug should be discontinued.2

In patients receiving concomitant oral ribavirin, dosage of interferon alfa-2b should be reduced by 50% if leukocyte count is 1000 to less than 1500/mm³, neutrophil count is 500 to less than 750/mm³, or platelet count is 25,000 to less than 50,000/mm³ (50,000 to less than 70,000/mm³ in children).349 Both interferon alfa-2b and ribavirin should be permanently discontinued if leukocyte count is less than 1000/mm³, neutrophil count is less than 500/mm³, platelet count is less than 25,000/mm³ (less than 50,000/mm³ in children), hemoglobin concentration is less than 8.5 g/dL, or serum creatinine is greater than 2 mg/dL (in children).349

In adults who have a history of stable cardiac disease, dosage of interferon alfa-2b should be decreased by 50% and ribavirin dosage decreased by 200 mg daily if hemoglobin concentrations decrease by 2 g/dL or more during any 4-week period.349 Both drugs should be permanently discontinued if hemoglobin concentrations are less than 8.5 g/dL (or less than 12 g/dL after 4 weeks of reduced dosage).349

Therapy with interferon alfa-2b and oral ribavirin should be discontinued in patients with severe depression and/or suicidal ideation, and appropriate psychiatric care should be initiated.2

External Genital and Perianal Warts

Interferon Alfa-2b (Intron® A)

For treatment of external genital and perianal exophytic warts (condylomata acuminata) caused by HPV, the usual intralesional dosage of nonconjugated interferon alfa-2b is 1 million units injected into each lesion 3 times weekly on alternate days for 3 weeks.2 No more than 5 warts (i.e., total dose of 5 million units) should be treated at one time.2 An additional course may be administered at 12-16 weeks.2

Interferon Alfa-n3 (Alferon® N)

The usual intralesional dosage of interferon alfa-n3 for treatment of external genital and perianal exophytic warts is 250,000 units per wart;3 the drug is administered twice weekly for up to 8 weeks.3 Large warts may be injected at multiple locations around their periphery, using a total dose of 250,000 units per lesion.3 The maximum recommended dose of intralesional interferon alfa-n3 per treatment session is 2.5 million units.3 In clinical studies, the mean number of warts treated in one treatment cycle was 5.3 The minimum effective intralesional dose of interferon alfa-n3 for treatment of genital and perianal exophytic warts has not been established.3 The dosage regimen may need to be modified and, in some instances, therapy discontinued in patients who experience moderate to severe adverse effects associated with interferon alfa-n3 therapy.3

Although genital and perianal warts usually begin to disappear after several weeks of interferon alfa-n3 treatment, patients should continue to receive usual dosages of the drug for a maximum of 8 weeks.3 The manufacturer of interferon alfa-n3 states that, because patients who achieve a partial resolution of warts during therapy may experience a further resolution of their warts after cessation of treatment and because many patients who achieve a complete response do not exhibit complete resolution of lesions until 3 months following cessation of therapy, no further treatment with the drug or other therapies should be administered for 3 months after the initial 8-week course of intralesional interferon alfa-n3 unless the warts enlarge or new lesions appear.3 The safety and efficacy of a second course of intralesional interferon alfa-n3 in patients with warts have not been determined.3

Special Populations

Renal Impairment

Concomitant interferon alfa-2b (Intron^® A) and oral ribavirin therapy is contraindicated in patients with creatinine clearances less than 50 mL/minute.2,349

Contraindications

Interferon alfa-2b (Intron^® A) is contraindicated in patients with known hypersensitivity (e.g., urticaria, angioedema, bronchoconstriction, anaphylaxis) to interferon alfa or any ingredient in the formulation.

Interferon alfa-n3 (Alferon^® N) is contraindicated in patients with known hypersensitivity to human interferon alfa proteins or any component in the formulation.3 Interferon alfa-n3 also is contraindicated in patients with a history of anaphylactic reactions to murine (mouse) immunoglobulin G (IgG), egg protein, or neomycin (see Sensitivity Reactions under Cautions: Warnings/Precautions);3 a history of allergy to chickens or feathers is not a contraindication.10

Interferon alfa-2b is contraindicated in patients with autoimmune hepatitis2 or hepatic decompensation (Child-Pugh score exceeding 6, class B and C).2 (See Hepatic Effects under Warnings/Precautions: Other Warnings/Precautions, in Cautions.)

Concomitant use of oral ribavirin is contraindicated in women who are or may become pregnant, men whose female partners are pregnant, patients with known hypersensitivity to ribavirin or any ingredient in the formulation, patients with hemoglobinopathies (e.g., thalassemia major, sickle cell anemia), and patients with creatinine clearances less than 50 mL/minute.2 (See Concomitant Oral Ribavirin under Warnings/Precautions: Warnings, in Cautions.)

Warnings/Precautions

Warnings

Serious Disorders

Interferon alfa may cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders.2 Patients should be closely monitored with periodic clinical and laboratory evaluations and the drug discontinued in those with persistently severe or worsening signs or symptoms of these disorders.2 In many, but not all cases, these disorders resolve after interferon alfa is discontinued.2 (See Other Warning/Precautions under Cautions: Warnings/Precautions.)

Concomitant Oral Ribavirin

The usual cautions, precautions, and contraindications associated with oral ribavirin should be observed when the drug is used concomitantly with interferon alfa for treatment of chronic hepatitis C virus (HCV) infection.349,403 (See Cautions in Ribavirin 8:18.32.)

Ribavirin may cause birth defects and/or fetal death.2,349,403 If oral ribavirin is used in conjunction with interferon alfa, extreme care must be taken to avoid pregnancy in female patients and female partners of male patients.2,349,403 (See Cautions: Pregnancy, Fertility, and Lactation, in Ribavirin 8:18.32.)

Ribavirin causes hemolytic anemia, which can result in worsening of cardiac disease.349

Sensitivity Reactions

Severe, acute hypersensitivity reactions, characterized by urticaria, angioedema, bronchoconstriction, or anaphylaxis, have been reported rarely in patients receiving interferon alfa.2

If a severe hypersensitivity reaction occurs during interferon alfa therapy, the drug should be discontinued and the patient given appropriate therapy.2

Interferon alfa-n3 (Alferon^® N) may contain trace amounts of murine (mouse) protein which can stimulate antibody formation in some patients.3 While no egg protein (ovalbumin) has been detected in Alferon^® N using an enzyme-linked immunosorbent assay (ELISA; sensitivity of 16 ng/mL), the Sendai virus used to induce production of interferon alfa by pooled human leukocytes during manufacture of the drug is propagated in chick embryo tissue culture, and the possibility exists that patients receiving the drug could develop hypersensitivity to egg protein.3 (See Cautions: Contraindications.)

Other Warnings/Precautions

Neuropsychiatric Effects

Depression is the most common adverse nervous system effect associated with interferon alfa therapy and one of the most common causes for discontinuance of the drug.3,26 Depression has been reported in 6-26% of patients receiving interferon alfa for treatment of chronic hepatitis B virus (HBV) or HCV infection and in approximately 2-3% of those receiving intralesional injection of the drug for treatment of external genital and perianal warts.2,3

Psychoses, suicidal ideation or suicidal attempts (resulting in death in some patients), hallucinations, aggressive or violent behavior, and rare cases of homicidal ideation have been associated with use of interferon alfa (alone or in conjunction with oral ribavirin) in patients with and without preexisting psychiatric disorders.2 Suicidal ideation or attempts have occurred more frequently in adolescents than in adults.2 While these effects are usually rapidly reversible upon discontinuance of the drug, severe episodes have taken up to 3 weeks for full resolution of symptoms.2

Obtundation, coma, and encephalopathy have been reported, primarily in geriatric patients treated with high interferon alfa dosage.2

Use of interferons may be associated with exacerbation of psychiatric symptoms in patients with concomitant psychiatric and substance use disorders.2 When initiating treatment in patients with a history of psychiatric conditions or substance use disorders, consideration should be given to the need for drug screening and periodic clinical evaluation, including psychiatric symptom monitoring.2 Re-emergence or development of neuropsychiatric symptoms or substance use should prompt early intervention.2

Interferon alfa should be used with caution in patients with a history of preexisting psychiatric disorders, especially those with a history of depression.2 All patients receiving interferon alfa should be informed that depression and suicidal ideation may be side effects of treatment and should be advised to immediately report these effects to a clinician if they occur.2 All patients should be closely monitored for evidence of depression and other psychiatric symptoms.2 Patients who develop such symptoms should be carefully monitored during therapy and for 6 months after discontinuing therapy.2 If symptoms persist or worsen, or suicidal ideation or aggressive behavior toward others is identified, interferon alfa should be discontinued and the patient followed with appropriate psychiatric intervention.2 If severe depression and/or other psychiatric condition develops, interferon alfa therapy should be discontinued immediately and appropriate psychiatric intervention provided.2

Cardiovascular Effects

Adverse cardiovascular effects, including hypotension,2 arrhythmia,2 tachycardia2 (150 beats/minute or greater),2 cardiomyopathy,2 and myocardial infarction,2 have occurred when interferon alfa was used in patients with or without a prior history of cardiovascular disease.2

Hypotension may occur during administration of the drug or up to 2 days posttherapy and may require supportive therapy, including fluid replacement to maintain intravascular volume.2 Supraventricular arrhythmias have occurred rarely and appeared to correlate with preexisting cardiovascular conditions and prior therapy with cardiotoxic agents.2 These adverse experiences were controlled by modifying dosage or discontinuing the drug, but may require additional specialized care.2

Electrocardiographic monitoring should be performed prior to initiating and periodically during interferon alfa therapy in patients with preexisting cardiac disease.2

Interferon alfa therapy should be used with caution and careful monitoring in patients with cardiovascular disease or a history of any cardiac condition, including myocardial infarction or arrhythmia.2 Patients with a history of substantial or unstable cardiac disease should not receive treatment with concomitant interferon alfa and oral ribavirin.349,403

Respiratory Effects

Adverse pulmonary effects, including dyspnea, pulmonary infiltrates, pneumonia, bronchiolitis obliterans, interstitial pneumonitis, pulmonary hypertension, and sarcoidosis, some resulting in respiratory failure and/or death, have occurred in patients receiving interferon alfa,2 principally in those receiving the drug for treatment of chronic HCV infection.2 The etiologic explanation for these pulmonary findings has yet to be established.2

One manufacturer recommends that baseline chest radiographs be performed before initiating interferon alfa therapy, and repeated when clinically indicated in patients who develop fever, cough, dyspnea, or other respiratory symptoms during therapy.2 Recurrence of respiratory failure has occurred with interferon rechallenge, and patients who resume treatment with interferon alfa should be closely monitored.2

Hepatic Effects

If manifestations of hepatic decompensation (e.g., jaundice, ascites, coagulopathy, decreased serum albumin concentrations) occur, interferon alfa should be immediately discontinued.2 Interferon alfa is contraindicated in patients with hepatic decompensation.2

Transient increase (greater than 2 times baseline) in serum ALT concentrations (“flare”) can occur during interferon alfa therapy for chronic HBV infection.2 These flares generally occurred 8-12 weeks following initiation of therapy in clinical studies in adults and children 1 year of age and older and were more frequent in responders (63% of adults, 59% of children) than in nonresponders (27% of adults, 35% of children).2 Interferon alfa generally should be continued in patients who experience these flares, unless signs and symptoms of liver failure are observed.2 However, clinical symptomatology and liver function tests, including serum ALT, alkaline phosphatase, albumin, and bilirubin concentrations and prothrombin time, should be monitored at approximately 2-week intervals during these occurrences.2 Patients with chronic HBV infection and evidence of decreasing hepatic synthetic function (e.g., decreasing serum albumin concentrations, prolonged prothrombin time) may be at increased risk of clinical decompensation if an increase in serum ALT concentration occurs during interferon alfa therapy and should receive the drug with caution and with close monitoring of clinical symptoms and liver function tests if serum ALT increases occur.2,10

Because interferon alfa has produced severe, potentially life-threatening exacerbations of autoimmune chronic active hepatitis, the possibility of this form of hepatitis should be ruled out whenever therapy with the drug is considered for the management of viral hepatitis.2 A liver biopsy to establish the diagnosis of chronic hepatitis, and testing for the presence of antibody to the virus is recommended when such therapy is considered.2 In addition, the presence of compensated liver disease and no evidence of hepatic failure should be established prior to initiating interferon alfa therapy for viral hepatitis.2 The manufacturer of interferon alfa-2b recommends that the following criteria used in clinical trials as indicators of compensated liver disease be considered prior to initiation of interferon therapy in patients with viral hepatitis: No history of hepatic encephalopathy, variceal bleeding, ascites, or other clinical signs of hepatic decompensation; serum bilirubin concentration not exceeding 2 mg/dL; serum albumin concentration stable and within normal limits; prothrombin time prolongation less than 3 seconds in adults and 2 seconds or less in children; leukocyte count of 3000/mm³ in adults with chronic HCV infection or 4000/mm³ in adults and children with chronic HBV infection; and platelet count at least 70,000/mm³ in adults with chronic HCV infection or 100,000/mm³ in adults and 150,000/mm³ in children with chronic HBV infection.2

Patients who develop liver function abnormalities (e.g., an increase in serum ALT concentration) during interferon alfa therapy should be closely monitored and therapy discontinued as needed.2 Because worsening liver disease, including jaundice, hepatic encephalopathy, hepatic failure, and death, has been reported in patients with decompensated liver disease, autoimmune hepatitis, a history of autoimmune disease, or immunosuppression (e.g., organ transplant recipients) treated with interferon alfa, the drug should not be used in these patients.2

Cerebrovascular Effects

Ischemic and hemorrhagic cerebrovascular events have been reported in patients receiving interferon alfa.2 Such events have occurred in patients with few or no risk factors for stroke, including patients younger than 45 years of age.2 A causal relationship between interferon alfa-based therapies and cerebrovascular events has not been established.2

Hematologic Effects

Interferon alfa is a myelosuppressive agent that may cause severe cytopenias and anemia, including aplastic anemia.2

In clinical studies, hemolytic anemia (hemoglobin less than 10 g/dL) has been observed in approximately 10% of patients with chronic HCV infection who received interferon alfa-2b (Intron^® A) in conjunction with oral ribavirin in clinical studies.2 Anemia generally occurs within 1-2 weeks following initiation of oral ribavirin.2

Complete blood counts (CBCs) should be obtained prior to initiation of interferon alfa therapy and CBCs should be monitored routinely during therapy.2 In patients with chronic HBV infection, CBCs should be obtained at baseline and at 1, 2, 4, 8, 12, and 16 weeks of therapy.2 In patients with chronic HCV infection, CBCs should be obtained at baseline, at weeks 1 and 2 of therapy, and monthly thereafter.2

Interferon alfa should be discontinued in patients who develop severe neutropenia (leukocyte count less than 500/mm³) or thrombocytopenia (platelet count less than 25,000/mm³).2

Patients with hemoglobinopathies (e.g., thalassemia, sickle cell anemia) should not be treated with concomitant interferon alfa and oral ribavirin therapy.2

Patients receiving intralesional interferon alfa for treatment of external genital and perianal warts appear to be less affected by adverse hematologic effects than those receiving the drug systemically.2 However, because mild to moderate leukopenia has been reported in patients receiving intralesional interferon alfa, hematologic monitoring also should be considered in these patients.2

Interferon alfa should be used with caution in patients with coagulation disorders (e.g., pulmonary embolism, thrombophlebitis, hemophilia).2,3 Interferon alfa also should be used with caution in patients with myelosuppression and in those receiving drugs that may be myelosuppressive (e.g., zidovudine).2,3 (See Drug Interactions: Myelosuppressive Agents.)

Flu-like Syndrome

A flu-like syndrome is the most frequently reported adverse effect of interferon alfa therapy.2 The flu-like syndrome generally is characterized by the development of fever,2 headache,2 chills,2 myalgia/arthralgia,2 fatigue,2 increased sweating,2 asthenia,2 rigors,2 dizziness,2 influenza-like symptoms,2 back pain,2 dry mouth,2 chest pain,2 malaise,2 and pain (unspecified).2 Development of persistent high fever during prolonged interferon alfa therapy should prompt consideration of other possible causes.2

A nonsteroidal anti-inflammatory agent (NSAIA) or acetaminophen may prevent or ameliorate the fever and headache associated with the syndrome.2,3,10

Because interferon alfa therapy has been associated with fever and flu-like symptoms, the drug should be used with caution in patients with debilitating diseases such as cardiac disease (e.g., unstable angina, uncontrolled congestive heart failure), severe pulmonary disease (e.g., chronic obstructive pulmonary disease), or diabetes mellitus (who may be prone to ketoacidosis).2,3

Pancreatitis

Pancreatitis, sometimes fatal, has occurred in patients receiving interferon.2

Interferon alfa should be suspended in patients with signs and symptoms of pancreatitis (e.g., abdominal pain, nausea, vomiting); the drug should be discontinued if a diagnosis of pancreatitis is established.2

Peripheral Neuropathy

Peripheral neuropathy has been reported in patients receiving telbivudine concomitantly with an interferon alfa.2 (See Drug Interactions: Telbivudine.)

Triglycerides

Increased serum triglyceride concentrations have been reported in patients receiving interferon alfa alone or in conjunction with oral ribavirin and such elevations should be managed as clinically appropriate.2 Severe hypertriglyceridemia (serum triglycerides concentrations exceeding 1000 mg/dL) may result in pancreatitis.2 (See Pancreatitis under Warnings/Precautions: Other Warnings/Precautions, in Cautions.)

Dental and Periodontal Disorders

Dental and periodontal disorders have been reported in patients receiving interferon alfa therapy in conjunction with oral ribavirin;2 dry mouth may contribute to damage of teeth and oral mucous membranes during long-term treatment.2

Patients should be advised to have regular dental examinations during treatment, to brush their teeth thoroughly twice daily, and to rinse their mouth thoroughly after vomiting.2

Autoimmune Disease

Development or exacerbation of autoimmune diseases, including autoimmune thrombocytopenia, idiopathic thrombocytopenic purpura, vasculitis, Raynaud's phenomenon, rheumatoid arthritis, psoriasis, interstitial nephritis, thyroiditis, lupus erythematosus, hepatitis, and rhabdomyolysis, has been reported in patients receiving interferon alfa.2 Fatalities have been reported rarely.2

Patients who develop an autoimmune disease while receiving interferon alfa therapy should be monitored closely and the drug discontinued if necessary.2

Ophthalmologic Effects

Decreased or loss of vision and retinopathy, including macular edema, optic neuritis, papilledema, retinal hemorrhages, cotton-wool spots, serous retinal detachment, and retinal artery or vein thrombosis, may be induced or aggravated by interferon alfa therapy.2

Baseline ophthalmologic examinations should be performed in all patients prior to initiation of interferon alfa therapy.2 Patients with preexisting ophthalmologic disorders (e.g., diabetic or hypertensive retinopathy) should receive ophthalmologic examinations periodically during therapy.2

A prompt and complete ophthalmologic examination should be performed in any patient who develops ocular symptoms.2

Interferon alfa therapy should be discontinued in patients who develop new or worsening ophthalmologic disorders.2

Endocrine and Metabolic Effects

Interferon alfa may cause or aggravate hypothyroidism and hyperthyroidism.2 Thyroid dysfunction (hypothyroidism or hyperthyroidism)2 has been reported in less than 5% of patients receiving interferon alfa,2,26 and has been reported in patients with no prior history of such dysfunction.2 Although thyroid dysfunction appears to occur more frequently in interferon alfa-treated patients with chronic HCV infection than those with chronic HBV infection,10 the possibility that any patient receiving the drug could develop thyroid abnormalities should be considered.2 In most case reports, thyroid function usually recovered within a few months following discontinuance of interferon alfa therapy; however, some patients may continue to require hormonal therapy.2,26

Serum thyrotropin (thyroid-stimulating hormone, TSH) concentrations should be evaluated prior to initiation of interferon alfa therapy.2 Patients who develop symptoms consistent with possible thyroid dysfunction during the course of interferon alfa therapy should have their thyroid function evaluated and appropriate treatment instituted.2 Such patients and those with preexisting thyroid dysfunction may continue to receive interferon alfa as long as their thyroid function can be normalized with antithyroid therapy or hormone replacement therapy, depending on the thyroid dysfunction.2

Development of diabetes mellitus and hyperglycemia has been rarely reported in patients receiving interferon alfa.2 Patients with preexisting diabetes mellitus and those who develop diabetes mellitus during interferon alfa therapy may continue to receive interferon alfa as long as their diabetes can be controlled with drug therapy.2

Risk of Transmissible Infectious Agents from Plasma-derived Preparations

Interferon alfa-2b (Intron^®A) powder for injection contains albumin (a derivative of human blood)2 and interferon alfa-n3 (Alferon^® N) is produced using human blood.3 Because of effective donor screening and product manufacturing processes, these preparations are associated with an extremely remote risk for transmission of viral diseases and a theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD).2,3

Antibody Formation

Serum anti-interferon neutralizing antibodies were detected in 7% of adults either during treatment or after completing 12-48 weeks of interferon alfa-2b therapy for treatment of chronic HCV infection (3 million units 3 times weekly), in 13% of adults who received the drug for chronic HBV infection (5 million units daily for 4 months), and in 3% of adults who received a dosage of 10 million units 3 times weekly.2 Serum anti-interferon neutralizing antibodies also were detected in 9% of children who received interferon alfa-2b therapy for chronic HBV infection (6 million units/m² 3 times weekly) and in 0.8% of patients who received the drug by intralesional injection for treatment of genital and perianal warts.2

No apparent correlation of antibody development to clinical response or adverse events was observed.2

Organ Transplant Recipients

Safety and efficacy of interferon alfa alone or in conjunction with oral ribavirin have not been established for treatment of chronic HCV infection in patients with liver or other transplants.2

Specific Populations

Pregnancy

Interferon alfa (alfa-2b, alfa-n3) monotherapy: Category C.2,3 (See Users Guide.)

Concomitant interferon alfa (alfa-2b) and oral ribavirin: Category X.2 (See Users Guide.) (See Concomitant Oral Ribavirin, under Warnings/Precautions: Warnings, in Cautions.)

Lactation

It is not known whether interferon alfa is distributed into milk.2,3 A decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman and potential risks to the infant.2,3

Pediatric Use

Safety and efficacy of nonconjugated interferon alfa-2b (Intron^® A) have not been established in pediatric patients for any indications other than treatment of chronic HBV and chronic HCV infection.2 For treatment of chronic HBV infection, safety and efficacy of interferon alfa-2b have not been established in infants younger than 1 year of age.2 For treatment of chronic HCV infection, safety and efficacy of interferon alfa-2b have not been established in treatment-naive pediatric patients younger than 3 years of age or in previously treated patients younger than 18 years of age.2 Safety and efficacy for treatment of chronic HCV infection in treatment-native children 3-16 years of age was established based on clinical studies in this age group.2

Safety and efficacy of intralesional injection of interferon alfa-2b (Intron^® A)2 and alfa-n3 (Alferon^® N) have not been established in children younger than 18 years of age.3 Studies have not been performed to date to evaluate use of interferon alfa-n3 in adolescents.3

Safety data from clinical studies in children 3-16 years of age indicate that injection site reactions (from subcutaneous injections of interferon alfa-2b), fever, anorexia, vomiting, and emotional lability occurred more frequently in pediatric patients receiving oral ribavirin concomitantly with nonconjugated interferon alfa-2b compared with adults receiving such therapy.349 Conversely, pediatric patients experienced less fatigue, dyspepsia, arthralgia, insomnia, irritability, impaired concentration, dyspnea, and pruritus compared with adults.349 Suicidal ideation or attempts occurred more frequently among pediatric patients (principally adolescents) compared to adults during treatment and off-therapy.349 Like adults, other adverse psychiatric effects (depression, emotional lability, somnolence), anemia, and neutropenia were also reported in pediatric patients.349

Delay in weight and height increases compared with baseline have been reported in pediatric patients receiving interferon alfa.2,12,52 Growth retardation was reported in some children receiving nonconjugated interferon alfa for treatment of chronic HBV infection, but growth velocity generally resumed to pretreatment rates following discontinuance of the drug.2,12,52 Some clinicians state that interferon alfa therapy should not be used for treatment of HBV infection in children 2 years of age or younger because of concerns that growth retardation during the first years of life may be detrimental to the overall development of the child.10,12,27 Although a decrease in the rate of linear growth (mean percentile assignment decrease of 7%) and a decrease in the rate of weight gain (mean percentile assignment decrease of 9%) were reported in pediatric patients with HCV infection who received a 48-week regimen of interferon alfa-2b and oral ribavirin, general reversal of these trends was noted during the 24-week posttreatment period.2

Geriatric Use

Clinical studies of interferon alfa-2b (Intron^® A) alone or in conjunction with oral ribavirin did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger patients.2 In clinical studies of interferon alfa-2b in conjunction with oral ribavirin, anemia was reported more frequently in geriatric patients than in younger patients.2 Other clinical and postmarketing experience has revealed a greater incidence of adverse cardiovascular events and confusion in geriatric patients compared with younger patients.2

Because of the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly, interferon alfa should be used with caution in this age group.2

Renal Impairment

Concomitant use of interferon alfa-2b (Intron^® A) and oral ribavirin is contraindicated in patients with creatinine clearances less than 50 mL/minute.2,349,403

Hepatic Impairment

Patients with chronic HBV infection may be at risk for transient acute exacerbations (flares) of HBV infection during treatment.2 (See Hepatic Effects under Warnings/Precautions: Other Warnings/Precautions, in Cautions.)

Interferon alfa-2b (Intron^® A) is contraindicated in patients with autoimmune hepatitis or hepatic decompensation (Child-Pugh score exceeding 6, class B and C).2

Common Adverse Effects

Adverse effects observed in 20% or more of patients with chronic HBV infection receiving interferon alfa in clinical studies include alopecia, anorexia, fatigue, fever, headache, myalgia, nausea, and rigors.2

Adverse effects observed in 20% or more of patients with chronic HCV infection receiving interferon alfa alone or in conjunction with ribavirin in clinical studies include abdominal pain,2 alopecia,2,349 anemia,2 anorexia,2 arthralgia,349 asthenia,2,349 depression,2,349 diarrhea,2 dizziness,2 dyspnea,349 fatigue,2,349 fever,2,349 headache,2,349 influenza-like symptoms,2 musculoskeletal pain,2 myalgia,2,349 nausea,2,349 neutropenia,2 pharyngitis,2 rigors,2 somnolence,2 vomiting,2 and weight loss.2

Adverse effects observed in 5% or more of patients receiving intralesional interferon alfa for treatment of external and perianal genital warts include arthralgia,2,3 back pain,2,3 chills,2,3 dizziness,2,3 fatigue,2,3 fever,2,3 headache,2,3 influenza-like syndrome,3 malaise,2,3 myalgia,2,3 and nausea.2,3

Myelosuppressive Agents

Because of the potential for synergistic myelosuppression, interferon alfa and other potentially myelosuppressive agents (e.g., zidovudine) should be used concomitantly with caution.2 Leukocyte counts should be monitored carefully during interferon alfa therapy in patients who are myelosuppressed or receiving other myelosuppressive agents.2

HCV Antivirals

In vitro, interferon alfa-2b and boceprevir have had additive effects against hepatitis C virus (HCV) without evidence of antagonism.185

In vitro, interferon alfa and simeprevir have had synergistic effects against HCV;120 there is no in vitro evidence of antagonism.120,187

There is no in vitro evidence of antagonistic anti-HCV effects between interferon alfa and sofosbuvir or telaprevir.184,188

Telbivudine

Peripheral neuropathy has been reported when telbivudine was used concomitantly with an interferon alfa.2 In one study, increased risk and severity of peripheral neuropathy occurred in patients receiving peginterferon alfa-2a concomitantly with telbivudine compared with those receiving telbivudine alone.2

Safety and efficacy of concomitant use of telbivudine with any interferon for treatment of chronic HBV infection have not been established.2

Theophylline

Concomitant use of interferon alfa and theophylline decreases theophylline clearance and results in a 100% increase in serum theophylline concentrations.2

Description

Interferon alfa is a naturally occurring protein with antiviral, antiproliferative, and immunomodulating activity.3 Human interferon alfa is commercially available in the US as interferon alfa-2b2 and interferon alfa-n3.3 Interferon alfa-2b also is commercially available as peginterferon alfa-2b, which contains the drug covalently bound to polyethylene glycol (PEG) monomethoxy ether (see Peginterferon Alfa 8:18.20 and see Peginterferon Alfa 10:00).48

Interferon alfa-2b (Intron^® A) is of recombinant DNA origin and exists as a single interferon subtype preparation.2 Interferon alfa-2b is obtained from the bacterial fermentation of a strain of Escherichia coli containing a genetically engineered plasmid with a human interferon alfa-2b gene.2

Interferon alfa-n3 (Alferon^® N) is a mixture of naturally occurring human interferon alfa proteins for which the precise subtype composition has not been determined.3 Interferon alfa-n3 is manufactured from pooled units of human leukocytes which have been induced by incomplete infection with a murine virus (Sendai virus) to produce interferon alfa-n3.3

Although the precise mechanisms of antiviral activity of interferon alfa have not been fully elucidated, interferons with antiviral activity appear to bind to specific membrane receptors on cell surfaces and initiate a complex sequence of intracellular events, including induction of certain enzymes, suppression of cell proliferation, various immunomodulating activities, and inhibition of viral replication in virus-infected cells.2,48

For additional information on interferon alfa, including information on chemistry, mechanism of action, pharmacokinetics, antineoplastic uses, and drug interactions, see Interferon Alfa 10:00. For information on peginterferon alfa-2a and peginterferon alfa-2b, see Peginterferon Alfa 8:18.20 and Peginterferon Alfa 10:00.

Advice to Patients

Advise patients receiving interferon alfa about appropriate use of the drug and the expected benefits and risks.2

Importance of reading the manufacturer's medication guide.2,112

Advise patients regarding proper disposal procedures and the importance of not reusing needles and syringes; provide patients with manufacturer's instructions for use.2,115

Caution patients not to change brands of interferon alfa without consulting their clinician.2

Importance of remaining well hydrated, especially during initial treatment.2

Advise patients with hepatitis C virus (HCV) infection that it is not known whether interferon alfa (alone or in conjunction with oral ribavirin) will prevent transmission of HCV infection to others or prevent long-term HCV-associated complications (cirrhosis, liver failure, liver cancer).2 Importance of taking precautions to prevent transmission of HCV.2

Advise patients that laboratory evaluations are required before starting and periodically during interferon alfa treatment.2

Patients receiving interferon alfa should be informed that hives, generalized urticaria, chest tightness, wheezing, and hypotension may be early signs of hypersensitivity reactions and that they should notify their clinician if any of these conditions occur.3

Importance of reporting any sign or symptom of depression or suicidal ideation to clinician.2,112 Advise patients that the drug may need to be immediately discontinued and psychiatric intervention instituted in severe cases.2,112

Advise patients to maintain good oral hygiene, including brushing their teeth twice daily and rinsing their mouth after vomiting.2

Advise patients that some adverse effects (e.g., fatigue, impaired concentration) may impair ability to perform certain tasks.2

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.2,3

Advise patients of the teratogenic/embryocidal risks associated with concomitant oral ribavirin and the necessity for females of childbearing potential and male patients with female partners of childbearing age to practice effective contraception during and for 6 months after ribavirin therapy.2

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.2,3

Importance of informing patients of other important precautionary information.2,3 (See Cautions.)

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

2. Schering Corporation. Intron^® A (interferon alfa-2b, recombinant) for injection prescribing information. Whitehouse Station, NJ; 2014 Apr.

3. Hemispherx Biopharma. Alferon N injection^® (interferon alfa-n3 [human leukocyte derived]) prescribing information. Philadelphia, PA; 2004 Jul.

6. Farci P, Mandas A, Coiana A et al. Treatment of chronic hepatitis D with interferon alfa-2a. N Engl J Med . 1994; 330:88-94. [PubMed 8259188]

9. Reichman RC, Oakes D, Bonnez W et al. Treatment of condyloma acuminatum with three different interferon-α preparations administered parenterally: a double-blind, placebo-controlled trial. J Infect Dis . 1990; 162:1270-6. [PubMed 2172401]

10. Reviewers' comments (personal observations).

12. Lok AS, Heathcote EJ, Hoofnagle JH. Management of hepatitis B: 2000-Summary of a workshop. Gastroenterology . 2001; 120:1828-53. [PubMed 11375963]

13. Hoofnagle JH, Peters M, Mullen KD et al. Randomized, controlled trial of recombinant human alpha-interferon in patients with chronic hepatitis B. Gastroenterol . 1988; 95:1318-25.

14. Perrillo RP, Schiffer, Davis GL et al and the Hepatitis Interventional Therapy Group. A randomized, control trial of interferon alfa-2b alone and after prednisone withdrawal for the treatment of chronic hepatitis B. N Engl J Med . 1990; 323:295-301. [PubMed 2195346]

15. Lee WM. Hepatitis B virus infection. N Engl J Med . 1997; 337:1733-45. [PubMed 9392700]

16. Wong DKH, Cheung AM, O'apos;Rourke K et al. Effect of alfa-interferon treatment in patients with hepatitis B e antigen-positive chronic hepatitis B: a meta-analysis. Ann Intern Med . 1993; 119:312-23. [PubMed 8328741]

17. Centers for Disease Control and Prevention (CDC). Sexually transmitted diseases treatment guidelines, 2010. MMWR Recomm Rep . 2010; 59(RR-12):1-110. [Web]

18. Friedman-Kien AE, Eron LJ, Conant M et al. Natural interferon alfa for treatment of condylomata accuminata. JAMA . 1988; 259:533-8. [PubMed 3336177]

19. Condylomata International Collaborative Study Group. Recurrent condylomata acuminata treated with recombinant interferon alfa-2a. JAMA . 1991; 265:2684-7. [PubMed 2023348]

20. Genentech. Pegasys^® (peginterferon alfa-2a) injection for subcutaneous use prescribing information. South San Francisco, CA; 2013 Jul.

25. Perez V, Tanno H, Villamil F et al. Recombinant interferon alfa-2b following prednisone withdrawal in the treatment of chronic type B hepatitis. J Hepatol . 1990; 11:S113-5. [PubMed 2079567]

26. Gervais A, Boyer N, Marcellin P. Tolerability of treatments for viral hepatitis. Drug Saf . 2001; 24:375-84. [PubMed 11419564]

27. Sokal EM, Conjeevaram HS, Roberts EA et al. Interferon alfa therapy for chronic hepatitis B in children: a multinational randomized controlled trial. Gastroenterology . 1998; 114:988-95. [PubMed 9558288]

29. Healy GB, Gelber RD, Trowbridge AL et al. Treatment of recurrent respiratory papillomatosis with human leukocyte interferon. N Engl J Med . 1988; 319:401-7. [PubMed 3398891]

31. Leventhal BG, Kashima HK, Mounts P et al. Long-term response of recurrent respiratory papillomatosis to treatment with lymphoblastoid interferon alfa-n1. N Engl J Med . 1991; 325:613-7. [PubMed 1861694]

32. Leventhal BG, Kashima HK, Weck PW et al. Randomized surgical adjuvant trial of interferon alfa-n1 in recurrent papillomatosis. Arch Otolaryngol Head Neck Surg . 1988; 114:1163-9. [PubMed 3046638]

35. Anon. Interferon plus ribavirin for chronic hepatitis C. Med Lett Drugs Ther . 1999; 41:53-4. [PubMed 10368698]

36. McHutchison JG, Gordon SC, Schiffer et al for the Hepatitis Interventional Therapy Group. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. N Engl J Med . 1998; 339:1485-92. [PubMed 9819446]

37. Poynard T, Marcellin P, Lee SS et al for the International Hepatitis Interventional Therapy Group (IHIT). Randomised trial of interferon alpha2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alpha2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. Lancet . 1998; 352:1426-32. [PubMed 9807989]

38. Davis GL, Esteban-Mur R, Rustgi V et al Interferon alfa-2b alone or in combination with ribavirin for the treatment of relapse of chronic hepatitis C. N Engl J Med . 1998; 339:1493-9.

39. Manns MP, McHutchison JG, Gordon SC et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet . 2001; 358:958-65. [PubMed 11583749]

46. Lundquist PG, Haglund S, C et al. Interferon therapy in juvenile laryngeal papillomatosis. Otolaryn Head Neck Surg . 1984; 92:386-91.

47. Booth JCL, O'Grady J, Neuberger J for the Royal College of Physicians of London and the British Society of Gastroenterology. Clinical guidelines on the management of hepatitis C. Gut . 2001; 49(Suppl):1-21.

48. Schering Corporation. PegIntron^® (peginterferon alfa-2b) injection, for subcutaneous use prescribing information. Whitehouse Station, NJ; 2014 Jul.

49. Schering Corporation. Sylatron^® (peginterferon alfa-2b) for injection, for subcutaneous use prescribing information. Whitehouse Station, NJ; 2013 Dec.

52. Comanor L, Minor J, Conjeevaram HS et al. Impact of chronic hepatitis B and interferon-alpha therapy on growth of children. J Viral Hepat . 2001; 8:139-47. [PubMed 11264734]

54. Simon DM, Gordon SC, Kaplan MM et al. Treatment of chronic hepatitis C with interferon alfa-n3: a multicenter, randomized, open-label trial. Hepatology . 1997; 26:1366-7.

62. Landau A, Batisse D, Piketty C et al. Long-term efficacy of combination therapy with interferon-alpha2b and ribavirin for severe chronic hepatitis C in HIV-infected patients. AIDS . 2001; 15:2149-55. [PubMed 11684934]

63. Bonacini M. Management issues in patients coinfected with hepatitis C virus and HIV. AIDS Read . 2002; 12:19-26. [PubMed 11862656]

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