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Interferon Alfa

Class: Antineoplastic Agents
- Biologic Response Modifiers
- Cytokines
VA Class: AM800
Chemical Name: Interferon α2b (human leukocyte clone Hif-SN206 protein moiety reduced)
Molecular Formula: C860H1353N229O255S9C860H1353N227O255S9
CAS Number: 99210-65-8
Brands: Intron A, Alferon N

Warning

  • May cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Monitor patients closely with periodic clinical and laboratory evaluations. Discontinue therapy in patients with persistently severe or worsening signs or symptoms of these conditions. In many, but not all cases, these disorders resolve after the drug is discontinued.

Introduction

Interferon alfa is a family of proteins and glycoproteins with antiviral, antineoplastic, and immunomodulating activities. Available in the US as interferon alfa-2b and interferon alfa-n3. Also available covalently bound to monomethoxy polyethylene glycol (PEG) (i.e., peginterferon alfa).

Uses for Interferon Alfa

Chronic HBV Infection

Interferon alfa-2b: Treatment of chronic HBV infection in adults, adolescents, and children ≥1 year of age with compensated liver disease.

Goal of antiviral therapy is sustained suppression of HBV replication and remission of liver disease; long-term goal is prevention of cirrhosis, hepatic failure, and hepatocellular carcinoma.

Currently available therapies (e.g., interferon alfa, peginterferon alfa, adefovir, entecavir, lamivudine, telbivudine, tenofovir) do not eradicate HBV and may have only limited long-term efficacy. When making decisions regarding treatment, consider 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.

American Association for the Study of Liver Diseases (AASLD) states that drugs of choice for initial treatment of chronic HBV infection in patients with compensated liver disease are peginterferon alfa, entecavir, or tenofovir, unless contraindicated or ineffective. Efficacy of peginterferon alfa and nonconjugated interferon alfa are considered similar, but peginterferon alfa dosage schedule more convenient and generally preferred.

Treatment of chronic HBV infection is complex and rapidly evolving and should be directed by clinicians familiar with the disease; consult specialist to obtain the most up-to-date information.

Chronic HCV Infection

Interferon alfa-2b: Has been used for treatment of chronic HCV infection in adults with compensated liver disease; used alone or in conjunction with oral ribavirin.

Interferon alfa-2b: Has been used for treatment of chronic HCV infection in treatment-naive children ≥3 years of age with compensated liver disease; used in conjunction with oral ribavirin.

Peginterferon alfa (not interferon alfa) recommended if an interferon is used for treatment of chronic HCV infection. Interferon alfa alone or in conjunction with oral ribavirin associated with lower response rates than peginterferon alfa in conjunction with oral ribavirin.

Treatment of chronic HCV infection is complex and rapidly evolving; consult a specialist to obtain the most up-to-date information. 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].

Chronic HDV Infection

Interferon alfa: Has been used with some limited success for treatment of chronic HDV infection in adults and children coinfected with HBV. Although interferon alfa may suppress viral activity in some patients, sustained response not obtained and relapse generally occurs after drug discontinued.

HDV infection only occurs in individuals with HBV infection since the virus depends on HBV for production of envelope proteins. Can be acquired as a coinfection with HBV or as a superinfection in HBV carriers. HDV superinfection in HBV carriers almost always results in chronic infection with both viruses and is associated with high risk of cirrhosis, hepatic decompensation, and hepatocellular carcinoma.

Human Papillomavirus (HPV) Infections

Interferon alfa-2b, interferon alfa-n3: Intralesional treatment of external genital and perianal exophytic warts (condylomata acuminata) caused by HPV.

CDC states that intralesional interferon alfa is an alternative (not preferred) option for treatment of external HPV warts because of higher frequency of adverse effects (including rare severe systemic adverse effects) and/or less efficacy data compared with other options.

No currently available option has been shown to eradicate HPV infectivity.

West Nile Virus Infection

Interferon alfa-2b, interferon alfa-n3: Have been investigated for treatment of serious West Nile virus (WNV) infection†.

Despite initial case reports suggesting some clinical benefits in neuroinvasive disease, efficacy not proven in controlled clinical trials. Unlikely to inhibit WNV replication following establishment of infection.

Hairy Cell Leukemia

Interferon alfa-2b: Treatment of hairy cell leukemia (leukemic reticuloendotheliosis).

Complete response achieved in 10% of patients and overall response achieved in approximately 80% of patients.

An alternative for hairy cell leukemia; cladribine or pentostatin preferred (achieve higher complete response rates than interferon alfa).

AIDS-related Kaposi’s Sarcoma

Interferon alfa-2b: Palliative treatment of AIDS-related Kaposi’s sarcoma in selected adults (designated an orphan drug by FDA for this indication).

Do not use in patients with rapidly progressive visceral or life-threatening disease; response generally is slow and poor.

Likelihood of response to interferon alfa is greater in patients without systemic symptoms who have limited lymphadenopathy and relatively intact immune systems as indicated by CD4+ T-cell counts.

All patients with AIDS-related Kaposi's sarcoma should be receiving highly active antiretroviral therapy; in some patients, initiation of antiretroviral therapy alone may result in tumor regression and resolution of lesions.

Non-Hodgkin’s and Cutaneous T-cell Lymphomas

Interferon alfa-2b: Although labeled by FDA for use in conjunction with an anthracycline for initial treatment of clinically aggressive follicular non-Hodgkin’s lymphoma in adults, other agents preferred.

Efficacy in patients with low-grade, low-tumor-burden follicular non-Hodgkin’s lymphoma not demonstrated.

Interferon alfa: Has been used for treatment of cutaneous T-cell lymphomas.

Melanoma

Interferon alfa-2b: Used as an adjunct to surgery (within 56 days of surgery) in adults with malignant melanoma who are disease free but at high risk for systemic recurrence.

Palliative treatment of metastatic melanoma in selected patients, alone and in conjunction with other therapies (e.g., radiation).

Basal Cell and Squamous Cell Skin Cancers

Interferon alfa: Has been used intralesionally for treatment of basal cell carcinoma and squamous cell carcinoma.

Chronic Myelogenous Leukemia

Interferon alfa-2b: Has been used for treatment of adult-type (Philadelphia chromosome-positive) chronic myelogenous (myelocytic, myeloid) leukemia (CML).

Renal Cell Carcinoma

Interferon alfa: Has been used for treatment of metastatic renal cell carcinoma in selected patients.

Bladder Cancer

Interferon alfa: Has been used intravesically for prophylaxis or treatment of superficial bladder cancer.

Ovarian Cancer

Interferon alfa: Has been used intraperitoneally for treatment of minimal residual epithelial ovarian cancer in a limited number of patients.

Interferon Alfa Dosage and Administration

General

  • Various interferon alfa subtypes (alfa-2b, n3) and dosage forms (powder for injection, solution for injection) are commercially available; preparation to be used and appropriate concentration depend on intended use. Ensure that correct preparation is used.

Administration

Interferon alfa-2b (Intron A): Administer by IM, sub-Q, or intralesional injection or by IV infusion.

Interferon alfa-n3 (Alferon N): Administer by intralesional injection.

Interferon alfa-2b may be self-administered if clinician determines that the patient and/or their caregiver are competent to prepare and safely administer the drug after appropriate training and with medical follow-up as necessary.

Administration in the evening or at bedtime may prevent or ameliorate some adverse effects (e.g., flu-like syndrome).

Administration of acetaminophen or other nonopiate analgesic at the time interferon alfa dose is given may reduce incidence of adverse effects.

IV Administration

Interferon Alfa-2b (Intron A)

Use single-dose vial of interferon alfa-2b powder for injection containing 10, 18, or 50 million units to prepare IV solutions. Do not use solution for injection available in multiple-dose vials for IV administration.

Melanoma (induction therapy): Reconstitute single-dose vial of powder for injection containing 10, 18, or 50 million units by adding 1 mL of sterile water for injection provided by manufacturer; resultant solution contains 10, 18, or 50 million units/mL. Withdraw appropriate dose of reconstituted solution and add to 100 mL of 0.9% sodium chloride injection. Do not dilute to final concentration <10 million units/100 mL (<100,000 units/mL).

Prepare IV solutions immediately before use.

Administer by IV infusion over 20 minutes.

IM Injection

Interferon Alfa-2b (Intron A)

Depending on indication and dosage, use single-dose vial of powder for injection or multiple-dose vial of solution.

When powder for injection is indicated for IM injection, reconstitute single-dose vial of powder for injection containing 10 or 50 million units by adding 1 mL of sterile water for injection provided by manufacturer; resultant solution contains 10 or 50 million units/mL, respectively. Withdraw appropriate dose and administer IM undiluted.

When multiple-dose vial containing 6 or 10 million units/mL is indicated for IM injection, withdraw appropriate dose and administer IM undiluted.

Administer IM into anterolateral thigh, upper arm, or outer area of the buttocks.

Chronic HBV infection: Use single-dose vial of powder for injection containing 10 million units or multiple-dose vial containing 10 million units/mL.

Chronic HCV infection: Use multiple-dose vial containing 6 million units/mL.

Hairy cell leukemia: Use single-dose vial of powder for injection containing 10 million units or multiple-dose vial containing 6 or 10 million units/mL. Do not use IM injection if platelet count <50,000/mm3.

AIDS-related Kaposi's sarcoma: Use single-dose vial of powder for injection containing 50 million units.

Sub-Q Injection

Interferon Alfa-2b (Intron A)

Depending on indication and dosage, use single-dose vial of powder for injection or multiple-dose vial of solution.

When powder for injection is indicated for sub-Q injection, reconstitute single-dose vial of powder for injection containing 10, 18, or 50 million units by adding 1 mL of sterile water for injection provided by manufacturer; resultant solution contains 10, 18, or 50 million units/mL, respectively. Withdraw appropriate dose and administer sub-Q undiluted.

When multiple-dose vial containing 6 or 10 million units/mL is indicated for sub-Q injection, withdraw appropriate dose and administer sub-Q undiluted.

Administer sub-Q into anterolateral thigh, upper arm, or abdomen (avoiding navel). Do not make sub-Q injections into areas where skin is irritated, red, bruised, infected, or has scars, stretch marks, or lumps.

Chronic HBV infection: Use single-dose vial of powder for injection containing 10 million units or multiple-dose vial containing 10 million units/mL.

Chronic HCV infection: Use multiple-dose vial containing 6 million units/mL.

Hairy cell leukemia: Use single-dose vial of powder for injection containing 10 million units or multiple-dose vial containing 6 or 10 million units/mL.

AIDS-related Kaposi's sarcoma: Use single-dose vial of powder for injection containing 50 million units. Do not use multiple-dose vials containing solution for injection.

Follicular non-Hodgkin's lymphoma: Use single-dose vial of powder for injection containing 10 million units or multiple-dose vial containing 6 or 10 million units/mL.

Melanoma (maintenance therapy): Use single-dose vial of powder for injection containing 10 or 18 million units or multiple-dose vial containing 6 or 10 million units/mL.

Intralesional Injection

Interferon Alfa-2b (Intron A)

Treatment of external genital and perianal warts (condylomata acuminata): Reconstitute single-dose vial of powder for injection containing 10 million units by adding 1 mL of sterile water for injection diluent provided by manufacturer; resultant solution contains 10 million units/mL. Withdraw appropriate dose and administer intralesionally undiluted. Alternatively, withdraw appropriate dose of solution for injection from multiple-dose vial containing 25 million units/mL and administer intralesionally undiluted.

Use a tuberculin or similar syringe and a 25- to 30-gauge short (e.g., 0.25- to 0.5-inch) needle. Direct needle toward center of base of wart, at an angle nearly parallel to the plane of the skin. Maintain needle at this angle to deliver the drug to dermal core of the lesion, infiltrating lesion and causing formation of a small wheal.

Do not use single-dose vials of powder for injection containing 18 or 50 million units or multiple-dose vials containing 6 million units/mL to prepare solutions for intralesional injection.

Interferon Alfa-n3 (Alferon N)

Treatment of external genital and perianal warts (condylomata acuminata): Administer intralesionally undiluted.

Use a 30-gauge needle. Direct needle toward base of wart.

Dosage

Because of differences in potencies and recommended dosages and routes of administration among the various commercially available interferon alfa preparations, use the interferon alfa preparation selected for the patient throughout the treatment regimen. Caution patients not to change brands or alter dosage without consulting clinician.

Pediatric Patients

Treatment of Chronic HBV Infection
Interferon Alfa-2b (Intron A)
Sub-Q

Children ≥1 year of age: 3 million units/m2 3 times weekly for first week, then 6 million units/m2 3 times weekly (maximum of 10 million units 3 times weekly).

Manufacturer recommends treatment duration of 16–24 weeks. AASLD recommends 16–24 weeks in hepatitis B e antigen (HBeAg) -positive patients and ≥12 months in HBeAg-negative patients. Duration of 24 months may increase rate of sustained response in HBeAg-negative patients.

Dosage modification for toxicity: Reduce dosage by 50% if leukocyte count <1500/mm3, granulocyte count <750/mm3, or platelet count <50,000/mm3. If leukocyte, granulocyte, and/or platelet counts return to normal or baseline values, resume at up to 100% of initial dosage. Permanently discontinue if leukocyte count <1000/mm3, granulocyte count <500/mm3, or platelet count <25,000/mm3.

Treatment of Chronic HCV Infection
Concomitant Interferon Alfa-2b (Intron A) and Oral Ribavirin
IM or Sub-Q

Children ≥3 years of age (treatment-naive): 3 million units 3 times weekly in conjunction with oral ribavirin.

Manufacturer of interferon alfa-2b recommends 18–24 months of concomitant therapy if well tolerated and serum ALT concentrations are normalized at 16 weeks; if ALT concentrations have not normalized or if high plasma HCV RNA levels persist after 16 weeks of treatment, consider discontinuance. Manufacturers of oral ribavirin recommend 24–48 weeks of concomitant therapy; consider discontinuance if plasma HCV RNA levels not below limits of detection at 24 weeks.

Dosage modification of interferon alfa-2b for toxicity: Reduce dosage by 50%; discontinue if reduced dosage not tolerated. Reduce dosage if leukocyte count 1000 to <1500/mm3, neutrophil count 500 to <750/mm3, or platelet count 50,000 to <70,000/mm3. Permanently discontinue if leukocyte count <1000/mm3, neutrophil count <500/mm3, platelet count <50,000/mm3, hemoglobin <8.5 g/dL, or Scr >2 mg/dL. If severe depression and/or suicidal ideation occurs, discontinue and initiate appropriate psychiatric care.

Adults

Treatment of Chronic HBV Infection
Interferon Alfa-2b (Intron A)
IM or Sub-Q

30–35 million units per week (given as 5 million units once daily or 10 million units 3 times weekly).

Manufacturer recommends treatment duration of 16 weeks. AASLD recommends 16–24 weeks in HBeAg-positive patients and ≥12 months in HBeAg-negative patients. Duration of 24 months may increase rate of sustained response in HBeAg-negative patients.

Dosage modification for toxicity: Reduce dosage by 50% if leukocyte count <1500/mm3, granulocyte count <750/mm3, or platelet count <50,000/mm3. If leukocyte, granulocyte, and/or platelet counts return to normal or baseline values, resume at up to 100% of initial dosage. Permanently discontinue if leukocyte count <1000/mm3, granulocyte count <500/mm3, or platelet count <25,000/mm3.

Treatment of Chronic HCV Infection
Concomitant Interferon Alfa-2b (Intron A) and Oral Ribavirin
IM or Sub-Q

3 million units 3 times weekly in conjunction with oral ribavirin.

Manufacturer of interferon alfa-2b recommends 18–24 months of concomitant therapy if well tolerated and serum ALT concentrations are normalized at 16 weeks; if ALT concentrations have not normalized or if high plasma HCV RNA levels persist after 16 weeks of treatment, consider discontinuance. Manufacturers of oral ribavirin recommend 24–48 weeks of concomitant therapy; consider discontinuance if plasma HCV RNA levels not below limits of detection at 24 weeks.

Dosage modification of interferon alfa-2b for toxicity: Reduce dosage by 50%; discontinue if reduced dosage not tolerated. Reduce dosage if leukocyte count 1000 to <1500/mm3, neutrophil count 500 to <750/mm3, or platelet count 25,000 to <50,000/mm3. Permanently discontinue if leukocyte count <1000/mm3, neutrophil count <500/mm3, platelet count <25,000/mm3, or hemoglobin concentration <8.5 g/dL. If severe depression and/or suicidal ideation occurs, decrease dosage and initiate appropriate psychiatric care.

Interferon Alfa-2b (Intron A) Monotherapy
IM or Sub-Q

3 million units 3 times weekly.

Manufacturer recommends treatment duration of 18–24 months if well tolerated and serum ALT concentrations are normalized at 16 weeks; if ALT concentrations have not normalized or if high plasma HCV RNA levels persist at 16 weeks, consider discontinuance.

Dosage modification for toxicity: If severe adverse effects develop, reduce dosage by 50% or temporarily interrupt therapy until adverse events resolve. Discontinue if intolerance persists after dosage adjustment.

Treatment of HPV Infections (External Genital and Perianal Warts)
Interferon Alfa-2b (Intron A)
Intralesional Injection

1 million units into each lesion (up to 5 lesions) 3 times weekly on alternate days for 3 weeks.

Another course may be administered after 12–16 weeks.

Interferon Alfa-n3 (Alferon N)
Intralesional Injection

250,000 units (0.05 mL) into each wart twice weekly for up to 8 weeks. Large warts may be injected at multiple locations around their periphery, using a total dose of 250,000 units per lesion. Maximum dose per treatment session is 2.5 million units.

Dosage modification for toxicity: Regimen may need to be modified or discontinued if moderate to severe adverse effects occur.

Delay administration of a second course or other therapy until 3 months after first course unless warts enlarge or new lesions develop; many patients do not exhibit complete resolution of lesions until 3 months following cessation of therapy.

Safety and efficacy of a second course not determined.

Hairy Cell Leukemia
Interferon Alfa-2b (Intron A)
IM or Sub-Q

2 million units/m2 3 times weekly. Administer sub-Q (not IM) if platelet count <50,000/mm3.

Optimum treatment duration not established. Manufacturer states continue for up to 6 months; patients not responding may benefit from continued treatment, but discontinue if disease progresses or fails to respond after 6 months of treatment. If no evidence of disease progression, some clinicians suggest continuing for at least 12 months before considering discontinuance for nonresponse.

Dosage modification for toxicity: If severe adverse effects develop, reduce dosage by 50% or temporarily interrupt therapy. If adverse effects abate, resume using reduced dosage (1 million units/m2 3 times weekly). Permanently discontinue if severe adverse effects persist or recur after dosage reduction.

AIDS-Related Kaposi’s Sarcoma
Interferon Alfa-2b (Intron A)
IM or Sub-Q

FDA-labeled dosage is 30 million units/m2 3 times weekly.

Response is slow; maximum effect occurs after ≥6 months of treatment. Continue until disease progresses or maximal response is achieved after 16 weeks of treatment.

Dosage modification for toxicity: If severe adverse effects develop, reduce dosage by 50% or temporarily interrupt therapy. If adverse effects abate, may resume using reduced dosage. Permanently discontinue if severe adverse effects persist or recur after dosage reduction.

Follicular non-Hodgkin’s Lymphoma
Interferon Alfa-2b (Intron A)
Sub-Q

5 million units 3 times weekly in conjunction with anthracycline-containing chemotherapy regimen. Continue interferon alfa-2b after completion of chemotherapy regimen; interferon alfa-2b is given for up to 18 months.

Doses of myelosuppressive drugs were reduced by 25% from full dose and cycle length increased by 33% (e.g., from 21 to 28 days) when interferon alfa was added to the regimen. Delay chemotherapy cycle if neutrophil counts <1500/mm3 or platelet counts <75,000/mm3.

Dosage modification of interferon alfa-2b for toxicity: Withhold if neutrophil count <1000/mm3 or platelet count <50,000/mm3. Reduce dosage by 50% (2.5 million units 3 times weekly) if neutrophil count >1000/mm3 but less than 1500/mm3. May reescalate to initial starting dosage (5 million units 3 times weekly) if hematologic toxicity resolves (ANC >1500/mm3). Permanently discontinue if AST >5 times ULN or Scr >2 mg/dL.

Melanoma
Interferon Alfa-2b (Intron A)
IV

Induction therapy: 20 million units/m2 daily for 5 consecutive days per week for 4 weeks.

Dosage modification for toxicity: Withhold for severe adverse effects (e.g., granulocyte count >250/mm3 but <500/mm3, ALT and/or AST >5 to 10 times ULN). When adverse effects abate, may reinitiate at 50% of previous dosage. Permanently discontinue if toxicity does not abate while drug withheld, serious adverse effects recur after reduced dosage, granulocyte count <250/mm3, or ALT and/or AST >10 times ULN.

Sub-Q

Maintenance therapy: 10 million units/m2 3 times weekly for 48 weeks.

Dosage modification for toxicity: Withhold for severe adverse effects (e.g., granulocyte count >250/mm3 but <500/mm3, ALT and/or AST >5 to 10 times ULN). When adverse effects abate, may reinitiate at 50% of previous dosage. Permanently discontinue if toxicity does not abate while drug withheld, serious adverse effects recur after reduced dosage, granulocyte count <250/mm3, or ALT and/or AST >10 times ULN.

Prescribing Limits

Pediatric Patients

Treatment of Chronic HBV Infection
Interferon Alfa-2b (Intron A)
Sub-Q

Maximum dosage is 10 million units 3 times weekly.

Adults

Treatment of HPV Infections (External Genital and Perianal Warts)
Interferon Alfa-2b (Intron A)
Intralesional Injection

Maximum 5 warts treated per course (total dose 5 million units).

Interferon Alfa-n3 (Alferon N)
Intralesional Injection

Maximum recommended dose per treatment session is 2.5 million units.

Special Populations

Renal Impairment

Treatment of Chronic HCV Infection
IM or Sub-Q

Concomitant interferon alfa-2b (Intron A) and oral ribavirin therapy contraindicated in patients with Clcr <50 mL/minute.

Cautions for Interferon Alfa

Contraindications

  • Interferon alfa-2a (Intron A): Known hypersensitivity (e.g., urticaria, angioedema, bronchoconstriction, anaphylaxis) to interferon alfa or any ingredient in the formulation.

  • Interferon alfa-n3 (Alferon N): Known hypersensitivity to human interferon alfa proteins or any component in the formulation; history of anaphylactic reactions to murine (mouse) IgG, egg protein, or neomycin. (See Sensitivity Reactions under Cautions.)

  • Interferon alfa-2b: Autoimmune hepatitis or hepatic decompensation (Child-Pugh score >6, class B and C). (See Hepatic Effects under Cautions.)

  • Interferon alfa-2b: Concomitant use of oral ribavirin 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 Clcr <50 mL/minute.

Warnings/Precautions

Warnings

Serious Disorders

May cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Monitor closely with periodic clinical and laboratory evaluations; discontinue in those with persistently severe or worsening signs or symptoms of these disorders. In many, but not all cases, these disorders resolve after interferon alfa discontinued. (See Other Warnings/Precautions under Cautions.)

Concomitant Oral Ribavirin

Observe usual cautions, precautions, and contraindications associated with oral ribavirin when the drug is used concomitantly with interferon alfa-2b for treatment of chronic HCV infection.

Ribavirin may cause birth defects and/or fetal death. If oral ribavirin used in conjunction with interferon alfa, extreme care must be taken to avoid pregnancy in female patients and female partners of male patients. (See Pregnancy under Cautions.)

Ribavirin causes hemolytic anemia, which may exacerbate cardiac disease.

Sensitivity Reactions

Serious, acute hypersensitivity reactions (e.g., urticaria, angioedema, bronchoconstriction, anaphylaxis) reported rarely in patients receiving interferon alfa.

If serious hypersensitivity reaction occurs, immediately discontinue interferon alfa and provide appropriate supportive care.

Transient rash reported; has not necessitated interruption of interferon alfa treatment.

Interferon alfa-n3: May contain trace amounts of murine (mouse) protein which can stimulate antibody formation in some patients. Although egg protein (ovalbumin) not detected in final product, manufacturing process includes propagation in chick embryo tissue culture and possibility exists that patients receiving the drug could develop hypersensitivity to egg protein. (See Contraindications under Cautions.)

Other Warnings/Precautions

Neuropsychiatric Effects

Depression, psychoses, suicidal ideation or suicidal attempts (including some fatalities), hallucinations, aggressive or violent behavior, and rare cases of homicidal ideation reported with interferon alfa (alone or in conjunction with oral ribavirin) in patients with and without preexisting psychiatric disorders.

Exacerbated symptoms of psychiatric disorders may occur in patients with both psychiatric and substance use disorders. If initiated in patient with history of psychiatric conditions or substance use disorders, consider need for drug screening and periodic clinical evaluation, including psychiatric symptom monitoring. Early intervention for new or re-emergent neuropsychiatric symptoms or substance use recommended.

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

Use with caution in patients with history of preexisting psychiatric disorders, especially those with history of depression. Closely monitor all patients for evidence of depression and other psychiatric symptoms and advise patients to immediately report any sign or symptom of depression or suicidal ideation to their clinician.

If severe depression and/or other psychiatric condition develops, immediately discontinue interferon alfa and provide appropriate psychiatric intervention.

Cardiovascular Effects

Hypotension, arrhythmia, tachycardia (≥150 bpm), cardiomyopathy, and MI reported in patients with or without history of cardiovascular disease.

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

Perform ECG prior to and periodically during interferon alfa therapy in patients with preexisting cardiac abnormalities and/or advanced stages of cancer.

Use with caution and close monitoring in those with cardiovascular disease or history of any cardiac condition, including MI or arrhythmia. Do not use concomitant interferon alfa and oral ribavirin in patients with history of substantial or unstable cardiac disease.

Cerebrovascular Effects

Ischemic and hemorrhagic cerebrovascular events, including hemorrhagic stroke, reported in patients receiving interferon alfa. Such events have occurred in patients with few or no risk factors for stroke, including patients <45 years of age.

Causal relationship not established.

Myelosuppression

Suppresses bone marrow function and may cause severe cytopenias and anemia, including aplastic anemia.

Do not use in patients with hemoglobinopathies (e.g., thalassemia, sickle cell anemia).

Perform CBCs prior to and routinely during interferon alfa therapy. Adjust dosage or discontinue drug if necessary. (See Dosage under Dosage and Administration.)

Because mild to moderate leukopenia has been reported in patients receiving intralesional interferon alfa, also consider hematologic monitoring in these patients.

Use with caution in patients with coagulation disorders (e.g., pulmonary embolism, thrombophlebitis, hemophilia). Also use with caution in patients with myelosuppression or receiving drugs that may be myelosuppressive (e.g., zidovudine). (See Specific Drugs under Interactions.)

Flu-like Syndrome

Most frequent adverse effect of interferon alfa is flu-like syndrome, generally characterized by fever, headache, chills, myalgia/arthralgia, fatigue, increased sweating, asthenia, rigors, dizziness, influenza-like symptoms, back pain, dry mouth, chest pain, malaise, and pain (unspecified). Consider other possible causes if persistent high fever occurs.

Use with caution in patients with debilitating diseases such as cardiac disease (e.g., unstable angina, uncontrolled CHF), severe pulmonary disease (e.g., COPD), or diabetes mellitus (prone to ketoacidosis).

Ophthalmologic Effects

Decrease 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.

Perform baseline ophthalmologic examinations in all patients prior to initiation of interferon alfa. Perform ophthalmologic examinations periodically during interferon alfa therapy in those with preexisting ophthalmologic disorders (e.g. diabetic or hypertensive retinopathy).

Perform prompt and complete eye examination in any patient who develops ocular symptoms.

Discontinue in patients who develop new or worsening ophthalmologic disorders.

Endocrine and Metabolic Effects

May cause or aggravate thyroid dysfunction (hypothyroidism or hyperthyroidism).

Evaluate TSH prior to initiation of interferon alfa. If symptoms consistent with possible thyroid dysfunction occur during interferon alfa therapy, evaluate thyroid function and initiate treatment if needed.

Interferon alfa can be continued in patients with hypothyroidism or hyperthyroidism if thyroid function can be normalized with antithyroid therapy or hormone replacement therapy.

Development of diabetes mellitus and hyperglycemia reported rarely in patients receiving interferon alfa. Interferon alfa can be continued in patients with diabetes mellitus as long as their diabetes can be controlled with drug therapy.

Hepatic Effects

Patients with chronic HBV infection may experience transient increase (>2 times baseline) in serum ALT (“flare”), usually 8–12 weeks following initiation of therapy. Interferon alfa generally can be continued, unless there are signs and symptoms of liver failure. Monitor symptomatology, liver function tests (serum ALT, alkaline phosphatase, albumin, bilirubin), and PT at approximately 2-week intervals during these occurrences. Patients with chronic HBV infection and evidence of decreasing hepatic synthetic function (e.g., decreasing serum albumin, prolonged PT) may be at increased risk of clinical decompensation if an increase in serum ALT occurs during interferon alfa therapy; use the drug with caution and close monitoring of symptoms and liver function tests if serum ALT increases.

Closely monitor patients who develop liver function abnormalities (e.g., increase in serum ALT) during interferon alfa therapy and discontinue the drug as needed.

Worsening liver disease, including jaundice, hepatic encephalopathy, hepatic failure, and death, reported in patients with decompensated liver disease, autoimmune hepatitis, history of autoimmune disease, or immunosuppression (e.g., organ transplant recipients) treated with interferon alfa; do not use the drug in these patients.

Immediately discontinue if manifestations of hepatic decompensation (e.g., jaundice, ascites, coagulopathy, decreased serum albumin concentrations) occur. Contraindicated in patients with hepatic decompensation. (See Contraindications under Cautions.)

Respiratory Effects

Dyspnea, pulmonary infiltrates, pneumonia, bronchiolitis obliterans, interstitial pneumonitis, pulmonary hypertension, and sarcoidosis reported; respiratory failure and/or death has occurred, principally in those receiving the drug for treatment of chronic HCV infection. Etiologic explanation for these findings not established.

One manufacturer suggests baseline chest radiographs in all patients before initiating interferon alfa and whenever clinically indicated in patients who develop fever, cough, dyspnea, or other respiratory symptoms during therapy.

Recurrence of respiratory failure has occurred with interferon rechallenge; closely monitor patients if interferon alfa resumed.

Autoimmune Disease

Development or exacerbation of autoimmune disease (e.g., autoimmune thrombocytopenia, idiopathic thrombocytopenic purpura, vasculitis, Raynaud’s phenomenon, rheumatoid arthritis, psoriasis, interstitial nephritis, thyroiditis, lupus erythematosus, hepatitis, rhabdomyolysis) reported in patients receiving interferon alfa. Fatalities reported rarely.

If autoimmune disease develops, closely monitor and discontinue the drug if necessary.

Risk of Transmissible Infectious Agents from Plasma-derived Preparations

Interferon alfa-2b contains albumin (a derivative of human blood); interferon alfa-n3 is produced using human leukocytes. 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).

Pancreatitis

Pancreatitis (sometimes fatal) reported in patients receiving interferon alfa.

Suspend interferon alfa in patients with signs and symptoms of pancreatitis (e.g., abdominal pain, nausea, vomiting); discontinue the drug if a diagnosis of pancreatitis is established.

Peripheral Neuropathy

Peripheral neuropathy reported in patients receiving telbivudine concomitantly with an interferon alfa. (See Specific Drugs under Interactions.)

Triglycerides

Increased serum triglycerides reported in patients receiving interferon alfa alone or in conjunction with oral ribavirin; severe hypertriglyceridemia may result in pancreatitis. (See Pancreatitis under Cautions.)

Consider discontinuing interferon alfa in patients with persistently elevated triglycerides (>1000 mg/dL) accompanied by symptoms suggestive of pancreatitis (abdominal pain, nausea, vomiting).

Dental and Periodontal Disorders

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

Advise patients to have regular dental examinations during treatment, brush their teeth thoroughly twice daily, and rinse their mouth thoroughly after vomiting.

Antibody Formation

Serum anti-interferon neutralizing antibodies may develop in patients receiving interferon alfa.

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

Organ Transplant Recipients

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

Specific Populations

Pregnancy

Interferon alfa (alfa-2b, alfa-n3) monotherapy: Category C.

Concomitant interferon alfa (alfa-2b) and oral ribavirin: Category X.

Lactation

Not known whether interferon alfa is distributed into milk; murine interferons distribute into milk in mice. Discontinue nursing or the drug.

Pediatric Use

Interferon alfa-2b: Safety and efficacy established for treatment of chronic HBV infection in children 1–17 years of age and for treatment of chronic HCV infection in treatment-naive children 3–16 years of age. Safety and efficacy not established for any other indications in pediatric patients.

Interferon alfa-n3: Safety and efficacy not established in children <18 years of age.

Suicidal ideation or attempted suicide reported more frequently in pediatric patients (principally adolescents) receiving interferon alfa than in adults receiving the drug; these events occurred during treatment and following discontinuance.

Delay in weight and height increases compared with baseline reported in pediatric patients receiving interferon alfa for treatment of chronic HBV or HCV infection.

Geriatric Use

Insufficient experience in those ≥65 years of age to determine whether they respond differently than younger adults.

Use with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.

Hepatic Impairment

Patients with chronic HBV infection may be at risk for transient acute exacerbations (flares) of HBV infection. (See Hepatic Effects under Cautions.)

Closely monitor clinical status and hepatic function; immediately discontinue interferon alfa if decompensation occurs. (See Hepatic Effects under Cautions.)

Interferon alfa-2b: Contraindicated in patients with autoimmune hepatitis or hepatic decompensation (Child-Pugh score >6, class B and C).

Renal Impairment

Concomitant interferon alfa-2b and oral ribavirin contraindicated if Clcr <50 mL/minute.

Common Adverse Effects

Flu-like symptoms (e.g., fever, headache, chills, myalgia/arthralgia, fatigue, increased sweating, asthenia, rigors, dizziness), abdominal pain, alopecia, anemia, anorexia, back pain, depression, diarrhea, dyspnea, musculoskeletal pain, nausea, neutropenia, pharyngitis, somnolence, vomiting, weight loss.

Interactions for Interferon Alfa

Drugs Metabolized by Hepatic Microsomal System

Interferons may inhibit hepatic CYP enzyme system.

Specific Drugs

Drug

Interaction

Comments

Aldesleukin

Hypersensitivity reactions, development or exacerbation of autoimmune disease and inflammatory disorders, and increased incidence of myocardial injury (e.g., MI, myocarditis, ventricular hypokinesia, severe rhabdomyolysis) reported

Antineoplastic agents

Additive or synergistic antineoplastic activity with certain cytotoxic agents (e.g., cisplatin, cyclophosphamide, doxorubicin, eflornithine, fluorouracil, mechlorethamine, melphalan, mitomycin, nitrosoureas, vinblastine, vincristine)

HCV antivirals

Boceprevir: In vitro evidence of additive effects with interferon alfa-2b against HCV; no in vitro evidence of antagonism

Simeprevir: In vitro evidence of synergistic effects with interferon alfa against HCV; no in vitro evidence of antagonism

Sofosbuvir: No in vitro evidence of antagonistic anti-HCV effects with interferon alfa

Telaprevir: No in vitro evidence of antagonistic anti-HCV effects with interferon alfa

Myelosuppressive agents

Increased risk of myelosuppression

Use concomitantly with caution; monitor WBC count

Phenobarbital

Possible increased phenobarbital concentrations and toxicity (e.g., lethargy, fatigue)

Radiation therapy

May result in severe toxicity

Close monitoring advised

Ribavirin

Possible additive hematologic toxicity (anemia)

Concomitant use with oral ribavirin contraindicated if Clcr <50 mL/minute

Telbivudine

Increased risk and severity of peripheral neuropathy

Safety and efficacy of concomitant telbivudine and any interferon for treatment of chronic HBV infection not established

Theophylline

Increased theophylline concentrations

Vinca alkaloids (vinblastine, vincristine)

Possible increased toxicity of interferon alfa

Increased incidence of neurotoxicity

Zidovudine

Increased risk of hematologic (e.g., neutropenia, thrombocytopenia) and hepatic toxicity

Use concomitantly with caution; monitor WBC count

Interferon Alfa Pharmacokinetics

Absorption

Bioavailability

Interferon alfa is well absorbed following IM or sub-Q injection; mean serum concentrations following IM injection comparable to those following sub-Q injection.

Following IV administration (interferon alfa-2b), peak serum concentrations achieved in 30 minutes.

Following IM or sub-Q injection (interferon alfa-2b), peak serum concentrations achieved in 3–12 hours.

Following intralesional injection (interferon alfa-2b dosage of 3 million units weekly per wart for 4 weeks), serum concentrations of the drug ranged from 5–40 units/mL. Peak serum concentrations reported to occur in 6 hours.

Following intralesional injection into anogenital warts (interferon alfa-n3), plasma concentrations of interferon were undetectable (detection limit 3 units/mL); some systemic absorption apparently occurs because adverse systemic effects were reported in these patients.

Distribution

Extent

Interferons are widely and rapidly distributed into body tissues after systemic administration; highest concentrations occur in spleen, kidney, liver, and lung.

Does not readily distribute into CSF following systemic administration of mixtures of naturally occurring human or recombinant interferons; low concentrations detected in CSF following administration of large systemic doses.

Not known whether interferon crosses the placenta in humans.

Distributed into milk in mice; not known whether interferon distributed into human milk.

Elimination

Metabolism

Interferon alfa appears to be metabolized principally in the kidney. Hepatic metabolism and subsequent biliary excretion may be a minor pathway.

Elimination Route

Interferon alfa generally undetectable or present only in trace quantities in urine.

Half-life

Following IV infusion (interferon alfa-2b): 2 hours (range: 0.5–2.9 hours).

Following IM or sub-Q injection (interferon alfa-2b): 2–3 hours.

Special Populations

Limited data indicate that serum concentrations and clearance of interferon not substantially altered in those with chronic renal failure. May accumulate in body fluids of patients with markedly depressed GFR and Clcr.

Stability

Storage

Parenteral

Solution for Injection

Interferon alfa-2b (Intron A) multiple-dose vials: 2–8°C; do not freeze or expose to heat. After initial dose is given, discard any solution remaining in vial after 1 month.

Interferon alfa-n3 (Alferon N): 2–8°C; protect from freezing.

Powder for Injection

Interferon alfa-2b (Intron A): 2–8°C. Use immediately after reconstitution; may be stored at 2–8°C for up to 24 hours.

Actions and Spectrum

  • Interferon alfa is a naturally occurring protein with antiviral, antineoplastic, and immunomodulating activity. Commercially available in US as interferon alfa-2b and interferon alfa-n3.

  • Interferon alfa-2b (Intron A): Single interferon subtype; recombinant preparation obtained from bacterial fermentation of Escherichia coli containing a genetically engineered plasmid with a human interferon alfa-2b gene.

  • Interferon alfa-n3 (Alferon N): Mixture of naturally occurring human interferon alfa proteins; precise subtype composition not determined; manufactured from pooled units of human leukocytes induced by incomplete infection with a murine virus (Sendai virus) to produce interferon alfa-n3.

  • Mechanisms of action of interferon alfa not fully elucidated.

  • Interferons 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.

Advice to Patients

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

  • Importance of reading the manufacturer's patient information and medication guide.

  • If patient and/or their caregiver is to administer IM or sub-Q interferon alfa, provide careful instructions on proper administration methods, disposal procedures, and the importance of not reusing needles and syringes; provide patient with manufacturer's instructions for use.

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

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

  • Advise patients with 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). Importance of taking precautions to prevent transmission of HCV.

  • Advise patients that laboratory evaluations are required before starting and periodically during treatment.

  • Advise patients 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.

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

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

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

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

  • 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.

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

  • Importance of advising patients of other important precautionary information. (See Cautions.)

Preparations

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

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

Interferon Alfa-2b (Recombinant DNA Origin)

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection

10 million units

Intron A (available as single-dose vials with sterile water for injection diluent)

Schering

18 million units

Intron A (available as single-dose vials with sterile water for injection diluent)

Schering

50 million units

Intron A (available as single-dose vials with sterile water for injection diluent)

Schering

Injection

6 million units/mL (18 million units)

Intron A (available as multiple-dose vials)

Schering

10 million units/mL (25 million units)

Intron A (available as multiple-dose vials)

Schering

Interferon Alfa-n3 (Human Leukocyte Origin)

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection

5 million units/mL

Alferon N (with albumin human and phenol)

Hemispherx

AHFS DI Essentials™. © Copyright 2021, Selected Revisions October 30, 2014. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

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