PDR MEMBER LOGIN:
  • PDR Search

    Required field
  • Advertisement
  • CLASSES

    Interferons, Beta
    MS Agents

    DEA CLASS

    Rx

    DESCRIPTION

    Recombinant interferon beta; not glycosylated
    Indicated for relapsing forms of multiple sclerosis, such as clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease
    May increase the risk for depression, suicidal ideation, and suicide attempts

    COMMON BRAND NAMES

    Betaseron, Extavia

    HOW SUPPLIED

    Betaseron/Extavia/Interferon Beta-1b Subcutaneous Inj Pwd F/Sol: 0.3mg

    DOSAGE & INDICATIONS

    For treatment of relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease.
    NOTE: Interferon beta-1b has been designated as an orphan drug by the FDA for this indication.
    Subcutaneous dosage
    Adults

    250 mcg subcutaneously every other day. To achieve the dose, incremental dose titration every 2 weeks is recommended (62.5 mcg subcutaneously every other day during weeks 1 and 2, 125 mcg subcutaneously every other day during weeks 3 and 4, 187.5 mcg subcutaneously every other day during weeks 5 and 6). In a large comparative study, a higher dose of 500 mcg subcutaneously every other day was not more efficacious in regard to relapse risk among treatment naive patients with an Expanded Disability Status Scale of 5 or less.[34226] Limited data have shown a lower dose (50 mcg subcutaneously every other day) is superior to placebo in regard to decreasing the overall exacerbation rate and moderate and severe exacerbation rate.[23837] [24498]

    MAXIMUM DOSAGE

    Adults

    250 mcg every other day subcutaneously.

    Geriatric

    250 mcg every other day subcutaneously.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    For storage information, see specific product information within the How Supplied section.

    Injectable Administration

    Interferon beta-1b is administered only by subcutaneous injection.
    The initial injection should be performed under the supervision of a healthcare professional. Patients and caregivers should be properly trained in all aspects of interferon beta-1b injection prior to independent use. See the "Instructions for Use" for the product prescribed. Assess the physical and cognitive abilities of the patient to properly self-administer and dispose of syringes. Patients with severe neurological deficits should not administer interferon beta-1b without assistance from a trained caregiver.
    The manufacturers of Betaseron and of Extavia offer materials to assist with training on subcutaneous injection administration for patients and their health care partners. Information may be obtained by calling 1-800-788-1467 for Betaseron and 1-888-669-6682 for Extavia.
    Premedication with acetaminophen or ibuprofen and administration of interferon at bedtime may lessen the severity of flu-like symptoms.
    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Do not use if particulate matter is present in the reconstituted product or if the solution is not colorless.

    Subcutaneous Administration

    Reconstitution (Betaseron or Extavia pre-filled syringes)
    Add the manufacturer supplied diluent (0.54% Sodium Chloride injection solution, 1.2 mL) as instructed in the product directions to the vial by using the vial adapter to attach the prefilled syringe that contains the diluent. Gently swirl the vial to aid in dissolution; do NOT shake. If foaming occurs, allow the vial to sit undisturbed until the foam settles. The final concentration is 250 mcg/mL.
    The removable rubber cap of the diluent for the Extavia product contains natural rubber latex, which may cause allergic reactions and should not be handled by individuals with latex hypersensitivity.
    Storage: If not used immediately, the reconstituted injection may be stored in the refrigerator for up to 3 hours; do not freeze the reconstituted product. Discard any unused portion after 3 hours.
    Subcutaneous injection
    Withdraw the desired amount of the reconstituted solution into the syringe by turning the vial and syringe to get the vial on top. Pull the plunger back to get the desired amount of product into the syringe. Turn the syringe to point the needle upward, and tap the syringe and release any air bubbles. Twist the vial adapter to remove it and the vial.
    Choose an injection site on the back of the upper arms; abdomen; buttocks; or front thighs. Do not inject within 2 inches of the navel or in a site where the skin is red, bruised, infected, broken, painful, uneven, or scabbed. Also, do not inject into the same site for consecutive injections. Rotate injection sites to minimize injection site reactions such as necrosis or localized infection.
    Inject subcutaneously. Take care not to inject intradermally.
    Use safe disposal procedures for needles and syringes; do not re-use needles or syringes.
     
    Subcutaneous injection of Betaseron using the Betaconnect autoinjector
    The optional Betaconnect autoinjector is not supplied with Betaseron, but is available for patients with a prescription for Betaseron by calling the BETAPLUS patient support program toll-free number in the U.S. at 1-800-788-1467.
    The autoinjector has 3 adjustable injection depth settings; the healthcare provider should determine proper depth setting and injection technique.
    Betaconnect must be charged fully before the first use. Turn the injector on. Wait for the power-on self-test to finish. When finished, the injection button will glow blue, and the green light bar will display the charge status. If the on/off button blinks green continuously or the light bar blinks red, consult troubleshooting instructions.
    Only use the syringes that come in the Betaseron packaging with the autoinjector. Prepare the syringes as above.
    Press the blue lid release button on the side of the autoinjector and fully open the lid. Place the syringe inside the autoinjector leaving the needle cap on. Close the lid.
    The autoinjector is ready for injection when the injection button displays a steady blue light.
    Choose an injection site such as the abdomen, back of the upper arm, thigh, or buttock. Do not inject in the area near the navel or waistline. Rotate injection sites with each injection.
    Remove the needle cap. Activate the safety release by holding the injector against the skin at a 90-degree angle.
    Inject subcutaneously. Press and release the injection button to start the injection. The blue light bar displays the progress of the injection. Injection is complete when blue, flashing bar displays blue and 2 short beeps occur.
    The unit will automatically power off when the injection is complete.
    Press the blue lid release button to open the lid and remove the syringe.
    Keep the safety release clean using a dry or slightly damp cloth or alcohol wipe.

    STORAGE

    Betaseron:
    - Discard unused portion. Do not store for later use.
    - Protect from freezing
    - Reconstituted product should be refrigerated and used within 3 hours if not used immediately
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Extavia:
    - Discard unused portion. Do not store for later use.
    - Protect from freezing
    - Reconstituted product should be refrigerated and used within 3 hours if not used immediately
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Pregnancy

    There are no data available on interferon beta-1b use during human pregnancy from well-controlled studies. Observational studies of interferon beta-1b in women have generally not indicated a drug-associated risk of major birth defects.[44450] However, spontaneous abortions were reported in 4 patients while receiving interferon beta-1b during clinical trials.[44449] Increased risks for lower mean birth weight, shorter mean birth length, and preterm birth (less than 37 weeks) without spontaneous abortion were reported during a systemic review of 761 interferon-beta exposed pregnancies; no increased risk for congenital anomalies was found.[63530] The National Multiple Sclerosis Society consensus guidelines and the product labels recommend that women discontinue interferon beta therapy when trying to conceive and throughout gestation due to insufficient evidence regarding safety to the human fetus; however, most women who happen to conceive while taking interferon beta appear to have healthy newborns. If a patient does become pregnant while receiving interferon therapy, she should be made aware of the risks; discontinuation of interferon therapy during pregnancy is recommended.[63530] [44450] [44449] The risks and benefits of continuing interferon beta therapy during pregnancy require careful consideration of the patient's level of disease activity, personal preferences, and the potential fetal risks. During animal studies, a dose-related abortifacient effect was observed when interferon beta-1b was given to pregnant rhesus monkeys at exposures of 3 or more times the human therapeutic dose of 0.25 mg on a body surface area (mg/m2) basis.[44450] The effects of interferon beta-1b during labor and delivery are unknown.[44450] [44449]

    Heart failure

    Interferon beta-1b should be used cautiously in patients with a history of heart failure. Patients with preexisting congestive heart failure (CHF) should be monitored for worsening of their cardiac condition during initiation of and continued treatment with interferon beta-1b. It is not known to be directly cardiotoxic, however, cases of CHF, cardiomyopathy, and cardiomyopathy with CHF have been reported in patients without known predisposition to these events, and without other known etiologies being established. In some cases, these events have been temporally related to the administration of interferon beta-1b. Upon rechallenge, CHF recurrence was observed in some patients. If CHF worsens without another etiology, consider cessation of interferon beta therapy. Flu-like symptoms have been reported in patients receiving interferon beta-1b in clinical trials. The flu-like symptoms associated with interferon beta-1b may place stress on patients with cardiac disease. Analgesics and/or antipyretics on treatment days may help ameliorate flu-like symptoms associated with interferon beta-1b.

    Albumin hypersensitivity, E. coli protein hypersensitivity, mannitol hypersensitivity

    Interferon beta-1b contains mannitol and human albumin. Interferon beta-1b is contraindicated in patients with albumin hypersensitivity and may be inappropriate for patients with mannitol hypersensitivity. Interferon beta-1b may also be inappropriate for patients with E. coli protein hypersensitivity, as the product contains trace amounts of E. coli protein.

    Breast-feeding

    There are limited data regarding the use of interferon beta-1b during breast-feeding, and its excretion into human milk is unknown.[44449] [44450] Due to its poor oral bioavailability, any drug present in the breast milk is unlikely to be systemically absorbed by the nursing infant.[61642] The estimated relative infant dose would be 0.006% of the maternal dose, according to one review.[61643] An infant who was exclusively breast-fed through 5 months of age had no adverse effects due to interferon beta exposure.[63531] The Multiple Sclerosis Centre of Excellence on Reproduction and Child Health considers interferon beta to be moderately safe for use during lactation since the molecular weight of the drug is likely to limit transfer to breast milk. Other reviews concur that interferon beta is likely compatible with breast-feeding. Glatiramer and interferon beta-1a are potential alternatives to consider for the treatment of multiple sclerosis. However, the standard of care based is to have a mother start disease-modifying therapy of any type only after complete weaning of their infant. A discussion about the risks and benefits of postponing the resumption of interferon beta treatment in order to breast-feed is important, particularly for women who experience highly-active disease or who had active multiple sclerosis in the year prior to conception.[61642] [61643] [62512] Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for interferon beta-1b and any potential adverse effects on the breast-fed infant.[44449] [44450]

    Children, infants, neonates

    The safety and efficacy of interferon beta-1b have not been established in neonates, infants, children and adolescents 18 years of age or younger.

    Depression, suicidal ideation

    Interferon beta-1b should be used with caution in patients with depression. Depression and suicide have been reported with interferon beta-1b treatment of multiple sclerosis. Patients treated with interferon beta should report immediately any symptoms of depression or suicidal ideation to their prescriber or health-care professional. If a patient develops depression, consider cessation of interferon beta therapy.

    Bone marrow suppression

    Patients with pre-existing bone marrow suppression or who are receiving myelosuppression therapy may be at increased risk of developing hematologic toxicity during interferon beta-1b therapy. Complete blood and differential white blood cell counts, platelet counts, and blood chemistries are recommended at 1, 3, and 6 months after interferon beta-1b initiation and periodically thereafter in the absence of clinical symptoms. Patients with myelosuppression may require more intensive monitoring of complete blood cell counts, with differential and platelet counts.

    Hyperthyroidism, hypothyroidism, thyroid disease

    Cautious use of interferon beta-1b is warranted for patients with thyroid disease such as hyperthyroidism or hypothyroidism. The drug may be associated with thyroid-related adverse effects. Thyroid function tests are recommended every six months for patients with a history of thyroid dysfunction or as clinically indicated.

    Hepatic disease, hepatitis

    Patients with hepatitis or other hepatic disease may not be appropriate candidates for interferon beta-1b receipt. Adverse hepatic events have been associated with the drug. Rare cases of severe hepatic injury including hepatic failure, some due to autoimmune hepatitis, have been reported. Consider the potential risk of hepatotoxicity when used in combination with known hepatotoxic drugs or other products (e.g., alcohol) prior to interferon beta-1b administration, or when adding new agents to the regimen if patients are currently receiving interferon beta-1b. Monitor for signs and symptoms of hepatic injury. Liver function tests are recommended at 1, 3, and 6 months after interferon beta-1b initiation and periodically thereafter in the absence of clinical symptoms. Consider discontinuing interferon beta-1b if serum transaminase levels significantly increase, or if they are associated with clinical symptoms such as jaundice.

    Seizures

    Interferon beta-1b should be used with caution in patients with pre-existing seizure disorders; seizures have been reported during clinical trials and post-marketing surveillance of interferons. However, it is not known whether these events were related to a primary seizure disorder, the effects of multiple sclerosis alone, to the use of beta interferons, or to some combination of these and other potential precipitants of seizures such as fever.

    Hemolytic-uremic syndrome, thrombotic thrombocytopenic purpura (TTP)

    Cases of thrombotic microangiopathy, including thrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome (HUS), have been reported with interferon beta-1b. Cases have been reported several weeks to years after treatment initiation. Some cases have been fatal. Discontinue therapy if clinical symptoms and laboratory parameters consistent with thrombotic microangiopathy develop, and manage as appropriate.

    Latex hypersensitivity

    The removable rubber cap of the diluent (0.54% Sodium Chloride Solution) pre-filled syringe for the Extavia formulation contains natural rubber latex, which may cause allergic reactions and should not be handled by individuals with latex hypersensitivity.

    ADVERSE REACTIONS

    Severe

    tissue necrosis / Early / 4.0-4.0
    vasculitis / Delayed / Incidence not known
    suicidal ideation / Delayed / Incidence not known
    pancreatitis / Delayed / Incidence not known
    cardiomyopathy / Delayed / Incidence not known
    heart failure / Delayed / Incidence not known
    hemolytic anemia / Delayed / Incidence not known
    spontaneous fetal abortion / Delayed / Incidence not known
    anaphylactic shock / Rapid / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    bronchospasm / Rapid / Incidence not known
    angioedema / Rapid / Incidence not known
    seizures / Delayed / Incidence not known
    capillary leak syndrome / Early / Incidence not known
    hepatic failure / Delayed / Incidence not known
    hemolytic-uremic syndrome / Delayed / Incidence not known
    thrombotic microangiopathy / Delayed / Incidence not known
    thrombotic thrombocytopenic purpura (TTP) / Delayed / Incidence not known
    lupus-like symptoms / Delayed / Incidence not known

    Moderate

    lymphopenia / Delayed / 86.0-86.0
    antibody formation / Delayed / 16.5-45.0
    hypertonia / Delayed / 40.0-40.0
    depression / Delayed / 30.0-30.0
    leukopenia / Delayed / 13.0-18.0
    neutropenia / Delayed / 13.0-13.0
    peripheral edema / Delayed / 12.0-12.0
    elevated hepatic enzymes / Delayed / 4.0-12.0
    chest pain (unspecified) / Early / 9.0-9.0
    impotence (erectile dysfunction) / Delayed / 8.0-8.0
    hypertension / Early / 6.0-6.0
    lymphadenopathy / Delayed / 6.0-6.0
    dyspnea / Early / 6.0-6.0
    myasthenia / Delayed / 0-2.0
    constipation / Delayed / 0-2.0
    sinus tachycardia / Rapid / 0-2.0
    palpitations / Early / 0-2.0
    peripheral vasodilation / Rapid / 0-2.0
    erythema / Early / Incidence not known
    confusion / Early / Incidence not known
    hypertriglyceridemia / Delayed / Incidence not known
    thrombocytopenia / Delayed / Incidence not known
    hyperthyroidism / Delayed / Incidence not known
    hypothyroidism / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known

    Mild

    injection site reaction / Rapid / 40.0-78.0
    asthenia / Delayed / 53.0-53.0
    headache / Early / 50.0-50.0
    fever / Early / 31.0-31.0
    myalgia / Early / 23.0-23.0
    chills / Rapid / 21.0-21.0
    insomnia / Early / 21.0-21.0
    rash / Early / 21.0-21.0
    abdominal pain / Early / 16.0-16.0
    menstrual irregularity / Delayed / 12.0-12.0
    urinary urgency / Early / 11.0-11.0
    malaise / Early / 6.0-6.0
    arthralgia / Delayed / 0-2.0
    muscle cramps / Delayed / 0-2.0
    dizziness / Early / 0-2.0
    anxiety / Delayed / 0-2.0
    dyspepsia / Early / 0-2.0
    nausea / Early / 0-2.0
    diarrhea / Early / 0-2.0
    menorrhagia / Delayed / 0-2.0
    dysmenorrhea / Delayed / 0-2.0
    weight gain / Delayed / 0-2.0
    alopecia / Delayed / 0-2.0
    anorexia / Delayed / Incidence not known
    diaphoresis / Early / Incidence not known
    emotional lability / Early / Incidence not known
    vomiting / Early / Incidence not known
    weight loss / Delayed / Incidence not known
    urticaria / Rapid / Incidence not known
    pruritus / Rapid / Incidence not known
    infection / Delayed / Incidence not known

    DRUG INTERACTIONS

    Abacavir: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
    Abacavir; Dolutegravir; Lamivudine: (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6). (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
    Abacavir; Lamivudine, 3TC: (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6). (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
    Abacavir; Lamivudine, 3TC; Zidovudine, ZDV: (Major) Use interferons and zidovudine together with caution. Closely monitor patients for treatment-associated toxicities, especially hematologic effects and hepatic decompensation, and manage as recommended for the individual therapies. Coadministration of alpha interferons may increase the hematologic toxicity of zidovudine. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) are also associated with hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. Interferon therapy may also reduce zidovudine clearance. (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6). (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
    Alemtuzumab: (Major) Concomitant use of interferon beta with alemtuzumab may increase the risk of immunosuppression. Avoid the use of these drugs together.
    Amprenavir: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. The HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART.
    Atazanavir: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. The HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART.
    Atazanavir; Cobicistat: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. The HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART.
    Bictegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
    Cabotegravir; Rilpivirine: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and rilpivirine can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving antiretroviral agents and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
    Chloroquine: (Moderate) Concurrent use of chloroquine and interferons is not recommended as there is an increased risk of retinal toxicity.
    Darunavir: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. The HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART.
    Darunavir; Cobicistat: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. The HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. The HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. The HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART.
    Delavirdine: (Major) The concomitant use of interferons and anti-retroviral non-nucleoside reverse transcriptase inhibitors (NNRTIs) should be done with caution as both can cause hepatic damage. NNRTIs may cause liver damage in the context of hypersensitivity reactions or by direct toxic effects. Many studies demonstrate that nevirapine is more hepatotoxic than efavirenz. Underlying chronic HCV infection enhances the risk of developing liver enzyme elevations in patients receiving nevirapine. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation.
    Dolutegravir; Lamivudine: (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6).
    Dolutegravir; Rilpivirine: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and rilpivirine can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving antiretroviral agents and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
    Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6).
    Efavirenz: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and efavirenz can both cause hepatotoxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
    Efavirenz; Emtricitabine; Tenofovir: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and efavirenz can both cause hepatotoxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6). (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and efavirenz can both cause hepatotoxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
    Emtricitabine: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and rilpivirine can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving antiretroviral agents and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and rilpivirine can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving antiretroviral agents and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
    Emtricitabine; Tenofovir alafenamide: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
    Emtricitabine; Tenofovir disoproxil fumarate: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
    Entecavir: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
    Ethanol: (Major) Consider the potential risk of interferon beta products used in combination with known hepatotoxic drugs or other products (e.g., alcohol) prior to use. Monitor hepatic function during interferon beta treatment. Patients should be advised to avoid drinking alcohol to reduce the chance of injury to the liver during interferon beta treatment. Alcohol may also potentiate drowsiness and dizziness. Patients who develop dizziness, confusion, somnolence, and fatigue with interferon beta treatment should be cautioned to avoid driving or operating machinery.
    Fosamprenavir: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. The HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART.
    Indinavir: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. The HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART.
    Lamivudine, 3TC: (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6).
    Lamivudine, 3TC; Zidovudine, ZDV: (Major) Use interferons and zidovudine together with caution. Closely monitor patients for treatment-associated toxicities, especially hematologic effects and hepatic decompensation, and manage as recommended for the individual therapies. Coadministration of alpha interferons may increase the hematologic toxicity of zidovudine. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) are also associated with hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. Interferon therapy may also reduce zidovudine clearance. (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6).
    Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6).
    Lopinavir; Ritonavir: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. The HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART.
    Natalizumab: (Major) Natalizumab should be used with caution with interferon beta because of the potential for increased risk of progressive multifocal leukoencephalopathy (PML) and other serious infections with combined use. Ordinarily, multiple sclerosis (MS) patients receiving chronic immunomodulatory therapy should not be treated with natalizumab; however, in some multiple sclerosis clinical trials, patients were allowed to continue interferon beta therapy. Due to the risk for infection and PML, natalizumab is only approved for monotherapy of MS. The safety and efficacy of natalizumab as an add-on therapy to interferon beta treatments has not been established. Sequential therapy (e.g., interferon beta followed by natalizumab) does not appear to increase the risk for PML.
    Nelfinavir: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. The HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART.
    Nevirapine: (Major) The concomitant use of interferons and nevirapine should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Nevirapine may cause liver damage in the context of hypersensitivity reactions or by direct toxic effects. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. Patients with signs or symptoms of hepatitis, or with increased transaminases combined with rash or other systemic symptoms, must discontinue nevirapine and seek medical evaluation immediately.
    Ocrelizumab: (Moderate) Ocrelizumab has not been studied in combination with other immunosuppressive or immune modulating therapies used for the treatment of multiple sclerosis, such as interferon beta-1a or interferon beta-1b. Concomitant use of ocrelizumab with interferon beta may increase the risk of immunosuppression.
    Ofatumumab: (Moderate) Concomitant use of ofatumumab with interferon beta may increase the risk of immunosuppression. Ofatumumab has not been studied in combination with other immunosuppressive or immune modulating therapies used for the treatment of multiple sclerosis, such as interferon beta. Consider the duration and mechanism of action of drugs with immunosuppressive effects when switching therapies for multiple sclerosis patients.
    Ombitasvir; Paritaprevir; Ritonavir: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. The HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART.
    Ozanimod: (Moderate) Concomitant use of ozanimod with interferon beta may increase the risk of immunosuppression. Ozanimod has not been studied in combination with other immunosuppressive or immune modulating therapies. Ozanimod can generally be started immediately after discontinuation of interferon beta.
    Pexidartinib: (Moderate) Monitor for evidence of hepatotoxicity if pexidartinib is coadministered with interferon beta. Avoid concurrent use in patients with increased serum transaminases, total bilirubin, or direct bilirubin (more than ULN) or active liver or biliary tract disease.
    Protease inhibitors: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. The HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART.
    Rilpivirine: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and rilpivirine can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving antiretroviral agents and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
    Riluzole: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and interferon beta. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Ritonavir: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. The HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART.
    Saquinavir: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. The HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART.
    Stavudine, d4T: (Major) Patients receiving stavudine with interferons (with or without ribavirin) should be closely monitored for treatment-associated toxicities, especially hepatic decompensation. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation compared to patients not receiving HAART. Additionally, stavudine has been associated with fatal and nonfatal lactic acidosis and hepatomegaly with or without steatosis and should be used cautiously in patients with hepatic disease. Discontinuation of stavudine should be considered as medically appropriate. Dose reduction or discontinuation of interferon, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6).
    Telbivudine: (Major) An increased risk and severity of peripheral neuropathy has been reported with telbivudine alone or in combination with pegylated interferon alfa-2a and other interferons. Patients should be advised to report any numbness, tingling, and/or burning sensations in the arms and/or legs, with or without gait disturbance. Interrupt telbivudine if peripheral neuropathy is suspected, and discontinue the drug if peripheral neuropathy is confirmed. Since both interferons and telbivudine may cause hepatotoxicity, hepatic function should also be closely monitored.
    Tipranavir: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. The HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART.
    Vigabatrin: (Major) Vigabatrin is associated with vision loss. The drug should not be used with interferons, which are associated with a potential for serious ophthalmic effects (e.g., retinopathy, optic neuritis, visual impairment), unless the benefit of treatment clearly outweighs the risks.
    Zalcitabine, ddC: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
    Zidovudine, ZDV: (Major) Use interferons and zidovudine together with caution. Closely monitor patients for treatment-associated toxicities, especially hematologic effects and hepatic decompensation, and manage as recommended for the individual therapies. Coadministration of alpha interferons may increase the hematologic toxicity of zidovudine. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) are also associated with hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. Interferon therapy may also reduce zidovudine clearance.

    PREGNANCY AND LACTATION

    Pregnancy

    There are no data available on interferon beta-1b use during human pregnancy from well-controlled studies. Observational studies of interferon beta-1b in women have generally not indicated a drug-associated risk of major birth defects.[44450] However, spontaneous abortions were reported in 4 patients while receiving interferon beta-1b during clinical trials.[44449] Increased risks for lower mean birth weight, shorter mean birth length, and preterm birth (less than 37 weeks) without spontaneous abortion were reported during a systemic review of 761 interferon-beta exposed pregnancies; no increased risk for congenital anomalies was found.[63530] The National Multiple Sclerosis Society consensus guidelines and the product labels recommend that women discontinue interferon beta therapy when trying to conceive and throughout gestation due to insufficient evidence regarding safety to the human fetus; however, most women who happen to conceive while taking interferon beta appear to have healthy newborns. If a patient does become pregnant while receiving interferon therapy, she should be made aware of the risks; discontinuation of interferon therapy during pregnancy is recommended.[63530] [44450] [44449] The risks and benefits of continuing interferon beta therapy during pregnancy require careful consideration of the patient's level of disease activity, personal preferences, and the potential fetal risks. During animal studies, a dose-related abortifacient effect was observed when interferon beta-1b was given to pregnant rhesus monkeys at exposures of 3 or more times the human therapeutic dose of 0.25 mg on a body surface area (mg/m2) basis.[44450] The effects of interferon beta-1b during labor and delivery are unknown.[44450] [44449]

    There are limited data regarding the use of interferon beta-1b during breast-feeding, and its excretion into human milk is unknown.[44449] [44450] Due to its poor oral bioavailability, any drug present in the breast milk is unlikely to be systemically absorbed by the nursing infant.[61642] The estimated relative infant dose would be 0.006% of the maternal dose, according to one review.[61643] An infant who was exclusively breast-fed through 5 months of age had no adverse effects due to interferon beta exposure.[63531] The Multiple Sclerosis Centre of Excellence on Reproduction and Child Health considers interferon beta to be moderately safe for use during lactation since the molecular weight of the drug is likely to limit transfer to breast milk. Other reviews concur that interferon beta is likely compatible with breast-feeding. Glatiramer and interferon beta-1a are potential alternatives to consider for the treatment of multiple sclerosis. However, the standard of care based is to have a mother start disease-modifying therapy of any type only after complete weaning of their infant. A discussion about the risks and benefits of postponing the resumption of interferon beta treatment in order to breast-feed is important, particularly for women who experience highly-active disease or who had active multiple sclerosis in the year prior to conception.[61642] [61643] [62512] Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for interferon beta-1b and any potential adverse effects on the breast-fed infant.[44449] [44450]

    MECHANISM OF ACTION

    Interferon beta-1b acts similarly to native interferon beta. Interferon beta belongs to the class of interferons, which are species-specific proteins produced in response to viruses as well as a variety of other natural and synthetic stimuli. Interferon beta is a Type I interferon. Interferon beta has 30% amino-acid homology with interferon alpha but only 1% homology with interferon gamma. Both interferon beta and interferon alpha are encoded on chromosome 9. Interferon beta binds to the type 1 interferon receptor with greater affinity than interferon alpha. In addition, interferon beta may bind to a distinct receptor that does not interact with interferon alpha. Interferon beta is produced by various cells including fibroblasts and macrophages, and has both antiviral and immune regulatory activities. Interferon beta increases the levels of 2,5-oligo-adenylate (2-5A) synthetase, an intracellular enzyme that is capable of degrading viral RNA. This activity may contribute to the antiviral and antiproliferative effects of interferon beta. Interferon beta has antiviral activity against herpes virus, human papillomavirus, hepatitis B, hepatitis C, and human immunodeficiency syndrome virus. There is some evidence that interferon beta has greater in vitro antiproliferative effects against many solid tumor cell lines than interferon alpha. The immunoregulatory effects of interferon beta include decreased expression of class II major histocompatibility complex (MHC) antigens, inhibition of T-helper cells, and decrease expression of pro-inflammatory cytokines, and upregulation of interleukin-10, which is an immunosuppressive cytokine that inhibits T-helper cells and interferon gamma and tumor necrosis factor release. The biologic responses of interferon beta therapy may be evaluated via the following markers: Beta2-microglobulin, neopterin, and tryptophan, and inhibition of concanavalin-stimulated proliferation of peripheral blood mononuclear cells.
     
    Interferon beta inhibits the expression of pro-inflammatory cytokines including interleukin (IL)-1beta, tumor necrosis factor- alpha and beta, interferon gamma (INF-G) and IL-6. Interferon gamma is believed to be a major factor responsible for triggering the autoimmune reaction leading to multiple sclerosis. It is thought that INF-G stimulates cytotoxic T-cells and induces macrophages to produce proteinases that degrade the myelin sheath around the spinal cord. INF-G causes upregulation of class II MHC antigens on nervous system tissue; cytotoxic T-cells recognize these antigens as receptor sites and attack the tissue. The result is a progressive neurologic dysfunction. Interferon beta downregulates INF-G production and INF-G-stimulated class II MHC expression. Interferon beta reduces T-cell migration across the blood-brain barrier. Interferon beta has also been found to increase production of nerve growth factor (NGF), which promotes oligodendrocyte survival and differentiation and axonal recovery. This may have a favorable effect on remyelination.

    PHARMACOKINETICS

    Interferon beta-1b is administered by subcutaneous injection.

    Intravenous Route

    After single IV doses, mean serum clearance was 9.4—28.9 mL/minute/kg, and the elimination half-life ranged between 8 minutes and 4.3 hours.

    Subcutaneous Route

    After subcutaneous injection of higher than recommended doses, peak serum concentrations were achieved between 1 and 8 hours in healthy volunteers. Bioavailability was approximately 50% after subcutaneous administration.