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  • CLASSES

    Interferons, Beta
    MS Drugs

    DEA CLASS

    Rx

    DESCRIPTION

    Recombinant, glycosylated interferon beta; identical amino acid sequence to endogenous interferon beta; the specific activity of interferon beta-1a Avonex® and Rebif® are 200 and 270 million IU/mg interferon beta-1a, respectively.

    COMMON BRAND NAMES

    Avonex, Rebif, Rebif Rebidose

    HOW SUPPLIED

    Avonex Intramuscular Inj Pwd F/Sol: 33mcg
    Avonex Intramuscular Inj Sol: 0.5mL, 30mcg
    Rebif/Rebif Rebidose Subcutaneous Inj Sol: 0.5mL, 22mcg, 44mcg, 8.8-22mcg

    DOSAGE & INDICATIONS

    For the treatment of remitting-relapsing forms of multiple sclerosis (MS) to slow physical disability and to decrease the frequency of clinical exacerbations.
    NOTE: Interferon beta-1a (Avonex) has been designated as an orphan drug by the FDA for this indication.
    NOTE: Safety and efficacy have not been established in patients with chronic progressive multiple sclerosis.
    To prevent or slow the development of clinically definite MS in patients who have experienced a first clinical episode and have MRI features consistent with MS.
    Intramuscular dosage (Avonex)
    Adults

    30 mcg (6 million international units) IM once per week. The indicated dose is based on data suggesting that early initiation of interferon beta-1a therapy delays the onset of clinically definite MS in high-risk patients who have recently experienced a demyelinating event but do not yet have clinical MS.

    Subcutaneous dosage (Rebif)†
    Adults

    22 mcg subcutaneously once weekly for 2 years led to clinically definite MS in 34% of 154 adults as compared with 45% of 154 adults who got placebo; all patients had a first episode of neurological dysfunction suggestive of MS within the previous 3 months.

    Intramuscular dosage (Avonex)
    Adults

    30 mcg (6 million international units) IM once per week. If a dose is missed, it should be given as soon as possible. The regular schedule may then be continued, but do not give 2 injections within 2 days of each other. As an alternative, to reduce the incidence and severity of flu-like symptoms, treatment may be initiated with an IM dose of 7.5 mcg once (week 1), with subsequent increases of 7.5 mcg each week until the recommended dose of 30 mcg/week is achieved (week 4). Doses of 60 mcg IM once weekly do not provide any additional benefits versus the 30 mcg dose.

    Subcutaneous dosage (Rebif)
    Adults

    22 or 44 mcg subcutaneously 3 times weekly (e.g., Monday, Wednesday, Friday), with each dose given at least 48 hours apart. Titrate patients to the full dose over a 4-week period using the Rebif titration pack, which contains 6 doses of 8.8 mcg/0.2 mL, and 6 doses of 22 mcg/0.5 mL. If the goal dose is 22 mcg, in weeks 1 to 2 administer 4.4 mcg/0.1 mL subcutaneously 3 times weekly; in weeks 3 to 4 give 11 mcg/0.25 mL 3 times weekly; then full dose therapy beginning week 5. If the goal dose is 44 mcg, in weeks 1 to 2 administer 8.8 mcg/0.2 mL subcutaneously 3 times weekly; in weeks 3 to 4 give 22 mcg/0.5 mL 3 times weekly; then full-dose therapy beginning week 5. The 2-year, placebo-controlled PRISMS trial has shown that Rebif 22 mcg or 44 mcg subcutaneously 3 times weekly significantly reduces the number of relapses, delays disability progression, and reduces disease activity and burden as measured by MRI. All patients got either of the 2 interferon beta-1a doses for the next 4 years; patients who had originally received placebo were randomized to one of the 2 interferon beta-1a dose groups (late treatment group). A long-term follow-up assessment was conducted at year 7 or 8 from the original PRISMS trial; data were available for 382 of the 560 patients and 275 of the 382 were still taking interferon beta-1a subcutaneously 3 times weekly. As compared with data from patients who got late treatment, patients who received interferon beta-1a initially had lower expanded disability status scale progression, relapse rate, and T2 disease burden up to 8 years later; the benefit was greater with the higher interferon beta-1a dose.

    For the treatment of chronic hepatitis C infection† in treatment naive patients.
    NOTE: Interferon beta-1a has been designated as an orphan drug by the FDA for this indication.
    Subcutaneous dosage (Rebif)
    Adults

    Guidelines recommend the use of a peginterferon product plus ribavirin as part of a combination regimen depending on patient factors and genotype. 44 mcg subcutaneously 3 times per week for 24 weeks led to an absence of detectable HCV RNA at both 24 and 48 weeks in 26.6% of 128 patients. In contrast, none of the 129 placebo recipients and 57.5% of 127 patients who got 24 weeks of both interferon beta-1a (44 mcg 3 times per week) plus ribavirin (1,000 mg PO daily for weight 75 kg or less, or 1,200 mg PO daily for weight more than 75 kg) met the endpoint. Significantly more patients with a HCV genotype 1 who got both interferon beta-1a and ribavirin had a SVR (37 of 80) as compared with interferon beta-1a monotherapy recipients (19 of 85). In another study, a negative HCV RNA 24 weeks after therapy cessation was obtained in 11 of 51 patients who got 22 mcg subcutaneously daily for 24 weeks and in 14 of 51 patients who also got ribavirin (1,000 mg PO daily for weight less than 70 kg and 1,200 mg PO daily for weight 70 kg or more).

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    For Rebif, 44 mcg subcutaneously every 48 hours; For Avonex, 30 mcg IM once a week.

    Geriatric

    For Rebif, 44 mcg subcutaneously every 48 hours; For Avonex, 30 mcg IM once a week.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Avonex: Use with caution in patients with hepatic disease. Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
    Rebif: Use with caution in patients with hepatic disease. Immediately discontinue Rebif if jaundice or other symptoms of liver dysfunction appear. Consider dose reduction if liver function tests are > 5-times the upper limit of normal. The dose may be slowly increased once the enzyme concentrations have normalized.

    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.
     
    NOTE: Variations in dosage exist among different interferon beta-1a products; these products are not equivalent. Therefore, do not use different interferon beta-1a products in a single treatment regimen.

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. The Rebif liquid is clear to slightly yellow. Do not use if it is cloudy, discolored, or has particles.

    Intramuscular Administration

    Interferon beta-1a (Avonex) 30 mcg is equivalent to 6 million International Units.
    Premedication with acetaminophen or ibuprofen and administration of interferon beta-1a at bedtime may lessen the severity of flu-like symptoms.
    Patients may self-inject only if their physician determines that it is appropriate, and with medical follow-up, and after proper training in intramuscular injection technique.
    The first injection should be performed under the supervision of an appropriately qualified health care professional.
    Refer to the Patient Medication Guide for detailed instructions for preparing and giving a dose.
    Wash hands prior to handling Dose Pack contents.
    Remove 1 Administration Dose Pack from refrigerator about 30 minutes prior to use to warm to room temperature. Do not use external heat sources such as hot water to warm.
    Do not inject into an area of the body where skin is irritated, reddened, bruised, infected, or scarred in any way.
    Use the alcohol wipe to clean the skin at the injection site you choose and allow it to dry prior to injection.
    After the injection, use gauze pad to apply pressure for a few seconds or rub gently in a circular motion.
    The injection site should be checked after 2 hours for redness, edema, or tenderness.
    Instruct patients to contact their health care provider if a skin reaction occurs that does not resolve in a few days.
    If a dose is missed, administer it as soon as possible. Continue the regular schedule but do not give 2 injections within 2 days of each other.
    Injection sites should be rotated with each administration to minimize the likelihood of injection site reactions.
    All products are for single-use only. Do not re-use needles, syringes, pre-filled syringes, titration devices, or autoinjectors.
    Dispose of used vials, needles, syringes, or titration devices in a puncture-resistant container and discard appropriately.
    The manufacturer of Avonex offers free training on intramuscular injection administration for patients and their health care partners. Contact MS ActiveSource for more information (800—456—2255).
     
    Reconstitution and Administration of Avonex lyophilized powder:
    Use appropriate aseptic technique for preparation of solution.
    Slowly add 1.1 ml sterile water for injection, USP, preservative-free (supplied by manufacturer) to the vial. Rapid addition of the diluent may cause foaming, making it difficult to withdraw the solution.
    Gently swirl the vial to aid in dissolution; do not shake. Final concentration should be 30 mcg/mL (i.e., 6 million International Units/mL)
    The reconstituted solution should be clear to slightly yellow without particles. Discard if the reconstituted product contains particulate matter or is discolored.
    Withdraw 1 ml of reconstituted solution into a syringe. Attach the sterile needle, and pull the protective cover straight off the needle; do not twist the cover off.
    Inject intramuscularly at a 90 degree angle into the thigh or upper arm.
    A 25 gauge, 1" needle for intramuscular injection may be substituted for the 23 gauge, 1 1/4" needle provided by the manufacturer, if deemed appropriate by the physician.
    Storage: Use within 6 hours of reconstitution; store reconstituted solution at 2—8 degrees C (36—46 degrees F); do NOT freeze. Discard any unused solution. Both drug and diluent vials are single-use only.
     
    Administration of Avonex pre-filled syringe:
    Hold the syringe so the cap is facing down and the 0.5 mL mark is at eye level. Be sure the amount of liquid in the syringe is the same or very close to the 0.5 mL mark. If the correct amount of liquid is not in the syringe, do not use it and call the pharmacist.
    Hold syringe upright so that the rubber cap faces up. Remove the cap by bending it at a 90 degree angle until it snaps free.
    Attach the needle by pressing it onto the syringe and turning it clockwise until it locks in place. Be careful not to push the plunger while attaching the needle.
    Pull the protective cover straight off the needle; do not twist the cover off.
    Inject intramuscularly at a 90 degree angle into the thigh or upper arm.
    If self-injecting, rotate between thighs. With help from another person, may rotate between thighs and upper arms.
    A 25 gauge, 1" needle for intramuscular injection may be substituted for the 23 gauge, 1 1/4" needle provided by the manufacturer, if deemed appropriate by the physician.
    Storage: Store at 2—8 degrees C (36—46 degrees F). If refrigeration is unavailable, may store at 77 degrees F or less for up to 7 days. After removal from refrigerator, do not store product above 25 degrees C. If the product has been exposed to conditions other than recommended, discard the product and do not use. Do not expose to high temperatures. Do not freeze. Protect from light.
     
    Administration of Avonex pre-filled syringe using the Avostartgrip titration kit:
    The dose may be titrated over 3 weeks using the titration kit. A titration device will only allow the administration of a fraction of the full syringe contents.
    Dosage schedule:
    Week 1: 1/4 dose (white device)
    Week 2: 1/2 dose (yellow device)
    Week 3: 3/4 dose (purple device)
    Week 4: a full dose
    Prepare the prefilled syringe and needle as described above before placing it into a titration device.
    Select the appropriate titration device for the weekly dose. Place the device on a flat surface with the door open.
    Position the prefilled syringe over the device. The syringe needle should point toward the narrow end of the device, and the plunger should point toward the thick end of the device that has a "collar".
    Push the syringe down into the device until both ends snap into place. Close the door over the syringe; a snap sound will occur when the door is closed correctly. Do not re-open the door.
    Pull the protective cover straight off the needle; do not twist the cover off.
    Inject intramuscularly at a 90 degree angle into the thigh or upper arm. Be sure to push the plunger all the way down until touches the collar.
     
    Administration of Avonex pre-filled autoinjector:
    Ensure tamper-evident cap has not been removed or is loose. Then grasp the cap and bend it at a 90 degree angle until it snaps off. Pull off the sterile foil from the needle cover.
    Hold the Avonex Pen with the glass syringe tip pointing up. Press the needle onto the glass syringe tip. Gently turn the needle clockwise until firmly attached. Do not remove plastic cover from the needle.
    Hold Pen with one hand and using other hand, hold onto the injector shield (grooved area) tightly and quickly pull up on the injector shield until the injector shield covers the needle all the way. The plastic needle cover will pop off after the injector shield has been fully extended.
    When the injector shield is extended the right way, there will be a small blue rectangular area next to the oval medication display window. Check the display window and make sure the Avonex is clear and colorless.
    Do not use the injection if the liquid is colored, cloudy, or has lumps or particles. Air bubbles will not affect your dose.
    Do not push down on the injector shield and the blue activation button at the same time until you are ready to give injection.
    Avonex Pen should be injected into the upper, outer thigh.
    Hold Pen at 90 degree angle to the injection site. Firmly push the body of the pen down against the thigh to release the safety lock. Safety lock is released when blue rectangle area above the oval medication display window is gone. Push down on blue activation button with thumb and count to 10. You will hear a click if the injection is given the right way.
    After counting to 10, pull the Pen straight out of the skin.
    The circular display window on the Pen will be yellow if you have received the full dose.
    Cover exposed needle with Pen cover. Do not hold the Pen cover with your hands while inserting the needle.
    Storage: Store at 2—8 degrees C (36—46 degrees F). If refrigeration is unavailable, may store at 77 degrees F or less for up to 7 days. After removal from refrigerator, do not store product above 25 degrees C. If the product has been exposed to conditions other than recommended, discard the product and do not use. Do not expose to high temperatures. Do not freeze. Protect from light.

    Subcutaneous Administration

    Interferon beta-1a (Rebif) is administered subcutaneously at the same time (preferably late in the afternoon or evening) on the same days of the week at least 48 hours apart.
    Do not give on two consecutive days. If a dose is missed, administer the dose as soon as possible then skip the following day. Return to the regular schedule the following week.
    Premedication with acetaminophen or ibuprofen may lessen the severity of flu-like symptoms.
    Interferon beta-1a (Rebif) 44 mcg is equivalent to 12 million IU.
    A 'Starter Pack' containing a lower dose of Rebif syringes is available for the initial titration period; the prefilled syringes must be used for titration if the target dose is 22 mcg. Patients and/or their caregivers should be trained and understand appropriate preparation and administration.
    The manufacturer offers complimentary services including injection training and reimbursement support. Contact MS LifeLines at 877—44—REBIF.
     
    Subcutaneous Injection (Rebif prefilled syringe only):
    Interferon beta-1a (Rebif) is available in a prefilled syringe with a 29-gauge needle. If desired, the product may be removed from the refrigerator about 30 minutes before use. If needed, expel some product to obtain desired dose.
    Pinch the skin, and insert the needle at a 90 degree angle. Inject subcutaneously using a dart-like motion into the outer surface of the upper arm, abdomen, thigh, or buttock. Do not inject the area near the navel or waistline. Also, do not inject into skin that is red, irritated, bruised, or infected. Release the skin and inject subcutaneously. Take care not to inject intradermally. Rotate injection sites.
    Discard any unused solution. Prefilled syringes do not contain preservatives and are single-use only.
    After 2 hours, check the injection site for redness, swelling, or tenderness. Local skin reactions may be reduced by applying ice or a cold compress to the site after injection.

    STORAGE

    Avonex:
    - Avoid excessive heat (above 104 degrees F)
    - Discard product that has been exposed to conditions other than those recommended
    - Do not freeze
    - Protect from light
    - Refrigerate (between 36 and 46 degrees F)
    - Store at temperatures not exceeding 77 degrees F for no more than 7 days if refrigeration is not available
    Rebif:
    - Avoid exposure to heat
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Protect from freezing
    - Protect from light
    - Refrigerate (between 36 and 46 degrees F)
    - Store at or below 77 degrees F for no more than 30 days if refrigeration is not available
    Rebif Rebidose:
    - Avoid exposure to heat
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Do not freeze
    - May be stored between 36 to 77 degrees F, away from heat and light, for up to 30 days if refrigeration is not available
    - Protect from light
    - Refrigerate (between 36 and 46 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    Albumin hypersensitivity, hamster protein hypersensitivity

    Some formulations of interferon beta-1a contain human albumin and are contraindicated in patients with albumin hypersensitivity. Additionally, interferon beta-1a should not be used in patients with hamster protein hypersensitivity. Allergic reactions, including anaphylaxis have been reported with interferon beta-1a use. Allergic reactions, possibly severe, may occur after prolonged use. Based on effective donor screening and product manufacturing processes, albumin carries an extremely remote risk of transmission of viral infections. A theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD) also is considered very remote. No cases of transmission of viral diseases or CJD have ever been identified for albumin.

    Latex hypersensitivity

    The pre-filled syringe cap of interferon beta-1a contains natural rubber (latex), which may cause hypersensitivity reactions in those patients with latex hypersensitivity.

    Subcutaneous administration

    Subcutaneous administration of interferon beta-1a should not be substituted for intramuscular administration. Subcutaneous and intramuscular administration have been observed to have non-equivalent pharmacokinetic and pharmacodynamic parameters after administration to healthy volunteers. Subcutaneous administration of the product is appropriate.

    Angina, cardiac arrhythmias, cardiac disease, heart failure, myocardial infarction

    Interferon beta-1a should be used cautiously in patients with a history of cardiac disease including angina, cardiac arrhythmias, heart failure, or myocardial infarction. Although interferon beta-1a is not directly cardiotoxic, serious cardiac adverse events have been reported in patients without a prior history of cardiac disease (see Adverse Reactions).

    Bone marrow suppression

    Patients with preexisting bone marrow suppression or who are receiving myelosuppression therapy may be at increased risk of developing hematologic toxicity during beta interferon therapy. Interferon beta-1a-induced hematologic toxicity is dose related. Monitoring of blood cell counts is recommended during interferon beta-1a therapy. Monitoring of blood cell counts is recommended at regular intervals (1, 3, and 6 months) following initiation of interferon beta-1a therapy and then periodically thereafter in absence of clinical symptoms. Patients with bone marrow suppression may require more intensive monitoring of hematologic parameters, including complete blood counts with differential and platelets.

    Alcoholism, hepatic disease, jaundice

    Interferon beta-1a therapy should be initiated with caution in patients with active hepatic disease, alcoholism, elevated SGPT (> 2.5-times the upper limit of normal, ULN), or a history of significant hepatic disease. Severe liver injury, including some cases of hepatic failure requiring liver transplantation, has been reported rarely in patients taking . Symptoms of liver dysfunction began from 1—6 months after  initiation. Patients should be closely monitored for signs of hepatic injury and caution exercised when interferon beta-1a is concomitantly with other drugs associated with hepatic injury (e.g., alcohol). The potential of additive effects from multiple drugs or other hepatotoxic agents has not been determined; however, caution is recommended if interferon beta-1a is given concurrently with any hepatotoxic agents. Hepatic injury including elevated hepatic enzymes, jaundice, and hepatitis, some of which have been severe, has been reported in patients receiving interferon beta-1a (see Adverse Reactions). A case of fulminant hepatic failure requiring liver transplantation in a patient who initiated interferon beta-1a therapy while taking other potentially hepatotoxic medications has been reported from a non-U.S. post-marketing report. Monitoring of liver function tests is recommended at regular intervals (1, 3, and 6 months recommended for Rebif) following initiation of therapy and then periodically thereafter in the absence of clinical symptoms. Dose reduction should be considered in the SGPT rises above 5-times the ULN. The dose may be gradually re-escalated when enzyme levels have normalized. Treatment with interferon beta-1a should be immediately stopped if jaundice or other clinical signs of liver dysfunction appear; the potential for rapid progression to liver failure exists if the drug is continued.

    Pregnancy

    Interferon beta-1a is classified as FDA pregnancy risk category C. No adequate or well-controlled pregnancy studies have been done. Use of interferons during pregnancy should be avoided due to the risk of spontaneous abortion. During clinical trials with interferon beta-1a there were 2 spontaneous abortions observed and 5 fetuses carried to term among 7 women in the treatment groups. Other published data support a potential abortive effect in humans. Abortifacient activity, menstrual irregularities, anovulation, and decreased serum progesterone levels have been observed in some animal studies, including studies in rhesus monkeys, during high dose use. Data from a large, multicenter trial of pregnant patients with MS suggest that patients have a decrease in the number and severity of MS relapses during pregnancy, despite discontinuation or lack of receipt of disease-modifying medications. If a patient does become pregnant while receiving interferon therapy, she should be made aware of the risk. Discontinuation of interferon therapy is recommended. Females of childbearing age should use appropriate birth control measures while receiving beta interferon therapy. Also, consider enrolling a woman who becomes pregnant while taking Avonex in the pregnancy registry by calling 800—456—2255. In 5 years time, the Rebif Pregnancy Registry only enrolled 36 exposed patients, and the Rebif Pregnancy Registry was closed in early 2008; the data of the study have been reported but firm conclusions cannot be drawn due to the low enrollment. The effects of interferon beta-1a during labor and delivery are unknown.

    Breast-feeding

    Use caution in using interferon beta-1a during breast-feeding, though clinical data suggest the drug may be used when needed by the mother. According to the manufacturer, it is not known if interferon beta-1a is excreted into breast milk, and due to the potential for serious adverse reactions in the nursing infant, a decision should be made to discontinue nursing or discontinue interferon beta-1a. However, a small number of nursing mothers receiving interferon beta-1a reported no adverse effects in their partially breast-fed infants, and the amount of interferon beta-1a excreted into breast milk appeared to be insignificant. Based upon breast milk samples obtained during the study, the authors estimated that the maximum weight-adjusted dosage that an infant would receive was 0.006% of the maternal dose. Glatiramer is a potential alternative to interferon beta-1a in the treatment of multiple sclerosis; the high molecular weight of the drug would suggest significant transfer to breast milk would be unlikely but no specific information regarding its use in breast-feeding is available. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Children

    The safety and efficacy of interferon beta-1a have not been established in children 18 years of age or younger.

    Depression, psychosis, suicidal ideation

    Interferon beta-1a should be used with caution in patients with depression. Patients with a history of depression 2 weeks prior to starting interferon beta-1a therapy may be at increased risk for developing depression during the first 2 months of therapy. Depression, suicidal ideation, suicide attempts, and development of new or worsening of preexisting psychiatric disorders, including psychosis, have been reported with interferon beta-1a (see Adverse Reactions). Patients treated with interferon beta should report immediately any symptoms of depression, suicidal ideation. or other symptoms of psychiatric disorders to their prescriber or health-care professional. If a patient develops depression and/or other severe psychiatric symptoms, cessation of interferon beta-1a therapy should be considered.

    Seizure disorder

    Exercise caution when administering interferon beta-1a to patients with a preexisting seizure disorder. Seizures occurred during placebo-controlled trials in 4 patients receiving interferon beta-1a. It is not known whether these events were related to the effects of multiple sclerosis alone, interferon beta-1a therapy, or a combination of both. The effect of interferon beta-1a on the medical management of patients with a seizure disorder is unknown.

    Autoimmune disease, thyroid disease

    Autoimmune disease of multiple target organs has been reported during interferon beta-1a therapy, including idiopathic thrombocytopenia, thyroid disease (hyperthyroidism or hypothyroidism), and rare cases of autoimmune hepatitis. Patients should be monitored for signs of these disorders. Thyroid function tests are recommended every 6 months in patients with a history of thyroid disease or as clinically indicated.

    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-1a. 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.

    ADVERSE REACTIONS

    Severe

    visual impairment / Early / 7.0-13.0
    seizures / Delayed / 1.0-5.0
    suicidal ideation / Delayed / 4.0-4.0
    tissue necrosis / Early / 1.0-3.0
    lupus-like symptoms / Delayed / Incidence not known
    skin atrophy / Delayed / Incidence not known
    retinopathy / Delayed / Incidence not known
    hepatic failure / Delayed / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    anaphylactic shock / Rapid / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    pancytopenia / Delayed / Incidence not known
    cardiomyopathy / Delayed / Incidence not known
    heart failure / Delayed / Incidence not known
    fetal abortion / Delayed / Incidence not known
    thrombotic thrombocytopenic purpura (TTP) / Delayed / Incidence not known
    hemolytic-uremic syndrome / Delayed / Incidence not known

    Moderate

    leukopenia / Delayed / 28.0-36.0
    antibody formation / Delayed / 5.0-31.0
    elevated hepatic enzymes / Delayed / 10.0-27.0
    depression / Delayed / 20.0-25.0
    lymphadenopathy / Delayed / 11.0-12.0
    chest pain (unspecified) / Early / 5.0-8.0
    thrombocytopenia / Delayed / 2.0-8.0
    hypertonia / Delayed / 6.0-7.0
    dyspnea / Early / 6.0-6.0
    hypothyroidism / Delayed / 4.0-6.0
    hyperthyroidism / Delayed / 4.0-6.0
    migraine / Early / 5.0-5.0
    anemia / Delayed / 3.0-5.0
    urinary incontinence / Early / 2.0-4.0
    hyperbilirubinemia / Delayed / 2.0-3.0
    peripheral vasodilation / Rapid / 2.0-2.0
    bleeding / Early / Incidence not known
    edema / Delayed / Incidence not known
    myasthenia / Delayed / Incidence not known
    psychosis / Early / Incidence not known
    jaundice / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known

    Mild

    injection site reaction / Rapid / 3.0-92.0
    headache / Early / 58.0-70.0
    fatigue / Early / 33.0-41.0
    myalgia / Early / 25.0-29.0
    fever / Early / 20.0-28.0
    back pain / Delayed / 23.0-25.0
    asthenia / Delayed / 24.0-24.0
    weakness / Early / 24.0-24.0
    nausea / Early / 23.0-23.0
    abdominal pain / Early / 8.0-22.0
    chills / Rapid / 19.0-19.0
    musculoskeletal pain / Early / 10.0-15.0
    dizziness / Early / 14.0-14.0
    sinusitis / Delayed / 14.0-14.0
    arthralgia / Delayed / 9.0-9.0
    increased urinary frequency / Early / 2.0-7.0
    infection / Delayed / 7.0-7.0
    ecchymosis / Delayed / 6.0-6.0
    menstrual irregularity / Delayed / 6.0-6.0
    malaise / Early / 4.0-5.0
    xerostomia / Early / 1.0-5.0
    maculopapular rash / Early / 4.0-5.0
    alopecia / Delayed / 4.0-4.0
    hyperhidrosis / Delayed / 4.0-4.0
    xerophthalmia / Early / 1.0-3.0
    paresthesias / Delayed / Incidence not known
    hypoesthesia / Delayed / Incidence not known
    rash (unspecified) / Early / Incidence not known
    vesicular rash / Delayed / Incidence not known
    urticaria / Rapid / Incidence not known
    menorrhagia / Delayed / Incidence not known

    DRUG INTERACTIONS

    Abacavir: (Major) The concomitant use of interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) should be done with caution. Interferon beta-1b has been shown to reduce zidovudine, ZDV, clearance by as much as 93% as interferon beta may interfere with the glucuronidation of zidovudine. Dosage reduction of zidovudine may be necessary when interferon beta and zidovudine are coadministered. Synergistic toxicity may occur with alpha interferons and zidovudine, as both can be myelosuppressive. Peripheral neuropathy has been reported with telbivudine alone or in combination with pegylated interferon alfa-2a and other interferons; however a clinical trial showed an increased risk and severity of peripheral neuropathy with the combination of telbivudine and pegylated interferon alfa-2a compared to telbivudine alone. Interferons and NRTIs can both cause hepatic damage. In a study of 14 patients with chronic, cirrhotic HCV co-infected with HIV, patients receiving NRTIs and alpha interferons appeared to be at increased risk for the development of hepatic decompensation (e.g., Childs-Pugh >= 6) compared to patients not receiving HAART. Additionally, NRTIs have been associated with fatal and nonfatal lactic acidosis and hepatomegaly with or without steatosis and should be used cautiously in patients with hepatic disease. Didanosine and stavudine are most frequently involved in liver-related mitochondrial toxicity. Additionally, the long-term use of didanosine is an independent factor for developing advanced liver fibrosis in HIV-positive patients in whom other causes of liver damage were excluded. 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.
    Abacavir; Dolutegravir; Lamivudine: (Major) Caution is advised with coadministration of lamivudine and interferons as hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy for HIV-1 and interferon alfa, with or without ribavirin. Additionally, NRTIs have been associated with fatal and nonfatal lactic acidosis and hepatomegaly with or without steatosis and should be used cautiously in patients with hepatic disease. Patients receiving interferon alfa, with or without ribavirin, and lamivudine should be closely monitored for treatment-associated toxicities, especially hepatic decompensation. Discontinuation of lamivudine should be considered as medically appropriate. Dose reduction or discontinuation of interferon alfa, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6). (Major) The concomitant use of interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) should be done with caution. Interferon beta-1b has been shown to reduce zidovudine, ZDV, clearance by as much as 93% as interferon beta may interfere with the glucuronidation of zidovudine. Dosage reduction of zidovudine may be necessary when interferon beta and zidovudine are coadministered. Synergistic toxicity may occur with alpha interferons and zidovudine, as both can be myelosuppressive. Peripheral neuropathy has been reported with telbivudine alone or in combination with pegylated interferon alfa-2a and other interferons; however a clinical trial showed an increased risk and severity of peripheral neuropathy with the combination of telbivudine and pegylated interferon alfa-2a compared to telbivudine alone. Interferons and NRTIs can both cause hepatic damage. In a study of 14 patients with chronic, cirrhotic HCV co-infected with HIV, patients receiving NRTIs and alpha interferons appeared to be at increased risk for the development of hepatic decompensation (e.g., Childs-Pugh >= 6) compared to patients not receiving HAART. Additionally, NRTIs have been associated with fatal and nonfatal lactic acidosis and hepatomegaly with or without steatosis and should be used cautiously in patients with hepatic disease. Didanosine and stavudine are most frequently involved in liver-related mitochondrial toxicity. Additionally, the long-term use of didanosine is an independent factor for developing advanced liver fibrosis in HIV-positive patients in whom other causes of liver damage were excluded. 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.
    Abacavir; Lamivudine, 3TC: (Major) Caution is advised with coadministration of lamivudine and interferons as hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy for HIV-1 and interferon alfa, with or without ribavirin. Additionally, NRTIs have been associated with fatal and nonfatal lactic acidosis and hepatomegaly with or without steatosis and should be used cautiously in patients with hepatic disease. Patients receiving interferon alfa, with or without ribavirin, and lamivudine should be closely monitored for treatment-associated toxicities, especially hepatic decompensation. Discontinuation of lamivudine should be considered as medically appropriate. Dose reduction or discontinuation of interferon alfa, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6). (Major) The concomitant use of interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) should be done with caution. Interferon beta-1b has been shown to reduce zidovudine, ZDV, clearance by as much as 93% as interferon beta may interfere with the glucuronidation of zidovudine. Dosage reduction of zidovudine may be necessary when interferon beta and zidovudine are coadministered. Synergistic toxicity may occur with alpha interferons and zidovudine, as both can be myelosuppressive. Peripheral neuropathy has been reported with telbivudine alone or in combination with pegylated interferon alfa-2a and other interferons; however a clinical trial showed an increased risk and severity of peripheral neuropathy with the combination of telbivudine and pegylated interferon alfa-2a compared to telbivudine alone. Interferons and NRTIs can both cause hepatic damage. In a study of 14 patients with chronic, cirrhotic HCV co-infected with HIV, patients receiving NRTIs and alpha interferons appeared to be at increased risk for the development of hepatic decompensation (e.g., Childs-Pugh >= 6) compared to patients not receiving HAART. Additionally, NRTIs have been associated with fatal and nonfatal lactic acidosis and hepatomegaly with or without steatosis and should be used cautiously in patients with hepatic disease. Didanosine and stavudine are most frequently involved in liver-related mitochondrial toxicity. Additionally, the long-term use of didanosine is an independent factor for developing advanced liver fibrosis in HIV-positive patients in whom other causes of liver damage were excluded. 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.
    Abacavir; Lamivudine, 3TC; Zidovudine, ZDV: (Major) Caution is advised with coadministration of lamivudine and interferons as hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy for HIV-1 and interferon alfa, with or without ribavirin. Additionally, NRTIs have been associated with fatal and nonfatal lactic acidosis and hepatomegaly with or without steatosis and should be used cautiously in patients with hepatic disease. Patients receiving interferon alfa, with or without ribavirin, and lamivudine should be closely monitored for treatment-associated toxicities, especially hepatic decompensation. Discontinuation of lamivudine should be considered as medically appropriate. Dose reduction or discontinuation of interferon alfa, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6). (Major) The concomitant use of interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) should be done with caution. Interferon beta-1b has been shown to reduce zidovudine, ZDV, clearance by as much as 93% as interferon beta may interfere with the glucuronidation of zidovudine. Dosage reduction of zidovudine may be necessary when interferon beta and zidovudine are coadministered. Synergistic toxicity may occur with alpha interferons and zidovudine, as both can be myelosuppressive. Peripheral neuropathy has been reported with telbivudine alone or in combination with pegylated interferon alfa-2a and other interferons; however a clinical trial showed an increased risk and severity of peripheral neuropathy with the combination of telbivudine and pegylated interferon alfa-2a compared to telbivudine alone. Interferons and NRTIs can both cause hepatic damage. In a study of 14 patients with chronic, cirrhotic HCV co-infected with HIV, patients receiving NRTIs and alpha interferons appeared to be at increased risk for the development of hepatic decompensation (e.g., Childs-Pugh >= 6) compared to patients not receiving HAART. Additionally, NRTIs have been associated with fatal and nonfatal lactic acidosis and hepatomegaly with or without steatosis and should be used cautiously in patients with hepatic disease. Didanosine and stavudine are most frequently involved in liver-related mitochondrial toxicity. Additionally, the long-term use of didanosine is an independent factor for developing advanced liver fibrosis in HIV-positive patients in whom other causes of liver damage were excluded. 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. (Major) The concomitant use of interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) should be done with caution. Interferon beta-1b has been shown to reduce zidovudine, ZDV, clearance by as much as 93% as interferon beta may interfere with the glucuronidation of zidovudine. Dosage reduction of zidovudine may be necessary when interferon beta and zidovudine are coadministered. Synergistic toxicity may occur with alpha interferons and zidovudine, as both can be myelosuppressive. Peripheral neuropathy has been reported with telbivudine alone or in combination with pegylated interferon alfa-2a and other interferons; however a clinical trial showed an increased risk and severity of peripheral neuropathy with the combination of telbivudine and pegylated interferon alfa-2a compared to telbivudine alone. Interferons and NRTIs can both cause hepatic damage. In a study of 14 patients with chronic, cirrhotic HCV co-infected with HIV, patients receiving NRTIs and alpha interferons appeared to be at increased risk for the development of hepatic decompensation (e.g., Childs-Pugh >= 6) compared to patients not receiving HAART. Additionally, NRTIs have been associated with fatal and nonfatal lactic acidosis and hepatomegaly with or without steatosis and should be used cautiously in patients with hepatic disease. Didanosine and stavudine are most frequently involved in liver-related mitochondrial toxicity. Additionally, the long-term use of didanosine is an independent factor for developing advanced liver fibrosis in HIV-positive patients in whom other causes of liver damage were excluded. 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.
    Amprenavir: (Major) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatic damage. Most protease inhibitors have been associated with episodes of liver toxicity, with lopinavir/low-dose ritonavir, fosamprenavir/low-dose ritonavir, and nelfinavir being less hepatotoxic and tipranavir/low-dose ritonavir being the most hepatotoxic. Hyperbilirubinemia is often associated with atazanavir and/or indinavir therapy but does not reflect liver damage and is related to the inhibition of UDP glucuronosyltransferase. 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.
    Atazanavir: (Major) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatic damage. Most protease inhibitors have been associated with episodes of liver toxicity, with lopinavir/low-dose ritonavir, fosamprenavir/low-dose ritonavir, and nelfinavir being less hepatotoxic and tipranavir/low-dose ritonavir being the most hepatotoxic. Hyperbilirubinemia is often associated with atazanavir and/or indinavir therapy but does not reflect liver damage and is related to the inhibition of UDP glucuronosyltransferase. 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.
    Atazanavir; Cobicistat: (Major) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatic damage. Most protease inhibitors have been associated with episodes of liver toxicity, with lopinavir/low-dose ritonavir, fosamprenavir/low-dose ritonavir, and nelfinavir being less hepatotoxic and tipranavir/low-dose ritonavir being the most hepatotoxic. Hyperbilirubinemia is often associated with atazanavir and/or indinavir therapy but does not reflect liver damage and is related to the inhibition of UDP glucuronosyltransferase. 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.
    Chloroquine: (Moderate) Concurrent use of chloroquine and interferons is not recommended as there is an increased risk of retinal toxicity.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Major) The concomitant use of interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) should be done with caution. Interferon beta-1b has been shown to reduce zidovudine, ZDV, clearance by as much as 93% as interferon beta may interfere with the glucuronidation of zidovudine. Dosage reduction of zidovudine may be necessary when interferon beta and zidovudine are coadministered. Synergistic toxicity may occur with alpha interferons and zidovudine, as both can be myelosuppressive. Peripheral neuropathy has been reported with telbivudine alone or in combination with pegylated interferon alfa-2a and other interferons; however a clinical trial showed an increased risk and severity of peripheral neuropathy with the combination of telbivudine and pegylated interferon alfa-2a compared to telbivudine alone. Interferons and NRTIs can both cause hepatic damage. In a study of 14 patients with chronic, cirrhotic HCV co-infected with HIV, patients receiving NRTIs and alpha interferons appeared to be at increased risk for the development of hepatic decompensation (e.g., Childs-Pugh >= 6) compared to patients not receiving HAART. Additionally, NRTIs have been associated with fatal and nonfatal lactic acidosis and hepatomegaly with or without steatosis and should be used cautiously in patients with hepatic disease. Didanosine and stavudine are most frequently involved in liver-related mitochondrial toxicity. Additionally, the long-term use of didanosine is an independent factor for developing advanced liver fibrosis in HIV-positive patients in whom other causes of liver damage were excluded. 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.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) The concomitant use of interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) should be done with caution. Interferon beta-1b has been shown to reduce zidovudine, ZDV, clearance by as much as 93% as interferon beta may interfere with the glucuronidation of zidovudine. Dosage reduction of zidovudine may be necessary when interferon beta and zidovudine are coadministered. Synergistic toxicity may occur with alpha interferons and zidovudine, as both can be myelosuppressive. Peripheral neuropathy has been reported with telbivudine alone or in combination with pegylated interferon alfa-2a and other interferons; however a clinical trial showed an increased risk and severity of peripheral neuropathy with the combination of telbivudine and pegylated interferon alfa-2a compared to telbivudine alone. Interferons and NRTIs can both cause hepatic damage. In a study of 14 patients with chronic, cirrhotic HCV co-infected with HIV, patients receiving NRTIs and alpha interferons appeared to be at increased risk for the development of hepatic decompensation (e.g., Childs-Pugh >= 6) compared to patients not receiving HAART. Additionally, NRTIs have been associated with fatal and nonfatal lactic acidosis and hepatomegaly with or without steatosis and should be used cautiously in patients with hepatic disease. Didanosine and stavudine are most frequently involved in liver-related mitochondrial toxicity. Additionally, the long-term use of didanosine is an independent factor for developing advanced liver fibrosis in HIV-positive patients in whom other causes of liver damage were excluded. 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.
    Darunavir: (Major) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatic damage. Most protease inhibitors have been associated with episodes of liver toxicity, with lopinavir/low-dose ritonavir, fosamprenavir/low-dose ritonavir, and nelfinavir being less hepatotoxic and tipranavir/low-dose ritonavir being the most hepatotoxic. Hyperbilirubinemia is often associated with atazanavir and/or indinavir therapy but does not reflect liver damage and is related to the inhibition of UDP glucuronosyltransferase. 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.
    Darunavir; Cobicistat: (Major) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatic damage. Most protease inhibitors have been associated with episodes of liver toxicity, with lopinavir/low-dose ritonavir, fosamprenavir/low-dose ritonavir, and nelfinavir being less hepatotoxic and tipranavir/low-dose ritonavir being the most hepatotoxic. Hyperbilirubinemia is often associated with atazanavir and/or indinavir therapy but does not reflect liver damage and is related to the inhibition of UDP glucuronosyltransferase. 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.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatic damage. Most protease inhibitors have been associated with episodes of liver toxicity, with lopinavir/low-dose ritonavir, fosamprenavir/low-dose ritonavir, and nelfinavir being less hepatotoxic and tipranavir/low-dose ritonavir being the most hepatotoxic. Hyperbilirubinemia is often associated with atazanavir and/or indinavir therapy but does not reflect liver damage and is related to the inhibition of UDP glucuronosyltransferase. 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.
    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.
    Didanosine, ddI: (Major) The concomitant use of interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) should be done with caution. Interferon beta-1b has been shown to reduce zidovudine, ZDV, clearance by as much as 93% as interferon beta may interfere with the glucuronidation of zidovudine. Dosage reduction of zidovudine may be necessary when interferon beta and zidovudine are coadministered. Synergistic toxicity may occur with alpha interferons and zidovudine, as both can be myelosuppressive. Peripheral neuropathy has been reported with telbivudine alone or in combination with pegylated interferon alfa-2a and other interferons; however a clinical trial showed an increased risk and severity of peripheral neuropathy with the combination of telbivudine and pegylated interferon alfa-2a compared to telbivudine alone. Interferons and NRTIs can both cause hepatic damage. In a study of 14 patients with chronic, cirrhotic HCV co-infected with HIV, patients receiving NRTIs and alpha interferons appeared to be at increased risk for the development of hepatic decompensation (e.g., Childs-Pugh >= 6) compared to patients not receiving HAART. Additionally, NRTIs have been associated with fatal and nonfatal lactic acidosis and hepatomegaly with or without steatosis and should be used cautiously in patients with hepatic disease. Didanosine and stavudine are most frequently involved in liver-related mitochondrial toxicity. Additionally, the long-term use of didanosine is an independent factor for developing advanced liver fibrosis in HIV-positive patients in whom other causes of liver damage were excluded. 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.
    Efavirenz: (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.
    Efavirenz; Emtricitabine; Tenofovir: (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. (Major) The concomitant use of interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) should be done with caution. Interferon beta-1b has been shown to reduce zidovudine, ZDV, clearance by as much as 93% as interferon beta may interfere with the glucuronidation of zidovudine. Dosage reduction of zidovudine may be necessary when interferon beta and zidovudine are coadministered. Synergistic toxicity may occur with alpha interferons and zidovudine, as both can be myelosuppressive. Peripheral neuropathy has been reported with telbivudine alone or in combination with pegylated interferon alfa-2a and other interferons; however a clinical trial showed an increased risk and severity of peripheral neuropathy with the combination of telbivudine and pegylated interferon alfa-2a compared to telbivudine alone. Interferons and NRTIs can both cause hepatic damage. In a study of 14 patients with chronic, cirrhotic HCV co-infected with HIV, patients receiving NRTIs and alpha interferons appeared to be at increased risk for the development of hepatic decompensation (e.g., Childs-Pugh >= 6) compared to patients not receiving HAART. Additionally, NRTIs have been associated with fatal and nonfatal lactic acidosis and hepatomegaly with or without steatosis and should be used cautiously in patients with hepatic disease. Didanosine and stavudine are most frequently involved in liver-related mitochondrial toxicity. Additionally, the long-term use of didanosine is an independent factor for developing advanced liver fibrosis in HIV-positive patients in whom other causes of liver damage were excluded. 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.
    Emtricitabine: (Major) The concomitant use of interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) should be done with caution. Interferon beta-1b has been shown to reduce zidovudine, ZDV, clearance by as much as 93% as interferon beta may interfere with the glucuronidation of zidovudine. Dosage reduction of zidovudine may be necessary when interferon beta and zidovudine are coadministered. Synergistic toxicity may occur with alpha interferons and zidovudine, as both can be myelosuppressive. Peripheral neuropathy has been reported with telbivudine alone or in combination with pegylated interferon alfa-2a and other interferons; however a clinical trial showed an increased risk and severity of peripheral neuropathy with the combination of telbivudine and pegylated interferon alfa-2a compared to telbivudine alone. Interferons and NRTIs can both cause hepatic damage. In a study of 14 patients with chronic, cirrhotic HCV co-infected with HIV, patients receiving NRTIs and alpha interferons appeared to be at increased risk for the development of hepatic decompensation (e.g., Childs-Pugh >= 6) compared to patients not receiving HAART. Additionally, NRTIs have been associated with fatal and nonfatal lactic acidosis and hepatomegaly with or without steatosis and should be used cautiously in patients with hepatic disease. Didanosine and stavudine are most frequently involved in liver-related mitochondrial toxicity. Additionally, the long-term use of didanosine is an independent factor for developing advanced liver fibrosis in HIV-positive patients in whom other causes of liver damage were excluded. 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.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Major) The concomitant use of interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) should be done with caution. Interferon beta-1b has been shown to reduce zidovudine, ZDV, clearance by as much as 93% as interferon beta may interfere with the glucuronidation of zidovudine. Dosage reduction of zidovudine may be necessary when interferon beta and zidovudine are coadministered. Synergistic toxicity may occur with alpha interferons and zidovudine, as both can be myelosuppressive. Peripheral neuropathy has been reported with telbivudine alone or in combination with pegylated interferon alfa-2a and other interferons; however a clinical trial showed an increased risk and severity of peripheral neuropathy with the combination of telbivudine and pegylated interferon alfa-2a compared to telbivudine alone. Interferons and NRTIs can both cause hepatic damage. In a study of 14 patients with chronic, cirrhotic HCV co-infected with HIV, patients receiving NRTIs and alpha interferons appeared to be at increased risk for the development of hepatic decompensation (e.g., Childs-Pugh >= 6) compared to patients not receiving HAART. Additionally, NRTIs have been associated with fatal and nonfatal lactic acidosis and hepatomegaly with or without steatosis and should be used cautiously in patients with hepatic disease. Didanosine and stavudine are most frequently involved in liver-related mitochondrial toxicity. Additionally, the long-term use of didanosine is an independent factor for developing advanced liver fibrosis in HIV-positive patients in whom other causes of liver damage were excluded. 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.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Major) The concomitant use of interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) should be done with caution. Interferon beta-1b has been shown to reduce zidovudine, ZDV, clearance by as much as 93% as interferon beta may interfere with the glucuronidation of zidovudine. Dosage reduction of zidovudine may be necessary when interferon beta and zidovudine are coadministered. Synergistic toxicity may occur with alpha interferons and zidovudine, as both can be myelosuppressive. Peripheral neuropathy has been reported with telbivudine alone or in combination with pegylated interferon alfa-2a and other interferons; however a clinical trial showed an increased risk and severity of peripheral neuropathy with the combination of telbivudine and pegylated interferon alfa-2a compared to telbivudine alone. Interferons and NRTIs can both cause hepatic damage. In a study of 14 patients with chronic, cirrhotic HCV co-infected with HIV, patients receiving NRTIs and alpha interferons appeared to be at increased risk for the development of hepatic decompensation (e.g., Childs-Pugh >= 6) compared to patients not receiving HAART. Additionally, NRTIs have been associated with fatal and nonfatal lactic acidosis and hepatomegaly with or without steatosis and should be used cautiously in patients with hepatic disease. Didanosine and stavudine are most frequently involved in liver-related mitochondrial toxicity. Additionally, the long-term use of didanosine is an independent factor for developing advanced liver fibrosis in HIV-positive patients in whom other causes of liver damage were excluded. 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.
    Emtricitabine; Tenofovir alafenamide: (Major) The concomitant use of interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) should be done with caution. Interferon beta-1b has been shown to reduce zidovudine, ZDV, clearance by as much as 93% as interferon beta may interfere with the glucuronidation of zidovudine. Dosage reduction of zidovudine may be necessary when interferon beta and zidovudine are coadministered. Synergistic toxicity may occur with alpha interferons and zidovudine, as both can be myelosuppressive. Peripheral neuropathy has been reported with telbivudine alone or in combination with pegylated interferon alfa-2a and other interferons; however a clinical trial showed an increased risk and severity of peripheral neuropathy with the combination of telbivudine and pegylated interferon alfa-2a compared to telbivudine alone. Interferons and NRTIs can both cause hepatic damage. In a study of 14 patients with chronic, cirrhotic HCV co-infected with HIV, patients receiving NRTIs and alpha interferons appeared to be at increased risk for the development of hepatic decompensation (e.g., Childs-Pugh >= 6) compared to patients not receiving HAART. Additionally, NRTIs have been associated with fatal and nonfatal lactic acidosis and hepatomegaly with or without steatosis and should be used cautiously in patients with hepatic disease. Didanosine and stavudine are most frequently involved in liver-related mitochondrial toxicity. Additionally, the long-term use of didanosine is an independent factor for developing advanced liver fibrosis in HIV-positive patients in whom other causes of liver damage were excluded. 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.
    Emtricitabine; Tenofovir disoproxil fumarate: (Major) The concomitant use of interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) should be done with caution. Interferon beta-1b has been shown to reduce zidovudine, ZDV, clearance by as much as 93% as interferon beta may interfere with the glucuronidation of zidovudine. Dosage reduction of zidovudine may be necessary when interferon beta and zidovudine are coadministered. Synergistic toxicity may occur with alpha interferons and zidovudine, as both can be myelosuppressive. Peripheral neuropathy has been reported with telbivudine alone or in combination with pegylated interferon alfa-2a and other interferons; however a clinical trial showed an increased risk and severity of peripheral neuropathy with the combination of telbivudine and pegylated interferon alfa-2a compared to telbivudine alone. Interferons and NRTIs can both cause hepatic damage. In a study of 14 patients with chronic, cirrhotic HCV co-infected with HIV, patients receiving NRTIs and alpha interferons appeared to be at increased risk for the development of hepatic decompensation (e.g., Childs-Pugh >= 6) compared to patients not receiving HAART. Additionally, NRTIs have been associated with fatal and nonfatal lactic acidosis and hepatomegaly with or without steatosis and should be used cautiously in patients with hepatic disease. Didanosine and stavudine are most frequently involved in liver-related mitochondrial toxicity. Additionally, the long-term use of didanosine is an independent factor for developing advanced liver fibrosis in HIV-positive patients in whom other causes of liver damage were excluded. 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.
    Entecavir: (Major) The concomitant use of interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) should be done with caution. Interferon beta-1b has been shown to reduce zidovudine, ZDV, clearance by as much as 93% as interferon beta may interfere with the glucuronidation of zidovudine. Dosage reduction of zidovudine may be necessary when interferon beta and zidovudine are coadministered. Synergistic toxicity may occur with alpha interferons and zidovudine, as both can be myelosuppressive. Peripheral neuropathy has been reported with telbivudine alone or in combination with pegylated interferon alfa-2a and other interferons; however a clinical trial showed an increased risk and severity of peripheral neuropathy with the combination of telbivudine and pegylated interferon alfa-2a compared to telbivudine alone. Interferons and NRTIs can both cause hepatic damage. In a study of 14 patients with chronic, cirrhotic HCV co-infected with HIV, patients receiving NRTIs and alpha interferons appeared to be at increased risk for the development of hepatic decompensation (e.g., Childs-Pugh >= 6) compared to patients not receiving HAART. Additionally, NRTIs have been associated with fatal and nonfatal lactic acidosis and hepatomegaly with or without steatosis and should be used cautiously in patients with hepatic disease. Didanosine and stavudine are most frequently involved in liver-related mitochondrial toxicity. Additionally, the long-term use of didanosine is an independent factor for developing advanced liver fibrosis in HIV-positive patients in whom other causes of liver damage were excluded. 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.
    Ethanol: (Major) The potential for hepatic injury should be considered when interferon beta-1a is used in combination with other drugs and products associated with a potential risk of hepatic injury, including ethanol.
    Etravirine: (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.
    Fosamprenavir: (Major) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatic damage. Most protease inhibitors have been associated with episodes of liver toxicity, with lopinavir/low-dose ritonavir, fosamprenavir/low-dose ritonavir, and nelfinavir being less hepatotoxic and tipranavir/low-dose ritonavir being the most hepatotoxic. Hyperbilirubinemia is often associated with atazanavir and/or indinavir therapy but does not reflect liver damage and is related to the inhibition of UDP glucuronosyltransferase. 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.
    Indinavir: (Major) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatic damage. Most protease inhibitors have been associated with episodes of liver toxicity, with lopinavir/low-dose ritonavir, fosamprenavir/low-dose ritonavir, and nelfinavir being less hepatotoxic and tipranavir/low-dose ritonavir being the most hepatotoxic. Hyperbilirubinemia is often associated with atazanavir and/or indinavir therapy but does not reflect liver damage and is related to the inhibition of UDP glucuronosyltransferase. 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.
    Lamivudine, 3TC: (Major) Caution is advised with coadministration of lamivudine and interferons as hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy for HIV-1 and interferon alfa, with or without ribavirin. Additionally, NRTIs have been associated with fatal and nonfatal lactic acidosis and hepatomegaly with or without steatosis and should be used cautiously in patients with hepatic disease. Patients receiving interferon alfa, with or without ribavirin, and lamivudine should be closely monitored for treatment-associated toxicities, especially hepatic decompensation. Discontinuation of lamivudine should be considered as medically appropriate. Dose reduction or discontinuation of interferon alfa, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6).
    Lamivudine, 3TC; Zidovudine, ZDV: (Major) Caution is advised with coadministration of lamivudine and interferons as hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy for HIV-1 and interferon alfa, with or without ribavirin. Additionally, NRTIs have been associated with fatal and nonfatal lactic acidosis and hepatomegaly with or without steatosis and should be used cautiously in patients with hepatic disease. Patients receiving interferon alfa, with or without ribavirin, and lamivudine should be closely monitored for treatment-associated toxicities, especially hepatic decompensation. Discontinuation of lamivudine should be considered as medically appropriate. Dose reduction or discontinuation of interferon alfa, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6). (Major) The concomitant use of interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) should be done with caution. Interferon beta-1b has been shown to reduce zidovudine, ZDV, clearance by as much as 93% as interferon beta may interfere with the glucuronidation of zidovudine. Dosage reduction of zidovudine may be necessary when interferon beta and zidovudine are coadministered. Synergistic toxicity may occur with alpha interferons and zidovudine, as both can be myelosuppressive. Peripheral neuropathy has been reported with telbivudine alone or in combination with pegylated interferon alfa-2a and other interferons; however a clinical trial showed an increased risk and severity of peripheral neuropathy with the combination of telbivudine and pegylated interferon alfa-2a compared to telbivudine alone. Interferons and NRTIs can both cause hepatic damage. In a study of 14 patients with chronic, cirrhotic HCV co-infected with HIV, patients receiving NRTIs and alpha interferons appeared to be at increased risk for the development of hepatic decompensation (e.g., Childs-Pugh >= 6) compared to patients not receiving HAART. Additionally, NRTIs have been associated with fatal and nonfatal lactic acidosis and hepatomegaly with or without steatosis and should be used cautiously in patients with hepatic disease. Didanosine and stavudine are most frequently involved in liver-related mitochondrial toxicity. Additionally, the long-term use of didanosine is an independent factor for developing advanced liver fibrosis in HIV-positive patients in whom other causes of liver damage were excluded. 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.
    Lopinavir; Ritonavir: (Major) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatic damage. Most protease inhibitors have been associated with episodes of liver toxicity, with lopinavir/low-dose ritonavir, fosamprenavir/low-dose ritonavir, and nelfinavir being less hepatotoxic and tipranavir/low-dose ritonavir being the most hepatotoxic. Hyperbilirubinemia is often associated with atazanavir and/or indinavir therapy but does not reflect liver damage and is related to the inhibition of UDP glucuronosyltransferase. 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.
    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: (Major) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatic damage. Most protease inhibitors have been associated with episodes of liver toxicity, with lopinavir/low-dose ritonavir, fosamprenavir/low-dose ritonavir, and nelfinavir being less hepatotoxic and tipranavir/low-dose ritonavir being the most hepatotoxic. Hyperbilirubinemia is often associated with atazanavir and/or indinavir therapy but does not reflect liver damage and is related to the inhibition of UDP glucuronosyltransferase. 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.
    Nevirapine: (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.
    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.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatic damage. Most protease inhibitors have been associated with episodes of liver toxicity, with lopinavir/low-dose ritonavir, fosamprenavir/low-dose ritonavir, and nelfinavir being less hepatotoxic and tipranavir/low-dose ritonavir being the most hepatotoxic. Hyperbilirubinemia is often associated with atazanavir and/or indinavir therapy but does not reflect liver damage and is related to the inhibition of UDP glucuronosyltransferase. 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.
    Protease inhibitors: (Major) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatic damage. Most protease inhibitors have been associated with episodes of liver toxicity, with lopinavir/low-dose ritonavir, fosamprenavir/low-dose ritonavir, and nelfinavir being less hepatotoxic and tipranavir/low-dose ritonavir being the most hepatotoxic. Hyperbilirubinemia is often associated with atazanavir and/or indinavir therapy but does not reflect liver damage and is related to the inhibition of UDP glucuronosyltransferase. 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.
    Ritonavir: (Major) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatic damage. Most protease inhibitors have been associated with episodes of liver toxicity, with lopinavir/low-dose ritonavir, fosamprenavir/low-dose ritonavir, and nelfinavir being less hepatotoxic and tipranavir/low-dose ritonavir being the most hepatotoxic. Hyperbilirubinemia is often associated with atazanavir and/or indinavir therapy but does not reflect liver damage and is related to the inhibition of UDP glucuronosyltransferase. 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.
    Saquinavir: (Major) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatic damage. Most protease inhibitors have been associated with episodes of liver toxicity, with lopinavir/low-dose ritonavir, fosamprenavir/low-dose ritonavir, and nelfinavir being less hepatotoxic and tipranavir/low-dose ritonavir being the most hepatotoxic. Hyperbilirubinemia is often associated with atazanavir and/or indinavir therapy but does not reflect liver damage and is related to the inhibition of UDP glucuronosyltransferase. 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.
    Stavudine, d4T: (Major) The concomitant use of interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) should be done with caution. Interferon beta-1b has been shown to reduce zidovudine, ZDV, clearance by as much as 93% as interferon beta may interfere with the glucuronidation of zidovudine. Dosage reduction of zidovudine may be necessary when interferon beta and zidovudine are coadministered. Synergistic toxicity may occur with alpha interferons and zidovudine, as both can be myelosuppressive. Peripheral neuropathy has been reported with telbivudine alone or in combination with pegylated interferon alfa-2a and other interferons; however a clinical trial showed an increased risk and severity of peripheral neuropathy with the combination of telbivudine and pegylated interferon alfa-2a compared to telbivudine alone. Interferons and NRTIs can both cause hepatic damage. In a study of 14 patients with chronic, cirrhotic HCV co-infected with HIV, patients receiving NRTIs and alpha interferons appeared to be at increased risk for the development of hepatic decompensation (e.g., Childs-Pugh >= 6) compared to patients not receiving HAART. Additionally, NRTIs have been associated with fatal and nonfatal lactic acidosis and hepatomegaly with or without steatosis and should be used cautiously in patients with hepatic disease. Didanosine and stavudine are most frequently involved in liver-related mitochondrial toxicity. Additionally, the long-term use of didanosine is an independent factor for developing advanced liver fibrosis in HIV-positive patients in whom other causes of liver damage were excluded. 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.
    Telbivudine: (Major) The concomitant use of interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) should be done with caution. Interferon beta-1b has been shown to reduce zidovudine, ZDV, clearance by as much as 93% as interferon beta may interfere with the glucuronidation of zidovudine. Dosage reduction of zidovudine may be necessary when interferon beta and zidovudine are coadministered. Synergistic toxicity may occur with alpha interferons and zidovudine, as both can be myelosuppressive. Peripheral neuropathy has been reported with telbivudine alone or in combination with pegylated interferon alfa-2a and other interferons; however a clinical trial showed an increased risk and severity of peripheral neuropathy with the combination of telbivudine and pegylated interferon alfa-2a compared to telbivudine alone. Interferons and NRTIs can both cause hepatic damage. In a study of 14 patients with chronic, cirrhotic HCV co-infected with HIV, patients receiving NRTIs and alpha interferons appeared to be at increased risk for the development of hepatic decompensation (e.g., Childs-Pugh >= 6) compared to patients not receiving HAART. Additionally, NRTIs have been associated with fatal and nonfatal lactic acidosis and hepatomegaly with or without steatosis and should be used cautiously in patients with hepatic disease. Didanosine and stavudine are most frequently involved in liver-related mitochondrial toxicity. Additionally, the long-term use of didanosine is an independent factor for developing advanced liver fibrosis in HIV-positive patients in whom other causes of liver damage were excluded. 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.
    Tipranavir: (Major) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatic damage. Most protease inhibitors have been associated with episodes of liver toxicity, with lopinavir/low-dose ritonavir, fosamprenavir/low-dose ritonavir, and nelfinavir being less hepatotoxic and tipranavir/low-dose ritonavir being the most hepatotoxic. Hyperbilirubinemia is often associated with atazanavir and/or indinavir therapy but does not reflect liver damage and is related to the inhibition of UDP glucuronosyltransferase. 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.
    Vigabatrin: (Major) Vigabatrin should not be used with interferons, which are associated with serious ophthalmic effects (e.g., retinopathy or glaucoma) unless the benefit of treatment clearly outweighs the risks.
    Zalcitabine, ddC: (Major) The concomitant use of interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) should be done with caution. Interferon beta-1b has been shown to reduce zidovudine, ZDV, clearance by as much as 93% as interferon beta may interfere with the glucuronidation of zidovudine. Dosage reduction of zidovudine may be necessary when interferon beta and zidovudine are coadministered. Synergistic toxicity may occur with alpha interferons and zidovudine, as both can be myelosuppressive. Peripheral neuropathy has been reported with telbivudine alone or in combination with pegylated interferon alfa-2a and other interferons; however a clinical trial showed an increased risk and severity of peripheral neuropathy with the combination of telbivudine and pegylated interferon alfa-2a compared to telbivudine alone. Interferons and NRTIs can both cause hepatic damage. In a study of 14 patients with chronic, cirrhotic HCV co-infected with HIV, patients receiving NRTIs and alpha interferons appeared to be at increased risk for the development of hepatic decompensation (e.g., Childs-Pugh >= 6) compared to patients not receiving HAART. Additionally, NRTIs have been associated with fatal and nonfatal lactic acidosis and hepatomegaly with or without steatosis and should be used cautiously in patients with hepatic disease. Didanosine and stavudine are most frequently involved in liver-related mitochondrial toxicity. Additionally, the long-term use of didanosine is an independent factor for developing advanced liver fibrosis in HIV-positive patients in whom other causes of liver damage were excluded. 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.
    Zidovudine, ZDV: (Major) The concomitant use of interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) should be done with caution. Interferon beta-1b has been shown to reduce zidovudine, ZDV, clearance by as much as 93% as interferon beta may interfere with the glucuronidation of zidovudine. Dosage reduction of zidovudine may be necessary when interferon beta and zidovudine are coadministered. Synergistic toxicity may occur with alpha interferons and zidovudine, as both can be myelosuppressive. Peripheral neuropathy has been reported with telbivudine alone or in combination with pegylated interferon alfa-2a and other interferons; however a clinical trial showed an increased risk and severity of peripheral neuropathy with the combination of telbivudine and pegylated interferon alfa-2a compared to telbivudine alone. Interferons and NRTIs can both cause hepatic damage. In a study of 14 patients with chronic, cirrhotic HCV co-infected with HIV, patients receiving NRTIs and alpha interferons appeared to be at increased risk for the development of hepatic decompensation (e.g., Childs-Pugh >= 6) compared to patients not receiving HAART. Additionally, NRTIs have been associated with fatal and nonfatal lactic acidosis and hepatomegaly with or without steatosis and should be used cautiously in patients with hepatic disease. Didanosine and stavudine are most frequently involved in liver-related mitochondrial toxicity. Additionally, the long-term use of didanosine is an independent factor for developing advanced liver fibrosis in HIV-positive patients in whom other causes of liver damage were excluded. 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.

    PREGNANCY AND LACTATION

    Pregnancy

    Interferon beta-1a is classified as FDA pregnancy risk category C. No adequate or well-controlled pregnancy studies have been done. Use of interferons during pregnancy should be avoided due to the risk of spontaneous abortion. During clinical trials with interferon beta-1a there were 2 spontaneous abortions observed and 5 fetuses carried to term among 7 women in the treatment groups. Other published data support a potential abortive effect in humans. Abortifacient activity, menstrual irregularities, anovulation, and decreased serum progesterone levels have been observed in some animal studies, including studies in rhesus monkeys, during high dose use. Data from a large, multicenter trial of pregnant patients with MS suggest that patients have a decrease in the number and severity of MS relapses during pregnancy, despite discontinuation or lack of receipt of disease-modifying medications. If a patient does become pregnant while receiving interferon therapy, she should be made aware of the risk. Discontinuation of interferon therapy is recommended. Females of childbearing age should use appropriate birth control measures while receiving beta interferon therapy. Also, consider enrolling a woman who becomes pregnant while taking Avonex in the pregnancy registry by calling 800—456—2255. In 5 years time, the Rebif Pregnancy Registry only enrolled 36 exposed patients, and the Rebif Pregnancy Registry was closed in early 2008; the data of the study have been reported but firm conclusions cannot be drawn due to the low enrollment. The effects of interferon beta-1a during labor and delivery are unknown.

    Use caution in using interferon beta-1a during breast-feeding, though clinical data suggest the drug may be used when needed by the mother. According to the manufacturer, it is not known if interferon beta-1a is excreted into breast milk, and due to the potential for serious adverse reactions in the nursing infant, a decision should be made to discontinue nursing or discontinue interferon beta-1a. However, a small number of nursing mothers receiving interferon beta-1a reported no adverse effects in their partially breast-fed infants, and the amount of interferon beta-1a excreted into breast milk appeared to be insignificant. Based upon breast milk samples obtained during the study, the authors estimated that the maximum weight-adjusted dosage that an infant would receive was 0.006% of the maternal dose. Glatiramer is a potential alternative to interferon beta-1a in the treatment of multiple sclerosis; the high molecular weight of the drug would suggest significant transfer to breast milk would be unlikely but no specific information regarding its use in breast-feeding is available. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Interferon beta-1a 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, decreased expression of pro-inflammatory cytokines including interleukin (IL)-1beta, tumor necrosis factor (TNF)- alpha and -beta, interferon gamma (INF-G) and IL-6, and upregulation of interleukin-10, which is an immunosuppressive cytokine that inhibits T-helper cells INF-G and TNF 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 INF-G, which 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 therapy 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-1a is administered by intramuscular (IM) or subcutaneous (SC) injection depending upon the product. Pharmacokinetic data from patients with multiple sclerosis are not available. Interferon beta is metabolized in the liver.

    Intramuscular Route

    Interferon beta-1a (Avonex): Avonex is administered as an IM injection. There are no data establishing that subcutaneous administration has pharmacokinetic and/or pharmacodynamic equivalence with the IM route. In healthy volunteers, peak serum concentrations are generally achieved 15 hours after an IM dose (range: 6—36 hours), with a serum elimination half-life of about 19 hours (range: 8—54 hours). Biologic response marker levels (e.g., neopterin, tryptophan, and beta2-microglobulin) increase within 12 hours of dosing and remain elevated for at least 4 days. Biologic response marker levels usually peak within 48 hours of dosing.

    Subcutaneous Route

    Interferon beta-1a (Rebif): Rebif is administered as a subcutaneous injection. In healthy volunteers, a Cmax of 5.1 International Units/mL was attained in a median of 16 hours (Tmax). The serum elimination half-life was 69 hours. Every other day dosing suggests accumulation of interferon beta-1a after repeat administration. Biologic response marker levels (e.g., 2—5A synthetase activity, neopterin, and beta2-microglobulin) peaked 12—48 hours of a 60 mcg subcutaneous dose and remained elevated for at least 4 days.