Interferon beta-1a is available through recombinant DNA technology. Interferon beta-1a had been shown to decrease both the number and severity of multiple sclerosis (MS) attacks (i.e., relapses) and to significantly slow the progression of physical disability associated with relapsing-remitting MS, such as clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease in adults. Early treatment of MS with proper therapy may delay cognitive and physical disability. The interferon beta medications are generally considered the initial treatment options for pediatric patients with MS. While this drug has been studied for hepatitis C, guidelines often recommend the use of a peginterferon product plus ribavirin as part of a combination regimen depending on patient factors and genotype. Interferon beta-1a has also been studied in the treatment of various malignancies including non-small cell lung cancer, chronic myelogenous leukemia, hairy cell leukemia, melanoma, and rheumatoid arthritis; many of these designations have been withdrawn. Two products are available; the FDA approved Avonex in May 1996 and approved Rebif in March 2002.
General Administration Information
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.
Route-Specific Administration
Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Do not use if it is cloudy, discolored, or has particles.
--Rebif product solution is clear to slightly yellow.
-Avonex product solution is a clear, colorless solution.
Intramuscular Administration
-Interferon beta-1a (Avonex) 30 mcg is equivalent to 6 million International Units.
-Premedication with acetaminophen or ibuprofen may lessen the severity of flu-like symptoms.
-The first injection should be performed under the supervision of an appropriately qualified health care provider. Patients may self-inject only if their prescriber determines that it is appropriate, and with medical follow-up, and after proper training in intramuscular injection technique. The manufacturer of Avonex offers free training on intramuscular injection administration for patients and their health care partners. Contact 1-800-456-2255 for more information.
-Refer to the specific 'Instructions for Use' from the manufacturer for the injection device prescribed.
-Remove 1 administration dose pack from refrigerator about 30 minutes prior to use to warm to room temperature. Do not use external heat sources.
-All products are for single-use only.
Intramuscular Injection (Avonex prefilled syringe):
-Hold the syringe with the cap facing down and the 0.5 mL mark 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. Do not inject into an area of the body where skin is irritated, reddened, bruised, infected, or scarred.
-Rotate injection sites to minimize the likelihood of injection site reactions.
-After 2 hours, check the injection site for redness, swelling, or tenderness. Instruct patients to contact their health care provider if a skin reaction occurs that does not resolve in a few days.
-A 25 gauge, 1 inch needle for intramuscular injection may be substituted for the 23 gauge, 1 1/4 inch needle provided by the manufacturer, if deemed appropriate by the physician.
-Storage: Store prefilled syringes at 2 to 8 degrees C (36 to 46 degrees F). If refrigeration is unavailable, may store at 25 degrees C (77 degrees F) or less for up to 7 days. Do not use product that is stored above 25 degrees C (77 degrees F). Do not freeze. Protect from light.
Intramuscular Injection (Avonex prefilled 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. Do not inject into an area of the body where skin is irritated, reddened, bruised, infected, or scarred.
-Rotate injection sites to minimize the likelihood of injection site reactions.
-After 2 hours, check the injection site for redness, swelling, or tenderness. Instruct patients to contact their health care provider if a skin reaction occurs that does not resolve in a few days.
Intramuscular Injection (Avonex pen 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 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 the 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 solution 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.
-Inject at a 90-degree angle into the upper, outer thigh. Do not inject into an area of the body where skin is irritated, reddened, bruised, infected, or scarred. 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.
-Pull the pen straight out of the skin after counting to 10. The circular display window on the pen will be yellow if you have received the full dose.
-Cover the exposed needle. Do not hold the cover with your hands while inserting the needle.
-After 2 hours, check the injection site for redness, swelling, or tenderness. Instruct patients to contact their health care provider if a skin reaction occurs that does not resolve in a few days.
-Rotate injection sites to minimize the likelihood of injection site reactions.
-Storage: Store the pen autoinjector at 2 to 8 degrees C (36 to 46 degrees F). If refrigeration is unavailable, may store at 25 degrees C (77 degrees F) or less for up to 7 days. Do not use product that is stored above 25 degrees C (77 degrees F). Do not freeze. Protect from light.
Subcutaneous Administration
-Interferon beta-1a (Rebif) 44 mcg is equivalent to 12 million International Units.
-Patients and/or their caregivers should be trained and understand appropriate preparation and administration. Users should demonstrate competency in all aspects of the injection prior to independent use. Patients with severe neurological deficits should not self-administer injections without assistance from a trained caregiver.
-The manufacturer offers complimentary services including injection training and reimbursement support. Contact MS LifeLines at 877-44-REBIF.
-Refer to the specific 'Instructions for Use' from the manufacturer for the specific device prescribed.
-Premedication with acetaminophen or ibuprofen may lessen the severity of flu-like symptoms.
-Remove the prefilled syringe or the Rebidose autoinjector from the refrigerator about 30 minutes before use and allow warming to room temperature.
-Give by subcutaneous injection on the same 3 days each week (e.g., Monday, Wednesday and Friday) and if possible, at the same time of day (preferably in the late afternoon or evening). Injection doses should be at least 48 hours apart.
Subcutaneous Injection (Rebif prefilled syringe):
-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.
Flu-like symptoms occur frequently in most patients treated with interferon beta-1a (49% with Avonex and 56-59% with Rebif). Symptoms of flu syndrome are most prominent at therapy initiation and decrease in frequency with continued treatment. Concurrent use of analgesics and/or antipyretics may help ameliorate flu-like symptoms on treatment days. Specific symptoms seen with Avonex include fever (20%), chills (19%), headache (58%), migraine (5%), peripheral vasodilation (2%), dizziness (14%), myalgia (29%), arthralgia (9%), chest pain (unspecified) (5%), nausea (23%), pain (23%), and asthenia (weakness) (24%). Among recipients of Rebif 22 mcg three times weekly, headache (65%), fatigue (33%), fever (25%), rigors (6%), chest pain (6%), malaise (4%), somnolence (4%), myalgia (25%), back pain (23%), and musculoskeletal pain (15%) were reported. Among recipients of Rebif 44 mcg three times weekly, headache (70%), fatigue (41%), fever (28%), rigors (13%), chest pain (8%), malaise (5%), somnolence (5%), myalgia (25%), back pain (25%), and musculoskeletal pain (10%) were reported. Lupus-like symptoms (i.e., drug-induced lupus erythematosus) have been reported during post-marketing use.
An injection site reaction occurred in 3% of patients after intramuscular (IM) injection of interferon beta-1a (Avonex). Injection site pain was noted in 8%, and injection site inflammation was noted in 6%. Ecchymosis (bruising) at the IM injection site has been reported (6%). Subcutaneous administration of Avonex has resulted in inflammation at the injection site in 52% of patients; use has also been associated with local skin necrosis, skin atrophy, edema, and bleeding (hematoma) at the subcutaneous injection site. Among recipients of Rebif 22 mcg three times weekly, 89% had an injection site reaction and 1% had injection site necrosis. Among recipients of Rebif 44 mcg three times weekly, 92% had an injection site reaction and 3% had injection site necrosis. All events of injection site necrosis resolved with conservative management, and Rebif was continued in all but 1 patient who had a brief interruption of drug receipt. Tissue necrosis, abscesses and cellulitis have been reported during postmarketing use of interferon beta-1a. Hospitalization for surgical drainage, debridement, skin grafting, and intravenous/systemic antibiotics were required in some cases. Advise patients of the importance of injection site rotation and aseptic injection technique to minimize the risk of tissue necrosis; periodically evaluate patient understanding and use of aseptic self-injection techniques and procedures. Also, instruct patients to promptly report any break in the skin, which may be associated with blue-black discoloration, swelling, or fluid drainage. Whether to discontinue interferon beta-1a after a single site of necrosis is dependent on the extent of necrosis.
During clinical trials for Rebif (administered 3 times weekly at doses of either 22 mcg or 44 mcg), hypertonia (6-7%), abnormal vision or visual impairment (3-13%), xerophthalmia (1-3%), and abnormal coordination (4-5%) were reported. Retinal vascular disorders such as retinopathy, cotton wool spots, or retinal artery or vein obstruction were noted post-marketing. Also noted post-marketing were transient neurological symptoms such as hypoesthesia, muscle spasm, paresthesias, difficulty walking, and musculoskeletal stiffness that mimic multiple sclerosis exacerbations of limited duration. The transient neurological symptoms were temporally related to the injections and were most prominent at therapy initiation. In some cases, these symptoms were associated with a flu-like syndrome; some patients have experienced myasthenia. In a trial with Avonex, 4% of patients had an eye disorder.
Use interferon beta-1a with caution in patients who exhibit depression or other mood disorders. Depression, suicidal ideation, and suicide attempts have been reported to occur with increased frequency in patients receiving interferon compounds. Advise patients to immediately report any symptoms of depression and/or suicidal ideation to the prescribing physician. If a patient develops depression or other severe psychiatric symptoms, consider interferon beta-1a cessation. During clinical trials, depression of any severity was reported in 20-25% of patients. Reports of depression in either Rebif- or placebo-treated patients was about 25%. Depression occurred equally during the initial trial with Avonex- and placebo-treated patients; however, in a second trial, Avonex-treated patients were more likely to experience depression than placebo-treated patients (20% vs. 13%, respectively). Suicidal ideation was reported in 4% of Avonex-treated patients and in 1% of placebo-treated patients. Additionally, there have been post-marketing reports of suicide, depression, suicidal ideation, and/or development of new or worsening of preexisting psychiatric disorders including psychosis. Some of these patients improved upon cessation of interferon beta-1a therapy.
Severe hepatic injury, including hepatic failure, has been reported rarely in patients taking interferon beta-1a. Some cases with Rebif have required liver transplantation. In the absence of clinical symptoms, liver function tests should be monitored at 1, 3, and 6 months, then periodically, with Rebif; monitor with Avonex use, as well, though guidelines were not given by the manufacturer. Of note, symptoms of liver dysfunction began from 1-6 months after Rebif initiation; if jaundice or other symptoms of liver dysfunction appear, immediately discontinue Rebif due to the potential for rapid progression to liver failure. Elevated transaminases are known to be dose-related laboratory abnormalities associated with the use of interferons; SGPT elevations are commonly asymptomatic. Elevated hepatic enzymes, some of which have been severe, have been reported post-marketing with Avonex; elevations recurred in some patients upon rechallenge. In clinical trial with Rebif (both 22 mcg and 44 mcg three times weekly), SGPT increased in 20-27% of patients and SGOT increased in 10-17%. Consider Rebif dose reduction for SGPT > 5 times the upper limit of normal; the dose may be gradually re-escalated when enzyme levels have normalized. Also in Rebif trials, abnormal hepatic function (4-9%), hyperbilirubinemia (2-3%), and xerostomia (1-5%) were noted. Abdominal pain was reported in both Avonex (8%) and Rebif (20-22%) in trials. Rare cases of autoimmune hepatitis were reported post-marketing with Avonex.
Seizures have been associated with the use of beta interferons, including Avonex and Rebif (1-5% rate reported in all trials). In the two placebo-controlled studies in multiple sclerosis, 4 of 351 (approximately 1%) patients receiving Avonex experienced seizures. Three of these 4 patients had no prior history of seizure, and no seizures occurred in the placebo groups. It is not known whether seizures were related to the effects of multiple sclerosis alone, to interferon beta-1a, or to a combination of both. Seizures in patients without a prior history have also been noted during the post-marketing surveillance period of Avonex. The effect of Avonex administration on the medical management of patients with seizure disorder is unknown. In clinical trials with Rebif, 5% of recipients of 22 mcg 3-times weekly and 4% of recipients of 44 mcg 3-times weekly had seizures. Seizures have also been noted during the post-marketing period of Rebif.
Anaphylactoid reactions including anaphylactic shock have been reported as a rare complication of interferon beta-1a use. Other allergic reactions have included difficulty breathing, bronchospasm (wheezing) (6%), angioedema, skin rash (unspecified), orolingual edema, and urticaria. Reactions have ranged from mild to severe without a clear relationship to dose or duration of treatment and both erythematous rash (5% to 7%) and maculopapular rash (4% to 5%) have been reported. Allergic reactions, some severe, have occurred after prolonged use. Postmarketing, erythema multiforme, vesicular rash, and Stevens-Johnson syndrome have been reported.
Leukopenia and thrombocytopenia are known to be dose-related laboratory abnormalities associated with the use of interferons. Leukopenia was reported in Rebif trials at a rate of 28% to 36%, but was not reported in Avonex trials. Thrombocytopenia was reported in 2% to 8% of patients in Rebif trials and has been reported postmarketing, rarely, with Avonex including cases where platelet nadirs have been less than 10,000/mm3; some cases reoccurred with rechallenge. Also, idiopathic thrombocytopenia has been reported postmarketing with Avonex. In Avonex trials anemia was reported in 4%; anemia was reported in Rebif trials in 3% to 5% of patients. Lymphadenopathy was reported in 11% to 12% of patients in Rebif clinical trials. During postmarketing experience, decreased peripheral blood counts in all cell lines, including rare cases of pancytopenia have been reported with Avonex, and hemolytic anemia has been reported with Rebif. Regular monitoring of hematologic parameters and for signs of hematological disorders is recommended during interferon beta-1a therapy. Blood cell counts are recommended at regular intervals (1, 3, and 6 months) after Rebif initiation and periodically thereafter in the absence of clinical symptoms. Complete blood and differential white blood cell counts and platelet counts are recommended during Avonex therapy. Patients with myelosuppression may require more intensive monitoring of complete blood cell counts. During the placebo-controlled studies in multiple sclerosis, these tests were performed at least every 6 months.
In recent studies of Avonex, neutralizing antibody formation was noted at one or more times in 5% of patients (21 of 390 patients) treated with Avonex for at least 1 year. During a 2-year study of Rebif (44 mcg 3-times weekly), neutralizing antibodies were detected one or more times in 24% of patients (45 of 184 patients). Among recipients of 22 mcg 3-times weekly, serum neutralizing antibodies to Rebif were detected in 31% of 189 patients. The significance of the appearance of serum neutralizing activity is unknown. Comparison of the incidence of antibodies between interferon beta-1a products may be misleading due to factors that affect testing of antibodies (e.g., sensitivity and specificity of the assay, handling, time of sample collection, concurrent medications, underlying medical conditions, etc.).
During trials with the Rebif formulation of interferon beta-1a (both 22 mcg and 44 mcg 3-times weekly recipients), urinary incontinence was reported in 2-4% and increased urinary frequency was reported in 2-7%. Abnormal urine constituents were noted in 3% of Avonex recipients.
Autoimmune reactions have been associated with interferon beta-1a therapy including hyperthyroidism and hypothyroidism. Thyroid disorder (unspecified) was reported during Rebif trials, with new or worsening thyroid abnormalities, in 4-6% of recipients. Monitor patients for signs of these disorders including periodic monitoring of thyroid function, especially if patients have or develop symptoms of thyroid dysfunction. Implement appropriate treatment when observed. For Rebif, thyroid function tests are recommended every 6 months in patients with a history of thyroid dysfunction or as clinically indicated.
Closely monitor patients with cardiac disease such as angina, congestive heart failure, or arrhythmia for worsening of their clinical condition during initiation and continued treatment with Avonex, as infrequent cases of congestive heart failure, cardiomyopathy, and cardiomyopathy with congestive heart failure have been reported during post-marketing of Avonex. The reports were in patients without known predisposition to these events and without other known etiologies being established. In rare cases, these events have been temporally related to the administration of Avonex, and, in some instances, recurrence upon rechallenge was observed. Interferon beta-1a is not known to be directly cardiotoxic.
In placebo-controlled trials in multiple sclerosis, 5% of patients receiving placebo and 6% of patients receiving Avonex experienced menstrual irregularity. Menorrhagia and metrorrhagia have also been reported in post-marketing experience with Avonex. If menstrual irregularities occur, it is not known how long they will persist after treatment. During clinical trials with Rebif there were 2 cases of spontaneous fetal abortion observed and 5 fetuses carried to term among 7 women in the Rebif-treated group. During animal primate studies, interferon beta-1a at doses approximately 2 times the cumulative weekly human dose based on either body weight or surface area either during the period of organogenesis or later in pregnancy has been associated with significant increases in embryolethal or abortifacient effects.
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.
Among interferon beta-1a (Avonex) recipients, 7% had an infection, 3% had a toothache, 14% had an upper respiratory tract infection, 14% had sinusitis, 8% had bronchitis, and 17% had urinary tract infection. Interferon beta-1a contains albumin, which is a derivative of human blood. An extremely remote risk for transmission of viral diseases exists, and a theoretical risk for transmission of Creutzfeldt- Jakob disease (CJD) also is considered extremely remote. No cases of transmission of viral diseases or CJD have ever been identified for albumin. Manufacturing processes and effective donor screening help reduce the risk of infection from interferon beta-1a.
Among interferon beta-1a recipients (Avonex), 4% had alopecia. In a clinical study evaluating interferon beta-1a (Rebif), 4% of patients experienced increased sweating (hyperhidrosis).
Cases of pulmonary arterial hypertension (PAH), some requiring hospitalization, have been reported in patients treated with interferon beta products in the absence of other contributory factors. One reported case required a lung transplant. Cases of pulmonary hypertension have been reported at various time points during treatment, and may occur years after treatment initiation. Assess patients who develop unexplained symptoms (e.g., dyspnea or new or increasing fatigue) for PAH. Discontinue therapy if a diagnosis of PAH is confirmed, and manage as appropriate.
Interferon beta-1a products are contraindicated in patients with a history of hypersensitivity to natural or recombinant interferon beta, or any other component of the formulation. Anaphylaxis has been reported as a rare complication of interferon beta-1a product use. Other allergic reactions have included dyspnea, orolingual edema, skin rash and urticaria. Discontinue interferon beta-1a therapy if anaphylaxis or other allergic reactions occur. Some formulations (e.g., Rebif products, and the no longer marketed lyophilized vials of Avonex) contain human albumin and are contraindicated in patients with human albumin hypersensitivity. Use interferon beta-1a products with caution in patients with hamster protein hypersensitivity as the products are produced by recombinant DNA technology using genetically engineered Chinese Hamster Ovary cells into which the human interferon beta gene has been introduced.
Use interferon beta-1a with caution in patients with active hepatic disease, alcohol abuse (alcoholism), increased serum SGPT (greater than 2.5 times the upper limit of normal or ULN), or a history of significant liver disease. Severe hepatic injury, including hepatitis, autoimmune hepatitis, and rare cases of severe hepatic failure requiring liver transplantation, have been reported with interferon beta-1a therapy. Elevation of liver function tests (LFTs) and bilirubin may occur and asymptomatic elevation of hepatic transaminases (particularly SGPT) is common with interferon treatment; some cases have recurred on rechallenge with interferon beta-1a. Symptoms of liver dysfunction began from 1 to 6 months following interferon beta-1a initiation. In some cases, events have occurred in the presence of other drugs that have been associated with hepatic injury. The potential hepatotoxicity risk of interferon beta therapies when used in combination with known hepatotoxic drugs or other products (e.g., ethanol ingestion) should be considered before their concurrent use. Monitor patients for signs and symptoms of hepatic injury. Monitoring of LFTs is recommended at regular intervals (e.g., 1, 3, and 6 months) 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 hepatic failure exists if the drug is continued.
Patients treated with interferon beta-1a and their caregivers should be advised to report immediately any symptoms of depression, suicidal ideation, and/or psychosis to their prescribing physicians. If a patient develops depression or other severe psychiatric symptoms, cessation of interferon beta-1a therapy should be considered. Depression and suicide have been reported to occur with increased frequency in patients receiving interferon beta-1a versus those receiving placebo. Additionally, there have been postmarketing reports of depression, suicidal ideation, and/or development of new or worsening of other pre-existing psychiatric disorders, including psychosis. For some of these patients, symptoms of depression improved upon cessation of interferon beta-1a.
Caution should be exercised when administering interferon beta-1a to patients with a pre-existing seizure disorder. Seizures have been temporally associated with the use of beta interferons, including interferon beta-1a, in clinical trials and in postmarketing reports.
Monitor patients with significant cardiac disease or pre-existing heart failure for worsening of their cardiac condition during initiation and continuation of treatment with interferon beta-1a. While beta interferons do not have any known direct cardiac toxicity, during the postmarketing period cases of congestive heart failure, cardiomyopathy, and cardiomyopathy with congestive heart failure have been reported in patients without known predisposition to these events, and without other etiologies being established. In some cases, these events have been temporally related to the administration of interferon beta-1a. In some of these instances recurrence upon rechallenge was observed.
Patients with bone marrow suppression or who are receiving myelosuppressive therapy may be at increased risk of developing hematologic toxicity during interferon beta-1a therapy. Decreased peripheral blood counts in all cell lines are possible, including rare cases of pancytopenia and severe thrombocytopenia. Monitoring of complete blood cell counts, differential white blood cell counts, and platelet counts is recommended during therapy (e.g., 1, 3, and 6 months following introduction and periodically thereafter). Patients with bone marrow suppression may require more intensive monitoring of blood cell counts.
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.
Use interferon beta-1a with caution in patients with pulmonary hypertension. Cases of pulmonary arterial hypertension (PAH), some requiring hospitalization, have been reported in patients treated with interferon beta products in the absence of other contributory factors. Assess patients who develop unexplained symptoms (e.g., dyspnea or new or increasing fatigue) for PAH. Discontinue therapy if a diagnosis of PAH is confirmed, and manage as appropriate. Cases of PAH have been reported at various time points during treatment, and may occur years after treatment initiation.
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. If a patient develops a new autoimmune disorder, consider stopping treatment.
Injection site reactions, including injection site tissue necrosis, abscess, and cellulitis, can occur with the use of interferon beta-1a. Some occurred more than 2 years after initiation of interferon beta treatment. Necrosis occurred at single and at multiple injection sites. Some cases reported postmarketing required hospitalization for surgical drainage and intravenous antibiotics. Periodically evaluate patient understanding and use of aseptic self-injection techniques and procedures, particularly if injection site necrosis has occurred. Decisions to discontinue therapy following tissue necrosis at an injection site should be based on the extent of the necrosis. For patients who continue therapy, avoid administration near the affected area until it is fully healed. If multiple lesions occur, change injection site or discontinue peginterferon beta-1a until healing occurs.
Epidemiological data do not suggest a clear relationship between interferon beta use and major congenital malformations, but interferon beta may cause fetal harm based on animal data. Findings regarding a potential risk for low birth weight or miscarriage with the use of interferon beta in human pregnancy have been inconsistent. It is unclear whether, as a class of products, administration of interferon beta therapies to pregnant animals at doses greater than those used clinically results in an increased rate of abortion. The potential for interferon beta-1a to have adverse effects on embryofetal development has not been fully assessed in animals. The majority of observational studies reporting on pregnancies exposed to interferon beta products did not identify an association between the use of interferon beta products during early pregnancy and an increased risk of major birth defects. In a population-based cohort study conducted in Finland and Sweden, data were collected from 1996 to 2014 in Finland and from 2005 to 2014 in Sweden on 2,831 pregnancy outcomes from women with Multiple Sclerosis. 797 pregnancies were in women exposed to interferon beta only. No evidence was found of an increased risk of major birth defects among women with MS exposed to interferon beta products compared to women with MS that were unexposed to any non-steroid therapy for MS (n=1,647) within the study. No increased risks were observed for miscarriages and ectopic pregnancies, though there were limitations in obtaining complete data capture for these outcomes, making the interpretation of the findings more difficult. Two small cohort studies that examined pregnancies exposed to interferon beta products (without differentiating between subtypes of interferon beta products) suggested that a decrease in mean birth weight may be associated with interferon beta exposure during pregnancy, but this finding was not confirmed in larger observational studies. Two small studies observed an increased prevalence of miscarriage, although the finding was only statistically significant in one study. Most studies enrolled patients later in pregnancy, which made it difficult to ascertain the true percentage of miscarriages. In one small cohort study, a significantly increased risk of preterm birth following interferon beta exposure during pregnancy was observed. In cynomolgus monkeys given interferon beta by subcutaneous injection every other day during early pregnancy, no teratogenic or other adverse effects on fetal development were observed; however, abortifacient activity was evident following 3 to 5 doses. The National Multiple Sclerosis Society consensus guidelines and the product labels recommend that women discontinue interferon beta therapy when trying to conceive and throughout gestation due to insufficient evidence regarding safety to the human fetus; however, most women who happen to conceive while taking interferon beta appear to have healthy newborns. If a patient does become pregnant while receiving interferon therapy, she should be made aware of the risks. The risks and benefits of continuing interferon beta therapy during pregnancy require careful consideration of the patient's level of disease activity, personal preferences, and the potential fetal risks. 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. 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. Limited data indicate the presence of interferon beta-1a products in human milk at low concentrations. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for interferon beta-1a and any potential adverse effects on the breastfed infant. A small number of nursing mothers (n = 5) receiving an interferon beta-1a dose of 30 mcg weekly 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 on the highest detected interferon beta-1a concentration in breast milk (179 pg/mL), the estimated relative infant dose was estimated to be 0.006% of the maternal interferon beta dose. Due to its poor oral bioavailability, any drug present in the breast milk is unlikely to be systemically absorbed by the nursing infant. The Multiple Sclerosis Centre of Excellence on Reproduction and Child Health considers the various interferon beta products to be moderately safe for use during lactation since the molecular weight of the drug is likely to limit transfer to breast milk. Other reviews concur that interferon beta-1a is likely compatible with breast-feeding. Glatiramer and interferon beta-1b are potential alternatives to consider for the treatment of multiple sclerosis. However, the standard of care based is to have a mother start disease-modifying therapy of any type only after complete weaning of their infant. A discussion about the risks and benefits of postponing the resumption of interferon beta treatment in order to breast-feed is important, particularly for women who experience highly-active disease or who had active multiple sclerosis in the year prior to conception.
The Avonex prefilled syringe and injector pen products contain natural rubber latex which may cause allergic reactions in those patients with latex hypersensitivity.
For the treatment of relapsing forms of multiple sclerosis, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease:
Intramuscular dosage (Avonex):
NOTE: Interferon beta-1a (Avonex) has been designated as an orphan drug by the FDA for this indication.
Adults: 7.5 mcg IM once weekly, initially. Increase the dose by 7.5 mcg/week up to the target dose of 30 mcg/week.
Subcutaneous dosage (Rebif):
Adults: 4.4 mcg subcutaneously 3 times weekly (at least 48 hours apart) for 2 weeks, then 11 mcg subcutaneously 3 times weekly for 2 weeks, and then 22 mcg subcutaneously 3 times weekly or 8.8 mcg subcutaneously 3 times weekly (at least 48 hours apart) for 2 weeks, then 22 mcg subcutaneously 3 times weekly for 2 weeks, and then 44 mcg subcutaneously 3 times weekly.
Maximum Dosage Limits:
-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.
Patients with Hepatic Impairment Dosing
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.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
Abacavir: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Abacavir; Dolutegravir; Lamivudine: (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6). (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Abacavir; Lamivudine, 3TC: (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6). (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Abacavir; Lamivudine, 3TC; Zidovudine, ZDV: (Major) Use interferons and zidovudine together with caution. Closely monitor patients for treatment-associated toxicities, especially hematologic effects and hepatic decompensation, and manage as recommended for the individual therapies. Coadministration of alpha interferons may increase the hematologic toxicity of zidovudine. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) are also associated with hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. Interferon therapy may also reduce zidovudine clearance. (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6). (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Alemtuzumab: (Major) Concomitant use of interferon beta with alemtuzumab may increase the risk of immunosuppression. Avoid the use of these drugs together.
Atazanavir: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. The HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART.
Atazanavir; Cobicistat: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. The HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART.
Bictegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Cabotegravir; Rilpivirine: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and rilpivirine can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving antiretroviral agents and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Chloroquine: (Moderate) Concurrent use of chloroquine and interferons is not recommended as there is an increased risk of retinal toxicity.
Darunavir: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. The HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART.
Darunavir; Cobicistat: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. The HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. The HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Delavirdine: (Major) The concomitant use of interferons and anti-retroviral non-nucleoside reverse transcriptase inhibitors (NNRTIs) should be done with caution as both can cause hepatic damage. NNRTIs may cause liver damage in the context of hypersensitivity reactions or by direct toxic effects. Many studies demonstrate that nevirapine is more hepatotoxic than efavirenz. Underlying chronic HCV infection enhances the risk of developing liver enzyme elevations in patients receiving nevirapine. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation.
Dolutegravir; Lamivudine: (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6).
Dolutegravir; Rilpivirine: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and rilpivirine can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving antiretroviral agents and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6).
Efavirenz: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and efavirenz can both cause hepatotoxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and efavirenz can both cause hepatotoxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6). (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and efavirenz can both cause hepatotoxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Emtricitabine: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and rilpivirine can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving antiretroviral agents and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and rilpivirine can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving antiretroviral agents and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Emtricitabine; Tenofovir alafenamide: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Entecavir: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Ethanol: (Major) Consider the potential risk of interferon beta products used in combination with known hepatotoxic drugs or other products (e.g., alcohol) prior to use. Monitor hepatic function during interferon beta treatment. Patients should be advised to avoid drinking alcohol to reduce the chance of injury to the liver during interferon beta treatment. Alcohol may also potentiate drowsiness and dizziness. Patients who develop dizziness, confusion, somnolence, and fatigue with interferon beta treatment should be cautioned to avoid driving or operating machinery.
Fosamprenavir: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. The HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART.
Indinavir: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. The HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART.
Lamivudine, 3TC: (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6).
Lamivudine, 3TC; Zidovudine, ZDV: (Major) Use interferons and zidovudine together with caution. Closely monitor patients for treatment-associated toxicities, especially hematologic effects and hepatic decompensation, and manage as recommended for the individual therapies. Coadministration of alpha interferons may increase the hematologic toxicity of zidovudine. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) are also associated with hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. Interferon therapy may also reduce zidovudine clearance. (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6).
Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6).
Lopinavir; Ritonavir: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. The HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART.
Natalizumab: (Major) Natalizumab should be used with caution with interferon beta because of the potential for increased risk of progressive multifocal leukoencephalopathy (PML) and other serious infections with combined use. Ordinarily, multiple sclerosis (MS) patients receiving chronic immunomodulatory therapy should not be treated with natalizumab; however, in some multiple sclerosis clinical trials, patients were allowed to continue interferon beta therapy. Due to the risk for infection and PML, natalizumab is only approved for monotherapy of MS. The safety and efficacy of natalizumab as an add-on therapy to interferon beta treatments has not been established. Sequential therapy (e.g., interferon beta followed by natalizumab) does not appear to increase the risk for PML.
Nelfinavir: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. The HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART.
Nevirapine: (Major) The concomitant use of interferons and nevirapine should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Nevirapine may cause liver damage in the context of hypersensitivity reactions or by direct toxic effects. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. Patients with signs or symptoms of hepatitis, or with increased transaminases combined with rash or other systemic symptoms, must discontinue nevirapine and seek medical evaluation immediately.
Nirmatrelvir; Ritonavir: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. The HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART.
Ocrelizumab: (Moderate) Ocrelizumab has not been studied in combination with other immunosuppressive or immune modulating therapies used for the treatment of multiple sclerosis, such as interferon beta-1a or interferon beta-1b. Concomitant use of ocrelizumab with interferon beta may increase the risk of immunosuppression.
Ofatumumab: (Moderate) Concomitant use of ofatumumab with interferon beta may increase the risk of immunosuppression. Ofatumumab has not been studied in combination with other immunosuppressive or immune modulating therapies used for the treatment of multiple sclerosis, such as interferon beta. Consider the duration and mechanism of action of drugs with immunosuppressive effects when switching therapies for multiple sclerosis patients.
Ozanimod: (Moderate) Concomitant use of ozanimod with interferon beta may increase the risk of immunosuppression. Ozanimod has not been studied in combination with other immunosuppressive or immune modulating therapies. Ozanimod can generally be started immediately after discontinuation of interferon beta.
Pexidartinib: (Moderate) Monitor for evidence of hepatotoxicity if pexidartinib is coadministered with interferon beta. Avoid concurrent use in patients with increased serum transaminases, total bilirubin, or direct bilirubin (more than ULN) or active liver or biliary tract disease.
Pretomanid: (Major) Avoid coadministration of pretomanid with interferon beta, especially in patients with impaired hepatic function, due to increased risk for hepatotoxicity. Monitor for evidence of hepatotoxicity if coadministration is necessary. If new or worsening hepatic dysfunction occurs, discontinue hepatotoxic medications.
Protease inhibitors: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. The HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART.
Rilpivirine: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and rilpivirine can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving antiretroviral agents and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Riluzole: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and interferon beta. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
Ritonavir: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. The HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART.
Saquinavir: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. The HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART.
Stavudine, d4T: (Major) Patients receiving stavudine with interferons (with or without ribavirin) should be closely monitored for treatment-associated toxicities, especially hepatic decompensation. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation compared to patients not receiving HAART. Additionally, stavudine has been associated with fatal and nonfatal lactic acidosis and hepatomegaly with or without steatosis and should be used cautiously in patients with hepatic disease. Discontinuation of stavudine should be considered as medically appropriate. Dose reduction or discontinuation of interferon, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6).
Tipranavir: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. The HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART.
Vigabatrin: (Major) Vigabatrin is associated with vision loss. The drug should not be used with interferons, which are associated with a potential for serious ophthalmic effects (e.g., retinopathy, optic neuritis, visual impairment), unless the benefit of treatment clearly outweighs the risks.
Zidovudine, ZDV: (Major) Use interferons and zidovudine together with caution. Closely monitor patients for treatment-associated toxicities, especially hematologic effects and hepatic decompensation, and manage as recommended for the individual therapies. Coadministration of alpha interferons may increase the hematologic toxicity of zidovudine. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) are also associated with hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. Interferon therapy may also reduce zidovudine clearance.
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.
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.
-Route-Specific Pharmacokinetics
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.