CLASSES
Interferons, Beta
MS Agents
DESCRIPTION
Recombinant, glycosylated interferon beta; identical amino acid sequence to endogenous interferon beta
Indicated for relapsing forms of multiple sclerosis, such as clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease
May increase the risk for depression, suicidal ideation, and suicide attempts
COMMON BRAND NAMES
Avonex, Rebif, Rebif Rebidose, Rebif Titration Pack
HOW SUPPLIED
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) such as 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
30 mcg (6 million international units) IM once per week is the target dose. 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). Max: 30 mg/week IM; higher doses do not improve clinical response. TRIALS: Slows the accumulation of physical disability and decreases the frequency of clinical exacerbations. Efficacy established in patients who have experienced a first clinical episode and have MRI features consistent with multiple sclerosis. MISSED DOSE: If a dose is missed, it should be given as soon as possible. The patient should then continue the regular schedule the following week. Do not administer the dose 2 days in a row.
Subcutaneous dosage (Rebif)
Adults
22 or 44 mcg subcutaneously 3 times weekly (e.g., Monday, Wednesday, Friday; each dose given at least 48 hours apart) is the target dose. Titrate to the full dose over a 4-week period using the titration pack. If the goal dose is 22 mcg: Administer 4.4 mcg subcutaneously 3 times weekly (weeks 1 and 2); then 11 mcg 3 times weekly (weeks 3 and 4); then full dose therapy beginning week 5. If the goal dose is 44 mcg: Administer 8.8 mcg subcutaneously 3 times weekly (weeks 1 and 2); then 22 mcg 3 times weekly (weeks 3 and 4); then full-dose therapy beginning week 5. TRIALS: These regimens significantly reduce the number of relapses, delay disability progression, and reduce disease activity and burden as measured by MRI. As compared with data from patients receiving late treatment, patients who received interferon beta-1a initially had lower expanded disability status scale progression, relapse rate, and T2 disease burden; the benefit was greater with the higher dose.
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 extreme temperatures
- Discard product if it contains particulate matter, is cloudy, or discolored
- Do not freeze
- Do not use if product has been frozen
- Protect from light
- Refrigerate (between 36 and 46 degrees F)
- See package insert for detailed storage information
- Store in original container
- Unrefrigerated product can be stored at temperatures not exceeding 77 degrees F for no more than 7 days prior to administration
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.
- 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)
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)
Rebif Titration Pack:
- 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
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. [49550] 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. [49550] [63530] 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.[33852] 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. [63530] 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. Consider enrolling a woman who becomes pregnant while taking Avonex in the pregnancy registry by calling 800-456-2255.[33852] In 5 years, 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.[49547] The effects of interferon beta-1a during labor and delivery are unknown. [49550]
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. 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.[61642] [61643] 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.[61642] [61643] [62512]
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
skin 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
hemolytic anemia / Delayed / Incidence not known
cardiomyopathy / Delayed / Incidence not known
heart failure / Delayed / Incidence not known
spontaneous fetal abortion / Delayed / Incidence not known
thrombotic thrombocytopenic purpura (TTP) / Delayed / Incidence not known
hemolytic-uremic syndrome / Delayed / Incidence not known
thrombotic microangiopathy / 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
hematoma / Early / Incidence not known
myasthenia / Delayed / Incidence not known
psychosis / Early / Incidence not known
jaundice / Delayed / Incidence not known
hepatitis / Delayed / Incidence not known
Mild
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
injection site reaction / Rapid / 3.0
paresthesias / Delayed / Incidence not known
hypoesthesia / Delayed / Incidence not known
rash / Early / Incidence not known
vesicular rash / Delayed / Incidence not known
urticaria / Rapid / Incidence not known
menorrhagia / Delayed / Incidence not known
DRUG INTERACTIONS
Abacavir: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Abacavir; Dolutegravir; Lamivudine: (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6). (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Abacavir; Lamivudine, 3TC: (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6). (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Abacavir; Lamivudine, 3TC; Zidovudine, ZDV: (Major) Use interferons and zidovudine together with caution. Closely monitor patients for treatment-associated toxicities, especially hematologic effects and hepatic decompensation, and manage as recommended for the individual therapies. Coadministration of alpha interferons may increase the hematologic toxicity of zidovudine. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) are also associated with hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. Interferon therapy may also reduce zidovudine clearance. (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6). (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Alemtuzumab: (Major) Concomitant use of interferon beta with alemtuzumab may increase the risk of immunosuppression. Avoid the use of these drugs together.
Atazanavir: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. The HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART.
Atazanavir; Cobicistat: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. The HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART.
Bictegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Cabotegravir; Rilpivirine: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and rilpivirine can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving antiretroviral agents and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Chloroquine: (Moderate) Concurrent use of chloroquine and interferons is not recommended as there is an increased risk of retinal toxicity.
Darunavir: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. The HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART.
Darunavir; Cobicistat: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. The HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. The HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. The HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART.
Delavirdine: (Major) The concomitant use of interferons and anti-retroviral non-nucleoside reverse transcriptase inhibitors (NNRTIs) should be done with caution as both can cause hepatic damage. NNRTIs may cause liver damage in the context of hypersensitivity reactions or by direct toxic effects. Many studies demonstrate that nevirapine is more hepatotoxic than efavirenz. Underlying chronic HCV infection enhances the risk of developing liver enzyme elevations in patients receiving nevirapine. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation.
Dolutegravir; Lamivudine: (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6).
Dolutegravir; Rilpivirine: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and rilpivirine can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving antiretroviral agents and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6).
Efavirenz: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and efavirenz can both cause hepatotoxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Efavirenz; Emtricitabine; Tenofovir 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.
Ombitasvir; Paritaprevir; Ritonavir: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. The HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART.
Ozanimod: (Moderate) Concomitant use of ozanimod with interferon beta may increase the risk of immunosuppression. Ozanimod has not been studied in combination with other immunosuppressive or immune modulating therapies. Ozanimod can generally be started immediately after discontinuation of interferon beta.
Pexidartinib: (Moderate) Monitor for evidence of hepatotoxicity if pexidartinib is coadministered with interferon beta. Avoid concurrent use in patients with increased serum transaminases, total bilirubin, or direct bilirubin (more than ULN) or active liver or biliary tract disease.
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).
Telbivudine: (Major) An increased risk and severity of peripheral neuropathy has been reported with telbivudine alone or in combination with pegylated interferon alfa-2a and other interferons. Patients should be advised to report any numbness, tingling, and/or burning sensations in the arms and/or legs, with or without gait disturbance. Interrupt telbivudine if peripheral neuropathy is suspected, and discontinue the drug if peripheral neuropathy is confirmed. Since both interferons and telbivudine may cause hepatotoxicity, hepatic function should also be closely monitored.
Tipranavir: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. The HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART.
Vigabatrin: (Major) Vigabatrin is associated with vision loss. The drug should not be used with interferons, which are associated with a potential for serious ophthalmic effects (e.g., retinopathy, optic neuritis, visual impairment), unless the benefit of treatment clearly outweighs the risks.
Zidovudine, ZDV: (Major) Use interferons and zidovudine together with caution. Closely monitor patients for treatment-associated toxicities, especially hematologic effects and hepatic decompensation, and manage as recommended for the individual therapies. Coadministration of alpha interferons may increase the hematologic toxicity of zidovudine. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) are also associated with hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. Interferon therapy may also reduce zidovudine clearance.
PREGNANCY AND LACTATION
Pregnancy
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. [49550] 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. [49550] [63530] 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.[33852] 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. [63530] 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. Consider enrolling a woman who becomes pregnant while taking Avonex in the pregnancy registry by calling 800-456-2255.[33852] In 5 years, 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.[49547] The effects of interferon beta-1a during labor and delivery are unknown. [49550]
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.[61642] [61643] 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.[61642] [61643] [62512]
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.