Avonex 30 mcg

As with all interferon products, proper monitoring of patients is required if AVONEX or AVONEX PS is given in combination with myelosuppressive agents.

No formal drug interaction studies have been conducted with AVONEX (interferon beta-1a) and AVONEX PS (interferon beta-1a). In the placebo-controlled study, corticosteroids or ACTH were administered for treatment of exacerbations in some patients concurrently receiving AVONEX. In addition, some patients receiving AVONEX were also treated with anti-depressant therapy and/or oral contraceptive therapy. No unexpected adverse events were associated with these concomitant therapies.

Intended for use under the guidance and supervision of a physician.

30 µg injected intramuscularly once per week.

Patients with relapsing progressive MS or secondary progressive MS with recurrent attacks of neurological dysfunction could benefit from an increase of their dose of AVONEX up to 60 µg.

Use the reconstituted product as soon as possible, but within 6 hours if stored at 2 to 8°C. Do not freeze the reconstituted solution.

AVONEX lyophilized powder must be reconstituted by adding 1.1 mL of supplied sterile Water for Injection to the single-use vial of lyophilized powder prior to intramuscular injection. The 1.0 mL is withdrawn for administration (see Information for the Patient).

AVONEX PS in the prefilled syringe does not require reconstitution prior to injection.

If a dose is missed, the next dose should be taken as soon as possible. The regular schedule should be continued the following week. Do not take AVONEX or AVONEX PS on two consecutive days.

Anaphylaxis and other allergic reactions and decreased peripheral blood counts have been reported in patients using AVONEX and AVONEX PS. Seizures, cardiovascular adverse events, and autoimmune disorders also have been reported in association with the use of AVONEX (see Warnings and Precautions).

Other events observed during premarket and postmarket evaluation of AVONEX, administered either SC or IM are listed below. Because most of the events were observed in open and uncontrolled studies, or in marketed use, the role of AVONEX and AVONEX PS in their causation cannot be reliably determined.

blood in stool, colitis, constipation, diverticulitis, dry mouth, gallbladder disorder, gastritis, gastrointestinal hemorrhage, gingivitis, gum hemorrhage, hepatitis, hepatoma, hepatomegaly, increased appetite, intestinal perforation, intestinal obstruction, liver function test abnormalities, periodontal abscess, periodontitis, proctitis, thirst, tongue disorder, vomiting.

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

abnormal vision, conjunctivitis, earache, eye pain, labyrinthitis, vitreous floaters.

abnormal healing, dehydration, hypoglycemia, hypomagnesemia, hypokalemia.

basal cell carcinoma, blisters, cold clammy skin, contact dermatitis, erythema, furunculosis, genital pruritus, nevus, pruritus, rash (including vesicular rash), seborrhea, skin ulcer, skin discoloration.

arthritis, bone pain, myasthenia, osteonecrosis, synovitis.

AVONEX has also been evaluated in 290 patients with diseases other than MS. The majority of these patients were enrolled in studies to evaluate AVONEX treatment of chronic viral hepatitis B and C with AVONEX, in which the doses studied ranged from 15 µg to 75 µg, given subcutaneously (SC), 3 times a week, for up to 6 months. The incidence of common adverse events in these studies was generally seen at a frequency similar to that seen in the placebo-controlled MS study. In these non-MS studies, inflammation at the site of the SC injection was seen in 52% of treated patients. In contrast, injection site inflammation was seen in 3% of MS patients receiving AVONEX, 30 µg by IM injection. SC injections were also associated with the following local reactions: injection site necrosis, injection site atrophy, injection site edema, and injection site hemorrhage. None of the above was observed in the MS patients participating in the placebo-controlled study of relapsing MS.

AVONEX PS has been shown to have comparable safety and immunogenicity profiles compared to what has been reported with the use of AVONEX in previous clinical trials and in clinical practice. In the safety and immunogenicity study with AVONEX PS liquid formulation, three of the five adverse events in which the incidence was greater than 20% (flu syndrome: 134 (88%); headache: 69 (45%); asthenia: 40 (26%)), were attributable to the flu-like syndrome associated with interferon therapy. Paresthesia occurred in 33 (22%) patients, and MS exacerbation, an event inherent to the relapsing form of MS, was seen in 50 (33%) patients. Depression, which is known to be associated with MS and potentially with interferon therapy, was observed in 23 (15%) patients. There were no reported suicide attempts or suicidal tendency in this study. The incidence of depression in this study is similar to that observed in the group treated with AVONEX in the clinical studies (15%). Twenty-five percent of subjects (38/153) experienced an adverse event related to the injection site, the most frequent of which were injection site ecchymosis (12%) and injection site pain (11 %). These rates are similar to those seen with AVONEX in previous clinical studies. There were no unexpected laboratory abnormalities in this trial. Mild shifts outside of the normal range occurred with an incidence similar to that seen with AVONEX.

abscess, ascites, cellulitis, facial edema, hernia, injection site fibrosis, injection site hypersensitivity, injection site reaction (including pain, inflammation, and very rare cases of abscess or cellulitis) lipoma, neoplasm, photosensitivity reaction, rigors, sepsis, sinus headache, tachycardia, toothache.

The safety data describing the use of AVONEX in MS patients are based on the placebo-controlled trial in which 158 patients with relapsing multiple sclerosis randomized to AVONEX were treated for up to 2 years.

arrhythmia, arteritis, congestive heart failure, heart arrest, hemorrhage, hypotension, palpitation, pericarditis, peripheral ischemia, peripheral vascular disorder, postural hypotension, pulmonary embolus, spider angioma, tachycardia, telangiectasia, vascular disorder.

hyperthyroidism, hypothyroidism.

abnormal gait, amnesia, anxiety, Bell's Palsy, clumsiness, confusion, depersonalization, drug dependence, emotional lability, facial paralysis, hyperesthesia, hypertonia, increased libido, neurosis, paresthesia, psychosis, transient severe weakness.

breast fibroadenosis, breast mass, dysuria, epididymitis, fibrocystic change of the breast, fibroids, gynecomastia, hematuria, kidney calculus, kidney pain, leukorrhea, menopause, nocturia, pelvic inflammatory disease, penis disorder, Peyronies Disease, polyuria, post menopausal hemorrhage, prostatic disorder, pyelonephritis, testis disorder, urethral pain, urinary urgency, urinary retention, urinary incontinence, vaginal hemorrhage.

The five most common adverse events associated (at p<0.075) with AVONEX (interferon beta-1a) and AVONEX PS (interferon beta-1a) treatment were flu-like symptoms (otherwise unspecified), muscle ache, fever, chills, and asthenia. The incidence of all 5 adverse events diminished with continued treatment.

In the placebo-controlled study of patients with relapsing MS, one patient in the placebo group and no AVONEX-treated patients attempted suicide. The incidence of depression was equal in the two treatment groups. However, since depression and suicide have been reported with other interferon products, AVONEX or AVONEX PS should be used with caution in patients with depression (see Warnings and Precautions). Four patients receiving AVONEX experienced seizures, while no seizures occurred in the placebo group. Of these four patients, three had no prior history of seizure. It is not known whether these events were related to the effects of MS alone, to AVONEX, or to a combination of both (see Warnings and Precautions).

In the study of patients experiencing a single demyelinating event, the most common adverse events associated with AVONEX (p≤0.05) during the first six months of treatment were flu-like syndrome (AVONEX: 39%, placebo: 22%), fever (AVONEX: 17%, placebo: 6%) and chills (AVONEX: 17%, placebo: 3%). A higher proportion of patients treated with AVONEX (20%) experienced depression, as compared with placebo (13%) (p=0.05) (see Warnings and Precautions).

Patients receiving AVONEX 60 µg IM once a week in the relapsing MS population showed similar adverse event and tolerability patterns to the 30 µg dose. Adverse events known to be associated with interferon administration (e.g. flu syndrome, asthenia, depression, headache, myalgia, nausea, fever, diarrhea, dizziness and chills) generally occurred at similar frequencies between the two dose groups, with the exception of flu syndrome (AVONEX 30 µg vs AVONEX 60 µg: 85% vs 92%, respectively).

Serious adverse events occurred in 52% of patients in the 30 µg dose group and 45% of patients in the 60 µg dose group. The incidence of serious adverse events was similar between the two treatment groups, with the exception of accidental injury, which occurred more often in the 30 µg group (30 µg vs 60 µg: 4% vs 1% respectively). Overall the safety profile of AVONEX 60 µg appeared to be similar to that of AVONEX 30 µg in subjects with relapsing MS.

emphysema, hemoptysis, hiccup, hyperventilation, laryngitis, pharyngeal edema, pneumonia.

coagulation time increased, ecchymosis, lymphadenopathy, petechia.

Safety and effectiveness have not been established in patients below the age of 18 years.

Clinical trials of AVONEX did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently than younger patients.

The clinical effects of AVONEX were investigated in another study comparing the safety and efficacy of 30 µg and 60 µg doses of AVONEX in relapsing MS patients, which included relapsing progressive MS (RPMS) patients similar to the patients with secondary progressive MS in the above study. The results of this dose-comparison study showed that patients meeting the definition of RPMS with a higher baseline EDSS demonstrated the benefit of the higher dose in an analysis of a number of EDSS milestones. For the overall RP group (n=120), no statistical difference between the two dose groups was found (p=0.902). However, statistical significance was reached for a small subgroup of subjects who had baseline EDSS >4.5 (n=25 each group, p=0.036). The advantage of 60 µg over 30 µg on time to reaching an EDSS of 6 or greater was most clear for RPMS patients with a high baseline EDSS. No evidence of an effect of 60 µg over 30 µg was observed for the same analysis in the RRMS patients in this study.

A randomized, double-blind, multicentre study was conducted to determine whether AVONEX, when compared to placebo, could delay the onset of clinically definite MS (CDMS) in 383 patients who have experienced a single episode of optic neuritis, incomplete transverse myelitis, or brainstem/cerebellar syndrome, and who had at least two subclinical multiple sclerosis-like lesions on brain MRI. Patients received either 6 million IU (30 µg) AVONEX (n=193) or placebo (n=190) by IM injection once weekly. All patients were initially treated with corticosteroids.

The primary outcome measure was time to development of CDMS. Secondary outcomes were brain MRI measures of the cumulative increase in new pathologic events (number of new or enlarging T2 lesions), the change in overall burden of disease (change in T2 lesion volume compared to baseline), and inflammatory activity at the time of the scan (gadolinium-enhancing lesions).

Time to development of CDMS was significantly delayed in patients treated with AVONEX compared to placebo (p=0.002). The rate of developing CDMS as documented by a second event was 44% lower in the group treated with AVONEX than in the placebo-treated group.

Brain MRI showed a statistically significant reduced T2 lesion volume, fewer new or enlarging T2 lesions, and fewer new Gd-enhancing lesions in the AVONEX-treated group than in the placebo-treated group after 6, 12, and 18 months of treatment. At 18 months, the AVONEX-treated group compared to the placebo group showed 91% (p<0.001) less increase in the median T2 lesion volume, a 58% (p<0.001) decrease in the mean number of new or enlarging T2 lesions, and a 71% (p<0.001) decrease in the mean number of Gd-enhancing lesions.

The safety and immunogenicity of 30 µg AVONEX PS human serum albumin (HSA)-free liquid formulation given IM once-a-week was investigated in a multicentre, single-arm, open-label study. The results were consistent with previously reported results in clinical studies of patients with relapsing forms of MS given either 30 µg or 60 µg AVONEX lyophilized powder formulation. The incidence of serum neutralizing antibodies was low (4.0%) and comparable to that observed with the lyophilized formulation (see Warnings and Precautions, Immune). AVONEX PS was well tolerated and comparable to results reported in clinical studies of AVONEX (see Adverse Reactions).

In a bioequivalence comparison of AVONEX PS and AVONEX , the results of the ANOVA analysis demonstrate that the liquid formulation is more bioavailable compared to the lyophilized formulation. However, this does not translate into clinical and immunological differences between the two formulations (as measured by the presence of binding and neutralizing antibodies to human interferon beta-1a).

The clinical effects of AVONEX in MS were studied in a randomized, multicentre, double-blind, placebo-controlled study in patients with relapsing (stable or progressive) MS. In this study, 301 patients received either 6 million IU (30 µg) of AVONEX (n=158) or placebo (n=143) by IM injection once weekly over 2 years.

The primary outcome assessment was time to progression in disability, and the secondary outcomes included exacerbation frequency and results of MRI scans of the brain including gadolinium (Gd)-enhanced lesion number and volume and T2-weighted lesion volume.

Time to onset of sustained progression in disability was significantly longer in patients treated with AVONEX than in patients receiving placebo (p=0.02). The percentage of patients progressing by the end of two years was 34.9% for placebo-treated patients and 21.9% for AVONEX-treated patients, indicating a 37% reduction in the risk of disability progression in patients treated with AVONEX.

AVONEX treatment significantly decreased the frequency of exacerbations (relapses) in patients who were enrolled in the study for at least two years, from 0.90 in the placebo-treated group to 0.61 in the AVONEX-treated group (p=0.002). This represents a 32% reduction in the annual exacerbation rate. The percent of exacerbation-free patients was 38% (p=0.03) in the group treated with AVONEX.

Patients treated with AVONEX demonstrated significantly lower Gd-enhanced lesions number and volume (p=0.05). The percentage change in T2-weighted lesion volume (at year 1) was significantly lower in AVONEX-treated patients (p=0.02). A similar significant effect was seen in the number of active (new and enlarging) T2 lesions over two years (p=0.002).

The clinical effects of AVONEX were also investigated in a randomized, multicentre, double-blind, placebo-controlled, parallel-group study in male and female patients with secondary progressive MS. Patients received either AVONEX 60 µg (n=217) or placebo (n=219) by IM injection once weekly for 2 years. The study used a composite outcome measure, the Multiple Sclerosis Functional Composite (MSFC). The MSFC consists of the Timed 25-Foot Walk, Nine Hole Peg Test (9HPT), and Paced Auditory Serial Addition Test (PASAT). In both groups, the mean baseline EDSS score was 5.2 (range 3.5 to 6.5).

In the patients treated with AVONEX 60 µg, compared to the placebo group, disease progression was reduced by approximately 27% (based on mean MSFC score) or 40% (based on median MSFC score) (p=0.033). This result was mainly based on the 9HPT (upper extremity function measure) and the PASAT (cognitive function measure). For the Timed 25-foot walk, a difference between treatment arms was observed although this did not reach statistical significance. Sustained progression when measured by the Kurtze Expanded Disability Status Scale (EDSS) was similar (p=0.901) for patients receiving AVONEX 60 µg (32%) or placebo (37%). AVONEX 60 µg demonstrated statistically significant reductions of relapse rate (32%, p=0.008) and on all MRI outcome measures (p<0.0001) compared to placebo.

The treatment effect was strongest and approached clinical significance (p=0.074) in patients who had experienced relapse in the previous year. In this subgroup, active treatment reduced disease progression by 44% (based on mean MSFC score) or 59% (based on median MSFC score). In patients who had not had a clinical relapse in the previous year, however, active treatment reduced disease progression by 9.5% (based on mean MSFC score) or 27% (based on median MSFC score) that did not approach statistical significance (p=0.206). This suggests that patients with secondary progressive MS who have had recent relapses would achieve the most benefit from AVONEX 60 µg.

Each single-use vial of sterile white to off-white lyophilized powder, contains: interferon beta-1a 33 µg (6.6 million IU) or 66 µg (13.2 million IU). Nonmedicinal ingredients: human serum albumin USP 16.5 mg, dibasic sodium phosphate USP 6.3 mg, monobasic sodium phosphate USP 1.3 mg and sodium chloride USP 6.4 mg. Preservative-free. Administration Dose Packs containing 1 vial of AVONEX (3 mL), 1 vial of sterile Water for Injection (10 mL), 2 alcohol wipes, 1 syringe (3 mL), 1 Micro Pin, 1 needle, 1 adhesive bandage, 1 gauze pad; packages of 4.

Each prefilled syringe of sterile liquid contains: interferon beta-1a 30 µg (6.0 million IU). Nonmedicinal ingredients: arginine hydrochloride USP 15.8 mg, glacial acetic acid USP 0.25 mg, polysorbate 20 0.025 mg, sodium acetate trihydrate USP 0.79 mg and Water for Injection USP 0.5 mL at a pH of 4.8. Administration Dose Packs containing 1 prefilled syringe of AVONEX PS liquid and 1 needle for injection and a reclosable accessory pouch containing 4 alcohol wipes, 4 gauze pads and 4 adhesive bandages; packages of 4.

No carcinogenicity data for interferon beta-1a are available in animals or humans.

Interferon beta-1a was not mutagenic when tested in the Ames bacterial test and in an in vitro cytogenetic assay in human lymphocytes in the presence and absence of metabolic activation. These assays are designed to detect agents that interact directly with and cause damage to cellular DNA. Interferon beta-1a is a glycosylated protein that does not directly bind to DNA.

AVONEX and AVONEX PS should be used with caution in patients with depression. Depression and suicide have been reported to occur in patients receiving other interferon compounds. Depression and suicidal ideation are known to occur at an increased frequency in the MS population. A relationship between the occurrence of depression and/or suicidal ideation and the use of AVONEX and AVONEX PS has not been established. An equal incidence of depression was seen in the placebo-treated and the patients treated with AVONEX in the placebo-controlled study of relapsing MS patients. In the study of patients with a single demyelinating event patients treated with AVONEX were more likely to experience depression than placebo-treated patients (p=0.05). Suicidal tendency occurred in one subject treated with placebo, and there were no reports of suicide attempts. Patients treated with AVONEX and AVONEX PS should be advised to report immediately any symptoms of depression and/or suicidal ideation to their prescribing physicians. If a patient develops depression, antidepressant therapy or cessation of AVONEX and AVONEX PS therapy should be considered.

The extent of exposure in pregnancy during clinical trials is: Limited: <1000 pregnancies.

AVONEX and AVONEX PS should not be administered in case of pregnancy. There are no adequate and well-controlled studies of AVONEX and AVONEX PS in pregnant women. Patients should be advised of the abortifacient potential of AVONEX and AVONEX PS. Fertile women receiving AVONEX and AVONEX PS should be advised to take adequate contraceptive measures. It is not known if interferons alter the efficacy of oral contraceptives.

If a woman becomes pregnant or plans to become pregnant while taking AVONEX or AVONEX PS, she should be informed of the potential hazards to the fetus, and it should be recommended that the woman discontinue therapy. The reproductive toxicity of AVONEX and AVONEX PS has not been studied in animals or humans. In pregnant monkeys given interferon beta at 100 times the recommended weekly human dose (based upon a body surface area comparison), no teratogenic or other adverse effects on fetal development were observed. Abortifacient activity was evident following 3 to 5 doses at this level. No abortifacient effects were observed in monkeys treated at two times the recommended weekly human dose (based upon a body surface area comparison). Although no teratogenic effects were seen in these studies, it is not known if teratogenic effects would be observed in humans. There are no adequate and well-controlled studies with interferons in pregnant women.

AVONEX and AVONEX PS, like other interferon beta products, have the potential for causing severe liver injury (see Adverse Reactions). Hepatic injury including elevated serum hepatic enzyme levels, hepatitis and autoimmune hepatitis (see Warnings and Precautions, Immune), some of which have been severe, has been reported post-marketing. In some patients a recurrence of elevated serum levels of hepatic enzymes have occurred upon AVONEX re-challenge. In some cases, these events have occurred in the presence of other drugs that have been associated with hepatic injury. The potential of additive effects from multiple drugs or other hepatotoxic agents (e.g., alcohol) has not been determined.

Cases of hepatic failure have been reported with interferon beta-1a in post-marketing, including very rare cases with AVONEX.

Patients should be monitored for signs of hepatic injury (see Monitoring and Laboratory Tests) and caution exercised when AVONEX or AVONEX PS is used concomitantly with other drugs associated with hepatic injury.

Clinical studies with AVONEX did not include sufficient numbers of patients >65 years to determine whether they respond differently than younger patients.

As with other interferon treatment, autoimmune disorders of multiple target organs have been reported post marketing including idiopathic thrombocytopenia, hyper and hypothyroidism, and rare cases of autoimmune hepatitis have also been reported. Patients should be monitored for signs of these disorders (see Monitoring and Laboratory Tests) and appropriate treatment implemented when observed.

Serum neutralizing antibodies were reported to develop in only 2% to 6% of patients treated with AVONEX and AVONEX PS. Although the exact clinical significance of antibodies has not been fully established, there are multiple literature reports indicating that the occurrence of neutralizing antibodies with beta interferon treatment impacts clinical efficacy, MRI measures and the induction of biological markers.

AVONEX (interferon beta-1a) and AVONEX PS (interferon beta-1a) should be used under the supervision of a physician. The first injection should be performed under the supervision of an appropriately qualified health care professional (see Dosage and Administration).

Patients should be informed of the following information:

• The most common adverse events associated with interferon beta administration, including symptoms of the flu-like syndrome (see Adverse Reactions). These symptoms tend to be most prominent at the initiation of therapy and decrease in frequency and severity with continued treatment.

  
  

• To not stop or modify their treatment unless instructed by their physician.

  
  

• To report depression or suicidal ideation.

  
  

• The risk of decreased blood counts including white blood cells and platelet counts and of the requirement for periodic laboratory testing. Patients should be advised to report immediately any clinical symptoms associated with blood cell count abnormalities and laboratory testing should be performed according to standard medical practice. Patients with myelosuppression may require more intensive monitoring of complete blood cell counts, with differential and platelet counts.

  
  

• The potential risk of liver injury with AVONEX and AVONEX PS therapy, and of the requirement for frequent laboratory testing. Patients should be informed of the symptoms of suggestive liver dysfunction, such as loss of appetite accompanied by other symptoms such as nausea, vomiting, and jaundice, and advised to consult with their physician immediately should such symptoms arise.

  
  

• To report any symptoms of thyroid dysfunction (hypo or hyperthyroidism) and thyroid function tests should be performed according to standard medical practice.

  
  

• Female patients should be advised about the abortifacient potential of AVONEX and AVONEX PS and instructed to take adequate contraceptive measures.

  
  

• When a physician determines that AVONEX or AVONEX PS can be used outside the physician's office, persons who will be administering AVONEX or AVONEX PS should receive instruction in reconstitution and injection, including the review of the injection procedures (see Information for the Patient). If a patient is to self-administer, the physical ability of the patient to self-inject intramuscularly should be assessed. If home use is chosen, the first injection should be performed under the supervision of a qualified health care professional. Patients should be advised of the importance of rotating sites of injection with each dose, to minimize the likelihood of injection site reactions. A puncture-resistant container for disposal of needles and syringes should be used. Patients should be instructed in the technique and importance of proper syringe and needle disposal and be cautioned against reuse of these items.

  
  

• Patients receiving AVONEX 60 µg IM once a week in the relapsing MS population showed similar adverse event and tolerability patterns to the 30 µg dose. Adverse events known to be associated with interferon administration (e.g. flu syndrome, asthenia, depression, headache, myalgia, nausea, fever, diarrhea, dizziness and chills) generally occurred at similar frequencies between the two dose groups, with the exception of flu syndrome (AVONEX 30 µg vs AVONEX 60 µg: 85% vs 92%, respectively).

Caution should be exercised when administering AVONEX or AVONEX PS to patients with pre-existing seizure disorder. In the two placebo-controlled studies of MS, four patients receiving AVONEX experienced seizures, while no seizures occurred in the placebo group. Of these four patients, three had no prior history of seizure. It is not known whether these events were related to the effects of MS alone, to AVONEX, or to a combination of both. For patients with no prior history of seizure who developed seizures during therapy with AVONEX and AVONEX PS, an etiologic basis should be established and appropriate anti-convulsant therapy instituted prior to considering resumption of treatment. The effect of AVONEX and AVONEX PS administration on the medical management of patients with seizure disorder is unknown.

Laboratory abnormalities are associated with the use of interferons. During the placebo-controlled trials in multiple sclerosis, liver function tests were performed at least every 6 months. Liver function tests including serum ALT are recommended during AVONEX and AVONEX PS therapy and should be performed at baseline, monthly at months 1 through 6, and every 6 months thereafter. AVONEX and AVONEX PS should be initiated with caution in patients with a history of significant liver disease, clinical evidence of active liver disease, alcohol abuse, increased serum ALT (>2.5 times ULN), and in patients receiving concomitant medications associated with hepatic injury. These patients may require more frequent monitoring of serum hepatic enzymes. Discontinuation or interruption of AVONEX and AVONEX PS should be considered if ALT rises above 5 times the ULN. Treatment with AVONEX and AVONEX PS should be stopped if jaundice or other clinical symptoms of liver dysfunction appear. In addition to those laboratory tests normally required for monitoring patients with MS, and in addition to liver enzyme monitoring (see Warnings and Precaution, Hepatic/Biliary/Pancreatic) complete blood cell counts and white blood cell differential, platelet counts, and blood chemistries are recommended during AVONEX and AVONEX PS therapy (see Warnings and Precautions, Hematologic and Adverse Reactions). These tests should be performed at baseline, months 1, 3, 6, and every 6 months thereafter. Patients with myelosuppression may require more intensive monitoring of complete blood cell counts, with differential and platelet counts.

Patients being treated with interferon beta may occasionally develop new or worsening thyroid abnormalities. Thyroid testing should be performed at baseline and every 6 months. In case of abnormal results or in patients with a past history of thyroid dysfunction, any necessary treatment and more frequent testing should be performed as clinically indicated.

Other interferons have been noted to reduce cytochrome P-450 oxidase-mediated drug metabolism. Formal hepatic drug metabolism studies with AVONEX or AVONEX PS in humans have not been conducted. Hepatic microsomes isolated from rhesus monkeys treated with AVONEX showed no influence of AVONEX on hepatic P-450 enzyme metabolism activity.

Safety and effectiveness have not been established.

Anaphylaxis has been reported as a rare complication of AVONEX and AVONEX PS use. Other allergic reactions have included dyspnea, orolingual edema, skin rash and urticaria (see Adverse Reactions).

Decreased peripheral blood counts in all cell lines, including very rare pancytopenia and thrombocytopenia have been reported from post-marketing experience (see Adverse Reactions). Some cases of thrombocytopenia have had nadirs below 10 000/mL. Some cases reoccur with re-challenge. Patients should be monitored for signs of these disorders (see Monitoring and Laboratory Tests).

No studies were conducted to evaluate the effects of interferon beta on fertility in normal women or women with MS. It is not known whether AVONEX and AVONEX PS can affect human reproductive capacity. Menstrual irregularities were observed in monkeys administered interferon beta at a dose 100 times the recommended weekly human dose (based upon a body surface area comparison). Anovulation and decreased serum progesterone levels were also noted transiently in some animals. These effects were reversible after discontinuation of drug.

Treatment of monkeys with interferon beta at two times the recommended weekly human dose (based upon a body surface area comparison) had no effects on cycle duration or ovulation.

The accuracy of extrapolating animal doses to human doses is not known. In the placebo-controlled study, 6% of patients receiving placebo and 5% of patients receiving AVONEX experienced menstrual disorder. If menstrual irregularities occur in humans, it is not known how long they will persist following treatment.

AVONEX and AVONEX PS should not be administered in case of lactation. It is not known whether AVONEX or AVONEX PS is excreted in human milk. Because of the potential of serious adverse reactions in nursing infants, a decision should be made to either discontinue nursing or to discontinue AVONEX and AVONEX PS.

Patients with cardiac disease, such as angina, congestive heart failure, or arrhythmia, should be closely monitored for worsening of their clinical condition during initiation and continued treatment with AVONEX or AVONEX PS. While AVONEX or AVONEX PS does not have any known direct-acting cardiac toxicity, during the post-marketing period infrequent cases of congestive heart failure, cardiomyopathy, and cardiomyopathy with congestive heart failure have been reported in patients without known predisposition to these events or other known etiologies. In rare cases, these events have been temporally related to the administration of AVONEX and have recurred upon re-challenge in patients with known predisposition.

Vials of AVONEX (interferon beta-1a) should be stored in a refrigerator at 2 to 8°C. Should refrigeration be unavailable, vials of AVONEX can be stored at up to 25°C for a period of up to 30 days. If the product has been exposed to conditions other than those recommended, discard the product and do not use.

Prefilled syringes of AVONEX PS (interferon beta-1a) should be stored in a refrigerator at 2 to 8°C. Once removed from the refrigerator, the prefilled syringe should be allowed to warm to room temperature (approximately 30 minutes). Do not use external heat sources, such as hot water, to warm the prefilled syringe. AVONEX PS can be stored at room temperature (between 15-30°C) for up to one week. If the product has been exposed to conditions other than those recommended, discard the product and do not use.

Additional information for AVONEX vial and AVONEX PS prefilled syringe:

• Do not expose to high temperatures.

  
  

• Do not freeze.

  
  

• Do not use beyond the expiration date stamped on the vial.

  
  

• Protect from light.

Interferons are a family of naturally occurring proteins and glycoproteins that are produced by eukaryotic cells in response to viral infection and other biological inducers. Interferon beta, one member of this family, is produced by various cell types including fibroblasts and macrophages. Natural interferon beta and interferon beta-1a are similarly glycosylated. Glycosylation of other proteins is known to affect their stability, activity, biodistribution, and half-life in blood. Glycosylation of other proteins also decreases aggregation of proteins. Protein aggregates are thought to be involved in the immunogenicity of recombinant proteins. Aggregated forms of interferon beta are known to have lower levels of specific activity than monomeric (non-aggregated) forms of interferon beta.

Interferons are cytokines that mediate antiviral, antiproliferative, and immunomodulatory activities in response to viral infection and other biological inducers. Three major interferons have been distinguished: alpha, beta, and gamma. Interferons alpha and beta form the Type I class of interferons and interferon gamma is a Type II interferon. These interferons have overlapping but clearly distinct biological activities.

Interferon beta exerts its biological effects by binding to specific receptors on the surface of human cells. This binding initiates a complex cascade of intracellular events that lead to the expression of numerous interferon-induced gene products and markers. These include 2', 5'-oligoadenylate synthetase, β₂-microglobulin, and neopterin. These products have been measured in the serum and cellular fractions of blood collected from patients treated with AVONEX (interferon beta-1a).

The specific interferon-induced proteins and mechanisms by which AVONEX exerts its effects in MS have not been fully defined. To understand the mechanism(s) of action of AVONEX, studies were conducted to determine the effect of IM injection of AVONEX on levels of the immunosuppressive cytokine interleukin 10 (IL-10) in serum and cerebrospinal fluid (CSF) of treated patients. IL-10, or cytokine synthesis inhibitory factor, is a potent immunosuppressor of a number of pro-inflammatory cytokines such as interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), interleukin 1 (IL-1), tumor necrosis factor beta (TNF-β), and interleukin 6 (IL-6), which are secreted by T lymphocyte helper-1 (Th1) cells and macrophages. Elevated serum IL-10 levels were seen after IM injection of AVONEX, from 48 hours post-injection through at least 7 days. Similarly, in the Phase III study, IL-10 levels in CSF were significantly increased in patients treated with AVONEX compared to placebo. CSF IL-10 levels correlated with a favourable clinical treatment response to AVONEX.

Upregulation of IL-10 represents a possible mechanism of action of interferon beta in relapsing MS. IL-10 has been demonstrated to decrease relapses in acute and chronic relapsing experimental autoimmune encephalomyelitis (EAE), an animal model resembling MS. However, no relationship has been established between the absolute levels of IL-10 and the clinical outcome in MS.