DEPRESSION AND SUICIDE
AVONEX® should be used with caution in patients with depression or other mood disorders, conditions that are common with multiple sclerosis. Depression and suicide have been reported to occur with increased frequency in patients receiving interferon compounds, including AVONEX®. Patients treated with AVONEX® should be advised to report immediately any symptoms of depression and/or suicidal ideation to their prescribing physicians. If a patient develops depression or other severe psychiatric symptoms, cessation of AVONEX® therapy should be considered. In Study 2, AVONEX®-treated patients were more likely to experience depression than placebo-treated patients. An equal incidence of depression was seen in the placebo-treated and AVONEX®-treated patients in Study 1. Additionally, there have been post-marketing reports of depression, suicidal ideation and/or development of new or worsening of pre-existing other psychiatric disorders, including psychosis. Some of these patients improved upon
cessation of AVONEX® dosing.
Anaphylaxis has been reported as a rare complication of AVONEX® use. Other allergic reactions have included dyspnea, orolingual edema, skin rash and urticaria (see ADVERSE REACTIONS).
DECREASED PERIPHERAL BLOOD COUNTS
Decreased peripheral blood counts in all cell lines, including rare pancytopenia and thrombocytopenia, have been reported from post-marketing experience (see ADVERSE REACTIONS). Some cases of thrombocytopenia have had nadirs below 10,000/µL. Some cases reoccur with rechallenge (see ADVERSE REACTIONS). Patients should be monitored for signs of these disorders (see Precautions: Laboratory Tests).
The lyophilized vial of AVONEX® contains albumin, a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries an extremely remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD) also is considered extremely remote. No cases of transmission of viral diseases or CJD have been identified for albumin. The prefilled syringe of AVONEX® does not contain albumin.
Caution should be exercised when administering AVONEX® to patients with pre-existing seizure disorders. In the two placebo-controlled studies in multiple sclerosis, 4 patients receiving AVONEX® experienced seizures, while no seizures occurred in the placebo group. Three of these 4 patients had no prior history of seizure (see ADVERSE REACTIONS). It is not known whether these events were related to the effects of multiple sclerosis alone, to AVONEX®, or to a combination of both. The effect of AVONEX® administration on the medical management of patients with seizure disorder is unknown.
CARDIOMYOPATHY AND CONGESTIVE HEART FAILURE
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®. While AVONEX® 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, and without other known etiologies being established. In rare cases, these events have been temporally related to the administration of AVONEX®. In some of these instances recurrence upon rechallenge was observed.
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 Precautions: Laboratory Tests) and appropriate treatment implemented when observed.
Hepatic injury including elevated serum hepatic enzyme levels and hepatitis, some of which have been severe, has been reported post-marketing. In some patients a recurrence of elevated serum levels of hepatic enzymes has occurred upon AVONEX® rechallenge. 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. Patients should be monitored for signs of hepatic injury (see Precautions: Laboratory Tests) and caution exercised when AVONEX® is used concomitantly with other drugs associated with hepatic injury.
INFORMATION TO PATIENTS
All patients should be instructed to read the AVONEX® Medication Guide supplied to them. Patients should be cautioned not to change the dosage or the schedule of administration without medical consultation.
Patients should be informed of the most serious (see WARNINGS) and the most common adverse events associated with AVONEX® administration, including symptoms associated with flu syndrome (see ADVERSE REACTIONS). Symptoms of flu syndrome are most prominent at the initiation of therapy and decrease in frequency with continued treatment. Concurrent use of analgesics and/or antipyretics may help ameliorate flu-like symptoms on treatment days.
Patients should be cautioned to report depression or suicidal ideation (see WARNINGS).
Patients should be advised about the abortifacient potential of AVONEX® (see Precautions: Pregnancy--Teratogenic Effects).
The prefilled syringe cap contains dry natural rubber.
When a physician determines that AVONEX® can be used outside of the physician's office, persons who will be administering AVONEX® should receive instruction in reconstitution and injection, including the review of the injection procedures. If a patient is to self-administer, the physical ability of that patient to self-inject intramuscularly should be assessed. The first injection should be performed under the supervision of a qualified health care professional. 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.
In addition to those laboratory tests normally required for monitoring patients with multiple sclerosis, complete blood and differential white blood cell counts, platelet counts, and blood chemistries, including liver function tests, are recommended during AVONEX® therapy (see WARNINGS: Decreased Peripheral Blood Counts and PRECAUTIONS: Cardiomyopathy and Congestive Heart Failure, and Autoimmune Disorders). During the placebo-controlled studies in multiple sclerosis, these tests were performed at least every 6 months. There were no significant differences between the placebo and AVONEX® groups in the incidence of liver enzyme elevation, leukopenia, or thrombocytopenia. However, these are known to be dose-related laboratory abnormalities associated with the use of interferons. Patients with myelosuppression may require more intensive monitoring of complete blood cell counts, with differential and platelet counts. Thyroid function should be monitored periodically. If patients have or develop symptoms of thyroid dysfunction (hypo- or hyperthyroidism), thyroid function tests should be performed according to standard medical practice.
No formal drug interaction studies have been conducted with AVONEX®. In the placebo-controlled studies in multiple sclerosis, 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.
CARCINOGENESIS, MUTAGENESIS, AND IMPAIRMENT OF FERTILITY
Carcinogenesis: No carcinogenicity data for AVONEX® are available in animals or humans.
Mutagenesis: AVONEX® 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. AVONEX® is a glycosylated protein that does not directly bind to DNA.
Impairment of Fertility: No studies were conducted to evaluate the effects of AVONEX® on fertility in normal women or women with multiple sclerosis. It is not known whether AVONEX® can affect human reproductive capacity.
Menstrual irregularities were observed in monkeys administered AVONEX® 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 AVONEX® at 2 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 studies in multiple sclerosis, 5% of patients receiving placebo and 6% of patients receiving AVONEX® experienced menstrual disorder. If menstrual irregularities occur in humans, it is not known how long they will persist following treatment.
Pregnancy Category C: The reproductive toxicity of AVONEX® has not been studied in animals or humans. In pregnant monkeys given AVONEX® 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 2 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. If a woman becomes pregnant or plans to become pregnant while taking AVONEX®, she should be informed of the potential hazards to the fetus, and discontinuation of AVONEX® therapy should be considered.
It is not known whether AVONEX® 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®.
Safety and effectiveness of AVONEX® in pediatric patients below the age of 18 years have not been evaluated.
Clinical studies of AVONEX® did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger patients.