Experience with Betaseron in patients with MS is limited to a total of 147 patients at the recommended dose of 0.25 mg every other day or more (see CLINICAL PHARMACOLOGY, Clinical Trials). Consequently, adverse events that are associated with the use of Betaseron in MS patients at a low incidence may not have been observed in premarketing studies. Clinical experience with Betaseron in other populations (patients with cancer, HIV positive patients, etc.) provides additional data regarding adverse reactions; however, experience in non-MS populations may not be fully applicable to the MS population.

Injection site reactions (85%) and injection site necrosis (5%) occurred after administration of Betaseron. Inflammation, pain, hypersensitivity, necrosis, and non-specific reactions were significantly associated (p<0.05) with the 0.25 mg Betaseron-treated group. Only inflammation, pain, and necrosis were reported as severe events (see WARNINGS and PRECAUTIONS sections). The incidence rate for injection site reactions was calculated over the course of 3 years. This incidence rate decreased over time, with 79% of patients experiencing the event during the first 3 months of treatment compared to 47% during the last 6 months. The median time to the first occurrence of an injection site reaction was 7 days. Patients with injection site reactions reported these events 183.7 days per year. Three patients withdrew from the 0.25 mg Betaseron-treated group for injection site pain.

Flu-like symptom complex was reported in 76% of the patients treated with 0.25 mg Betaseron. A patient was defined as having a flu-like symptom complex if flu-like symptoms or at least two of the following symptoms were concurrently reported: fever, chills, myalgia, malaise, or sweating. Only myalgia, fever, and chills were reported as severe in more than 5% of the patients. The incidence rate for flu-like symptom complex was also calculated over the course of 3 years. The incidence rate of these events decreased over time, with 60% of patients experiencing the event during the first 3 months of treatment compared to 10% during the last 6 months. The median time to the first occurrence of flu-like symptom complex was 3.5 days and the median duration per patient was 7.5 days per year.

Laboratory abnormalities included absolute neutrophil count less than 1500/mm³ (18%) (no patients had absolute neutrophil counts less than 500/mm³), WBC less than 3000/mm³ (16%), SGPT greater than 5 times baseline value (19%), and total bilirubin greater than 2.5 times baseline value (6%). Three patients were withdrawn from treatment with 0.25 mg Betaseron for abnormal liver enzymes including one following dose reduction (see PRECAUTIONS, Laboratory Tests).

Twenty-one (28%) of the 76 premenopausal females treated at 0.25 mg Betaseron and 10 (13%) of the 76 premenopausal females treated with placebo reported menstrual disorders. All of these reports were of mild to moderate severity and included: intermenstrual bleeding and spotting, early or delayed menses, decreased days of menstrual flow, and clotting and spotting during menstruation.

Mental disorders have been observed in patients in this study. Symptoms included depression, anxiety, emotional lability, depersonalization, suicide attempts, confusion, etc. In the treatment group, two patients withdrew for confusion. One suicide and four attempted suicides were also reported. It is not known whether these symptoms may be related to the underlying neurological basis of MS, to Betaseron treatment, or to a combination of both. Some similar symptoms have been noted in patients receiving interferon alfa and both interferons are thought to act through the same receptor. Patients who experience these symptoms should be closely monitored and cessation of therapy considered.

*Significantly associated with Betaseron treatment.

Additional common adverse clinical and laboratory events associated with the use of Betaseron^® (Interferon beta-1b) are listed in the following paragraphs. These events occurred at an incidence of 5% or more in the 124 MS patients treated with 0.25 mg of Betaseron every other day for periods of up to 3 years in the controlled trial, and at an incidence that was at least twice that observed in the 123 placebo patients. Common adverse clinical and laboratory events associated with the use of Betaseron were: injection site reaction (85%), injection site necrosis (5%), palpitation (8%), hypertension (7%), tachycardia (6%), peripheral vascular disorders (5%), gastrointestinal disorders (6%), absolute neutrophil count <1500/mm³ (18%), WBC <3000/mm³ (16%), SGPT >5 times baseline value (19%), total bilirubin >2.5 times baseline value (6%), somnolence (6%), dyspnea (8%), laryngitis (6%), menstrual disorder (17%), cystitis (8%), breast pain (7%), pelvic pain (6%), and menorrhagia (6%).

A total of 277 MS patients have been treated with Betaseron^® (Interferon beta-1b) in doses ranging from 0.025 mg to 0.5 mg. During the first 3 years of treatment, withdrawals due to clinical adverse events or laboratory abnormalities not mentioned above included: fatigue (2%, 6 patients), cardiac arrhythmia (<1%, 1 patient), allergic urticarial skin reaction to injections (<1%, 1 patient), headache (<1%, 1 patient), unspecified adverse events (<1%, 1 patient), and "felt sick" (<1%, 1 patient).

Table 2 enumerates adverse events and laboratory abnormalities that occurred at an incidence of 2% or more among the 124 MS patients treated with 0.25 mg Betaseron every other day for periods of up to 3 years in the controlled trial and at an incidence that was at least 2% more than that observed in the 123 placebo patients. Reported adverse events have been reclassified using the standard COSTART glossary to reduce the total number of terms employed in the table. In Table 2, terms so general as to be uninformative, and those events where a drug cause was remote have been excluded.

It should be noted that the figures cited in the table cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. The cited figures do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence rate in the population studied.

Other events observed during premarketing evaluation of various doses of Betaseron in 1440 patients are listed in the paragraph that follows. Because most of the events were observed in open and uncontrolled studies, the role of Betaseron in their causation cannot be reliably determined.

Body as a Whole: abscess, adenoma, anaphylactoid reaction, ascites, cellulitis, hernia, hydrocephalus, hypothermia, infection, peritonitis, photosensitivity, sarcoma, sepsis, and shock;

Cardiovascular System: angina pectoris, arrhythmia, atrial fibrillation, cardiomegaly, cardiac arrest, cerebral hemorrhage, cerebral ischemia, endocarditis, heart failure, hypotension, myocardial infarct, pericardial effusion, postural hypotension, pulmonary embolus, spider angioma, subarachnoid hemorrhage, syncope, thrombophlebitis, thrombosis, varicose vein, vasospasm, venous pressure increased, ventricular extrasystoles, and ventricular fibrillation;

Digestive System: aphthous stomatitis, cardiospasm, cheilitis, cholecystitis, cholelithiasis, duodenal ulcer, dry mouth, enteritis, esophagitis, fecal impaction, fecal incontinence, flatulence, gastritis, gastrointestinal hemorrhage, gingivitis, glossitis, hematemesis, hepatic neoplasia, hepatitis, hepatomegaly, ileus, increased salivation, intestinal obstruction, melena, nausea, oral leukoplakia, oral moniliasis, pancreatitis, periodontal abscess, proctitis, rectal hemorrhage, salivary gland enlargement, stomach ulcer, and tenesmus;

Endocrine System: Cushing's Syndrome, diabetes insipidus, diabetes mellitus, hypothyroidism, and inappropriate ADH;

Hemic and Lymphatic System: chronic lymphocytic leukemia, hemoglobin less than 9.4 g/100 mL, petechia, platelets less than 75,000/mm³, and splenomegaly;

Metabolic and Nutritional Disorders: alcohol intolerance, alkaline phosphatase greater than 5 times baseline value, BUN greater than 40 mg/dL, calcium greater than 11.5 mg/dL, cyanosis, edema, glucose greater than 160 mg/dL, glycosuria, hypoglycemic reaction, hypoxia, ketosis, and thirst;

Musculoskeletal System: arthritis, arthrosis, bursitis, leg cramps, muscle atrophy, myopathy, myositis, ptosis, and tenosynovitis;

Nervous System: abnormal gait, acute brain syndrome, agitation, apathy, aphasia, ataxia, brain edema, chronic brain syndrome, coma, delirium, delusions, dementia, depersonalization, diplopia, dystonia, encephalopathy, euphoria, facial paralysis, foot drop, hallucinations, hemiplegia, hypalgesia, hyperesthesia, incoordination, intracranial hypertension, libido decreased, manic reaction, meningitis, neuralgia, neuropathy, neurosis, nystagmus, oculogyric crisis, ophthalmoplegia, papilledema, paralysis, paranoid reaction, psychosis, reflexes decreased, stupor, subdural hematoma, torticollis, tremor, and urinary retention;

Respiratory System: apnea, asthma, atelectasis, carcinoma of lung, hemoptysis, hiccup, hyperventilation, hypoventilation, interstitial pneumonia, lung edema, pleural effusion, pneumonia, and pneumothorax;

Skin and Appendages: contact dermatitis, erythema nodosum, exfoliative dermatitis, furunculosis, hirsutism, leukoderma, lichenoid dermatitis, maculopapular rash, psoriasis, seborrhea, skin benign neoplasm, skin carcinoma, skin hypertrophy, skin necrosis, skin ulcer, urticaria, and vesiculobullous rash;

Special Senses: blepharitis, blindness, deafness, dry eyes, ear pain, iritis, keratoconjunctivitis, mydriasis, otitis externa, otitis media, parosmia, photophobia, retinitis, taste loss, taste perversion, and visual field defect;

Urogenital System: anuria, balanitis, breast engorgement, cervicitis, epididymitis, gynecomastia, hematuria, impotence, kidney calculus, kidney failure, kidney tubular disorder, leukorrhea, nephritis, nocturia, oliguria, polyuria, salpingitis, urethritis, urinary incontinence, uterine fibroids enlarged, uterine neoplasm, and vaginal hemorrhage.

DRUG ABUSE AND DEPENDENCE

No evidence or experience suggests that abuse or dependence occurs with Betaseron^® (Interferon beta-1b) therapy; however, the risk of dependence has not been systematically evaluated.

Interactions between Betaseron and other drugs have not been fully evaluated. Although studies designed to examine drug interactions have not been done, it was noted that corticosteroid or ACTH treatment of relapses for periods of up to 28 days has been administered to patients (N=180) receiving Betaseron.

Betaseron administration to three cancer patients over a dose range of 0.025 mg to 2.2 mg led to a dose-dependent inhibition of antipyrine elimination.¹⁴ The effect of alternate-day administration of 0.25 mg of Betaseron on drug metabolism in MS patients is unknown.

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