Betaseron

Interactions with herbal products have not been established.

Interactions with food have not been established.

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

BETASERON administered in three cancer patients over a dose range of 0.025 mg (0.8 MIU) to 2.2 mg (71 MIU) led to a dose-dependent inhibition of antipyrine elimination. The effect of alternate-day administration of 0.25 mg (8 MIU) BETASERON on drug metabolism in MS patients is unknown.

Interferons have been reported to reduce the activity of hepatic cytochrome P450-dependent enzymes in humans and animals. Caution should be exercised when BETASERON is administered in combination with agents that have a narrow therapeutic index and are largely dependent on the hepatic cytochrome P450 system for clearance.

Interactions with laboratory tests have not been established.

To reconstitute lyophilized BETASERON for injection, use the vial adapter to inject the entire contents of the prefilled diluent syringe containing Sodium Chloride 0.54% Solution into the BETASERON vial. Gently swirl the vial of BETASERON to dissolve the drug completely; do not shake. Inspect the reconstituted product visually and discard the product before use if it contains particulate matter or is discolored. After reconstitution with diluent, each mL of solution contains 0.25 mg (8 MIU) interferon beta-1b, 13 mg Albumin Human USP and 13 mg Mannitol USP.

For subcutaneous use only.

BETASERON (interferon beta-1b) should only be prescribed by (or following consultation with) clinicians who are experienced in the diagnosis and management of multiple sclerosis.

Withdraw 1 mL of reconstituted solution from the vial back into the syringe, fitted with a ½-inch needle, and inject the solution subcutaneously. Sites for self-injection include arms, abdomen, buttocks and thighs. All components are suitable for single use only; unused portions should be discarded (see Information for the Patient, Proper Use of this Medication section for self-injection procedure.)

If an injection is missed, it should be given as soon as feasible. The next injection should be given two days later.

In the secondary-progressive MS study, patients initiated treatment with half the dose (4 MIU s.c. every other day) for a period of 2 weeks prior to escalating to the recommended dose of 8 MIU (s.c. every other day).

Efficacy of treatment for longer than 2 years has not been substantially demonstrated in relapsing-remitting multiple sclerosis. For secondary-progressive multiple sclerosis, safety and efficacy data beyond 3 years are not available.

In patients with a single clinical event suggestive of MS, efficacy has been demonstrated over a period of three years.

balanitis, breast engorgement, cervicitis, epididymitis, gynecomastia, impotence, leukorrhea, salpingitis and uterine fibroids enlarged.

blepharitis, blindness, dry eyes, diplopia, iritis, keratoconjunctivitis, mydriasis, photophobia, retinitis and visual field defect.

Cushing's syndrome, diabetes insipidus, diabetes mellitus, hypothyroidism and inappropriate ADH.

Rare post-marketing cases of adverse hepatic reactions have been reported, including autoimmune hepatitis, hepatitis and hepatic failure requiring liver transplantation.

alcohol intolerance, calcium greater than 11.5 mg/dL, glucose greater than 160 mg/dL, glycosuria, hypoglycemic reaction, ketosis and thirst.

Significantly more patients on active therapy (14.4% vs 4.7% on placebo) had elevated ALT values (>5 times baseline value). Elevations were also observed in AST and gamma-GT values in the BETASERON group throughout the study. In the BETASERON group, most ALT abnormalities resolved spontaneously with continued treatment whereas some resolved upon dose reduction or temporary discontinuation of treatment.

Lymphopenia (<1500/mm³) was observed in 90.9% of BETASERON patients compared to 74.3% of placebo patients and neutropenia (<1400/mm³) was noted in 18.0% BETASERON and 5.1% placebo patients.

The following adverse events were observed in placebo-controlled clinical studies of BETASERON (interferon beta-1b), at the recommended dose of 0.25 mg (8 MIU), in patients with relapsing-remitting MS (n=124) and secondary-progressive MS (n=360), and in patients with a single clinical event suggestive of MS (n=292). 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.

edema, hernia, hypothermia and photosensitivity.

angina pectoris, arrhythmia, atrial fibrillation, cardiomegaly, cardiac arrest, cerebral ischemia, endocarditis, heart failure, myocardial infarct, pericardial effusion, syncope, ventricular extrasystoles and ventricular fibrillation.

deafness, ear pain, otitis externa and otitis media.

apnea, asthma, atelectasis, cyanosis, hemoptysis, hiccup, hyperventilation, hypoventilation, hypoxia, interstitial pneumonia, lung edema, parosmia, pleural effusion, pneumonia and pneumothorax.

abnormal gait, acute brain syndrome, aphasia, ataxia, brain edema, chronic brain syndrome, coma, delirium, encephalopathy, facial paralysis, foot drop, hemiplegia, hydrocephalus, hypalgesia, hyperesthesia, incoordination, libido decreased, meningitis, neuralgia, neuropathy, nystagmus, oculogyric crisis, ophthalmoplegia, papilledema, paralysis, reflexes decreased, shock, subdural hematoma, torticollis and tremor.

anuria, BUN greater than 40 mg/dL, hematuria, kidney calculus, kidney failure, kidney tubular disorder, nephritis, nocturia, oliguria, polyuria, urethritis, urinary incontinence and urinary retention.

The following laboratory abnormalities were reported at a significantly higher incidence in the BETASERON group: lymphocyte count <1500/mm³: BETASERON 79.1% vs placebo 45.5%; ALT >5 times baseline value: BETASERON 17.8% vs placebo 4.5%; absolute neutrophil count <1500/mm³: BETASERON 10.6% vs placebo 2.3%; WBC <3000/mm³: BETASERON 10.6% vs placebo 1.7%; AST >5 times baseline value: BETASERON 6.2% vs placebo 0.6%.

Bilirubin values of Grade 3 or 4 were reported in five BETASERON patients and in one placebo patient.

Five patients discontinued BETASERON due to elevated liver function tests (see Warnings and Precautions, Monitoring and Laboratory Tests).

There were no relevant differences between the BETASERON and placebo groups for lipid profile, thyroid function parameters, other serum chemistry parameters or urinalysis parameters.

contact dermatitis, erythema nodosum, exfoliative dermatitis, furunculosis, hirsutism, leukoderma, lichenoid dermatitis, maculopapular rash, psoriasis, seborrhea, skin hypertrophy, skin necrosis, skin ulcer, urticaria and vesiculobullous rash.

Flu-like symptoms and injection site reactions were observed less frequently than in the other pivotal trials. To increase tolerability of BETASERON, dose titration was performed and NSAIDs were administered at start of therapy. Moreover, an autoinjector was used by the majority of patients throughout the study.

Other events observed during pre-marketing evaluation of various doses of BETASERON in 1440 patients are listed in the paragraphs that follow. Given that most of the events were observed in open and uncontrolled studies, the role of BETASERON in their causation cannot be reliably determined.

arthritis, arthrosis, bursitis, dystonia, leg cramps, muscle atrophy, myopathy, myositis, ptosis and tenosynovitis.

abscess, cellulitis, infection, periodontal abscess, peritonitis and sepsis.

alkaline phosphatase greater than 5 times baseline value, hepatitis and hepatomegaly.

cerebral hemorrhage, gastrointestinal hemorrhage, hypotension, intracranial hypertension, postural hypotension, pulmonary embolus, rectal hemorrhage, subarachnoid hemorrhage, thrombophlebitis, thrombosis, vaginal hemorrhage, varicose vein, vasospasm and venous pressure increased.

In the relapsing-remitting MS study, the most common laboratory abnormalities included: lymphocyte count <1500/mm³ (82%); ALT >5 times baseline value (19%); absolute neutrophil count <1500/mm³ (18%) (no patients had absolute neutrophil counts <500/mm³); WBC <3000/mm³ (16%); total bilirubin >2.5 times baseline value (6%).

Three patients were withdrawn from treatment with 0.25 mg (8 MIU) BETASERON for abnormal liver enzymes including one following dose reduction (see Warnings and Precautions, Monitoring and Laboratory Tests).

adenoma, carcinoma of the lung, hepatic neoplasia, sarcoma, skin benign neoplasm, skin carcinoma, spider angioma and uterine neoplasm.

Seventy-four (74) patients discontinued treatment due to adverse events (23 on placebo and 51 on BETASERON). Injection site reactions were significantly associated with early termination of treatment in the BETASERON group compared to placebo (p<0.05). The highest frequency of adverse events leading to discontinuation involved the nervous system, of which depression (7 on placebo and 11 on BETASERON) was the most common.

The most frequently observed adverse reactions are a flu-like symptom complex (fever, chills, arthralgia, malaise, sweating, headache or myalgia) and injection site reactions. Flu-like symptoms may be reduced by administration of acetaminophen or NSAIDs. Dose titration was used at the start of treatment in the clinically isolated syndrome and secondary-progressive MS studies in order to increase the tolerability of BETASERON (see Dosage and Administration).

chronic lymphocytic leukemia, hemoglobin less than 9.4 g/100 mL, petechia, platelets less than 75 000/mm³ and splenomegaly.

anaphylactoid reaction.

agitation, apathy, delusions, dementia, depersonalization, euphoria, hallucinations, manic reaction, neurosis, paranoid reaction, psychosis and stupor.

aphthous stomatitis, ascites, cardiospasm, cheilitis, cholecystitis, cholelithiasis, duodenal ulcer, dry mouth, enteritis, esophagitis, fecal impaction, fecal incontinence, flatulence, gastritis, gingivitis, glossitis, hematemesis, ileus, increased salivation, intestinal obstruction, melena, nausea, oral leukoplakia, oral moniliasis, pancreatitis, proctitis, salivary gland enlargement, stomach ulcer, taste loss, taste perversion and tenesmus.

Safety and efficacy in children under 18 years of age have not been established.

As with all therapeutic proteins, there is a potential for immunogenicity. Serum samples in controlled clinical trials were collected every 3 months for monitoring of development of antibodies to BETASERON.

In the different controlled clinical trials, between 23% and 41% of the patients developed serum interferon beta-1b neutralizing activity confirmed by at least two consecutive positive titres; of these patients, between 43% and 55% converted to a stable antibody negative status (based on two consecutive negative titres) during the subsequent observational period of the respective study.

The development of neutralizing activity is associated with a reduction in clinical efficacy only with regard to relapse activity. Some analyses suggest that this effect might be larger in patients with higher titre levels of neutralizing activity.

In the study of patients with a single clinical event suggestive of multiple sclerosis, neutralizing activity measured every 6 months was observed at least once in 32% (88) of the patients treated early with BETASERON; of these, 47% (41) returned to negative status over a 3 year period. Within this period, the development of neutralizing activity was not associated with a reduction in clinical efficacy (with regard to time to clinically definite multiple sclerosis (CDMS), and time to confirmed EDSS progression).

New adverse events have not been associated with the development of neutralizing activity.

It has been demonstrated in vitro that BETASERON cross reacts with natural interferon beta. However, this has not been investigated in vivo and its clinical significance is uncertain.

There are sparse and inconclusive data on patients who have developed neutralizing activity and have completed BETASERON therapy.

The decision to continue or discontinue treatment should be based on clinical disease activity rather than on neutralizing activity status.

BETASERON was not teratogenic at doses up to 0.42 mg (13.3 MIU)/kg/day in rhesus monkeys, but demonstrated dose-related abortifacient activity when administered at doses ranging from 0.028 mg (0.89 MIU)/kg/day (2.8 times the recommended human dose based on body surface area comparison) to 0.42 mg (13.3 MIU)/kg/day (40 times the recommended human dose based on body surface area comparison). The extrapolability of animal doses to human doses is not known. Lower doses were not studied in monkeys. Spontaneous abortions while on treatment were reported in 4 patients who participated in the BETASERON RR-MS clinical trial, whereas there was one induced abortion in each of the placebo and BETASERON groups in the SP-MS trial. BETASERON given to rhesus monkeys on gestation days 20 to 70 did not cause teratogenic effects; however, it is not known if teratogenic effects exist in humans. There are no adequate and well-controlled studies in pregnant women.

It is recommended that the first injection be administered by, or under the direct supervision of, a physician. Appropriate instructions for reconstitution of BETASERON and self-injection, using aseptic techniques, should be given to the patient. A careful review of Information for the Patient is also recommended.

Patients should be cautioned against the re-use of needles or syringes and instructed in safe disposal procedures. Information on how to acquire a puncture-resistant container for disposal of used needles and syringes should be given to the patient along with instructions for safe disposal of full containers.

Overall, 80% of patients in the two controlled clinical trials reported injection site reactions at one or more times during therapy. Post-marketing experience has been consistent with this finding, with infrequent reports of injection site necrosis.

The onset of injection site necrosis usually appears early in therapy with most cases reported to have occurred in the first two to three months of therapy. The number of sites where necrosis has been observed was variable.

Rarely, the area of necrosis has extended to subcutaneous fat or fascia. Response to treatment of injection site necrosis with antibiotics and/or steroids has been variable. In some of these patients elective debridement and, less frequently, skin grafting took place to facilitate healing which could take from three to six months.

Some patients experienced healing of necrotic skin lesions while BETASERON therapy continued. In other cases new necrotic lesions developed even after therapy was discontinued. The nature and severity of all reported reactions should be carefully assessed.

To minimize the risk of injection site necrosis patients should be advised to use an aseptic injection technique and rotate the injection sites with each dose. Patient understanding and use of aseptic self-injection technique and procedures should be periodically re-evaluated.

The incidence of injection site reactions may be reduced by the use of an autoinjector. In the pivotal study of patients with a single clinical event suggestive of MS an autoinjector was used by the majority of patients. Injection site reactions, as well as injection site necrosis, were observed less frequently in this study than in the other pivotal studies.

Flu-like symptoms are not uncommon following initiation of therapy with BETASERON. In the controlled MS clinical trials, acetaminophen and non-steroidal anti-inflammatory drugs (NSAIDs) were permitted for relief of fever or myalgia.

Patients should be cautioned not to change the dosage or the schedule of administration without medical consultation.

Patients should be advised about the common adverse events associated with the use of BETASERON, particularly injection site reactions and the flu-like symptom complex (see Adverse Reactions).

Patients should be cautioned to report depression or suicidal ideation (see Warnings and Precautions, Psychiatric).

Patients should be advised about the abortifacient potential of BETASERON (see Warnings and Precautions, Special Populations, Pregnant Women).

In the RR-MS clinical trial, one suicide and four attempted suicides were observed among 372 study patients during a 3-year period. All five patients received BETASERON (three in the 0.05 mg [1.6 MIU] group and two in the 0.25 mg [8.0 MIU] group). There were no attempted suicides in patients on study who did not receive BETASERON. In the SP-MS study there were 5 suicide attempts in the placebo group and 3 in the BETASERON group including one patient in each group who committed suicide. Depression and suicide have been reported to occur in patients receiving interferon alpha, a related compound. Patients treated with BETASERON should be informed that depression and suicidal ideation may be a side effect of the treatment and should report these symptoms immediately to the prescribing physician. Patients exhibiting depression should be monitored closely and cessation of therapy should be considered.

Rare post-market cases of serious hepatic injury, including autoimmune hepatitis, hepatitis and hepatic failure, have been reported with interferon beta treatment for multiple sclerosis.

It is recommended that liver function testing occur at baseline, every month for the first 6 months of treatment and at 6-month intervals thereafter. Dose reduction or discontinuation of therapy should be considered if alanine aminotransferase (ALT) levels increase 5 times above the upper limit of normal.

Interferon beta therapy should be initiated with caution in patients with a history of significant liver disease or alcohol abuse and in patients with clinical evidence of acute liver disease.

Caution must be exercised when prescribing drugs with documented hepatotoxicity to patients on interferon beta therapy for multiple sclerosis.

In rare cases, pancreatitis has been observed with BETASERON use, often associated with hypertriglyceridemia.

No evidence or experience suggests that abuse or dependence occurs with BETASERON therapy; however, the risk of dependence has not been systematically evaluated.

Serious hypersensitivity reactions (rare but severe acute reactions such as bronchospasm, anaphylaxis and urticaria) may occur.

The administration of cytokines to patients with pre-existing monoclonal gammopathy has been associated with the development of systemic capillary leak syndrome with shock-like symptoms and fatal outcome.

Rare cases of seizures have been reported with interferon beta therapy. BETASERON should be administered with caution to patients with a history of seizure disorders.

This product contains human albumin and hence carries an extremely remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD) is also considered extremely remote.

The effect of BETASERON on the ability to drive and use machinery has not been investigated.

Women of childbearing potential should take reliable contraceptive measures. If the patient becomes pregnant or plans to become pregnant while taking BETASERON, the patient should discontinue therapy. It is not known if interferons alter the efficacy of oral contraceptives.

The following laboratory tests are recommended prior to initiating BETASERON therapy and at periodic intervals thereafter: thyroid function test, hemoglobin, complete and differential white blood cell counts, platelet counts and blood chemistries including liver function tests. It is recommended that liver function testing occur at baseline, every month for the first 6 months of treatment and at 6-month intervals thereafter. Dose reduction or discontinuation of therapy should be considered if alanine aminotransferase (ALT) levels increase 5 times above the upper limit of normal. A pregnancy test, chest roentgenogram and ECG should also be performed prior to initiating BETASERON therapy.

In the controlled MS trials, patients were monitored every 3 months. The study protocol stipulated that BETASERON therapy be discontinued in the event the absolute neutrophil count fell below 750/mm³. When the absolute neutrophil count had returned to a value greater than 750/mm³, therapy could be restarted at a 50% reduced dose. No patients were withdrawn or dose-reduced for neutropenia or lymphopenia. Similarly, if AST/ALT levels exceeded 10 times the upper limit of normal, or if the serum bilirubin exceeded 5 times the upper limit of normal, therapy was discontinued. In each instance, hepatic enzyme abnormalities returned to normal following discontinuation of therapy. When measurements had decreased to below these levels, therapy could be restarted at a 50% dose reduction, if clinically appropriate. Dose was reduced in two patients due to increased liver enzymes; one continued on treatment and one was ultimately withdrawn.

In the study conducted in patients with a single clinical event suggestive of MS, five BETASERON patients (1.7%) were withdrawn due to increased hepatic enzymes (AST/ALT), two of them after a dose reduction.

Rare cases of thyroid dysfunction (hyper- as well as hypothyroidism) associated with the use of BETASERON have been reported.

Safety and efficacy in children under 18 years of age have not been established.

Studies in female rhesus monkeys with normal menstrual cycles, at doses up to 0.33 mg (10.7 MIU)/kg/day (equivalent to 32 times the recommended human dose based on body surface area comparison) showed no apparent adverse effects on the menstrual cycle or on associated hormonal profiles (progesterone and estradiol) when administered over 3 consecutive menstrual cycles. The extrapolability of animal doses to human doses is not known. Effects of BETASERON on women with normal menstrual cycles are not known.

It is not known whether BETASERON is excreted in human milk. Given that many drugs are excreted in human milk, there is a potential for serious adverse reactions in nursing infants, therefore a decision should be made whether to discontinue nursing or discontinue BETASERON treatment.

Patients should be informed of the potential risk of liver injury with interferon beta therapy, and of the requirement for frequent laboratory testing for liver function (see Monitoring and Laboratory Tests). Patients should be informed of the symptoms suggesting liver dysfunction, such as jaundice, malaise, fatigue, nausea, vomiting, abdominal pain, dark urine and pruritus, and advised to consult their physician immediately if such symptoms arise.

Patients should be instructed in injection techniques to assure the safe self-administration of BETASERON (see below and Information for the Patient).

Rare cases of cardiomyopathy have been reported. If this occurs, and a relationship to BETASERON (interferon beta-1b) is suspected, treatment should be discontinued.

Symptoms of flu syndrome observed with BETASERON therapy may prove stressful to patients with severe cardiac conditions. Patients with cardiac disease such as angina, congestive heart failure, or arrhythmia should be monitored closely for worsening of their clinical conditions.

The reconstituted product contains no preservative. If not used immediately, store under refrigeration between 2 and 8°C and use within 3 hours of reconstitution. Do not freeze.

Store between 2-25°C. Excursions between 25 and 30°C are permitted as long as they do not exceed a maximum of 30 days. Do not freeze. Do not use beyond the expiration date indicated on the labels of the BETASERON vial and the prefilled diluent syringe.