Betaseron
(interferon beta-1b)Dosage & Administration
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Betaseron Prescribing Information
BETASERON is indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.
Dosing Information
The recommended starting dose is 0.0625 mg (0.25 mL) subcutaneously every other day, with dose increases over a six-week period to the recommended dose of 0.25 mg (1 mL) every other day (see Table 1).
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BETASERON Dose * | Percentage of recommended dose | Volume | |
Weeks 1-2 | 0.0625 mg | 25% | 0.25 mL |
Weeks 3-4 | 0.125 mg | 50% | 0.5 mL |
Weeks 5-6 | 0.1875 mg | 75% | 0.75 mL |
Week 7 and thereafter | 0.25 mg | 100% | 1 mL |
If a dose of BETASERON is missed, then it should be taken as soon as the patient remembers or is able to take it. The patient should not take BETASERON on two consecutive days. The next injection should be taken about 48 hours (two days) after that dose. If the patient accidentally takes more than their prescribed dose, or takes it on two consecutive days, they should be instructed to call their healthcare provider immediately.
Reconstitution of the Lyophilized Powder
(a) Prior to reconstitution, verify that the vial containing lyophilized BETASERON is not cracked or damaged. Do not use cracked or damaged vials.
(b) To reconstitute lyophilized BETASERON for injection, attach the pre-filled syringe containing the diluent (Sodium Chloride, 0.54% Solution) to the BETASERON vial using the vial adapter.
(c) Slowly inject 1.2 mL of diluent into the BETASERON vial.
(d) Gently swirl the vial to dissolve the lyophilized powder completely; do not shake. Foaming may occur during reconstitution or if the vial is swirled or shaken too vigorously. If foaming occurs, allow the vial to sit undisturbed until the foam settles.
(e) 1 mL of reconstituted BETASERON solution contains 0.25 mg of interferon beta-1b.
(f) After reconstitution, if not used immediately, refrigerate the reconstituted BETASERON solution at 35°F to 46°F (2°C to 8°C) and use within three hours. Do not freeze.
Important Administration Instructions
(a) BETASERON is intended for use under the guidance and supervision of a physician. If patients or caregivers are to administer BETASERON, train them in the proper technique for self‐administering subcutaneous injections using the prefilled syringe or the optional injection device. The BETACONNECT autoinjector has three adjustable injection depth settings; the healthcare provider should determine the proper depth setting and injection technique. Use only the syringes in the BETASERON packaging with the BETACONNECT autoinjector.
The initial BETASERON injection should be performed under the supervision of an appropriately qualified healthcare provider. Users should demonstrate competency in all aspects of the BETASERON injection prior to independent use. If a patient is to self‐administer BETASERON, the physical and cognitive ability of that patient to self‐administer and properly dispose of syringes should be assessed. Patients with severe neurological deficits should not self‐administer injections without assistance from a trained caregiver.
Appropriate instruction for self‐injection or injection by another person should be provided to the patient or their caregiver, including careful review of the BETASERON Medication Guide, the prefilled syringe Instructions for Use, and the BETACONNECT autoinjector Instructions for Use that accompanies the product.
(b) Visually inspect the reconstituted BETASERON solution before use; discard if it contains particulate matter or is discolored.
(c) Keeping the syringe and vial adapter in place, turn the assembly over so that the vial is on top. Withdraw the appropriate dose of BETASERON solution. Remove the vial from the vial adapter before injecting BETASERON.
(d) Use safe disposal procedures for needles and syringes.
(e) Do not re-use needles or syringes.
(f) Advise patients and caregivers to rotate sites for subcutaneous injections to minimize the likelihood of severe injection site reactions, including necrosis or localized infection [see Warnings and Precautions (5.5)].
Premedication for Flu-like Symptoms
Concurrent use of analgesics and/or antipyretics on treatment days may help ameliorate flu-like symptoms associated with BETASERON use [see Warnings and Precautions ].
For injection: 0.3 mg lyophilized powder in a single-dose vial for reconstitution.
Pregnancy
Risk Summary
Although there have been no well-controlled studies in pregnant women, available data, which includes prospective observational studies, have not generally indicated a drug-associated risk of major birth defects with interferon beta-1b during pregnancy. Administration of BETASERON to monkeys during gestation resulted in increased embryo-fetal death at or above exposures greater than 3 times the human therapeutic dose (see Animal Data).
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.
Data
Human Data
The majority of the observational studies reporting on pregnancies exposed to interferon beta-1b did not identify an association between the use of interferon beta-1b during pregnancy and an increased risk of major birth defects
Animal Data
When BETASERON (doses ranging from 0.028 to 0.42 mg/kg/day) was administered to pregnant rhesus monkeys throughout the period of organogenesis (gestation days 20 to 70), a dose-related abortifacient effect was observed. The low-effect dose is approximately 3 times the recommended human dose of 0.25 mg on a body surface area (mg/m2) basis. A no-effect dose for embryo-fetal developmental toxicity in rhesus monkeys was not established.
Lactation
Risk Summary
There are no data on the presence of BETASERON in human milk, the effects on the breastfed infant, or the effects of the drug on milk production.
The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for BETASERON and any potential adverse effects on the breastfed child from BETASERON or from the underlying maternal condition.
Pediatric Use
Safety and efficacy in pediatric patients have not been established.
Geriatric Use
Clinical studies of BETASERON did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger patients.
BETASERON is contraindicated in patients with a history of hypersensitivity to natural or recombinant interferon beta, Albumin (Human), or any other component of the formulation.
Hepatic Injury
Severe hepatic injury including cases of hepatic failure, some of which have been due to autoimmune hepatitis, has been rarely reported in patients taking BETASERON. In some cases, these events have occurred in the presence of other drugs or comorbid medical conditions that have been associated with hepatic injury. Consider the potential risk of BETASERON used in combination with known hepatotoxic drugs or other products (eg, alcohol) prior to BETASERON administration, or when adding new agents to the regimen of patients already on BETASERON. Monitor patients for signs and symptoms of hepatic injury. Consider discontinuing BETASERON if serum transaminase levels significantly increase, or if they are associated with clinical symptoms such as jaundice.
Asymptomatic elevation of serum transaminases is common in patients treated with BETASERON. In controlled clinical trials, elevations of SGPT to greater than five times baseline value were reported in 12% of patients receiving BETASERON (compared to 4% on placebo), and increases of SGOT to greater than five times baseline value were reported in 4% of patients receiving BETASERON (compared to 1% on placebo), leading to dose-reduction or discontinuation of treatment in some patients [see Adverse Reactions ]. Monitor liver function tests [see Warnings and Precautions ( 5.12)].
Anaphylaxis and Other Allergic Reactions
Anaphylaxis has been reported as a rare complication of BETASERON use. Other allergic reactions have included dyspnea, bronchospasm, tongue edema, skin rash and urticaria [see Adverse Reactions ]. Discontinue BETASERON if anaphylaxis occurs.
Depression and Suicide
Depression and suicide have been reported to occur with increased frequency in patients receiving interferon beta products, including BETASERON. Advise patients to report any symptom of depression and/or suicidal ideation to their healthcare provider. If a patient develops depression, discontinuation of BETASERON therapy should be considered.
In randomized controlled clinical trials, there were three suicides and eight suicide attempts among the 1532 patients on BETASERON compared to one suicide and four suicide attempts among 965 patients on placebo.
Congestive Heart Failure
Monitor patients with pre-existing congestive heart failure (CHF) for worsening of their cardiac condition during initiation of and continued treatment with BETASERON. While beta interferons do not have any known direct-acting cardiac toxicity, cases of CHF, cardiomyopathy, and cardiomyopathy with CHF have been reported in patients without known predisposition to these events, and without other known etiologies being established. In some cases, these events have been temporally related to the administration of BETASERON. Recurrence upon rechallenge was observed in some patients. Consider discontinuation of BETASERON if worsening of CHF occurs with no other etiology.
Injection Site Reactions Including Necrosis
Injection site reactions, including injection site necrosis, can occur with the use of interferon beta products, including BETASERON. Injection site necrosis (ISN) was reported in 4% of BETASERON-treated patients in controlled clinical trials (compared to 0% on placebo) [see Adverse Reactions ]. Typically, ISN occurs within the first four months of therapy, although postmarketing reports have been received of ISN occurring over one year after initiation of therapy. The necrotic lesions are typically 3 cm or less in diameter, but larger areas have been reported. Generally the necrosis has extended only to subcutaneous fat, but has extended to the fascia overlying muscle. In some lesions where biopsy results are available, vasculitis has been reported. For some lesions, debridement, and/or skin grafting have been required. In most cases healing was associated with scarring.
In controlled clinical trials, injection site reactions occurred in 78% of patients receiving BETASERON with injection site necrosis in 4%. Injection site inflammation (42%), injection site pain (16%), injection site hypersensitivity (4%), injection site necrosis (4%), injection site mass (2%), injection site edema (2%), and nonspecific reactions were significantly associated with BETASERON treatment. The incidence of injection site reactions tended to decrease over time. Approximately 69% of patients experienced injection site reactions during the first three months of treatment, compared to approximately 40% at the end of the studies.
Injection site abscesses and cellulitis have been reported in the postmarketing setting with use of interferon beta products including BETASERON. Some cases required treatment with hospitalization for surgical drainage and intravenous antibiotics. Periodically evaluate patient understanding and use of aseptic self-injection techniques and procedures, particularly if injection site necrosis has occurred. Patients should be advised of the importance of rotating injection sites with each dose. Whether to discontinue therapy following a single site of necrosis is dependent on the extent of necrosis. For patients who continue therapy with BETASERON after injection site necrosis has occurred, avoid administration of BETASERON into the affected area until it is fully healed. If multiple lesions occur, change injection site or discontinue therapy until healing occurs.
Leukopenia
In controlled clinical trials, leukopenia was reported in 18% of patients receiving BETASERON (compared to 6% on placebo), leading to a reduction of the dose of BETASERON in some patients [see Adverse Reactions ]. Monitoring of complete blood and differential white blood cell counts is recommended. Patients with myelosuppression may require more intensive monitoring of complete blood cell counts, with differential and platelet counts.
Thrombotic Microangiopathy
Cases of thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura and hemolytic uremic syndrome, some fatal, have been reported with interferon beta products, including BETASERON.
Cases have been reported several weeks to years after starting interferon beta products. If clinical symptoms and laboratory findings consistent with TMA occur and a relationship to BETASERON is suspected, discontinue treatment and manage as clinically indicated.
5.8 Pulmonary Arterial Hypertension
Cases of pulmonary arterial hypertension (PAH) have been reported with interferon beta products, including BETASERON. PAH has occurred in patients treated with interferon beta products in the absence of other contributory factors. Many of the reported cases required hospitalization, including one case with interferon beta in which the patient underwent a lung transplant. PAH has developed at various time points after initiating therapy with interferon beta products and may occur several years after starting treatment.
Patients who develop unexplained symptoms (e.g., dyspnea, new or increasing fatigue) should be assessed for PAH. If alternative etiologies have been ruled out and a diagnosis of PAH is confirmed, discontinue treatment and manage as clinically indicated.
Flu-like Symptom Complex
In controlled clinical trials, the rate of flu-like symptom complex for patients on BETASERON was 57% [see Adverse Reactions ]. The incidence decreased over time, with 10% of patients reporting flu-like symptom complex at the end of the studies. The median duration of flu-like symptom complex in Study 1 was 7.5 days [see Clinical Studies ]. Analgesics and/or antipyretics on treatment days may help ameliorate flu-like symptoms associated with BETASERON use.
Seizures
Seizures have been temporally associated with the use of beta interferons in clinical trials and postmarketing safety surveillance. It is not known whether these events were related to a primary seizure disorder, the effects of multiple sclerosis alone, the use of beta interferons, other potential precipitants of seizures (eg, fever), or to some combination of these.
Drug-induced Lupus Erythematosus
Cases of drug-induced lupus erythematosus have been reported with some interferon beta products, including BETASERON. Signs and symptoms of drug-induced lupus reported in BETASERON-treated patients have included rash, serositis, polyarthritis, nephritis, and Raynaud’s phenomenon. Cases have occurred with positive serologic testing (including positive anti-nuclear and/or anti-double-stranded DNA antibody testing). If BETASERON-treated patients develop new signs and symptoms characteristic of this syndrome, BETASERON therapy should be stopped.
Monitoring for Laboratory Abnormalities
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 at regular intervals (one, three, and six months) following introduction of BETASERON therapy, and then periodically thereafter in the absence of clinical symptoms.