Interferon, Beta-1b (Systemic)
VA CLASSIFICATION
Primary: CN900; IM409
Commonly used brand name(s): Betaseron.
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).
Category:
Multiple sclerosis (MS) therapy agent{01}—
Indications
Accepted
Multiple sclerosis (treatment)—Interferon beta-1b is indicated for use in ambulatory patients with relapsing-remitting multiple sclerosis (MS) to reduce the frequency of clinical exacerbations {01}. The safety and efficacy of interferon beta-1b in chronic-progressive MS have not been evaluated {01}.
Pharmacology/Pharmacokinetics
Physicochemical characteristics:
Source—
Synthetic. Interferon beta-1b is a sterile lyophilized protein product produced by recombinant DNA techniques {01}. It is manufactured by bacterial fermentation of a strain of Escherichia coli that bears a genetically engineered plasmid containing the gene for human interferon beta ser17 {01}. The native gene was obtained from human fibroblasts and altered in a way that substitutes serine for the cysteine residue found at position 17 {01}. Interferon beta-1b is a highly purified protein with 165 amino acids; it does not include the carbohydrate side chains found in the natural material {01}.
Chemical group—
Interferons are a family of naturally occurring proteins {01}. Three major classes have been identified: alfa, beta, and gamma {01}. Interferon alfa, interferon beta-1b, and interferon gamma have overlapping yet distinct biologic activities {01}; the activities of interferon beta-1b are species-restricted {01}.
Molecular weight—
Approximately 18,500 daltons {01}
Mechanism of action/Effect:
Interferon beta-1b has both antiviral and immunoregulatory properties {01}. The mechanism by which it exerts its effects in multiple sclerosis (MS) are not clearly understood {01}. It is known, however, that the biologic response-modifying properties of interferon beta-1b are mediated through its interactions with specific cell receptors found on the surface of human cells {01}. Binding of interferon beta-1b to these receptors induces the expression of a number of interferon-induced gene products (e.g., 2',5'-oligoadenylate synthetase, protein kinase, and indoleamine 2, 3-dioxygenase) that are believed to be the mediators of this interferon"s biological actions {01}.
Pharmacokinetics
Pharmacokinetic information on patients with multiple sclerosis (MS) receiving the recommended dose of interferon beta-1b is not available because serum concentrations following subcutaneous administration of £ 0.25 mg are low or undetectable {01}. Healthy volunteers who received single or multiple daily subcutaneous doses of 0.5 mg generally had serum interferon beta-1b concentrations of less than 100 international units per mL (IU/mL) {01}. Pharmacokinetic parameters in non-MS patients following single and multiple intravenous doses of interferon beta-1b were comparable {01}, and dosing three times a week for two weeks did not result in accumulation of interferon beta-1b in these patients {01}.
Absorption:
Bioavailability was approximately 50%, based on a total dose of 0.5 mg given as two subcutaneous injections at different sites to healthy volunteers {01}.
Distribution:
Mean steady-state volume of distribution (Vol D) values ranged from 0.25 to 2.88 L per kg in healthy volunteers and non-MS patients who received single intravenous doses of up to 2 mg of interferon beta-1b {01}.
Half-life:
Terminal elimination:
Mean, 8 minutes to 4.3 hours in non-MS patients who received single intravenous doses of up to 2 mg of interferon beta-1b {01}.
Time to peak concentration:
1 to 8 hours following subcutaneous administration of 0.5 mg to healthy volunteers {01}.
Peak serum concentration:
Mean, 40 IU/mL following subcutaneous administration of 0.5 mg to healthy volunteers {01}. Increases in serum concentrations were dose-proportional in non-MS patients receiving single intravenous doses of up to 2 mg of interferon beta-1b {01}.
Elimination:
Mean serum clearance values ranged from 9.4 to 28.9 mL/minute x kg, and were independent of dose {01}.
Precautions to Consider
Carcinogenicity
No carcinogenicity data in humans or animals are available {01}. However, the effect of interferon beta-1b on the morphological transformation of the mammalian cell line BALBc-3T3 was studied to evaluate carcinogenic potential, and no significant increases in transformation frequency were noted {01}.
Mutagenicity
Interferon beta-1b was not mutagenic when assayed for genotoxicity in the Ames bacterial test in the presence or absence of metabolic activation {01}.
Pregnancy/Reproduction
Fertility—
The effects of interferon beta-1b on normally cycling human females are not known {01}. Studies on female rhesus monkeys showed no apparent adverse effects on the menstrual cycle or on associated hormonal profiles when interferon beta-1b was administered at doses of up to 32 times the recommended human dose (based on body surface area comparison) over three consecutive menstrual cycles {01}.
Pregnancy—
Adequate and well-controlled studies have not been done in humans {01}. Spontaneous abortions were reported in four women who participated in the premarketing clinical trial {01}.
Studies in female rhesus monkeys demonstrated a dose-related abortifacient activity when interferon beta-1b was administered at doses ranging from 2.8 to 40 times the recommended human dose based on body surface area comparison {01}. It is not known if animal doses can be extrapolated to human doses {01}. Interferon beta-1b administered to female rhesus monkeys on gestation days 20 to 70 did not cause teratogenic effects; it is not known if teratogenic effects would occur in humans {01}.
FDA Pregnancy Category C {01}.
Breast-feeding
It is not known if interferon beta-1b is distributed into human milk {01}; however, because of the potential for serious adverse reactions in nursing infants {01}, risk-benefit must be considered {01}.
Pediatrics
Safety and efficacy in children up to 18 years of age have not been established {01}.
Geriatrics
The premarketing clinical trial of interferon beta-1b enrolled patients ranging from 18 to 50 years of age {01}. No information is available on the effects of interferon beta-1b in geriatric patients.
Drug interactions and/or related problems
Note: Studies designed to evaluate drug interactions with interferon beta-1b have not been conducted {01}. However, ACTH or corticosteroids have been administered for periods of up to 28 days to treat relapses in patients receiving interferon beta-1b {01}. The effect of alternate-day administration on drug metabolism in MS patients is unknown {01}. Interferon beta-1b administered to three cancer patients over a dose range of 0.025 to 2.2 mg led to dose-dependent inhibition of antipyrine elimination {01}.
Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):
With physiology/laboratory test values
Alanine aminotransferase, serum (ALT [SGPT]) (values more than five times baseline occurred in 19% of patients receiving interferon beta-1b, as compared with 6% of patients receiving placebo in the premarketing clinical trial {01})
Aspartate aminotransferase, serum (AST [SGOT]) (values more than five times baseline occurred in 4% of patients receiving interferon beta-1b, as compared with 0% of patients receiving placebo in the premarketing clinical trial {01})
Bilirubin, total (concentrations greater than 2.5 times the baseline occurred in 6% of patients receiving interferon beta-1b, as compared with 2% of patients receiving placebo in the premarketing clinical trial {01})
Glucose, blood (concentrations of less than 55 mg/dL occurred in 15% of patients receiving interferon beta-1b, as compared with 13% of patients receiving placebo in the premarketing clinical trial {01})
Lymphocyte count (counts less than 1500/mm 3 occurred in 82% of patients receiving interferon beta-1b, as compared with 67% of patients receiving placebo in the premarketing clinical trial {01})
Neutrophil count, absolute (counts less than 1500/mm 3 occurred in 18% of patients receiving interferon beta-1b, as compared with 6% of patients receiving placebo in the premarketing clinical trial {01})
Protein, urine (values greater than 1+ occurred in 5% of patients receiving interferon beta-1b, as compared with 3% of patients receiving placebo in the premarketing clinical trial {01})
White blood cell count (counts less than 3000/mm 3 occurred in 16% of patients receiving interferon beta-1b, as compared with 5% of patients receiving placebo in the premarketing clinical trial {01})
Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).
Risk-benefit should be considered when the following medical problems exist
» Depression, mental, especially with suicidal ideation (condition may be exacerbated; patients should be closely monitored)
Sensitivity to natural or recombinant interferon beta, Albumin Human USP, or dextrose
Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):
» Blood chemistry values, including liver function tests{01} and
» Hemoglobin{01} and
» Platelet counts{01} and
» White blood cell counts, complete and differential{01} (recommended prior to initiation of therapy and at periodic intervals thereafter {01})
Side/Adverse Effects
Note: In the premarketing clinical trial, one suicide and four attempted suicides were observed among 372 study patients during a 3-year period {01}. All five of these cases were patients receiving interferon beta-1b; no attempted suicides occurred in study patients who were not receiving interferon beta-1b {01}. Depression and suicide also have been reported in patients receiving interferon alfa, a related compound {01}. Patients should be informed of these side effects and instructed to report symptoms of depression and suicidal ideation immediately to the prescribing physician {01}. If depression occurs, the patient should be closely monitored, and discontinuation of interferon beta-1b should be considered {01}.
Injection site necrosis (ISN) was reported in 5% of patients in premarketing clinical trials {01}. Although typically occurring within the first 4 months of interferon beta-1b therapy, postmarketing surveillance reports ISN occurring over a year after initiation of therapy {01}. ISN may occur at single or multiple injection sites {01}; lesions are typically 3 cm or less in diameter, although larger areas have been reported {01}. While necrosis has commonly extended only to subcutaneous fat, there are reports of necrosis extending to and including fascia overlying muscle {01}. In some lesions, vasculitis has been reported {01}. Debridement and, infrequently, skin grafting have been required for some lesions {01}. Any infection of the necrotic site should be treated appropriately {01}. Time to healing varies depending on the severity of the necrosis {01}; in most cases, healing has been associated with scarring {01}. In some patients, healing of necrotic skin lesions has occurred while interferon beta-1b therapy has continued {01}. The decision to discontinue therapy following a single site of necrosis is dependent on the extent of necrosis {01}. If patients continue using interferon beta-1b after ISN has occurred, injection into the affected area should be avoided until the site is fully healed {01}. If multiple lesions have occurred, therapy should be discontinued until healing is complete {01}. Patients should be instructed to contact the physician promptly if any break in the skin, which may be associated with blue-black discoloration, swelling, or drainage of fluid from the injection site, occurs {01}.
Other injection site reactions, including redness, pain, swelling, and discoloration, occurred in 85% of patients at one or more times during the controlled MS trial {01}. In general, these reactions were transient and did not require discontinuation of therapy, but the nature and severity of all reported reactions need to be carefully assessed {01}.
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Those indicating need for medical attention
Incidence more frequent
Abdominal pain{01}
headache{01} or migraine{01}
hypertension{01} (high blood pressure)
injection site reactions{01} including hypersensitivity{01} (hives; itching; swelling), inflammation{01} (redness; feeling of heat), necrosis{01} (break in the skin, especially associated with blue-black discoloration, swelling, or drainage of fluid), and pain{01}
influenza-like syndrome{01}
including chills{01}
fever{01}
increased sweating{01}
malaise{01} (general feeling of discomfort or illness), and myalgia{01} (muscle pain)
palpitations{01} (irregular or pounding heartbeat)
sinusitis{01} (headache; stuffy nose)
Incidence less frequent
Abnormal vision{01} (any change in vision)
breast pain{01}
cystitis{01} (bloody or cloudy urine; difficult, burning, or painful urination; frequent urge to urinate)
dyspnea{01} (troubled breathing)
lymphadenopathy{01} (swollen lymph glands)
pain{01}
pelvic pain{01}
peripheral vascular disorder{01} (cold hands and feet)
tachycardia{01} (fast or racing heartbeat)
weight gain, unusual{01}
Incidence rare
Amnesia{01} (loss of memory)
breast neoplasm{01} (abnormal growth in breast)
confusion{01}
conjunctivitis{01} (red, itching, or swollen eyes)
cyst{01} (abnormal growth filled with fluid or semisolid material)
edema, generalized{01} (bloating or swelling)
fibrocystic breast{01} (benign lumps in breast)
goiter{01} (dry, puffy skin; increased weight gain; swelling of front part of neck; changes in menstrual periods; decreased sexual ability in males; feeling cold)
hemorrhage{01} (bleeding problems)
hyperkinesia{01} (hyperactivity)
hypertonia{01} (increased muscle tone)
mental depression with suicidal ideation{01} (depression with thoughts of suicide)
seizure{01}
speech disorder{01} (problems in speaking)
urinary urgency{01} (increased urge to urinate)
weight loss, unusual{01}
Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
Asthenia{01} (unusual tiredness or weakness)
constipation{01}
diarrhea{01}
dizziness{01}
dysmenorrhea or other menstrual disorders{01} (menstrual pain or other menstrual changes)
laryngitis{01}
Incidence less frequent
Alopecia{01} (hair loss)
anxiety{01}
nervousness{01}
somnolence{01} (drowsiness)
vomiting{01}
Overdose
For information on the management of overdose of interferon beta-1b, contact a Poison Control Center (see Poison Control Center Listing ).
Patient Consultation
In providing consultation, consider emphasizing the following selected information (» = major clinical significance)
Before using this medication
» Conditions affecting use, especially:
Sensitivity to interferon beta-1b, Albumin Human USP, or dextrose
Pregnancy—Not recommended
Breast-feeding—Possible need to avoid during interferon beta-1b therapy because of risk of serious adverse effects on infant
Other medical problems, especially mental depression with suicidal ideation
Proper use of this medication
» Proper administration:
• Importance of aseptic technique
• Choosing an appropriate injection site
• Importance of rotating injection sites
» Proper dosing
Missed dose: Using as soon as remembered; the next injection should be scheduled about 48 hours later
» Proper storage
Side/adverse effects
Signs of potential side effects, especially abdominal pain; headache or migraine; hypertension; injection site reactions including hypersensitivity, inflammation, necrosis, and pain; influenza-like syndrome including chills, fever, increased sweating, malaise, and myalgia; palpitations; sinusitis; abnormal vision; breast pain; cystitis; dyspnea; lymphadenopathy; pain; pelvic pain; peripheral vascular disorder; tachycardia; unusual weight gain; amnesia; breast neoplasm; confusion; conjunctivitis; cyst; edema, generalized; fibrocystic breast; goiter; hemorrhage; hyperkinesia; hypertonia; mental depression with suicidal ideation; seizure; speech disorder; urinary urgency; unusual weight loss
General Dosing Information
Activity of interferon beta-1b is approximately 32 million international units (IU) per mg {01}. The unit measurement is derived by comparing the antiviral activity of the product to the World Health Organization (WHO) reference standard of recombinant human interferon beta {01}. Prior to 1993, a different analytical standard was used to determine potency; it assigned 54 million IU to 0.3 mg interferon beta-1b, as compared with the currently assigned potency of 9.6 million IU per 0.3 mg interferon beta-1b {01}.
Patient understanding and use of aseptic self-injection techniques and procedures should be reevaluated periodically, particularly if injection site necrosis (ISN) has occurred {01}.
Patient understanding of the importance of rotating areas of injection to minimize the likelihood of severe injection site reactions should be reinforced {01}.
Taking interferon beta-1b at bedtime may help lessen the impact of influenza-like symptoms {01}.
Parenteral Dosage Forms
INTERFERON BETA-1b FOR INJECTION
Usual adult dose
Relapsing-remitting multiple sclerosis
Subcutaneously, 0.25 mg every other day {01}.
Usual pediatric dose
Safety and efficacy in patients up to 18 years of age have not been established {01}.
Strength(s) usually available
U.S.—
0.3 mg (Rx) [Betaseron (diluent: sodium chloride 0.54%) (Albumin Human USP 15 mg) (Dextrose USP 15 mg)]
Packaging and storage:
Store between 2 and 8 ºC (36 and 46 ºF) {01}. Do not freeze {01}.
If refrigeration is not possible, the drug and diluent should be kept as cool as possible (below 30 ºC [86 ºF]), stored away from heat and light, and used within 7 days {01}.
Preparation of dosage form:
Using aseptic technique, 1.2 mL of the supplied diluent should be transferred into the lyophilized interferon beta-1b vial {01}. The vial should be swirled gently until the solid material is completely dissolved {01}. If particulate matter remains or the reconstituted product is discolored, it should be discarded before use {01}. Following reconstitution with the accompanying diluent, the resulting solution will contain 0.25 mg interferon beta-1b per mL.
After reconstitution, withdraw 1 mL of solution into a sterile syringe fitted with a new 27-gauge needle to be injected subcutaneously {01}.
Stability:
Interferon beta-1b contains no preservatives; after reconstitution, if not immediately used, it should be refrigerated and used within 3 hours {01}.
Auxiliary labeling:
• Refrigerate {01}.
• Do not freeze {01}.
Developed: 06/16/1998
References
- Betaseron package insert (Berlex—US), Rev 10/96, Rec 7/25/97.
