Betaferon倍泰龍

Betaferon

interferon beta-1b

Manufacturer:

Bayer

Distributor:

Zuellig
/
Firma Chun Cheong
Full Prescribing Info
Contents
Recombinant interferon beta-1b.
Description
Recombinant interferon beta-1b* 250 microgram (8.0 million IU) per ml when reconstituted.
Betaferon contains 300 microgram (9.6 million IU) of recombinant interferon beta-1b per vial.
* produced by genetic engineering from a strain of Escherichia coli.
Excipients/Inactive Ingredients: Vial (with powder for solution for injection): Human albumin, Mannitol.
Solvent (sodium chloride solution 5.4 mg/ml (0.54% w/v)):
Sodium chloride, Water for injection.
Action
Pharmacotherapeutic group: Cytokines, Interferons. ATC Code: L03AB08.
Pharmacology: Pharmacodynamics: Mechanism of action: Interferons belong to the family of cytokines, which are naturally occurring proteins. Interferons have molecular weights ranging from 15,000 to 21,000 Daltons. Three major classes of interferons have been identified: alpha, beta, and gamma. Interferon alpha, interferon beta, and interferon gamma have overlapping yet distinct biologic activities. The activities of interferon beta-1b are species-restricted and therefore, the most pertinent pharmacological information on interferon beta-1b is derived from studies of human cells in culture or in human in vivo studies.
Interferon beta-1b has been shown to possess both antiviral and immunoregulatory activities. The mechanisms by which interferon beta-1b exerts its actions in multiple sclerosis are not clearly understood. However, it is known 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. The binding of interferon beta-1b to these receptors induces the expression of a number of gene products that are believed to be the mediators of the biological actions of interferon beta-1b. A number of these products have been measured in the serum and cellular fractions of blood collected from patients treated with interferon beta-1b. Interferon beta-1b both decreases the binding affinity and enhances the internalization and degradation of the interferon-gamma receptor. Interferon beta-1b also enhances the suppressor activity of peripheral blood mononuclear cells.
No separate investigations were performed regarding the influence of Betaferon on the cardiovascular system, respiratory system and the function of endocrine organs.
Clinical efficacy and safety: RR-MS: One controlled clinical trial with Betaferon in patients with relapsing-remitting multiple sclerosis and able to walk unaided (baseline EDSS 0 to 5.5) was performed. Patients receiving Betaferon showed a reduction in frequency (30%) and severity of clinical relapses, as well as the number of hospitalisations due to disease. Furthermore, there was a prolongation of the relapse-free interval. There is no evidence of an effect of Betaferon on the duration of relapses or on symptoms in between relapses, and no significant effect was seen on the progression of the disease in relapsing-remitting multiple sclerosis.
SP-MS: Two controlled clinical trials with Betaferon involving a total of 1,657 patients with secondary progressive multiple sclerosis (baseline EDSS 3 to 6.5, i.e. patients were able to walk) were performed. Patients with mild disease and those unable to walk were not studied. The two studies showed inconsistent results for the primary endpoint time to confirmed progression, representing delay of disability progression: One of the two studies demonstrated a statistically significant delay in the time to disability progression (Hazard Ratio = 0.69, 95% confidence interval (0.55, 0.86), p=0.0010, corresponding to a 31% risk reduction due to Betaferon) and in the time to becoming wheelchair bound (Hazard Ratio = 0.61, 95% confidence interval (0.44, 0.85), p=0.0036, corresponding to a 39% risk reduction due to Betaferon) in patients who received Betaferon. This effect continued over the observation period of up to 33 months. The treatment effect occurred in patients at all levels of disability investigated and independent of relapse activity.
In the second trial of Betaferon in secondary progressive multiple sclerosis, no delay in the time to disability progression was observed. There is evidence that the patients included in this study had overall less active disease than in the other study in secondary progressive multiple sclerosis.
In retrospective meta-analyses including the data of both studies, an overall treatment effect was found which was statistically significant (p=0.0076; 8.0 million IU Betaferon versus all placebo patients).
Retrospective analyses in subgroups showed that a treatment effect on disability progression is most likely in patients with active disease before treatment commences (Hazard Ratio 0.72, 95% confidence interval (0.59, 0.88), p=0.0011, corresponding to a 28 % risk reduction due to Betaferon in patients with relapses or pronounced EDSS progression, 8.0 million IU Betaferon versus all placebo patients).
From these retrospective subgroup analyses there was evidence to suggest that relapses as well as pronounced EDSS progression (EDSS >1 point or >0.5 point for EDSS ≥6 in the previous two years) can help to identify patients with active disease.
In both trials secondary progressive multiple sclerosis patients receiving Betaferon showed a reduction in frequency (30%) of clinical relapses. There is no evidence of Betaferon having an effect on the duration of relapses.
Single clinical event suggestive of MS: One controlled clinical trial with Betaferon was performed in patients with a single clinical event and MRI features suggestive of multiple sclerosis (at least two clinically silent lesions on the T2-weighted MRI). Patients with monofocal or multifocal onset of the disease were included (i.e. patients with clinical evidence for a single or at least two lesions, respectively, of the central nervous system). Any disease other than multiple sclerosis that could better explain signs and symptoms of the patient had to be excluded. This study consisted of two phases, a placebo-controlled phase followed by a pre-planned follow-up phase. The placebo-controlled phase lasted for 2 years or until the patient developed clinically definite multiple sclerosis (CDMS), whichever came first. After the placebo-controlled phase, patients entered a pre-planned follow-up phase with Betaferon to evaluate the effects of immediate versus delayed start of Betaferon-treatment, comparing patients initially randomized to Betaferon ("immediate treatment group") or to placebo ("delayed treatment group"). Patients and investigators remained blinded to the initial treatment allocation. (See Table 1.)

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In the placebo-controlled phase, Betaferon delayed the progression from the first clinical event to CDMS in a statistically significant and clinically meaningful manner. The robustness of the treatment effect was also shown by the delay of progression to multiple sclerosis according to McDonald criteria (Table 1).
Subgroup analyses according to baseline factors demonstrated evidence of efficacy on progression to CDMS in all subgroups evaluated. The risk for progression to CDMS within 2 years was higher in monofocal patients with at least 9 T2-lesions or Gd-enhancement on brain MRI at baseline. In multifocal patients, the risk for CDMS was independent from MRI findings at baseline, indicating a high risk for CDMS because of the dissemination of the disease based on clinical findings. For the time being there is no well established definition of a high risk patient, although a more conservative approach is to accept at least nine T2 hyperintense lesions on the initial scan and at least one new T2 or one new Gd-enhancing lesion on a follow-up scan taken at least 1 month after the initial scan. In any case, treatment should only be considered for patients classified as high risk.
Therapy with Betaferon was well accepted as indicated by a high rate of trial completion (93% in the Betaferon group). To increase tolerability of Betaferon, a dose titration was applied and non-steroidal anti-inflammatory drugs were administered at start of therapy. Moreover, an autoinjector was used by the majority of patients throughout the study.
In the open label follow-up phase, the treatment effect on CDMS was still evident after 3 and 5 years (Table 1), even though the majority of patients from the placebo-group was treated with Betaferon at least from the second year onwards. EDSS progression (confirmed increase in EDSS of at least one point compared to baseline) was lower in the immediate treatment group (Table 1, significant effect after 3 years, no significant effect after 5 years). The majority of patients in both treatment groups had no disability progression over the 5-year period. Robust evidence for benefit on this outcome parameter could not be demonstrated for 'immediate' treatment. No benefit, attributable to immediate Betaferon treatment, in quality of life (as measured by FAMS - Functional Assessment of MS: Treatment Outcomes Index) was seen.
RR-MS, SP-MS and single clinical event suggestive of MS: Betaferon was effective in all multiple sclerosis studies to reduce disease activity (acute inflammation in the central nervous system and permanent tissue alterations) as measured by magnetic resonance imaging (MRI). The relation of multiple sclerosis disease activity as measured by MRI and clinical outcome is currently not fully understood.
Pharmacokinetics: Betaferon serum levels were followed in patients and volunteers by means of a not completely specific bioassay. Maximum serum levels of about 40 IU/ml were found 1-8 hours after subcutaneous injection of 500 microgram (16.0 million IU) interferon beta-1b. From various studies mean clearance rates and half-lives of disposition phases from serum were estimated to be at most 30 ml·min-1·kg-1 and 5 hours, respectively.
Betaferon injections given every other day do not lead to serum level increases, and the pharmacokinetics do not seem to change during therapy.
The absolute bioavailability of subcutaneously administered interferon beta-1b was approximately 50%.
Toxicology: Preclinical safety data: No acute toxicity studies have been carried out. As rodents do not react to human interferon beta, repeated dose studies were carried out with rhesus monkeys. Transitory hyperthermia was observed, as well as a significant rise in lymphocytes and a significant decrease in thrombocytes and segmented neutrophils.
No long-term studies have been conducted. Reproduction studies with rhesus monkeys revealed maternal toxicity and an increased rate of abortions, resulting in prenatal mortality. No malformations have been observed in the surviving animals.
No investigations on fertility have been conducted. No influence on the monkey oestrous cycle has been observed. Experience with other interferons suggest a potential for impairment of male and female fertility.
In one single genotoxicity study (Ames test), no mutagenic effect has been observed. Carcinogenicity studies have not been performed. An in vitro cell transformation test gave no indication of tumorigenic potential.
Indications/Uses
Betaferon is indicated for the treatment of: Patients with a single demyelinating event with an active inflammatory process, if it is severe enough to warrant treatment with intravenous corticosteroids, if alternative diagnoses have been excluded, and if they are determined to be at high risk of developing clinically definite multiple sclerosis (see Pharmacology: Pharmacodynamics under Actions).
Patients with relapsing-remitting multiple sclerosis and two or more relapses within the last two years.
Patients with secondary progressive multiple sclerosis with active disease, evidenced by relapses.
Dosage/Direction for Use
The treatment with Betaferon should be initiated under the supervision of a physician experienced in the treatment of the disease.
Posology: Adults: The recommended dose of Betaferon is 250 microgram (8.0 million IU), contained in 1 ml of the reconstituted solution (see Patient Counselling Information), to be injected subcutaneously every other day.
Paediatric population: No formal clinical trials or pharmacokinetic studies have been conducted in children or adolescents. However, limited published data suggest that the safety profile in adolescents from 12 to 16 years of age receiving Betaferon 8.0 million IU subcutaneously every other day is similar to that seen in adults. There is no information on the use of Betaferon in children under 12 years of age. Therefore Betaferon should not be used in this population.
Generally, dose titration is recommended at the start of treatment.
Patients should be started at 62.5 microgram (0.25 ml) subcutaneously every other day, and increased slowly to a dose of 250 microgram (1.0 ml) every other day (see Table 2). The titration period may be adjusted, if any significant adverse reaction occurs. In order to obtain adequate efficacy, a dose of 250 microgram (1.0 ml) every other day should be reached. (See Table 2.)

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The optimal dose has not been fully clarified.
At the present time it is not known how long the patient should be treated for. There are follow-up data under controlled clinical conditions for patients with relapsing-remitting MS for up to 5 years and for patients with secondary progressive MS for up to 3 years. For relapsing-remitting MS, efficacy has been demonstrated for therapy for the first 2 years. The available data for the additional 3 years are consistent with sustained treatment efficacy of Betaferon over the whole time period. In patients with a single clinical event suggestive of multiple sclerosis, the progression to clinically definite multiple sclerosis was significantly delayed over a period of five years.
Treatment is not recommended in patients with relapsing-remitting multiple sclerosis who have experienced less than 2 relapses in the previous 2 years or in patients with secondary-progressive multiple sclerosis who have had no active disease in the previous 2 years.
If the patient fails to respond, for example a steady progression in EDSS for 6 months occurs or treatment with at least 3 courses of ACTH or corticosteroids during a one year period is required despite Betaferon therapy, treatment with Betaferon should be stopped.
Method of administration: For subcutaneous injection.
For instructions on reconstitution of the medicinal product before administration, see Patient Counselling Information.
Overdosage
Interferon beta-1b has been given without serious adverse events compromising vital functions to adult cancer patients at individual doses as high as 5,500 microgram (176 million IU) intravenously three times a week.
Contraindications
Patients with a history of hypersensitivity to natural or recombinant interferon beta, human albumin or to any of the excipients listed in Description.
Patients with current severe depression and/or suicidal ideation (see Precautions and Adverse Reactions).
Patients with decompensated liver disease (see Precautions, Interactions and Adverse Reactions).
Special Precautions
Traceability: In order to improve traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
Immune system disorders: The administration of cytokines to patients with a pre-existing monoclonal gammopathy has been associated with the development of systemic capillary leak symptoms with shock-like symptoms and fatal outcome.
Gastrointestinal disorders: In rare cases, pancreatitis was observed with Betaferon use, often associated with hypertriglyceridaemia.
Nervous system disorders: Betaferon should be administered with caution to patients with previous or current depressive disorders, in particular to those with antecedents of suicidal ideation (see Contraindications).
Depression and suicidal ideation are known to occur with increased frequency in the multiple sclerosis population and in association with interferon use. Patients treated with Betaferon should be advised to report any symptoms of depression and/or suicidal ideation to their prescribing physician immediately. Patients exhibiting depression should be monitored closely during therapy with Betaferon and treated appropriately. Cessation of therapy with Betaferon should be considered (see also Contraindications and Adverse Reactions).
Betaferon should be administered with caution to patients with a history of seizures and to those receiving treatment with anti-epileptics, particularly if their epilepsy is not adequately controlled with anti-epileptics (see Interactions and Adverse Reactions).
This product contains human albumin and hence carries a potential risk for transmission of viral diseases. A risk for transmission of Creutzfeld-Jacob disease (CJD) cannot be excluded.
Laboratory tests: Thyroid function tests are recommended regularly in patients with a history of thyroid dysfunction or as clinically indicated.
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 (e.g. AST (SGOT), ALT (SGPT) and γ-GT), are recommended prior to initiation and at regular intervals following introduction of Betaferon therapy, and then periodically thereafter in the absence of clinical symptoms.
Patients with anaemia, thrombocytopenia, leukopenia (alone or in any combination) may require more intensive monitoring of complete blood cell counts, with differential and platelet counts. Patients who develop neutropenia should be monitored closely for the development of fever or infection. There have been reports of thrombocytopenia, with profound decreases in platelet count.
Hepatobiliary disorders: Asymptomatic elevations of serum transaminases, in most cases mild and transient, occurred very commonly in patients treated with Betaferon during clinical trials. As for other beta interferons, severe hepatic injury, including cases of hepatic failure, has been reported rarely in patients treated with Betaferon. The most serious events often occurred in patients exposed to other drugs or substances known to be associated with hepatotoxicity or in the presence of comorbid medical conditions (e.g. metastasizing malignant disease, severe infection and sepsis, alcohol abuse).
Patients should be monitored for signs of hepatic injury. The occurrence of elevations in serum transaminases should lead to close monitoring and investigation. Withdrawal of Betaferon should be considered if the levels significantly increase or if they are associated with clinical symptoms such as jaundice. In the absence of clinical evidence for liver damage and after normalization of liver enzymes a reintroduction of therapy could be considered with appropriate follow-up of hepatic functions.
Renal and urinary disorders: Caution should be used and close monitoring considered when administering interferon beta to patients with severe renal failure.
Nephrotic syndrome: Cases of nephrotic syndrome with different underlying nephropathies including collapsing focal segmental glomerulosclerosis (FSGS), minimal change disease (MCD), membranoproliferative glomerulonephritis (MPGN) and membranous glomerulopathy (MGN) have been reported during treatment with interferon-beta products. Events were reported at various time points during treatment and may occur after several years of treatment with interferon-beta. Periodic monitoring of early signs or symptoms, e.g. oedema, proteinuria and impaired renal function is recommended, especially in patients at higher risk of renal disease. Prompt treatment of nephrotic syndrome is required and discontinuation of treatment with Betaferon should be considered.
Cardiac disorders: Betaferon should also be used with caution in patients who suffer from pre-existing cardiac disorders. Patients with pre-existing significant cardiac disease, such as congestive heart failure, coronary artery disease or arrhythmia, should be monitored for worsening of their cardiac condition, particularly during initiation of treatment with Betaferon.
While Betaferon does not have any known direct-acting cardiac toxicity, symptoms of the flu-like syndrome associated with beta interferons may prove stressful to patients with pre-existing significant cardiac disease. During the post marketing period very rare reports have been received of worsening of cardiac status in patients with pre-existing significant cardiac disease temporarily associated with the initiation of Betaferon therapy.
Rare cases of cardiomyopathy have been reported. If this occurs and a relationship to Betaferon is suspected, treatment should be discontinued.
Thrombotic microangiopathy (TMA): Cases of thrombotic microangiopathy, manifested as thrombotic thrombocytopenic purpura (TTP) or haemolytic uraemic syndrome (HUS), including fatal cases, have been reported with interferon beta products. Events were reported at various time points during treatment and may occur several weeks to several years after starting treatment with interferon beta. Early clinical features include thrombocytopenia, new onset hypertension, fever, central nervous system symptoms (e.g. confusion, paresis) and impaired renal function. Laboratory findings suggestive of TMA include decreased platelet counts, increased serum lactate dehydrogenase (LDH) due to haemolysis and schistocytes (erythrocyte fragmentation) on a blood film. Therefore if clinical features of TMA are observed, further testing of blood platelet levels, serum LDH, blood films and renal function is recommended. If TMA is diagnosed, prompt treatment is required (considering plasma exchange) and immediate discontinuation of Betaferon is recommended.
General disorders and administration site conditions: Serious hypersensitivity reactions (rare but severe acute reactions such as bronchospasm, anaphylaxis and urticaria) may occur. If reactions are severe, Betaferon should be discontinued and appropriate medical intervention instituted.
Injection site necrosis has been reported in patients using Betaferon (see Adverse Reactions). It can be extensive and may involve muscle fascia as well as fat and therefore can result in scar formation. Occasionally debridement and, less often, skin grafting are required and healing may take up to 6 months.
If the patient experiences any break in the skin, which may be associated with swelling or drainage of fluid from the injection site, the patient should be advised to consult with his/her physician before continuing injections with Betaferon.
If the patient has multiple lesions Betaferon should be discontinued until healing has occurred. Patients with single lesions may continue on Betaferon provided the necrosis is not too extensive, as some patients have experienced healing of injection site necrosis whilst on Betaferon.
To minimize the risk of injection site necrosis patients should be advised to: use an aseptic injection technique; rotate the injection sites with each dose.
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 multiple sclerosis an autoinjector was used in the majority of patients. Injection site reactions as well as injection site necroses were observed less frequently in this study than in the other pivotal studies.
The procedure for the self-administration by the patient should be reviewed periodically especially if injection site reactions have occurred.
Immunogenicity: 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 Betaferon.
In the different controlled clinical trials in relapsing-remitting multiple sclerosis and secondary progressive multiple sclerosis, between 23% and 41% of the patients developed serum interferon beta-1b neutralising 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 neutralising activity in these studies 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 neutralising activity.
In the study of patients with a single clinical event suggestive of multiple sclerosis, neutralising activity measured every 6 months was observed at least once in 32% (89) of the patients treated immediately with Betaferon; of these, 60% (53) returned to negative status based on the last available assessment within the 5 year period. Within this period, the development of neutralising activity was associated with a significant increase in newly active lesions and T2 lesion volume on magnetic resonance imaging. However, this did not seem to be associated with a reduction in clinical efficacy (with regard to time to clinically definite multiple sclerosis (CDMS), time to confirmed EDSS progression and relapse rate).
New adverse events have not been associated with the development of neutralising activity.
It has been demonstrated in vitro that Betaferon 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 neutralising activity and have completed Betaferon therapy.
The decision to continue or discontinue treatment should be based on all aspects of the patient's disease status rather than on neutralising activity status alone.
Excipients: This medicinal product contains less than 1 mmol sodium (23 mg) per ml, that is to say essentially 'sodium-free'.
Effects on ability to drive or use machines: No studies of the effects on the ability to drive and use machines have been performed.
Central nervous system-related adverse events associated with the use of Betaferon might influence the ability to drive and use machines in susceptible patients.
Use In Pregnancy & Lactation
Pregnancy: A large amount of data (more than 1000 pregnancy outcomes) from interferon beta registries, national registries and post-marketing experience indicates no increased risk of major congenital anomalies after pre-conception exposure or exposure during the first trimester of pregnancy. However, the duration of exposure during the first trimester is uncertain, because data were collected when interferon beta use was contraindicated during pregnancy, and treatment likely interrupted when pregnancy was detected and/or confirmed. Experience with exposure during the second and third trimester is very limited.
Based on animal data (see Pharmacology: Toxicology: Preclinical safety data under Actions), there is a possibly increased risk for spontaneous abortion. The risk of spontaneous abortions in pregnant women exposed to interferon beta cannot adequately be evaluated based on the currently available data, but the data do not suggest an increased risk so far.
If clinically needed, the use of Betaferon may be considered during pregnancy.
Breast-feeding: Limited information available on the transfer of interferon beta-1b into breast milk, together with the chemical / physiological characteristics of interferon beta, suggests that levels of interferon beta-1b excreted in human milk are negligible. No harmful effects on the breastfed newborn/infant are anticipated.
Betaferon can be used during breast feeding.
Fertility: No investigations on fertility have been conducted (see Pharmacology: Toxicology: Preclinical safety data under Actions).
Adverse Reactions
Summary of the safety profile: At the beginning of treatment adverse reactions are common but in general they subside with further treatment. The most frequently observed adverse reactions are a flu-like symptom complex (fever, chills, arthralgia, malaise, sweating, headache, or myalgia), which is mainly due to the pharmacological effects of the medicinal product, and injection site reactions. Injection site reactions occurred frequently after administration of Betaferon. Redness, swelling, discolouration, inflammation, pain, hypersensitivity, necrosis and non-specific reactions were significantly associated with 250 microgram (8.0 million IU) Betaferon treatment.
Generally, dose titration is recommended at the start of treatment in order to increase tolerability to Betaferon (see Dosage & Administration). Flu-like symptoms may also be reduced by administration of non-steroidal anti-inflammatory drugs. The incidence of injection site reactions may be reduced by the use of an autoinjector.
Tabulated list of adverse reactions: The following adverse event listing is based on reports from clinical trials (Table 3, adverse events and laboratory abnormalities) and from the post-marketing surveillance (Table 4, frequencies - where known-based on pooled clinical trials (very common ≥ 1/10, common ≥ 1/100 to <1/10, uncommon ≥ 1/1000 to <1/100, rare ≥ 1/10,000 to <1/1,000, very rare <1/10,000)) of Betaferon use. Experience with Betaferon in patients with MS is limited, consequently those adverse events which occur very rarely may not yet have been observed. (See Tables 3A and 3B.)

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The most appropriate MedDRA term is used to describe a certain reaction and its synonyms and related conditions. (See Table 4.)

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The most appropriate MedDRA term is used to describe a certain reaction and its synonyms and related conditions.
Pulmonary arterial hypertension: Cases of pulmonary arterial hypertension (PAH) have been reported with interferon beta products. Events were reported at various time points including up to several years after starting treatment with interferon beta.
Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the local reporting system.
Drug Interactions
No interaction studies have been performed.
The effect of alternate-day administration of 250 microgram (8.0 million IU) of Betaferon on drug metabolism in multiple sclerosis patients is unknown. Corticosteroid or ACTH treatment of relapses for periods of up to 28 days has been well tolerated in patients receiving Betaferon.
Due to the lack of clinical experience in multiple sclerosis patients, the use of Betaferon together with immunomodulators other than corticosteroids or ACTH is not recommended.
Interferons have been reported to reduce the activity of hepatic cytochrome P450-dependent enzymes in humans and animals. Caution should be exercised when Betaferon is administered in combination with medicinal products that have a narrow therapeutic index and are largely dependent on the hepatic cytochrome P450 system for clearance, e.g. anti-epileptics. Additional caution should be exercised with any co-medication which has an effect on the haematopoietic system.
No interaction studies with anti-epileptics have been carried out.
Caution For Usage
Special precautions for disposal and other handling: Reconstitution: To reconstitute lyophilised interferon beta-1b for injection, connect the vial adaptor with the attached needle on the vial. Connect the pre-filled syringe with solvent to the vial adapter and inject the 1.2 ml of the solvent (sodium chloride solution, 5.4 mg/ml (0.54% w/v)) into the Betaferon vial. Dissolve the powder completely without shaking.
After reconstitution, draw 1.0 ml from the vial into the syringe for the administration of 250 microgram Betaferon. For the dose titration at the start of treatment, draw the respective volume as given in Dosage & Administration.
Remove the vial with the vial adapter from the pre-filled syringe before injection.
Betaferon may also be administered with a suitable autoinjector.
Inspection prior to use: Inspect the reconstituted product visually before use. The reconstituted product is colourless to light yellow and slightly opalescent to opalescent.
Discard the product before use if it contains particulate matter or is discoloured.
Disposal: Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Incompatibilities: This medicinal product must not be mixed with other medicinal products except for the supplied solvent mentioned previously.
Storage
Do not store above 25°C.
Do not freeze.
For storage conditions of the reconstituted medicinal product, see Shelf life as follows.
Shelf life: 2 years.
After reconstitution, immediate use is recommended. However, the in-use stability has been demonstrated for 3 hours at 2-8°C.
Patient Counseling Information
Self-injection procedure: The following instructions explain how to prepare Betaferon for injection and how to inject Betaferon yourself. Please read the instructions carefully and follow them step by step. Your doctor or nurse will help you to learn the process of self-administration. Do not attempt to inject yourself until you are sure that you understand how to prepare the injection solution and give the injection to yourself.
STEP BY STEP INSTRUCTIONS: A) General advice: Get a good start. You will find that within a few weeks your therapy will become a natural part of your routine. As you get started, you may find the following helpful: Set up a permanent storage area in a convenient location out of the sight and reach of children so your Betaferon and other supplies are always easy to find.
For details on storage conditions, see Storage.
Try to give your injection at the same time of day. This makes it easier to remember and easier to plan a block of time when you will not be interrupted.
Prepare each dose only when you are ready for an injection. After mixing Betaferon, you should give the injection immediately (if Betaferon is not used immediately, see Shelf life under Storage).
Important tips to keep in mind: Be consistent - use Betaferon as described in Dosage & Administration. Always double-check your dosage.
Keep your syringes and syringe disposal unit out of the sight and reach of children; lock the supplies away if possible.
Never re-use syringes or needles.
Always use a sterile (aseptic) technique as described.
Always place the used syringes in the proper disposal unit.
B) Getting ready to inject: Choosing an injection site: Before preparing your injection, decide where you are going to inject. You should inject Betaferon into the fatty layer between the skin and muscle (that is, subcutaneously, about 8 to 12 mm under the skin). The best places for injections are where the skin is loose and soft, and away from joints, nerves, or bones, for example the abdomen, arm, thigh or buttocks.
Important: Do not use any area where you can feel lumps, bumps, firm knots, pain or an area that is discoloured, indented, scabbed, or where the skin is broken. Talk to your doctor or nurse about these or any other unusual conditions you may find.
You should rotate the injection site at every injection. If some areas are too difficult for you to reach, you may need a family member or friend to help you with these injections. Follow the sequence described in the schedule (see Rotating injection sites as follows) and you will come back to your first injection site area after 8 injections (16 days). This will give each injection site a chance to fully recover before receiving another injection.
Please refer to the rotation schedule to learn how to choose an injection site. An example of a medication record is also included (see as follows). This should give you an idea of how you can keep track of your injection sites and dates.
Checking the content of the pack: In the Betaferon pack you will find: 1 Betaferon vial (with powder for solution for injection), 1 pre-filled syringe of solvent for Betaferon (sodium chloride solution 5.4 mg/ml (0.54% w/v)), 1 vial adapter with a pre-attached needle, 2 alcohol swabs to clean the skin and vial.
In addition you will need a disposal unit for used syringes and needles.
For skin disinfection use an appropriate disinfectant.
C) Reconstituting the solution, step by step: 1 - Wash your hands thoroughly with soap and water before beginning this process.
2 - Open the Betaferon vial and put it on the table. It is best to use your thumb rather than your nail as it could break.
3 - Clean the top of the vial with an alcohol wipe, moving the wipe in one direction only. Leave the wipe on top of the vial.
4 - Open the blister pack containing the vial adapter, but leave the vial adapter inside.
Do not remove the vial adapter from the blister pack at this stage.
Do not touch the vial adapter. This is to keep it sterile.
5 - Before attaching the adapter, remove and discard the alcohol wipe and rest the vial on a flat surface.
6 - Hold the blister pack on the outside and place it on top of the vial. Push it down firmly until you feel it snap into place on the vial.
7 - Remove the blister pack from the vial adapter, holding the blister edges. Now you are ready to attach the pre-filled solvent syringe to the vial adapter.
8 - Pick up the syringe. Be sure that the orange tip cap is firmly attached to the solvent syringe.
Remove the tip cap by twisting it off. Throw away the tip cap.
9 - Connect the syringe to the opening on the side of the vial adapter by inserting the end of the syringe and tightening carefully by a clockwise "push and twist" motion. This will form the syringe assembly.
10 - Hold the syringe assembly at the bottom of the vial. Slowly push the plunger of the syringe in all the way to transfer all of the solvent into the vial. Release the plunger, which may go back to its original position.
11 - With the syringe assembly still attached, swirl the vial around gently to completely dissolve the dry Betaferon powder.
Do not shake the vial.
12 - Examine the solution carefully. It should be clear and contain no particles. If the solution is discoloured or contains particles, discard it and start again with a new single pack of supplies. If foam is present - which can happen if the vial is shaken or swirled too much - let the vial sit undisturbed until the foam settles.
D) Drawing up the injection: 13 - If the plunger has moved back to its original position, push it in again and hold it in place. To prepare your injection, turn the assembly over so that the vial is on top, cap side pointing down. Doing this allows the solution to flow down into the syringe.
Keep the syringe horizontal.
Slowly pull the plunger back to withdraw all the solution out of the vial and into the syringe.
14 - After drawing up the solution, turn the syringe assembly so that the needle is pointing up. This allows any air bubbles to rise to the top of the solution.
15 - Remove any air bubbles by gently tapping the syringe and pushing the plunger to the 1-ml mark, or to the volume prescribed by your doctor.
If too much solution enters the vial along with the air bubbles, get back into the horizontal position and pull the plunger back a little to withdraw the solution back into the syringe.
16 - Next, hold the blue vial adapter with the attached vial and remove it from the syringe by twisting it and then pulling it down, away from the syringe.
Only hold the blue plastic adapter when removing. Keep the syringe in a horizontal position and the vial below the syringe.
Removing the vial and adapter from the syringe ensures that the solution will flow out from the needle when injected.
17 - Dispose of the vial and any unused portion of the solution in the disposal unit.
18 - You are now ready to inject.
If, for some reason, you are not able to inject the Betaferon immediately, you can keep the reconstituted solution in the syringe in a refrigerator for up to 3 hours before using. Do not freeze the solution, and do not wait longer than 3 hours to inject it. If more than 3 hours pass, discard the reconstituted Betaferon solution and prepare a new injection. When you use the solution, warm it up in your hands before injecting to avoid pain.
E) Making the injection: 1 - Choose an area for the injection, and make a note of it in your medication record.
2 - Use an alcohol wipe to clean the skin at the injection site. Let the skin air-dry. Throw the wipe away.
For skin disinfection use an appropriate disinfectant.
3 - Remove the cap from the needle by pulling not twisting it.
4 - Gently pinch the skin together around the disinfected injection site (to raise it up a little).
5 - Holding the syringe like a pencil or a dart, push the needle straight into the skin at a 90° angle with a quick, firm motion. Please note: Betaferon can also be administered with an auto-injector.
6 - Inject the medicine using a slow, steady push on the plunger. (Push the plunger all the way in until the syringe is empty.)
7 - Discard the syringe in the disposal unit.
F) Quick review of the process: Take out the required content for one injection; Attach vial adapter to the vial; Connect the syringe to the vial adapter; Push syringe plunger to transfer all the solvent into the vial; Turn the syringe assembly over and draw up the prescribed amount of the solution; Remove vial from syringe - you are now ready to inject.
NOTE: The injection should be administered immediately after mixing (if the injection is delayed, refrigerate the solution and inject it within 3 hours). Do not freeze.
ROTATING INJECTION SITES: You need to choose a new site for each injection to allow the area time to recover and help prevent infection. Advice on which areas to choose is given previously. It is a good idea to know where you plan to inject before you prepare your syringe. The schedule as follows will help you to vary the sites appropriately. For example, give the first injection into the right side of the abdomen, choose the left side for the second injection, then move to the right thigh for the third, and so on until all suitable areas of the body have been used. Keep a record of where and when you last gave yourself an injection. One way to do that is to note the injection site on the enclosed medication record card.
By following this schedule, you will come back to your first area (e.g. the right side of the abdomen) after 8 injections (16 days). This is called a Rotation Cycle. On our example schedule each area is split again into 6 injection sites (which adds up to 48 injection sites all together), left and right, upper, middle and lower part of each area. If you come back to an area after one Rotation Cycle, choose the most distant injection site within this area. If an area becomes sore, talk to your doctor or nurse about choosing other injection sites.
Rotation Schedule: To help you rotate the injection sites appropriately, we recommend that you keep a record of the date and location of your injection. You can use the following rotation schedule.
Work through each rotation cycle in turn. Each cycle will be 8 injections (16 days), given in area 1 through to area 8 in turn. By following this sequence, you will give each area a chance to recover before receiving another injection.
Rotation Cycle 1: Upper left section of each area.
Rotation Cycle 2: Lower right section of each area.
Rotation Cycle 3: Middle left section of each area.
Rotation Cycle 4: Upper right section of each area.
Rotation Cycle 5: Lower left section of each area.
Rotation Cycle 6: Middle right section of each area.
Area 1: Right Arm (upper back portion); 10-15 cm from shoulder, 10-15 cm from elbow.
Area 2: Left Arm (upper back portion); 10-15 cm from shoulder, 10-15 cm from elbow.
Area 3: Right Abdomen (leave about 5 cm on right side of navel).
Area 4: Left Abdomen (leave about 5 cm on left side of navel).
Area 5: Right Thigh; 10-15 cm from groin, 10-15 cm from knee.
Area 6: Left Thigh; 10-15 cm from groin, 10-15 cm from knee.
Area 7: Right Buttock.
Area 8: Left Buttock.
BETAFERON MEDICATION RECORD: Instructions for keeping track of your injection sites and dates: Select an injection site for your first injection.
Clean the injection site with an alcohol wipe and let it air-dry.
After your injection, fill in the used injection site and date on the table in your injection record.
ATC Classification
L03AB08 - interferon beta-1b ; Belongs to the class of interferons. Used as immunostimulants.
Presentation/Packing
Powd & solvent for soln for inj (vial) (sterile white to off-white powder) 0.25 mg/mL + 0.54% NaCl soln (pre-filled syringe) x 15's.
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