What is the active ingredient in BETAFERON 250MCG/ML Powder and solvent for solution for injection?

Interferonum beta-1b (Interferonum beta-1b)

Is BETAFERON 250MCG/ML Powder and solvent for solution for injection OTC or prescription only?

BETAFERON 250MCG/ML Powder and solvent for solution for injection requires a doctor's prescription.

What are the side effects of BETAFERON 250MCG/ML Powder and solvent for solution for injection?

Summary of the safety profile Adverse reactions are common at the beginning of treatment but generally diminish with continued therapy. The most commonly observed adverse reactions are the 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 were common following administration of Betaferon. Redness, swellin

Does BETAFERON 250MCG/ML Powder and solvent for solution for injection interact with other medications?

No interaction studies have been performed. The effect of administering 250 micrograms (8.0 million IU) of Betaferon every other day on drug metabolism in patients with multiple sclerosis is unknown. Corticosteroid or ACTH treatment of relapses for periods of up to 28 days has been well tolerated in patients treated with Betaferon. Due to the lack of clinical experience in patients with multiple sclerosis, concurrent use of Betaferon with immunomodulators other than corticoster

Can BETAFERON 250MCG/ML Powder and solvent for solution for injection be used during pregnancy?

Pregnancy A large amount of data (more than 1,000 pregnancy outcomes) from registries monitoring interferon beta-containing products, national registries and post-marketing experience does not suggest an increased risk of major congenital anomalies after exposure to interferon beta before conception or during the first trimester of pregnancy. However, the duration of exposure during the first trimester is uncertain, as data were collected at a time when the use of interferon be

BETAFERON 250MCG/ML Powder and solvent for solution for injection

This information is for educational purposes only. It is not intended as medical advice. Always consult a qualified healthcare professional.

Pharmacotherapeutic group: cytokines, interferons ATC code: L03AB08 Mechanism of action Interferons belong to the group of cytokines, which are naturally occurring proteins.‍‍‍‍‍‍‍‍‍‍‍‍‍ Interferons have molecular weights ranging from 15,000 to 21,000 daltons. Three major groups of interferons are known: alpha, beta and gamma. Interferon alpha, interferon beta and interferon gamma have overlapping yet distinct biological activities. Interferon beta-1b is species-specific, and therefore the most relevant pharmacological information on interferon beta-1b is derived from studies in human cell cultures or in vivo studies in humans. Interferon beta-1b has both antiviral and immunoregulatory activities. The mechanism of action of interferon beta-1b in multiple sclerosis is not yet precisely known. However, it is established that the biological response-modifying properties of interferon beta-1b in multiple sclerosis are mediated through its interaction 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 considered to be mediators of the biological actions of interferon beta-1b. A number of these products have been measured in the serum and in the cellular fraction of blood collected from patients treated with interferon beta-1b. Interferon beta-1b reduces the binding affinity and enhances the internalization and degradation of interferon gamma receptors. Interferon beta-1b also enhances the suppressor activity of peripheral blood mononuclear cells. No specific investigations have been conducted regarding the effect of Betaferon on the cardiovascular system, respiratory system and endocrine organ function. Clinical efficacy and safety RR-MS One controlled clinical trial was conducted in patients with relapsing-remitting multiple sclerosis who were ambulatory (baseline EDSS 0–5.5). Patients receiving Betaferon showed a reduction in the frequency (30%) and severity of clinical relapses, as well as in the number of MS-related hospitalisations. There was also a prolongation of the relapse-free interval. There is no evidence of an effect of Betaferon on the duration of relapses or on symptoms between relapses, and no significant effect was observed on the progression of disease in relapsing-remitting MS. SP-MS Two clinical trials were conducted in 1,657 patients with secondary progressive MS (baseline EDSS 3–6.5, i.e. patients were ambulatory). Patients with mild disease and patients who were non-ambulatory were not studied. The two trials yielded inconsistent results for the primary endpoint of confirmed disease progression represented by time to delay in disability progression: The first of these two studies demonstrated a statistically significant delay in progression (Hazard Ratio = 0.69, 95% confidence interval (0.55, 0.86), p=0.0010, corresponding to a 31% reduction in risk attributed to Betaferon) and a delay in progression to wheelchair-bound disability (Hazard Ratio = 0.61, 95% confidence interval (0.44, 0.85), p=0.0036, corresponding to a 39% reduction in risk attributed to Betaferon) in patients treated with Betaferon. This effect was sustained over the observation period of up to 33 months. The effect was observed across all levels of assessed disability and was independent of relapse activity. In the second study evaluating Betaferon treatment in secondary progressive MS, no delay in time to disability progression was observed. There is evidence that the patients enrolled in this study had overall less active disease than patients with secondary progressive MS in the first study. In retrospective meta-analyses including data from both studies, an overall treatment effect was found that was statistically significant (p=0.0076, 8.0 million IU Betaferon versus all placebo-treated patients). Retrospective subgroup analyses showed that a treatment effect on disability progression is most likely in patients with active disease prior to initiation of treatment (Hazard Ratio = 0.72, 95% confidence interval (0.59, 0.88), p=0.0011, corresponding to a 28% reduction in risk attributed to Betaferon in patients with relapses or pronounced EDSS progression, 8.0 million IU Betaferon versus all placebo-treated patients). From these retrospective subgroup analyses it is apparent that relapses as well as pronounced EDSS progression (EDSS >1 point or >0.5 points for EDSS ≥6 in the preceding two years) may help identify patients with active disease. In both studies, patients with secondary progressive MS treated with Betaferon showed a reduction in the frequency of clinical relapses (30%). There is no evidence that Betaferon has an effect on the duration of relapses. Single clinical event suggestive of MS One controlled clinical trial of Betaferon was conducted in patients with a single clinical event suggestive of multiple sclerosis supported by MRI findings (at least two clinically silent lesions on T2-weighted images). The study included patients with monofocal or multifocal onset of disease (i.e. patients with clinical evidence of a single lesion or at least two lesions of the central nervous system). Other diseases that could better explain the patient's symptoms 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 two years or until the patient developed clinically definite multiple sclerosis (CDMS), whichever came first. Following the placebo-controlled phase, patients entered the pre-planned follow-up phase with Betaferon to evaluate the effects of immediate versus delayed Betaferon treatment, comparing patients initially randomised to the Betaferon group ("immediate treatment group") or placebo ("delayed treatment group"). The original treatment assignment remained blinded to patients and investigators. Table 2: Primary efficacy results from the BENEFIT study and the BENEFIT follow-up phase. Placebo-controlled phase, results at 2 years Open-label follow-up phase, results at 3 years Open-label follow-up phase, results at 5 years Betaferon 250 mcg n=292 Placebo n=176 Immediate treatment with Betaferon 250 mcg n=292 Delayed treatment with Betaferon 250 mcg n=176 Immediate treatment with Betaferon 250 mcg n=292 Delayed treatment with Betaferon 250 mcg n=176 Number of patients who completed the study phase 271 (93%) 166 (94%) 249 (85%) 143 (81%) 235 (80%) 123 (70%) Primary efficacy variables Time to CDMS Kaplan-Meier estimate 28% 45% 37% 51% 46% 57% Risk reduction 47% versus placebo 41% versus delayed Betaferon treatment 37% versus delayed Betaferon treatment Hazard ratio with 95% confidence interval HR = 0.53 [0.39; 0.73] p < 0.0001 HR = 0.59 [0.42; 0.83] p = 0.0011 HR = 0.63 [0.48; 0.83] p = 0.0027 log-rank test Betaferon prolonged the time to CDMS by 363 days, from 255 days in the placebo group to 618 days in the Betaferon group (based on 25th percentiles) Time to MS according to McDonald criteria Kaplan-Meier estimate 69% 85% No primary endpoint No primary endpoint Risk reduction 43% versus placebo Hazard ratio with 95% confidence interval HR = 0.57 [0.46; 0.71] p < 0.00001 log-rank test Time to confirmed EDSS progression Kaplan-Meier estimate No primary endpoint 16% 24% 25% 29% Risk reduction 40% versus delayed Betaferon treatment 24% versus delayed Betaferon treatment Hazard ratio with 95% confidence interval HR = 0.60 [0.39; 0.92] HR = 0.76 [0.52; 1.11] p = 0.022 p = 0.177 log-rank test In the placebo-controlled phase, Betaferon delayed progression from the first clinical event to CDMS in a statistically significant and clinically meaningful manner. The robustness of the treatment effect was also demonstrated by the delay in progression to MS according to McDonald criteria (Table 2). Subgroup analyses by baseline factors demonstrated efficacy on progression to CDMS across all evaluated subgroups. The risk of progression to CDMS within two years was higher in patients with monofocal disease with more than 9 T2-weighted lesions or Gd-enhancing findings on baseline brain MRI. In patients with multifocal disease, the risk of CDMS was independent of baseline MRI findings, indicating a high risk of CDMS due to dissemination of disease established by clinical findings. A definition of high-risk patients is not currently well established, although a rather conservative approach considers high-risk patients as those with at least nine hyperintense T2-weighted lesions on the initial scan and at least one new T2-weighted lesion or one new Gd-enhancing lesion on a subsequent scan performed no earlier than 1 month after the initial scan. In any case, treatment should only be considered for patients classified as high risk. Betaferon treatment was very well tolerated, as indicated by the high completion rate (93% in the Betaferon group). Dose titration was used at the start of therapy and non-steroidal anti-inflammatory drugs were administered to improve tolerability of Betaferon. In addition, the majority of patients in the study used an autoinjector. In the open-label follow-up phase, the treatment effect on CDMS was still apparent at 3 and 5 years (Table 2), although the majority of patients in the placebo group had been treated with Betaferon from at least the second year onwards. EDSS progression (confirmed increase in EDSS of at least one point compared with baseline) was lower in the immediate treatment group (Table 2, significant effect at 3 years, no significant effect at 5 years). The majority of patients in both treatment groups did not experience confirmed disability progression over the 5-year period. The robustness of the treatment effect with respect to this parameter could not be demonstrated in the immediate treatment group. No benefit of immediate Betaferon treatment was observed on quality of life (measured using FAMS — Functional Assessment of MS: Treatment Outcomes Index). RR-MS, SP-MS and single clinical event suggestive of MS Across all multiple sclerosis studies, Betaferon had an effect on disease activity (acute inflammation in the central nervous system and permanent tissue damage) as measured by magnetic resonance imaging (MRI). The relationship between MRI-measured MS activity and clinical outcome is not yet fully understood.

⚠️ Warnings

Traceability In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded. Immune system disorders 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 a fatal outcome. Gastrointestinal disorders In rare cases, pancreatitis has been observed with the use of Betaferon, often associated with hypertriglyceridaemia. Nervous system disorders Betaferon should be administered with caution to patients with a current or past history of depressive disorders, in particular to those with prior suicidal ideation (see section 4.8). Betaferon should be administered with caution to patients with a history of seizures and to those receiving anti-epileptic therapy, especially if their epilepsy is not adequately controlled with anti-epileptics (see sections 4.8). This product contains human albumin, and therefore carries a potential risk of transmission of viral diseases.‍‍‍‍‍‍‍‍‍‍‍‍‍ A risk of transmission of Creutzfeldt-Jakob disease (CJD) cannot be excluded. Laboratory tests Regular thyroid function testing is recommended in patients with a history of thyroid dysfunction or when clinically indicated. In addition to the laboratory tests normally required for monitoring patients with multiple sclerosis, it is recommended that complete blood counts with differential white blood cell counts, platelet counts and blood chemistry, including liver function tests (e.g. AST (SGOT), ALT (SGPT) and gamma-GT), be performed before starting Betaferon therapy and at regular intervals after initiation of therapy, then periodically thereafter in the absence of clinical symptoms. Patients with anaemia, thrombocytopenia, leukopenia (alone or in any combination) require more intensive monitoring of complete blood counts with differential white blood cell counts and platelet counts. Patients who develop neutropenia should be monitored more closely for fever or signs of infection. Thrombocytopenia with a marked decrease in platelet count has been reported. Hepatobiliary disorders In clinical trials, asymptomatic elevation of serum transaminases occurred very commonly in patients treated with Betaferon; in the majority of cases this was mild and transient. As with other interferon betas, severe liver injury, including cases of hepatic failure, has been rarely reported in patients treated with Betaferon. The most serious cases occurred frequently in patients exposed to other medicinal products or substances known to be associated with hepatotoxicity, or in the presence of comorbid conditions (e.g. metastatic malignant disease, severe infection and sepsis, alcohol abuse). Patients should be monitored for signs of liver injury. Elevation of serum transaminases should prompt careful monitoring and investigation. Discontinuation of Betaferon should be considered if levels are significantly elevated or if associated with clinical symptoms such as jaundice. In the absence of clinical signs of liver injury, resumption of therapy may be considered once hepatic enzyme levels have normalised, with appropriate ongoing monitoring of hepatic function. Renal and urinary disorders Caution should be exercised and close monitoring performed when administering interferon beta to patients with severe renal impairment. 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-containing products. Events were reported at various time points during treatment and may occur after several years of interferon beta therapy. Regular monitoring for 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 Betaferon treatment should be considered. Cardiac disorders Caution should also be exercised when administering Betaferon to patients with pre-existing cardiac disease. Patients with significant pre-existing cardiac conditions, such as congestive heart failure, coronary artery disease or arrhythmia, should be monitored for potential worsening of their cardiac function, particularly at the start of Betaferon treatment. While Betaferon has no known direct cardiac toxicity, symptoms of the flu-like syndrome associated with beta interferons may be a stressor in patients with pre-existing significant cardiac conditions. Post-marketing experience has very rarely described cases of worsening cardiac function in patients with pre-existing cardiac disease temporally associated with the initiation of Betaferon treatment. Cardiomyopathy has been reported rarely; if this occurs and a relationship to Betaferon is suspected, treatment should be discontinued. Thrombotic microangiopathy (TMA) and haemolytic anaemia (HA) Cases of thrombotic microangiopathy manifesting as thrombotic thrombocytopenic purpura (TTP) or haemolytic uraemic syndrome (HUS), including fatal cases, have been reported with interferon beta-containing products. 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 count, elevated serum lactate dehydrogenase (LDH) due to haemolysis, and schistocytes (fragmented red blood cells) on blood smear. Therefore, if clinical features of TMA are observed, further testing of platelet counts, serum LDH, blood smears and renal function is recommended. Cases of HA not related to TMA, including immune HA, have also been reported with interferon beta-containing products. Life-threatening and fatal cases have been reported. Cases of TMA and/or HA have been reported at various time points during treatment and may occur several weeks to several years after starting interferon beta therapy. If TMA and/or HA is diagnosed and a relationship to Betaferon is suspected, treatment must be initiated promptly (plasma exchange should be considered in the case of TMA) and immediate discontinuation of Betaferon treatment is recommended. Hypersensitivity reactions Severe hypersensitivity reactions may occur (rare but severe acute reactions such as bronchospasm, anaphylaxis and urticaria). If reactions are severe, Betaferon treatment should be discontinued and appropriate medical intervention initiated. Injection site reactions Injection site reactions, including infection and injection site necrosis, have been reported in patients treated with Betaferon (see section 4.8). Injection site necrosis may be extensive and may involve muscle fascia as well as fatty tissue, potentially causing scar formation. Debridement may be necessary in some cases, and less commonly skin grafting may be required, with healing taking up to 6 months. If a patient experiences any break in the skin that may be associated with swelling or drainage of fluid from the injection site, the patient should be advised to consult their physician before continuing Betaferon injections. If the patient has multiple lesions, Betaferon treatment should be discontinued until healing occurs. A patient with a single lesion may continue Betaferon treatment provided the necrosis is not too extensive, as some patients have experienced healing of injection site necrosis while continuing Betaferon treatment. To minimise the risk of injection site infection and necrosis, patients should be advised to: use aseptic injection technique, rotate injection sites with each dose. The incidence of injection site reactions may be reduced with the use of an autoinjector. In the pivotal study in 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 necrosis were observed less frequently in this study compared to other pivotal studies. Self-injection procedure should be checked regularly, particularly 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 to monitor the development of antibodies to Betaferon. In various controlled clinical trials in relapsing-remitting multiple sclerosis and secondary progressive multiple sclerosis, 23% to 41% of patients developed serum neutralising activity against interferon beta-1b, confirmed by at least two consecutive positive titres; 43% to 55% of these patients subsequently converted to a stable antibody-negative status (based on two consecutive negative titres) during the subsequent follow-up period of the respective studies. The development of neutralising activity in these studies was associated with reduced clinical efficacy only with regard to relapse rate. Some analyses suggest that this effect may be greater in patients with higher titres 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 patients treated immediately with Betaferon; of these, 60% (53) reverted to antibody-negative status according to the last available assessment over the 5-year period. During this period, the development of neutralising activity was associated with a significant increase in new active lesions and T2 lesion volume as measured by MRI. However, this did not appear to be associated with reduced clinical efficacy (as measured by time to CDMS, time to confirmed EDSS progression, and relapse rate). No new adverse reactions have been associated with the development of neutralising activity. Cross-reactivity between Betaferon and natural interferon beta has been demonstrated in vitro. However, this has not been investigated in vivo and its clinical significance is uncertain. Data from patients who developed neutralising activity and who completed Betaferon treatment are limited and inconclusive. The decision to continue or discontinue therapy should be based on all aspects of the patient's disease status rather than on the status of neutralising activity alone. Excipients This medicinal product contains less than 1 mmol (23 mg) sodium per ml, that is to say essentially 'sodium-free'.

BETAFERON 250MCG/ML Powder and solvent for solution for injection

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