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.
- Initiation of treatment in pregnancy.
-
- Patients with current severe depression and/or suicidal ideation.
- Patients with decompensated liver disease.
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 Extavia. Redness, swelling, discolouration, inflammation, pain, hypersensitivity, necrosis and non-specific reactions were significantly associated with 250 microgram (8.0 million IU) Extavia treatment.
Generally, dose titration is recommended at the start of treatment in order to increase tolerability to Extavia. 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 1, adverse events and laboratory abnormalities) and from the post-marketing surveillance (Table 2, frequencies - where known- based on pooled clinical trials (very common >1/10, common >1/100 to <1/10, uncommon > 1/1,000 to < 1/100, rare >1/10,000 to <1/1,000, very rare < 1/10,000)) of Extavia use. Experience with Extavia in patients with MS is limited, consequently those adverse events which occur very rarely may not yet have been observed.
Table 1: Adverse events and laboratory abnormalities with incidence rates > 10% and the respective percentages under placebo; significantly associated side effects < 10% based on reports from clinical trials
| System Organ Class Adverse Event and Laboratory Abnormalities | Single Event suggestive of Multiple Sclerosis (BENEFIT) # | Secondary Progressive Multiple Sclerosis (European Study) | Secondary Progressive Multiple Sclerosis (North American Study) | Relapsing-Remitting Multiple Sclerosis |
| Extavia 250 microgram (Placebo) n=292 (n=176) | Extavia 250 microgram (Placebo) n=360 (n=358) | Extavia 250 microgram (Placebo) n=317 (n=308) | Extavia 250 microgram (Placebo) n=124 (n=123) | |
| Infections and infestations | ||||
| Infection | 6% (3%) | 13% (11%) | 11% (10%) | 14% (13%) |
| Abscess | 0% (1%) | 4% (2%) | 4% (5%) | 1% (6%) |
| Blood and lymphatic system disorders | ||||
| Lymphocyte count decreased (<1,500/mm3) × Λ ° | 79% (45%) | 53% (28%) | 88% (68%) | 82% (67%) |
| Absolute neutrophil count decreased (<1,500/mm3) × Λ * ° | 11% (2%) | 18% (5%) | 4% (10%) | 18% (5%) |
| White blood cell count decreased (<3,000/mm3) × Λ * ° | 11% (2%) | 13% (4%) | 13% (4%) | 16% (4%) |
| Lymphadenopathy | 1% (1%) | 3% (1%) | 11% (5%) | 14% (11%) |
| Metabolism and nutrition disorders | ||||
| Blood glucose decreased (<55 mg/dl) × | 3% (5%) | 27% (27%) | 5% (3%) | 15% (13%) |
| Psychiatric disorders | ||||
| Depression | 10% (11%) | 24% (31%) | 44% (41%) | 25% (24%) |
| Anxiety | 3% (5%) | 6% (5%) | 10% (11%) | 15% (13%) |
| Nervous system disorders | ||||
| Headache Λ | 27% (17%) | 47% (41%) | 55% (46%) | 84% (77%) |
| Dizziness | 3% (4%) | 14% (14%) | 28% (26%) | 35% (28%) |
| Insomnia | 8% (4%) | 12% (8%) | 26% (25%) | 31% (33%) |
| Migraine | 2% (2%) | 4% (3%) | 5% (4%) | 12% (7%) |
| Paraesthesia | 16% (17%) | 35% (39%) | 40% (43%) | 19% (21%) |
| Eye disorders | ||||
| Conjunctivitis | 1% (1%) | 2% (3%) | 6% (6%) | 12% (10%) |
| Abnormal vision Λ | 3% (1%) | 11% (15%) | 11% (11%) | 7% (4%) |
| Ear and labyrinth disorders | ||||
| Ear pain | 0% (1%) | <1% (1%) | 6% (8%) | 16% (15%) |
| Cardiac disorders | ||||
| Palpitation * | 1% (1%) | 2% (3%) | 5% (2%) | 8% (2%) |
| Vascular disorders | ||||
| Vasodilatation | 0% (0%) | 6% (4%) | 13% (8%) | 18% (17%) |
| Hypertension ° | 2% (0%) | 4% (2%) | 9% (8%) | 7% (2%) |
| Respiratory, thoracic and mediastinal disorders | ||||
| Upper respiratory infection | 18% (19%) | 3% (2%) |
|
|
| Sinusitis | 4% (6%) | 6% (6%) | 16% (18%) | 36% (26%) |
| Cough increased | 2% (2%) | 5% (10%) | 11% (15%) | 31% (23%) |
| Dyspnoea * | 0% (0%) | 3% (2%) | 8% (6%) | 8% (2%) |
| Gastrointestinal disorders | ||||
| Diarrhoea | 4% (2%) | 7% (10%) | 21% (19%) | 35% (29%) |
| Constipation | 1% (1%) | 12% (12%) | 22% (24%) | 24% (18%) |
| Nausea | 3% (4%) | 13% (13%) | 32% (30%) | 48% (49%) |
| Vomiting Λ | 5% (1%) | 4% (6%) | 10% (12%) | 21% (19%) |
| Abdominal pain ° | 5% (3%) | 11% (6%) | 18% (16%) | 32% (24%) |
| Hepatobiliary disorders | ||||
| Alanine aminotransferase increased (SGPT> 5 times baseline) × Λ * ° | 18% (5%) | 14% (5%) | 4% (2%) | 19% (6%) |
| Aspartate aminotransferase increased (SGOT > 5 times baseline) × Λ * ° | 6% (1%) | 4% (1%) | 2% (1%) | 4% (0%) |
| Skin and subcutaneous tissue disorders | ||||
| Skin disorder | 1% (0%) | 4% (4%) | 19% (17%) | 6% (8%) |
| Rash Λ ° | 11% (3%) | 20% (12%) | 26% (20%) | 27% (32%) |
| Musculoskeletal and connective tissue disorders | ||||
| Hypertonia° | 2% (1%) | 41% (31%) | 57% (57%) | 26% (24%) |
| Myalgia * ° | 8% (8%) | 23% (9%) | 19% (29%) | 44% (28%) |
| Myasthenia | 2% (2%) | 39% (40%) | 57% (60%) | 13% (10%) |
| Back pain | 10% (7%) | 26% (24%) | 31% (32%) | 36% (37%) |
| Pain in extremity | 6% (3%) | 14% (12%) |
| 0% (0%) |
| Renal and urinary disorders | ||||
| Urinary retention | 1% (1%) | 4% (6%) | 15% (13%) |
|
| Urinary protein positive (> 1+)× | 25% (26%) | 14% (11%) | 5% (5%) | 5% (3%) |
| Urinary frequency | 1% (1%) | 6% (5%) | 12% (11%) | 3% (5%) |
| Urinary incontinence | 1% (1%) | 8% (15%) | 20% (19%) | 2% (1%) |
| Urinary urgency | 1% (1%) | 8% (7%) | 21% (17%) | 4% (2%) |
| Reproductive system and breast disorders | ||||
| Dysmenorrhoea | 2% (0%) | <1% (<1%) | 6% (5%) | 18% (11%) |
| Menstrual disorder * | 1% (2%) | 9% (13%) | 10% (8%) | 17% (8%) |
| Metrorrhagia | 2% (0%) | 12% (6%) | 10% (10%) | 15% (8%) |
| Impotence | 1% (0%) | 7% (4%) | 10% (11%) | 2% (1%) |
| General disorders and administration site conditions | ||||
| Injection site reaction (various kinds) Λ * ° § | 52% (11%) | 78% (20%) | 89% (37%) | 85% (37%) |
| Injection site necrosis * ° | 1% (0%) | 5% (0%) | 6% (0%) | 5% (0%) |
| Flu-like symptoms & Λ *° | 44% (18%) | 61% (40%) | 43% (33%) | 52% (48%) |
| Fever Λ * ° | 13% (5%) | 40% (13%) | 29% (24%) | 59% (41%) |
| Pain | 4% (4%) | 31% (25%) | 59% (59%) | 52% (48%) |
| Chest pain ° | 1% (0%) | 5% (4%) | 15% (8%) | 15% (15%) |
| Peripheral oedema | 0% (0%) | 7% (7%) | 21% (18%) | 7% (8%) |
| Asthenia * | 22% (17%) | 63% (58%) | 64% (58%) | 49% (35%) |
| Chills Λ * ° | 5% (1%) | 23% (7%) | 22% (12%) | 46% (19%) |
| Sweating * | 2% (1%) | 6% (6%) | 10% (10%) | 23% (11%) |
| Malaise * | 0% (1%) | 8% (5%) | 6% (2%) | 15% (3%) |
| × Laboratory abnormality Λ Significantly associated with Extavia treatment for patients with first event suggestive of MS, p < 0.05 * Significantly associated with Extavia treatment for RRMS, p < 0.05 ° Significantly associated with Extavia treatment for SPMS, p < 0.05 § Injection site reaction (various kinds) comprises all adverse events occurring at the injection site, i.e. the following terms: injection site haemorrhage, injection site hypersensitivity, injection site inflammation, injection site mass, injection site necrosis, injection site pain, injection site reaction, injection site oedema, and injection site atrophy & “Flu-like symptom complex†denotes flu syndrome and/or a combination of at least two AEs from fever, chills, myalgia, malaise, sweating. # During the BENEFIT follow-up study, no change in the known risk profile of Extavia was observed. | ||||
The most appropriate MedDRA term is used to describe a certain reaction and its synonyms and related conditions.
Table 2: Adverse drug reactions (ADRs) identified during post-marketing surveillance (frequencies - where known - calculated based on pooled clinical trial data N= 1093)
| System Organ Class | Very common (> 1/10) 1 | Common ( > 1/100 to < 1/10) 1 | Uncommon (> 1/1,000 to < 1/100) 1 | Rare ( > 1/10,000 to < 1/1,000) 1 | Frequency not known |
| Blood and lymphatic system disorders | Anaemia | Thrombocytopenia | Thrombotic microangiopathy including thrombotic thrombocytopenic purpura/ haemolytic uraemic syndrome3 | ||
| Immune system disorders | Anaphylactic reactions | Capillary leak syndrome in pre-existing monoclonal gammopathy2 | |||
| Endocrine disorders | Hypothyroidism | Hyperthyroidism, Thyroid disorders | |||
| Metabolism and nutrition disorders | Weight increased, Weight decreased | Blood triglycerides increased | Anorexia2 | ||
| Psychiatric disorders | Confusional state | ), Emotional lability | |||
| Nervous system disorders | Convulsion | ||||
| Cardiac disorders | Tachycardia | Cardiomyopathy2 | |||
| Respiratory, thoracic and mediastinal disorders | Bronchospasm2 | Pulmonary arterial hypertension4 | |||
| Gastrointestinal disorders | Pancreatitis | ||||
| Hepatobiliary disorders | Blood bilirubin increased | Gamma-glutamyl-transferase increased, Hepatitis | Hepatic injury (including hepatitis), Hepatic failure2 | ||
| Skin and subcutaneous tissue disorders | Urticaria, Pruritus, Alopecia | Skin discolouration | |||
| Musculoskeletal and connective tissue disorders | Arthralgia | Drug-induced lupus erythematosus | |||
| Renal and urinary disorders | Nephrotic syndrome, glomerulosclerosis 2 | ||||
| Reproductive system and breast disorders | Menorrhagia | ||||
| 1 frequencies based on pooled clinical trials (very common >1/10, common >1/100 to <1/10, uncommon > 1/1,000 to < 1/100, rare >1/10,000 to <1/1,000, very rare < 1/10,000). 2 ADRs derived only during post-marketing 3 Class label for interferon beta products. 4 Class label for interferon products, see below Pulmonary arterial hypertension. | |||||
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 the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
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 abortion, 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.
Extavia 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.
- 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.
Pharmacotherapeutic group: Cytokines, Interferons,
ATC Code: L03 AB 08
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 internalisation 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 Extavia on the cardiovascular system, respiratory system and the function of endocrine organs.
Clinical efficacy and safety
RR-MS
One controlled clinical trial with Extavia in patients with relapsing-remitting multiple sclerosis and able to walk unaided (baseline EDSS 0 to 5.5) was performed. Patients receiving Extavia 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 Extavia 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 Extavia 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 Extavia) 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 Extavia) in patients who received Extavia. 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 Extavia 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 Extavia 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 Extavia in patients with relapses or pronounced EDSS progression, 8.0 million IU Extavia 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 Extavia showed a reduction in frequency (30%) of clinical relapses. There is no evidence of Extavia having an effect on the duration of relapses.
Single clinical event suggestive of MS
One controlled clinical trial with Extavia 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 Extavia to evaluate the effects of immediate versus delayed start of Extavia treatment, comparing patients initially randomized to Extavia ("immediate treatment group") or to placebo ("delayed treatment group"). Patients and investigators remained blinded to the initial treatment allocation.
Table 3: Primary efficacy results of the BENEFIT and the BENEFIT Follow-up study
| Year 2 results Placebo-controlled phase | Year 3 results Open-label follow-up | Year 5 results Open-label follow-up | ||||
| Extavia 250 mcg n=292 | Placebo n=176 | Immediate Extavia 250 mcg n=292 | Delayed Extavia 250 mcg n=176 | Immediate Extavia 250 mcg n=292 | Delayed Extavia 250 mcg n=176 | |
| Number of patients completed the trial phase | 271 (93%) | 166 (94%) | 249 (85%) | 143 (81%) | 235 (80%) | 123 (70%) |
| Primary efficacy variables | ||||||
| Time to CDMS | ||||||
| Kaplan-Meier estimates | 28% | 45% | 37% | 51% | 46% | 57% |
| Risk reduction Hazard ratio with 95% confidence interval log-rank test | 47% versus placebo HR = 0.53 [0.39, 0.73] p < 0.0001 Extavia prolonged the time to CDMS by 363 days, from 255 days in the placebo group to 618 days in the Extavia group (based on the 25th percentiles) | 41% versus delayed Extavia HR = 0.59 [0.42, 0.83] p = 0.0011 | 37% versus delayed Extavia HR = 0.63 [0.48, 0.83] p = 0.0027 | |||
| Time to McDonald MS | ||||||
| Kaplan-Meier estimates | 69% | 85% | No primary endpoint | No primary endpoint | ||
| Risk reduction Hazard ratio with 95% confidence interval log-rank test | 43% versus placebo HR = 0.57 [0.46, 0.71] p < 0.00001 | |||||
| Time to confirmed EDSS progression | ||||||
| Kaplan-Meier estimates | No primary endpoint | 16% | 24% | 25% | 29% | |
| Risk reduction Hazard ratio with 95% confidence interval log-rank test | 40% versus delayed Extavia HR = 0.60 [0.39, 0.92] p = 0.022 | 24% versus delayed Extavia HR = 0.76 [0.52, 1.11] p=0.177 | ||||
In the placebo-controlled phase, Extavia 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 3).
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 Extavia was well accepted as indicated by a high rate of trial completion (93% in the Extavia group). To increase tolerability of Extavia, 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 3) even though the majority of patients from the placebo-group was treated with Extavia 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 3, 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 Extavia 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
Extavia 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.
Extavia 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.
Extavia 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 approxi-mately 50%.
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 syndrome with shock-like symptoms and fatal outcome.
Gastrointestinal disorders
In rare cases, pancreatitis was observed with Extavia use, often associated with hypertriglyceridaemia.
Nervous system disorders
Extavia should be administered with caution to patients with previous or current depressive disorders, in particular to those with antecedents of suicidal ideation.8).
Extavia 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.
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 test
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 Extavia 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 Extavia during clinical trials. As for other beta interferons, severe hepatic injury, including cases of hepatic failure, has been reported rarely in patients treated with Extavia. 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. metastasising 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 Extavia 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 normalisation 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 Extavia should be considered.
Cardiac disorders
Extavia 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 Extavia.
While Extavia 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 Extavia therapy.
Rare cases of cardiomyopathy have been reported. If this occurs and a relationship to Extavia 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 Extavia 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, Extavia should be discontinued and appropriate medical intervention instituted.
Injection site necrosis has been reported in patients using Extavia. 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 Extavia.
If the patient has multiple lesions Extavia should be discontinued until healing has occurred. Patients with single lesions may continue on Extavia provided the necrosis is not too extensive, as some patients have experienced healing of injection site necrosis whilst on Extavia.
To minimise 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 Extavia.
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 Extavia; 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 Extavia 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 Extavia 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.
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 Extavia might influence the ability to drive and use machines in susceptible patients.
The treatment with Extavia should be initiated under the supervision of a physician experienced in the treatment of the disease.
Posology
Adults
The recommended dose of Extavia is 250 microgram (8.0 million IU), contained in 1 ml of the reconstituted solution , 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 Extavia 8.0 million IU subcutaneously every other day is similar to that seen in adults. There is no information on the use of Extavia in children under 12 years of age. Therefore Extavia 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 A). 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.
A titration pack composed of four triple packs is available for the titration period and the patient's initial treatment with Extavia. This package meets the patient's needs for the first 12 injections. The triple packs are highlighted in different colours.
Table A: Schedule for dose titration*
| treatment day | dose | volume |
| 1, 3, 5 | 62.5 microgram | 0.25 ml |
| 7, 9, 11 | 125 microgram | 0.5 ml |
| 13, 15, 17 | 187.5 microgram | 0.75 ml |
| 19, 21, 23 et seq. | 250 microgram | 1.0 ml |
* The titration period may be adjusted, if any significant adverse reaction occurs.
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 two years. The available data for the additional three years are consistent with sustained treatment efficacy of Extavia 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 Extavia therapy, treatment with Extavia should be stopped.
Method of administration
For subcutaneous injection.
Reconstitution:
To reconstitute lyophilised interferon beta-1b for injection, connect the vial adapter 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 Extavia 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 Extavia.
Remove the vial with the vial adapter from the pre-filled syringe before injection.
Extavia 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.
