Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Biogen Netherlands B.V., Prins Mauritslaan 13, 1171 LP, Badhoevedorp, The Netherlands
In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
AVONEX should be administered with caution to patients with previous or current depressive disorders, in particular to those with antecedents of suicidal ideation (see section 4.3). Depression and suicidal ideation are known to occur in increased frequency in the multiple sclerosis population and in association with interferon use. Patients should be advised to immediately report any symptoms of depression and/or suicidal ideation to their prescribing physician.
Patients exhibiting depression should be monitored closely during therapy and treated appropriately. Cessation of therapy with AVONEX should be considered (see also sections 4.3 and 4.8).
AVONEX should be administered with caution to patients with a history of seizures, to those receiving treatment with anti-epileptics, particularly if their epilepsy is not adequately controlled with anti-epileptics (see sections 4.5 and 4.8).
Caution should be used and close monitoring considered when administering AVONEX to patients with severe renal and hepatic failure and to patients with severe myelosuppression.
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 AVONEX is recommended.
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 AVONEX should be considered.
Hepatic injury including elevated serum hepatic enzyme levels, hepatitis, autoimmune hepatitis and hepatic failure has been reported with interferon beta in post-marketing (see section 4.8). In some cases, these reactions have occurred in the presence of other medicinal products that have been associated with hepatic injury. The potential of additive effects from multiple medicinal products or other hepatotoxic agents (e.g. alcohol) has not been determined. Patients should be monitored for signs of hepatic injury and caution exercised when interferons are used concomitantly with other medicinal products associated with hepatic injury.
Patients with cardiac disease, such as angina, congestive heart failure or arrhythmia, should be closely monitored for worsening of their clinical condition during treatment with AVONEX. Flu-like symptoms associated with AVONEX therapy may prove stressful to patients with underlying cardiac conditions.
Laboratory abnormalities are associated with the use of interferons. Therefore, in addition to those laboratory tests normally required for monitoring patients with MS, complete and differential white blood cell counts, platelet counts, and blood chemistry, including liver function tests, are recommended during AVONEX therapy. Patients with myelosuppression may require more intensive monitoring of complete blood cell counts, with differential and platelet counts.
Patients may develop antibodies to AVONEX. The antibodies of some of those patients reduce the activity of interferon beta-1a in vitro (neutralising antibodies). Neutralising antibodies are associated with a reduction in the in vivo biological effects of AVONEX and may potentially be associated with a reduction of clinical efficacy. It is estimated that the plateau for the incidence of neutralising antibody formation is reached after 12 months of treatment. Recent clinical studies with patients treated up to three years with AVONEX suggest that approximately 5% to 8% develop neutralising antibodies.
The use of various assays to detect serum antibodies to interferons limits the ability to compare antigenicity among different products.
No formal interaction studies have been performed in humans.
The interaction of AVONEX with corticosteroids or adrenocorticotropic hormone (ACTH) has not been studied systematically. The clinical studies indicate that MS patients can receive AVONEX and corticosteroids or ACTH during relapses.
Interferons have been reported to reduce the activity of hepatic cytochrome P450-dependent enzymes in humans and animals. The effect of high-dose AVONEX administration on P450-dependent metabolism in monkeys was evaluated and no changes in liver metabolising capabilities were observed. Caution should be exercised when AVONEX 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. some classes of antiepileptics and antidepressants.
A large amount of data (more than 1000 pregnancy outcomes) from registries and post-marketing experience indicates no increased risk of major congenital anomalies after pre-conception exposure to interferon beta or such 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 section 5.3), 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 Avonex may be considered during pregnancy.
Limited information available on the transfer of interferon beta-1a into breast milk, together with the chemical/physiological characteristics of interferon beta, suggests that levels of interferon beta-1a excreted in human milk are negligible. No harmful effects on the breastfed newborn/infant are anticipated.
Avonex can be used during breast-feeding.
Fertility and developmental studies in rhesus monkeys have been carried out with a related form of interferon beta-1a. At very high doses, anovulatory and abortifacient effects in test animals were observed (see section 5.3).
No information is available on the effects of interferon beta-1a on male fertility.
No studies on the effects of AVONEX on the ability to drive and use machines have been performed. Central nervous system-related adverse reactions may have a minor influence on the ability to drive and use machines in susceptible patients (see section 4.8).
The highest incidence of adverse reactions associated with AVONEX therapy is related to flu-like symptoms. The most commonly reported flu-like symptoms are myalgia, fever, chills, sweating, asthenia, headache and nausea. Titrating AVONEX at the initiation of therapy has demonstrated a reduction in the severity and incidence of flu-like symptoms. Flu-like symptoms tend to be most prominent at the initiation of therapy and decrease in frequency with continued treatment.
Transient neurological symptoms that may mimic MS exacerbations may occur following injections. Transient episodes of hypertonia and/or severe muscular weakness that prevent voluntary movements may occur at any time during treatment. These episodes are of limited duration, temporally related to the injections and may recur after subsequent injections. In some cases these symptoms are associated with flu-like symptoms.
The frequencies of adverse reactions are expressed in patient-years, according to the following categories:
Very common (≥1/10 patient-years);
Common (≥1/100 to <1/10 patient-years);
Uncommon (≥1/1, 000 to <1/100 patient-years);
Rare (≥1/10, 000 to <1/1,000 patient-years);
Very rare (<1/10,000 patient-years);
Not known (cannot be estimated from the available data).
Patient-time is the sum of individual units of time that the patient in the study has been exposed to AVONEX before experiencing the adverse reaction. For example, 100 person-years could be observed in 100 patients who were on treatment for one year or in 200 patients who were on treatment for half a year.
Adverse reactions identified from studies (clinical trials and observational studies, with a period of follow-up ranging from two years to six years) and other adverse reactions identified through spontaneous reporting from the market, with unknown frequency, are provided in the table below.
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
common: lymphocyte count decreased, white blood cell count decreased, neutrophil count decreased, hematocrit decreased, blood potassium increased, blood urea nitrogen increased
uncommon: platelet count decreased
not known: weight decreased, weight increased, liver function tests abnormal
not known: cardiomyopathy, congestive heart failure (see section 4.4), palpitations, arrhythmia, tachycardia
not known: pancytopenia, thrombocytopenia
rare: thrombotic microangiopathy including thrombotic thrombocytopenic purpura/haemolytic uraemic syndrome*
very common: headache2
common: muscle spasticity, hypoesthesia
not known: neurological symptoms, syncope3, hypertonia, dizziness, paraesthesia, seizures, migraine
common: rhinorrhoea
rare: dyspnoea
not known: pulmonary arterial hypertension┼
common: vomiting, diarrhoea, nausea2
common: rash, sweating increased, contusion
uncommon: alopecia
not known: angioneurotic oedema, pruritus, rash vesicular, urticaria, aggravation of psoriasis
common: muscle cramp, neck pain, myalgia2, arthralgia, pain in extremity, back pain, muscle stiffness, musculoskeletal stiffness
not known: systemic lupus erythematosus, muscle weakness, arthritis
rare: nephrotic syndrome, glomerulosclerosis (see section 4.4 ‘special warnings and precautions’)
not known: hypothyroidism, hyperthyroidism
common: anorexia
not known: injection site abscess1
common: flushing
not known: vasodilatation
very common: flu-like symptoms, pyrexia2, chills2, sweating2
common: injection site pain, injection site erythema, injection site bruising, asthenia2, pain, fatigue2, malaise, night sweats
uncommon: injection site burning
not known: injection site reaction, injection site inflammation, injection site cellulitis1, injection site necrosis, injection site bleeding, chest pain
not known: anaphylactic reaction, anaphylactic shock, hypersensitivity reactions (angioedema, dyspnoea, urticaria, rash, pruritic rash)
not known: hepatic failure (see section 4.4), hepatitis, autoimmune hepatitis
uncommon: metrorrhagia, menorrhagia
common: depression (see section 4.4), insomnia
not known: suicide, psychosis, anxiety, confusion, emotional lability
* Class label for interferon beta products (see section 4.4).
┼ Class label for interferon products, see below Pulmonary arterial hypertension.
1 Injection site reactions including pain, inflammation and very rare cases of abscess or cellulitis that may require surgical intervention have been reported.
2 The frequency of occurrence is higher at the beginning of treatment.
3 A syncope episode may occur after AVONEX injection, it is normally a single episode that usually appears at the beginning of the treatment and does not recur with subsequent injections.
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.
Limited published data suggest that the safety profile in adolescents from 12 to 16 years of age receiving AVONEX 30 micrograms IM once per week is similar to that seen in adults.
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 national reporting system listed in Appendix V.
Not applicable.
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