Adverse reactions : תופעות לוואי

4.8      Undesirable effects

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, infection, necrosis and non- specific reactions were significantly associated with 250 microgram (8.0 million IU) Betaferon treatment.
The most serious adverse reactions reported include thrombotic microangiopathy (TMA) and haemolytic anaemia (HA).

Generally, dose titration is recommended at the start of treatment in order to increase tolerability to Betaferon (see section 4.2). 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 and from the post- marketing surveillance (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 Betaferon use.


The most appropriate MedDRA term is used to describe a certain reaction and its synonyms and related conditions.


Table 1: Adverse drug reactions (ADRs) based on reports from clinical trials and identified during post-marketing surveillance (frequencies - where known - calculated based on pooled clinical trial data)

System Organ        Very common Common                  Uncommon             Rare                 Frequency Class               (≥ 1/10)    ( ≥ 1/100 to            (≥ 1/1,000 to        ( ≥ 1/10,000 to      not known < 1/10)                 < 1/100)             < 1/1,000)

Blood and            Lymphocyte      Lymphadenopathy, Thrombocytopenia Thrombotic                 Haemolytic lymphatic           count decreased Anaemia                            microangiopathyd           anaemiaa, d system              (< 1500/mm3) e,                                    including disorders           White blood cell                                   thrombotic count decreased                                    thrombocytopenic
(< 3000/mm3) e,                                    purpura/
Absolute                                           haemolytic neutrophil count                                   uraemic decreased (<                                       syndromeb
1500/mm3)e
Immune system                                                          Anaphylactic               Capillary leak disorders                                                              reactions                  syndrome in pre-existing monoclonal gammopathya
Endocrine                            Hypothyroidism                          Hyperthyroidism, disorders                                                                    Thyroid disorders Metabolism and                       Weight            Blood triglycerides nutrition                            increased,        increased             Anorexiaa disorders                            Weight decreased
Psychiatric                          Confusional state Suicide attempt                            Depression, disorders                                              (see also section                          Anxiety 4.4),
Emotional lability
System Organ       Very common Common                     Uncommon                  Rare               Frequency Class              (≥ 1/10)    ( ≥ 1/100 to               (≥ 1/1,000 to             ( ≥ 1/10,000 to    not known < 1/10)                    < 1/100)                  < 1/1,000)

Nervous system Headache,                                  Convulsion                                   Dizziness disorders      Insomnia

Cardiac                                Tachycardia                                  Cardiomyopathya    Palpitation disorders

Vascular                               Hypertension                                                    Vasodilatation disorders


Respiratory,                           Dyspnoea                                     Bronchospasma      Pulmonary thoracic and                                                                                           arterial mediastinal                                                                                            hypertensionc disorders
Gastrointestinal   Abdominal pain                                                   Pancreatitis       Nausea, disorders                                                                                              Vomiting, Diarrhoea

Hepatobiliary      Alanine             Aspartate          Gamma-glutamyl-           Hepatic injury, disorders          aminotransferase    aminotransferase   transferase               Hepatic failurea increased           increased          increased,
(ALAT > 5           (ASAT > 5 times    Hepatitis times baseline)e    baseline)e,
Blood bilirubin increased
Skin and         Rash,                 Urticaria,         Skin discolouration subcutaneous     Skin disorder         Pruritus,
tissue disorders                       Alopecia

Musculoskeletal, Myalgia,                                                                              Drug-induced and connective Hypertonia                                                                              lupus tissue disorders Arthralgia                                                                            erythematosus Renal and          Urinary                                Nephrotic urinary            urgency                                syndrome,
disorders                                                 Glomerulosclerosis (see section 4.4 ) a, b
Reproductive                           Menorrhagia                                                     Menstrual system and                             Impotence,                                                      disorder breast disorders                       Metrorrhagia

General            Injection site      Injection site                                                  Sweating disorders and      reaction (various   necrosis,
administration     kindsf),            Chest pain,
site conditions    Flu-like            Malaise symptoms
(complex g),
Pain,
Fever,
Chills,
Peripheral oedema,
Asthenia
System Organ           Very common Common                    Uncommon               Rare                  Frequency Class                  (≥ 1/10)    ( ≥ 1/100 to              (≥ 1/1,000 to          ( ≥ 1/10,000 to       not known < 1/10)                   < 1/100)               < 1/1,000)
 a
ADRs derived only during post-marketing b
Class label for interferon beta products (see section 4.4).
c
Class label for interferon products, see below Pulmonary arterial hypertension.
d   life-threatening and/or fatal cases have been reported.
e laboratory abnormality f
‘Injection site reaction (various kinds)’ comprises all adverse events occurring at the injection site (except injection site necrosis), e.g. the following terms: injection site atrophy, injection site edema, injection site haemorrhage, injection site hypersensitivity, injection site infection, injection site inflammation, injection site mass, injection site pain and injection site reaction.
g
Flu-like symptom complex’ denotes flu syndrome and/or a combination of at least two Adverse Events from fever, chills, myalgia, malaise, sweating.


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.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form: https://sideeffects.health.gov.il/