Adverse reactions : תופעות לוואי

4.8     Undesirable effects
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.

Investigations
 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



Cardiac disorders
 not known                                cardiomyopathy, congestive heart failure (see section 4.4), palpitations, arrhythmia,
tachycardia

Blood and lymphatic system disorders
 not known                                pancytopenia, thrombocytopenia  rare                                     thrombotic microangiopathy including thrombotic thrombocytopenic purpura/haemolytic uraemic syndrome.*

Nervous system disorders
 very common                              headache2 common                                   muscle spasticity, hypoesthesia  not known                                neurological symptoms, syncope3, hypertonia, dizziness, paraesthesia,
seizures, migraine

Respiratory, thoracic and mediastinal disorders
 common                                   rhinorrhoea rare                                     dyspnoea
 not known                                pulmonary arterial hypertension┼ 
Gastrointestinal disorders
2 common                                   vomiting, diarrhoea, nausea

Skin and subcutaneous tissue disorders common                                   rash, sweating increased, contusion  uncommon                                 alopecia
 not known                                angioneurotic oedema, pruritus, rash vesicular, urticaria, aggravation of psoriasis

Musculoskeletal and connective tissue disorders
 common                                   muscle cramp, neck pain, myalgia2, arthralgia, pain in extremity, back pain,
muscle stiffness, musculoskeletal stiffness
 not known                                systemic lupus erythematosus, muscle weakness, arthritis


Renal and urinary disorders nephrotic syndrome, glomerulosclerosis (see rare                                        section 4.4 special warnings and precautions ) 
Endocrine disorders
 not known                                   hypothyroidism, hyperthyroidism 
Metabolism and nutrition disorders
 common                                      anorexia
Infections and infestations
 not known                                   injection site abscess1

Vascular disorders common                                      flushing
 not known                                   vasodilatation

General disorders and administration site conditions very common                                 flu-like symptoms, pyrexia2, chills2, sweating2  injection site pain, injection site erythema,
common                                      injection site bruising, asthenia2, pain, fatigue2, malaise, night sweats
 injection site burning uncommon injection site reaction, injection site not known                                   inflammation, injection site cellulitis1, injection site necrosis, injection site bleeding,
chest pain

Immune system disorders
 not known                                   anaphylactic reaction, anaphylactic shock, hypersensitivity reactions (angioedema,
dyspnoea, urticaria, rash, pruritic rash)

Hepatobiliary disorders
 not known                                   hepatic failure (see section 4.4), hepatitis, autoimmune hepatitis

Reproductive system and breast disorders
 uncommon                                    metrorrhagia, menorrhagia 


Psychiatric disorders
 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.



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.

Paediatric population

Paediatric population: 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 of suspected adverse reactions

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