Adverse reactions : תופעות לוואי

4.8    Undesirable effects

Summary of safety profile

The most common adverse drug reactions (ADR) (at a higher incidence than placebo) for Plegridy 125 micrograms subcutaneously every 2 weeks were injection site erythema, influenza like illness, pyrexia, headache, myalgia, chills, injection site pain, asthenia, injection site pruritus, and arthralgia.
The most commonly reported adverse reaction leading to discontinuation in patients treated with Plegridy 125 micrograms subcutaneously every 2 weeks was influenza-like illness (<1%).

Tabulated list of adverse reactions

In clinical studies, a total of 1468 patients received Plegridy for up to 278 weeks with an overall exposure equivalent of 4217 person-years. 1285 patients received at least 1 year, 1124 patients have received at least 2 years, 947 patients received at least 3 years, and 658 patients received at least 4 years of treatment with
Plegridy. The experience in the randomised, uncontrolled phase (year 2) of the ADVANCE study and in the extension study ATTAIN (treatment received for up to 4 years) was consistent with the experience in the 1 year placebo-controlled phase of the ADVANCE study.

Table 2 summarizes ADRs (incidence above placebo and with a reasonable possibility of causality) from 512 patients treated with Plegridy 125 micrograms subcutaneously every 2 weeks and 500 patients who received placebo for up to 48 weeks and post marketing data.

The ADRs are presented as MedDRA preferred terms under the MedDRA System Organ Class. The incidence of the adverse reactions below are expressed according to the following categories: -     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)
-     Not known (cannot be estimated from the available data)

Table 2 Tabulated summary of adverse drug reactions
MedDRA System Organ Class       Adverse reaction                           Frequency category Blood and lymphatic system      Thrombocytopenia                           Uncommon disorders
Thrombotic microangiopathy                 Rare including thrombotic thrombocytopenic purpura/haemolytic uraemic syndrome*
Immune system disorders         Angioedema                                 Uncommon Hypersensitivity
Anaphylaxis1                               Not Known
Psychiatric disorders           Depression                                 Common Nervous system disorders        Headache                                   Very common Seizure                                    Uncommon
Respiratory, thoracic and       Pulmonary arterial hypertension┼           Not known mediastinal disorders
Gastrointestinal disorders      Nausea                                     Common Vomiting
Skin and subcutaneous tissue    Alopecia$                                  Common disorders                       Pruritus
Urticaria                                  Uncommon
Musculoskeletal and connective  Myalgia                                    Very common tissue disorders                Arthralgia
Renal and urinary disorders     Nephrotic syndrome,                        Rare glomerulosclerosis



MedDRA System Organ Class             Adverse reaction                      Frequency category General disorders and                                                       Very common administration site conditions        Influenza like illness
Pyrexia
Chills
Injection site erythema
Injection site pain
Injection site pruritus
Asthenia
Hyperthermia                          Common
Injection site inflammation
Pain
Injection site haematoma
Injection site swelling
Injection site oedema
Injection site rash
Injection site warmth
Injection site discolouration
Injection site necrosis               Rare
Investigations                        Body temperature increased            Common Alanine aminotransferase increased
Aspartate aminotransferase increased
Gamma-glutamyl-transferase increased
Haemoglobin decreased
White blood cell count decreased
Platelet count decreased              Uncommon


*Class label for interferon beta products (see section 4.4).
┼
Class label for interferon products, see below Pulmonary arterial hypertension.
$
Class label for interferon products
1
Adverse reactions derived only during post marketing experience

Description of selected adverse reactions

Flu-like symptoms
Influenza-like illness was experienced by 47% of patients receiving Plegridy 125 micrograms every 2 weeks and 13% of patients receiving placebo. The incidence of flu-like symptoms (e.g. influenza-like illness, chills, hyperpyrexia, musculoskeletal pain, myalgia, pain, pyrexia) was highest at the initiation of treatment and generally decreased over the first 6 months. Of the patients who reported flu-like symptoms 90% reported them as mild or moderate in severity. None were considered serious in nature. Less than 1% of patients who received Plegridy during the placebo controlled phase of the ADVANCE study discontinued treatment due to flu-like symptoms. An open-label study in patients switching from interferon beta therapy to Plegridy evaluated the onset and duration of prophylactically treated flu-like symptoms. In patients experiencing flu- like symptoms, the median time to onset was 10 hours (interquartile range, 7 to 16 hours) after injection, and the median duration was 17 hours (interquartile range, 12 to 22 hours).

Injection site reactions (ISRs)

Injection site reactions (e.g. injection site erythema, pain, pruritus, or oedema) were reported by 66% of patients who received Plegridy 125 micrograms every 2 weeks compared to 11% of patients receiving placebo. Injection site erythema was the most commonly reported injection site reaction. Of the patients who experienced injection site reactions 95% reported them as mild or moderate in severity. One patient out of 1468 patients who received Plegridy in clinical studies experienced an injection site necrosis which resolved with standard medical treatment.

Hepatic transaminase abnormalities

The incidence of hepatic transaminase increases was greater in patients receiving Plegridy compared to placebo. The majority of enzyme elevations were <3 times the upper limit of normal (ULN). Elevations of alanine aminotransferase and aspartate aminotransferase (>5 times ULN), were reported in 1% and <1% of placebo-treated patients and 2% and <1% of patients treated with Plegridy respectively. Elevations of serum hepatic transaminases combined with elevated bilirubin were observed in two patients who had pre-existing liver test abnormalities prior to receiving Plegridy in the clinical trials. Both cases resolved following discontinuation of Plegridy.

Haematological disorders

Decreases in white blood cell (WBC) counts of <3.0 x 109/L were observed in 7% of patients receiving Plegridy and in 1% receiving placebo. Mean white blood cell counts remained within normal limits in patients treated with Plegridy. Decreases in white blood cell counts were not associated with an increased risk of infections or serious infections. The incidence of potentially clinically significant decreases in lymphocyte counts (<0.5 x 109/L) (<1%), neutrophil counts (≤1.0 x 109/L) (<1%) and platelet counts (≤100 x 109/L) (≤1%) was similar in Plegridy-treated patients compared to placebo-treated patients. Two serious cases were reported in patients treated with Plegridy: one patient (<1%) experienced severe thrombocytopenia (platelet count <10 x 109/L), another patient (<1%) experienced severe neutropenia (neutrophil count <0.5 x 109/L). In both patients, cell counts recovered after discontinuation of Plegridy.
Slight decreases in mean red blood cell (RBC) counts were observed in Plegridy treated patients. The incidence of potentially clinically significant decreases in RBC counts (<3.3 x 1012/L) was similar in Plegridy-treated patients compared to placebo-treated patients.

Hypersensitivity reactions

Hypersensitivity events were reported in 16% of patients treated with Plegridy 125 micrograms every 2 weeks and 14% of patients who received placebo. Less than 1% of Plegridy treated patients experienced a serious hypersensitivity event (e.g. angioedema, urticaria) and they recovered promptly after treatment with anti-histamines and/or corticosteroids. In post marketing experience, serious hypersensitivity events including cases of anaphylaxis (frequency not known) have been reported following Plegridy administration.


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 authorization 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