Adverse reactions : תופעות לוואי

4.8    Undesirable effects

Summary of the safety profile
The most common adverse reactions (incidence >10%) for patients treated with Dimethyl fumarate were flushing and gastrointestinal events (i.e. diarrhoea, nausea, abdominal pain, abdominal pain upper). Flushing and gastrointestinal events tend to begin early in the course of treatment (primarily during the first month) and in patients who experience flushing and gastrointestinal events, these events may continue to occur intermittently throughout treatment with Dimethyl fumarate. The most commonly reported adverse reactions leading to discontinuation (incidence >1%) in patients treated with Dimethyl fumarate were flushing (3%) and gastrointestinal events (4%).
In placebo-controlled and uncontrolled clinical studies, a total of 2,513 patients have received Dimethyl fumarate for periods up to12 years with an overall exposure equivalent to 11,318 person-years. A total of 1,169 patients have received at least 5 years of treatment with Dimethyl fumarate and 426 patients have received at least 10 years of treatment with Dimethyl fumarate.. The experience in uncontrolled clinical trials is consistent with the experience in the placebo-controlled clinical trials 
Tabulated summary of adverse reactions

Adverse reactions, which were more frequently reported in Dimethyl fumarate versus placebo-treated patients, are presented in the table below. These data were derived from 2 pivotal Phase 3 placebo- controlled, double-blind clinical trials with a total of 1,529 patients treated with Dimethyl fumarate and for up to 24 months with an overall exposure of 2,371 person-years (see section 5.1). The frequencies described in the table below are based on 769 patients treated with Dimethyl fumarate 240 mg twice a day and 771 patients treated with placebo.

The adverse reactions are presented as MedDRA preferred terms under the MedDRA System Organ Class. The incidence of the adverse reactions below is 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 (frequency cannot be estimated from the available data) 
MedDRA System Organ Class           Adverse reaction                        Frequency category Infections and infestations         Gastroenteritis                         Common Progressive multifocal                  Not known leukoencephalopathy (PML)
Herpes Zoster
Not known

Blood and lymphatic system          Lymphopenia                             Common disorders                           Leucopenia                              Common Thrombocytopenia                        Uncommon              |
Immune system disorders             Hypersensitivity                        Uncommon Anaphylaxis                             Not known
Dyspnoea                                Not known
Hypoxia                                 Not known


                                          Hypotension                            Not known
Angioedema                             Not known
Nervous system disorders                Burning sensation                      Common Vascular disorders                      Flushing                               Very common Hot flush                              Common
Respiratory, thoracic and mediastinal   Rhinorrhoea                            Not known disorders

Gastrointestinal disorders              Diarrhoea                              Very common Nausea                                 Very common
Abdominal pain upper                   Very common
Abdominal pain                         Very common
Vomiting                               Common
Dyspepsia                              Common
Gastritis                              Common
Gastrointestinal disorder              Common
Hepatobiliary disorders                 Aspartate aminotransferase increased   Common Alanine aminotransferase increased     Common
Drug-induced liver injury              Not known
Skin and subcutaneous tissue            Pruritus                               Common disorders                               Rash                                   Common Erythema                               Common
Alopecia                               Common
Renal and urinary disorders             Proteinuria                            Common General disorders and                   Feeling hot                            Common administration site conditions
Ketones measured in urine              Very common
Investigations                          Albumin urine present                  Common White blood cell count decreased       Common


Description of selected adverse reactions

Flushing

In the placebo-controlled studies, the incidence of flushing (34% versus 4%) and hot flush (7% versus 2%) was increased in patients treated with Dimethyl fumarate compared to placebo, respectively.
Flushing is usually described as flushing or hot flush, but can include other events (e.g. warmth, redness, itching, and burning sensation). Flushing events tend to begin early in the course of treatment (primarily during the first month) and in patients who experience flushing, these events may continue to occur intermittently throughout treatment with Dimethyl fumarate. In patients with flushing, the majority had flushing events that were mild or moderate in severity. Overall, 3% of patients treated with Dimethyl fumarate discontinued due to flushing. The incidence of serious flushing, which may be characterised by generalised erythema, rash and/or pruritus, was seen in less than 1% of patients treated with Dimethyl fumarate (see sections 4.2, 4.4 and 4.5).

Gastrointestinal

The incidence of gastrointestinal events (e.g. diarrhoea [14% versus 10%], nausea [12% versus 9%], upper abdominal pain [10% versus 6%], abdominal pain [9% versus 4%], vomiting [8% versus 5%] and dyspepsia [5% versus 3%]) was increased in patients treated with Dimethyl fumarate compared to placebo, respectively. Gastrointestinal events tend to begin early in the course of treatment (primarily during the first month) and in patients who experience gastrointestinal events, these events may continue to occur intermittently throughout treatment with Dimethyl fumarate. In the majority of patients who experienced gastrointestinal events, it was mild or moderate in severity. Four per cent (4%) of patients treated with Dimethyl fumarate discontinued due to gastrointestinal events. The incidence of serious gastrointestinal events, including gastroenteritis and gastritis, was seen in 1% of patients treated with Dimethyl fumarate (see section 4.2).
 Hepatic function

Based on data from placebo-controlled studies, the majority of patients with elevations had hepatic transaminases that were <3 times the upper limit of normal (ULN). The increased incidence of elevations of hepatic transaminases in patients treated with Dimethyl fumarate relative to placebo was primarily seen during the first 6 months of treatment. Elevations of alanine aminotransferase and aspartate aminotransferase ≥3 times ULN, respectively, were seen in 5% and 2% of patients treated with placebo and 6% and 2% of patients treated with Dimethyl fumarate. Discontinuations due to elevated hepatic transaminases were <1% and similar in patients treated with Dimethyl fumarate or placebo.
Elevations in transaminases ≥3 times ULN with concomitant elevations in total bilirubin >2 times ULN, were not observed in placebo-controlled studies.

Increase of liver enzymes and cases of drug-induced liver injury (elevations in transaminases ≥3 times ULN with concomitant elevations in total bilirubin >2 times ULN), have been reported in post marketing experience following Dimethyl fumarate administration, which resolved upon treatment discontinuation.

Lymphopenia

In the placebo-controlled studies most patients (>98%) had normal lymphocyte values prior to initiating treatment. Upon treatment with Dimethyl fumarate, mean lymphocyte counts decreased over the first year with a subsequent plateau. On average, lymphocyte counts decreased by approximately 30% of baseline value. Mean and median lymphocyte counts remained within normal limits. Lymphocyte counts <0.5x109/l were observed in <1% of patients treated with placebo and 6% of patients treated with Dimethyl fumarate. A lymphocyte count <0.2x109/l was observed in 1 patient treated with Dimethyl fumarate and in no patients treated with placebo.

In clinical studies (both controlled and uncontrolled), 41% of patients treated with Dimethyl fumarate had lymphopenia (defined in these studies as <0.91x109/L). Mild lymphopenia (counts >0.8x109/L and <0.91 x109/L) was observed in 28% of patients; moderate lymphopenia (counts >0.5x109/L and <0.8x109/L) persisting for at least six months was observed in 10% of patients; severe lymphopenia (counts <0.5x109/L) persisting for at least six months was observed in 2% of patients. In the group with severe lymphopenia, the majority of lymphocyte counts remained <0.5x109/L with continued therapy.

In addition, in an uncontrolled, prospective, post-marketing study, at week 48 of treatment with Dimethyl fumarate (n=185) CD4+ T cells were moderately (counts >0.2x109/L to <0.4x109/L) or severely (<0.2x109/L) decreased in up to 37 % or 6 % of patients, respectively, while CD8+ T cells were more frequently reduced with up to 59 % of patients at counts <0.2x109/L and 25 % of patients at counts <0.1x109/L.

In controlled and uncontrolled clinical studies, patients who discontinued Dimethyl fumarate therapy with lymphocyte counts below the lower limit of normal (LLN) were monitored for recovery of lymphocyte count to the LLN (see section 5.1).

Infections, including PML and opportunistic infections

Cases of infections with John Cunningham virus (JCV) causing Progressive Multifocal Leukoencephalopathy (PML) have been reported with Dimethyl fumarate (see section 4.4). PML may be fatal or result in severe disability. In one of the clinical trials, one patient taking Dimethyl fumarate developed PML in the setting of prolonged severe lymphopenia (lymphocyte counts predominantly <0.5x109/L for 3.5 years), with a fatal outcome. In the post-marketing setting, PML has also occurred in the presence of moderate and mild lymphopenia (>0.5x109/L to 50 years.

Herpes zoster infections have been reported with Dimethyl fumarate use. In an ongoing long-term extension study, in which 1736 MS patients are treated with Dimethyl fumarate, approximately 5% experienced one or more events of herpes zoster, the majority of which were mild to moderate in severity. Most subjects, including those who experienced a serious herpes zoster infection, had lymphocyte counts above the lower limit of normal. In a majority of patients with concurrent lymphocyte counts below the LLN, lymphopenia was rated moderate or severe. In the post-marketing setting, most cases of herpes zoster infection were non-serious and resolved with treatment. Limited data is available on ALC in patients with herpes zoster infection in the post-marketing setting. However, when reported, most patients experienced moderate (<0.8x109/L to 0.5x109/L) or severe (<0.5x109/L to 0.2x109/L) lymphopenia (see section 4.4).


Laboratory abnormalities
In the placebo-controlled studies, measurement of urinary ketones (1+ or greater) was higher in patients treated with Dimethyl fumarate (45%) compared to placebo (10%). No untoward clinical consequences were observed in clinical trials.

Levels of 1,25-dihydroxyvitamin D decreased in Dimethyl fumarate treated patients relative to placebo (median percentage decrease from baseline at 2 years of 25% versus 15%, respectively) and levels of parathyroid hormone (PTH) increased in Dimethyl fumarate treated patients relative to placebo (median percentage increase from baseline at 2 years of 29% versus 15%, respectively). Mean values for both parameters remained within normal range.

A transient increase in mean eosinophil counts was seen during the first 2 months of therapy.

Paediatric population
The safety of Dimethyl fumarate in paediatric patients with multiple sclerosis below the age of 18 has not yet been established. In a small 24-week open-label uncontrolled study in paediatric patients with RRMS aged 13 to 17 years (120 mg twice a day for 7 days followed by 240 mg twice a day for the remainder of treatment; safety population, n=22), followed by a 96 week extension study (240mg twice per day ; safety population n=20) the safety profile appeared similar to that observed in adult patients.

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 Regulations by using an online form https://sideeffects.health.gov.il/