Adverse reactions : תופעות לוואי

6         ADVERSE REACTIONS
The following serious adverse reactions are discussed in greater detail in other sections of the labeling: •    Infusion Reactions [see Warnings and Precautions (5.1)]
•    Infections [see Warnings and Precautions (5.2)]
•    Progressive Multifocal Leukoencephalopathy [see Warnings and Precautions (5.3)] •    Reduction in Immunoglobulins [see Warnings and Precautions (5.4)] •    Malignancies [see Warnings and Precautions (5.5)]
•    Immune-Mediated Colitis [see Warnings and Precautions (5.6)]

6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
The safety of OCREVUS has been evaluated in 1311 patients across MS clinical studies, which included 825 patients in active-controlled clinical trials in patients with relapsing forms of MS (RMS) and 486 patients in a placebo-controlled study in patients with primary progressive MS (PPMS).
Adverse Reactions in Patients with Relapsing Forms of MS
In active-controlled clinical trials (Study 1 and Study 2), 825 patients with RMS received OCREVUS 600 mg intravenously every 24 weeks (initial treatment was given as two separate 300 mg infusions at Weeks 0 and 2) [see Clinical Studies (14.1)]. The overall exposure in the 96-week controlled treatment periods was 1448 patient- years.
The most common adverse reactions in RMS trials (incidence ≥ 10%) were upper respiratory tract infections and infusion reactions. Table 2 summarizes the adverse reactions that occurred in RMS trials (Study 1 and Study 2).
Table 2       Adverse Reactions in Adult Patients with RMS with an Incidence of at least 5% for OCREVUS and Higher than REBIF

Studies 1 and 2
OCREVUS                         REBIF
Adverse Reactions                                       600 mg IV                     44 mcg SQ Every 24 Weeks1             3 Times per Week
(n=825)                      (n=826)
%                            %
Upper respiratory tract infections                           40                           33 Infusion reactions                                           34                           10 Studies 1 and 2
OCREVUS                        REBIF
Adverse Reactions                                                     600 mg IV                    44 mcg SQ Every 24 Weeks1            3 Times per Week
(n=825)                     (n=826)
%                           %
Depression                                                                 8                           7 Lower respiratory tract infections                                         8                           5 Back pain                                                                  6                           5 Herpes virus- associated infections                                        6                           4 Pain in extremity                                                          5                           4 1
The first dose was given as two separate 300 mg infusions at Weeks 0 and 2.

Adverse Reactions in Patients with Primary Progressive MS
In a placebo-controlled clinical trial (Study 3), a total of 486 patients with PPMS received one course of OCREVUS (600 mg of OCREVUS administered as two 300 mg infusions two weeks apart) given intravenously every 24 weeks and 239 patients received placebo intravenously [see Clinical Studies (14.2)]. The overall exposure in the controlled treatment period was 1416 patient-years, with median treatment duration of 3 years.
The most common adverse reactions in the PPMS trial (incidence ≥ 10%) were upper respiratory tract infections, infusion reactions, skin infections, and lower respiratory tract infections. Table 3 summarizes the adverse reactions that occurred in the PPMS trial (Study 3).


Table 3          Adverse Reactions in Adult Patients with PPMS with an Incidence of at least 5% for OCREVUS and Higher than Placebo

Study 3
OCREVUS           Placebo
600 mg IV
Adverse Reactions
Every 24
Weeks1
(n=486)          (n=239)
%                %
Upper respiratory tract infections                       49               43 Infusion reactions                                       40               26 Skin infections                                          14               11 Lower respiratory tract infections                       10               9 Cough                                                     7               3 Diarrhea                                                  6               5 Edema peripheral                                          6               5 Herpes virus associated infections                        5               4 1 One   dose of OCREVUS (600 mg administered as two 300 mg infusions two weeks apart) 

Adverse Reactions in Patients who Received 2-hour Infusions
Study 4 was designed to characterize the safety profile of OCREVUS infusions administered over 2 hours in patients with Relapsing-Remitting Multiple Sclerosis who did not experience a serious infusion reaction with any previous OCREVUS infusion. In this study, the incidence, intensity, and types of symptoms of infusion reactions were consistent with those of infusions administered over 3.5 hours [see Clinical Studies (14.3)].

Laboratory Abnormalities
Decreased Immunoglobulins
OCREVUS decreased total immunoglobulins with the greatest decline seen in IgM levels; however, a decrease in IgG levels was associated with an increased rate of serious infections.
In the active-controlled (RMS) trials (Study 1 and Study 2), the proportion of patients at baseline reporting IgG, IgA, and IgM below the lower limit of normal (LLN) in OCREVUS-treated patients was 0.5%, 1.5%, and 0.1%, respectively. Following treatment, the proportion of OCREVUS-treated patients reporting IgG, IgA, and IgM below the LLN at 96 weeks was 1.5%, 2.4%, and 16.5%, respectively.
In the placebo-controlled (PPMS) trial (Study 3), the proportion of patients at baseline reporting IgG, IgA, and IgM below the LLN in OCREVUS-treated patients was 0.0%, 0.2%, and 0.2%, respectively. Following treatment, the proportion of OCREVUS-treated patients reporting IgG, IgA, and IgM below the LLN at 120 weeks was 1.1%, 0.5%, and 15.5%, respectively.
The pooled data of OCREVUS clinical studies (RMS and PPMS) and their open-label extensions (up to approximately 7 years of exposure) have shown an association between decreased levels of IgG and increased rates of serious infections. The type, severity, latency, duration, and outcome of serious infections observed during episodes of immunoglobulins below LLN were consistent with the overall serious infections observed in patients treated with OCREVUS.
Decreased Neutrophil Levels
In the PPMS clinical trial (Study 3), decreased neutrophil counts occurred in 13% of OCREVUS-treated patients compared to 10% in placebo patients. The majority of the decreased neutrophil counts were only observed once for a given patient treated with OCREVUS and were between LLN - 1.5 x 109/L and 1.0 x 109/L. Overall, 1% of the patients in the OCREVUS group had neutrophil counts less than 1.0 x 109/L and these were not associated with an infection.
6.2 Immunogenicity
As with all therapeutic proteins, there is potential for immunogenicity. Immunogenicity data are highly dependent on the sensitivity and specificity of the test methods used. Additionally, the observed incidence of a positive result in a test method may be influenced by several factors, including sample handling, timing of sample collection, drug interference, concomitant medication, and the underlying disease. Therefore, comparison of the incidence of antibodies to OCREVUS with the incidence of antibodies to other products may be misleading.
Patients in MS trials (Study 1, Study 2, and Study 3) were tested at multiple time points (baseline and every 6 months post-treatment for the duration of the trial) for anti-drug antibodies (ADAs). Out of 1311 patients treated with OCREVUS, 12 (~1%) tested positive for ADAs, of which 2 patients tested positive for neutralizing antibodies. These data are not adequate to assess the impact of ADAs on the safety and efficacy of OCREVUS.
6.3    Postmarketing Experience
The following adverse reactions have been identified during postapproval use of OCREVUS. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Gastrointestinal Disorders: Immune-mediated colitis [see Warnings and Precautions (5.6)] Infections and Infestations: Serious herpes infections [see Warnings and Precautions (5.2)], progressive multifocal leukoencephalopathy [see Warnings and Precautions (5.3)], and babesiosis.
Skin: Pyoderma gangrenosum


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