Adverse reactions : תופעות לוואי

4.8    Undesirable effects

Experience from non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia in adults 
Summary of the safety profile

The overall safety profile of MabThera in non-Hodgkin’s lymphoma and CLL is based on data from patients from clinical trials and from post-marketing surveillance. These patients were treated either 

with MabThera monotherapy (as induction treatment or maintenance treatment following induction treatment) or in combination with chemotherapy.

The most frequently observed adverse reactions in patients receiving MabThera were IRRs which occurred in the majority of patients during the first infusion. The incidence of infusion-related symptoms decreases substantially with subsequent infusions and is less than 1% after eight doses of MabThera.

Infectious events (predominantly bacterial and viral) occurred in approximately 30-55 % of patients during clinical trials in patients with NHL and in 30-50 % of patients during clinical trials in patients with CLL.

The most frequently reported or observed serious adverse reactions were:
•    IRRs (including cytokine-release syndrome, tumour-lysis syndrome), see section 4.4.
•    Infections, see section 4.4.
•    Cardiovascular events, see section 4.4.

Other serious adverse reactions reported include hepatitis B reactivation and PML (see section 4.4.).

Tabulated list of adverse reactions

The frequencies of adverse reactions reported with MabThera alone or in combination with chemotherapy are summarised in Table 1. Frequencies are defined as very common ( 1/10), common ( 1/100 to < 1/10), uncommon ( 1/1,000 to < 1/100), rare ( 1/10,000 to < 1/1000), very rare (< 1/10,000) and not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in the order of decreasing seriousness.

The adverse reactions identified only during post-marketing surveillance, and for which a frequency could not be estimated, are listed under “not known”, see footnotes..

Table 1      Adverse reactions reported in clinical trials or during post-marketing surveillance in patients with NHL and CLL disease treated with MabThera monotherapy/maintenance or in combination with chemotherapy
MedDRA
Very
Common            Uncommon          Rare         Very Rare       Not known System Organ      Common
Class
Infections and   bacterial      sepsis,                             serious viral   PML           enteroviral + infestations     infections,      pneumonia,                        infection2,                   meningoencephal + viral            febrile                           pneumocystis                  itis2, 3 infections,    infection,                          jirovecii
+              + bronchitis     herpes zoster,
+ respiratory tract infection, fungal infections,
infections of unknown aetiology, +acute bronchitis,
+ sinusitis,
hepatitis B 1
Blood and        neutropenia,   anaemia,              coagulation                   transient     late neutropenia4 + lymphatic        leucopenia,      pancytopenia,       disorders,                    increase in +              + system             febrile        granulocytopeni     aplastic                      serum IgM disorders        neutropenia,   a                     anaemia,                      levels4 + thrombocyt                         haemolytic openia                               anaemia,
lymphadenop athy


MedDRA
Very
Common           Uncommon             Rare          Very Rare            Not known System Organ      Common
Class
Immune           infusion      hypersensitivity                      anaphylaxis      tumour lysis       infusion-related system           related                                                              syndrome,          acute reversible disorders        reactions5,                                                          cytokine           thrombocytopeni angioedema                                                           release            a5 syndrome5,
serum sickness
Metabolism                     hyperglycaemia,
and nutrition                  weight decrease,
disorders                      oedema peripheral, face oedema,
increased LDH,
hypocalcaemia
Psychiatric                                         depression,
disorders                                           nervousness,
Nervous                        paraesthesia,        dysgeusia                         peripheral         cranial system                         hypoaesthesia,                                         neuropathy,        neuropathy, disorders                      agitation,                                             facial nerve       loss of other insomnia,                                              palsy6             senses6 vasodilatation,
dizziness,
anxiety
Eye disorders                  lacrimation                                            severe vision disorder,                                              loss 6 conjunctivitis
Ear and                        tinnitus, ear pain                                                        hearing loss6 labyrinth disorders
+                    +
Cardiac                          myocardial           left           severe cardiac   heart failure5,7 disorders                      infarction5,7,       ventricular      disorders5,7 arrhythmia,          failure,
+                    + atrial               supraventric fibrillation,        ular tachycardia,         tachycardia,
+                    + cardiac disorder     ventricular tachycardia,
+ angina,
+ myocardial ischaemia,
bradycardia
Vascular                       hypertension,                                          vasculitis disorders                      orthostatic                                            (predominatel hypotension,                                           y cutaneous),
hypotension                                            leukocytoclas tic vasculitis
Respiratory,                   bronchospasm5,       asthma,          interstitial     respiratory        lung infiltration, thoracic and                   respiratory          bronchiolitis    lung disease8    failure5, mediastinal                    disease, chest       obliterans,
disorders                      pain, dyspnoea,      lung disorder,
increased cough,     hypoxia rhinitis
Gastrointestin   nausea        vomiting ,           abdominal                         gastro- al disorders                   diarrhoea,           enlargement                       intestinal abdominal pain,                                        perforation8 dysphagia,
stomatitis,
constipation,
dyspepsia,
anorexia, throat irritation



MedDRA
Very
Common              Uncommon               Rare            Very Rare            Not known System Organ          Common
Class
Skin and            pruritus,         urticaria,                                                   severe subcutaneous        rash,             sweating, night                                              bullous skin + tissue                alopecia        sweats, +skin                                                reactions, disorders                             disorder                                                     Stevens- Johnson syndrome,
toxic epidermal necrolysis
(Lyell’s syndrome) 8
Musculoskelet                         hypertonia,
al and                                myalgia,
connective                            arthralgia, back tissue                                pain, neck pain,
disorders                             pain
Renal and                                                                                          renal failure5 urinary disorders
General             fever , chills,   tumour pain,           infusion site disorders and       asthenia,         flushing,              pain administratio       headache          malaise, cold n site                                syndrome,
+ conditions                              fatigue,
+ shivering,
+ multi-organ failure5
Investigations      decreased
IgG levels
For each term, the frequency count was based on reactions of all grades (from mild to severe), except for terms marked with "+" where the frequency count was based only on severe (≥ grade 3 NCI common toxicity criteria) reactions. Only the highest frequency observed in the trials is reported
1 includes reactivation and primary infections; frequency based on R-FC regimen in relapsed/refractory CLL 2 see also section infection below
3 observed during post-marketing surveillance
4 see also section haematologic adverse reactions below
5 see also section infusion-related reactions below. Rarely fatal cases reported 6 signs and symptoms of cranial neuropathy. Occurred at various times up to several months after completion of MabThera therapy 7 observed mainly in patients with prior cardiac condition and/or cardiotoxic chemotherapy and were mostly associated with infusion-related reactions
8 includes fatal cases


The following terms have been reported as adverse reactions during clinical trials, however, were reported at a similar or lower incidence in the MabThera arms compared to control arms: haematotoxicity, neutropenic infection, urinary tract infection, sensory disturbance, pyrexia.

Signs and symptoms suggestive of an infusion-related reaction were reported in more than 50% of patients in clinical trials, and were predominantly seen during the first infusion, usually in the first one to two hours. These symptoms mainly comprised fever, chills and rigors. Other symptoms included flushing, angioedema, bronchospasm, vomiting, nausea, urticaria/rash, fatigue, headache, throat irritation, rhinitis, pruritus, pain, tachycardia, hypertension, hypotension, dyspnoea, dyspepsia, asthenia and features of tumour lysis syndrome. Severe infusion-related reactions (such as bronchospasm, hypotension) occurred in up to 12% of the cases. Additional reactions reported in some cases were myocardial infarction, atrial fibrillation, pulmonary oedema and acute reversible thrombocytopenia. Exacerbations of pre-existing cardiac conditions such as angina pectoris or congestive heart failure or severe cardiac disorders (heart failure, myocardial infarction, atrial fibrillation), pulmonary oedema, multi-organ failure, tumour lysis syndrome, cytokine release syndrome, renal failure, and respiratory failure were reported at lower or unknown frequencies. The incidence of infusion-related symptoms decreased substantially with subsequent infusions and is <1% of patients by the eighth cycle of MabThera (containing) treatment.


Description of selected adverse reactions
Infections
MabThera induces B-cell depletion in about 70-80% of patients, but was associated with decreased serum immunoglobulins only in a minority of patients.

Localised candida infections as well as Herpes zoster were reported at a higher incidence in the MabThera-containing arm of randomised studies. Severe infections were reported in about 4% of patients treated with MabThera monotherapy. Higher frequencies of infections overall, including grade 3 or 4 infections, were observed during MabThera maintenance treatment up to 2 years when compared to observation.There was no cumulative toxicity in terms of infections reported over a 2- year treatment period. In addition, other serious viral infections either new, reactivated or exacerbated, some of which were fatal, have been reported with MabThera treatment. The majority of patients had received MabThera in combination with chemotherapy or as part of a haematopoetic stem cell transplant. Examples of these serious viral infections are infections caused by the herpes viruses (Cytomegalovirus, Varicella Zoster Virus and Herpes Simplex Virus), JC virus (progressive multifocal leukoencephalopathy (PML)), enterovirus (meningoencephalitis) and hepatitis C virus (see section 4.4.). Cases of fatal PML that occurred after disease progression and retreatment have also been reported in clinical trials. Cases of hepatitis B reactivation, have been reported, the majority of which were in patients receiving MabThera in combination with cytotoxic chemotherapy. In patients with relapsed/refractory CLL, the incidence of grade 3/4 hepatitis B infection (reactivation and primary infection) was 2% in R-FC vs 0% FC. Progression of Kaposi’s sarcoma has been observed in MabThera-exposed patients with pre-existing Kaposi’s sarcoma. These cases occurred in non- approved indications and the majority of patients were HIV positive.

Haematologic adverse reactions
In clinical trials with MabThera monotherapy given for 4 weeks, haematological abnormalities occurred in a minority of patients and were usually mild and reversible. Severe (grade 3/4) neutropenia was reported in 4.2%, anaemia in 1.1% and thrombocytopenia in 1.7 % of the patients. During MabThera maintenance treatment for up to 2 years, leucopenia (5% vs. 2%, grade 3/4) and neutropenia (10% vs. 4 %, grade 3/4) were reported at a higher incidence when compared to observation. The incidence of thrombocytopenia was low (<1%, grade 3/4) and was not different between treatment arms. During the treatment course in studies with MabThera in combination with chemotherapy, grade 3/4 leucopenia (R-CHOP 88% vs. CHOP 79%, R-FC 23% vs. FC 12%), neutropenia (R-CVP 24% vs. CVP 14%; R-CHOP 97% vs. CHOP 88%, R-FC 30% vs. FC 19% in previously untreated CLL), pancytopenia (R-FC 3% vs. FC 1% in previously untreated CLL) were usually reported with higher frequencies when compared to chemotherapy alone. However, the higher incidence of neutropenia in patients treated with MabThera and chemotherapy was not associated with a higher incidence of infections and infestations compared to patients treated with chemotherapy alone. Studies in previously untreated and relapsed/refractory CLL have established that in up to 25% of patients treated with R-FC neutropenia was prolonged (defined as neutrophil count remaining below 1x109 /L between Day 24 and 42 after the last dose) or occurred with a late onset (defined as neutrophil count below 1x109/L later than 42 days after last dose in patients with no previous prolonged neutropenia or who recovered prior to Day 42) following treatment with MabThera plus FC. There were no differences reported for the incidence of anaemia. Some cases of late neutropenia occurring more than four weeks after the last infusion of MabThera were reported. In the CLL first- line study, Binet stage C patients experienced more adverse events in the R-FC arm compared to the FC arm (R-FC 83% vs. FC 71%). In the relapsed/refractory CLL study grade 3/4 thrombocytopenia was reported in 11% of patients in the R-FC group compared to 9% of patients in the FC group.

In studies of MabThera in patients with Waldenstrom’s macroglobulinaemia, transient increases in serum IgM levels have been observed following treatment initiation, which may be associated with hyperviscosity and related symptoms. The transient IgM increase usually returned to at least baseline level within 4 months.

Cardiovascular adverse reactions


Cardiovascular reactions during clinical trials with MabThera monotherapy were reported in 18.8% of patients with the most frequently reported events being hypotension and hypertension. Cases of grade 3 or 4 arrhythmia (including ventricular and supraventricular tachycardia) and angina pectoris during infusion were reported. During maintenance treatment, the incidence of grade 3/4 cardiac disorders was comparable between patients treated with MabThera and observation. Cardiac events were reported as serious adverse reactions (including atrial fibrillation, myocardial infarction, left ventricular failure, myocardial ischaemia) in 3% of patients treated with MabThera compared to <1% on observation. In studies evaluating MabThera in combination with chemotherapy, the incidence of grade 3 and 4 cardiac arrhythmias, predominantly supraventricular arrhythmias such as tachycardia and atrial flutter/fibrillation, was higher in the R-CHOP group (14 patients, 6.9%) as compared to the CHOP group (3 patients, 1.5%). All of these arrhythmias either occurred in the context of a MabThera infusion or were associated with predisposing conditions such as fever, infection, acute myocardial infarction or pre-existing respiratory and cardiovascular disease. No difference between the R-CHOP and CHOP group was observed in the incidence of other grade 3 and 4 cardiac events including heart failure, myocardial disease and manifestations of coronary artery disease. In CLL, the overall incidence of grade 3 or 4 cardiac disorders was low both in the first-line study (4% R-FC, 3% FC) and in the relapsed/refractory study (4% R-FC, 4% FC).


Respiratory system
Cases of interstitial lung disease, some with fatal outcome have been reported.
Neurologic disorders
During the treatment period (induction treatment phase comprising of R-CHOP for at most eight cycles), four patients (2 %) treated with R-CHOP, all with cardiovascular risk factors, experienced thromboembolic cerebrovascular accidents during the first treatment cycle. There was no difference between the treatment groups in the incidence of other thromboembolic events. In contrast, three patients (1.5%) had cerebrovascular events in the CHOP group, all of which occurred during the follow-up period. In CLL, the overall incidence of grade 3 or 4 nervous system disorders was low both in the first-line study (4% R-FC, 4% FC) and in the relapsed/refractory study (3% R-FC, 3% FC).

Cases of posterior reversible encephalopathy syndrome (PRES) / reversible posterior leukoencephalopathy syndrome (RPLS) have been reported. Signs and symptoms included visual disturbance, headache, seizures and altered mental status, with or without associated hypertension. A diagnosis of PRES/RPLS requires confirmation by brain imaging. The reported cases had recognised risk factors for PRES/RPLS, including the patients’ underlying disease, hypertension, immunosuppressive therapy and/or chemotherapy.

Gastrointestinal disorders
Gastrointestinal perforation in some cases leading to death has been observed in patients receiving MabThera for treatment of non- Hodgkin’s lymphoma. In the majority of these cases, MabThera was administered with chemotherapy.

IgG levels
In the clinical trial evaluating MabThera maintenance treatment in relapsed/refractory follicular lymphoma, median IgG levels were below the lower limit of normal (LLN) (< 7 g/L) after induction treatment in both the observation and the MabThera groups. In the observation group, the median IgG level subsequently increased to above the LLN, but remained constant in the MabThera group. The proportion of patients with IgG levels below the LLN was about 60% in the MabThera group throughout the 2 year treatment period, while it decreased in the observation group (36% after 2 years).

A small number of spontaneous and literature cases of hypogammaglobulinaemia have been observed in paediatric patients treated with MabThera, in some cases severe and requiring long-term immunoglobulin substitution therapy. The consequences of long term B cell depletion in paediatric patients are unknown.


Skin and subcutaneous tissue disorders
Toxic Epidermal Necrolysis (Lyell syndrome) and Stevens-Johnson syndrome, some with fatal outcome, have been reported very rarely.

Patient subpopulations - MabThera monotherapy
Elderly ( 65 years and above):
The incidence of adverse reactions of all grades and grade 3 /4 adverse reactions was similar in elderly patients compared to younger patients (below 65 years).

Bulky disease
There was a higher incidence of grade 3/4 adverse reactions in patients with bulky disease than in patients without bulky disease (25.6 % vs. 15.4 %). The incidence of adverse reactions of any grade was similar in these two groups.

Re-treatment
The percentage of patients reporting adverse reactions upon re-treatment with further courses of MabThera was similar to the percentage of patients reporting adverse reactions upon initial exposure (any grade and grade 3/4 adverse reactions).

Patient subpopulations - MabThera combination therapy
Elderly ( 65 years and above)
The incidence of grade 3/4 blood and lymphatic adverse events was higher in elderly patients compared to younger patients (below 65 years), with previously untreated or relapsed/refractory CLL.

Experience from rheumatoid arthritis

Summary of the safety profile
The overall safety profile of MabThera in rheumatoid arthritis is based on data from patients from clinical trials and from post-marketing surveillance.

The safety profile of MabThera in patients with moderate to severe rheumatoid arthritis (RA) is summarised in the sections below. In clinical trials more than 3100 patients received at least one treatment course and were followed for periods ranging from 6 months to over 5 years; approximately 2400 patients received two or more courses of treatment with over 1000 having received 5 or more courses. The safety information collected during post marketing experience reflects the expected adverse reaction profile as seen in clinical trials for MabThera (see section 4.4).

Patients received 2 x 1000 mg of MabThera separated by an interval of two weeks; in addition to methotrexate (10-25 mg/week). MabThera infusions were administered after an intravenous infusion of 100 mg methylprednisolone; patients also received treatment with oral prednisone for 15 days.

Tabulated list of adverse reactions

Adverse reactions are listed in Table 2. Frequencies are defined as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥ 1/10,000 to < 1/1000), very rare (<1/10,000) and not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

The adverse reactions identified only during post marketing surveillance, and for which a frequency could not be estimated, are listed under “not known”, see footnotes.

The most frequent adverse reactions considered due to receipt of MabThera were IRRs. The overall incidence of IRRs in clinical trials was 23% with the first infusion and decreased with subsequent infusions. Serious IRRs were uncommon (0.5% of patients) and were predominantly seen during the initial course. In addition to adverse reactions seen in RA clinical trials for MabThera, progressive 

multifocal leukoencephalopathy (PML) (see section 4.4) and serum sickness-like reaction have been reported during post marketing experience.

Table 2      Summary of adverse reactions reported in clinical trials or during post-marketing surveillance occurring in patients with rheumatoid arthritis receiving MabThera MedDRA
Very                                                                             Not known System Organ                            Common           Uncommon          Rare       Very rare Common
Class
Infections and   upper             bronchitis,                                        PML,          serious viral infestations     respiratory       sinusitis,                                         reactivatio   infection1,2, tract             gastroenteritis,                                   n of          enteroviral infection,        tinea pedis                                        hepatitis B   meningoencephaliti urinary tract                                                                      s2 infections
Blood and                          neutropenia3                          late         serum lymphatic                                                                neutropeni   sickness- system                                                                   a4           like disorders                                                                             reaction 5                                       5
Immune            infusion                                infusion system           related                                 related disorders        reactions                               reactions
General          (hypertensio                            (generalised disorders and    n, nausea,                              oedema,
administratio    rash,                                   bronchospas n site           pyrexia,                                m, wheezing, conditions       pruritus,                               laryngeal urticaria,                              oedema,
throat                                  angioneurotic irritation, hot                         oedema,
flush,                                  generalised hypotension,                            pruritus,
rhinitis,                               anaphylaxis,
rigors,                                 anaphylactoi tachycardia,                            d reaction) fatigue,
oropharynge al pain,
oedema peripheral,
erythema)
Metabolism                         hypercholesterolem and nutrition                      ia disorders
Psychiatric                        depression, anxiety disorders
Nervous          headache          paraesthesia,
system                             migraine,
disorders                          dizziness, sciatica



MedDRA
Very                                                                                 Not known System Organ                           Common             Uncommon           Rare         Very rare Common
Class
Cardiac                                                                   angina          atrial disorders                                                                 pectoris,       flutter atrial fibrillation,
heart failure,
myocardial infarction
Gastrointestin                    dyspepsia,
al disorders                      diarrhoea, gastro- oesophageal reflux,
mouth ulceration,
upper abdominal pain
Skin and                          alopecia                                                toxic subcutaneous                                                                              epidermal tissue                                                                                    necrolysis disorders                                                                                 (Lyell’s syndrome)
, Stevens-
Johnson syndrome7
Musculo                           arthralgia / skeletal                          musculoskeletal disorders and                     pain, osteoarthritis,
connective                        bursitis tissue disorders
Investigations      decreased        decreased IgG
IgM levels6      levels6
1
See also section infections below.
2
Observed during post-marketing surveillance
3
Frequency category derived from laboratory values collected as part of routine laboratory monitoring in clinical trials 4
Frequency category derived from post-marketing data.
5
Reactions occurring during or within 24 hours of infusion. See also infusion-related reactions below. IRRs may occur as a result of hypersensitivity and/or to the mechanism of action.
6
Includes observations collected as part of routine laboratory monitoring.
7
Includes fatal cases


Multiple courses
Multiple courses of treatment are associated with a similar adverse reaction profile to that observed following first exposure. The rate of all adverse reactions following first MabThera exposure was highest during the first 6 months and declined thereafter. This is mostly accounted for by IRRs (most frequent during the first treatment course), RA exacerbation and infections, all of which were more frequent in the first 6 months of treatment.



Description of selected adverse reactions

Infusion-related reactions
The most frequent adverse reactions following receipt of MabThera in clinical studies were IRRs (refer to Table 2). Among the 3189 patients treated with MabThera, 1135 (36%) experienced at least one IRR with 733/3189 (23%) of patients experiencing an IRR following first infusion of the first exposure to MabThera. The incidence of IRRs declined with subsequent infusions. In clinical trials fewer than 1% (17/3189) of patients experienced a serious IRR. There were no CTC Grade 4 IRRs and no deaths due to IRRs in the clinical trials. The proportion of CTC Grade 3 events and of IRRs leading to withdrawal decreased by course and were rare from course 3 onwards. Premedication with intravenous glucocorticoid significantly reduced the incidence and severity of IRRs (see sections 4.2 and 4.4). Severe IRRs with fatal outcome have been reported in the post-marketing setting.

In a trial designed to evaluate the safety of a more rapid MabThera infusion in patients with rheumatoid arthritis, patients with moderate-to-severe active RA who did not experience a serious IRR during or within 24 hours of their first studied infusion were allowed to receive a 2-hour intravenous infusion of MabThera. Patients with a history of a serious infusion reaction to a biologic therapy for RA were excluded from entry. The incidence, types and severity of IRRs were consistent with that observed historically. No serious IRRs were observed.

Infections
The overall rate of infection reported from clinical trials was approximately 94 per 100 patient years in MabThera treated patients. The infections were predominately mild to moderate and consisted mostly of upper respiratory tract infections and urinary tract infections. The incidence of infections that were serious or required IV antibiotics was approximately 4 per 100 patient years. The rate of serious infections did not show any significant increase following multiple courses of MabThera. Lower respiratory tract infections (including pneumonia) have been reported during clinical trials, at a similar incidence in the MabThera arms compared to control arms.

In the post marketing setting, serious viral infections have been reported in RA patients treated with rituximab.

Cases of progressive multifocal leukoencephalopathy with fatal outcome have been reported following use of MabThera for the treatment of autoimmune diseases. This includes rheumatoid arthritis and off- label autoimmune diseases, including Systemic Lupus Erythematosus (SLE) and vasculitis.

In patients with non-Hodgkin’s lymphoma receiving MabThera in combination with cytotoxic chemotherapy, cases of hepatitis B reactivation have been reported (see non-Hodgkin’s lymphoma).
Reactivation of hepatitis B infection has also been very rarely reported in RA patients receiving MabThera (see Section 4.4).

Cardiovascular adverse reactions
Serious cardiac reactions were reported at a rate of 1.3 per 100 patient years in the MabThera treated patients compared to 1.3 per 100 patient years in placebo treated patients. The proportions of patients experiencing cardiac reactions (all or serious) did not increase over multiple courses.

Neurologic events
Cases of posterior reversible encephalopathy syndrome (PRES) / reversible posterior leukoencephalopathy syndrome (RPLS) have been reported. Signs and symptoms included visual disturbance, headache, seizures and altered mental status, with or without associated hypertension. A diagnosis of PRES/RPLS requires confirmation by brain imaging. The reported cases had recognised risk factors for PRES/RPLS, including the patients’ underlying disease, hypertension, immunosuppressive therapy and/or chemotherapy.

Neutropenia



Events of neutropenia were observed with MabThera treatment, the majority of which were transient and mild or moderate in severity. Neutropenia can occur several months after the administration of MabThera (see section 4.4).

In placebo-controlled periods of clinical trials, 0.94% (13/1382) of MabThera treated patients and 0.27% (2/731) of placebo patients developed severe neutropenia.

Neutropenic events, including severe late onset and persistent neutropenia, have been rarely reported in the post-marketing setting, some of which were associated with fatal infections.

Skin and subcutaneous tissue disorders
Toxic Epidermal Necrolysis (Lyell’s syndrome) and Stevens-Johnson syndrome, some with fatal outcome, have been reported very rarely.

Laboratory abnormalities
Hypogammaglobulinaemia (IgG or IgM below the lower limit of normal) has been observed in RA patients treated with MabThera. There was no increased rate in overall infections or serious infections after the development of low IgG or IgM (see section 4.4).

A small number of spontaneous and literature cases of hypogammaglobulinaemia have been observed in paediatric patients treated with MabThera, in some cases severe and requiring long-term immunoglobulin substitution therapy. The consequences of long term B cell depletion in paediatric patients are unknown.

Experience from granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) 
In the GPA/MPA study, 99 patients were treated with MabThera (375 mg/m2 , once weekly for 4 weeks) and glucocorticoids (see section 5.1).

The adverse reaction s listed in Table 3 with a frequency categorisation of "common" or "very common" were all adverse events which occurred at an incidence of ≥ 5% in the MabThera group and at a higher frequency than the comparator group.

The adverse reactions identified only during post marketing surveillance, and for which a frequency could not be estimated, are listed under “not known”, see footnotes.

Table 3      Adverse reactions occurring at 6-months in ≥ 5% of adult patients receiving MabThera in GPA/MPA Study (Rituximab n=99), at a higher frequency than the comparator group, or during post-marketing surveillance

MedDRA System Organ Class           Very Common                    Common                   Not known Infections and infestations                            urinary tract infection,     serious viral infection1,2, bronchitis,                  enteroviral herpes zoster,               meningoencephalitis1 nasopharyngitis
Blood and lymphatic system                             thrombocytopenia disorders
Immune system disorders                                cytokine release syndrome Metabolism and nutrition                               hyperkalaemia disorders
Psychiatric disorders         insomnia
Nervous system disorders      dizziness,
tremor
Vascular disorders            hypertension             flushing
Respiratory, thoracic and     cough,                   nasal congestion mediastinal disorders         dyspnoea,
epistaxis
Gastrointestinal disorders    diarrhoea                dyspepsia,
constipation


MedDRA System Organ Class              Very Common                   Common                Not known Skin and subcutaneous tissue                              acne disorders
Musculoskeletal and              muscle spasms,           muscle weakness, connective tissue disorders      arthralgia,              musculoskeletal pain, back pain                pain in extremities
General disorders and            oedema peripheral administration site conditions
Investigations                                            decreased haemoglobin 1
Observed during post-marketing surveillance.
2
See also section infections below.

Description of selected adverse reactions
Infusion related reactions
IRRs in the GPA and MPA clinical trial were defined as any adverse event occurring within 24 hours of an infusion and considered to be infusion-related by investigators in the safety population. Of the 99 patients treated with MabThera and 12% experienced at least one IRR. All IRRs were CTC Grade 1 or 2. The most common IRRs included cytokine release syndrome, flushing, throat irritation, and tremor.
MabThera was given in combination with intravenous glucocorticoids which may reduce the incidence and severity of these events.

Infections
In the 99 MabThera patients, the overall rate of infection was approximately 237 per 100 patient years (95% CI 197 - 285) at the 6-month primary endpoint. Infections were predominately mild to moderate and consisted mostly of upper respiratory tract infections, herpes zoster and urinary tract infections.
The rate of serious infections was approximately 25 per 100 patient years. The most frequently reported serious infection in the MabThera group was pneumonia at a frequency of 4%.

In the post marketing setting, serious viral infections have been reported in GPA/MPA patients treated with rituximab.


Malignancies
The incidence of malignancy in MabThera treated patients in the GPA and MPA clinical study was 2.00 per 100 patient years at the study common closing date (when the final patient had completed the follow-up period). On the basis of standardised incidence ratios, the incidence of malignancies appears to be similar to that previously reported in patients with ANCA-associated vasculitis.

Cardiovascular adverse reactions
Cardiac events occurred at a rate of approximately 273 per 100 patient years (95% CI 149-470) at the 6-month primary endpoint. The rate of serious cardiac events was 2.1 per 100 patient years (95% CI 3 -15). The most frequently reported events were tachycardia (4%) and atrial fibrillation (3%) (see Section 4.4).

Neurologic events
Cases of posterior reversible encephalopathy syndrome (PRES) / reversible posterior leukoencephalopathy syndrome (RPLS) have been reported in autoimmune conditions. Signs and symptoms included visual disturbance, headache, seizures and altered mental status, with or without associated hypertension. A diagnosis of PRES/RPLS requires confirmation by brain imaging. The reported cases had recognised risk factors for PRES/RPLS, including the patients’ underlying disease, hypertension, immunosuppressive therapy and/or chemotherapy.

Hepatitis-B reactivation
A small number of cases of hepatitis-B reactivation, some with fatal outcome, have been reported in granulomatosis with polyangiitis and microscopic polyangiitis patients receiving MabThera in the post-marketing setting.

Hypogammaglobulinaemia

Hypogammaglobulinaemia (IgA, IgG or IgM below the lower limit of normal) has been observed in GPA and MPA patients treated with MabThera.
In GPA/MPA Study, at 6 months, in the MabThera group, 27%, 58% and 51% of patients with normal immunoglobulin levels at baseline, had low IgA, IgG and IgM levels, respectively compared to 25%, 50% and 46% in the cyclophosphamide group. The rate of overall infections and serious infections was not increased after the development of low IgA, IgG or IgM.

Neutropenia
In GPA/MPA Study, 24% of patients in the MabThera group (single course) and 23% of patients in the cyclophosphamide group developed CTC grade 3 or greater neutropenia. Neutropenia was not associated with an observed increase in serious infection in MabThera-treated patients. The effect of multiple MabThera courses on the development of neutropenia in GPA and MPA patients has not been studied in clinical trials.

Skin and subcutaneous tissue disorders
Toxic Epidermal Necrolysis (Lyell’s syndrome) and Stevens-Johnson syndrome, some with fatal outcome, have been reported very rarely.

Experience from pemphigus vulgaris

The overall safety profile of MabThera in pemphigus vulgaris is based on data from patients from 2 clinical trials and from post marketing surveillance.

Summary of the safety profile in PV Study 1 (Study ML22196) and PV Study 2 (Study WA29330) The safety profile of MabThera in combination with short-term, low-dose glucocorticoids in the treatment of patients with pemphigus vulgaris was studied in a Phase 3, randomised, controlled, multicentre, open-label study in pemphigus patients that included 38 pemphigus vulgaris (PV) patients randomised to the MabThera group (PV Study 1). Patients randomised to the MabThera group received an initial 1000 mg IV on Study Day 1 and a second 1000 mg IV on Study Day 15.
Maintenance doses of 500 mg IV were administered at months 12 and 18. Patients could receive 1000 mg IV at the time of relapse (see section 5.1).
In PV Study 2, a randomised, double-blind, double-dummy, active-comparator, multicentre study evaluating the efficacy and safety of MabThera compared with mycophenolate mofetil (MMF) in patients with moderate-to-severe PV requiring oral corticosteroids, 67 PV patients received treatment with MabThera (initial 1000 mg IV on Study Day 1 and a second 1000 mg IV on Study Day 15 repeated at Weeks 24 and 26) for up to 52 weeks (see section 5.1).


The safety profile of MabThera in PV was consistent with the established safety profile in other approved autoimmune indications.


Tabulated list of adverse reactions for PV Studies 1 and 2, or during post-marketing surveillance 
The adverse reactions from PV Studies 1 and 2 with a frequency categorisation of "common" or "very common" are presented in Table 4. In PV Study 1, adverse reactions were defined as adverse events which occurred at a rate of  5% among MabThera-treated PV patients, with a  2% absolute difference in incidence between the MabThera-treated group and the standard-dose prednisone group up to Month 24. No patients were withdrawn due to adverse reactions in Study 1. In PV Study 2, adverse reactions were defined as adverse events occurring in ≥5% of patients in the MabThera arm and assessed as related.

The adverse reactions identified only during post marketing surveillance, and for which a frequency could not be estimated, are listed under “not known”, see footnotes.



Table 4        Adverse reactions in MabThera-treated pemphigus vulgaris patients in PV Study 1 (up to Month 24) and PV Study 2 (up to Week 52), or during post-marketing surveillance

MedDRA System Organ Class                Very Common                        Common                    Not known Infections and infestations          upper respiratory tract      herpes virus infection       serious viral infection1,2 infection                    herpes zoster                enteroviral oral herpes                  meningoencephalitis1 conjunctivitis nasopharyngitis oral candidiasis urinary tract infection

Neoplasms benign, malignant                                       skin papilloma and unspecified (incl cysts and polyps)
Psychiatric disorders                persistent depressive        major depression disorder                     irritability
Nervous system disorders             headache                     dizziness 
Cardiac disorders                                                 tachycardia Gastrointestinal disorders                                        abdominal pain upper Skin and subcutaneous tissue         alopecia                     pruritus disorders                                                         urticaria skin disorder
Musculoskeletal and connective                                    musculoskeletal pain tissue disorders                                                  arthralgia back pain
General disorders and                                             fatigue administration site conditions                                    asthenia pyrexia
Injury, poisoning and                infusion-related procedural complications             reactions3
1
Observed during post-marketing surveillance.
2
See also section infections below.
3
Infusion-related reactions for PV Study 1 included symptoms collected on the next scheduled visit after each infusion, and adverse reactions occurring on the day of or one day after the infusion. The most common infusion-related reaction symptoms/Preferred Terms for PV Study 1 included headaches, chills, high blood pressure, nausea, asthenia and pain.

The most common infusion-related reaction symptoms/Preferred Terms for PV Study 2 were dyspnoea, erythema, hyperhidrosis, flushing/hot flush, hypotension/low blood pressure and rash/rash pruritic.

Description of selected adverse reactions

Infusion-related reactions
In PV Study 1, infusion-related reactions were common (58%). Nearly all infusion-related reactions were mild to moderate. The proportion of patients experiencing an infusion- related reaction was 29% (11 patients), 40% (15 patients), 13% (5 patients), and 10% (4 patients) following the first, second, third, and fourth infusions, respectively. No patients were withdrawn from treatment due to infusion- related reactions. Symptoms of infusion-related reactions were similar in type and severity to those seen in RA and GPA/MPA patients.

In PV Study 2, IRRs occurred primarily at the first infusion and the frequency of IRRs decreased with subsequent infusions: 17.9%, 4.5%, 3% and 3% of patients experienced IRRs at the first, second, third, and fourth infusions, respectively. In 11/15 patients who experienced at least one IRR, the IRRs were Grade 1 or 2. In 4/15 patients, Grade ≥3 IRRs were reported and led to discontinuation of MabThera treatment; three of the four patients experienced serious (life-threatening) IRRs. Serious IRRs occurred at the first (2 patients) or second (1 patient) infusion and resolved with symptomatic treatment.


Infections
In PV Study 1, 14 patients (37%) in the MabThera group experienced treatment-related infections compared to 15 patients (42%) in the standard-dose prednisone group. The most common infections in the MabThera group were herpes simplex and zoster infections, bronchitis, urinary tract infection, fungal infection and conjunctivitis. Three patients (8%) in the MabThera group experienced a total of 5 serious infections (Pneumocystis jirovecii pneumonia, infective thrombosis, intervertebral discitis, lung infection, Staphylococcal sepsis) and one patient (3%) in the standard-dose prednisone group experienced a serious infection (Pneumocystis jirovecii pneumonia).

In PV Study 2, 42 patients (62.7%) in the MabThera arm experienced infections. The most common infections in the MabThera group were upper respiratory tract infection, nasopharyngitis, oral candidiasis and urinary tract infection. Six patients (9%) in the MabThera arm experienced serious infections.

In the post marketing setting, serious viral infections have been reported in PV patients treated with rituximab.


Laboratory abnormalities
PV Study 2, in the MabThera arm, transient decreases in lymphocyte count, driven by decreases in the peripheral T-cell populations, as well as a transient decrease in phosphorus level were very commonly observed post-infusion. These were considered to be induced by IV methylprednisolone premedication infusion.

In PV Study 2, low IgG levels were commonly observed and low IgM levels were very commonly observed; however, there was no evidence of an increased risk of serious infections after the development of low IgG or IgM.

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