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

The most frequently observed adverse reactions in patients receiving rituximab 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 rituximab.

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 rituximab 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 < 1/1,000), 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 rituximab monotherapy/maintenance or in combination with chemotherapy
MedDRA
System Organ     Very Common            Common            Uncommon       Rare         Very Rare      Not Known Class
Infections and   bacterial           sepsis,                          serious viral   PML          enteroviral infestations     infections, viral   +pneumonia,                      infection2,                  meningoencephal infections,         +febrile infection,
pneumocystis                 itis2, 3
+bronchitis         +herpes zoster,                  jirovecii
+respiratory tract
 infection, fungal infections,
infections of unknown aetiology, +acute bronchitis,
+sinusitis,
 hepatitis B1

   MedDRA
System Organ   Very Common          Common              Uncommon                Rare              Very Rare            Not Known Class
Blood and       neutropenia,     anaemia,             coagulation                               transient increase late neutropenia4 lymphatic       leucopenia,      +pancytopenia,       disorders, aplastic                       in serum IgM +febrile         +granulocytopeni system                                                anaemia,                                  levels4 disorders       neutropenia,     a                    haemolytic
+thrombocytopen anaemia,
ia                                    lymphadenopathy
Immune          infusion-related hypersensitivity                           anaphylaxis         tumour lysis         infusion-related system          reactions5,                                                                     syndrome,            acute reversible disorders       angioedema                                                                      cytokine release     thrombocytopenia5 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 neuropathy, system                           hypoaesthesia,                                                 neuropathy,          loss of other disorders                        agitation,                                                     facial nerve         senses6 insomnia,                                                      palsy6 vasodilatation,
dizziness, anxiety
Eye disorders                    lacrimation                                                    severe vision disorder,                                                      loss6 conjunctivitis
Ear and                          tinnitus, ear pain                                                                  hearing loss6 labyrinth disorders
+myocardial           +left ventricular
Cardiac                                                                     severe cardiac      heart failure5, 7 disorders                        infarction5 , 7,      failure,             disorders 5,7 +supraventricular arrhythmia,
+atrial fibrillation, tachycardia,
+ventricular tachycardia,
+cardiac disorder     tachycardia,
+angina,
+myocardial
 ischaemia,
bradycardia
Vascular                         hypertension,                                                  vasculitis disorders                        orthostatic                                                    (predominately hypotension,                                                   cutaneous), hypotension                                                    leukocytoclastic vasculitis
Respiratory,                     Bronchospasm5,       asthma,               interstitial lung   respiratory          lung infiltration thoracic and                     respiratory          bronchiolitis         disease8            failure5 mediastinal                      disease, chest       obliterans, lung disorders                        pain, dyspnoea,      disorder, hypoxia increased cough,
rhinitis
Gastrointestina nausea           vomiting,            abdominal                                 gastro- intestinal l disorders                      diarrhoea,           enlargement                               perforation8 abdominal pain,
dysphagia,
stomatitis,
constipation,
dyspepsia,
anorexia, throat irritation



    MedDRA
System Organ      Very Common           Common              Uncommon              Rare           Very Rare           Not Known Class
Skin and          pruritus, rash,    urticaria,                                                severe bullous subcutaneous      +alopecia          sweating, night                                           skin reactions, tissue                               sweats, +skin                                             Stevens-Johnson disorders                            disorder                                                  syndrome, toxic epidermal necrolysis
(Lyell’s syndrome)8
Musculoskeleta                       hypertonia,
l and                                myalgia,
connective                           arthralgia, back tissue                               pain, neck pain,
disorders                            pain
Renal and                                                                                      renal failure5 urinary disorders
General         fever, chills,       tumour pain,       infusion site pain disorders and   asthenia,            flushing, malaise,
administration headache              cold syndrome,
site 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 rituximab 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 rituximab 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 rituximab (containing) treatment.


Description of selected adverse reactions

Infections
Rituximab 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 rituximab-containing arm of randomised studies. Severe infections were reported in about 4% of patients treated with rituximab monotherapy. Higher frequencies of infections overall, including grade 3 or 4 infections, were observed during rituximab 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 rituximab treatment. The majority of patients had received rituximab in combination with chemotherapy or as part of a hematopoietic 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 re-treatment have also been reported in clinical trials. Cases of hepatitis B reactivation, have been reported, the majority of which were in patients receiving rituximab 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 rituximab-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 rituximab 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 rituximab 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 rituximab 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 rituximab 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 1 x 109/L between Day 24 and 42 after the last dose) or occurred with a late onset (defined as neutrophil count below 1 x 109/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 rituximab 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 rituximab 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 rituximab 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 rituximab 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 rituximab 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 rituximab compared to < 1% on observation. In studies evaluating rituximab 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 rituximab 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 rituximab for treatment of non-Hodgkin's lymphoma. In the majority of these cases, rituximab was administered with chemotherapy.

IgG levels
In the clinical trial evaluating rituximab 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 rituximab groups. In the observation group, the median IgG level subsequently increased to above the LLN, but remained constant in the rituximab group. The proportion of patients with IgG levels below the LLN was about 60% in the rituximab 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 rituximab, 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 - rituximab 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 rituximab was similar to the percentage of patients reporting adverse reactions upon initial exposure (any grade and grade 3/4 adverse reactions).

Patient subpopulations - rituximab 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 rituximab in rheumatoid arthritis is based on data from patients from clinical trials and from post-marketing surveillance.

The safety profile of rituximab 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 rituximab (see section 4.4).

Patients received 2 x 1000 mg of rituximab separated by an interval of two weeks; in addition to methotrexate (10-25 mg/week). Rituximab 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 < 1/1,000), 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 rituximab 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 rituximab, 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 rituximab MedDRA                                                                                                                           Not known Very            Commo
System                                        Uncommon                Rare                           Very rare Common             n
Organ Class
Infections      upper              bronchiti                                           PML, reactivation of hepatitis B      serious and             respiratory        s,                                                                                        viral infestations    tract              sinusitis,                                                                                infection1,2, infection,         gastroent                                                                                 enteroviral urinary tract      eritis,                                                                                   meningoencephaliti infections         tinea                                                                                     s2 pedis
Blood and                          neutrope                         late               serum sickness-like reaction lymphatic                          nia3                             neutropenia4 system disorders
5                               5
Immune            infusion-relat                  infusion-relate system          ed reactions                    d reactions disorders       (hypertension,                  (generalised nausea, rash,                   oedema,
pyrexia,                        bronchospasm,
pruritus,                       wheezing,
urticaria,                      laryngeal throat                          oedema,
General         irritation, hot                 angioneurotic disorders       flush,                          oedema,
and             hypotension,                    generalised administrati    rhinitis,                       pruritus,
on site         rigors,                         anaphylaxis,
conditions      tachycardia,                    anaphylactoid fatigue,                        reaction) oropharyngea l pain,
oedema peripheral,
erythema)
Metabolism                         hypercho and                                lesterole nutrition                          mia disorders
Psychiatric                        depressio disorders                          n,
anxiety
Nervous         headache           paraesthe system                             sia,
disorders                          migraine,
dizziness
, sciatica
Cardiac                                                             angina             atrial flutter disorders                                                           pectoris, atrial fibrillation,
heart failure,
myocardial infarction
Gastrointesti                      dyspepsi nal disorders                      a,
diarrhoea
,
gastro-oe sophagea l reflux,
mouth ulceratio n, upper abdomin al pain
Skin and                           alopecia                                            toxic epidermal necrolysis (Lyell’s subcutaneou                                                                            syndrome), Stevens-Johnson s tissue                                                                               syndrome7 disorders



MedDRA                                                                                                                       Not known Very           Commo
System                                         Uncommon               Rare                        Very rare Common            n
Organ Class
Musculoskel                         arthralgia etal                                / disorders                           musculos and                                 keletal connective                          pain,
tissue                              osteoarth disorders                           ritis,
bursitis
Investigation      decreased        decrease s                  IgM levels6      d IgG 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 rituximab 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 rituximab in clinical studies were IRRs (refer to Table 2). Among the 3189 patients treated with rituximab, 1135 (36%) experienced at least one IRR with 733/3189 (23%) of patients experiencing an IRR following first infusion of the first exposure to rituximab. 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 rituximab 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 rituximab. 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 rituximab 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 rituximab. Lower respiratory tract infections (including pneumonia) have been reported during clinical trials, at a similar incidence in the rituximab 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 rituximab 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 rituximab 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 rituximab (see section 4.4).

Cardiovascular adverse reactions
Serious cardiac reactions were reported at a rate of 1.3 per 100 patient years in the rituximab 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 rituximab treatment, the majority of which were transient and mild or moderate in severity. Neutropenia can occur several months after the administration of rituximab (see section 4.4).

In placebo-controlled periods of clinical trials, 0.94% (13/1382) of rituximab 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 rituximab. 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 rituximab, 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 rituximab (375 mg/m2, once weekly for 4 weeks) and glucocorticoids (see section 5.1).

The adverse reactions 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 rituximab 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 rituximab in GPA/MPA Study, (Rituximab n=99) ,at a higher frequency than the comparator group, or during post- marketing surveillance.

MedDRA System                Very Common               Common                 Not known Organ Class
Infections and                                         Urinary tract          Serious viral infection 1,2, infestations                                           infection,             enteroviral bronchitis , herpes    meningoencephalitis zoster,
nasopharyngitis,
Blood and lymphatic                                    thrombocytopenia system disorders
Immune system                                          cytokine release disorders                                              syndrome
Metabolism and                                         hyperkalaemia nutrition disorders
Psychiatric disorders        insomnia
Nervous system               dizziness, tremor disorders
Vascular disorders           hypertension              flushing
Respiratory, thoracic        cough, dyspnoea,          nasal congestion and mediastinal              epistaxis disorders
Gastrointestinal             diarrhoea                 Dyspepsia,
disorders                                              constipation
Skin and subcutaneous                                  acne tissue disorders
Musculoskeletal and          Muscle spasms,            Muscle weakness, connective tissue            arthralgia, back pain     Musculoskeletal disorders                                              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 rituximab 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.
Rituximab was given in combination with intravenous glucocorticoids which may reduce the incidence and severity of these events.




Infections
In the 99 rituximab 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 rituximab 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 rituximab 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 rituximab 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 rituximab.


GPA/MPA Study, at 6 months, in the rituximab 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 rituximab 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 rituximab-treated patients. The effect of multiple rituximab 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 rituximab 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 rituximab 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 rituximab group (PV Study 1). Patients randomised to the rituximab 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, multicenter study evaluating the efficacy and safety of rituximab compared with mycophenolate mofetil (MMF) in patients with moderate-to-severe PV requiring oral corticosteroids, 67 PV patients received treatment with rituximab (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 rituximab 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 rituximab-treated PV patients, with a ≥ 2% absolute difference in incidence between the rituximab-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 rituximab 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 rituximab-treated pemphigus vulgaris patients in PV Study 1 (up to Month 24) and PV Study 2 (up to Week 52), or during postmarketing 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, oral herpes,   Enteroviral conjunctivitis,               meningoencephalitis1 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, urticaria, skin disorders                                                          disorder Musculoskeletal and connective                                     musculoskeletal pain, tissue disorders                                                   arthralgia, back pain General disorders and                                              fatigue, asthenia, pyrexia administration site conditions
Injury, poisoning and                infusion-related reactions3 procedural complications
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 rituximab 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 rituximab group experienced treatment-related infections compared to 15 patients (42%) in the standard-dose prednisone group. The most common infections in the rituximab group were herpes simplex and zoster infections, bronchitis, urinary tract infection, fungal infection and conjunctivitis. Three patients (8%) in the rituximab 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 rituximab arm experienced infections. The most common infections in the rituximab group were upper respiratory tract infection, nasopharyngitis, oral candidiasis and urinary tract infection. Six patients (9%) in the rituximab 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 rituximab 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/