Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Experience from non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia 
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 drug reactions (ADRs) 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 drug 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 ADRs reported include hepatitis B reactivation and PML (see section 4.4.).
Tabulated list of adverse reactions
The frequencies of ADRs reported with rituximab alone or in combination with chemotherapy are summarised in Table 1. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. 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 ADRs identified only during post-marketing surveillance, and for which a frequency could not be estimated, are listed under “not known”.
Table 1          ADRs 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
System Organ          Very
Common             Uncommon             Rare            Very Rare                Not known Class           Common
Infections and     bacterial      sepsis,                                serious viral      PML                    enteroviral +pneumonia,
infestations       infections,                                           infection2                                meningoencephal viral          +febrile infection,                    Pneumocystis                              itis2, 3 +herpes infections,             zoster,                       jirovecii
+bronchitis    +respiratory tract
 infection, fungal infections,
infections of unknown aetiology, +acute bronchitis,
+sinusitis,
 hepatitis B1
Blood and          neutropenia,   anaemia,              coagulation                         transient              late neutropenia3 +pancytopenia,
lymphatic          leucopenia,                          disorders,                          increase in +febrile       +granulocytopeni system                                                  aplastic                            serum IgM disorders          neutropenia,   a                     anaemia,                            levels3 +thrombocyt                          haemolytic openia                               anaemia,
lymphadenopa thy
Immune             infusion       hypersensitivity                       anaphylaxis        tumour lysis           infusion-related system             related                                                                  syndrome,              acute reversible disorders          reactions4,                                                              cytokine               thrombocytopenia angioedema                                                               release                4  syndrome4,
serum sickness
Metabolism                        hyperglycaemia,
and nutrition                     weight decrease,
disorders                         peripheral oedema, 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,                                                 palsy5                 senses5 vasodilatation,
dizziness, anxiety
Eye disorders                     lacrimation                                               severe vision disorder,                                                 loss5 conjunctivitis
Ear and                           tinnitus, ear pain                                                               hearing loss5 labyrinth disorders
+myocardial           +left
Cardiac                                                                  severe cardiac     heart failure4 and 6 disorders                         infarction4 and 6,    ventricular      disorders4 and 6 arrhythmia,           failure,
+atrial               +supraventricu
 fibrillation,         lar tachycardia,          tachycardia,
+cardiac disorder     +ventricular
 tachycardia,
+angina,
+myocardial ischaemia,
bradycardia
System Organ            Very
Common              Uncommon                Rare            Very Rare             Not known Class             Common
Vascular                               hypertension,                                                 vasculitis disorders                              orthostatic                                                   (predominatel hypotension,                                                  y cutaneous), hypotension                                                   leukocytoclast ic vasculitis
Respiratory,                           Bronchospasm4,         asthma,             interstitial       respiratory         lung infiltration thoracic and                           respiratory            bronchiolitis       lung disease7      failure4 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,                                               perforation7 dysphagia,
stomatitis,
constipation,
dyspepsia,
anorexia, throat irritation
Skin and             pruritus,         urticaria,                                                    severe bullous subcutaneous         rash,             sweating, night                                               skin reactions, tissue               +alopecia         sweats, +skin                                                 Stevens- disorders                              disorder                                                      Johnson syndrome,
toxic epidermal necrolysis
(Lyell’s syndrome) 7
Musculoskelet                          hypertonia,
al, connective                         myalgia,
tissue and                             arthralgia, back bone disorders                         pain, neck pain,
pain
Renal and                                                                                            renal failure4 urinary disorders
General              fever, chills,    tumour pain,           infusion site disorders and        asthenia,         flushing, malaise,     pain administration       headache          cold syndrome,
+fatigue,
site conditions
+shivering,
+multi-organ
 failure4
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 events 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.

Localized 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 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 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 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 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 events (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 patients (≥65 years)
The incidence of ADRs of all grades and grade 3/4 ADR was similar in elderly patients compared to younger patients (<65 years).

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

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

Patient subpopulations - rituximab combination therapy
Elderly patients (≥65 years)
The incidence of grade 3/4 blood and lymphatic adverse events was higher in elderly patients compared to younger patients (<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 < 1/1000), 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 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 postmarketing surveillance occurring in patients with rheumatoid arthritis receiving rituximab
MedDRA                 Very
Common                 Uncommon           Rare        Very rare       Not System Organ
Common                                                                                   known Class
Infections and       upper             Bronchitis, sinusitis,                                      PML,           Serious Infestations         respiratory       gastroenteritis, tinea                                      reactivation viral tract             pedis                                                       of hepatitis infection1, infection,                                                                    B            enterovira urinary tract                                                                              meningoenc infections                                                                                 ephaliti s2
Blood and                              neutropenia2                                 late           Serum lymphatic                                                                           neutropenia3   sickness- system                                                                                             like disorders                                                                                          reaction 4                                          4
Immune                Infusion                                   Infusion related System               related                                    reactions Disorders            reactions                                  (generalized General              (hypertension,                             oedema, disorders and        nausea, rash,                              bronchospasm, administration       pyrexia,                                   wheezing, site conditions      pruritus,                                  laryngeal urticaria,                                 oedema,
throat                                     angioneurotic irritation, hot                            oedema,
flush,                                     generalized hypotension,                               pruritus,
rhinitis,                                  anaphylaxis,
rigors,                                    anaphylactoid tachycardia,                               reaction) fatigue,
oropharyngeal pain,
peripheral oedema,
erythema)
Metabolism                             hypercholesterolemia and nutrition
Disorders
Psychiatric                            depression, anxiety disorders
Nervous System       headache          paraesthesia,
disorders                              migraine, dizziness,
sciatica
MedDRA
Very                                                                                      Not System Organ                               Common               Uncommon              Rare         Very rare Common                                                                                    known Class
Cardiac                                                                            angina          atrial disorders                                                                          pectoris,       flutter atrial fibrillation,
heart failure,
myocardial infarction
Gastrointestinal                      Dyspepsia,
Disorders                             diarrhoea, gastro- oesophageal reflux,
mouth ulceration,
upper abdominal pain
Skin and                              alopecia                                                     Toxic Subcutaneous                                                                                       Epidermal Tissue                                                                                             Necrolysis Disorders                                                                                          (Lyell’s syndrome),
Stevens-
Johnson syndrome6
Musculo                               arthralgia / skeletal                              musculoskeletal disorders and                         pain, osteoarthritis,
connective                            bursitis tissue disorders
Investigations         decreased       decreased IgG
IgM levels5     levels5
1
See also section infections below.
2
Frequency category derived from laboratory values collected as part of routine laboratory monitoring in clinical trials
3
Frequency category derived from post-marketing data.
4
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.
5
Includes observations collected as part of routine laboratory monitoring.
6
Includes fatal cases


Multiple courses
Multiple courses of treatment are associated with a similar ADR profile to that observed following first exposure. The rate of all ADRs 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 ADRs 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 (GPA) with polyangiitis and microscopic polyangiitis (MPA) 
Induction of remission (GPA/MPA Study 1)
In the GPA/MPA study 1, 99 patients were treated for induction of remission of GPA and MPA with rituximab (375 mg/m2, once weekly for 4weeks) and glucocorticoids (see section 5.1).

The ADRs listed in Table 3 were all adverse events which occurred at an incidence of ≥ 5% in the rituximab group and at a higher frequency than the comparator group.


Table 3     Adverse reactions occurring at 6 months in ≥ 5% of patients receiving rituximab in GPA / MPA Study 1 (Rituximab n=99 at a higher frequency than the comparator group), or during postmarketing surveillance.


MedDRA System organ class
Adverse reaction                                         Frequency
Infections and infestations
Urinary tract infection                                    7%
Bronchitis                                                 5%
Herpes zoster                                              5%
Nasopharyngitis                                            5%
Serious viral infection1                               not known
Enteroviral meningoencephalitis
1,2 not known
Blood and lymphatic system disorders
Thrombocytopenia                                           7%
Immune system disorders
Cytokine release syndrome                                  5%
Metabolism and nutrition disorders
Hyperkalaemia                                              5%
Psychiatric disorders
Insomnia                                                  14%
Nervous system disorders
Dizziness                                                 10%
Tremor                                                    10%
Vascular disorders
Hypertension                                              12%
Flushing                                                   5%
Respiratory, thoracic and mediastinal disorders
Cough                                                     12%
Dyspnoea                                                  11%
Epistaxis                                                 11%
Nasal congestion                                           6%
Gastrointestinal disorders
Diarrhoea                                                 18%
Dyspepsia                                                  6%
Constipation                                               5%
MedDRA System organ class
Adverse reaction                                                           Frequency Skin and subcutaneous tissue disorders
Acne                                                                            7% Musculoskeletal and connective tissue disorders
Muscle spasms                                                                   18% Arthralgia                                                                      15% Back pain                                                                       10% Muscle weakness                                                                  5% Musculoskeletal pain                                                             5% Pain in extremities                                                              5% General disorders and administration site conditions
Peripheral oedema                                                               16% Investigations
Decreased haemoglobin                                                           6% 1
Observed during post-marketing surveillance. See also section infections below.
2
See also infections below


Maintenance treatment (GPA/PA Study2)

In GPA/MPA Study 2, a total of 57 severe, active GPA and MPA were treated with rituximab for the maintenance of remission (see section 5.1).

Table 4         Adverse reactions occurring in ≥ 5% of patients receiving rituximab in GPA/MPA Study 2 (Rituximab n=57), and at a higher frequency than the comparator group, or during postmarketing surveillance.

MedDRA System Organ Class                                         Frequency Adverse reaction
Infections and infestations
Bronchitis                                                        14% Rhinitis                                                          5%
Serious viral infection1                                          not known General disorders and administration site conditions
Pyrexia                                                           9%
Influenza-like illness                                            5%
Oedema peripheral                                                 5%
Gastrointestinal disorders
Diarrhoea                                                         7%
Respiratory, thoracic and mediastinal disorders

Dyspnoea                                                          9%
Injury, poisoning and procedural complications
Infusion-related reactions2                                       12% 1Observed  during post-marketing surveillance. See also section infections below.
2Details on infusion related reactions are provided in the description of selected adverse drug reactions section.



The overall safety profile was consistent with the well-established safety profile for rituximab in approved autoimmune indications, including GPA and MPA. Overall, 4% of patients in the rituximab arm experienced adverse events leading to discontinuation. Most adverse events in the rituximab arm were mild or moderate in intensity. No patients in the rituximab arm had fatal adverse events.
The most commonly reported events considered as ADRs were infusion-related reactions and infections.

Long-term follow-up (GPA/MPA Study 3)
In a long-term observational safety study, 97 GPA and MPA patients received treatment with rituximab (mean of 8 infusions [range 1-28]) for up to 4 years, according to their physician’s standard practice and discretion. The overall safety profile was consistent with the well-established safety profile of rituximab in GPA and MPA and no new adverse drug reactions were reported.


Description of selected adverse drug reactions
Infusion related reactions
In GPA/MPA Study 1 (adult induction of remission study), IRRs 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 and 12 (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.
In GPA/MPA Study 2 (adult maintenance study),7/57 (12%) patients in the rituximab arm experienced at least one infusion-related reaction. The incidence of IRR symptoms was highest during or after the first infusion (9%) and decreased with subsequent infusions (<4%). All IRR symptoms were mild or moderate and most of them were reported from the SOCs Respiratory, Thoracic and Mediastinal Disorders and Skin and Subcutaneous Tissue disorders.

Infections
In GPA/MPA Study 1, 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 GPA/MPA Study 2, 30/57 (53%) patients in the rituximab arm experienced infections. The incidence of all grade infections was similar between the arms. Infections were predominately mild to moderate. The most common infections in the rituximab arm included upper respiratory tract infections, gastroenteritis, urinary tract infections and herpes zoster. The incidence of serious infections was similar in both arms (approximately 12%). The most commonly reported serious infection in the rituximab group was mild or moderate bronchitis.

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


Malignancies
In GPA/MPA Study 1, the incidence of malignancy in rituximab treated patients in the granulomatosis with polyangiitis and microscopic polyangiitis 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 standardized incidence ratios, the incidence of malignancies appears to be similar to that previously reported in patients with ANCA-associated vasculitis.

Cardiovascular adverse reactions
In GPA/MPA Study 1, 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 GPA and MPA 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.
In GPA/MPA Study 1, 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.

In GPA/MPA Study 2, no clinically meaningful differences between the two treatment arms or decreases in total immunoglobulin, IgG, IgM or IgA levels were observed throughout the trial.

Neutropenia
In GPA/MPA Study 1, 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.
In GPA/MPA Study 2, the incidence of all-grade neutropenia was 0% for rituximab- treated patients vs 5% for azathioprine treated patients.

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

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, multicenter, 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 randomized, 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

Adverse reactions from PV Studies 1 and 2 are presented in Table 5. In PV Study 1, ADRs 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 ADRs in Study 1. In PV Study 2, ADRs were defined as adverse events occurring in ≥ 5% of patients in the rituximab arm and assessed as related.

Table 5          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 post- marketing surveillance

MedDRA System Organ Class                  Very Common
Common                    Not known
Infections and                        Upper respiratory tract          Herpes virus infection    Serious viral infection1,2 infestations                          infection                        Herpes zoster             Enteroviral meningoencephalitis1 Oral herpes
Conjunctivitis
Nasopharyngitis
Oral candidiasis
Urinary tract infection

Neoplasms Benign,                                                      Skin papilloma Malignant 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, connective                                            Musculoskeletal pain tissue and bone disorders                                              Arthralgia Back pain
General disorders and                                                  Fatigue administration site conditions                                         Asthenia Pyrexia
Injury, Poisoning and                 Infusion-related
Procedural                            reactions2
Complications
1 Observed     during post-marketing surveillance. See also section infections below.
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 events 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 dyspnea, 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 (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
In 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