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 < 1/1000), very rare (< 1/10,000) and not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in the order of decreasing seriousness.

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

Table 1          Adverse reactions reported in clinical trials or during post-marketing surveillance in patients with NHL and CLL disease treated with rituximab monotherapy/maintenance or in combination with chemotherapy
MedDRA
Very
System Organ                        Common             Uncommon            Rare             Very Rare      Not known Common
Class
Infections        bacterial      sepsis,                                serious viral    PML                enteroviral and               infections,    +pneumonia,                            infection2                          meningoence infestations      viral          +febrile infection,
Pneumocystis                        phalitis2, 3 infections,    +herpes zoster,
jirovecii
+bronchitis    +respiratory tract
 infection, fungal infections,
infections of unknown aetiology, +acute bronchitis,
+sinusitis,
 hepatitis B1
Blood and         neutropenia,   anaemia,              coagulation                       transient          late lymphatic         leucopenia,    +pancytopenia,        disorders,                        increase in        neutropenia4 system            +febrile       +granulocytopenia aplastic                          serum IgM disorders         neutropenia,                         anaemia,                          levels4 +thrombocyt haemolytic openia                               anaemia,
lymphadenopa thy
Immune            infusion       hypersensitivity                       anaphylaxis      tumour lysis       infusion-rel system            related                                                                syndrome,          ated acute disorders         reactions5,                                                            cytokine           reversible angioedema                                                             release            thrombocyt syndrome5,         openia5 serum sickness
Metabolism                       hyperglycaemia,
and nutrition                    weight decrease,
disorders                        oedema peripheral, face oedema,
increased LDH,
hypocalcaemia
Psychiatric                                            depression,
disorders                                              nervousness,
Nervous                          paraesthesia,         dysgeusia                         peripheral         cranial system                           hypoaesthesia,                                          neuropathy,        neuropathy, disorders                        agitation,                                              facial nerve       loss of other insomnia,                                               palsy6             senses6 vasodilatation,
dizziness, anxiety
Eye disorders                    lacrimation                                             severe vision disorder,                                               loss6 conjunctivitis
Ear and                          tinnitus, ear pain                                                         hearing labyrinth                                                                                                   loss6 disorders
Cardiac                          +myocardial           +left            severe cardiac   heart failure5,7 disorders                        infarction5,7,        ventricular      disorders5,7 arrhythmia,           failure,
+atrial               +supraventricu
 fibrillation,         lar tachycardia,          tachycardia,
+cardiac disorder     +ventricular
 tachycardia,
+angina,
+myocardial


MedDRA
Very
System Organ                            Common             Uncommon             Rare            Very Rare          Not known Common
Class ischaemia,
bradycardia
Vascular                             hypertension,                                            vasculitis disorders                            orthostatic                                              (predominately hypotension,                                             cutaneous),
hypotension                                              leukocytoclastic vasculitis
Respiratory,                         Bronchospasm5,        asthma,          interstitial      respiratory          lung thoracic and                         respiratory           bronchiolitis    lung disease8     failure5             infiltration mediastinal                          disease, chest        obliterans, disorders                            pain, dyspnoea,       lung disorder, increased cough,      hypoxia rhinitis
Gastrointestin     nausea            vomiting,             abdominal                          gastro-intestinal al disorders                         diarrhoea,            enlargement                        perforation8 abdominal pain,
dysphagia,
stomatitis,
constipation,
dyspepsia,
anorexia, throat irritation
Skin and           pruritus,         urticaria,                                               severe bullous subcutaneous       rash,             sweating, night                                          skin reactions, tissue             +alopecia sweats, +skin                                            Stevens-Johnson disorders                            disorder                                                 syndrome, toxic epidermal necrolysis
(Lyell’s syndrome)8

Musculoskelet                        hypertonia,
al and                               myalgia,
connective                           arthralgia, back tissue                               pain, neck pain,
disorders                            pain
Renal and                                                                                     renal failure5 urinary disorders
General            fever, chills,    tumour pain,          infusion site disorders and      asthenia,         flushing, malaise,    pain 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 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 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 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 2 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 2       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 Organ         Very Common           Common                   Not known Class
Infections and infestations                       urinary tract infection, Serious viral infection1,2 , bronchitis,              Enteroviral herpes zoster,           meningoencephalitis1 nasopharyngitis
Blood and lymphatic                                      thrombocytopenia system disorders
Immune system disorders                                   cytokine release syndrome
Metabolism and nutrition                                   hyperkalaemia disorders
Psychiatric disorders          insomnia
Nervous system disorders       dizziness,
tremor
Vascular disorders             hypertension             flushing
Respiratory, thoracic and      cough,                   nasal congestion mediastinal disorders          dyspnoea,
epistaxis

Gastrointestinal               diarrhoea                dyspepsia,
disorders                                               constipation
Skin and subcutaneous                                   acne tissue disorders
Musculoskeletal                muscle spasms,           muscle weakness, and connective                 arthralgia,              musculoskeletal pain, tissue disorders               back pain                pain in extremities General disorders              oedema peripheral and 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 (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.

In 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, multicentre 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 3. 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 3             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 infestations                  upper respiratory tract       herpes virus infection          serious viral infection1,2 infection                     herpes zoster                   enteroviral oral herpes                     meningoencephalitis1 conjunctivitis nasopharyngitis oral candidiasis urinary tract infection

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

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

Description of selected adverse reactions

Infusion-related reactions
In PV Study 1, infusion-related reactions were common (58%). Nearly all infusion-related reactions were mild to moderate. The proportion of patients experiencing an infusion-related reaction was 29% (11 patients), 40% (15 patients), 13% (5 patients), and 10% (4 patients) following the first, second, third, and fourth infusions, respectively. No patients were withdrawn from treatment due to infusion- related reactions. Symptoms of infusion-related reactions were similar in type and severity to those seen in 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
Additionally, you can also report to Padagis via the following address: Padagis.co.il