Source: European Medicines Agency (EU) Revision Year: 2023 Publisher: Celltrion Healthcare Hungary Kft., 1062 Budapest, Váci út 1-3. WestEnd Office Building B torony, Hungary
Hypersensitivity to the active substance or to murine proteins, or to any of the other excipients listed in section 6.1.
Active, severe infections (see section 4.4).
Patients in a severely immunocompromised state.
Hypersensitivity to the active substance or to murine proteins, or to any of the other excipients listed in section 6.1.
Active, severe infections (see section 4.4).
Patients in a severely immunocompromised state.
Severe heart failure (New York Heart Association Class IV) or severe, uncontrolled cardiac disease (see section 4.4 regarding other cardiovascular diseases).
In order to improve traceability of biological medicinal products, the tradename and batch number of the administered product should be clearly recorded (or stated) in the patient file.
All patients treated with rituximab for rheumatoid arthritis, GPA, MPA or pemphigus vulgaris must be given the patient alert card with each infusion. The alert card contains important safety information for patients regarding potential increased risk of infections, including PML.
Very rare cases of fatal PML have been reported following the use of rituximab. Patients must be monitored at regular intervals for any new or worsening neurological symptoms or signs that may be suggestive of PML. If PML is suspected, further dosing must be suspended until PML has been excluded. The clinician should evaluate the patient to determine if the symptoms are indicative of neurological dysfunction, and if so, whether these symptoms are possibly suggestive of PML. Consultation with a neurologist should be considered as clinically indicated.
Cases of enteroviral meningoencephalitis including fatalities have been reported following use of rituximab.
False negative serologic testing of infections:
Due to the risk of false negative serologic testing of infections, alternative diagnostic tools should be considered in case of patients presenting with symptoms indicative of rare infectious disease e.g. West Nile virus and neuroborreliosis.
If any doubt exists, further evaluation, including MRI scan preferably with contrast, cerebrospinal fluid (CSF) testing for JC Viral DNA and repeat neurological assessments, should be considered.
The physician should be particularly alert to symptoms suggestive of PML that the patient may not notice (e.g. cognitive, neurological or psychiatric symptoms). Patients should also be advised to inform their partner or caregivers about their treatment, since they may notice symptoms that the patient is not aware of.
If a patient develops PML, the dosing of rituximab must be permanently discontinued.
Following reconstitution of the immune system in immunocompromised patients with PML, stabilisation or improved outcome has been seen. It remains unknown if early detection of PML and suspension of rituximab therapy may lead to similar stabilisation or improved outcome.
Rituximab is associated with infusion-related reactions, which may be related to release of cytokines and/or other chemical mediators. Cytokine release syndrome may be clinically indistinguishable from acute hypersensitivity reactions.
This set of reactions which includes syndrome of cytokine release, tumour lysis syndrome and anaphylactic and hypersensitivity reactions are described below.
Severe infusion-related reactions with fatal outcome have been reported during post-marketing use of the rituximab intravenous formulation, with an onset ranging within 30 minutes to 2 hours after starting the first rituximab intravenous infusion. They were characterised by pulmonary events and in some cases included rapid tumour lysis and features of tumour lysis syndrome in addition to fever, chills, rigors, hypotension, urticaria, angioedema and other symptoms (see section 4.8).
Severe cytokine release syndrome is characterised by severe dyspnoea, often accompanied by bronchospasm and hypoxia, in addition to fever, chills, rigors, urticaria, and angioedema. This syndrome may be associated with some features of tumour lysis syndrome such as hyperuricaemia, hyperkalaemia, hypocalcaemia, hyperphosphataemia, acute renal failure, elevated lactate dehydrogenase (LDH) and may be associated with acute respiratory failure and death. The acute respiratory failure may be accompanied by events such as pulmonary interstitial infiltration or oedema, visible on a chest X-ray. The syndrome frequently manifests itself within one or two hours of initiating the first infusion. Patients with a history of pulmonary insufficiency or those with pulmonary tumour infiltration may be at greater risk of poor outcome and should be treated with increased caution. Patients who develop severe cytokine release syndrome should have their infusion interrupted immediately (see section 4.2) and should receive aggressive symptomatic treatment. Since initial improvement of clinical symptoms may be followed by deterioration, these patients should be closely monitored until tumour lysis syndrome and pulmonary infiltration have been resolved or ruled out. Further treatment of patients after complete resolution of signs and symptoms has rarely resulted in repeated severe cytokine release syndrome.
Patients with a high tumour burden or with a high number (≥25 × 109/L) of circulating malignant cells such as patients with CLL, who may be at higher risk of especially severe cytokine release syndrome, should be treated with extreme caution. These patients should be very closely monitored throughout the first infusion. Consideration should be given to the use of a reduced infusion rate for the first infusion in these patients or a split dosing over two days during the first cycle and any subsequent cycles if the lymphocyte count is still >25 × 109/L.
Infusion-related adverse reactions of all kinds have been observed in 77% of patients treated with rituximab (including cytokine release syndrome accompanied by hypotension and bronchospasm in 10% of patients) see section 4.8. These symptoms are usually reversible with interruption of rituximab infusion and administration of an anti-pyretic, an antihistaminic and occasionally oxygen, intravenous sodium chloride solution or bronchodilators, and glucocorticoids if required. Please see cytokine release syndrome above for severe reactions.
Anaphylactic and other hypersensitivity reactions have been reported following the intravenous administration of proteins to patients. In contrast to cytokine release syndrome, true hypersensitivity reactions typically occur within minutes after starting infusion. Medicinal products for the treatment of hypersensitivity reactions, e.g. epinephrine (adrenaline), antihistamines and glucocorticoids, should be available for immediate use in the event of an allergic reaction during administration of rituximab. Clinical manifestations of anaphylaxis may appear similar to clinical manifestations of the cytokine release syndrome (described above). Reactions attributed to hypersensitivity have been reported less frequently than those attributed to cytokine release.
Additional reactions reported in some cases were myocardial infarction, atrial fibrillation, pulmonary oedema and acute reversible thrombocytopenia.
Since hypotension may occur during rituximab administration, consideration should be given to withholding anti-hypertensive medicinal product 12 hours prior to the rituximab infusion.
Angina pectoris, cardiac arrhythmias such as atrial flutter and fibrillation, heart failure and/or myocardial infarction have occurred in patients treated with rituximab. Therefore, patients with a history of cardiac disease and/or cardiotoxic chemotherapy should be monitored closely.
Although rituximab is not myelosuppressive in monotherapy, caution should be exercised when considering treatment of patients with neutrophils <1.5 × 109/L and/or platelet counts <75 × 109/L as clinical experience in this population is limited. Rituximab has been used in 21 patients who underwent autologous bone marrow transplantation and other risk groups with a presumable reduced bone marrow function without inducing myelotoxicity.
Regular full blood counts, including neutrophil and platelet counts, should be performed during rituximab therapy.
Serious infections, including fatalities, can occur during therapy with rituximab (see section 4.8). Rituximab should not be administered to patients with an active, severe infection (e.g. tuberculosis, sepsis and opportunistic infections, see section 4.3).
Physicians should exercise caution when considering the use of rituximab in patients with a history of recurring or chronic infections or with underlying conditions which may further predispose patients to serious infection (see section 4.8).
Cases of hepatitis B reactivation have been reported in subjects receiving rituximab including fulminant hepatitis with fatal outcome. The majority of these subjects were also exposed to cytotoxic chemotherapy. Limited information from one study in relapsed/refractory CLL patients suggests that rituximab treatment may also worsen the outcome of primary hepatitis B infections. Hepatitis B virus (HBV) screening should be performed in all patients before initiation of treatment with rituximab. At minimum this should include HBsAg-status and HBcAb-status. These can be complemented with other appropriate markers as per local guidelines. Patients with active hepatitis B disease should not be treated with rituximab. Patients with positive hepatitis B serology (either HBsAg or HBcAb) should consult liver disease experts before start of treatment and should be monitored and managed following local medical standards to prevent hepatitis B reactivation.
Very rare cases of progressive multifocal leukoencephalopathy (PML) have been reported during post-marketing use of rituximab in NHL and CLL (see section 4.8). The majority of patients had received rituximab in combination with chemotherapy or as part of a haematopoietic stem cell transplant.
The safety of immunisation with live viral vaccines, following rituximab therapy has not been studied for NHL and CLL patients and vaccination with live virus vaccines is not recommended. Patients treated with rituximab may receive non-live vaccinations; however, with non-live vaccines response rates may be reduced. In a non-randomised study, adult patients with relapsed low-grade NHL who received rituximab monotherapy when compared to healthy untreated controls had a lower rate of response to vaccination with tetanus recall antigen (16% vs. 81%) and Keyhole Limpet Haemocyanin (KLH) neoantigen (4% vs. 76% when assessed for >2-fold increase in antibody titer). For CLL patients, similar results are assumable considering similarities between both diseases but that has not been investigated in clinical trials.
Mean pre-therapeutic antibody titres against a panel of antigens (Streptococcus pneumoniae, influenza A, mumps, rubella, varicella) were maintained for at least 6 months after treatment with rituximab.
Severe skin reactions such as Toxic Epidermal Necrolysis (Lyell’s syndrome) and Stevens-Johnson syndrome, some with fatal outcome, have been reported (see section 4.8). In case of such an event, with a suspected relationship to rituximab, treatment should be permanently discontinued.
Only limited data are available for patients under 3 years of age. See section 5.1 for further information.
The use of rituximab is not recommended in MTX-naïve patients since a favourable benefit risk relationship has not been established.
Rituximab is associated with infusion related reactions (IRRs), which may be related to release of cytokines and/or other chemical mediators.
Severe IRRs with fatal outcome have been reported in rheumatoid arthritis patients in the post-marketing setting. In rheumatoid arthritis most infusion-related events reported in clinical trials were mild to moderate in severity. The most common symptoms were allergic reactions like headache, pruritus, throat irritation, flushing, rash, urticaria, hypertension, and pyrexia. In general, the proportion of patients experiencing any infusion reaction was higher following the first infusion than following the second infusion of any treatment course. The incidence of IRR decreased with subsequent courses (see section 4.8). The reactions reported were usually reversible with a reduction in rate, or interruption, of rituximab infusion and administration of an anti-pyretic, an antihistamine, and, occasionally, oxygen, intravenous sodium chloride solution or bronchodilators, and glucocorticoids if required. Closely monitor patients with pre-existing cardiac conditions and those who experienced prior cardiopulmonary adverse reactions. Depending on the severity of the IRR and the required interventions, temporarily or permanently discontinue rituximab. In most cases, the infusion can be resumed at a 50% reduction in rate (e.g. from 100 mg/h to 50 mg/h) when symptoms have completely resolved.
Medicinal products for the treatment of hypersensitivity reactions, e.g. epinephrine (adrenaline), antihistamines and glucocorticoids, should be available for immediate use in the event of an allergic reaction during administration of rituximab.
There are no data on the safety of rituximab in patients with moderate heart failure (NYHA class III) or severe, uncontrolled cardiovascular disease. In patients treated with rituximab, the occurrence of pre-existing ischemic cardiac conditions becoming symptomatic, such as angina pectoris, has been observed, as well as atrial fibrillation and flutter. Therefore, in patients with a known cardiac history, and those who experienced prior cardiopulmonary adverse reactions the risk of cardiovascular complications resulting from infusion reactions should be considered before treatment with rituximab and patients closely monitored during administration. Since hypotension may occur during rituximab infusion, consideration should be given to withholding anti-hypertensive medicinal product 12 hours prior to the rituximab infusion.
IRRs in patients with GPA, MPA and pemphigus vulgaris were consistent with those seen for rheumatoid arthritis patients in clinical trials and in the post-marketing setting (see section 4.8).
Angina pectoris, cardiac arrhythmias such as atrial flutter and fibrillation, heart failure and/or myocardial infarction have occurred in patients treated with rituximab. Therefore patients with a history of cardiac disease should be monitored closely (see Infusion-related reactions, above).
Based on the mechanism of action of rituximab and the knowledge that B cells play an important role in maintaining normal immune response, patients have an increased risk of infection following rituximab therapy (see section 5.1). Serious infections, including fatalities, can occur during therapy with rituximab (see section 4.8). Rituximab should not be administered to patients with an active, severe infection (e.g. tuberculosis, sepsis and opportunistic infections, see section 4.3) or severely immunocompromised patients (e.g. where levels of CD4 or CD8 are very low). Physicians should exercise caution when considering the use of rituximab in patients with a history of recurring or chronic infections or with underlying conditions which may further predispose patients to serious infection, e.g. hypogammaglobulinaemia (see section 4.8). It is recommended that immunoglobulin levels are determined prior to initiating treatment with rituximab.
Patients reporting signs and symptoms of infection following rituximab therapy should be promptly evaluated and treated appropriately. Before giving a subsequent course of rituximab treatment, patients should be re-evaluated for any potential risk for infections.
Very rare cases of fatal progressive multifocal leukoencephalopathy (PML) have been reported following use of rituximab for the treatment of rheumatoid arthritis and autoimmune diseases including Systemic Lupus Erythematosus (SLE) and vasculitis.
Cases of enteroviral meningoencephalitis including fatalities have been reported following use of rituximab.
False negative serologic testing of infections:
Due to the risk of false negative serologic testing of infections, alternative diagnostic tools should be considered in case of patients presenting with symptoms indicative of rare infectious disease e.g. West Nile virus and neuroborreliosis.
Cases of hepatitis B reactivation, including those with a fatal outcome, have been reported in rheumatoid arthritis, GPA and MPA patients receiving rituximab.
Hepatitis B virus (HBV) screening should be performed in all patients before initiation of treatment with rituximab. At minimum this should include HBsAg-status and HBcAb-status. These can be complemented with other appropriate markers as per local guidelines. Patients with active hepatitis B disease should not be treated with rituximab. Patients with positive hepatitis B serology (either HBsAg or HBcAb) should consult liver disease experts before start of treatment and should be monitored and managed following local medical standards to prevent hepatitis B reactivation.
Measure blood neutrophils prior to each course of rituximab, and regularly up to 6-months after cessation of treatment, and upon signs or symptoms of infection (see section 4.8).
Severe skin reactions such as Toxic Epidermal Necrolysis (Lyell’s syndrome) and Stevens-Johnson syndrome, some with fatal outcome, have been reported (see section 4.8). In case of such an event with a suspected relationship to rituximab, treatment should be permanently discontinued.
Physicians should review the patient’s vaccination status and patients should, if possible, be brought up- to-date with all immunisations in agreement with current immunisation guidelines prior to initiating rituximab therapy. Vaccination should be completed at least 4 weeks prior to first administration of rituximab.
The safety of immunisation with live viral vaccines following rituximab therapy has not been studied. Therefore vaccination with live virus vaccines is not recommended whilst on rituximab or whilst peripherally B cell depleted.
Patients treated with rituximab may receive non-live vaccinations; however, response rates to non-live vaccines may be reduced. In a randomised trial, patients with rheumatoid arthritis treated with rituximab and methotrexate had comparable response rates to tetanus recall antigen (39% vs. 42%), reduced rates to pneumococcal polysaccharide vaccine (43% vs. 82% to at least 2 pneumococcal antibody serotypes), and KLH neoantigen (47% vs. 93%), when given 6 months after rituximab as compared to patients only receiving methotrexate. Should non-live vaccinations be required whilst receiving rituximab therapy, these should be completed at least 4 weeks prior to commencing the next course of rituximab.
In the overall experience of rituximab repeat treatment over one year in rheumatoid arthritis, the proportions of patients with positive antibody titres against S. pneumoniae, influenza, mumps, rubella, varicella and tetanus toxoid were generally similar to the proportions at baseline.
The concomitant use of rituximab and anti-rheumatic therapies other than those specified under the rheumatoid arthritis indication and posology is not recommended.
There are limited data from clinical trials to fully assess the safety of the sequential use of other DMARDs (including TNF inhibitors and other biologics) following rituximab (see section 4.5). The available data indicate that the rate of clinically relevant infection is unchanged when such therapies are used in patients previously treated with rituximab, however patients should be closely observed for signs of infection if biologic agents and/or DMARDs are used following rituximab therapy.
Immunomodulatory medicinal products may increase the risk of malignancy. However, available data do not suggest an increased risk of malignancy for rituximab used in autoimmune indications beyond the malignancy risk already associated with the underlying autoimmune condition.
This medicinal product contains 2.3 mmol (or 52.6 mg) sodium per 10 mL vial and 11.5 mmol (or 263.2 mg) sodium per 50 mL vial, equivalent to 2.6% (for 10 ml vial) and 13.2% (for 50 ml vial) of the WHO recommended maximum daily intake of 2 g sodium for an adult.
Currently, there are limited data on possible drug interactions with rituximab.
In CLL patients, co-administration with rituximab did not appear to have an effect on the pharmacokinetics of fludarabine or cyclophosphamide. In addition, there was no apparent effect of fludarabine and cyclophosphamide on the pharmacokinetics of rituximab.
Co-administration with methotrexate had no effect on the pharmacokinetics of rituximab in rheumatoid arthritis patients.
Patients with human anti-mouse antibody (HAMA) or anti-drug antibody (ADA) titres may have allergic or hypersensitivity reactions when treated with other diagnostic or therapeutic monoclonal antibodies.
In patients with rheumatoid arthritis, 283 patients received subsequent therapy with a biologic DMARD following rituximab. In these patients the rate of clinically relevant infection while on rituximab was 6.01 per 100 patient years compared to 4.97 per 100 patient years following treatment with the biologic DMARD.
Due to the long retention time of rituximab in B cell depleted patients, women of childbearing potential should use effective contraceptive methods during and for 12 months following treatment with rituximab.
IgG immunoglobulins are known to cross the placental barrier. B cell levels in human neonates following maternal exposure to rituximab have not been studied in clinical trials. There are no adequate and well-controlled data from studies in pregnant women, however transient B-cell depletion and lymphocytopenia have been reported in some infants born to mothers exposed to rituximab during pregnancy. Similar effects have been observed in animal studies (see section 5.3). For these reasons rituximab should not be administered to pregnant women unless the possible benefit outweighs the potential risk.
Limited data on rituximab excretion into breast milk suggest very low rituximab concentrations in milk (relative infant dose less than 0.4%). Few cases of follow-up of breastfed infants describe normal growth and development up to 2years. However, as these data are limited and the long-term outcomes of breastfed infants remain unknown, breastfeeding is not recommended while being treated with rituximab and optimally for 6 months following rituximab treatment.
Animal studies did not reveal deleterious effects of rituximab on reproductive organs.
Rituximab has no or negligible influence on the ability to drive and use machines.
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 frequent reported or observed serious adverse drug reactions were:
Other serious ADRs reported include hepatitis B reactivation and PML (see section 4.4).
The frequencies of ADRs reported with rituximab alone or in combination with chemotherapy are summarised in Table 3. 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 ADRs identified only during post-marketing surveillance, and for which a frequency could not be estimated, are listed under “not known”.
Table 3. 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:
| MedDRA system organ class | Very common | Common | Uncommon | Rare | Very rare | Not known |
|---|---|---|---|---|---|---|
| Infections and infestations | bacterial infections, viral infections, +bronchitis | sepsis, +pneumonia, +febrile infection, +herpes zoster, +respiratory tract infection, fungal infections, infections of unknown aetiology, +acute bronchitis, +sinusitis, hepatitis B1 | serious viral infection2 pneumocystis jirovecii | PML | enteroviral meningoencephalitis2,3 | |
| Blood and lymphatic system disorders | neutropenia, leucopenia, +febrile neutropenia, +thrombocytopenia | anaemia, +pancytopenia, +granulocytopenia | coagulation disorders, aplastic anaemia, haemolytic anaemia, lymphadenopathy | transient increase in serum IgM levels4 | late neutropenia4 | |
| Immune system disorders | infusion-related reactions5, angioedema | hypersensitivity | anaphylaxis | tumour lysis syndrome, cytokine release syndrome5, serum sickness | infusion-related acute reversible thrombocytopenia5 | |
| Metabolism and nutrition disorders | hyperglycaemia, weight decrease, peripheral oedema, face oedema, increased LDH, hypocalcaemia | |||||
| Psychiatric disorders | depression, nervousness | |||||
| Nervous system disorders | paraesthesia, hypoaesthesia, agitation, insomnia, vasodilatation, dizziness, anxiety | dysgeusia | peripheral neuropathy, facial nerve palsy6 | cranial neuropathy, loss of other senses6 | ||
| Eye disorders | lacrimation disorder, conjunctivitis | severe vision loss6 | ||||
| Ear and labyrinth disorders | tinnitus, ear pain | hearing loss6 | ||||
| Cardiac disorders | +myocardial Infarction5,7, arrhythmia, +atrial fibrillation, tachycardia, +cardiac disorder | +left ventricular failure, +supraventricular tachycardia, +ventricular tachycardia, +angina, +myocardial ischaemia, bradycardia | severe cardiac disorders5,7 | heart failure5,7 | ||
| Vascular disorders | hypertension, orthostatic hypotension, hypotension | vasculitis (predominately cutaneous), leukocytoclastic vasculitis | ||||
| Respiratory, thoracic and mediastinal disorders | Bronchospasm5, respiratory disease, chest pain, dyspnoea, increased cough, rhinitis | asthma, bronchiolitis obliterans, lung disorder, hypoxia | interstitial lung disease8 | respiratory failure5 | lung infiltration | |
| Gastrointestinal disorders | nausea | vomiting, diarrhoea, abdominal pain, dysphagia, stomatitis, constipation, dyspepsia, anorexia, throat irritation | abdominal enlargement | gastrointestinal perforation8 | ||
| Skin and subcutaneous tissue disorders | pruritus, rash, +alopecia | urticaria, sweating, night sweats, +skin disorder | severe bullous skin reactions, Stevens- Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome)8 | |||
| Musculoskeletal, connective tissue disorders | hypertonia, myalgia, arthralgia, back pain, neck pain, pain | |||||
| Renal and urinary renal failure disorders | renal failure5 | |||||
| General disorders and administration site conditions | fever, chills, asthenia, headache | tumour pain, flushing, malaise, cold syndrome, +fatigue, +shivering, +multi-organ Failure5 | infusion site pain | |||
| 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.
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 19 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 ¾ 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 ¾) 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 ¾) and neutropenia (10% vs. 4%, grade ¾) were reported at a higher incidence when compared to observation. The incidence of thrombocytopenia was low (<1%, grade ¾) and was not different between treatment arms. During the treatment course in studies with rituximab in combination with chemotherapy, grade ¾ 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 ¾ 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 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 ¾ 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).
Cases of interstitial lung disease, some with fatal outcome, have been reported.
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 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.
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.
Toxic Epidermal Necrolysis (Lyell’s syndrome) and Stevens-Johnson syndrome, some with fatal outcome, have been reported very rarely.
The incidence of ADRs of all grades and grade ¾ ADR was similar in elderly patients compared to younger patients (<65 years).
There was a higher incidence of grade ¾ 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.
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 ¾ ADRs).
The incidence of grade ¾ blood and lymphatic adverse events was higher in elderly patients compared to younger patients (<65 years), with previously untreated or relapsed/refractory CLL.
A multicenter, open-label randomized study of Lymphome Malin B chemotherapy (LMB) with or without rituximab was conducted in paediatric patients (aged ≥6 months to <18 years old) with previously untreated advanced stage CD20 positive DLBCL/BL/BAL/BLL.
A total of 309 paediatric patients received rituximab and were included in the safety analysis population. Paediatric patients randomized to the LMB chemotherapy arm with rituximab, or enrolled in the single arm part of the study, were administered rituximab at a dose of 375mg/m² BSA and received a total of six intravenous infusions of rituximab (two during each of the two induction courses and one during each of the two consolidation courses of the LMB scheme).
The safety profile of rituximab in paediatric patients (aged ≥ 6 months to <18 years old) with previously untreated advanced stage CD20 positive DLBCL/BL/BAL/BLL was generally consistent in type, nature and severity with the known safety profile in adult NHL and CLL patients. Addition of rituximab to chemotherapy did result in an increased risk of some events including infections (including sepsis) compared to chemotherapy only.
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 3,100 patients received at least one treatment course and were followed for periods ranging from 6 months to over 5 years; approximately 2,400 patients received two or more courses of treatment with over 1,000 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 × 1,000 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.
Adverse reactions are listed in Table 4. Frequencies are defined as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), 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 4. Summary of adverse drug reactions reported in clinical trials or during post-marketing surveillance occurring in patients with rheumatoid arthritis receiving rituximab:
| MedDRA system organ class | Very common | Common | Uncommon | Rare | Very rare | Not known |
|---|---|---|---|---|---|---|
| Infections and infestations | upper respiratory tract infection, urinary tract infections | bronchitis, sinusitis, gastroenteritis, tinea pedís | PML, reactivation of hepatitis B | Serious viral infection1, enteroviral meningoencephalitis2 | ||
| Blood and lymphatic system disorders | Neutropenia3 | late neutropenia4 | serum sickness-like reaction | |||
| Immune system disorders | 5infusion-related reactions (hypertension, nausea, rash, pyrexia, pruritus, urticaria, throat irritation, hot flush, hypotension, rhinitis, rigors, tachycardia, fatigue, oropharyngeal pain, peripheral oedema, erythma) | 5infusion-related reactions (generalised oedema, bronchospasm, wheezing, laryngeal oedema, angioneurotic oedema, generalised pruritis, anaphylaxis, anaphylactoid reaction) | ||||
| General disorders and administration site conditions | ||||||
| Metabolism and nutritional disorders | hypercholesterolemia | |||||
| Psychiatric disorders | depression, anxiety | |||||
| Nervous system disorders | headache | paraesthesia, migraine, dizziness, sciatica | ||||
| Cardiac disorders | angina pectoris, atrial fibrillation, heart failure, myocardial infarction | atrial flutter | ||||
| Gastrointestinal disorders | dyspepsia, diarrhoea, gastro- oesophageal reflux, mouth ulceration, upper abdominal pain | |||||
| Skin and subcutaneous tissue disorders | alopecia | toxic epidermal necrolysis (Lyell’s syndrome), Stevens- Johnson syndrome7 | ||||
| Musculoskeletal disorders | arthralgia / musculoskeletal pain, osteoarthritis, bursitis | |||||
| Investigations | decreased IgM levels6 | decreased 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.
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.
The most frequent ADRs following receipt of rituximab in clinical trials were IRRs (refer to Table 4). Among the 3189 patients treated with rituximab, 1,135 (36%) experienced at least one IRR with 733/3,189 (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.
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 intravenous 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 rheumatoid arthritis patients receiving rituximab (see section 4.4).
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.
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.
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-treated 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.
Toxic Epidermal Necrolysis (Lyell’s syndrome) and Stevens-Johnson syndrome, some with fatal outcome, have been reported very rarely.
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.
In GPA/MPA Study 1, 99 adult patients were treated for induction of remission of GPA and MPA with rituximab (375 mg/m², once weekly for 4 weeks) and glucocorticoids (see section 5.1).
The ADRs listed in Table 5 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 5. Adverse drug reactions occurring at 6-months in ≥5% of adult patients receiving rituximab in GPA/MPA Study 1 (Rituximab n=99, and at a higher frequency than the comparator group), or during postmarketing surveillance:
| MedDRA system organ class Adverse reactions | Frequency |
|---|---|
| Infections and infestations | |
| Urinary tract infection | 7% |
| Bronchitis | 5% |
| Herpes zoster | 5% |
| Nasopharyngitis | 5% |
| Serious viral infection1,2 | Not known |
| Enteroviral meningoencephalitis1 | 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% |
| 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.
2 See also section infections below.
In GPA/MPA Study 2, a total of 57 adult patients with severe, active GPA and MPA were treated with rituximab for the maintenance of remission (see section 5.1).
Table 6. Adverse reactions occurring in ≥5% of adult patients receiving rituximab in GPA/MPA Study 2 (Rituximab n=57), at a higher frequency than the comparator group, or during postmarketing surveillance:
| MedDRA system organ class Adverse reaction | Frequency |
|---|---|
| Infections and infestations | |
| Bronchitis | 14% |
| Rhinitis | 5% |
| Serious viral infection1,2 | Not known |
| Enteroviral meningoencephalitis1 | 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 reactions3 | 12% |
1 Observed during post-marketing surveillance.
2 See also section infections below.
3 Details 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.
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 RA and GPA and MPA and no new adverse drug reactions were reported.
An open-label, single arm study was conducted in 25 paediatric patients with severe, active GPA or MPA. The overall study period consisted of a 6-month remission induction phase with a minimum 18-month follow-up, up to 4.5 years overall. During the follow-up phase, rituximab was given at the discretion of the investigator (17 out of 25 patients received additional rituximab treatment). Concomitant treatment with other immunosuppressive therapy was permitted (see section 5.1).
ADRs were considered as adverse events that occurred at an incidence of ≥10%. These included: infections (17 patients [68%] in the remission induction phase; 23 patients [92%] in the overall study period), IRRs (15 patients [60%] in the remission induction phase; 17 patients [68%] in the overall study period), and nausea (4 patients [16%] in the remission induction phase; 5 patients [20%] in the overall study period).
During the overall study period, the safety profile of rituximab was consistent with that reported during the remission induction phase.
The safety profile of rituximab in paediatric GPA or MPA patients was consistent in type, nature and severity with the known safety profile in adult patients in the approved autoimmune indications, including adult GPA or MPA.
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, 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%).
In the clinical trial in paediatric patients with GPA or MPA, the reported IRRs were predominantly seen with the first infusion (8 patients [32%]), and then decreased over time with the number of rituximab infusions (20% with the second infusion, 12% with the third infusion and 8% with the fourth infusion). The most common IRR symptoms reported during the remission induction phase were: headache, rash, rhinorrhea and pyrexia (8%, for each symptom). The observed symptoms of IRRs were similar to those known in adult GPA or MPA patients treated with rituximab. The majority of IRRs were Grade 1 and Grade 2, there were two non-serious Grade 3 IRRs, and no Grade 4 or 5 IRRs reported. One serious Grade 2 IRR (generalized oedema which resolved with treatment) was reported in one patient (see section 4.4).
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 clinical trial in paediatric patients with severe, active GPA and MPA, 91% of reported infections were non-serious and 90% were mild to moderate.
The most common infections in the overall phase were: upper respiratory tract infections (URTIs) (48%), influenza (24%), conjunctivitis (20%), nasopharyngitis (20%), lower respiratory tract infections (16%), sinusitis (16%), viral URTIs (16%), ear infection (12%), gastroenteritis (12%), pharyngitis (12%), urinary tract infection (12%). Serious infections were reported in 7 patients (28%), and included: influenza (2 patients [8%]) and lower respiratory tract infection (2 patients [8%]) as the most frequently reported events.
In the post marketing setting, serious viral infections have been reported in GPA/MPA patients treated with rituximab.
In GPA/MPA Study 1, the incidence of malignancy in rituximab treated patients in the GPA and MPA clinical trial 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.
In the paediatric clinical trial, no malignancies were reported with a follow-up period of up to 54 months.
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).
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.
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 (IgA, IgG or IgM below the lower limit of normal) has been observed in adult and peadiatric 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.
In the paediatric clinical trial, during the overall study period, 3/25 (12%) patients reported an event of hypogammaglobulinaemia, 18 patients (72%) had prolonged (defined as Ig levels below lower limit of normal for at least 4 months) low IgG levels (of whom 15 patients also had prolonged low IgM). Three patients received treatment with intravenous immunoglobulin (IV-IG). Based on limited data, no firm conclusions can be drawn regarding whether prolonged low IgG and IgM led to an increased risk of serious infection in these patients. The consequences of long term B cell depletion in paediatric patients are unknown.
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.
Toxic Epidermal Necrolysis (Lyell’s syndrome) and Stevens-Johnson syndrome, some with fatal outcome, have been reported very rarely.
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 intravenous on Study Day 1 and a second 1000 mg intravenous on Study Day 15. Maintenance doses of 500 mg intravenous were administered at months 12 and 18. Patients could receive 1000 mg intravenous 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 intravenous on Study Day 1 and a second 1000 mg intravenous 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.
Adverse reactions from PV Studies 1 and 2 are presented in Table 7. 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 7. 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 infection | Herpes virus infection Herpes zoster Oral herpes Conjunctivitis Nasopharyngitis Oral candidiasis Urinary tract infection | Serious viral infection1,2 Enteroviral meningoencephalitis1 |
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | Skin papilloma | ||
| Psychiatric disorders | Persistent depressive disorder | Major depression Irritability | |
| Nervous system disorders | Headache | Dizziness | |
| Cardiac disorders | Tachycardia | ||
| Gastrointestinal disorders | Abdominal pain upper | ||
| Skin and subcutaneous tissue disorders | Alopecia | Pruritus Urticaria Skin disorder | |
| Musculoskeletal, connective tissue and bone disorders | Musculoskeletal pain Arthralgia Back pain | ||
| General disorders and administration site conditions | Fatigue Asthenia Pyrexia | ||
| Injury, poisoning and procedural complications | Infusion-related 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 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 dyspnoea, erythema, hyperhidrosis, flushing/hot flush, hypotension/low blood pressure and rash/rash pruritic.
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.
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.
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 intravenous 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 suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
No incompatibilities between rituximab and polyvinyl chloride or polyethylene bags or infusion sets have been observed.
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