Source: Health Products Regulatory Authority (ZA) Publisher: Dr. Reddys Laboratories (Pty) Ltd., Block B, 204 Rivonia Road, Morningside, Sandton, 2057
Very rare cases of fatal PML have been reported following 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.
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 REDDITUX 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 REDDITUX 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 rituximab 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 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 saline or bronchodilators, and glucocorticoids if required.
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 REDDITUX. 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 medicines 12 hours prior to the REDDITUX 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 REDDITUX 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 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 REDDITUX therapy.
Serious infections, including fatalities, can occur during therapy with rituximab. REDDITUX should not be administered to patients with an active, severe infection (e.g., tuberculosis, sepsis and opportunistic infections, see Section 4.3).
Medical practitioners should exercise caution when considering the use of REDDITUX 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 and reports of fulminant hepatitis, some of which were fatal have been reported in patients receiving rituximab. The majority of these subjects were also exposed to cytotoxic chemotherapy. The reports were confounded by both the underlying disease state and the 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 REDDITUX. At minimum this should include HBsAg-status and HBcAb-status. Patients with active hepatitis B disease should not be treated with REDDITUX. 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 hematopoietic stem cell transplant.
The safety of immunisation with live viral vaccines, following rituximab therapy has not been studied for NHL and CLL patients. Vaccination with live virus vaccines is therefore not recommended.
Patients treated with REDDITUX may receive non-live vaccinations. However, with non-live vaccines response rates may be reduced. In a non-randomised study, 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 titre). 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, and 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. In case of such an event, with a suspected relationship to REDDITUX, treatment should be permanently discontinued.
See section "4.2 Posology and method of administration, Special populations."
Rituximab is associated with infusion related reactions (IRRs), which may be related to release of cytokines and/or other chemical mediators.
Most infusion events reported 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 saline 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 infusion-related reaction and the required interventions, temporarily or permanently discontinue REDDITUX. 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 REDDITUX.
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 REDDITUX infusion, consideration should be given to withholding anti-hypertensive medications 12 hours prior to the REDDITUX 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 known 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 may have an increased risk of infection following rituximab therapy. Serious infections, including fatalities, can occur during therapy with rituximab (see Section 4.8). REDDITUX 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). Medical practitioners should exercise caution when considering the use of REDDITUX in patients with a history of recurring or chronic infections or with underlying conditions which may further predispose patients to serious infection, e.g., hypogammaglobulinemia (see Section 4.8). It is recommended that immunoglobulin levels are determined prior to initiating treatment with REDDITUX.
Patients reporting signs and symptoms of infection following REDDITUX therapy should be promptly evaluated and treated appropriately. Before giving a subsequent course of REDDITUX 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 autoimmune diseases including Systemic Lupus Erythematosus (SLE) and vasculitis.
Cases of hepatitis B reactivation, including those with a fatal outcome, have been reported in patients with granulomatosis with polyangiitis and microscopic polyangiitis.
Hepatitis B virus (HBV) screening should be performed in all patients before initiation of treatment with REDDITUX. At minimum this should include HBsAg-status and HBcAb-status. Patients with active hepatitis B disease should not be treated with REDDITUX. 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 REDDITUX, 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 a fatal outcome, have been reported (see Section 4.8). In case of such an event, treatment should be permanently discontinued.
Medical practitioners should review the patient’s vaccination status and follow current immunisation guidelines prior to REDDITUX therapy. Vaccination should be completed at least 4 weeks prior to first administration of REDDITUX.
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 REDDITUX therapy or whilst peripherally B cell depleted. Patients treated with REDDITUX may receive non-live vaccinations. However, response rates to non-live vaccines may be reduced. 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 REDDITUX.
Immuno-modulatory medicines may increase the risk of malignancy.
A diagnosis of any form of active tuberculosis should be explicitly excluded in patients considered for treatment with REDDITUX. Furthermore, a history of previous tuberculosis, HIV-infection, or a diagnosis of latent TB infection pose a risk for reactivation of tuberculosis disease and appropriate preventive therapy is indicated, regardless of HIV-status. Diagnosis and treatment of latent infection, following national guidelines, should be initiated prior to use of REDDITUX.
People initiating REDDITUX treatment, who initially tested negative for active or latent tuberculosis, should be systematically tested for latent TB infection during treatment with REDDITUX, and preventive treatment instituted if indicated.
REDDITUX 100 and 500 contains 2,27 mmol (or 52,26 mg) and 11,36 mmol (or 261,34 mg) sodium per 10 ml and 50 ml vial respectively. This needs to be taken into consideration by patients on a controlled sodium diet.
Limited data on possible drug interactions with rituximab is currently available.
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.
Patients with human anti-mouse antibody or human anti-chimeric antibody (HAMA/HACA) titres may have allergic or hypersensitivity reactions when treated with other diagnostic or therapeutic monoclonal antibodies.
Safety in pregnancy and lactation has not been established.
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. For these reasons REDDITUX should not be administered to pregnant women unless the possible benefit outweighs the potential risk.
It is not known if rituximab is excreted in human milk. However, because maternal IgG is excreted in human milk, and rituximab was detectable in milk from lactating monkeys, women should not breastfeed while being treated with REDDITUX and for 12 months following REDDITUX treatment.
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 REDDITUX.
Animal studies did not reveal deleterious effects of rituximab on reproductive organs.
No studies on the effects of rituximab on the ability to drive and use machines have been performed. Pharmacological activity and adverse reactions reported to date suggest that rituximab would have no or negligible influence on the ability to drive and use machines.
The overall safety profile of rituximab in non Hodgkin lymphoma and chronic lymphocytic leukaemia 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 infusion-related reactions, 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 to 55% of patients during clinical trials in patients with NHL and in 30 to 50% of patients during clinical trial 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 the tables below. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Frequencies are defined as very common (≥1/10), common (≥1/100 to <1/10) uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1000) and very rare (<1/10,000). The ADRs identified only during post-marketing surveillance, and for which a frequency could not be estimated, are listed under “unknown”.
Table 1. ADRs reported in clinical trials or during post-marketing surveillance in patients with NHL and CLL disease treated with rituximab monotherapy/maintenance or in combination with chemotherapy:
| System Organ Class | Very Common | Common | Uncommon | Rare | Very Rare | Unknown8 |
|---|---|---|---|---|---|---|
| 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 | ||
| Blood and lymphatic system disorders | neutropenia, leukopenia, +febrile neutropenia, +thrombocytopenia | anaemia, +pancytopenia, +granulocytopenia | coagulation disorders, aplastic anaemia, haemolytic anaemia, lymphadenopathy | transient increase in serum IgM levels3 | late neutropenia3 | |
| Immune system disorders | infusion related reactions4, angioedema | hypersensitivity | anaphylaxis | tumour lysis syndrome4, cytokine release syndrome4, serum sickness | infusion–related acute reversible thrombocytopenia4 | |
| Metabolism and nutrition disorders | hyperglycaemia, weight decrease, peripheral oedema, face oedema, increased LDH, hypocalcaemia | |||||
| Psychiatric disorders | depression, nervousness | |||||
| Nervous system disorders | paraesthesia, hypoesthesia, agitation, insomnia, vasodilatation, dizziness, anxiety | dysgeusia | peripheral neuropathy, facial nerve palsy5 | cranial neuropathy, loss of other senses5 | ||
| Eye disorders | lacrimation disorder, conjunctivitis | severe vision loss5 | ||||
| Ear and labyrinth disorders | tinnitus, ear pain | hearing loss5 | ||||
| Cardiac disorders | +myocardial infarction4,6, arrhythmia, +atrial fibrillation, tachycardia, +cardiac disorder | +left ventricular failure, +supraventricular tachycardia, +ventricular tachycardia, +angina, +myocardial ischaemia, bradycardia | severe cardiac events4,6 | heart failure4,6 | ||
| Vascular disorders | hypertension, orthostatic hypotension, hypotension | vasculitis (predominately cutaneous), leukocytoclastic vasculitis | ||||
| Respiratory, thoracic and mediastinal disorders | bronchospasm4, Respiratory disease, Chest pain, dyspnoea, increased cough, rhinitis | asthma, bronchiolitis obliterans, lung disorder, hypoxia | interstitial lung disease7 | respiratory failure4 | lung infiltration | |
| Gastro- intestinal disorders | nausea | vomiting, diarrhoea, abdominal pain, dysphagia, stomatitis, constipation, dyspepsia, anorexia, throat irritation | abdominal enlargement | gastro- intestinal perforation7 | ||
| Skin and sub- cutaneous tissue disorders | pruritus, rash, +alopecia | urticaria, sweating, night sweats, +skin disorder | severe bullous skin reactions, Stevens- Johnson syndrome, toxic epidermal necrolysis (Lyell’s Syndrome)7 | |||
| Musculo- skeletal, connective tissue and bone disorders | hypertonia, myalgia, arthralgia, back pain, neck pain, pain | |||||
| Renal and urinary disorders | renal failure4 | |||||
| General disorders and administration site conditions | fever, chills, asthenia, headache | tumour pain, flushing, malaise, cold syndrome, +fatigue, +shivering, +multi-organ failure4 | 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 see also section hematologic adverse reactions below
4 see also section infusion-related reactions below. Rarely fatal cases reported
5 signs and symptoms of cranial neuropathy. Occurred at various times up to several months after completion of rituximab therapy
6 observed mainly in patients with prior cardiac condition and/or cardiotoxic chemotherapy and were mostly associated with infusionrelated reactions
7 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: hematotoxicity, 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 and pulmonary oedema and acute reversible thrombocytopenia. Exacerbations of pre-existing cardiac conditions such as angina pectoris or congestive heart failure or severe cardiac events (heart failure, myocardial infarction, atrial fibrillation), pulmonary oedema, multi-organ failure, tumour lysis syndrome, cytokine release syndrome, renal failure, acute respiratory distress syndrome, ventricular fibrillation, cardiogenic shock 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 to 80% of patients, but was associated with decreased serum immunoglobulins only in a minority of patients.
Localised candida infections as well as Herpes zoster was reported at a higher incidence in the rituximab-containing arm of randomized studies. Severe infections were reported in about 4% of patients treated with rituximab monotherapy. Higher frequencies of infections overall, including grade 3 or 4 infections, were observed during rituximab maintenance treatment up to 2 years when compared to observation. There was no cumulative toxicity in terms of infections reported over a 2-year treatment period. In addition, other serious viral infections either new, reactivated or exacerbated, some of which were fatal, have been reported with rituximab treatment. The majority of patients had received rituximab in combination with chemotherapy or as part of a hematopoietic stem cell transplant. Examples of these serious viral infections are infections caused by the herpes viruses (Cytomegalovirus, Varicella Zoster Virus and Herpes Simplex Virus), JC virus (progressive multifocal leukoencephalopathy (PML)) and hepatitis C virus. 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 subjects 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.
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. 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 thrombocytopenias was reported in 11% of patients in the R-FC group compared to 9% of patients in the FC group.
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 ischemia) 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, 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% RFC, 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 recognized 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 lymphoma. In the majority of these cases, rituximab was administered with chemotherapy.
In the clinical trial evaluating rituximab maintenance treatment, 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.
The incidence of ADRs of all grades and grade 3/4 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.
99 patients were treated for induction of remission of GPA and MPA in an innovator’s clinical trial with rituximab (375 mg/m², once weekly for 4 weeks) and glucocorticoids. The ADRs listed in Table 2 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 2. Adverse drug reactions occurring at 6-months in ≥5% of patients receiving rituximab for induction of remission of GPA and MPA, and at a higher frequency than the comparator group:
| MedDRA System Organ Class Adverse Event | Rituximab (n=99) |
|---|---|
| Infections and infestations | |
| Urinary tract infection | 7% |
| Bronchitis | 5% |
| Herpes zoster | 5% |
| Nasopharyngitis | 5% |
| 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% |
In a further clinical study, a total of 57 severe, active GPA and MPA patients in disease remission were treated with rituximab for the maintenance of remission.
Table 3. Adverse drug reactions occurring in ≥5% of patients receiving rituximab for maintenance treatment of GPA and MPA, and at a higher frequency than the comparator group:
| MedDRA System organ class Adverse reaction | Rituximab (n=57) |
|---|---|
| Infections and infestations | |
| Bronchitis | 14% |
| Rhinitis | 5% |
| Respiratory, thoracic and mediastinal disorders | |
| Dyspnoea | 9% |
| Gastrointestinal disorders | |
| Diarrhoea | 7% |
| General disorders and administration site conditions | |
| Pyrexia | 9% |
| Influenza-like illness | 5% |
| Oedema peripheral | 5% |
| Injury, poisoning and procedural complications | |
| Infusion-related reactions1 | 12% |
1 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/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/MPA patients received treatment with rituximab (mean of 8 infusions [range 1 to 28]) for up to 4 years, according to their physician’s standard practice and discretion. The overall safety profile was consistent with the well-established safety profile of rituximab in GPA/MPA and no new adverse drug reactions were reported.
In the clinical trial conducted by innovator studying induction of remission with severe active GPA and MPA, 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 the maintenance therapy clinical trial, 7/57 (12%) patients in the rituximab arm experienced at least one infusion-related reaction. The incidence of IRR symptoms was highest during or after the first infusion (9%) and decreased with subsequent infusions (<4%). All IRR symptoms were mild or moderate and most of them were reported from the SOCs Respiratory, Thoracic and Mediastinal Disorders and Skin and Subcutaneous Tissue disorders.
In the clinical trial on induction of remission, which included 99 rituximab-treated patients, the overall rate of infection was approximately 237 per 100 patient years (95% CI 197 to 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 maintenance therapy clinical trial, 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 on induction of remission, the incidence of malignancy in rituximab treated patients in the granulomatosis with polyangiitis and microscopic polyangiitis clinical study was 2,00 per 100 patient years at the study common closing date (when the final patient had completed the follow-up period). On the basis of standardised incidence ratios, the incidence of malignancies appears to be similar to that previously reported in patients with ANCAassociated vasculitis.
In the clinical trial on induction of remission, cardiac events occurred at a rate of approximately 273 per 100 patient years (95% CI 149 to 470) at the 6-month primary endpoint. The rate of serious cardiac events was 2.1 per 100 patient years (95% CI 3 to 15). The most frequently reported events were tachycardia (4%) and atrial fibrillation (3%).
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 granulomatosis with polyangiitis and microscopic polyangiitis patients treated with rituximab. The rate of overall infections and serious infections was not increased after the development of low IgA, IgG or IgM.
In the induction of remission clinical trial, 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.
In the maintenance therapy clinical trial, 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 induction of remission clinical trial, 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 the maintenance therapy clinical trial, 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 an innovator’s Phase 3, randomised, controlled, multicenter, open-label study in pemphigus patients that included 38 pemphigus vulgaris (PV) patients randomised to the Rituximab group. 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.
The safety profile of Rituximab in patients with PV was consistent with that observed in GPA/MPA patients.
Adverse drug reactions presented in Table 4 were 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.
Table 4. Adverse drugs reactions for Rituximab-treated pemphigus vulgaris patients in the clinical study up to month 24:
| System Organ Class Adverse drug reaction | Rituximab + low-dose prednisone (n=38) |
|---|---|
| Injury, Poisoning and Procedural Complications | |
| Infusion-related reactions* | 58% |
| Skin and Subcutaneous Tissue Disorders | |
| Alopecia | 13% |
| Pruritus | 5% |
| Urticaria | 5% |
| Skin disorder | 5% |
| Psychiatric Disorders | |
| Persistent depressive disorder | 13% |
| Major depression | 5% |
| Irritability | 5% |
| Infections and Infestations | |
| Herpes virus infection | 8% |
| Herpes zoster | 5% |
| Oral herpes | 5% |
| Conjunctivitis | 5% |
| General Disorders and Administration Site Conditions | |
| Fatigue | 8% |
| Pyrexia | 5% |
| Nervous System Disorders | |
| Headache | 5% |
| Dizziness | 5% |
| Gastrointestinal Disorders | |
| Abdominal pain upper | 5% |
| Cardiac Disorders | |
| Tachycardia | 5% |
| Musculoskeletal and Connective Tissue Disorders | |
| Musculoskeletal pain | 5% |
| Neoplasms Benign, Malignant and Unspecified (incl. cysts and polyps) | |
| Skin papilloma | 5% |
* Infusion-related reactions 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 included headaches, chills, high blood pressure, nausea, asthenia and pain.
Infusion-related reactions in the pemphigus vulgaris clinical study 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.
Fourteen 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). The ADRs listed in Table 5 and SADRs listed in Table 6 are based on clinical trial data obtained from “multi-centre, double-blind, parallel group, randomised comparative clinical trial (RI-01-002) conducted by Dr. Reddy's between DRL-Rituximab (REDDITUX) and RMP (MabThera) in the treatment of DLBCL in previously untreated patients receiving CHOP”.
A total of 151 patients were randomised, of which 76 were assigned to treatment with DRLRituximab (REDDITUX) and 75 with RMP, safety data obtained from the reference medicinal product in the same clinical trial is also reported for comparison.
Table 5. Summary of most common related TEAEs (preferred term occurring in ≥10% patients) by MedDRA system organ class and preferred term in patients treated in first line for CD20 positive Diffuse Large B-cell Lymphoma with DRL-Rituximab (REDDITUX) (375 mg/m²) associated to standard CHOP chemotherapy in every 3 weeks cycles:
| MedDRA SOC Preferred Term | DRL-Rituximab Related adverse reactions | RMP Related adverse reactions |
|---|---|---|
| Patients with at least 1 treatment-related TEAE | 51 (67,1) | 39 (52,0) |
| Blood and lymphatic system disorders | 38 (50,0) | 27 (36,0) |
| Neutropenia | 29 (38,2) | 19 (25,3) |
| Leukopenia | 16 (21,1) | 8 (10,7) |
| Thrombocytopenia | 11 (14,5) | 11 (14,7) |
| Anaemia | 15 (19,7) | 5 (6,7) |
| Febrile neutropenia | 4 (5,3) | 10 (13,3) |
| Metabolism and nutrition disorders | 10 (13,2) | 3 (4,0) |
| Hyperglycaemia | 4 (5,3) | 1 (1,3) |
| Decreased appetite | 1 (1,3) | 0 |
| Respiratory, thoracic and mediastinal disorders | 2 (2,6) | 4 (5,3) |
| Cough | 1 (1,3) | 2 (2,7) |
| Gastrointestinal disorders | 12 (15,8) | 7 (9,3) |
| Vomiting | 4 (5,3) | 3 (4,0) |
| Nausea | 3 (3,9) | 1 (1,3) |
| Abdominal pain | 2 (2,6) | 1 (1,3) |
| Skin and subcutaneous tissue disorders | 5 (6,6) | 0 |
| Alopecia | 3 (3,9) | 0 |
| Musculoskeletal and connective tissue disorders | 2 (2,6) | 1 (1,3) |
| Back pain | 0 | 0 |
| General disorders and administration site conditions | 10 (13,2) | 12 (16,0) |
| Pyrexia | 5 (6,6) | 5 (6,7) |
| Asthenia | 2 (2,6) | 4 (5,3) |
| Pain | 0 | 2 (2,7) |
| Investigations | 17 (22,4) | 15 (20,0) |
| White blood cell count decreased | 6 (7,9) | 14 (18,7) |
| Neutrophil count decreased | 9 (11,8) | 9 (12,0) |
| Weight decreased | 2 (2,6) | 1 (1,3) |
Table 6. Summary of treatment-related serious TEAEs by MedDRA system organ class, preferred term in patients treated in first line for CD20 positive Diffuse Large B-cell Lymphoma with DRL-Rituximab (REDDITUX) (375 mg/m²) associated to standard CHOP chemotherapy in every 3 weeks cycles:
| MedDRA SOC Preferred Term | DRL-Rituximab Related serious adverse reactions | RMP Related serious adverse reactions |
|---|---|---|
| Total number of treatment- emergent SAE related to the study drug | 38 | 37 |
| Patients with at least 1 treatment-emergent SAE related to the study drug | 16 (21,1) | 17 (22,7) |
| Infections and infestations | 9 | 6 (8,0) |
| Sepsis | 1 (1,3) | 2 (2,7) |
| Lower respiratory tract infection | 2 (2,6) | 0 |
| Pulmonary tuberculosis | 1 (1,3) | 1 (1,3) |
| Diarrhoea infectious | 1 (1,3) | 0 |
| Gastroenteritis | 1 (1,3) | 0 |
| Herpes zoster disseminated | 0 | 1 (1,3) |
| Septic shock | 0 | 1 (1,3) |
| Upper respiratory tract infection | 0 | 1 (1,3) |
| Neoplasms benign, malignant and unspecified (including cysts and polyps) | 1 (1,3) | 0 |
| Tumour pain | 1 (1,3) | 0 |
| Blood and lymphatic system disorders | 10 (13,2) | 12 (16,0) |
| Febrile neutropenia | 4 (5,3) | 10 (13,3) |
| Neutropenia | 4 (5,3) | 5 (6,7) |
| Leukopenia | 3 (3,9) | 0 |
| Anaemia | 1 (1,3) | 1 (1,3) |
| Pancytopenia | 0 | 1 (1,3) |
| Metabolism and nutrition disorders | 2 (2,6) | 0 |
| Hypokalaemia | 1 (1,3) | 0 |
| Tumour lysis syndrome | 1 (1,3) | 0 |
| Hepatobiliary disorders | 1 (1,3) | 0 |
| Jaundice | 1 (1,3) | 0 |
| Vascular disorders | 1 (1,3) | 0 |
| Deep vein thrombosis | 1 (1,3) | 0 |
| Gastrointestinal disorders | 4 (5,3) | 2 (2,7) |
| Vomiting | 1 (1,3) | 1 (1,3) |
| Abdominal distension | 1 (1,3) | 0 |
| Abdominal pain | 1 (1,3) | 0 |
| Constipation | 1 (1,3) | 0 |
| Diarrhoea | 0 | 1 (1,3) |
| Gastritis | 1 (1,3) | 0 |
| Intestinal obstruction | 1 (1,3) | 0 |
| General disorders and administration site conditions | 5 (6,6) | 1 (1,3) |
| Pyrexia | 3 (3,9) | 0 |
| Death | 1 (1,3) | 0 |
| Disease progression | 1 (1,3) | 0 |
| Fatigue | 0 | 1 (1,3) |
| Investigations | 0 | 1 (1,3) |
| White blood cell count decreased | 0 | 1 (1,3) |
The reporting frequencies in this section (rare, very rare) are based on estimated marketed exposures and largely data derived from spontaneous reports. As part of the continuing post-marketing surveillance of rituximab safety, the following severe adverse reactions have been observed:
Infusion-related reactions: Additional cases of severe infusion-related reactions have been reported during post-marketing use of rituximab.
Cardiovascular system: Severe cardiac events, including heart failure and myocardial infarction have been observed mainly in patients with prior cardiac condition and/or cardiotoxic chemotherapy and mostly associated with infusion related reactions. Vasculitis, predominantly cutaneous, such as leukocytoclastic vasculitis, has been reported.
Respiratory system: Respiratory failure/insufficiency, lung infiltration in the context of infusion-related reactions (see Section 4.4). In addition to pulmonary events associated with infusions, interstitial ling disease, some with fatal outcome, has been reported.
Blood and lymphatic system: Cases of infusion-related acute reversible thrombocytopenia have been reported.
Skin and Appendages: Severe bullous skin reactions including fatal cases of toxic epidermal necrolysis have been reported.
Nervous system: Cases of posterior reversible encephalopathy syndrome (PRES)/reversible posterior leukoencephalopathy syndrome (RPLS) have been reported. Signs and symptoms include 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 such as patients underlying disease, hypertension, immunosuppressive therapy and/or chemotherapy.
Cases of cranial neuropathy with or without peripheral neuropathy have been reported rarely. Signs and symptoms of cranial neuropathy, such as severe vision loss, hearing loss, loss of other senses, facial nerve palsy occurred at various times up to several months after completion of rituximab therapy.
Body as a whole: Serum sickness-like reactions have been reported rarely.
Infections and infestations: Cases of hepatitis B reactivation have been reported, the majority of which were in subjects receiving rituximab in combination with cytotoxic chemotherapy (see Section 4.4).
Other serious viral infections (e.g., viral infections are infection caused by the herpes viruses (cytomegalovirus (CMV), Varicella zoster virus and Herpes simplex virus), JC virus (progressive multifocal leukoencephalopathy (PML) and Hepatitis C virus), either new, reactivation or exacerbation, some of which were fatal, have been reported with rituximab in treatment. The majority of the patients had received rituximab in combination with chemotherapy or as part of a hematopoietic stem cell transplant.
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 the patients were HIV positive.
Gastro-intestinal system: Gastro-intestinal perforation, in some cases leading to death, has been observed in patients receiving rituximab in combination with chemotherapy or non Hodgkin lymphoma.
Neutropenia: The onset of neutropenia has occurred more than four weeks after the last infusion of rituximab.
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the “6.04 Adverse Drug Reactions Reporting Form”, found online under SAHPRA’s publications: https://www.sahpra.org.za/Publications/Index/8
No incompatibilities between REDDITUX and polyvinyl chloride or polyethylene bags or infusion sets have been observed.
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