Rituximab 500 mg Solution

Non-Hodgkin's lymphoma (NHL)
Rituximab Equity is indicated for the treatment of:

• patients with relapsed or chemo-resistant low-grade or follicular, CD20-positive, B-cell non-Hodgkinu2019s lymphoma
• previously untreated patients with stage III-IV follicular lymphoma in combination with chemotherapy
• patients with follicular lymphoma as maintenance treatment, after response to induction therapy
• patients with high grade CD20-positive diffuse large B-cell non-Hodgkinu2019s lymphoma in combination with CHOP (Cyclophosphamide - C, Doxorubicin - H, Vincristine - O, Prednisone - P) chemotherapy

Rituximab Equity infusions should be administered in an environment where full resuscitation facilities are immediately available, and under the close supervision of an experienced healthcare professional. Pre-medication consisting of an anti-pyretic and an antihistaminic, e.g. paracetamol and diphenhydramine, should always be administered 30 to 60 minutes prior to each infusion of Rituximab Equity. Pre-medication with glucocorticoids should also be considered, particularly if Rituximab Equity is not given in combination with steroid-containing chemotherapy.
Low-grade/CD20 positive or follicular B-cell non-Hodgkin's lymphoma:
a) Initial treatment, weekly for 4 doses: The recommended dosage of Rituximab Equity used as a single agent/monotherapy for adult patients is 375 mg/m2 body surface area (BSA), administered as an intravenous infusion once weekly for four doses.
b) Initial treatment, bulky disease, weekly for 4 doses: The recommended dosage of Rituximab Equity used as a single agent/monotherapy for adult patients is 375 mg/m2 BSA, administered as an intravenous infusion once weekly for four doses.
c) Re-treatment following relapse, weekly for 4 doses: Patients who have responded to Rituximab Equity initially have been treated again with Rituximab Equity at a dose of 375 mg/m2 BSA, administered as an IV infusion once weekly for 4 weeks.
d) Combination therapy: The recommended dosage of Rituximab Equity in combination with chemotherapy for induction treatment of previously untreated or relapsed/refractory patients with follicular NHL is 375 mg/m2 BSA per cycle for 8 cycles (21 days/cycle). Rituximab Equity should be administered on day 1 of each chemotherapy cycle, after IV administration of the glucocorticoid component of the chemotherapy, if applicable.
e) Maintenance therapy: Previously untreated patients after response to induction treatment with R-CHOP may receive maintenance therapy with Rituximab Equity given at 375 mg/m2 BSA once every 2 months until disease progression or for a maximum period of two years (12 infusions). Efficacy has not been demonstrated in patients who previously received Rituximab Equity plus CVP or with FCM.
High grade/CD20 positive or diffuse large B-cell non-Hodgkin's lymphoma: Rituximab Equity should be used in combination with CHOP chemotherapy (R-CHOP). The recommended dosage is 375 mg/m2 BSA, administered on day 1 of each chemotherapy cycle for 8 cycles after IV administration of the glucocorticoid component of CHOP. The other components of CHOP should be given after the administration of Rituximab Equity.
First infusion: The recommended initial rate for infusion is 50 mg/hr; which can subsequently be escalated in 50 mg/hr increments every 30 minutes, to a maximum of 400 mg/hr.
Subsequent infusions: Subsequent doses of Rituximab Equity can be infused at an initial rate of 100 mg/hr, and increased by 100 mg/hr increments at 30-minute intervals, to a maximum of 400 mg/hr.
Alternative 90-minute subsequent infusions: Patients who do not experience a Grade 3 or 4 infusion-related adverse event with Cycle 1 are eligible for an alternative 90-minute subsequent infusion in Cycle 2. The alternative infusion rate can be started at a rate of 20 % of the total dose given in the first 30 minutes and the remaining 80 % of the total dose given over the next 60 minutes for a total infusion time of 90 minutes. Patients who tolerate the first 90-minute Rituximab Equity infusion (Cycle 2) can continue to receive subsequent Rituximab Equity infusions at the 90-minute rate for the remainder of the treatment regimen (through Cycle 6 or Cycle 8). Patients who have clinically significant cardiovascular disease or who have a circulating lymphocyte count > 5 000/mm3 before Cycle 2 should not receive the 90-minute infusion.
Dosage adjustments during treatment: No dose reductions of Rituximab Equity are recommended. When Rituximab Equity is given in combination with CHOP or CVP chemotherapy, standard dose reductions for the chemotherapeutic medicines should be applied.

u2022 Hypersensitivity to the active substance or to murine proteins, or to any of the other excipients listed in section 6.1.
u2022 Active, severe infections (see section 4.4).
u2022 Patients in a severely immunocompromised state.
u2022 Severe heart failure (New York Heart Association Class IV) or severe, uncontrolled cardiac disease (see section 4.4 and 4.8 regarding other cardiovascular diseases).

Traceability: In order to improve traceability of biological medicines, the trade name and batch number of the administered product should be clearly recorded (or stated) in the patient file.
Screening for tuberculosis should be undertaken prior to commencement of treatment with Rituximab Equity. A diagnosis of any form of active tuberculosis should be explicitly excluded in patients considered for treatment with Rituximab Equity. Furthermore, a history of previous tuberculosis, HIV-infection, or a diagnosis of latent tuberculosis 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 Rituximab Equity.
People starting Rituximab Equity treatment, who initially tested negative for active or latent tuberculosis, should be systematically tested for latent tuberculosis infection during treatment with Rituximab Equity, and preventive treatment instituted if indicated.
Progressive multifocal leukoencephalopathy (PML): All patients treated with Rituximab Equity for rheumatoid arthritis, GPA or MPA 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 progressive multifocal leukoencephalopathy (PML). Fatal PML have been reported following the use of Rituximab Equity. 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 medical practitioner 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 medical practitioner 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 Equity 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 Equity therapy may lead to similar stabilisation or improved outcome.
Non-Hodgkinu2019s lymphoma and chronic lymphocytic leukaemia: Infusion-related reactions: Rituximab Equity 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 Equity intravenous formulation, with an onset ranging within 30 minutes to 2 hours after starting the first 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 less frequently resulted in repeated severe cytokine release syndrome. Patients with a high tumour burden or with a high number (u2265 25 x 109/L) of circulating malignant cells such as patients with CLL and mantle cell lymphoma, who may be at higher risk of especially severe cytokine release syndrome, should be treated with extreme caution and only when other therapeutic alternatives have been exhausted. 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 x 109/L. Infusion-related adverse reactions of all kinds have been observed in 77 % of patients treated with Rituximab Equity (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 Equity infusion and administration of an anti-pyretic, an antihistaminic, and occasionally oxygen, intravenous saline 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. Medicines 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 Equity. 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 Equity administration, consideration should be given to withholding anti-hypertensive medicines 12 hours prior to the Rituximab Equity infusion.

Currently, there are limited data on possible medicine interactions with Rituximab Equity. In CLL patients, co-administration with Rituximab Equity 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 Equity. Co-administration with methotrexate had no effect on the pharmacokinetics of Rituximab Equity 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 receiving subsequent therapy with a biologic DMARD following Rituximab Equity, the rate of clinically relevant infection while on Rituximab Equity was 6,01 per 100 patient years compared to 4,97 per 100 patient years following treatment with the biologic DMARD.

Safety in pregnancy and lactation has not been established.
Women of childbearing potential / Contraception in males and females: 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 Equity.
Pregnancy: IgG immunoglobulins are known to cross the placental barrier. B-cell levels in human neonates following maternal exposure to Rituximab Equity 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, as contained in Rituximab Equity, during pregnancy. Similar effects have been observed in animal studies (see section 5.3). For these reasons Rituximab Equity should not be administered to pregnant women.
Breastfeeding: Whether rituximab is excreted in human milk is not known. However, because maternal IgG is excreted in human milk, women should not breastfeed while treated with Rituximab Equity and for 12 months following Rituximab Equity treatment.
Fertility: Animal studies did not reveal deleterious effects of rituximab on reproductive organs.

No studies on the effects of Rituximab Equity on the ability to drive and use machines have been performed, although the pharmacological activity and adverse reactions reported to date suggest that Rituximab Equity would have no or negligible influence on the ability to drive and use machines.

Experience from non-Hodgkinu2019s lymphoma and chronic lymphocytic leukaemia
Summary of the safety profile: The overall safety profile of Rituximab Equity in non-Hodgkinu2019s lymphoma and CLL is based on data from patients from clinical trials and from post-marketing surveillance. These patients were treated either with rituximab (as contained in Rituximab Equity) 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 (as contained in Rituximab Equity) were infusion-related reactions (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 Equity. Infectious events (predominantly bacterial and viral) occurred in approximately 30 u2013 55 % of patients during clinical trials in patients with NHL and in 30 u2013 50 % of patients during clinical trials in patients with CLL. The most frequent reported or observed serious adverse drug reactions were:

• IRRs (including cytokine-release syndrome, tumour-lysis syndrome), see section 4.4.
• Infections, see section 4.4.
• Cardiovascular events, see section 4.4.

Limited experience with doses higher than the approved dose of intravenous Rituximab Equity is available. The highest intravenous dose of rituximab, as contained in Rituximab Equity, tested in humans to date is 5 000 mg (2 250 mg/m2), tested in a dose escalation study in patients with CLL. No additional safety signals were identified. Patients who experience overdose should have immediate interruption of their infusion and be closely monitored. Consideration should be given to the need for regular monitoring of blood cell count and for increased risk of infections while patients are B-cell depleted. In the post-marketing setting five cases of rituximab (as contained in Rituximab Equity) overdose have been reported. Three cases had no reported adverse event. The two adverse events that were reported were flu-like symptoms, with a dose of 1,8 g of rituximab and fatal respiratory failure, with a dose of 2 g of rituximab.