Mabthera Sc 1400 Mg 120 mg Solution for subcutaneous injection

MabThera SC 1400 mg is indicated for the treatment of Non-Hodgkinu2019s lymphoma (NHL):

• 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.

General Subcutaneous Formulations

Substitution by any other biological medicinal product requires the consent of the prescribing healthcare professional. It is important to check the product labels to ensure that the appropriate formulation (IV or SC) is being given to the patient, as prescribed. MabThera SC 1400 mg should be administered in an environment where full resuscitation facilities are immediately available, and under the close supervision of an experienced healthcare professional (see section 4.4). The safety and efficacy of alternating or switching between MabThera SC 1400 mg and products that are biosimilar but not deemed interchangeable has not been established. Therefore, the benefit-risk of alternating or switching needs to be carefully considered.

Premedication and Prophylactic Medications

Premedication consisting of an analgesic/anti-pyretic and an antihistaminic, e.g. paracetamol/acetaminophen and diphenhydramine, should always be given before each administration of MabThera. Premedication with glucocorticoids should also be considered, particularly if MabThera is not given in combination with steroid-containing chemotherapy (see section 4.4).

Method of administration

MabThera SC 1400 mg is NOT intended for intravenous administration (see Section 6.6). MabThera SC 1400 mg is intended for subcutaneous administration in non-Hodgkinu2019s lymphoma (NHL) only, and in patients who tolerated a first IV administration. MabThera SC 1400 mg should be injected subcutaneously into the abdominal wall and never into areas where the skin is red, bruised, tender, or hard areas where there are moles or scars. No data are available on performing the injection in other sites of the body, therefore injections should be restricted to the abdominal wall. During the treatment course with MabThera SC 1400 mg, other medications for subcutaneous administration should preferably be administered at different sites. MabThera SC 1400 mg injection should be administered over approximately 5 minutes. The hypodermic injection needle must only be attached to the syringe immediately prior to administration to avoid potential needle clogging. If an injection is interrupted it can be resumed or another location may be used, if appropriate.

Posology

The recommended dose of MabThera SC formulation used for adult patients is a subcutaneous injection at a fixed dose of 1400 mg irrespective of the patientu2019s body surface area. Dosage adjustments during treatment: No dose reductions of MabThera are recommended. When MabThera is given in combination with chemotherapy, standard dose reductions for the chemotherapeutics medicines should be applied.

Low-grade/CD20 positive or Follicular B-cell Non-Hodgkin's lymphoma

All patients must always receive their first dose of MabThera by intravenous administration. During their first cycle the patient is at the highest risk of experiencing an infusion/administration related reaction. Beginning therapy with MabThera IV infusion allows management of infusion/administration related reactions by slowing or stopping the intravenous infusion (see section 4.4). The subcutaneous formulation must only be given at the second or subsequent cycles (see u201cFirst administration: Intravenous formulationu201d and u201cSubsequent administrations: Subcutaneous formulationu201d sub-sections, below).

First administration: MabThera IV: The first administration of MabThera must always be given by intravenous infusion at a dose of 375 mg/mu00b2 body surface area (BSA). Subsequent administrations: Patients unable to receive the full MabThera intravenous infusion dose should continue to receive subsequent cycles with MabThera IV until a full IV dose is successfully administered. For patients who tolerate the full MabThera IV infusion dose well, the second or subsequent MabThera dose can be given subcutaneously using the MabThera SC 1400 mg (see section 4.4).

Initial treatment: Follicular B-cell Non-Hodgkin's lymphoma:

• Subcutaneous monotherapy: The recommended dosage of MabThera SC 1400 mg used as monotherapy for adult patients is subcutaneous injection at a fixed dose of 1400 mg irrespective of the patientu2019s body surface area, once weekly for 3 weeks following MabThera IV at week 1 (1st week R-IV then 3 weeks R-SC; 4 weeks in total).
• Subcutaneous combination therapy: The recommended dose of MabThera in combination with chemotherapy for induction treatment of previously untreated or relapsed/refractory patients with follicular lymphoma is: first cycle with MabThera intravenous formulation 375 mg/mu00b2 body surface area, followed by subsequent cycles with MabThera subcutaneous formulation injected at a fixed dose of 1400 mg per cycle for up to 8 cycles. MabThera SC 1400 mg should be administered on day 0 or day 1 of each chemotherapy cycle after administration of the glucocorticoid component of the chemotherapy, if applicable. The recommended dosage in combination with any chemotherapy is MabThera IV (R-IV) 375 mg/mu00b2 BSA intravenously for the first cycle followed by subcutaneous injection of MabThera SC (R-SC) at a fixed dose of 1400 mg irrespective of the patientu2019s body surface area.

• Hypersensitivity to rituximab or to any of the excipients or to murine proteins.
• Active, severe infections.
• Patients in a severely immunocompromised state.
• Severe heart failure (New York Heart Association Class IV) or severe, uncontrolled cardiac disease (see section 4.4 and section 4.8).
• Pregnancy and lactation.

WARNING Infusion-related reactions: Infusion-related deaths (death within 24 hours of infusion) have been reported. These events appear as manifestations of an infusion-related complex and include hypoxia, lung infiltration, adult respiratory distress syndrome, myocardial infarction, ventricular fibrillation or cardiogenic shock. Most fatal infusion-related events occurred in association with the first infusion.

Tumour Lysis Syndrome (TLS): Acute renal failure requiring dialysis and with instances of fatal outcome has been reported. Prophylaxis for TLS should be considered for patients at risk of developing rapid tumour lysis (e.g. patients with a high tumour burden or with a high number (>25 x 109/L) of circulating malignant cells such as patients with CLL or mantle cell lymphoma). These patients should be followed closely and appropriate laboratory monitoring performed. Appropriate medical therapy should be provided for patients who develop signs and symptoms consistent with rapid tumour lysis. See section 4.4.

General: In order to improve the traceability of biological medicinal products, the trade name and batch number of the administered product should be clearly recorded (or stated) in the patient file. The information provided in this section pertains to the use of MabThera SC 1400 mg. For information related to the other indications, please refer to the professional information of MabThera intravenous formulation. The use of MabThera SC 1400 mg as monotherapy in patients with stage III-IV follicular lymphoma who are chemoresistant or are in their second or subsequent relapse after chemotherapy cannot be recommended as the safety of the once weekly subcutaneous administration has not been established.

Progressive Multifocal Leukoencephalopathy (PML) Use of MabThera SC 1400 mg may be associated with an increased risk of progressive multifocal leukoencephalopathy (PML) (see section 4.8). The majority of patients had received MabThera IV in combination with chemotherapy or as part of a haematopoietic stem cell transplant. 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 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 MabThera 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 MabThera therapy may lead to similar stabilisation or improved outcome.

Non-Hodgkinu2019s Lymphoma Patients Infusion/Administration-related reactions: MabThera is associated with infusion-related reactions (IRRs) in most patients, 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, tumor lysis syndrome and anaphylactic and hypersensitivity reactions are described below. They are not specifically related to the route of administration of MabThera and can be observed with both formulations. Severe infusion-related reactions with fatal outcome have been reported during post-marketing use of the MabThera intravenous formulation, with an onset ranging within 30 minutes to 2 hours after starting the first MabThera 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). Patients with a high number (> 25 x 109/L) of circulating malignant cells or high tumour burden who may be at higher risk of especially severe IRRs should only 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 x 109/L (see section 4.8). Infusion related adverse reactions of all kinds have been observed in 77 % of patients treated with MabThera intravenous formulation (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 MabThera 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.

Administration related reactions have been observed in up to 50 % of patients treated with MabThera subcutaneous formulation in clinical trials. The reactions occurring within 24 hours of the subcutaneous injection consisted primarily of erythema pruritus, rash and injections site reactions such as pain, swelling and redness and were generally of mild or moderate (grade 1 or 2) and transient nature (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. Fatal outcomes have been reported for patients who developed severe cytokine release syndrome, occasionally associated with signs and symptoms of tumour lysis syndrome leading to multi-organ failure, respiratory failure and renal failure. 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.

Hypersensitivity reactions / Anaphylaxis: 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. Medications 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 MabThera. Clinical manifestations of anaphylaxis may appear similar to clinical manifestations of the cytokine release syndrome. 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.

Administration-related reactions: Local cutaneous reactions, including injection site reactions, have been reported in patients receiving MabThera SC 1400 mg. Symptoms included pain, swelling, induration, haemorrhage, erythema, pruritus and rash (see section 4.8). Some local cutaneous reactions occurred more than 24 hours after the SC administration. The majority of local cutaneous reactions seen following administration of the SC formulation were mild or moderate and resolved without any specific treatment. All patients must always receive their first dose of MabThera by intravenous administration in order to avoid an irreversible administration of the full MabThera SC dose during Cycle 1. During this cycle the patient would have the highest risk of experiencing an IRR that can be treated effectively by slowing or stopping the infusion. The subcutaneous formulation must only be given at the second or subsequent cycles. Patients, unable to tolerate the full MabThera IV infusion dose should continue to receive subsequent cycles with MabThera IV until the full IV dose is successfully administered. For patients who are able to receive the full MabThera IV infusion dose, the second or subsequent MabThera dose can be given subcutaneously using MabThera SC 1400 mg formulation (see section 4.2). Therefore, the switch to MabThera SC 1400 mg can only occur at the second or subsequent cycles of treatment. As with the intravenous formulation, MabThera SC 1400 mg should be administered in an environment where full resuscitation facilities are immediately available and under the close supervision of a healthcare professional. Premedication consisting of an analgesic/antipyretic and an antihistamine should always be administered before each dose of MabThera SC. Premedication with glucocorticoids should also be considered. Patients should be observed for at least 15 minutes following MabThera SC 1400 mg administration. A longer period may be appropriate in patients with an increased risk of hypersensitivity reactions. Patients should be instructed to contact their treating medical practitioner immediately if symptoms that are suggestive of severe hypersensitivity reactions or cytokine release syndrome occur at any time after administration.

Pulmonary events: Pulmonary events have included hypoxia, lung infiltration, and acute respiratory failure. Some of these events have been preceded by severe bronchospasm and dyspnea. In some cases, symptoms worsened over time, while in others initial improvement was followed by clinical deterioration. Therefore, patients experiencing pulmonary events or other severe infusion-related symptoms should be closely monitored until complete resolution of their symptoms occurs.

Rapid tumour lysis: MabThera IV/SC mediates the rapid lysis of benign and malignant CD20-positive cells. Signs and symptoms (e.g., hyperuricaemia, hyperkalaemia, hypocalcaemia, hyperphosphataemia, acute renal failure, elevated LDH) consistent with tumour lysis syndrome (TLS) have been reported to occur within 30 minutes to 2 hours after the first MabThera IV infusion in patients with high numbers of circulating malignant lymphocytes. If these signs and symptoms develop, treatment should be stopped immediately. Prophylaxis for TLS should be considered for patients at risk of developing rapid tumour lysis (e.g. patients with a high tumour burden or with a high number [> 25 x 109/L] of circulating malignant cells such as patients with CLL or mantle cell lymphoma). Patients at risk of developing rapid tumour lysis should be followed closely and appropriate laboratory monitoring performed. Appropriate medical therapy should be provided for patients who develop signs and symptoms consistent with rapid tumour lysis. Following treatment for and complete resolution of signs and symptoms, subsequent MabThera IV therapy has been administered in conjunction with prophylactic therapy for TLS in a limited number of cases.

Cardiovascular: Since hypotension may occur during MabThera IV/SC administration, consideration should be given to withholding antihypertensive medicines 12 hours prior to and throughout MabThera IV/SC administration. Angina pectoris or cardiac dysrhythmia, such as atrial flutter and fibrillation, heart failure or myocardial infarction have occurred in patients treated with MabThera IV/SC. Less frequently, patients experienced an exacerbation of pre-existing cardiac conditions such as angina pectoris or congestive heart failure. Therefore, in patients with a known cardiac history, the risk of cardiovascular complications resulting from infusion reactions should be considered before treatment with MabThera and patients should be closely monitored.

Monitoring of blood counts (haematological toxicities): Although MabThera is not myelosuppressive in monotherapy, caution should be exercised when considering treatment of patients with neutrophil counts of < 1,5 x 109/L and/or platelet counts of < 75 x 109/L, as clinical experience with such patients is limited. MabThera IV has been used in patients who underwent autologous bone marrow transplantation and in other risk groups with a presumable reduced bone marrow function without inducing myelotoxicity. Consideration should be given to the need for regular full blood counts, including platelet counts, during monotherapy with MabThera IV/SC. When MabThera IV/SC is given in combination with CHOP or CVP chemotherapy, regular full blood counts should be performed according to usual medical practice.

Infections: MabThera treatment should not be initiated in patients with severe active infections. Based on the mechanism of action of MabThera and the knowledge that B-cells play an important role in maintaining normal immune response, patients may have an increased risk of infection following MabThera IV therapy. It is recommended that immunoglobulin levels are determined prior to initiating treatment with MabThera. Serious infections, including fatalities, can occur during therapy with MabThera. MabThera treatment should not be administered to patients with 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 MabThera 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). Patients treated with MabThera should avoid exposure to patients with tuberculosis and should avoid contact with children and adults recently vaccinated with attenuated live vaccines. Patients who develop infection following MabThera IV therapy should be promptly evaluated and treated appropriately.

Tuberculosis: All patients should be screened for active or latent tuberculosis (TB) infection prior to starting MabThera therapy. Patients with active or latent TB should be treated with standard anti-mycobacterial therapy before initiating MabThera.

Risks of tuberculosis disease

• Cases of tuberculosis (and tuberculosis reactivation) have been observed in patients treated with TNF-alpha inhibitors and similar immune-modulatory medicines, including MabThera.
• Tuberculosis in these patients may be due to reactivation of latent tuberculosis infection or due to new infections.
• Prophylactic treatment of a latent tuberculosis infection should be initiated prior to starting treatment with MabThera.
• Patients may become infected with tuberculosis during the course of therapy with MabThera and medical practitioners should continue to monitor the patient for signs and symptoms of tuberculosis, including patients who have tested negative for latent tuberculosis at the start of therapy.
• Treatment of tuberculosis should follow current national guidelines.

Hepatitis B Infections: In patients with non-Hodgkinu2019s Lymphoma, and CLL, receiving MabThera in combination with cytotoxic chemotherapy, cases of hepatitis B reactivation have been reported, including reports of fulminant hepatitis, some of which were fatal. The reports were confounded by both the underlying disease state and the cytotoxic chemotherapy. Hepatitis B virus (HBV) screening should be performed in all patients before initiation of treatment with MabThera. At a 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 MabThera. Patients with positive hepatitis B serology should be monitored and managed following local medical standards to prevent hepatitis B reactivation. Very rare cases of PML have been reported during post-marketing use of the MabThera intravenous formulation in NHL (see section 4.8). The majority of patients had received rituximab in combination with chemotherapy or as part of a hematopoietic stem cell transplant.

Skin reactions: Severe skin reactions such as Toxic Epidermal Necrolysis and Stevens-Johnson Syndrome, some with fatal outcome, have been reported (see Post-Marketing). In case of such an event, with a suspected relationship to MabThera, treatment should be permanently discontinued.

Immunisation: The safety of immunisation with live viral vaccines, following MabThera IV/SC therapy has not been studied and vaccination with live virus vaccines is not recommended whilst on MabThera or whilst peripherally B-cell depleted (see section 4.3). Patients treated with MabThera IV/SC 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 MabThera IV 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). 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 MabThera IV.

Currently, limited data are available on possible medicine interactions with MabThera SC 1400 mg. Co-administration with MabThera 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 MabThera IV in rheumatoid arthritis (RA) patients. 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.

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 treatment and up to 12 months following MabThera therapy.

Pregnancy

MabThera is contraindicated in pregnancy and lactation. Pregnant women should not be treated with MabThera SC. IgG immunoglobulins are known to cross the placental barrier. B-cell levels in human neonates following maternal exposure to MabThera 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.

Breastfeeding

Women who are breastfeeding their babies, should not be treated with MabThera SC. Whether rituximab is excreted in human milk is not known. However, because maternal IgG is excreted in human milk, MabThera should not be given to women who are breastfeeding.

Fertility

Animal studies did not reveal deleterious effects of rituximab or recombinant human hyaluronidase (rHuPH20) on reproductive organs.

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

The information provided in this section pertains to the use of MabThera SC 1400 mg in oncology. For information related to the autoimmune indications, please refer to the professional information for MabThera intravenous formulation.

Summary of the safety profile: During the developmental programme, the safety profile of MabThera SC 1400mg was comparable to that of the IV formulation with the exception of local cutaneous reactions. Local cutaneous reactions, including injection site reactions, were very common (u2265 1/10) in patients receiving MabThera SC 1400 mg. In the phase 3 SABRINA (BO22334) study, local cutaneous reactions were reported in up to 23 % of patients receiving MabThera SC 1400 mg. The most common local cutaneous reactions in the MabThera SC 1400 mg arm were: injection site erythema (13 %), injection site pain (8 %), and injection site oedema (4 %). Similar events were observed in the SAWYER (BO25341) study and were reported in up to 42 % of patients in the MabThera SC arm. The most common local cutaneous reactions were: injection site erythema (26 %), injection site pain (16 %), and injection site swelling (5 %). Events seen following subcutaneous administration were mild to moderate, apart from the one patient who reported a local cutaneous reaction Grade 3 intensity (injection site rash) following the first MabThera SC administration (Cycle 2). Local cutaneous reactions of any Grade in the MabThera SC 1400 mg arm were most common during the first subcutaneous cycle (Cycle 2), followed by the second, and the incidence decreased with subsequent injections. No cases of anaphylaxis or severe hypersensitivity reactions, cytokine release syndrome or tumour lysis syndrome were observed following subcutaneous administration during the MabThera SC 1400 mg development program.

Adverse reactions reported in MabThera SC 1400 mg usage: The risk of acute administration-related reactions associated with the subcutaneous formulation of MabThera was assessed in three clinical studies. In the SparkThera (BP22333) study no severe administration-related reactions were reported. In the SABRINA (BO22334) study severe administration-related reactions (Grade u22653) were reported in two patients (1 %) following MabThera SC administration. These events were Grade 3 injection site rash and dry mouth. In the SAWYER (BO25341) study severe administration-related reactions (Grade u22653) were reported in four patients (5 %) following MabThera SC administration. These events were Grade 4 thrombocytopenia and Grade 3 anxiety, injection-site erythema and urticaria.

Adverse reactions reported in MabThera intravenous formulation usage: Experience from Non-Hodgkinu2019s Lymphoma and Chronic Lymphocytic Leukaemia. The overall safety profile of MabThera in non-Hodgkinu2019s 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 MabThera IV 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 MabThera IV 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 MabThera IV. 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 infusion-related reactions (including cytokine-release syndrome, tumour-lysis syndrome), infections and cardiovascular events. Other serious ADRs reported include hepatitis B reactivation and PML (See section 4.4). The frequencies of ADRs reported with MabThera alone or in combination with chemotherapy are summarised in the tables below. Within each frequency grouping, side effects are presented in order of decreasing seriousness. Frequencies are defined as very common (u2265 1/10), common (u2265 1/100 to < 1/10) and uncommon (u2265 1/1 000 to < 1/100) and rare (u2265 1/10 000 to < 1/1 000). The ADRs identified only during post-marketing surveillance, and for which a frequency could not be estimated, are listed under u201cnot knownu201d.

Patients who experience overdose should have immediate interruption or reduction 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. Three patients in the MabThera SC SABRINA (BO22334) study were inadvertently administered the SC formulation through the IV route up to a maximum rituximab dose of 2 780 mg, with no untoward effect. Patients who experience overdose or medication error with MabThera SC should be closely monitored. In the post-marketing setting five cases of MabThera 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.