Ruxience - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

Ruxience 100 mg concentrate for solution for infusion

Ruxience 500 mg concentrate for solution for infusion

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Ruxience 100 mg concentrate for solution for infusion

Each mL contains 10 mg of rituximab.

Each 10 mL vial contains 100 mg of rituximab.

Ruxience 500 mg concentrate for solution for infusion

Each mL contains 10 mg of rituximab.

Each 50 mL vial contains 500 mg of rituximab.

Rituximab is a genetically engineered chimeric mouse/human monoclonal antibody representing a glycosylated immunoglobulin with human IgG1 constant regions and murine light-chain and heavy-chain variable region sequences. The antibody is produced by mammalian (Chinese hamster ovary) cell suspension culture and purified by affinity chromatography and ion exchange, including specific viral inactivation and removal procedures.

Excipient with known effect

This medicinal product contains less than 1 mmol sodium (23 mg) per dose.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Concentrate for solution for infusion (sterile concentrate).

Clear to slightly opalescent, colourless to pale brownish-yellow liquid.

4. CLINICAL PARTICULARS4.1 Therapeutic indications

Ruxience is indicated in adults for the following indications:

Non-Hodgkin’s lymphoma (NHL)

Ruxience is indicated for the treatment of previously untreated adult patients with stage III-IV follicular lymphoma in combination with chemotherapy.

Ruxience maintenance therapy is indicated for the treatment of adult follicular lymphoma patients responding to induction therapy.

Ruxience monotherapy is indicated for treatment of adult patients with stage III-IV follicular lymphoma who are chemoresistant or are in their second or subsequent relapse after chemotherapy.

Ruxience is indicated for the treatment of adult patients with CD20 positive diffuse large B cell non-Hodgkin’s lymphoma in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) chemotherapy.

Ruxience in combination with chemotherapy is indicated for the treatment of paediatric patients (aged > 6 months to <18 years old) with previously untreated advanced stage CD20 positive diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma (BL)/Burkitt leukaemia (mature B-cell acute leukaemia) (BAL) or Burkitt-like lymphoma (BLL).

Chronic lymphocytic leukaemia (CLL)

Ruxience in combination with chemotherapy is indicated for the treatment of patients with previously untreated and relapsed/refractory CLL. Only limited data are available on efficacy and safety for patients previously treated with monoclonal antibodies including rituximab or patients refractory to previous rituximab plus chemotherapy.

See section 5.1 for further information.

Rheumatoid arthritis

Ruxience in combination with methotrexate is indicated for the treatment of adult patients with severe active rheumatoid arthritis who have had an inadequate response or intolerance to other disease-modifying anti-rheumatic drugs (DMARD) including one or more tumour necrosis factor (TNF) inhibitor therapies.

Ruxience has been shown to reduce the rate of progression of joint damage as measured by X-ray and to improve physical function, when given in combination with methotrexate.

Granulomatosis with polyangiitis and microscopic polyangiitis

Ruxience, in combination with glucocorticoids, is indicated for the treatment of adult patients with severe, active granulomatosis with polyangiitis (Wegener’s) (GPA) and microscopic polyangiitis (MPA).

Ruxience, in combination with glucocorticoids, is indicated for the induction of remission in paediatric patients (aged > 2 to < 18 years old) with severe, active GPA (Wegener’s) and MPA.

Pemphigus vulgaris

Ruxience is indicated for the treatment of patients with moderate to severe pemphigus vulgaris (PV).

4.2 Posology and method of administration

Ruxience should be administered under the close supervision of an experienced healthcare professional, and in an environment where full resuscitation facilities are immediately available (see section 4.4).

Premedication and prophylactic medications

Premedication consisting of an anti-pyretic and an antihistaminic, e.g. paracetamol and diphenhydramine, should always be given before each administration of Ruxience.

In adult patients with non-Hodgkin’s lymphoma and CLL, premedication with glucocorticoids should be considered if Ruxience is not given in combination with glucocorticoid-containing chemotherapy.

In paediatric patients with non-Hodgkin’s lymphoma, premedication with paracetamol and H1 antihistamine (= diphenhydramine or equivalent) should be administered 30 to 60 minutes before the start of the infusion of Ruxience. In addition, prednisone should be given as indicated in Table 1.

Prophylaxis with adequate hydration and administration of uricostatics starting 48 hours prior to start of therapy is recommended for CLL patients to reduce the risk of tumour lysis syndrome. For CLL patients whose lymphocyte counts are > 25 × 109/L, it is recommended to administer prednisone/pred­nisolone 100 mg intravenous shortly before infusion with Ruxience to decrease the rate and severity of acute infusion reactions and/or cytokine release syndrome.

In patients with rheumatoid arthritis, GPA or MPA or pemphigus vulgaris, premedication with 100 mg intravenous methylprednisolone should be completed 30 minutes prior to each infusion of Ruxience to decrease the incidence and severity of infusion-related reactions (IRRs).

In adult patients with GPA or MPA, methylprednisolone given intravenously for 1 to 3 days at a dose of 1000 mg per day is recommended prior to the first infusion of Ruxience (the last dose of methylprednisolone may be given on the same day as the first infusion of Ruxience). This should be followed by oral prednisone 1 mg/kg/day (not to exceed 80 mg/day, and tapered as rapidly as possible based on clinical need) during and after the 4 week induction course of Ruxience treatment.

Pneumocystis jirovecii pneumonia (PJP) prophylaxis is recommended for adult patients with GPA/MPA or PV during and following Ruxience treatment, as appropriate according to local clinical practice guidelines.

Paediatric population

In paediatric patients with GPA or MPA, prior to the first Ruxience IV infusion, methylprednisolone should be given IV for three daily doses of 30 mg/kg/day (not to exceed 1 g/day) to treat severe vasculitis symptoms. Up to three additional daily doses of 30 mg/kg IV methylprednisolone can be given prior to the first Ruxience infusion.

Following completion of IV methylprednisolone administration, patients should receive oral prednisone 1 mg/kg/day (not to exceed 60 mg/day) and tapered as rapidly as possible per clinical need (see section 5.1).

Pneumocystis jirovecii pneumonia (PJP) prophylaxis is recommended for paediatric patients with GPA or MPA during and following Ruxience treatment, as appropriate.

Posology

It is important to check the medicinal product labels to ensure that the appropriate formulation is being given to the patient, as prescribed.

Non-Hodgkin’s lymphoma

Follicular non-Hodgkin's lymphoma

Combination therapy

The recommended dose of Ruxience in combination with chemotherapy for induction treatment of previously untreated or relapsed/refractory patients with follicular lymphoma is: 375 mg/m2 body surface area per cycle, for up to 8 cycles.

Ruxience should be administered on day 1 of each chemotherapy cycle, after intravenous administration of the glucocorticoid component of the chemotherapy if applicable.

Maintenance therapy

• • Previously untreated follicular lymphoma

The recommended dose of Ruxience used as a maintenance treatment for patients with previously untreated follicular lymphoma who have responded to induction treatment is: 375 mg/m2 body surface area once every 2 months (starting 2 months after the last dose of induction therapy) until disease progression or for a maximum period of two years (12 infusions in total).

• • Relapsed/refractory follicular lymphoma

The recommended dose of Ruxience used as a maintenance treatment for patients with relapsed/refractory follicular lymphoma who have responded to induction treatment is: 375 mg/m2 body surface area once every 3 months (starting 3 months after the last dose of induction therapy) until disease progression or for a maximum period of two years (8 infusions in total).

Monotherapy

• • Relapsed/refractory follicular lymphoma

The recommended dose of Ruxience monotherapy used as induction treatment for adult patients with stage III-IV follicular lymphoma who are chemoresistant or are in their second or subsequent relapse after chemotherapy is: 375 mg/m2 body surface area, administered as an intravenous infusion once weekly for four weeks.

For re-treatment with Ruxience monotherapy for patients who have responded to previous treatment with rituximab monotherapy for relapsed/refractory follicular lymphoma, the recommended dose is: 375 mg/m2 body surface area, administered as an intravenous infusion once weekly for four weeks (see section 5.1).

Adult diffuse large B cell non-Hodgkin's lymphoma

Ruxience should be used in combination with CHOP chemotherapy. The recommended dosage is 375 mg/m2 body surface area, administered on day 1 of each chemotherapy cycle for 8 cycles after intravenous infusion of the glucocorticoid component of CHOP. Safety and efficacy of rituximab have not been established in combination with other chemotherapies in diffuse large B cell non-Hodgkin’s lymphoma.

Dose adjustments during treatment

No dose reductions of Ruxience are recommended. When Ruxience is given in combination with chemotherapy, standard dose reductions for the chemotherapeutic medicinal products should be applied.

Chronic lymphocytic leukaemia

The recommended dosage of Ruxience in combination with chemotherapy for previously untreated and relapsed/refractory patients is 375 mg/m2 body surface area administered on day 0 of the first treatment cycle followed by 500 mg/m2 body surface area administered on day 1 of each subsequent cycle for 6 cycles in total. The chemotherapy should be given after Ruxience infusion.

Rheumatoid arthritis

Patients treated with Ruxience must be given the patient alert card with each infusion.

A course of Ruxience consists of two 1000 mg intravenous infusions. The recommended dosage of Ruxience is 1000 mg by intravenous infusion followed by a second 1000 mg intravenous infusion two weeks later.

The need for further courses should be evaluated 24 weeks following the previous course. Re-treatment should be given at that time if residual disease activity remains, otherwise re-treatment should be delayed until disease activity returns.

Available data suggest that clinical response is usually achieved within 16 – 24 weeks of an initial treatment course. Continued therapy should be carefully reconsidered in patients who show no evidence of therapeutic benefit within this time period.

Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA)

Patients treated with Ruxience must be given the patient alert card with each infusion.

Adult induction of remission

The recommended dosage of Ruxience for induction of remission therapy in adult patients with GPA and MPA is 375 mg/m2 body surface area, administered as an intravenous infusion once weekly for 4 weeks (four infusions in total).

Adult maintenance treatment

Following induction of remission with Ruxience, maintenance treatment in adult patients with GPA and MPA should be initiated no sooner than 16 weeks after the last Ruxience infusion.

Following induction of remission with other standard of care immunosuppressants, Ruxience maintenance treatment should be initiated during the 4 week period that follows disease remission.

Ruxience should be administered as two 500 mg IV infusions separated by two weeks, followed by a 500 mg IV infusion every 6 months thereafter. Patients should receive Ruxience for at least 24 months after achievement of remission (absence of clinical signs and symptoms). For patients who may be at higher risk for relapse, physicians should consider a longer duration of Ruxience maintenance therapy, up to 5 years.

Pemphigus vulgaris

Patients treated with Ruxience must be given the patient alert card with each infusion.

The recommended dosage of Ruxience for the treatment of pemphigus vulgaris is 1000 mg administered as an IV infusion followed two weeks later by a second 1000 mg IV infusion in combination with a tapering course of glucocorticoids.

Maintenance treatment

A maintenance infusion of 500 mg IV should be administered at months 12 and 18, and then every 6 months thereafter if needed, based on clinical evaluation.

Treatment of relapse

In the event of relapse, patients may receive 1000 mg IV. The healthcare provider should also consider resuming or increasing the patient’s glu­cocorticoid dose based on clinical evaluation.

Subsequent infusions may be administered no sooner than 16 weeks following the previous infusion.

Special populations

Paediatric population

Non-Hodgkin’s lymphoma

In paediatric patients from > 6 months to <18 years of age with previously untreated, advanced stage CD20 positive DLBCL/BL/BAL/BLL, Ruxience should be used in combination with systemic Lymphome Malin B (LMB) chemotherapy (see Tables 1 and 2). The recommended dosage of Ruxience is 375 mg/m2 BSA, administered as an IV infusion. No Ruxience dose adjustments, other than by BSA, are required.

The safety and efficacy of rituximab in paediatric patients > 6 months to < 18 years of age has not been established in indications other than previously untreated advanced stage CD20 positive DLBCL/BL/BAL/BLL. Only limited data are available for patients under 3 years of age. See section 5.1 for further information.

Ruxience should not be used in paediatric patients from birth to < 6 months of age with CD20 positive diffuse large B-cell lymphoma (see section 5.1).

Table 1 Posology of Ruxience administration for Non-Hodgkin’s lymphoma paediatric patients

Table 2 Treatment plan for Non-Hodgkin’s lymphoma paediatric patients: Concomitant

__________ chemotherapy with Ruxience _____________­________________________­________

Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA)

Induction of remission

The recommended dosage of Ruxience for induction of remission therapy in paediatric patients with severe, active GPA or MPA is 375 mg/m2 BSA, administered as an IV infusion once weekly for 4 weeks.

The safety and efficacy of rituximab in paediatric patients (> 2 to < 18 years of age) has not been established in indications other than severe, active GPA or MPA.

Ruxience should not be used in paediatric patients less than 2 years of age with severe, active GPA or MPA as there is a possibility of an inadequate immune response towards childhood vaccinations against common, vaccine preventable childhood diseases (e.g. measles, mumps, rubella, and poliomyelitis) (see section 5.1).

Elderly

No dose adjustment is required in elderly patients (aged > 65 years).

Method of administration

The prepared Ruxience solution should be administered as an intravenous infusion through a dedicated line. It should not be administered as an intravenous push or bolus.

Patients should be closely monitored for the onset of cytokine release syndrome (see section 4.4). Patients who develop evidence of severe reactions, especially severe dyspnoea, bronchospasm or hypoxia should have the infusion interrupted immediately. Patients with non-Hodgkin’s lymphoma should then be evaluated for evidence of tumour lysis syndrome including appropriate laboratory tests and, for pulmonary infiltration, with a chest X-ray. In all patients, the infusion should not be restarted until complete resolution of all symptoms, and normalisation of laboratory values and chest X-ray findings. At this time, the infusion can be initially resumed at not more than one-half the previous rate. If the same severe adverse reactions occur for a second time, the decision to stop the treatment should be seriously considered on a case by case basis.

Mild or moderate infusion-related reactions (IRR) (see section 4.8) usually respond to a reduction in the rate of infusion. The infusion rate may be increased upon improvement of symptoms.

First infusion

The recommended initial rate for infusion is 50 mg/hour; after the first 30 minutes, it can be escalated in 50 mg/hour increments every 30 minutes, to a maximum of 400 mg/hour.

Subsequent infusions

All indications

Subsequent doses of Ruxience can be infused at an initial rate of 100 mg/hour, and increased by 100 mg/hour increments at 30 minute intervals, to a maximum of 400 mg/hour.

Paediatric patients – non-Hodgkin’s lymphoma

First infusion

The recommended initial rate for infusion is 0.5 mg/kg/hour (maximum 50 mg/hour); it can be escalated by 0.5 mg/kg/hour every 30 minutes if there is no hypersensitivity or infusion-related reactions, to a maximum of 400 mg/hour.

Subsequent infusions

Subsequent doses of Ruxience can be infused at an initial rate of 1 mg/kg/hour (maximum 50 mg/hour); it can be increased by 1 mg/kg/hour every 30 minutes to a maximum of 400 mg/hour.

Rheumatoid arthritis only

Alternative subsequent, faster, infusion schedule

If patients did not experience a serious infusion-related reaction with their first or subsequent infusions of a dose of 1000 mg Ruxience administered over the standard infusion schedule, a more rapid infusion can be administered for second and subsequent infusions using the same concentration as in previous infusions (4 mg/mL in a 250 mL volume). Initiate at a rate of 250 mg/hour for the first 30 minutes and then 600 mg/hour for the next 90 minutes. If the more rapid infusion is tolerated, this infusion schedule can be used when administering subsequent infusions.

Patients who have clinically significant cardiovascular disease, including arrhythmias, or previous serious infusion reactions to any prior biologic therapy or to rituximab, should not be administered the more rapid infusion.

4.3 Contraindications

Contraindications for use in non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia

Hypersensitivity to the active substance or to murine proteins, or to any of the other excipients listed in section 6.1.

Active, severe infections (see section 4.4).

Patients in a severely immunocompromised state.

Contraindications for use in rheumatoid arthritis, granulomatosis with polyangiitis, microscopic polyangiitis and pemphigus vulgaris

Hypersensitivity to the active substance or to murine proteins, or to any of the other excipients listed in section 6.1.

Active, severe infections (see section 4.4).

Patients in a severely immunocompromised state.

Severe heart failure (New York Heart Association Class IV) or severe, uncontrolled cardiac disease (see section 4.4 regarding other cardiovascular diseases).

4.4 Special warnings and precautions for use

Traceability

In order to improve the traceability of biological medicinal products, the tradename and the batch number of the administered product should be clearly recorded.

Progressive multifocal leukoencephalo­pathy

All patients treated with Ruxience for rheumatoid arthritis, GPA, MPA or pemphigus vulgaris must be given the patient alert card with each infusion. The alert card contains important safety information for patients regarding potential increased risk of infections, including progressive multifocal leukoencephalo­pathy (PML).

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 Ruxience must be permanently discontinued.

Following reconstitution of the immune system in immunocompromised patients with PML, stabilisation or improved outcome has been seen. It remains unknown if early detection of PML and suspension of rituximab therapy may lead to similar stabilisation or improved outcome.

Non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia

Infusion-related reactions

Rituximab is associated with infusion-related reactions, which may be related to release of cytokines and/or other chemical mediators. Cytokine release syndrome may be clinically indistinguishable from acute hypersensitivity reactions.

This set of reactions which includes syndrome of cytokine release, tumour lysis syndrome and anaphylactic and hypersensitivity reactions are described below.

Severe infusion-related reactions with fatal outcome have been reported during post-marketing use of the rituximab intravenous formulation, with an onset ranging within 30 minutes to 2 hours after starting the first rituximab intravenous infusion. They were characterised by pulmonary events and in some cases included rapid tumour lysis and features of tumour lysis syndrome in addition to fever, chills, rigors, hypotension, urticaria, angioedema and other symptoms (see section 4.8).

Severe cytokine release syndrome is characterised by severe dyspnoea, often accompanied by bronchospasm and hypoxia, in addition to fever, chills, rigors, urticaria, and angioedema. This syndrome may be associated with some features of tumour lysis syndrome such as hyperuricaemia, hyperkalaemia, hypocalcaemia, hyperphosphataemia, acute renal failure, elevated lactate dehydrogenase (LDH) and may be associated with acute respiratory failure and death. The acute respiratory failure may be accompanied by events such as pulmonary interstitial infiltration or oedema, visible on a chest X-ray. The syndrome frequently manifests itself within one or two hours of initiating the first infusion. Patients with a history of pulmonary insufficiency or those with pulmonary tumour infiltration may be at greater risk of poor outcome and should be treated with increased caution. Patients who develop severe cytokine release syndrome should have their infusion interrupted immediately (see section 4.2) and should receive aggressive symptomatic treatment. Since initial improvement of clinical symptoms may be followed by deterioration, these patients should be closely monitored until tumour lysis syndrome and pulmonary infiltration have been resolved or ruled out. Further treatment of patients after complete resolution of signs and symptoms has rarely resulted in repeated severe cytokine release syndrome.

Patients with a high tumour burden or with a high number (> 25 × 109/L) of circulating malignant cells such as patients with CLL, who may be at higher risk of especially severe cytokine release syndrome, should be treated with extreme caution. These patients should be very closely monitored throughout the first infusion. Consideration should be given to the use of a reduced infusion rate for the first infusion in these patients or a split dosing over two days during the first cycle and any subsequent cycles if the lymphocyte count is still > 25 × 109/L.

Infusion-related adverse reactions of all kinds have been observed in 77% of patients treated with rituximab (including cytokine release syndrome accompanied by hypotension and bronchospasm in 10% of patients) (see section 4.8). These symptoms are usually reversible with interruption of rituximab infusion and administration of an anti-pyretic, an antihistaminic and occasionally oxygen, intravenous 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. Medicinal products for the treatment of hypersensitivity reactions, e.g. epinephrine (adrenaline), antihistamines and glucocorticoids, should be available for immediate use in the event of an allergic reaction during administration of rituximab. Clinical manifestations of anaphylaxis may appear similar to clinical manifestations of the cytokine release syndrome (described above). Reactions attributed to hypersensitivity have been reported less frequently than those attributed to cytokine release.

Additional reactions reported in some cases were myocardial infarction, atrial fibrillation, pulmonary oedema and acute reversible thrombocytopenia.

Since hypotension may occur during rituximab administration, consideration should be given to withholding anti-hypertensive medicinal products for 12 hours prior to the Ruxience infusion.

Cardiac disorders

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.

Haematological toxicities

Although rituximab is not myelosuppressive in monotherapy, caution should be exercised when considering treatment of patients with neutrophils < 1.5 × 109/L and/or platelet counts < 75 × 109/L as clinical experience in this population is limited. Rituximab has been used in 21 patients who underwent autologous bone marrow transplantation and other risk groups with a presumable reduced bone marrow function without inducing myelotoxicity.

Regular full blood counts, including neutrophil and platelet counts, should be performed during Ruxience therapy.

Infections

Serious infections, including fatalities, can occur during therapy with rituximab (see section 4.8). Ruxience should not be administered to patients with an active, severe infection (e.g. tuberculosis, sepsis and opportunistic infections, see section 4.3).

Physicians should exercise caution when considering the use of Ruxience in patients with a history of recurring or chronic infections or with underlying conditions which may further predispose patients to serious infection (see section 4.8).

Cases of hepatitis B reactivation have been reported in subjects receiving rituximab including fulminant hepatitis with fatal outcome. The majority of these subjects were also exposed to cytotoxic chemotherapy. Limited information from one study in relapsed/refractory CLL patients suggests that rituximab treatment may also worsen the outcome of primary hepatitis B infections. Hepatitis B virus (HBV) screening should be performed in all patients before initiation of treatment with Ruxience. At minimum this should include HBsAg-status and HBcAb-status. These can be complemented with other appropriate markers as per local guidelines. Patients with active hepatitis B disease should not be treated with Ruxience. Patients with positive hepatitis B serology (either HBsAg or HBcAb) should consult liver disease experts before start of treatment and should be monitored and managed following local medical standards to prevent hepatitis B reactivation.

Very rare cases of progressive multifocal leukoencephalopathy (PML) have been reported during post-marketing use of rituximab in NHL and CLL (see section 4.8). The majority of patients had received rituximab in combination with chemotherapy or as part of a haematopoietic stem cell transplant.

Immunisations

The safety of immunisation with live viral vaccines, following rituximab therapy has not been studied for NHL and CLL patients and vaccination with live virus vaccines is not recommended. Patients treated with Ruxience may receive non-live vaccinations; however with non-live vaccines response rates may be reduced. In a non-randomised study, adult patients with relapsed low-grade NHL who received rituximab monotherapy when compared to healthy untreated controls had a lower rate of response to vaccination with tetanus recall antigen (16% vs. 81%) and Keyhole Limpet Haemocyanin (KLH) neoantigen (4% vs. 76% when assessed for > 2-fold increase in antibody 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, varicella) were maintained for at least 6 months after treatment with rituximab.

Skin reactions

Severe skin reactions such as Toxic Epidermal Necrolysis (Lyell’s syndrome) and Stevens-Johnson syndrome, some with fatal outcome, have been reported (see section 4.8). In case of such an event, with a suspected relationship to rituximab, treatment should be permanently discontinued.

Paediatric population

Only limited data are available for patients under 3 years of age. See section 5.1 for further information.

Rheumatoid arthritis, granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), and pemphigus vulgaris

Methotrexate (MTX) naïve populations with rheumatoid arthritis

The use of rituximab is not recommended in MTX-naïve patients since a favourable benefit-risk relationship has not been established.

Infusion-related reactions

Rituximab is associated with infusion-related reactions (IRRs), which may be related to release of cytokines and/or other chemical mediators.

Severe IRRs with fatal outcome have been reported in rheumatoid arthritis patients in the post-marketing setting. In rheumatoid arthritis most infusion-related events reported in clinical trials were mild to moderate in severity. The most common symptoms were allergic reactions like headache, pruritus, throat irritation, flushing, rash, urticaria, hypertension, and pyrexia. In general, the proportion of patients experiencing any infusion reaction was higher following the first infusion than following the second infusion of any treatment course. The incidence of IRR decreased with subsequent courses (see section 4.8). The reactions reported were usually reversible with a reduction in rate, or interruption, of rituximab infusion and administration of an anti-pyretic, an antihistamine, and, occasionally, oxygen, intravenous 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 IRR and the required interventions, temporarily or permanently discontinue Ruxience. In most cases, the infusion can be resumed at a 50% reduction in rate (e.g. from 100 mg/hour to 50 mg/hour) 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 Ruxience.

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 Ruxience and patients closely monitored during administration. Since hypotension may occur during rituximab infusion, consideration should be given to withholding anti-hypertensive medicinal products for 12 hours prior to the Ruxience infusion.

IRRs in patients with GPA, MPA and pemphigus vulgaris were consistent with those seen for rheumatoid arthritis patients in clinical trials and in the post-marketing setting (see section 4.8).

Cardiac disorders

Angina pectoris, cardiac arrhythmias such as atrial flutter and fibrillation, heart failure and/or myocardial infarction have occurred in patients treated with rituximab. Therefore, patients with a history of cardiac disease should be monitored closely (see Infusion-related reactions, above).

Infections

Based on the mechanism of action of rituximab and the knowledge that B cells play an important role in maintaining normal immune response, patients have an increased risk of infection following rituximab therapy (see section 5.1). Serious infections, including fatalities, can occur during therapy with rituximab (see section 4.8). Ruxience should not be administered to patients with an active, severe infection (e.g. tuberculosis, sepsis and opportunistic infections, see section 4.3) or severely immunocompromised patients (e.g. where levels of CD4 or CD8 are very low). Physicians should exercise caution when considering the use of rituximab in patients with a history of recurring or chronic infections or with underlying conditions which may further predispose patients to serious infection, e.g. hypogammaglobu­linaemia (see section 4.8). It is recommended that immunoglobulin levels are determined prior to initiating treatment with Ruxience.

Patients reporting signs and symptoms of infection following Ruxience therapy should be promptly evaluated and treated appropriately. Before giving a subsequent course of Ruxience treatment, patients should be re-evaluated for any potential risk for infections.

Very rare cases of fatal progressive multifocal leukoencephalopathy (PML) have been reported following use of rituximab for the treatment of rheumatoid arthritis and autoimmune diseases including Systemic Lupus Erythematosus (SLE) and vasculitis.

Hepatitis B Infections

Cases of hepatitis B reactivation, including those with a fatal outcome, have been reported in rheumatoid arthritis, GPA and MPA patients receiving rituximab.

Hepatitis B virus (HBV) screening should be performed in all patients before initiation of treatment with Ruxience. At minimum this should include HBsAg-status and HBcAb-status. These can be complemented with other appropriate markers as per local guidelines. Patients with active hepatitis B disease should not be treated with rituximab. Patients with positive hepatitis B serology (either HBsAg or HBcAb) should consult liver disease experts before start of treatment and should be monitored and managed following local medical standards to prevent hepatitis B reactivation.

Late neutropenia

Measure blood neutrophils prior to each course of Ruxience, and regularly up to 6-months after cessation of treatment, and upon signs or symptoms of infection (see section 4.8).

Skin reactions

Severe skin reactions such as Toxic Epidermal Necrolysis (Lyell’s syndrome) and Stevens-Johnson syndrome, some with fatal outcome, have been reported (see section 4.8). In case of such an event with a suspected relationship to Ruxience, treatment should be permanently discontinued.

Immuni sation

Physicians should review the patient’s vac­cination status and patients should, if possible, be brought up-to-date with all immunisations in agreement with current immunisation guidelines prior to initiating Ruxience therapy. Vaccination should be completed at least 4 weeks prior to first administration of Ruxience.

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 Ruxience or whilst peripherally B cell depleted.

Patients treated with Ruxience may receive non-live vaccinations; however, response rates to non-live vaccines may be reduced. In a randomised trial, patients with rheumatoid arthritis treated with rituximab and methotrexate had comparable response rates to tetanus recall antigen (39% vs. 42%), reduced rates to pneumococcal polysaccharide vaccine (43% vs. 82% to at least 2 pneumococcal antibody serotypes), and KLH neoantigen (47% vs. 93%), when given 6 months after rituximab as compared to patients only receiving methotrexate. Should non-live vaccinations be required whilst receiving rituximab therapy, these should be completed at least 4 weeks prior to commencing the next course of rituximab.

In the overall experience of rituximab repeat treatment over one year in rheumatoid arthritis, the proportions of patients with positive antibody titres against S. pneumoniae, influenza, mumps, rubella, varicella and tetanus toxoid were generally similar to the proportions at baseline.

Concomitant/se­quential use of other DMARDs in rheumatoid arthritis

The concomitant use of Ruxience and anti-rheumatic therapies other than those specified under the rheumatoid arthritis indication and posology is not recommended.

There are limited data from clinical trials to fully assess the safety of the sequential use of other DMARDs (including TNF inhibitors and other biologics) following rituximab (see section 4.5). The available data indicate that the rate of clinically relevant infection is unchanged when such therapies are used in patients previously treated with rituximab, however patients should be closely observed for signs of infection if biologic agents and/or DMARDs are used following rituximab therapy.

Malignancy

Immunomodulatory drugs may increase the risk of malignancy. However, available data do not suggest an increased risk of malignancy for rituximab used in autoimmune indications beyond the malignancy risk already associated with the underlying autoimmune condition.

Excipients

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’.

4.5 Interaction with other medicinal products and other forms of interaction

Currently, there are limited data on possible drug interactions with rituximab.

In CLL patients, co-administration with rituximab did not appear to have an effect on the pharmacokinetics of fludarabine or cyclophosphamide. In addition, there was no apparent effect of fludarabine and cyclophosphamide on the pharmacokinetics of rituximab.

Co-administration with methotrexate had no effect on the pharmacokinetics of rituximab in rheumatoid arthritis patients.

Patients with human anti-mouse antibody (HAMA) or anti-drug antibody (ADA) titres may have allergic or hypersensitivity reactions when treated with other diagnostic or therapeutic monoclonal antibodies.

In patients with rheumatoid arthritis, 283 patients received subsequent therapy with a biologic DMARD following rituximab. In these patients the rate of clinically relevant infection while on rituximab was 6.01 per 100 patient years compared to 4.97 per 100 patient years following treatment with the biologic DMARD.

4.6 Fertility, pregnancy and lactation

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 Ruxience.

Pregnancy

IgG immunoglobulins are known to cross the placental barrier.

B cell levels in human neonates following maternal exposure to rituximab have not been studied in clinical trials. There are no adequate and well-controlled data from studies in pregnant women, however transient B-cell depletion and lymphocytopenia have been reported in some infants born to mothers exposed to rituximab during pregnancy. Similar effects have been observed in animal studies (see section 5.3). For these reasons Ruxience should not be administered to pregnant women unless the possible benefit outweighs the potential risk.

Breast-feeding

Limited data on rituximab excretion into breast milk suggest very low milk levels (relative infant dose less than 0.4%). Few cases of follow-up of breastfed infants describe normal growth and development up to 1.5 years. However, as these data are limited and the long-term outcomes of breastfed infants remain unknown, breast-feeding is not recommended while being treated with rituximab and optimally for 12 months following rituximab treatment.

Fertility

Animal studies did not reveal deleterious effects of rituximab on reproductive organs.

4.7 Effects on ability to drive and use machines

No studies on the effects of rituximab on the ability to drive and use machines have been performed, although the 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.

4.8 Undesirable effects

Experience from non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia in adults

Summary of the safety profile

The overall safety profile of rituximab in non-Hodgkin’s lymphoma and CLL is based on data from patients from clinical trials and from post-marketing surveillance. These patients were treated either with rituximab monotherapy (as induction treatment or maintenance treatment following induction treatment) or in combination with chemotherapy.

The most frequently observed adverse reactions (ADRs) in patients receiving rituximab were IRRs which occurred in the majority of patients during the first infusion. The incidence of infusion-related symptoms decreases substantially with subsequent infusions and is less than 1% after eight doses of rituximab.

Infectious events (predominantly bacterial and viral) occurred in approximately 30–55% of patients during clinical trials in patients with NHL and in 30–50% of patients during clinical trials in patients with CLL.

The most frequently reported or observed serious adverse reactions were:

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

Other serious ADRs reported include hepatitis B reactivation and PML (see section 4.4.).

Tabulated list of adverse reactions

The frequencies of ADRs reported with rituximab alone or in combination with chemotherapy are summarised in Table 3. Frequencies are defined as very common (> 1/10), common (> 1/100 to < 1/10), uncommon (> 1/1,000 to < 1/100), rare (> 1/10,000 to < 1/1,000), very rare (< 1/10,000) and not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in the order of decreasing seriousness.

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

Table 3 ADRs reported in clinical trials or during post-marketing surveillance in patients

with NHL and CLL disease treated with rituximab monotherapy/ma­intenance or in combination with chemotherapy

The following terms have been reported as adverse events during clinical trials, however, were reported at a similar or lower incidence in the rituximab arms compared to control arms: haematotoxicity, neutropenic infection, urinary tract infection, sensory disturbance, pyrexia.

Signs and symptoms suggestive of an infusion-related reaction were reported in more than 50% of patients in clinical trials, and were predominantly seen during the first infusion, usually in the first one to two hours. These symptoms mainly comprised fever, chills and rigors. Other symptoms included flushing, angioedema, bronchospasm, vomiting, nausea, urticaria/rash, fatigue, headache, throat irritation, rhinitis, pruritus, pain, tachycardia, hypertension, hypotension, dyspnoea, dyspepsia, asthenia and features of tumour lysis syndrome. Severe infusion-related reactions (such as bronchospasm, hypotension) occurred in up to 12% of the cases.

Additional reactions reported in some cases were myocardial infarction, atrial fibrillation, pulmonary oedema and acute reversible thrombocytopenia. Exacerbations of pre-existing cardiac conditions such as angina pectoris or congestive heart failure or severe cardiac disorders (heart failure, myocardial infarction, atrial fibrillation), pulmonary oedema, multi-organ failure, tumour lysis syndrome, cytokine release syndrome, renal failure, and respiratory failure were reported at lower or unknown frequencies. The incidence of infusion-related symptoms decreased substantially with subsequent infusions and is < 1% of patients by the eighth cycle of rituximab (containing) treatment.

Description of selected adverse reactions

Infections

Rituximab induces B-cell depletion in about 70–80% of patients, but was associated with decreased serum immunoglobulins only in a minority of patients.

Localised candida infections as well as Herpes zoster were reported at a higher incidence in the rituximab-containing arm of randomised studies. Severe infections were reported in about 4% of patients treated with rituximab monotherapy. Higher frequencies of infections overall, including grade 3 or 4 infections, were observed during rituximab maintenance treatment up to 2 years when compared to observation. There was no cumulative toxicity in terms of infections reported over a 2-year treatment period. In addition, other serious viral infections either new, reactivated or exacerbated, some of which were fatal, have been reported with rituximab treatment. The majority of patients had received rituximab in combination with chemotherapy or as part of a haematopoietic 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 re-treatment have also been reported in clinical trials. Cases of hepatitis B reactivation, have been reported, the majority of which were in patients receiving rituximab in combination with cytotoxic chemotherapy. In patients with relapsed/refractory CLL, the incidence of grade 3/4 hepatitis B infection (reactivation and primary infection) was 2% in R-FC vs. 0% FC. Progression of Kaposi’s sarcoma has been observed in rituximab-exposed patients with pre-existing Kaposi’s sarcoma. These cases occurred in non-approved indications and the majority of patients were HIV positive.

Haematologic adverse reactions

In clinical trials with rituximab monotherapy given for 4 weeks, haematological abnormalities occurred in a minority of patients and were usually mild and reversible. Severe (grade 3/4) neutropenia was reported in 4.2%, anaemia in 1.1% and thrombocytopenia in 1.7% of the patients. During rituximab maintenance treatment for up to 2 years, leucopenia (5% vs. 2%, grade 3/4) and neutropenia (10% vs. 4%, grade 3/4) were reported at a higher incidence when compared to observation. The incidence of thrombocytopenia was low (< 1%, grade 3/4) and was not different between treatment arms. During the treatment course in studies with rituximab in combination with chemotherapy, grade 3/4 leucopenia (R-CHOP 88% vs. CHOP 79%, R-FC 23% vs. FC 12%), neutropenia (R-CVP 24% vs. CVP 14%; R-CHOP 97% vs. CHOP 88%, R-FC 30% vs. FC 19% in previously untreated CLL), pancytopenia (R-FC 3% vs. FC 1% in previously untreated CLL) were usually reported with higher frequencies when compared to chemotherapy alone. However, the higher incidence of neutropenia in patients treated with rituximab and chemotherapy was not associated with a higher incidence of infections and infestations compared to patients treated with chemotherapy alone. Studies in previously untreated and relapsed/refractory CLL have established that in up to 25% of patients treated with R-FC neutropenia was prolonged (defined as neutrophil count remaining below 1 × 109/L between day 24 and 42 after the last dose) or occurred with a late onset (defined as neutrophil count below 1 × 109/L later than 42 days after last dose in patients with no previous prolonged neutropenia or who recovered prior to day 42) following treatment with rituximab plus FC. There were no differences reported for the incidence of anaemia. Some cases of late neutropenia occurring more than four weeks after the last infusion of rituximab were reported. In the CLL first-line study, Binet stage C patients experienced more adverse events in the R-FC arm compared to the FC arm (R-FC 83% vs. FC 71%). In the relapsed/refractory CLL study grade 3/4 thrombocytopenia was reported in 11% of patients in the R-FC group compared to 9% of patients in the FC group.

In studies of rituximab in patients with Waldenstrom’s ma­croglobulinae­mia, transient increases in serum IgM levels have been observed following treatment initiation, which may be associated with hyperviscosity and related symptoms. The transient IgM increase usually returned to at least baseline level within 4 months.

Cardiovascular adverse reactions

Cardiovascular reactions during clinical trials with rituximab monotherapy were reported in 18.8% of patients with the most frequently reported events being hypotension and hypertension. Cases of grade 3 or 4 arrhythmia (including ventricular and supraventricular tachycardia) and angina pectoris during infusion were reported. During maintenance treatment, the incidence of grade 3/4 cardiac disorders was comparable between patients treated with rituximab and observation. Cardiac events were reported as serious adverse events (including atrial fibrillation, myocardial infarction, left ventricular failure, myocardial ischaemia) in 3% of patients treated with rituximab compared to < 1% on observation. In studies evaluating rituximab in combination with chemotherapy, the incidence of grade 3 and 4 cardiac arrhythmias, predominantly supraventricular arrhythmias such as tachycardia and atrial flutter/fibri­llation, was higher in the R-CHOP group (14 patients, 6.9%) as compared to the CHOP group (3 patients, 1.5%). All of these arrhythmias either occurred in the context of a rituximab infusion or were associated with predisposing conditions such as fever, infection, acute myocardial infarction or pre-existing respiratory and cardiovascular disease. No difference between the R-CHOP and CHOP group was observed in the incidence of other grade 3 and 4 cardiac events including heart failure, myocardial disease and manifestations of coronary artery disease. In CLL, the overall incidence of grade 3 or 4 cardiac disorders was low both in the first-line study (4% R-FC, 3% FC) and in the relapsed/refractory study (4% R-FC, 4% FC).

Respiratory system

Cases of interstitial lung disease, some with fatal outcome have been reported.

Neurologic disorders

During the treatment period (induction treatment phase comprising of R-CHOP for at most eight cycles), four patients (2%) treated with R-CHOP, all with cardiovascular risk factors, experienced thromboembolic cerebrovascular accidents during the first treatment cycle. There was no difference between the treatment groups in the incidence of other thromboembolic events. In contrast, three patients (1.5%) had cerebrovascular events in the CHOP group, all of which occurred during the follow-up period. In CLL, the overall incidence of grade 3 or 4 nervous system disorders was low both in the first-line study (4% R-FC, 4% FC) and in the relapsed/refractory study (3% R-FC, 3% FC).

Cases of posterior reversible encephalopathy syndrome (PRES) / reversible posterior leukoencephalopathy syndrome (RPLS) have been reported. Signs and symptoms included visual disturbance, headache, seizures and altered mental status, with or without associated hypertension. A diagnosis of PRES/RPLS requires confirmation by brain imaging. The reported cases had recognised risk factors for PRES/RPLS, including the patients’ underlying disease, hypertension, immunosuppressive therapy and/or chemotherapy.

Gastrointestinal disorders

Gastrointestinal perforation in some cases leading to death has been observed in patients receiving rituximab for treatment of non-Hodgkin lymphoma. In the majority of these cases, rituximab was administered with chemotherapy.

IgG levels

In the clinical trial evaluating rituximab maintenance treatment in relapsed/refractory follicular lymphoma, median IgG levels were below the lower limit of normal (LLN) (< 7 g/L) after induction treatment in both the observation and the rituximab groups. In the observation group, the median IgG level subsequently increased to above the LLN, but remained constant in the rituximab group. The proportion of patients with IgG levels below the LLN was about 60% in the rituximab group throughout the 2 year treatment period, while it decreased in the observation group (36% after 2 years).

A small number of spontaneous and literature cases of hypogammaglobu­linaemia have been observed in paediatric patients treated with rituximab, in some cases severe and requiring long-term immunoglobulin substitution therapy. The consequences of long-term B cell depletion in paediatric patients are unknown.

Skin and subcutaneous tissue disorders

Toxic Epidermal Necrolysis (Lyell syndrome) and Stevens-Johnson syndrome, some with fatal outcome, have been reported very rarely.

Patient subpopulations – rituximab monotherapy

Elderly (> 65 years)

The incidence of ADRs of all grades and grade 3/4 ADR was similar in elderly patients compared to younger patients (< 65 years).

Bulky disease

There was a higher incidence of grade 3/4 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.

Re-treatment

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 3/4 ADRs).

Patient subpopulations – rituximab combination therapy

Elderly (> 65 years)

The incidence of grade 3/4 blood and lymphatic adverse events was higher in elderly patients compared to younger patients (< 65 years), with previously untreated or relapsed/refrac­tory CLL.

Experience from paediatric DLBCL/BL/BAL/BLL

Summary of the safety profile

A multicentre, open-label randomised study of Lymphome Malin B chemotherapy (LMB) with or without rituximab was conducted in paediatric patients (aged > 6 months to < 18 years old) with previously untreated advanced stage CD20 positive DLBCL/BL/BAL/BLL.

A total of 309 paediatric patients received rituximab and were included in the safety analysis population. Paediatric patients randomised to the LMB chemotherapy arm with rituximab, or enrolled in the single arm part of the study, were administered rituximab at a dose of 375 mg/m2 BSA and received a total of six IV infusions of rituximab (two during each of the two induction courses and one during each of the two consolidation courses of the LMB scheme).

The safety profile of rituximab in paediatric patients (aged > 6 months to <18 years old) with previously untreated advanced stage CD20 positive DLBCL/BL/BAL/BLL was generally consistent in type, nature and severity with the known safety profile in adult NHL and CLL patients. Addition of rituximab to chemotherapy did result in an increased risk of some events including infections (including sepsis) compared to chemotherapy only.

Experience from rheumatoid arthritis

Summary of the safety profile

The overall safety profile of rituximab in rheumatoid arthritis is based on data from patients from clinical trials and from post-marketing surveillance.

The safety profile of rituximab in patients with moderate to severe rheumatoid arthritis (RA) is summarised in the sections below. In clinical trials more than 3100 patients received at least one treatment course and were followed for periods ranging from 6 months to over 5 years; approximately 2400 patients received two or more courses of treatment with over 1000 having received 5 or more courses. The safety information collected during post-marketing experience reflects the expected adverse reaction profile as seen in clinical trials for rituximab (see section 4.4).

Patients received 2 × 1000 mg of rituximab separated by an interval of two weeks; in addition to methotrexate (10–25 mg/week). Rituximab infusions were administered after an intravenous infusion of 100 mg methylprednisolone; patients also received treatment with oral prednisone for 15 days.

Tabulated list of adverse reactions

Adverse reactions are listed in Table 4. Frequencies are defined as very common (> 1/10), common (> 1/100 to < 1/10), uncommon (> 1/1,000 to < 1/100), rare (> 1/10,000 to < 1/1,000), and very rare (< 1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

The most frequent adverse reactions considered due to receipt of rituximab were IRRs. The overall incidence of IRRs in clinical trials was 23% with the first infusion and decreased with subsequent infusions. Serious IRRs were uncommon (0.5% of patients) and were predominantly seen during the initial course. In addition to adverse reactions seen in RA clinical trials for rituximab, progressive multifocal leukoencephalopathy (PML) (see section 4.4) and serum sickness-like reaction have been reported during post-marketing experience.

Table 4 Summary of adverse reactions reported in clinical trials or during post-marketing surveillance occurring in patients with rheumatoid arthritis receiving rituximab

Multiple courses

Multiple courses of treatment are associated with a similar ADR profile to that observed following first exposure. The rate of all ADRs following first rituximab exposure was highest during the first

6 months and declined thereafter. This is mostly accounted for by IRRs (most frequent during the first treatment course), RA exacerbation and infections, all of which were more frequent in the first

6 months of treatment.

Description of selected adverse reactions

Infusion-related reactions

The most frequent ADRs following receipt of rituximab in clinical studies were IRRs (refer to Table 4). Among the 3189 patients treated with rituximab, 1135 (36%) experienced at least one IRR with 733/3189 (23%) of patients experiencing an IRR following first infusion of the first exposure to rituximab. The incidence of IRRs declined with subsequent infusions. In clinical trials fewer than 1% (17/3189) of patients experienced a serious IRR. There were no CTC Grade 4 IRRs and no deaths due to IRRs in the clinical trials. The proportion of CTC Grade 3 events and of IRRs leading to withdrawal decreased by course and were rare from course 3 onwards. Premedication with intravenous glucocorticoid significantly reduced the incidence and severity of IRRs (see sections 4.2 and 4.4). Severe IRRs with fatal outcome have been reported in the post-marketing setting.

In a trial designed to evaluate the safety of a more rapid rituximab infusion in patients with rheumatoid arthritis, patients with moderate-to-severe active RA who did not experience a serious IRR during or within 24 hours of their first studied infusion were allowed to receive a 2-hour intravenous infusion of rituximab. Patients with a history of a serious infusion reaction to a biologic therapy for RA were excluded from entry. The incidence, types and severity of IRRs were consistent with that observed historically. No serious IRRs were observed.

Infections

The overall rate of infection was approximately 94 per 100 patient years in rituximab treated patients. The infections were predominately mild to moderate and consisted mostly of upper respiratory tract infections and urinary tract infections. The incidence of infections that were serious or required IV antibiotics was approximately 4 per 100 patient years. The rate of serious infections did not show any significant increase following multiple courses of rituximab. Lower respiratory tract infections (including pneumonia) have been reported during clinical trials, at a similar incidence in the rituximab arms compared to control arms.

Cases of progressive multifocal leukoencephalopathy with fatal outcome have been reported following use of rituximab for the treatment of autoimmune diseases. This includes rheumatoid arthritis and off-label autoimmune diseases, including Systemic Lupus Erythematosus (SLE) and vasculitis.

In patients with non-Hodgkin’s lymphoma receiving rituximab in combination with cytotoxic chemotherapy, cases of hepatitis B reactivation have been reported (see non-Hodgkin’s lym­phoma). Reactivation of hepatitis B infection has also been very rarely reported in rheumatoid arthritis patients receiving rituximab (see section 4.4).

Cardiovascular adverse reactions

Serious cardiac reactions were reported at a rate of 1.3 per 100 patient years in the rituximab treated patients compared to 1.3 per 100 patient years in placebo treated patients. The proportions of patients experiencing cardiac reactions (all or serious) did not increase over multiple courses.

Neurologic events

Cases of posterior reversible encephalopathy syndrome (PRES)/reversible posterior leukoencephalopathy syndrome (RPLS) have been reported. Signs and symptoms included visual disturbance, headache, seizures and altered mental status, with or without associated hypertension. A diagnosis of PRES/RPLS requires confirmation by brain imaging. The reported cases had recognised risk factors for PRES/RPLS, including the patients’ underlying disease, hypertension, immunosuppressive therapy and/or chemotherapy.

Neutropenia

Events of neutropenia were observed with rituximab treatment, the majority of which were transient and mild or moderate in severity. Neutropenia can occur several months after the administration of rituximab (see section 4.4).

In placebo-controlled periods of clinical trials, 0.94% (13/1382) of rituximab treated patients and 0.27% (2/731) of placebo patients developed severe neutropenia.

Neutropenic events, including severe late onset and persistent neutropenia, have been rarely reported in the post-marketing setting, some of which were associated with fatal infections.

Skin and subcutaneous tissue disorders

Toxic Epidermal Necrolysis (Lyell’s syndrome) and Stevens-Johnson syndrome, some with fatal outcome, have been reported very rarely.

Laboratory abnormalities

Hypogammaglobu­linaemia (IgG or IgM below the lower limit of normal) has been observed in RA patients treated with rituximab. There was no increased rate in overall infections or serious infections after the development of low IgG or IgM (see section 4.4).

A small number of spontaneous and literature cases of hypogammaglobu­linaemia have been observed in paediatric patients treated with rituximab, in some cases severe and requiring long-term immunoglobulin substitution therapy. The consequences of long-term B cell depletion in paediatric patients are unknown.

Experience from granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA)

Adult induction of remission (GPA/MPA Study 1)

In GPA/MPA Study 1, 99 adult patients were treated for induction of remission of GPA and MPA with rituximab (375 mg/m2, once weekly for 4 weeks) and glucocorticoids (see section 5.1).

The ADRs listed in Table 5 were all adverse reactions which occurred at an incidence of >5% in the rituximab group and at a higher frequency than the comparator group.

Table 5 Adverse reactions occurring at 6-months in > 5% of adult patients receiving

rituximab in GPA/MPA Study 1, and at a higher frequency than the comparator group

Adult maintenance treatment (GPA/MPA Study 2)

In GPA/MPA Study 2, a total of 57 adult patients with severe, active GPA and MPA were treated with rituximab for the maintenance of remission (see section 5.1).

Table 6 Adverse reactions occurring in > 5% of adult patients receiving rituximab in

GPA/MPA Study 2, and at a higher frequency than the comparator group

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.

Long-term follow-up (GPA/MPA Study 3)

In a long-term observational safety study, 97 GPA/MPA patients received treatment with rituximab (mean of 8 infusions [range 1–28]) for up to 4 years, according to their physician’s stan­dard practice and discretion. The overall safety profile was consistent with the well-established safety profile of rituximab in RA and GPA/MPA and no new adverse reactions were reported.

Paediatric population

An open-label, single arm study was conducted in 25 paediatric patients with severe, active GPA or MPA. The overall study period consisted of a 6-month remission induction phase with a minimum 18-month follow-up, up to 4.5 years overall. During the follow-up phase, rituximab was given at the discretion of the investigator (17 out of 25 patients received additional rituximab treatment).

Concomitant treatment with other immunosuppressive therapy was permitted (see section 5.1).

ADRs were considered as adverse events that occurred at an incidence of > 10%. These included: infections (17 patients [68%] in the remission induction phase; 23 patients [92%] in the overall study period), IRRs (15 patients [60%] in the remission induction phase; 17 patients [68%] in the overall study period), and nausea (4 patients [16%] in the remission induction phase; 5 patients [20%] in the overall study period).

During the overall study period, the safety profile of rituximab was consistent with that reported during the remission induction phase.

The safety profile of rituximab in paediatric GPA or MPA patients was consistent in type, nature and severity with the known safety profile in adult patients in the approved autoimmune indications, including adult GPA or MPA.

Description of selected adverse reactions

Infusion-related reactions

In GPA/MPA Study 1 (adult induction of remission study), IRRs were defined as any adverse event occurring within 24 hours of an infusion and considered to be infusion-related by investigators in the safety population. Of the 99 patients treated with rituximab, 12 (12%) experienced at least one IRR. All IRRs were CTC Grade 1 or 2. The most common IRRs included cytokine release syndrome, flushing, throat irritation, and tremor. Rituximab was given in combination with intravenous glucocorticoids which may reduce the incidence and severity of these events.

In GPA/MPA Study 2 (adult maintenance study), 7/57 (12%) patients in the rituximab arm experienced at least one infusion-related reaction. The incidence of IRR symptoms was highest during or after the first infusion (9%) and decreased with subsequent infusions (< 4%). 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 in paediatric patients with GPA or MPA, the reported IRRs were predominantly seen with the first infusion (8 patients [32%]), and then decreased over time with the number of rituximab infusions (20% with the second infusion, 12% with the third infusion and 8% with the fourth infusion). The most common IRR symptoms reported during the remission induction phase were: headache, rash, rhinorrhea and pyrexia (8%, for each symptom). The observed symptoms of IRRs were similar to those known in adult GPA or MPA patients treated with rituximab. The majority of IRRs were Grade 1 and Grade 2, there were two non-serious Grade 3 IRRs, and no Grade 4 or 5 IRRs reported. One serious Grade 2 IRR (generalized oedema which resolved with treatment) was reported in one patient (see section 4.4).

Infections

In GPA/MPA Study 1, the overall rate of infection was approximately 237 per 100 patient years (95% CI 197 – 285) at the 6-month primary endpoint. Infections were predominately mild to moderate and consisted mostly of upper respiratory tract infections, herpes zoster and urinary tract infections. The rate of serious infections was approximately 25 per 100 patient years. The most frequently reported serious infection in the rituximab group was pneumonia at a frequency of 4%.

In GPA/MPA Study 2, 30/57 (53%) patients in the rituximab arm experienced infections. The incidence of all grade infections was similar between the arms. Infections were predominately mild to moderate. The most common infections in the rituximab arm included upper respiratory tract infections, gastroenteritis, urinary tract infections and herpes zoster. The incidence of serious infections was similar in both arms (approximately 12%). The most commonly reported serious infection in the rituximab group was mild or moderate bronchitis.

In the clinical trial in paediatric patients with severe, active GPA and MPA, 91% of reported infections were non-serious and 90% were mild to moderate.

The most common infections in the overall phase were: upper respiratory tract infections (URTIs) (48%), influenza (24%), conjunctivitis (20%), nasopharyngitis (20%), lower respiratory tract infections (16%), sinusitis (16%), viral URTIs (16%), ear infection (12%), gastroenteritis (12%), pharyngitis (12%), urinary tract infection (12%). Serious infections were reported in 7 patients (28%), and included: influenza (2 patients [8%]) and lower respiratory tract infection (2 patients [8%]) as the most frequently reported events.

Malignancies

In GPA/MPA Study 1, the incidence of malignancy in rituximab treated patients in the GPA and MPA clinical study was 2.00 per 100 patient years at the study common closing date (when the final patient had completed the follow-up period). On the basis of standardised incidence ratios, the incidence of malignancies appears to be similar to that previously reported in patients with ANCA-associated vasculitis.

In the paediatric clinical trial, no malignancies were reported with a follow-up period of up to 54 months.

Cardiovascular adverse reactions

In GPA/MPA Study 1, cardiac events occurred at a rate of approximately 273 per 100 patient years (95% CI 149–470) at the 6-month primary endpoint. The rate of serious cardiac events was 2.1 per 100 patient years (95% CI 3–15). The most frequently reported events were tachycardia (4%) and atrial fibrillation (3%) (see section 4.4).

Neurologic events

Cases of posterior reversible encephalopathy syndrome (PRES)/reversible posterior leukoencephalopathy syndrome (RPLS) have been reported in autoimmune conditions. Signs and symptoms included visual disturbance, headache, seizures and altered mental status, with or without associated hypertension. A diagnosis of PRES/RPLS requires confirmation by brain imaging. The reported cases had recognised risk factors for PRES/RPLS, including the patients’ underlying disease, hypertension, immunosuppressive therapy and/or chemotherapy.

Hepatitis-B reactivation

A small number of cases of hepatitis-B reactivation, some with fatal outcome, have been reported in granulomatosis with polyangiitis and microscopic polyangiitis patients receiving rituximab in the post-marketing setting.

Hypogammaglobu­linaemia

Hypogammaglobu­linaemia (IgA, IgG or IgM below the lower limit of normal) has been observed in adult and paediatric GPA and MPA patients treated with rituximab.

In GPA/MPA Study 1, at 6 months, in the rituximab group, 27%, 58% and 51% of patients with normal immunoglobulin levels at baseline had low IgA, IgG and IgM levels, respectively compared to 25%, 50% and 46% in the cyclophosphamide group. The rate of overall infections and serious infections was not increased after the development of low IgA, IgG or IgM.

In GPA/MPA Study 2, no clinically meaningful differences between the two treatment arms or decreases in total immunoglobulin, IgG, IgM or IgA levels were observed throughout the trial.

In the paediatric clinical trial, during the overall study period, 3/25 (12%) patients reported an event of hypogammaglobu­linaemia, 18 patients (72%) had prolonged (defined as Ig levels below lower limit of normal for at least 4 months) low IgG levels (of whom 15 patients also had prolonged low IgM). Three patients received treatment with intravenous immunoglobulin (IV-IG). Based on limited data, no firm conclusions can be drawn regarding whether prolonged low IgG and IgM led to an increased risk of serious infection in these patients. The consequences of long-term B cell depletion in paediatric patients are unknown.

Neutropenia

In GPA/MPA Study 1, 24% of patients in the rituximab group (single course) and 23% of patients in the cyclophosphamide group developed CTC grade 3 or greater neutropenia. Neutropenia was not associated with an observed increase in serious infection in rituximab-treated patients.

In GPA/MPA Study 2, the incidence of all-grade neutropenia was 0% for rituximab-treated patients vs 5% for azathioprine treated patients.

Skin and subcutaneous tissue disorders

Toxic Epidermal Necrolysis (Lyell’s syndrome) and Stevens-Johnson syndrome, some with fatal outcome, have been reported very rarely.

Experience from pemphigus vulgaris

Summary of the safety profile in PV Study 1 (Study ML22196) and PV Study 2 (Study WA29330) The safety profile of rituximab in combination with short-term, low-dose glucocorticoids in the treatment of patients with pemphigus vulgaris was studied in a Phase 3, randomised, controlled, multicentre, open-label study in pemphigus patients that included 38 pemphigus vulgaris (PV) patients randomised to the rituximab group (PV Study 1). Patients randomised to the rituximab group received an initial 1000 mg IV on Study Day 1 and a second 1000 mg IV on Study Day 15. Maintenance doses of 500 mg IV were administered at months 12 and 18. Patients could receive 1000 mg IV at the time of relapse (see section 5.1).

In PV Study 2, a randomised, double-blind, double-dummy, active-comparator, multicentre study evaluating the efficacy and safety of rituximab compared with mycophenolate mofetil (MMF) in patients with moderate-to-severe PV requiring oral corticosteroids, 67 PV patients received treatment with rituximab (initial 1000 mg IV on Study Day 1 and a second 1000 mg IV on Study Day 15 repeated at Weeks 24 and 26) for up to 52 weeks (see section 5.1).

The safety profile of rituximab in PV was consistent with the established safety profile in other approved autoimmune indications.

Tabulated list of adverse reactions for PVStudies 1 and 2

Adverse reactions from PV Studies 1 and 2 are presented in Table 7. In PV Study 1, ADRs were defined as adverse events which occurred at a rate of >5% among rituximab-treated PV patients, with a > 2% absolute difference in incidence between the rituximab-treated group and the standard-dose prednisone group up to month 24. No patients were withdrawn due to ADRs in PV Study 1. In PV Study 2, ADRs were defined as adverse events occurring in > 5% of patients in the rituximab arm and assessed as related.

Table 7 Adverse reactions in rituximab-treated pemphigus vulgaris patients in PV Study 1

(up to Month 24) and PV Study 2 (up to Week 52)

Description of selected adverse reactions

Infusion-related reactions

In PV Study 1, infusion-related reactions were common (58%). Nearly all infusion-related reactions were mild to moderate. The proportion of patients experiencing an infusion-related reaction was 29% (11 patients), 40% (15 patients), 13% (5 patients), and 10% (4 patients) following the first, second, third, and fourth infusions, respectively. No patients were withdrawn from treatment due to infusion-related reactions. Symptoms of infusion-related reactions were similar in type and severity to those seen in RA and GPA/MPA patients.

In PV Study 2, IRRs occurred primarily at the first infusion and the frequency of IRRs decreased with subsequent infusions: 17.9%, 4.5%, 3% and 3% of patients experienced IRRs at the first, second, third, and fourth infusions, respectively. In 11/15 patients who experienced at least one IRR, the IRRs were Grade 1 or 2. In 4/15 patients, Grade > 3 IRRs were reported and led to discontinuation of rituximab treatment; three of the four patients experienced serious (life-threatening) IRRs. Serious IRRs occurred at the first (2 patients) or second (1 patient) infusion and resolved with symptomatic treatment.

Infections

In PV Study 1, 14 patients (37%) in the rituximab group experienced treatment-related infections compared to 15 patients (42%) in the standard-dose prednisone group. The most common infections in the rituximab group were herpes simplex and zoster infections, bronchitis, urinary tract infection, fungal infection and conjunctivitis. Three patients (8%) in the rituximab group experienced a total of 5 serious infections (Pneumocystis jirovecii pneumonia, infective thrombosis, intervertebral discitis, lung infection, Staphylococcal sepsis) and one patient (3%) in the standard-dose prednisone group experienced a serious infection (Pneumocystis jirovecii pneumonia).

In PV Study 2, 42 patients (62.7%) in the rituximab arm experienced infections. The most common infections in the rituximab group were upper respiratory tract infection, nasopharyngitis, oral candidiasis and urinary tract infection. Six patients (9%) in the rituximab arm experienced serious infections.

Laboratory abnormalities

In PV Study 2, in the rituximab arm, transient decreases in lymphocyte count, driven by decreases in the peripheral T-cell populations, as well as a transient decrease in phosphorus level were very commonly observed post-infusion. These were considered to be induced by IV methylprednisolone premedication infusion.

In PV Study 2, low IgG levels were commonly observed and low IgM levels were very commonly observed; however, there was no evidence of an increased risk of serious infections after the development of low IgG or IgM.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

4.9 Overdose

5.  PHARMACOLOGICAL PROPERTIES

5.1  Pharmacodynamic properties

5.2 Pharmacokinetic properties

Adult Non-Hodgkin’s lymphoma

Based on a population pharmacokinetic analysis in 298 NHL patients who received single or multiple infusions of rituximab as a single agent or in combination with CHOP therapy (applied rituximab doses ranged from 100 to 500 mg/m2), the typical population estimates of nonspecific clearance (CL1), specific clearance (CL2) likely contributed by B cells or tumour burden, and central compartment volume of distribution (V1) were 0.14 L/day, 0.59 L/day, and 2.7 L, respectively. The estimated median terminal elimination half-life of rituximab was 22 days (range, 6.1 to 52 days). Baseline CD19-positive cell counts and size of measurable tumour lesions contributed to some of the variability in CL2 of rituximab in data from 161 patients given 375 mg/m2 as an intravenous infusion for 4 weekly doses. Patients with higher CD19-positive cell counts or tumour lesions had a higher CL2. However, a large component of inter-individual variability remained for CL2 after correction for CD19-positive cell counts and tumour lesion size. V1 varied by body surface area (BSA) and CHOP therapy. This variability in V1 (27.1% and 19.0%) contributed by the range in BSA (1.53 to 2.32 m2) and concurrent CHOP therapy, respectively, were relatively small. Age, gender and WHO performance status had no effect on the pharmacokinetics of rituximab. This analysis suggests that dose adjustment of rituximab with any of the tested covariates is not expected to result in a meaningful reduction in its pharmacokinetic variability.

Rituximab, administered as an intravenous infusion at a dose of 375 mg/m2 at weekly intervals for 4 doses to 203 patients with NHL naive to rituximab, yielded a mean Cmax following the fourth infusion of 486 gg/mL (range, 77.5 to 996.6 gg/mL). Rituximab was detectable in the serum of patients 3 –6 months after completion of last treatment.

Upon administration of rituximab at a dose of 375 mg/m2 as an intravenous infusion at weekly intervals for 8 doses to 37 patients with NHL, the mean Cmax increased with each successive infusion, spanning from a mean of 243 gg/mL (range, 16 – 582 gg/mL) after the first infusion to 550 gg/mL (range, 171 – 1177 gg/mL) after the eighth infusion.

The pharmacokinetic profile of rituximab when administered as 6 infusions of 375 mg/m2 in combination with 6 cycles of CHOP chemotherapy was similar to that seen with rituximab alone.

Paediatric DLBCL/BL/BAL/BLL

In the clinical trial studying paediatric DLBCL/BL/BAL/BLL, the PK was studied in a subset of 35 patients aged 3 years and older. The PK was comparable between the two age groups (> 3 to < 12 years vs. > 12 to < 18 years). After two rituximab IV infusions of 375 mg/m2 in each of the two induction cycles (cycle 1 and 2) followed by one rituximab IV infusion of 375 mg/m2 in each of the consolidation cycles (cycle 3 and 4) the maximum concentration was highest after the fourth infusion (cycle 2) with a geometric mean of 347 gg/mL followed by lower geometric mean maximum concentrations thereafter (Cycle 4: 247 gg/mL). With this dose regimen, trough levels were sustained (geometric means: 41.8 gg/mL (pre-dose Cycle 2; after 1 cycle), 67.7 gg/mL (pre-dose Cycle 3, after 2 cycles) and 58.5 gg/mL (pre-dose Cycle 4, after 3 cycles)). The median elimination half-life in paediatric patients aged 3 years and older was 26 days.

The PK characteristics of rituximab in paediatric patients with DLBCL/BL/BAL/BLL were similar to what has been observed in adult NHL patients.

No PK data are available in the > 6 months to < 3 years age group, however, population PK prediction supports comparable systemic exposure (AUC, Ctrough) in this age group compared to > 3 years (Table 24). Smaller baseline tumour size is related to higher exposure due to lower time dependent clearance, however, systemic exposures impacted by different tumour sizes remain in the range of exposure that was efficacious and had an acceptable safety profile.

Table 24 Predicted PK parameters following the Rituximab dosing regimen in paediatric

DLBCL/BL/BAL/BLL

Results are presented as median (min – max); Ctrough is pre-dose Cycle 4.

Chronic lymphocytic leukaemia

Rituximab was administered as an intravenous infusion at a first-cycle dose of 375 mg/m2 increased to 500 mg/m2 each cycle for 5 doses in combination with fludarabine and cyclophosphamide in CLL patients. The mean Cmax (N=15) was 408 pg/mL (range, 97 – 764 pg/mL) after the fifth 500 mg/m2 infusion and the mean terminal half-life was 32 days (range, 14 – 62 days).

Rheumatoid arthritis

Following two intravenous infusions of rituximab at a dose of 1000 mg, two weeks apart, the mean terminal half-life was 20.8 days (range, 8.58 to 35.9 days), mean systemic clearance was 0.23 L/day (range, 0.091 to 0.67 L/day), and mean steady-state distribution volume was 4.6 l (range, 1.7 to 7.51 L). Population pharmacokinetic analysis of the same data gave similar mean values for systemic clearance and half-life, 0.26 L/day and 20.4 days, respectively. Population pharmacokinetic analysis revealed that BSA and gender were the most significant covariates to explain inter-individual variability in pharmacokinetic parameters. After adjusting for BSA, male subjects had a larger volume of distribution and a faster clearance than female subjects. The gender- related pharmacokinetic differences are not considered to be clinically relevant and dose adjustment is not required. No pharmacokinetic data are available in patients with hepatic or renal impairment.

The pharmacokinetics of rituximab were assessed following two intravenous (IV) doses of 500 mg and 1000 mg on Days 1 and 15 in four studies. In all these studies, rituximab pharmacokinetics were dose proportional over the limited dose range studied. Mean Cmax for serum rituximab following first infUsion ranged from 157 to 171 pg/mL for 2 × 500 mg dose and ranged from 298 to 341 pg/mL for 2 × 1000 mg dose. Following second infUsion, mean Cmax ranged from 183 to 198 pg/mL for the 2 × 500 mg dose and ranged from 355 to 404 pg/mL for the 2 × 1000 mg dose. Mean terminal elimination half-life ranged from 15 to 16 days for the 2 × 500 mg dose group and 17 to 21 days for the 2 × 1000 mg dose group. Mean Cmax was 16 to 19% higher following second infusion compared to the first infusion for both doses.

The pharmacokinetics of rituximab were assessed following two IV doses of 500 mg and 1000 mg upon re-treatment in the second course. Mean Cmax for serum rituximab following first infusion was 170 to 175 pg/mL for 2 × 500 mg dose and 317 to 370 pg/mL for 2 × 1000 mg dose. Cmaxfollowing second infUsion, was 207 pg/mL for the 2 × 500 mg dose and ranged from 377 to 386 pg/mL for the 2 × 1000 mg dose. Mean terminal elimination half-life after the second infusion, following the second course, was 19 days for 2 × 500 mg dose and ranged from 21 to 22 days for the 2 × 1000 mg dose. PK parameters for rituximab were comparable over the two treatment courses.

The pharmacokinetic (PK) parameters in the anti-TNF inadequate responder population, following the same dosage regimen (2 × 1000 mg, IV, 2 weeks apart), were similar with a mean maximum serum concentration of 369 pg/mL and a mean terminal half-life of 19.2 days.

Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA)

Adult Population

Based on the population pharmacokinetic analysis of data in 97 patients with granulomatosis with polyangiitis and microscopic polyangiitis who received 375 mg/m2 rituximab once weekly for four doses, the estimated median terminal elimination half-life was 23 days (range, 9 to 49 days). Rituximab mean clearance and volume of distribution were 0.313 L/day (range, 0.116 to 0.726 L/day) and 4.50 L (range 2.25 to 7.39 L) respectively. Maximum concentration during the first 180 days (Cmax), minimum concentration at Day 180 (C180) and Cumulative area under the curve over 180 days (AUC180) were (median [range]) 372.6 (252.3–533.5) Lig/ml„ 2.1 (0–29.3) Lig/ml, and 10302 (365321874) |ag/mL*davs, respectively. The PK parameters of rituximab in adult GPA and MPA patients appear similar to what has been observed in rheumatoid arthritis patients.

Paediatric Population

Based on the population pharmacokinetic analysis of 25 children (6–17 years old) with GPA and MPA who received 375 mg/m2 rituximab once weekly for four doses, the estimated median terminal elimination half-life was 22 days (range, 11 to 42 days). Rituximab mean clearance and volume of distribution were 0.221 L/day (range, 0.0996 to 0.381 L/day) and 2.27 L (range 1.43 to 3.17 L), respectively. Maximum concentration during the first 180 days (Cmax), minimum concentration at Day 180 (C180) and Cumulative area under the curve over 180 days (AUC180) were (median [range]) 382.8 (270.6–513.6) ^g/mL, 0.9 (0–17.7) ^g/mL and 9787 (4838–20446) ^g/mL*day, respectively.The PK parameters of rituximab in paediatric patients with GPA or MPA were similar to those in adults with GPA or MPA, once taking into account the BSA effect on clearance and volume of distribution parameters.

Pemphigus vulgaris

The PK parameters in adult PV patients receiving rituximab 1000 mg at Days 1, 15, 168, and 182 are summarized in Table 25.

Table 25 ______ Population PK in adult PV patients from PV Study 2

Following the first two rituximab administrations (at day 1 and 15, corresponding to cycle 1), the PK parameters of rituximab in patients with PV were similar to those in patients with GPA/MPA and patients with RA. Following the last two administrations (at day 168 and 182, corresponding to cycle 2), rituximab clearance decreased while the central volume of distribution remained unchanged.

5.3 Preclinical safety data

Rituximab has shown to be highly specific to the CD20 antigen on B cells. Toxicity studies in cynomolgus monkeys have shown no other effect than the expected pharmacological depletion of B cells in peripheral blood and in lymphoid tissue.

Developmental toxicity studies have been performed in cynomolgus monkeys at doses up to 100 mg/kg (treatment on gestation days 20–50) and have revealed no evidence of toxicity to the foetus due to rituximab. However, dose-dependent pharmacologic depletion of B cells in the lymphoid organs of the foetuses was observed, which persisted postnatally and was accompanied by a decrease in IgG level in the newborn animals affected. B cell counts returned to normal in these animals within 6 months of birth and did not compromise the reaction to immunisation.

Standard tests to investigate mutagenicity have not been carried out, since such tests are not relevant for this molecule. No long-term animal studies have been performed to establish the carcinogenic potential of rituximab.

Specific studies to determine the effects of rituximab on fertility have not been performed. In general toxicity studies in cynomolgus monkeys no deleterious effects on reproductive organs in males or females were observed.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

L-histidine

L-histidine hydrochloride monohydrate

Disodium edetate

Polysorbate 80 (E433)

Sucrose

Water for injection

6.2 Incompatibilities

No incompatibilities between Ruxience and polyvinyl chloride or polyethylene bags or infusion sets have been observed.

6.3 Shelf life

Unopened vial

24 months

Diluted medicinal product

• • After aseptic dilution in sodium chloride solution

The prepared infusion solution of Ruxience in 0.9% sodium chloride solution is physically and chemically stable for 35 days at 2 °C – 8 °C plus an additional 24 hours at < 30 °C.

• • After aseptic dilution in D-glucose solution

6.4 Special precautions for storage

Store in a refrigerator (2 °C – 8 °C). Keep the container in the outer carton in order to protect from light.

For storage conditions after dilution of the medicinal product, see section 6.3.

6.5 Nature and contents of container

Ruxience 100 mg concentrate for solution for infusion

Clear Type I glass vials with chlorobutyl rubber stopper containing 100 mg of rituximab in 10 mL. Pack of 1 vial.

Ruxience 500 mg concentrate for solution for infusion

Clear Type I glass vials with chlorobutyl rubber stopper containing 500 mg of rituximab in 50 mL. Pack of 1 vial.

6.6 Special precautions for disposal and other handling

Ruxience is provided in sterile, preservative-free, non-pyrogenic, single use vials.

Use a sterile needle and syringe to prepare Ruxience. Aseptically withdraw the necessary amount of Ruxience and dilute to a calculated concentration of 1 to 4 mg/mL rituximab into an infusion bag containing sterile, pyrogen-free sodium chloride 9 mg/mL (0.9%) solution for injection or 5% D-Glucose in water. For mixing the solution, gently invert the bag in order to avoid foaming. Care must be taken to ensure the sterility of prepared solutions. Since the medicinal product does not contain any anti-microbial preservative or bacteriostatic agents, aseptic technique must be observed. Parenteral medicinal products should be inspected visually for particulate matter and discolouration prior to administration.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

Pfizer Europe MA EEIG Boulevard de la Plaine 17 1050 Bruxelles

Belgium

8. MARKETING AUTHORISATION NUMBER(S)

Ruxience 100 mg concentrate for solution for infusion

EU/1/20/1431/001

Ruxience 500 mg concentrate for solution for infusion

EU/1/20/1431/002

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 01 April 2020