Blitzima - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

Blitzima 100 mg concentrate for solution for infusion

Blitzima 500 mg concentrate for solution for infusion

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Blitzima 100mg concentrate for solution for infusion

Each mL contains 10 mg of rituximab.

Each 10 mL vial contains 100 mg of rituximab.

Blitzima 500mg 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.

Excipients with known effects:

Each 10 mL vial contains 2.3 mmol (52. 6mg) sodium.

Each 50 mL vial contains 11.5 mmol (263.2 mg) sodium.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Concentrate for solution for infusion.

Clear, colourless liquid with pH of 6.3 – 6.8 and osmolality of 329 – 387 mOsmol/kg.

4. CLINICAL PARTICULARS4.1 Therapeutic indications

Blitzima is indicated in adults for the following indications:

Non-Hodgkin’s lymphoma (NHL)

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

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

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

Blitzima 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.

Blitzima 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)

Blitzima 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 Blitzima or patients refractory to previous Blitzima plus chemotherapy.

See section 5.1 for further information.

Granulomatosis with polyangiitis and microscopic polyangiitis

Blitzima, 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).

Blitzima, 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

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

4.2 Posology and method of administration

Blitzima 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 Blitzima.

In adult patients with non-Hodgkin’s lymphoma and CLL, premedication with glucocorticoids should be considered if Blitzima 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 Blitzima. 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 Blitzima to decrease the rate and severity of acute infusion reactions and/or cytokine release syndrome.

In patients with GPA or MPA in disease remission or pemphigus vulgaris, premedication with 100 mg intravenous methylprednisolone should be completed 30 minutes prior to each infusion of Blitzima 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 Blitzima (the last dose of methylprednisolone may be given on the same day as the first infusion of Blitzima). 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 Blitzima treatment.

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

Paediatric population

In paediatric patients with GPA or MPA, prior to the first Blitzima 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 Blitzima 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 Blitzima treatment, as appropriate.

Posology

Non-Hodgkin’s lymphoma

Follicular non-Hodgkin's lymphoma

Combination therapy

The recommended dose of Blitzima 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.

Blitzima 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 Blitzima 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 Blitzima 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 Blitzima 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 retreatment with Blitzima monotherapy for patients who have responded to previous treatment with Blitzima 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

Blitzima 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 Blitzima 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 Blitzima are recommended. When Blitzima is given in combination with chemotherapy, standard dose reductions for the chemotherapeutic medicinal products should be applied.

Chronic lymphocytic leukaemia

The recommended dosage of Blitzima 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 Blitzima infusion.

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

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

Adult induction of remission

The recommended dosage of Blitzima 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 Blitzima, maintenance treatment in adult patients with GPA and MPA should be initiated no sooner than 16 weeks after the last Blitzima infusion.

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

Blitzima 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 Blitzima 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 Blitzima maintenance therapy, up to 5 years.

Pemphigus vulgaris

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

The recommended dosage of Blitzima 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

Elderly

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

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, Blitzima should be used in combination with systemic Lymphome Malin B (LMB) chemotherapy (see Tables 1 and 2). The recommended dosage of Blitzima is 375mg/m2 BSA, administered as an IV infusion. No Blitzima dose adjustments, other than by BSA, are required.

The safety and efficacy of Blitzima 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.

Blitzima 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 Blitzima administration for Non-Hodgkin’s lymphoma paediatric

patients

Cycle	Day of treatment	Administration details
Prephase (COP)	No Blitzima given	–
Induction course 1 (COPDAM1)	Day –2 (corresponding to day 6 of the prephase) 1st Blitzima infusion	During the 1st induction course, prednisone is given as part of the chemotherapy course, and should be administered prior to Blitzima.
	Day 1 2nd Blitzima infusion	Blitzima will be given 48 hours after thefirst infusion of Blitzima.
Induction course 2 (COPDAM2)	Day –2 3rd Blitzima infusion	In the 2nd induction course, prednisone is not given at the time of Blitzima administration.
	Day 1 4th Blitzima infusion	Blitzima will be given 48 hours after the third infusion of Blitzima.
Consolidation course 1 (CYM/CYVE)	Day 1 5th Blitzima infusion	Prednisone is not given at the time of Blitzima administration.
Consolidation course 2	Day 1 6th Blitzima infusion

(CYM/CYVE)		Prednisone is not given at the time of Blitzima administration.
Maintenance course 1 (M1)	Day 25 to 28 of consolidation course 2 (CYVE) No Blitzima given	Starts when peripheral counts have recovered from consolidation course 2 (CYVE) with ANC> 1.0 × 109/l and platelets > 100 × 109/l
Maintenance course 2 (M2)	Day 28 of maintenance course 1 (M1) No Blitzima given	–
ANC = Absolute Neutrophil Count; COP = Cyclophosphamide, Vincristine, Prednisone; COPDAM = Cyclophosphamide, Vincristine, Prednisolone, Doxorubicin, Methotrexate; CYM = CYtarabine (Aracytine, Ara-C), Methotrexate; CYVE = CYtarabine (Aracytine, Ara-C), VEposide (VP16)

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

__________ Chemotherapy with Blitzima _____________­________________________­________

Treatment Plan	Patient Staging	Administration details
Group B	Stage III with high LDH level (> N x 2), Stage IV CNS negative	Prephase followed by 4 courses: 2 induction courses (COPADM) with HDMTX 3g/m2 and 2 consolidation courses (CYM)
Group C	Group C1: B- AL CNS negative, Stage IV & BAL CNS positive and CSF negative	Prephase followed by 6 courses: 2 induction courses (COPADM) with HDMTX 8g/m2, 2 consolidation courses (CYVE) and 2 maintenance courses (M1 and M2)
	Group C3: BAL CSF positive, Stage IV CSF positive
Consecutive courses should be given as soon as blood count recovery and patient’s condition allows except for the maintenance courses which are given at 28 day intervals
BAL = Burkitt leukaemia (mature B-cell acute leukaemia); CSF = Cerebrospinal Fluid; CNS = Central Nervous System; HDMTX = High-dose Methotrexate; LDH = Lactic Acid Dehydrogenase

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

Induction of remission

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

Blitzima 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).

Method of administration

The prepared Blitzima 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 (IRRs) (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/h; after the first 30 minutes, it can be escalated in 50 mg/h increments every 30 minutes, to a maximum of 400 mg/h.

Subsequent infusions

All indications

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

Paediatric patients – non-Hodgkin ’s lymphoma

First infusion

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

Subsequent infusions

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

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 traceability of biological medicinal products, the tradename and batch number of the administered product should be clearly recorded (or stated) in the patient file.

Progressive multifocal leukoencephalopathy (PML)

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

Very rare cases of fatal PML have been reported following the use of rituximab. Patients must be monitored at regular intervals for any new or worsening neurological symptoms or signs that may be suggestive of PML. If PML is suspected, further dosing must be suspended until PML has been excluded. The clinician should evaluate the patient to determine if the symptoms are indicative of neurological dysfunction, and if so, whether these symptoms are possibly suggestive of PML. Consultation with a neurologist should be considered as clinically indicated.

If any doubt exists, further evaluation, including MRI scan preferably with contrast, cerebrospinal fluid (CSF) testing for JC Viral DNA and repeat neurological assessments, should be considered.

The physician should be particularly alert to symptoms suggestive of PML that the patient may not notice (e.g. cognitive, neurological or psychiatric symptoms). Patients should also be advised to inform their partner or caregivers about their treatment, since they may notice symptoms that the patient is not aware of.

If a patient develops PML, the dosing of rituximab must be permanently discontinued.

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

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 medicines 12 hours prior to the rituximab 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 rituximab therapy.

Infections

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

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

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

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

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 rituximab may receive non-live vaccinations; however, with non-live vaccines response rates may be reduced. In a non-randomised study, adult patients with relapsed low-grade NHL who received rituximab monotherapy when compared to healthy untreated controls had a lower rate of response to vaccination with tetanus recall antigen (16% vs. 81%) and Keyhole Limpet Haemocyanin (KLH) neoantigen (4% vs. 76% when assessed for >2-fold increase in antibody titer). For CLL patients, similar results are assumable considering similarities between both diseases but that has not been investigated in clinical trials.

Mean pre-therapeutic antibody titres against a panel of antigens (Streptococcus pneumoniae, influenza A, mumps, rubella, varicella) were maintained for at least 6 months after treatment with rituximab.

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), 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 rituximab. In most cases, the infusion can be resumed at a 50% reduction in rate (e.g. from 100 mg/h to 50 mg/h) when symptoms have completely resolved.

Medicinal products for the treatment of hypersensitivity reactions, e.g. epinephrine (adrenaline), antihistamines and glucocorticoids, should be available for immediate use in the event of an allergic reaction during administration of rituximab.

There are no data on the safety of rituximab in patients with moderate heart failure (NYHA class III) or severe, uncontrolled cardiovascular disease. In patients treated with rituximab, the occurrence of pre-existing ischemic cardiac conditions becoming symptomatic, such as angina pectoris, has been observed, as well as atrial fibrillation and flutter. Therefore, in patients with a known cardiac history, and those who experienced prior cardiopulmonary adverse reactions the risk of cardiovascular complications resulting from infusion reactions should be considered before treatment with rituximab and patients closely monitored during administration. Since hypotension may occur during rituximab infusion, consideration should be given to withholding anti-hypertensive medicinal product 12 hours prior to the rituximab infusion.

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

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). Rituximab should not be administered to patients with an active, severe infection (e.g. tuberculosis, sepsis and opportunistic infections, see section 4.3) or severely immunocompromised patients (e.g. where levels of CD4 or CD8 are very low). Physicians should exercise caution when considering the use of rituximab in patients with a history of recurring or chronic infections or with underlying conditions which may further predispose patients to serious infection, e.g. hypogammaglobu­linaemia (see section 4.8). It is recommended that immunoglobulin levels are determined prior to initiating treatment with rituximab.

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

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

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

Late neutropenia

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

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.

Immunisation

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 rituximab therapy. Vaccination should be completed at least 4 weeks prior to first administration of rituximab.

The safety of immunisation with live viral vaccines following rituximab therapy has not been studied. Therefore vaccination with live virus vaccines is not recommended whilst on rituximab or whilst peripherally B cell depleted.

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

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

Concomitant/se­quential use of other DMARDs in rheumatoid arthritis

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

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

Malignancy

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

This medicinal product contains 2.3 mmol (or 52.6 mg) sodium per 10 mL vial and 11.5 mmol (or 263.2 mg) sodium per 50 mL vial, equivalent to 2.6% (for 10 mL vial) and 13.2% (for 50 mL vial) of the WHO recommended maximum daily intake of 2 g sodium for an adult.

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 rituximab.

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 rituximab 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, breastfeeding is not recommended while 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, breastfeeding is not recommended treated with rituximab and optimally and 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 adult

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

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

The most frequent reported or observed serious adverse drug reactions were:

• • 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 < 1/1000), very rare (< 1/10,000) and not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

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

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

patients with NHL and CLL disease treated with rituximab

monotherapy/ma­intenance or in combination with chemotherapy

MedDRA System organ class	Very Common	Common	Uncommon	Rare	Very Rare	Not known
Infections and infestations	bacterial infections, viral infections,	sepsis, +pneumonia, febrile infection,		serious viral infection2 pneumocystis jirovecii	PML

	+bronchitis	+herpes zoster, +respiratory tract infection, fungal infections, infections of unknown aetiology, +acute bronchitis, +sinusitis, hepatitis B1
Blood and lymphatic system disorders	neutropenia, leucopenia, +febrile neutropenia, + thrombocyt o penia	anaemia, +pancytopenia, +granulocytope nia	coagulation disorders, aplastic anaemia, haemolytic anaemia, lymphadenop athy		transient increase in serum IgM levels3	late neutropenia3
Immune system disorders	infusion-relate d reactions4, angioedema	hypersensitivity		anaphylaxis	tumour lysis syndrome, cytokine release syndrome4, serum sickness	infusion-relate d acute reversible thrombocytop enia4
Metabolism and nutrition disorders		hyperglycaemia , weight decrease, peripheral oedema, face oedema, increased LDH, hypocalcaemia
Psychiatric disorders			depression, nervousness,
Nervous system disorders		paraesthesia, hypoaesthesia, agitation, insomnia, vasodilatation, dizziness, anxiety	dysgeusia		peripheral neuropathy, facial nerve palsy5	cranial neuropathy, loss of other senses5
Eye disorders		lacrimation disorder, conjunctivitis			severe vision loss5
Ear and labyrinth disorders		tinnitus, ear pain				hearing loss5
Cardiac disorders		+myocardial infarction4and 6, arrhythmia, +atrial fibrillation, tachycardia, +cardiac disorder	+left ventricular failure, +supraventri-cular tachycardia, +ventricular tachycardia, +angina, +myocardial ischaemia, bradycardia	severe cardiac disorders4and 6	heart failure4 and 6
Vascular disorders		hypertension, orthostatic hypotension, hypotension			vasculitis (predominatel y cutaneous), leukocytoclast ic vasculitis
Respiratory, thoracic and		bronchospasm4, respiratory	asthma, bronchiolitis	interstitial lung disease7	respiratory failure4	lung infiltration

mediastinal disorders		disease, chest pain, dyspnoea, increased cough, rhinitis	obliterans, lung disorder, hypoxia
Gastrointesti nal disorders	nausea	vomiting , diarrhoea, abdominal pain, dysphagia, stomatitis, constipation, dyspepsia, anorexia, throat irritation	abdominal enlargement		gastro-intestin al perforation7
Skin and Subcutaneou s tissue disorders	pruritus, rash, +alopecia	urticaria, sweating, night sweats, +skin disorder			severe bullous skin reactions, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome)7
Musculoskele tal, connective tissue disorders		hypertonia, myalgia, arthralgia, back pain, neck pain, pain
Renal and urinary disorders					renal failure4
General disorders and administrate n site conditions	fever, chills, asthenia, headache	tumour pain, flushing, malaise, cold syndrome, +fatigue, +shivering, +multi-organ failure4	infusion site pain
Investigation s	decreased IgG levels

For each term, the frequency count was based on reactions of all grades (from mild to severe), except for terms marked with „+“ where the frequency count was based only on severe (> grade 3 NCI common toxicity criteria) reactions. Only the highest frequency observed in the trials is reported

• 1 includes reactivation and primary infections; frequency based on R-FC regimen in relapsed/refrac­tory CLL

• 2 see also section infection below

• 3 see also section haematologic adverse reactions below

• 4 see also section infusion-related reactions below. Rarely fatal cases reported

• 5 signs and symptoms of cranial neuropathy. Occurred at various times up to several months after completion of rituximab therapy

• 6 observed mainly in patients with prior cardiac condition and/or cardiotoxic chemotherapy and were mostly associated with infusion-related reactions

• 7 includes fatal cases

4.9 Overdose

Limited experience with doses higher than the approved dose of intravenous rituximab formulation is available from clinical trials in humans. The highest intravenous dose of rituximab tested in humans to date is 5000 mg (2250 mg/m2), tested in a dose escalation study in patients with CLL. No additional safety signals were identified.

Patients who experience overdose should have immediate interruption of their infusion and be closely monitored.

In the post-marketing setting five cases of rituximab overdose have been reported. Three cases had no reported adverse event. The two adverse events that were reported were flu-like symptoms, with a dose of 1.8 g of rituximab and fatal respiratory failure, with a dose of 2 g of rituximab.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: antineoplastic agents, monoclonal antibodies, ATC code: L01FA01.

Blitzima is a biosimilar medicinal product. Detailed information is available on the website of the European Medicines Agency.

Rituximab binds specifically to the transmembrane antigen, CD20, a non-glycosylated phosphoprotein, located on pre-B and mature B lymphocytes. The antigen is expressed on > 95% of all B cell non-Hodgkin’s lym­phomas.

CD20 is found on both normal and malignant B cells, but not on haematopoietic stem cells, pro-B cells, normal plasma cells or other normal tissue. This antigen does not internalize upon antibody binding and is not shed from the cell surface. CD20 does not circulate in the plasma as a free antigen and, thus, does not compete for antibody binding.

The Fab domain of rituximab binds to the CD20 antigen on B lymphocytes and the Fc domain can recruit immune effector functions to mediate B cell lysis. Possible mechanisms of effector-mediated cell lysis include complement-dependent cytotoxicity (CDC) resulting from C1q binding, and antibody-dependent cellular cytotoxicity (ADCC) mediated by one or more of the Fcy receptors on the surface of granulocytes, macrophages and NK cells. Rituximab binding to CD20 antigen on B lymphocytes has also been demonstrated to induce cell death via apoptosis.

Peripheral B cell counts declined below normal following completion of the first dose of rituximab. In patients treated for haematological malignancies, B cell recovery began within 6 months of treatment and generally returned to normal levels within 12 months after completion of therapy, although in some patients this may take longer (up to a median recovery time of 23 months post-induction therapy). In rheumatoid arthritis patients, immediate depletion of B cells in the peripheral blood was observed following two infusions of 1000 mg rituximab separated by a 14 day interval. Peripheral blood B cell counts begin to increase from week 24 and evidence for repopulation is observed in the majority of patients by week 40, whether rituximab was administered as monotherapy or in combination with methotrexate. A small proportion of patients had prolonged peripheral B cell depletion lasting 2 years or more after their last dose of rituximab. In patients with GPA or MPA, the number of peripheral blood B cells decreased to < 10 cells/pL after two weekly infusions of rituximab 375 mg/m2, and remained at that level in most patients up to the 6 month time point. The majority of patients (81%) showed signs of B cell return, with counts > 10 cells/pL by month 12, increasing to 87% of patients by month 18.

Clinical experience in non-Hodgkin’s lymphoma and in chronic lymphocytic leukaemia

Follicular lymphoma

Monotherapy

Initial treatment, weekly for 4 doses

In the pivotal trial, 166 patients with relapsed or chemoresistant low-grade or follicular B cell NHL received 375 mg/m2 of rituximab as an intravenous infusion once weekly for four weeks. The overall response rate (ORR) in the intent-to-treat (ITT) population was 48% (CI95% 41% – 56%) with a 6% complete response (CR) and a 42% partial response (PR) rate. The projected median time to progression (TTP) for responding patients was 13.0 months. In a subgroup analysis, the ORR was higher in patients with IWF B, C, and D histological subtypes as compared to IWF A subtype (58% vs. 12%), higher in patients whose largest lesion was < 5 cm vs. > 7 cm in greatest diameter (53% vs. 38%), and higher in patients with chemosensitive relapse as compared to chemoresistant (defined as duration of response < 3 months) relapse (50% vs. 22%). ORR in patients previously treated with autologous bone marrow transplant (ABMT) was 78% versus 43% in patients with no ABMT. Neither age, sex, lymphoma grade, initial diagnosis, presence nor absence of bulky disease, normal or high LDH nor presence of extranodal disease had a statistically significant effect (Fisher’s exact test) on response to rituximab. A statistically significant correlation was noted between response rates and bone marrow involvement. 40% of patients with bone marrow involvement responded compared to 59% of patients with no bone marrow involvement (p=0.0186). This finding was not supported by a stepwise logistic regression analysis in which the following factors were identified as prognostic factors: histological type, bcl-2 positivity at baseline, resistance to last chemotherapy and bulky disease.

Initial treatment, weekly for 8 doses

In a multicentre, single-arm trial, 37 patients with relapsed or chemoresistant, low grade or follicular B cell NHL received 375 mg/m2 of rituximab as intravenous infusion weekly for eight doses. The ORR was 57% (95% Confidence interval (CI); 41% – 73%; CR 14%, PR 43%) with a projected median TTP for responding patients of 19.4 months (range 5.3 to 38.9 months).

Initial treatment, bulky disease, weekly for 4 doses

In pooled data from three trials, 39 patients with relapsed or chemoresistant, bulky disease (single lesion > 10 cm in diameter), low grade or follicular B cell NHL received 375 mg/m2 of rituximab as intravenous infusion weekly for four doses. The ORR was 36% (CI95% 21% — 51%; CR 3%, PR 33%) with a median TTP for responding patients of 9.6 months (range 4.5 to 26.8 months).

Re-treatment, weekly for 4 doses

In a multicentre, single-arm trial, 58 patients with relapsed or chemoresistant low grade or follicular B cell NHL, who had achieved an objective clinical response to a prior course of rituximab, were re-treated with 375 mg/m2 of rituximab as intravenous infusion weekly for four doses. Three of the patients had received two courses of rituximab before enrolment and thus were given a third course in the study. Two patients were re-treated twice in the study. For the 60 re-treatments on study, the ORR was 38% (CI95% 26% – 51%; 10% CR, 28% PR) with a projected median TTP for responding patients of 17.8 months (range 5.4 – 26.6). This compares favourably with the TTP achieved after the prior course of rituximab (12.4 months).

Initial treatment, in combination with chemotherapy

In an open-label randomised trial, a total of 322 previously untreated patients with follicular lymphoma were randomised to receive either CVP chemotherapy (cyclophosphamide 750 mg/m2, vincristine 1.4 mg/m2 up to a maximum of 2 mg on day 1, and prednisolone 40 mg/m2/day on days 1–5) every 3 weeks for 8 cycles or rituximab 375 mg/m2 in combination with CVP (R-CVP). Rituximab was administered on the first day of each treatment cycle. A total of 321 patients (162 R-CVP, 159 CVP) received therapy and were analysed for efficacy. The median follow-up of patients was 53 months. R-CVP led to a significant benefit over CVP for the primary endpoint, time to treatment failure (27 months vs. 6.6 months, p < 0.0001, log-rank test). The proportion of patients with a tumour response (CR, CRu, PR) was significantly higher (p< 0.0001 Chi-Square test) in the R-CVP group (80.9%) than the CVP group (57.2%). Treatment with R-CVP significantly prolonged the time to disease progression or death compared to CVP, 33.6 months and 14.7 months, respectively (p < 0.0001, log-rank test). The median duration of response was 37.7 months in the R-CVP group and was 13.5 months in the CVP group (p < 0.0001, log-rank test).

The difference between the treatment groups with respect to overall survival showed a significant clinical difference (p=0.029, log-rank test stratified by centre): survival rates at 53 months were 80.9% for patients in the R-CVP group compared to 71.1% for patients in the CVP group.

Results from three other randomised trials using rituximab in combination with chemotherapy regimen other than CVP (CHOP, MCP, CHVP/Interferon-a) have also demonstrated significant improvements in response rates, time-dependent parameters as well as in overall survival. Key results from all four studies are summarised in Table 8.

Table 8 Summary of key results from four phase III randomised studies evaluating

the benefit of rituximab with different chemotherapy regimens in follicular lymphoma

Study	Treatment, N	Median FU, months	ORR, %	CR,%	Median TTF/PFS/ EFS months	OS rates, %
M39021	CVP, 159 R-CVP, 162	53	57 81	10 41	Median TTP: 14.7 33.6 P<0.0001	53-months 71.1 80.9 p=0.029
GLSG’00	CHOP, 205 R-CHOP, 223	18	90 96	17 20	Median TTF: 2.6 years Not reached p < 0.001	18-months 90 95 p = 0.016
OSHO-39	MCP, 96 R-MCP,	47	75 92	25 50	Median PFS: 28.8 Not	48-months 74

Study	Treatment, N	Median FU, months	ORR, %	CR,%	Median TTF/PFS/ EFS months	OS rates, %
	105				reached p < 0.0001	87 p = 0.0096
FL2000	CHVP-IFN, 183 R-CHVP-IFN, 175	42	85 94	49 76	Median EFS: 36 Not reached p < 0.0001	42-months 84 91 p = 0.029

EFS – Event Free Survival

TTP – Time to progression or death

PFS – Progression-Free Survival

TTF – Time to Treatment Failure

OS rates – survival rates at the time of the analyses

Maintenance therapy

Previously untreated follicular lymphoma

In a prospective, open label, international, multicentre, phase III trial 1193 patients with previously untreated advanced follicular lymphoma received induction therapy with R-CHOP (n=881), R-CVP (n=268) or R-FCM (n=44), according to the investigators’ choice. A total of 1078 patients responded to induction therapy, of which 1018 were randomised to rituximab maintenance therapy (n=505) or observation (n=513). The two treatment groups were well balanced with regards to baseline characteristics and disease status. Rituximab maintenance treatment consisted of a single infusion of rituximab at 375 mg/m2 body surface area given every 2 months until disease progression or for a maximum period of two years.

The pre-specified primary analysis was conducted at a median observation time of 25 months from randomisation, maintenance therapy with rituximab resulted in a clinically relevant and statistically significant improvement in the primary endpoint of investigator assessed progressionfree survival (PFS) as compared to observation in patients with previously untreated follicular lymphoma (Table 9).

Significant benefit from maintenance treatment with rituximab was also seen for the secondary endpoints event-free survival (EFS), time to next anti-lymphoma treatment (TNLT) time to next chemotherapy (TNCT) and overall response rate (ORR) in the primary analysis (Table 9).

Data from extended follow-up of patients in the study (median follow-up 9 years) confirmed the long-term benefit of rituximab maintenance therapy in terms of PFS, EFS, TNLT and TNCT (Table 9).

Table 9 Overview of efficacy results for rituximab maintenance vs. observation at the

protocol-defined primary analysis and after 9 years median follow-up (final analysis)

	Primary analysis (median FU: 25 months)	Final analysis (median FU: 9.0 years)
	Observation   Rituximab N=513       N=505	Observation   Rituximab N=513       N=505
Primary efficacy Progression-free survival (median) log-rank p value hazard ratio (95% CI) risk reduction	NR       NR <0.0001 0.50 (0.39, 0.64) 50%	4.06 years     10.49 years <0.0001 0.61 (0.52, 0.73) 39%
Secondary efficacy Overall survival (median) log-rank p value hazard ratio (95% CI) risk reduction	NR       NR 0.7246 0.89 (0.45, 1.74) 11%	NR       NR 0.7948 1.04 (0.77, 1.40) –6%

Event-free survival (median) log-rank p value hazard ratio (95% CI) risk reduction	38 months       NR <0.0001 0.54 (0.43, 0.69) 46%	4.04 years      9.25 years <0.0001 0.64 (0.54, 0.76) 36%
TNLT (median) log-rank p value hazard ratio (95% CI) risk reduction	NR       NR 0.0003 0.61 (0.46, 0.80) 39%	6.11 years        NR <0.0001 0.66 (0.55, 0.78) 34%
TNCT (median) log-rank p value hazard ratio (95% CI) risk reduction	NR       NR 0.0011 0.60 (0.44, 0.82) 40%	9.32 years        NR 0.0004 0.71 (0.59, 0.86) 39%
Overall response rate* chi-squared test p value odds ratio (95% CI)	55%        74% <0.0001 2.33 (1.73, 3.15)	61%        79% <0.0001 2.43 (1.84, 3.22)
Complete response (CR/CRu) rate* chi-squared test p value odds ratio (95% CI)	48%       67% <0.0001 2.21 (1.65, 2.94)	53%        67% <0.0001 2.34 (1.80, 3.03)

* at end of maintenance/ob­servation; final analysis results based on median follow-up of 73 months.

CI: confidence interval; FU: follow-up; OS: overall survival; TNLT: time to next anti-lymphoma treatment; TNCT: time to next chemotherapy treatment; NR: not reached at time of clinical cut-off.

Rituximab maintenance treatment provided consistent benefit in all predefined subgroups tested: gender (male, female), age (< 60 years, > 60 years), FLIPI score (<1, 2 or > 3), induction therapy (R-CHOP, R-CVP or R-FCM) and regardless of the quality of response to induction treatment (CR, CRu or PR). Exploratory analyses of the benefit of maintenance treatment showed a less pronounced effect in elderly patients (> 70 years of age), however sample sizes were small.

Relapsed/Refrac­tory follicular lymphoma

In a prospective, open label, international, multicentre, phase III trial, 465 patients with relapsed/refractory follicular lymphoma were randomised in a first step to induction therapy with either CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone; n=231) or rituximab plus CHOP (R-CHOP, n=234). The two treatment groups were well balanced with regard to baseline characteristics and disease status. A total of 334 patients achieving a complete or partial remission following induction therapy were randomised in a second step to rituximab maintenance therapy (n=167) or observation (n=167). Rituximab maintenance treatment consisted of a single infusion of rituximab at 375 mg/m2 body surface area given every 3 months until disease progression or for a maximum period of two years.

The final efficacy analysis included all patients randomised to both parts of the study. After a median observation time of 31 months for patients randomised to the induction phase, R-CHOP significantly improved the outcome of patients with relapsed/refractory follicular lymphoma when compared to CHOP (see Table 10).

Table 10 Induction phase: overview of efficacy results for CHOP vs. R-CHOP (31 months median observation time)

	CHOP	R-CHOP	p-value	Risk Reduction 1)
Primary efficacy
ORR2)	74%	87%	0.0003	NA
CR2)	16%	29%	0.0005	NA
PR2)	58%	58%	0.9449	NA

1) Estimates were calculated by hazard ratios

2) Last tumour response as assessed by the investigator. The “primary” statistical test for “response” was the trend test of CR versus PR versus non-response (p < 0.0001)

Abbreviations: NA, not available; ORR: overall response rate; CR: complete response; PR: partial response

For patients randomised to the maintenance phase of the trial, the median observation time was 28 months from maintenance randomisation. Maintenance treatment with rituximab led to a clinically relevant and statistically significant improvement in the primary endpoint, PFS, (time from maintenance randomisation to relapse, disease progression or death) when compared to observation alone (p< 0.0001 log-rank test). The median PFS was 42.2 months in the rituximab maintenance arm compared to 14.3 months in the observation arm. Using a cox regression analysis, the risk of experiencing progressive disease or death was reduced by 61% with rituximab maintenance treatment when compared to observation (95% CI; 45%-72%). Kaplan-Meier estimated progression-free rates at 12 months were 78% in the rituximab maintenance group vs. 57% in the observation group. An analysis of overall survival confirmed the significant benefit of rituximab maintenance over observation (p=0.0039 log-rank test). Rituximab maintenance treatment reduced the risk of death by 56% (95% CI; 22%-75%).

Table 11 Maintenance phase: overview of efficacy results rituximab vs. observation (28 months median observation time)

Efficacy Parameter	Kaplan-Meier Estimate of Median Time to Event (months)			Risk Reduction
	Observation (N = 167)	Rituximab (N=167)	Log-rank p value
Progression-free   survival (PFS)	14.3	42.2	< 0.0001	61%
Overall survival	NR	NR	0.0039	56%
Time to new lymphoma treatment	20.1	38.8	< 0.0001	50%
Disease-free survival3	16.5	53.7	0.0003	67%
Subgroup analysis PFS
CHOP	11.6	37.5	< 0.0001	71%
R-CHOP	22.1	51.9	0.0071	46%
CR	14.3	52.8	0.0008	64%
PR	14.3	37.8	< 0.0001	54%
OS
CHOP	NR	NR	0.0348	55%
R-CHOP	NR	NR	0.0482	56%

NR: not reached; a: only applicable to patients achieving a CR

The benefit of rituximab maintenance treatment was confirmed in all subgroups analysed, regardless of induction regimen (CHOP or R-CHOP) or quality of response to induction treatment (CR or PR) (Table 11). Rituximab maintenance treatment significantly prolonged median PFS in patients responding to CHOP induction therapy (median PFS 37.5 months vs. 11.6 months, p< 0.0001) as well as in those responding to R-CHOP induction (median PFS 51.9 months vs. 22.1 months, p=0.0071). Although subgroups were small, rituximab maintenance treatment provided a significant benefit in terms of overall survival for both patients responding to CHOP and patients responding to R-CHOP, although longer follow-up is required to confirm this observation.

Adult Diffuse large B cell non-Hodgkin S lymphoma

In a randomised, open-label trial, a total of 399 previously untreated elderly patients (age 60 to 80 years) with diffuse large B cell lymphoma received standard CHOP chemotherapy (cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine 1.4 mg/m2 up to a maximum of 2 mg on day 1, and prednisolone 40 mg/m2/day on days 1–5) every 3 weeks for eight cycles, or rituximab 375 mg/m2 plus CHOP (R-CHOP). Rituximab was administered on the first day of the treatment cycle.

The final efficacy analysis included all randomised patients (197 CHOP, 202 R-CHOP), and had a median follow-up duration of approximately 31 months. The two treatment groups were well balanced in baseline disease characteristics and disease status. The final analysis confirmed that R-CHOP treatment was associated with a clinically relevant and statistically significant improvement in the duration of event-free survival (the primary efficacy parameter; where events were death, relapse or progression of lymphoma, or institution of a new anti-lymphoma treatment) (p=0.0001). Kaplan Meier estimates of the median duration of event-free survival were 35 months in the R-CHOP arm compared to 13 months in the CHOP arm, representing a risk reduction of 41%. At 24 months, estimates for overall survival were 68.2% in the R-CHOP arm compared to 57.4% in the CHOP arm. A subsequent analysis of the duration of overall survival, carried out with a median follow-up duration of 60 months, confirmed the benefit of R-CHOP over CHOP treatment (p=0.0071), representing a risk reduction of 32%.

The analysis of all secondary parameters (response rates, progression-free survival, disease-free survival, duration of response) verified the treatment effect of R-CHOP compared to CHOP. The complete response rate after cycle 8 was 76.2% in the R-CHOP group and 62.4% in the CHOP group (p=0.0028). The risk of disease progression was reduced by 46% and the risk of relapse by 51%. In all patient subgroups (gender, age, age adjusted IPI, Ann Arbor stage, ECOG, P2 microglobulin, LDH, albumin, B symptoms, bulky disease, extranodal sites, bone marrow involvement), the risk ratios for event-free survival and overall survival (R-CHOP compared with CHOP) were less than 0.83 and 0.95 respectively. R-CHOP was associated with improvements in outcome for both high- and low-risk patients according to age adjusted IPI.

Clinical laboratory findings

Of 67 patients evaluated for human anti-mouse antibody (HAMA), no responses were noted. Of 356 patients evaluated for anti-drug antibody (ADA), 1.1% (4 patients) were positive.

Chronic lymphocytic leukaemia

In two open-label randomised trials, a total of 817 previously untreated patients and 552 patients with relapsed/refractory CLL were randomised to receive either FC chemotherapy (fludarabine 25 mg/m2, cyclophosphamide 250 mg/m2, days 1–3) every 4 weeks for 6 cycles or rituximab in combination with FC (R-FC). Rituximab was administered at a dosage of 375 mg/m2 during the first cycle one day prior to chemotherapy and at a dosage of 500 mg/m2 on day 1 of each subsequent treatment cycle. Patients were excluded from the study in relapsed/refractory CLL if they had previously been treated with monoclonal antibodies or if they were refractory (defined as failure to achieve a partial remission for at least 6 months) to fludarabine or any nucleoside analogue. A total of 810 patients (403 R-FC, 407 FC) for the first-line study (Table 12a and Table 12b) and 552 patients (276 R-FC, 276 FC) for the relapsed/refractory study (Table 13) were analysed for efficacy.

In the first-line study, after a median observation time of 48.1 months, the median PFS was 55 months in the R-FC group and 33 months in the FC group (p < 0.0001, log-rank test). The analysis of overall survival showed a significant benefit of R-FC treatment over FC chemotherapy alone (p=0.0319, log-rank test) (Table 12a). The benefit in terms of PFS was consistently observed in most patient subgroups analysed according to disease risk at baseline (i.e. Binet stages A-C) (Table 12b).

Table 12a    First-line treatment of chronic lymphocytic leukaemia

Overview of efficacy results for rituximab plus FC vs. FC alone – 48.1 months median observation time

Efficacy Parameter	Kaplan-Meier Estimate of Median Time to Event (months)			Risk Reduction
	FC (N = 409)	R-FC (N=408)	Log-rank p value
Progression-free survival (PFS)	32.8	55.3	<0.0001	45%
Overall survival	NR	NR	0.0319	27%

Event free survival	31.3	51.8	<0.0001	44%
Response rate (CR, nPR, or PR)	72.6%	85.8%	<0.0001	N/A
CR rates	16.9%	36.0%	<0.0001	N/A
Duration of response*	36.2	57.3	<0.0001	44%
Disease free survival (DFS)	48.9	60.3	0.0520	31%
Time to new treatment	47.2	69.7	<0.0001	42%

Response rate and CR rates analysed using Chi-squared Test. NR: not reached; N/A: not applicable

: only applicable to patients achieving a CR, nPR, PR

: only applicable to patients achieving a CR

Table 12b    First-line treatment of chronic lymphocytic leukaemia

Hazard ratios of progression-free survival according to Binet stage

(ITT) – 48.1 months med	ian observation time
Progression -free Survival (PFS)	Number of Patients		Hazard Ratio (95% CI)	p-value (Wald test, not adjusted)
	FC	R -FC
Binet stage A	22	18	0.39 (0.15; 0.98)	0.0442
Binet stage B	259	263	0.52 (0.41; 0.66)	<0.0001
Binet stage C	126	126	0.68 (0.49; 0.95)	0.0224

CI: Confidence Interval

In the relapsed/refractory study, the median progression-free survival (primary endpoint) was 30.6 months in the R-FC group and 20.6 months in the FC group (p=0.0002, log-rank test). The benefit in terms of PFS was observed in almost all patient subgroups analysed according to disease risk at baseline. A slight but not significant improvement in overall survival was reported in the R-FC compared to the FC arm.

Table 13 Treatment of relapsed/refractory chronic lymphocytic leukaemia – overview

of efficacy results for rituximab plus FC vs. FC alone (25.3 months median observation time)

Efficacy Parameter	Kaplan-Meier Estimate of Median Time to Event (months)			Risk Reduction
	FC (N = 276)	R-FC (N=276)	Log-Rank p value
Progression-free survival (PFS)	20.6	30.6	0.0002	35%
Overall survival	51.9	NR	0.2874	17%
Event free survival	19.3	28.7	0.0002	36%
Response rate (CR, nPR, or PR)	58.0%	69.9%	0.0034	N/A
CR rates	13.0%	24.3%	0.0007	N/A
Duration of response	27.6	39.6	0.0252	31%
Disease free survival (DFS)	42.2	39.6	0.8842	–6%
Time to new CLL treatment	34.2	NR	0.0024	35%

Response rate and CR rates analysed using Chi-squared Test. NR: not reached; N/A: not applicable

: only applicable to patients achieving a CR, nPR, PR;

: only applicable to patients achieving a CR;

Results from other supportive studies using rituximab in combination with other chemotherapy regimens (including CHOP, FCM, PC, PCM, bendamustine and cladribine) for the treatment of previously untreated and/or relapsed/refractory CLL patients have also demonstrated high overall response rates with benefit in terms of PFS rates, albeit with modestly higher toxicity (especially myelotoxicity). These studies support the use of rituximab with any chemotherapy.

Data in approximately 180 patients pre-treated with rituximab have demonstrated clinical benefit (including CR) and are supportive for rituximab re-treatment.

Paediatric population

A multicenter, open-label, randomized study of Lymphome Malin B (LMB) chemotherapy (corticosteroids, vincristine, cyclophosphamide, high-dose methotrexate, cytarabine, doxorubicin, etoposide and triple drug [methotrexate/cy­tarabine/ corticosteroid] intrathecal therapy) alone or in combination with rituximab was conducted in paediatric patients with previously untreated advanced stage CD20 positive DLBCL/BL/BAL/BLL. Advanced stage is defined as Stage III with elevated LDH level (“B-high”), [LDH > twice the institutional upper limit of the adult normal values (> Nx2)] or any stage IV or BAL. Patients were randomized to receive either LMB chemotherapy or six IV infusions of rituximab at a dose of 375mg/m2 BSA in combination with LMB chemotherapy (two during each of the two induction courses and one during each of the two consolidation courses) as per the LMB scheme. A total of 328 randomized patients were included in the efficacy analyses, of which one patient under 3 years of age received rituximab in combination with LMB chemotherapy.

The two treatment arms, LMB (LMB chemotherapy) and R-LMB (LMB chemotherapy with rituximab), were well balanced with regards to baseline characteristics. Patients had a median age of 7 and 8 years in the LMB arm and R-LMB arm, respectively. Approximately half of patients were in Group B (50.6% in the LMB arm and 49.4% in the R-LMB arm), 39.6% in Group C1 in both arms, and 9.8% and 11.0% were in Group C3 in the LMB and R-LMB arms, respectively. Based on Murphy staging, most patients were either BL stage III (45.7% in the LMB arm and 43.3% in the R-LMB arm) or BAL, CNS negative (21.3% in the LMB arm and 24.4% in the R-LMB arm). Less than half of the patients (45.1% in both arms) had bone marrow involvement, and most patients (72.6% in the LMB arm and 73.2% in the R-LMB arm) had no CNS involvement. The primary efficacy endpoint was EFS, where an event was defined as occurrence of progressive disease, relapse, second malignancy, death from any cause, or non-response as evidenced by detection of viable cells in residue after the second CYVE course, whichever occurs first. The secondary efficacy endpoints were OS and CR (complete remission).

At the pre-specified interim analysis with approximately 1 year of median follow-up, clinically relevant improvement in the primary endpoint of EFS was observed, with 1-year rate estimates of 94.2% (95% CI, 88.5% – 97.2%) in the R-LMB arm vs. 81.5% (95% CI, 73.0% – 87.8%) in the LMB arm, and adjusted Cox HR 0.33 (95% CI, 0.14 – 0.79). Upon IDMC (independent data monitoring committee) recommendation based on this result, the randomization was halted and patients in the LMB arm were allowed to cross over to receive rituximab.

Primary efficacy analyses were performed in 328 randomized patients with a median follow-up of 3.1 years. The results are described in Table 14.

Table 14: _____ Overview of Primary Efficacy Results (ITT population) _____________­_________

Analysis	LMB (N = 164)	R-LMB (N=164)
EFS	28 events	10 events
	One-sided log-rank test p-value 0.0006
	Adjusted Cox HR 0.32 (90% CI: 0.17, 0.58)

3-year EFS rates	82.3% (95% CI: 75.7%, 87.5%)	93.9% (95% CI: 89.1%, 96.7%)
OS	20 deaths	8 deaths
	One-sided log-rank test p-value 0.0061
	Adjusted Cox model HR 0.36 (95% CI: 0.16; 0.81)
3-year OS rates	87.3% (95% CI: 81.2%, 91.6%)	95.1% (95% CI: 90.5%, 97.5%)
CR rate	93.6% (95% CI: 88.2%; 97.0%)	94.0% (95% CI: 88.8%, 97.2%)

The primary efficacy analysis showed an EFS benefit of rituximab addition to LMB chemotherapy over LMB chemotherapy alone, with an EFS HR 0.32 (90% CI 0.17 – 0.58) from a Cox regression analysis adjusting for national group, histology, and therapeutic group. While no major differences in numbers of patients achieving CR was observed between the two treatment groups, the benefit of rituximab addition to LMB chemotherapy was also shown in the secondary endpoint of OS, with the OS HR of 0.36 (95% CI, 0.16 – 0.81).

The European Medicines Agency has waived the obligation to submit the results of studies with rituximab in all subsets of the paediatric population with follicular lymphoma and chronic lymphocytic leukaemia, and in the paediatric population from birth to < 6 months of age in CD20 positive diffuse large B-cell lymphoma. See section 4.2 for information on paediatric use.

Clinical experience in rheumatoid arthritis

The efficacy and safety of rituximab in alleviating the symptoms and signs of rheumatoid arthritis in patients with an inadequate response to TNF-inhibitors was demonstrated in a pivotal randomised, controlled, double-blind, multicentre trial (Trial 1).

Trial 1 evaluated 517 patients that had experienced an inadequate response or intolerance to one or more TNF inhibitor therapies. Eligible patients had active rheumatoid arthritis, diagnosed according to the criteria of the American College of Rheumatology (ACR). Rituximab was administered as two IV infusions separated by an interval of 15 days. Patients received 2 × 1000 mg intravenous infusions of rituximab or placebo in combination with MTX. All patients received concomitant 60 mg oral prednisone on days 2–7 and 30 mg on days 8–14 following the first infusion. The primary endpoint was the proportion of patients who achieved an ACR20 response at week 24. Patients were followed beyond week 24 for long-term endpoints, including radiographic assessment at 56 weeks and at 104 weeks. During this time, 81% of patients, from the original placebo group received rituximab between weeks 24 and 56, under an open label extension study protocol.

Trials of rituximab in patients with early arthritis (patients without prior methotrexate treatment and patients with an inadequate response to methotrexate, but not yet treated with TNF-alpha inhibitors) have met their primary endpoints. Rituximab is not indicated for these patients, since the safety data about long-term rituximab treatment are insufficient, in particular concerning the risk of development of malignancies and PML.

Disease activity outcomes

Rituximab in combination with methotrexate significantly increased the proportion of patients achieving at least a 20% improvement in ACR score compared with patients treated with methotrexate alone (Table 15). Across all development studies the treatment benefit was similar in patients independent of age, gender, body surface area, race, number of prior treatments or disease status.

Clinically and statistically significant improvement was also noted on all individual components of the ACR response (tender and swollen joint counts, patient and physician global assessment, disability index scores (HAQ), pain assessment and C-Reactive Proteins (mg/dL).

Table 15 Clinical response outcomes at primary endpoint in Trial 1 (ITT population)

	Outcome!	Placebo+MTX	Rituximab+MTX (2 × 1000 mg)
Trial 1		N= 201	N= 298
	ACR20 ACR50 ACR70	36 (18%) 11 (5%) 3 (1%)	153 (51%) _ *** 80 (27%) _ *** 37 (12%)
	EULAR Response (Good/Moderate)	44 (22%)	193 (65%)
	Mean change in DAS	–0.34	__ –1.83

f Outcome at 24 weeks

Significant difference from placebo + MTX at the primary time point: p < 0.0001

Patients treated with rituximab in combination with methotrexate had a significantly greater reduction in disease activity score (DAS28) than patients treated with methotrexate alone (Table 15). Similarly, a good to moderate European League Against Rheumatism (EULAR) response was achieved by significantly more rituximab treated patients treated with rituximab and methotrexate compared to patients treated with methotrexate alone (Table 15).

Radiographic response

Structural joint damage was assessed radiographically and expressed as change in modified Total Sharp Score (mTSS) and its components, the erosion score and joint space narrowing score.

In Trial 1, conducted in patients with inadequate response or intolerance to one or more TNF inhibitor therapies, receiving rituximab in combination with methotrexate demonstrated significantly less radiographic progression than patients originally receiving methotrexate alone at 56 weeks. Of the patients originally receiving methotrexate alone, 81% received rituximab either as rescue between weeks 16–24 or in the extension trial, before week 56. A higher proportion of patients receiving the original rituximab/MTX treatment also had no erosive progression over 56 weeks (Table 16).

Table 16 Radiographic outcomes at 1 year (mITT population)
	Placebo+MTX	Rituximab +MTX 2 × 1000 mg
Trial 1	(n=184)	(n=273)
Mean change from baseline:
Modified total sharp score	2.30	1.01
Erosion score	1.32	* 0.60
Joint space narrowing score	0.98	** 0.41
Proportion of patients with no radiographic change	46%	53%, NS
Proportion of patients with no erosive change	52%	60%, NS

150 patients originally randomised to placebo + MTX in Trial 1 received at least one course of RTX + MTX by one year

* p <0.05, ** p < 0.001. Abbre­viation: NS: non significant

Inhibition of the rate of progressive joint damage was also observed long term. Radiographic analysis at 2 years in Trial 1 demonstrated significantly reduced progression of structural joint damage in patients receiving rituximab in combination with methotrexate compared to methotrexate alone as well as a significantly higher proportion of patients with no progression of joint damage over the 2-year period.

Physical function and quality of life outcomes

Significant reductions in disability index (HAQ-DI) and fatigue (FACIT-Fatigue) scores were observed in patients treated with rituximab compared to patients treated with methotrexate alone. The proportions of rituximab treated patients showing a minimal clinically important difference (MCID) in HAQ-DI (defined as an individual total score decrease of >0.22) was also higher than among patients receiving methotrexate alone (Table 17).

Significant improvement in health related quality of life was also demonstrated with significant improvement in both the physical health score (PHS) and mental health score (MHS) of the SF-36. Further, significantly higher proportion of patients achieved MCIDs for these scores (Table 17).

Table 17 Physical function and quality of life outcomes at week 24 in Trial 1

Outcome!	Placebo+MTX	Rituximab+MTX (2 × 1000 mg)
Mean change in HAQ-DI	n=201 0.1	n=298 –0.4
% HAQ-DI MCID	20%	51%
Mean change in FACIT-T	–0.5	–9.1
Mean change in SF-36 PHS	n=197 0.9	n=294 5.8
% SF-36 PHS MCID	13%	48%
Mean change in SF-36 MHS	1.3	. --, 4.7
% SF-36 MHS MCID	20%	* 38%

f Outcome at 24 weeks

Significant difference from placebo at the primary time point: * p < 0.05, p < 0.001 p < 0.0001

MCID HAQ-DI >0.22, MCID SF-36 PHS >5.42, MCID SF-36 MHS >6.33

Efficacy in autoantibody (RF and or anti-CCP) seropositive patients

Patients seropositive to Rheumatoid Factor (RF) and/or anti-Cyclic Citrullinated Peptide (anti-CCP) who were treated with rituximab in combination with methotrexate showed an enhanced response compared to patients negative to both.

Efficacy outcomes in rituximab treated patients were analysed based on autoantibody status prior to commencing treatment. At Week 24, patients who were seropositive to RF and/or anti-CCP at baseline had a significantly increased probability of achieving ACR20 and 50 responses compared to seronegative patients (p=0.0312 and p=0.0096) (Table 18). These findings were replicated at Week 48, where autoantibody seropositivity also significantly increased the probability of achieving ACR70. At week 48 seropositive patients were 2–3 times more likely to achieve ACR responses compared to seronegative patients. Seropositive patients also had a significantly greater decrease in DAS28-ESR compared to seronegative patients (Figure 1).

Table 18 Summary of efficacy by baseline autoantibody status

Week 24

Week 48

	Seropositive (n=514)	Seronegative (n=106)	Seropositive (n=506)	Seronegative (n=101)
ACR20 (%)	62.3*	50.9	71. 1*	51.5
ACR50 (%)	32.7*	19.8	44.9	22.8
ACR70 (%)	12.1	5.7	20.9*	6.9
EULAR Response (%)	74.8*	62.9	84.3*	72.3
Mean change DAS28-ESR	–1.97	–1.50	—2.48	–1.72
Significance levels were defined as * p<0.05, **p<0.001, ***p<0.0001.

Figure 1:     Change from baseline of DAS28-ESR by baseline autoantibody status

 Anti-CCP +ve and/or RF +ve (N=562)        S —Q- B Anti-CCP -ve and RF -ve <N= 116)

Long-term efficacy with multiple course therapy

Treatment with rituximab in combination with methotrexate over multiple courses resulted in sustained improvements in the clinical signs and symptoms of RA, as indicated by ACR, DAS28-ESR and EULAR responses which was evident in all patient populations studied (Figure 2).

Sustained improvement in physical function as indicated by the HAQ-DI score and the proportion of patients achieving MCID for HAQ-DI were observed.

Figure 2:    ACR responses for 4 treatment courses (24 weeks after each course (within

patient, within visit) in patients with an inadequate response to TNF-inhibitors (n=146)

Clinical laboratory findings

A total of 392/3095 (12.7%) patients with rheumatoid arthritis tested positive for ADA in clinical studies following therapy with rituximab. The emergence of ADA was not associated with clinical deterioration or with an increased risk of reactions to subsequent infusions in the majority of patients. The presence of ADA may be associated with worsening of infusion or allergic reactions after the second infusion of subsequent courses.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with rituximab in all subsets of the paediatric population with autoimmune arthritis. See section 4.2 for information on paediatric use.

Clinical experience in granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA)

Adult induction of remission

In GPA/MPA Study 1,a total of 197 patients aged 15 years or older with severe active GPA (75%) and MPA (24%) were enrolled and treated in an active-comparator, randomised, double-blind, multicentre, non-inferiority trial.

Patients were randomised in a 1:1 ratio to receive either oral cyclophosphamide daily (2 mg/kg/day) for 3–6 months or rituximab (375 mg/m2) once weekly for 4 weeks. All patients in the cyclophosphamide arm received azathioprine maintenance therapy during follow-up. Patients in both arms received 1000 mg of pulse intravenous (IV) methylprednisolone (or another equivalent-dose glucocorticoid) per day for 1 to 3 days, followed by oral prednisone (1 mg/kg/day, not exceeding 80 mg/day). Prednisone tapering was to be completed by 6 months from the start of study treatment.

The primary outcome measure was achievement of complete remission at 6 months defined as a Birmingham Vasculitis Activity Score for Wegener’s gra­nulomatosis (BVAS/WG) of 0, and off glucocorticoid therapy. The pre-specified non-inferiority margin for the treatment difference was 20%. The trial demonstrated non-inferiority of rituximab to cyclophosphamide for complete remission (CR) at 6 months (Table 19).

Efficacy was observed both for patients with newly diagnosed disease and for patients with relapsing disease (Table 20).

Table 19 Percentage of adult patients who achieved complete remission at 6 months

(Intent-to-treat population*)

	Rituximab (n = 99)	Cyclophosphamide (n = 98)	Treatment difference (Rituximab -cyclophosphamide)
Rate	63.6%	53.1%	10.6% 95.1%bCI (-3.2%, 24.3%) a

CI = confidence interval.

–     * Worst case imputation

a Non-inferiority was demonstrated since the lower bound (-3.2%) was higher than the pre-determined non-inferiority margin (- 20%).

b The 95.1% confidence level reflects an additional 0.001 alpha to account for an interim efficacy analysis.

Table 20 _____ Complete remission at 6-months by disease status _____________­____________

Rituximab

Cyclophosphamide

Difference (CI 95%)

All patients	n=99	n=98
Newly diagnosed	n=48	n=48
Relapsing	n=51	n=50
Complete remission
All Patients	63.6%	53.1%	10.6% (-3.2, 24.3)
Newly diagnosed	60.4%	64.6%	– 4.2% (- 23.6, 15.3)
Relapsing	66.7%	42.0%	24.7% (5.8, 43.6)

Worst case imputation is applied for patients with missing data

Complete remission at 12 and 18 months

In the rituximab group, 48% of patients achieved CR at 12 months, and 39% of patients achieved CR at 18 months. In patients treated with cyclophosphamide (followed by azathioprine for maintenance of complete remission), 39% of patients achieved CR at 12 months, and 33% of patients achieved CR at 18 months. From month 12 to month 18, 8 relapses were observed in the rituximab group compared with four in the cyclophosphami­de group.

Laboratory evaluations

A total of 23/99 (23%) rituximab-treated patients from the induction of remission trial tested positive for ADA by 18 months. None of the 99 rituximab-treated patients were ADA positive at screening. There was no apparent trend or negative impact of the presence of ADA on safety or efficacy in the induction of the remission trial.

Adult maintenance treatment

A total of 117 patients (88 with GPA, 24 with MPA, and 5 with renal-limited ANCA-associated vasculitis) in disease remission were randomised to receive azathioprine (59 patients) or rituximab (58 patients) in a prospective, multi-center, controlled, open-label study. Included patients were 21 to 75 years of age and had newly diagnosed or relapsing disease in complete remission after combined treatment with glucocorticoids and pulse cyclophosphamide. The majority of patients were ANCApositive at diagnosis or during the course of their disease; had histologically confirmed necrotizing small-vessel vasculitis with a clinical phenotype of GPA or MPA, or renal limited ANCA-associated vasculitis; or both.

Remission-induction therapy included IV prednisone, administered as per the investigator’s dis­cretion, preceded in some patients by methylprednisolone pulses, and pulse cyclophosphamide until remission was attained after 4 to 6 months. At that time, and within a maximum of 1 month after the last cyclophosphamide pulse, patients were randomly assigned to receive either rituximab (two 500 mg IV infusions separated by two weeks (on Day 1 and Day 15) followed by 500 mg IV every 6 months for 18 months) or azathioprine (administered orally at a dose of 2 mg/kg/day for 12 months, then 1.5 mg/kg/day for 6 months, and finally 1 mg/kg/day for 4 months (treatment discontinuation after these 22 months)). Prednisone treatment was tapered and then kept at a low dose (approximately 5 mg per day) for at least 18 months after randomization. Prednisone dose tapering and the decision to stop prednisone treatment after month 18 were left at the investigator’s dis­cretion.

All patients were followed until month 28 (10 or 6 months, respectively, after the last rituximab infusion or azathioprine dose). Pneumocystis jirovecii pneumonia prophylaxis was required for all patients with CD4+ T-lymphocyte counts less than 250 per cubic millimeter.

The primary outcome measure was the rate of major relapse at month 28.

Results

At month 28, major relapse (defined by the reappearance of clinical and/or laboratory signs of vasculitis activity ([BVAS] > 0) that could lead to organ failure or damage or could be life threatening) occurred in 3 patients (5%) in the rituximab group and 17 patients (29%) in the azathioprine group (p=0.0007). Minor relapses (not life threatening and not involving major organ damage) occurred in seven patients in the rituximab group (12%) and eight patients in the azathioprine group (14%).

The cumulative incidence rate curves showed that time to first major relapse was longer in patients with rituximab starting from month 2 and was maintained up to month 28 (Figure 3).

Figure 3:     Cumulative incidence over time of first major relapse

Survival Time (Months)

Number of Subjects with Major Relapse
Azathioprine	0	0	3	3	5	5	8	8	9	9	9	10	13	15	17
Rituximab	0	0	0	0	1	1	1	1	1	1	1	1	3	3	3
Number of subjects at risk
Azathioprine	59	56	52	50	47	47	44	44	42	41	40	39	36	34	0
Rituximab	58	56	56	56	55	54	54	54	54	54	54	54	52	50	0

Note: Patients were censored at month 28 if they had no event.

Laboratory evaluations

A total of 6/34 (18%) of rituximab treated patients from the maintenance therapy clinical trial developed ADA. There was no apparent trend or negative impact of the presence of ADA on safety or efficacy in the maintenance therapy clinical trial.

Paediatric population

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

Study WA25615 (PePRS) was a multicenter, open-label, single-arm, uncontrolled study in 25 paediatric patients (> 2 to < 18 years old) with severe, active GPA or MPA. The median age of patients in the study was: 14 years (range: 6–17 years) and the majority of patients (20/25 [80%]) were female. A total of 19 patients (76%) had GPA and 6 patients (24%) had MPA at baseline. Eighteen patients (72%) had newly diagnosed disease upon study entry (13 patients with GPA and 5 patients with MPA) and 7 patients had relapsing disease (6 patients with GPA and 1 patient with MPA).

The study design consisted of an initial 6-month remission induction phase, with a minimum 18-month follow-up, up to a maximum of 54 months (4.5 years) overall. Patients were to receive a minimum of 3 doses of IV methylprednisolone (30 mg/kg/day, not exceeding 1 g/day) prior to the first rituximab IV infusion. If clinically indicated, additional daily doses (up to three), of IV methylprednisolone could be given. The remission induction regimen consisted of four once weekly

IV infusions of rituximab at a dose of 375 mg/m2 BSA, on study days 1, 8, 15 and 22 in combination with oral prednisolone or prednisone at 1 mg/kg/day (max 60 mg/day) tapered to 0.2 mg/kg/day minimum (max 10 mg/day) by Month 6. After the remission induction phase, patients could, at the discretion of the investigator, receive subsequent rituximab infusions on or after Month 6 to maintain PVAS remission and control disease activity (including progressive disease or flare) or to achieve first remission.

All 25 patients completed all four once weekly IV infusions for the 6-month remission induction phase. A total of 24 out of 25 patients completed at least 18 months of follow-up.

The objectives of this study were to evaluate safety, PK parameters, and efficacy of rituximab in paediatric GPA and MPA patients (> 2 to < 18 years old). The efficacy objectives of the study were exploratory and principally assessed using the Pediatric Vasculitis Activity Score (PVAS) (Table 21).

Cumulative Glucocorticoid dose (IV and Oral) by Month 6:

Twenty-four out of 25 patients (96%) in Study WA25615 achieved oral glucocorticoid taper to 0.2 mg/kg/day (or less than or equal to 10 mg/day, whichever was lower) at or by Month 6 during the protocol-defined oral steroid taper.

A decrease in median overall oral glucocorticoid use was observed from Week 1 (median = 45 mg prednisone equivalent dose [IQR: 35 – 60]) to Month 6 (median = 7.5 mg [IQR: 4–10]), which was subsequently maintained at Month 12 (median = 5 mg [IQR: 2–10]) and Mmonth 18 (median =5 mg [IQR: 1–5]).

Follow-Up Treatment

During the Overall Study Period, patients received between 4 and 28 infusions of rituximab (up to 4.5 yrs [53.8 months]). Patients received up to 375 mg/m2 × 4 of rituximab, approximately every 6 months at the discretion of the investigator. In total, 17 out of 25 patients (68%) received additional rituximab treatment at or post Month 6 until the Common Close Out, 14 out of these 17 patients received additional rituximab treatment between Month 6 and Month 18.

Table 21: Study WA25615 (PePRS) – PVAS Remission at Month 1, 2, 4, 6, 12 and 18

Study visit	Number of Responders in PVAS Remission* (response rate [%]) n=25	95% CIa
Month 1	0	0.0%, 13.7%
Month 2	1 (4.0%)	0.1%, 20.4%
Month 4	5 (20.0%)	6.8%, 40.7%
Month 6	13 (52.0%)	31.3%, 72.2%
Month 12	18 (72.0%)	50.6%, 87.9%
Month 18	18 (72.0%)	50.6%, 87.9%
* PVAS of 0 and achieved glucocorticoid taper to 0.2 mg/kg/day (or 10 mg/day, whichever is lower) at the assessment time-point. at he efficacy results are exploratory and no formal statistical testing was performed for these endpoints rituximab, treatment (375 mg/m2 × 4 infusions) up to Month 6 was identical for all patients. Follow-up treatment post Month 6 was at the discretion of the investigator.

Laboratory evaluations

A total of 4/25 patients (16%) developed ADA during the overall study period. Limited data shows there was no trend observed in the adverse reactions reported in ADA positive patients.

There was no apparent trend or negative impact of the presence of ADA on safety or efficacy in the paediatric GPA and MPA clinical trials.

The European Medicines Agency has waived the obligation to submit the results of studies with rituximab in paediatric population < 2 years of age in severe, active GPA or MPA. See section 4.2 for information on paediatric use.

Clinical experience in pemphigus vulgaris

PV Study 1 (Study ML22196)

The efficacy and safety of rituximab in combination with short-term, low-dose glucocorticoid (prednisone) therapy were evaluated in newly diagnosed patients with moderate to severe pemphigus (74 pemphigus vulgaris [PV] and 16 pemphigus foliaceus [PF]) in this randomised, open-label, controlled, multicenter study. Patients were between 19 and 79 years of age and had not received prior therapies for pemphigus. In the PV population, 5 (13%) patients in the rituximab group and 3 (8%) patients in the standard prednisone group had moderate disease and 33 (87%) patients in the rituximab group and 33 (92%) patients in the standard-dose prednisone group had severe disease according to disease severity defined by Harman’s criteria.

Patients were stratified by baseline disease severity (moderate or severe) and randomised 1:1 to receive either rituximab and low-dose prednisone or standard-dose prednisone. Patients randomised to the rituximab group received an initial intravenous infusion of 1000 mg rituximab on Study Day 1 in combination with 0.5 mg/kg/day oral prednisone tapered off over 3 months if they had moderate disease or 1 mg/kg/day oral prednisone tapered off over 6 months if they had severe disease, and a second intravenous infusion of 1000 mg on Study Day 15. Maintenance infusions of rituximab 500 mg were administered at months 12 and 18. Patients randomised to the standard-dose prednisone group received an initial 1 mg/kg/day oral prednisone tapered off over 12 months if they had moderate disease or 1.5 mg/kg/day oral prednisone tapered off over 18 months if they had severe disease.

Patients in the rituximab group who relapsed could receive an additional infusion of rituximab 1000 mg in combination with reintroduced or escalated prednisone dose. Maintenance and relapse infusions were administered no sooner than 16 weeks following the previous infusion.

The primary objective for the study was complete remission (complete epithelialisation and absence of new and/or established lesions) at month 24 without the use of prednisone therapy for two months or more (CRoff for >2 months).

PV Study 1 Results

The study showed statistically significant results of rituximab and low-dose prednisone over standarddose prednisone in achieving CRoff > 2 months at month 24 in PV patients (see Table 22).

Table 22 Percentage of PV patients who achieved complete remission off corticosteroid

therapy for two months or more at month 24 (Intent-to-Treat Population – PV)

	Rituximab + Prednisone N=38	Prednisone N=36	p-value a	95% CI b
Number of responders (response rate [%])	34 (89.5%)	10 (27.8%)	<0.0001	61.7% (38.4, 76.5)
a p-value is from Fisher’s exact test with mid-p correction b 95% confidence interval is corrected Newcombe interval

The number of rituximab plus low-dose prednisone patients off prednisone therapy or on minimal therapy (prednisone dose of 10 mg or less per day) compared to standard-dose prednisone patients over the 24-month treatment period shows a steroid-sparing effect of rituximab (Figure 4).

Figure 4:  Number of patients who were off or on minimal corticosteroid (<10 mg/day) therapy

over time

Post-hoc retrospective laboratory evaluation

A total of 19/34 (56%) patients with PV, who were treated with rituximab, tested positive for ADA antibodies by 18 months. The clinical relevance of ADA formation in rituximab-treated PV patients is unclear.

PV Study 2 (Study WA29330)

In a randomized, double-blind, double-dummy, active-comparator, multicenter study, the efficacy and safety of rituximab compared with mycophenolate mofetil (MMF) were evaluated in patients with moderate-to-severe PV receiving 60–120 mg/day oral prednisone or equivalent (1.0–1.5 mg/kg/day) at study entry and tapered to reach a dose of 60 or 80 mg/day by Day 1. Patients had a confirmed diagnosis of PV within the previous 24 months and evidence of moderate-to-severe disease (defined as a total Pemphigus Disease Area Index, PDAI, activity score of > 15).

One hundred and thirty-five patients were randomized to treatment with rituximab 1000 mg administered on Day 1, Day 15, Week 24 and Week 26 or oral MMF 2 g/day for 52 weeks in combination with 60 or 80 mg oral prednisone with the aim of tapering to 0 mg/day prednisone by Week 24.

The primary efficacy objective for this study was to evaluate at week 52, the efficacy of rituximab compared with MMF in achieving sustained complete remission defined as achieving healing of lesions with no new active lesions (i.e., PDAI activity score of 0) while on 0 mg/day prednisone or equivalent, and maintaining this response for at least 16 consecutive weeks, during the 52-week treatment period.

PV Study 2 Results

The study demonstrated the superiority of rituximab over MMF in combination with a tapering course of oral corticosteroids in achieving CR off corticosteroid > 16 weeks at Week 52 in PV patients (Table 23).The majority of patients in the mITT population were newly diagnosed (74%) and 26% of patients had established disease (duration of illness > 6 months and received prior treatment for PV).

Table 23 Percentage of PV Patients Who Achieved Sustained Complete Remission Off

Corticosteroid Therapy for 16 Weeks or More at Week 52 (Modified Intent-to-Treat

___________ Population) _____________­________________________­_________________________

	Rituximab (N=62)	MMF (N=63)	Difference (95% CI)	p-value
Number of responders (response rate [%]) Newly diagnosed patients Patients with established disease	25 (40.3%) 19 (39.6%) 6 (42.9%)	6 (9.5%) 4 (9.1%) 2 (10.5%)	30.80% (14.70%, 45.15%)	<0.0001
MMF = Mycophenolate mofetil. CI = Confidence Interval. Newly diagnosed patients = duration of illness < 6 months or no prior treatment for PV. Patients with established disease = duration of illness > 6 months and received prior treatment for PV. Cochran-Mantel-Haenszel test is used for p-value.

The analysis of all secondary parameters (including cumulative oral corticosteroid dose, the total number of disease flares, and change in health-related quality of life, as measured by the Dermatology Life Quality Index) verified the statistically significant results of rituximab compared to MMF. Testing of secondary endpoints were controlled for multiplicity.

Glucocorticoid exposure

The cumulative oral corticosteroid dose was significantly lower in patients treated with rituximab. The median (min, max) cumulative prednisone dose at Week 52 was 2775 mg (450, 22180) in the rituximab group compared to 4005 mg (900, 19920) in the MMF group (p=0.0005).

Disease flare

The total number of disease flares was significantly lower in patients treated with rituximab compared to MMF (6 vs. 44, p<0.0001) and there were fewer patients who had at least one disease flare (8.1% vs. 41.3%).

Laboratory evaluations

By week 52, a total of 20/63 (31.7%) (19 treatment-induced and 1 treatment-enhanced) rituximab -treated PV patients tested positive for ADA. There was no apparent negative impact of the presence of ADA on safety or efficacy in PV Study 2.

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 ^g/mL (range, 77.5 to 996.6 ^g/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 ^g/mL (range, 16 – 582 ^g/mL) after the first infusion to 550 |Jg/mL (range, 171 – 1177 ^g/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 (s3 to <12 years vs. s12 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 ig/mL followed by lower geometric mean maximum concentrations thereafter (Cycle 4: 247 fg/mL). With this dose regimen, trough levels were sustained (geometric means: 41.8 ^g/mL (pre-dose Cycle 2; after 1 cycle), 67.7 ^g/mL (pre-dose Cycle 3, after 2 cycles) and 58.5 |Jg/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 tumor size is related to higher exposure due to lower time dependent clearance, however, systemic exposures impacted by different tumor 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

Age group	^ 6 mo to < 3 years	^ 3 to < 12 years	^ 12 to < 18 years
Ctrough (pg/mL)	47.5 (0.01–179)	51.4 (0.00–182)	44.1 (0.00–149)
AUC1–4 cycles (pg*day/mL)	13501 (278–31070)	11609 (135–31157)	11467 (110–27066)

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 gg/mL for 2 × 500 mg dose and ranged from 298 to 341 ^g/mL for 2 × 1000 mg dose. Following second infusion, mean Cmax ranged from 183 to 198 ^g/mL for the 2 × 500 mg dose and ranged from 355 to 404 ^g/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 ^g/mL for 2 × 500 mg dose and 317 to 370 ^g/mL for 2 × 1000 mg dose. Cmax following second infusion, was 207 gg/mL for the 2 × 500 mg dose and ranged from 377 to 386 ^g/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 ^g/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) ^g/mL, 2.1 (0–29.3) ^g/mL and 10302 (3653–21874)|jg/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

Parameter	Infusion Cycle
	1st cycle of 1000 mg Day 1 and Day 15 N=67	2nd cycle of 1000 mg Day 168 and Day 182 N=67
Terminal Half-life (days) Median (Range)	21.0 (9.3–36.2)	26.5 (16.4–42.8)
Clearance (L/day) Mean (Range)	391 (159–1510)	247 (128–454)
Central Volume of Distribution (L) Mean (Range)	3.52 (2.48–5.22)	3.52 (2.48–5.22)

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 post natally 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

Sodium chloride

Tri-sodium citrate dihydrate (E331)

Polysorbate 80 (E433)

Water for injections

6.2 Incompatibilities

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

6.3 Shelf life

Unopened vial 4 years

Diluted product

The prepared infusion solution of rituximab in 0.9% sodium chloride solution is physically and chemically stable for 30 days at 2 °C – 8 °C and subsequently 24 hours at room temperature (not more than 30 °C).

The prepared infusion solution of rituximab in 5% glucose solution is physically and chemically stable for 24 hours at 2 °C – 8 °C and subsequently 12 hours at room temperature (not more than 30 °C).

From a microbiological point of view, the prepared infusion solution should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 °C – 8 °C, unless dilution has taken place in controlled and validated aseptic conditions.

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

Blitzima 100 mg concentrate for solution for infusion

Clear Type I glass vials with butyl rubber stopper containing 100 mg of rituximab in 10 mL. Pack of 2 vials.

Blitzima 500 mg concentrate for solution for infusion

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

6.6 Special precautions for disposal and other handling

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

Use sterile needle and syringe to prepare Blitzima. Aseptically withdraw the necessary amount of Blitzima, 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

Celltrion Healthcare Hungary Kft.

1062 Budapest

Vaci ut 1–3. WestEnd Office Building B torony

Hungary

8. MARKETING AUTHORISATION NUMBER(S)

Blitzima 100 mg concentrate for solution for infusion

EU/1/17/1205/002

Blitzima 500 mg concentrate for solution for infusion

EU/1/17/1205/001

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 13 July 2017