rituximab: prescribing information – dosing, contraindications, interactions, side effects

Non-Hodgkin’s lymphoma (NHL)

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

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

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

MabThera 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.

MabThera in combination with chemotherapy is indicated for the treatment of paediatric patients (aged 6 months to less than 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)

MabThera in combination with chemotherapy is indicated for the treatment of adult 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 MabThera or patients refractory to previous MabThera plus chemotherapy.

See section 5.1 for further information.

Rheumatoid arthritis

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

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

Granulomatosis with polyangiitis and microscopic polyangiitis

MabThera, 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).

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

Pemphigus vulgaris

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

MabThera is indicated in adults for non-Hodgkin’s lymphoma (NHL):

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

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

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

MabThera is indicated in adults in combination with chemotherapy for the treatment of patients with previously untreated and relapsed/refractory chronic lymphocytic leukaemia (CLL). Only limited data are available on efficacy and safety for patients previously treated with monoclonal antibodies including MabThera or patients refractory to previous MabThera plus chemotherapy.

See section 5.1 for further information.

MabThera 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

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

Non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia
In adult patients with non-Hodgkin’s lymphoma and CLL, premedication with glucocorticoids should be considered if MabThera 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 MabThera. 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 x 109/L it is recommended to administer prednisone/prednisolone 100 mg intravenous shortly before infusion with MabThera to decrease the rate and severity of acute infusion reactions and/or cytokine release syndrome.

Rheumatoid arthritis, granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), and pemphigus vulgaris In patients with rheumatoid arthritis, GPA or MPA or pemphigus vulgaris, premedication with 100 mg intravenous methylprednisolone should be completed 30 minutes prior to each infusion of MabThera 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 MabThera (the last dose of methylprednisolone may be given on the same day as the first infusion of MabThera). 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 MabThera treatment.

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

In paediatric patients with GPA or MPA, prior to the first MabThera 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 MabThera infusion.

Following completion of IV methylprednisolone administration, paediatric 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).

Posology

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

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

Non-Hodgkin’s lymphoma

Follicular non-Hodgkin's lymphoma

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

MabThera 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 MabThera 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 MabThera 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 MabThera 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 MabThera monotherapy for patients who have responded to previous treatment with MabThera 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

MabThera 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 MabThera have not been established in combination with other chemotherapies in diffuse large B-cell non-Hodgkin’s lymphoma.

Chronic lymphocytic leukaemia

The recommended dosage of MabThera 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 MabThera infusion.

Rheumatoid arthritis

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

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

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

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

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

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

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

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

MabThera 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 MabThera 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 MabThera maintenance therapy, up to 5 years.

Pemphigus vulgaris

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

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

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

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

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

Special populations

Paediatric population

Non-Hodgkin’s lymphoma

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

The safety and efficacy of MabThera in paediatric patients aged 6 months to less than 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.

MabThera 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 MabThera administration for non-Hodgkin’s lymphoma paediatric patients

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

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

Premedication with glucocorticoids should be considered if MabThera is not given in combination with glucocorticoid-containing chemotherapy.

Posology

The recommended dose of MabThera subcutaneous formulation used for adult patients is a subcutaneous injection at a fixed dose of 1400 mg irrespective of the patient’s body surface area.

Before starting MabThera subcutaneous injections, all patients must always receive beforehand, a full dose of MabThera by intravenous infusion, using MabThera intravenous formulation (see section 4.4).

If patients were not able to receive one full MabThera intravenous infusion dose prior to the switch, they should continue the subsequent cycles with MabThera intravenous formulation until a full intravenous dose is successfully administered.
Therefore, the switch to MabThera subcutaneous formulation can only occur at the second or subsequent cycles of treatment.

It is important to check the medicinal product labels to ensure that the appropriate formulation (intravenous or subcutaneous formulation) and strength is being given to the patient, as prescribed.

MabThera subcutaneous formulation is not intended for intravenous administration and should be given via subcutaneous injection only. The 1400 mg strength is intended for subcutaneous use in non-Hodgkin’s lymphoma (NHL) only.

Follicular non-Hodgkin's lymphoma

Combination therapy
The recommended dose of MabThera in combination with chemotherapy for induction treatment of previously untreated or relapsed/refractory patients with follicular lymphoma is: first cycle with MabThera intravenous formulation 375 mg/m2 body surface area, followed by subsequent cycles with MabThera subcutaneous formulation injected at a fixed dose of 1400 mg per cycle for up to 8 cycles.

MabThera should be administered on Day 1 of each chemotherapy cycle, after administration of the glucocorticoid component of the chemotherapy if applicable.

Maintenance therapy
●
Previously untreated follicular lymphoma
The recommended dose of MabThera subcutaneous formulation used as a maintenance treatment for patients with previously untreated follicular lymphoma who have responded to induction treatment is:
1400 mg 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 administrations in total).

●
Relapsed/refractory follicular lymphoma
The recommended dose of MabThera subcutaneous formulation used as a maintenance treatment for patients with relapsed/refractory follicular lymphoma who have responded to induction treatment is:
1400 mg 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 administrations in total).

Diffuse large B-cell non-Hodgkin's lymphoma

MabThera should be used in combination with CHOP chemotherapy. The recommended dose is: first cycle, MabThera intravenous formulation: 375 mg/m2 body surface area, followed by subsequent cycles with MabThera subcutaneous formulation injected at a fixed dose of 1400 mg per cycle. In total: 8 cycles.

MabThera is administered on Day 1 of each chemotherapy cycle after intravenous infusion of the glucocorticoid component of CHOP.

Safety and efficacy of MabThera 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 MabThera are recommended. When MabThera is given in combination with chemotherapy, standard dose reductions for the chemotherapeutic medicinal products should be applied (see section 4.8).

Special populations

Paediatric population
The safety and efficacy of MabThera in children aged below 18 years has not been established. No data are available.

Elderly
No dose adjustment is required in patients aged 65 years and above.

Method of administration

Subcutaneous injections:
MabThera 1400 mg subcutaneous formulation should be administered as subcutaneous injection only, over approximately 5 minutes. The hypodermic injection needle must only be attached to the syringe immediately prior to administration to avoid potential needle clogging.

MabThera subcutaneous formulation should be injected subcutaneously into the abdominal wall and never into areas where the skin is red, bruised, tender, hard or areas where there are moles or scars.

No data are available on performing the injection in other sites of the body, therefore injections should be restricted to the abdominal wall.

During the treatment course with MabThera subcutaneous formulation, other medicinal products for subcutaneous administration should preferably be given at different sites.

If an injection is interrupted it can be resumed at the same site or another location may be used, if appropriate.

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

Premedication with glucocorticoids should be considered if MabThera is not given in combination with glucocorticoid-containing chemotherapy.

Posology

The recommended dose of MabThera subcutaneous formulation used for adult patients is a subcutaneous injection at a fixed dose of 1600 mg irrespective of the patient’s body surface area.

Before starting MabThera subcutaneous injections, all patients must always receive beforehand, a full dose of MabThera by intravenous infusion, using MabThera intravenous formulation (see section 4.4).

If patients were not able to receive one full MabThera intravenous infusion dose prior to the switch, they should continue the subsequent cycles with MabThera intravenous formulation until a full intravenous dose is successfully administered. Therefore, the switch to MabThera subcutaneous formulation can only occur at the second or subsequent cycles of treatment.

It is important to check the medicinal product labels to ensure that the appropriate formulation (intravenous or subcutaneous formulation) and strength is being given to the patient, as prescribed.

MabThera subcutaneous formulation is not intended for intravenous administration and should be given via subcutaneous injection only. The 1600 mg strength is intended for subcutaneous use in CLL only.

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 x 109/L it is recommended to administer prednisone/prednisolone 100 mg intravenous shortly before administration with MabThera to decrease the rate and severity of acute infusion reactions and/or cytokine release syndrome.

The recommended dosage of MabThera in combination with chemotherapy for previously untreated and relapsed/refractory patients is: MabThera intravenous formulation 375 mg/m2 body surface area administered on Day 0 of the first cycle of treatment followed by MabThera subcutaneous formulation injected at a fixed dose of 1600 mg per cycle, on Day 1 of each subsequent cycle (in total: 6 cycles).
The chemotherapy should be given after MabThera administration.

Dose adjustments during treatment

No dose reductions of MabThera are recommended. When MabThera is given in combination with chemotherapy, standard dose reductions for the chemotherapeutic medicinal products should be applied (see section 4.8).

Special populations

Paediatric population
The safety and efficacy of MabThera in children aged below 18 years has not been established. No data are available.

Elderly
No dose adjustment is required in elderly patients (aged 65 years and above).

Method of administration

Subcutaneous injections
MabThera 1600 mg subcutaneous formulation should be administered as subcutaneous injection only, over approximately 7 minutes. The hypodermic injection needle must only be attached to the syringe immediately prior to administration to avoid potential needle clogging.

MabThera subcutaneous formulation should be injected subcutaneously into the abdominal wall and never into areas where the skin is red, bruised, tender, hard or areas where there are moles or scars.

No data are available on performing the injection in other sites of the body, therefore injections should be restricted to the abdominal wall.

During the treatment course with MabThera subcutaneous formulation, other medicinal products for subcutaneous administration should preferably be given at different sites.

If an injection is interrupted it can be resumed at the same site or another location may be used, if appropriate.

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

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

Active, severe infections (see section 4.4).

Patients in a severely immunocompromised state.

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

Summary of the safety profile

The overall safety profile of MabThera 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 MabThera monotherapy (as induction treatment or maintenance treatment following induction treatment) or in combination with chemotherapy.

The most frequently observed adverse reactions in patients receiving MabThera 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 MabThera.

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

The most frequently reported or observed serious adverse reactions were:
- IRRs (including cytokine-release syndrome, tumour-lysis syndrome), see section 4.4.
- Infections, see section 4.4.
- Cardiovascular events, see section 4.4.

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

Tabulated list of adverse reactions

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

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

Table 3
Adverse reactions reported in clinical trials or during post-marketing surveillance in patients with NHL and CLL disease treated with MabThera 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,
+bronchitis sepsis,
+pneumonia,
+febrile infection,
+herpes zoster,
+respiratory tract infection, fungal infections, infections of unknown aetiology, +acute bronchitis, +sinusitis, hepatitis B1 serious viral infection2, pneumocystis jirovecii pneumonia progressive multifocal leukoencephalopa thy enteroviral meningoencephalit is2, 3 Blood and lymphatic system disorders neutropenia, leucopenia, +febrile neutropenia, +thrombocytope nia anaemia, +pancytopenia, +granulocytopeni a coagulation disorders, aplastic anaemia, haemolytic anaemia, lymphadenopathy transient increase in serum IgM levels4 late neutropenia4 Immune system disorders infusion-related reactions5, angioedema hypersensitivity anaphylaxis tumour lysis syndrome, cytokine release syndrome5, serum sickness infusion-related acute reversible thrombocytopeni a5 Metabolism and nutrition disorders

hyperglycaemia, weight decrease, oedema peripheral, face oedema, increased LDH, hypocalcaemia

Psychiatric disorders

depression, nervousness

Nervous system disorders

paraesthesia, hypoaesthesia, agitation, insomnia, vasodilatation, dizziness, anxiety dysgeusia

peripheral neuropathy, facial nerve palsy6 cranial neuropathy, loss of other senses6 Eye disorders

lacrimation disorder, conjunctivitis

severe vision loss6

Ear and labyrinth disorders

tinnitus, ear pain

hearing loss6

MedDRA

System Organ
Class

Very Common

Common

Uncommon

Rare

Very Rare

Not known
Cardiac disorders
+myocardial infarction5, 7, arrhythmia,
+atrial fibrillation, tachycardia,
+cardiac disorder
+left ventricular failure,
+supraventricular tachycardia,
+ventricular tachycardia,
+angina,
+myocardial ischaemia, bradycardia severe cardiac disorders5, 7 heart failure5, 7

Vascular disorders

hypertension, orthostatic hypotension, hypotension

vasculitis
(predominately cutaneous), leukocytoclastic vasculitis

Respiratory, thoracic and mediastinal disorders

bronchospasm5, respiratory disease, chest pain, dyspnoea, increased cough, rhinitis asthma, bronchiolitis obliterans, lung disorder, hypoxia interstitial lung disease8 respiratory failure5 lung infiltration Gastrointestinal disorders nausea vomiting, diarrhoea, abdominal pain, dysphagia, stomatitis, constipation, dyspepsia, anorexia, throat irritation abdominal enlargement

gastro-intestinal perforation8

Skin and subcutaneous tissue disorders pruritus, rash,
+alopecia urticaria, sweating, night sweats,
+skin disorder

severe bullous skin reactions,
Stevens-Johnson syndrome, toxic epidermal necrolysis
(Lyell’s syndrome)8

Musculoskeletal and connective tissue disorders

hypertonia, myalgia, arthralgia, back pain, neck pain, pain

Renal and urinary disorders

renal failure5

General disorders and administration site conditions fever, chills, asthenia, headache tumour pain, flushing, malaise, cold syndrome, +fatigue, +shivering, +multi-organ failure5 infusion site pain

Investigations decreased IgG levels

MedDRA

System Organ
Class

Very Common

Common

Uncommon

Rare

Very Rare

Not known
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 observed during post-marketing surveillance 4 see also section haematologic adverse reactions below 5 see also section infusion-related reactions below. Rarely fatal cases reported 6 signs and symptoms of cranial neuropathy. Occurred at various times up to several months after completion of MabThera therapy 7 observed mainly in patients with prior cardiac condition and/or cardiotoxic chemotherapy and were mostly associated with infusion-related reactions 8 includes fatal cases

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

Signs and symptoms suggestive of an infusion-related reaction were reported in more than 50% of patients in clinical trials, and were predominantly seen during the first infusion, usually in the first one to two hours. These symptoms mainly comprised fever, chills and rigors. Other symptoms included flushing, angioedema, bronchospasm, vomiting, nausea, urticaria/rash, fatigue, headache, throat irritation, rhinitis, pruritus, pain, tachycardia, hypertension, hypotension, dyspnoea, dyspepsia, asthenia and features of tumour lysis syndrome. Severe infusion-related reactions (such as bronchospasm, hypotension) occurred in up to 12% of the cases. Additional reactions reported in some cases were myocardial infarction, atrial fibrillation, pulmonary oedema and acute reversible thrombocytopenia.
Exacerbations of pre-existing cardiac conditions such as angina pectoris or congestive heart failure or severe cardiac disorders (heart failure, myocardial infarction, atrial fibrillation), pulmonary oedema, multi-organ failure, tumour lysis syndrome, cytokine release syndrome, renal failure, and respiratory failure were reported at lower or unknown frequencies. The incidence of infusion-related symptoms decreased substantially with subsequent infusions and is < 1% of patients by the eighth cycle of MabThera (containing) treatment.

Description of selected adverse reactions

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

Localised candida infections as well as Herpes zoster were reported at a higher incidence in the MabThera-containing arm of randomised studies. Severe infections were reported in about 4% of patients treated with MabThera monotherapy. Higher frequencies of infections overall, including grade 3 or 4 infections, were observed during MabThera maintenance treatment up to 2 years when compared to observation. There was no cumulative toxicity in terms of infections reported over a 2-year treatment period. In addition, other serious viral infections either new, reactivated or exacerbated, some of which were fatal, have been reported with MabThera treatment. The majority of patients had received MabThera in combination with chemotherapy or as part of a haematopoetic stem cell transplant. Examples of these serious viral infections are infections caused by the herpes viruses (Cytomegalovirus, Varicella Zoster Virus and Herpes Simplex Virus), JC virus (progressive multifocal leukoencephalopathy (PML)), enterovirus (meningoencephalitis) and hepatitis C virus (see section 4.4.). Cases of fatal PML that occurred after disease progression and retreatment have also been reported in clinical trials. Cases of hepatitis B reactivation, have been reported, the majority of which were in patients receiving MabThera in combination with cytotoxic chemotherapy. In patients with relapsed/refractory CLL, the incidence of grade 3/4 hepatitis B infection (reactivation and primary infection) was 2% in R-FC vs 0% FC. Progression of Kaposi’s sarcoma has been observed in

MabThera-exposed patients with pre-existing Kaposi’s sarcoma. These cases occurred in non-approved indications and the majority of patients were HIV positive.

Haematologic adverse reactions
In clinical trials with MabThera monotherapy given for 4 weeks, haematological abnormalities occurred in a minority of patients and were usually mild and reversible. Severe (grade 3/4) neutropenia was reported in 4.2%, anaemia in 1.1% and thrombocytopenia in 1.7% of the patients. During MabThera maintenance treatment for up to 2 years, leucopenia (5% vs. 2%, grade 3/4) and neutropenia (10% vs.
4%, grade 3/4) were reported at a higher incidence when compared to observation. The incidence of thrombocytopenia was low (<1%, grade 3/4) and was not different between treatment arms. During the treatment course in studies with MabThera in combination with chemotherapy, grade 3/4 leucopenia (R-CHOP 88% vs. CHOP 79%, R-FC 23% vs. FC 12%), neutropenia (R-CVP 24% vs. CVP 14%;
R-CHOP 97% vs. CHOP 88%, R-FC 30% vs. FC 19% in previously untreated CLL), pancytopenia (R-FC 3% vs. FC 1% in previously untreated CLL) were usually reported with higher frequencies when compared to chemotherapy alone. However, the higher incidence of neutropenia in patients treated with MabThera and chemotherapy was not associated with a higher incidence of infections and infestations compared to patients treated with chemotherapy alone. Studies in previously untreated and relapsed/refractory CLL have established that in up to 25% of patients treated with R-FC neutropenia was prolonged (defined as neutrophil count remaining below 1x109/L between Day 24 and 42 after the last dose) or occurred with a late onset (defined as neutrophil count below 1x109/L later than 42 days after last dose in patients with no previous prolonged neutropenia or who recovered prior to Day 42) following treatment with MabThera plus FC. There were no differences reported for the incidence of anaemia. Some cases of late neutropenia occurring more than four weeks after the last infusion of MabThera were reported. In the CLL first-line study, Binet stage C patients experienced more adverse events in the R-FC arm compared to the FC arm (R-FC 83% vs. FC 71%). In the relapsed/refractory CLL study grade 3/4 thrombocytopenia was reported in 11% of patients in the R-FC group compared to 9% of patients in the FC group.

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

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

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

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

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

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

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

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

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

Patient subpopulations - MabThera monotherapy
Elderly (65 years and above):
The incidence of adverse reactions of all grades and grade 3/4 adverse reactions was similar in elderly patients compared to younger patients (below 65 years).

Bulky disease
There was a higher incidence of grade 3/4 adverse reactions in patients with bulky disease than in patients without bulky disease (25.6% vs. 15.4%). The incidence of adverse reactions of any grade was similar in these two groups.

Re-treatment
The percentage of patients reporting adverse reactions upon re-treatment with further courses of MabThera was similar to the percentage of patients reporting adverse reactions upon initial exposure (any grade and grade 3/4 adverse reactions).

Patient subpopulations - MabThera combination therapy
Elderly (65 years and above)
The incidence of grade 3/4 blood and lymphatic adverse events was higher in elderly patients compared to younger patients (below 65 years), with previously untreated or relapsed/refractory CLL.

Experience from paediatric DLBCL/BL/BAL/BLL

Summary of the safety profile

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

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

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

Experience from rheumatoid arthritis

Summary of the safety profile

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

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

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

Tabulated list of adverse reactions

Adverse reactions are listed in Table 4. Frequencies are defined as very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1 000 to < 1/100), rare (≥ 1/10 000 to < 1/1 000), 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 adverse reactions identified only during post marketing surveillance, and for which a frequency could not be estimated, are listed under “not known”, see footnotes.

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

Table 4
Summary of adverse reactions reported in clinical trials or during post-marketing surveillance occurring in patients with rheumatoid arthritis receiving MabThera MedDRA System Organ Class Very Common Common Uncommon Rare Very rare Not known Infections and infestations upper respiratory tract infection, urinary tract infections bronchitis, sinusitis, gastroenteritis, tinea pedis progressive multifocal leukoencephalo pathy, reactivation of hepatitis B serious viral infection1, 2, enteroviral meningoencephal itis2 Blood and lymphatic system disorders neutropenia3 late neutropenia4 serum sickness-like reaction

Immune system disorders
5infusion-related reactions
(hypertension, nausea, rash, pyrexia, pruritus, urticaria, throat irritation, hot flush, hypotension, rhinitis, rigors, tachycardia, fatigue, oropharyngeal pain, oedema peripheral, erythema) 5infusion-related reactions (generalised oedema, bronchospasm, wheezing, laryngeal oedema, angioneurotic oedema, generalised pruritus, anaphylaxis, anaphylactoid reaction) General disorders and administration site conditions Metabolism and nutrition disorders hyper- cholesterolemia Psychiatric disorders depression, anxiety Nervous system disorders headache paraesthesia, migraine, dizziness, sciatica Cardiac disorders

angina pectoris, atrial fibrillation, heart failure, myocardial infarction atrial flutter Gastrointestinal disorders

dyspepsia, diarrhoea, gastro- oesophageal reflux, mouth ulceration, upper abdominal pain Skin and subcutaneous tissue disorders

alopecia toxic epidermal necrolysis
(Lyell’s syndrome),
Stevens-
Johnson syndrome7
Musculoskeletal disorders and connective tissue disorders

arthralgia / musculoskeletal pain, osteoarthritis, bursitis

MedDRA System
Organ Class
Very Common
Common
Uncommon
Rare
Very rare
Not known
Investigations decreased IgM levels6 decreased IgG levels6

1 See also section infections below.
2 Observed during post-marketing surveillance
3 Frequency category derived from laboratory values collected as part of routine laboratory monitoring in clinical trials 4 Frequency category derived from post-marketing data.
5 Reactions occurring during or within 24 hours of infusion. See also infusion-related reactions below. IRRs may occur as a result of hypersensitivity and/or to the mechanism of action.
6 Includes observations collected as part of routine laboratory monitoring.
7 Includes fatal cases

Multiple courses
Multiple courses of treatment are associated with a similar adverse reaction profile to that observed following first exposure. The rate of all adverse reactions following first MabThera exposure was highest during the first 6 months and declined thereafter. This is mostly accounted for by IRRs (most frequent during the first treatment course), RA exacerbation and infections, all of which were more frequent in the first 6 months of treatment.

Description of selected adverse reactions

Infusion-related reactions
The most frequent adverse reactions following receipt of MabThera in clinical studies were IRRs (refer to Table 4). Among the 3 189 patients treated with MabThera, 1 135 (36%) experienced at least one IRR with 733/3 189 (23%) of patients experiencing an IRR following first infusion of the first exposure to MabThera. The incidence of IRRs declined with subsequent infusions. In clinical trials fewer than 1% (17/3 189) of patients experienced a serious IRR. There were no CTC Grade 4 IRRs and no deaths due to IRRs in the clinical trials. The proportion of CTC Grade 3 events and of IRRs leading to withdrawal decreased by course and were rare from course 3 onwards. Premedication with intravenous glucocorticoid significantly reduced the incidence and severity of IRRs (see sections 4.2 and 4.4). Severe IRRs with fatal outcome have been reported in the post-marketing setting.

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

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

In the post marketing setting, serious viral infections have been reported in RA patients treated with rituximab.

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

In patients with non-Hodgkin’s lymphoma receiving MabThera in combination with cytotoxic chemotherapy, cases of hepatitis B reactivation have been reported (see non-Hodgkin’s lymphoma).

Reactivation of hepatitis B infection has also been very rarely reported in RA patients receiving MabThera (see Section 4.4).

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

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

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

In placebo-controlled periods of clinical trials, 0.94% (13/1 382) of MabThera treated patients and 0.27% (2/731) of placebo patients developed severe neutropenia.

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

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

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

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

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

The overall safety profile of MabThera in adult and paediatric GPA/MPA patients is based on data from patients from 3 clinical trials and from post-marketing surveillance.

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

The adverse reactions from GPA/MPA Study 1 listed in Table 5 with a frequency categorisation of "common" or "very common" were all adverse events which occurred at an incidence of ≥ 5% in the MabThera group and at a higher frequency than the comparator group.

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

Table 5
Adverse reactions occurring at 6-months in ≥ 5% of adult patients receiving
MabThera in GPA/MPA Study 1 (Rituximab n=99), at a higher frequency than the comparator group, or during post-marketing surveillance

MedDRA System Organ Class
Very Common
Common
Not known
Infections and infestations

urinary tract infection, bronchitis, herpes zoster, nasopharyngitis serious viral infection1,2, enteroviral meningoencephalitis1 Blood and lymphatic system disorders

thrombocytopenia

Immune system disorders

cytokine release syndrome

Metabolism and nutrition disorders

hyperkalaemia

Psychiatric disorders insomnia

Nervous system disorders dizziness, tremor

Vascular disorders hypertension flushing

Respiratory, thoracic and mediastinal disorders cough, dyspnoea, epistaxis nasal congestion

Gastrointestinal disorders diarrhoea dyspepsia, constipation

Skin and subcutaneous tissue disorders

acne

Musculoskeletal and connective tissue disorders muscle spasms, arthralgia, back pain muscle weakness, musculoskeletal pain, pain in extremities

General disorders and administration site conditions oedema peripheral

Investigations

decreased haemoglobin

1 Observed during post-marketing surveillance.
2 See also section infections below.

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

Table 6
Adverse reactions occurring in ≥ 5% of adult patients receiving MabThera in
GPA/MPA Study 2 (Rituximab n=57), at a higher frequency than the comparator group, or during post-marketing surveillance

MedDRA System Organ
Class
Very Common
Common
Not known
Infections and infestations bronchitis rhinitis serious viral infection1,2, enteroviral meningoencephalitis1 Respiratory, thoracic and mediastinal disorders

dyspnoea

Gastrointestinal disorders

diarrhoea

General disorders and administration site conditions

pyrexia, influenza-like illness, oedema peripheral

Injury, poisoning and procedural complications infusion-related reactions3

1 Observed during post-marketing surveillance.
2 See also section infections below.
3 Details on infusion-related reactions are provided in the description of selected adverse reactions section.

The overall safety profile was consistent with the well-established safety profile for MabThera in approved autoimmune indications, including GPA/MPA. Overall, 4% of patients in the MabThera arm

experienced adverse events leading to discontinuation. Most adverse events in the MabThera arm were mild or moderate in intensity. No patients in the MabThera arm had fatal adverse events.

The most commonly reported events considered as adverse reactions were infusion-related reactions and infections.

Long-term follow-up (GPA/MPA Study 3)
In a long-term observational safety study, 97 GPA/MPA patients received treatment with MabThera (mean of 8 infusions [range 1-28]) for up to 4 years, according to their physician’s standard practice and discretion. The overall safety profile was consistent with the well-established safety profile of MabThera in RA and GPA/MPA and no new adverse reactions were reported.

Paediatric population
An open-label, single arm study was conducted in 25 paediatric patients with severe, active GPA or MPA. The overall study period consisted of a 6-month remission induction phase with a minimum 18-month follow-up, up to 4.5 years overall. During the follow-up phase, MabThera was given at the discretion of the investigator (17 out of 25 patients received additional MabThera treatment).
Concomitant treatment with other immunosuppressive therapy was permitted (see section 5.1).

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

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

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

Description of selected adverse reactions

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

In GPA/MPA Study 2 (adult maintenance study), 7/57 (12%) patients in the MabThera arm experienced at least one infusion-related reaction. The incidence of IRR symptoms was highest during or after the first infusion (9%) and decreased with subsequent infusions (< 4%). All IRR symptoms were mild or moderate and most of them were reported from the SOCs Respiratory, Thoracic and Mediastinal Disorders and Skin and Subcutaneous Tissue disorders.

In the clinical trial in paediatric patients with GPA or MPA, the reported IRRs were predominantly seen with the first infusion (8 patients [32%]), and then decreased over time with the number of MabThera infusions (20% with the second infusion, 12% with the third infusion and 8% with the fourth infusion).
The most common IRR symptoms reported during the remission induction phase were: headache, rash, rhinorrhoea and pyrexia (8%, for each symptom). The observed symptoms of IRRs were similar to those known in adult GPA or MPA patients treated with MabThera. The majority of IRRs were Grade 1 and Grade 2, there were two non-serious Grade 3 IRRs, and no Grade 4 or 5 IRRs reported. One serious Grade 2 IRR (generalised oedema which resolved with treatment) was reported in one patient (see section 4.4).

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

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

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

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

In the post marketing setting, serious viral infections have been reported in GPA/MPA patients treated with rituximab.

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

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

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

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

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

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

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

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

In the paediatric clinical trial, during the overall study period, 3/25 (12%) patients reported an event of hypogammaglobulinaemia, 18 patients (72%) had prolonged (defined as Ig levels below lower limit of normal for at least 4 months) low IgG levels (of whom 15 patients also had prolonged low IgM).

Three patients received treatment with intravenous immunoglobulin (IV-IG). Based on limited data, no firm conclusions can be drawn regarding whether prolonged low IgG and IgM led to an increased risk of serious infection in these patients. The consequences of long term B-cell depletion in paediatric patients are unknown.

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

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

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

Experience from pemphigus vulgaris
The overall safety profile of MabThera in pemphigus vulgaris is based on data from patients from 2 clinical trials and from post-marketing surveillance.

Summary of the safety profile in PV Study 1 (Study ML22196) and PV Study 2 (Study WA29330)

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

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

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

Tabulated list of adverse reactions for PV Studies 1 and 2, or during post-marketing surveillance

The adverse reactions from PV Studies 1 and 2 with a frequency categorisation of "common" or "very common" are presented in Table 7. In PV Study 1, adverse reactions were defined as adverse events which occurred at a rate of ≥ 5% among MabThera-treated PV patients, with a ≥ 2% absolute difference in incidence between the MabThera-treated group and the standard-dose prednisone group up to Month 24. No patients were withdrawn due to adverse reactions in Study 1. In PV Study 2, adverse reactions were defined as adverse events occurring in ≥ 5% of patients in the MabThera arm and assessed as related.

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

Table 7
Adverse reactions in MabThera-treated pemphigus vulgaris patients in PV Study 1
(up to Month 24) and PV Study 2 (up to Week 52), or during post-marketing surveillance MedDRA System Organ Class Very Common Common Not known Infections and infestations upper respiratory tract infection herpes virus infection, herpes zoster, oral herpes, conjunctivitis, nasopharyngitis, oral candidiasis, urinary tract infection serious viral infection1, 2, enteroviral meningoencephalitis1 Neoplasms benign, malignant and unspecified (incl cysts and polyps) skin papilloma

Psychiatric disorders persistent depressive disorder major depression, irritability

Nervous system disorders headache dizziness

Cardiac disorders tachycardia

Gastrointestinal disorders abdominal pain upper

Skin and subcutaneous tissue disorders alopecia pruritus, urticaria, skin disorder

Musculoskeletal and connective tissue disorders musculoskeletal pain, arthralgia, back pain

General disorders and administration site conditions fatigue, asthenia, pyrexia

Injury, poisoning and procedural complications infusion-related reactions3
1 Observed during post-marketing surveillance.
2 See also section infections below.
3 Infusion-related reactions for PV Study 1 included symptoms collected on the next scheduled visit after each infusion, and adverse reactions occurring on the day of or one day after the infusion. The most common infusion-related reaction symptoms/Preferred Terms for PV Study 1 included headaches, chills, high blood pressure, nausea, asthenia and pain.
The most common infusion-related reaction symptoms/Preferred Terms for PV Study 2 were dyspnoea, erythema, hyperhidrosis, flushing/hot flush, hypotension/low blood pressure and rash/rash pruritic.

Description of selected adverse reactions

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

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

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

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

In the post marketing setting, serious viral infections have been reported in PV patients treated with rituximab.

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

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

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

The information provided in this section pertains to the use of MabThera in oncology.
For information related to the autoimmune indications, please refer to the SmPC of MabThera intravenous formulation.

Summary of the safety profile

During the development programme, the safety profile of MabThera subcutaneous formulation was comparable to that of the intravenous formulation with the exception of local cutaneous reactions.
Local cutaneous reactions, including injection site reactions were very common in patients receiving MabThera subcutaneous formulation. In the phase 3 SABRINA trial (BO22334), local cutaneous reactions were reported in up to 20% of patients receiving subcutaneous MabThera. The most common local cutaneous reactions in the MabThera subcutaneous arm were injection erythema (13%), injection pain (7%) and injection site oedema (4%). Events seen following subcutaneous administration were mild or moderate, apart from one patient who reported a local cutaneous reaction of Grade 3 intensity (injection site rash) following the first MabThera subcutaneous administration (Cycle 2). Local cutaneous reactions of any grade in the MabThera subcutaneous arm were most common during the first subcutaneous cycle (Cycle 2), followed by the second, and the incidence decreased with subsequent injections.

Adverse reactions reported in MabThera subcutaneous formulation usage

The risk of acute administration-related reactions associated with the subcutaneous formulation of MabThera was assessed in two open-label trials involving patients with follicular lymphoma during induction and maintenance (SABRINA/BO22334) and during maintenance only (SparkThera/BP22333). In SABRINA, severe administration-related reactions (grade ≥ 3) were reported in two patients (2%) following administration of MabThera subcutaneous formulation. These events were Grade 3 injection site rash and dry mouth. In SparkThera, no severe administration-related reactions were reported.

Adverse reactions reported in MabThera intravenous formulation usage

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

The overall safety profile of MabThera 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 MabThera monotherapy (as induction treatment or maintenance treatment following induction treatment) or in combination with chemotherapy.

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

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 trial in patients with CLL.

The most frequent reported or observed serious adverse reactions were:
●
Infusion-related reactions (including cytokine-release syndrome, tumour-lysis syndrome), see section 4.4.
●
Infections, see section 4.4.
●
Cardiovascular disorders, see section 4.4.

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

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

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

Tabulated list of adverse reactions

Table 1
Adverse reactions reported in clinical trials or during post-marketing surveillance in patients with NHL and CLL disease treated with MabThera 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, +bronchitis sepsis, +pneumonia, +febrile infection, +herpes zoster, +respiratory tract infection, fungal infections, infections of unknown aetiology, +acute bronchitis, +sinusitis, hepatitis B1 serious viral infection2, pneumocystis jirovecii pneumonia progressive multifocal leukoencephalopat hy enteroviral meningoencephal itis2,3

MedDRA
System Organ
Class
Very
Common
Common
Uncommon
Rare
Very Rare
Not known
Blood and lymphatic system disorders neutropenia, leucopenia,
+febrile neutropenia,
+thrombocytopeni a anaemia,
+pancytopenia,
+granulocytopeni a coagulation disorders, aplastic anaemia, haemolytic anaemia, lymphadenopathy transient increase in serum IgM levels4 late neutropenia4 Immune system disorders Infusion-related reactions5, angioedema hypersensitivity anaphylaxis tumour lysis syndrome, cytokine release syndrome5, serum sickness infusion-related acute reversible thrombocytopeni a5 Metabolism and nutrition disorders hyperglycaemia, weight decrease, oedema peripheral, face oedema, increased LDH, hypocalcaemia Psychiatric disorders depression, nervousness, Nervous system disorders paraesthesia, hypoaesthesia, agitation, insomnia, vasodilatation, dizziness, anxiety dysgeusia peripheral neuropathy, facial nerve palsy6 cranial neuropathy, loss of other senses6 Eye disorders lacrimation disorder, conjunctivitis severe vision loss6 Ear and labyrinth disorders tinnitus, ear pain hearing loss6 Cardiac disorders +myocardial infarction5, 7, arrhythmia, +atrial fibrillation, tachycardia, +cardiac disorder +left ventricular failure, +supraventricular tachycardia, +ventricular tachycardia, +angina, +myocardial ischaemia, bradycardia severe cardiac disorders5, 7 heart failure5, 7 Vascular disorders hypertension, orthostatic hypotension, hypotension vasculitis (predominately cutaneous), leukocytoclastic vasculitis Respiratory, thoracic and mediastinal disorders bronchospasm5, respiratory disease, chest pain, dyspnoea, increased cough, rhinitis asthma, bronchiolitis obliterans, lung disorder, hypoxia interstitial lung disease8 respiratory failure5 lung infiltration

MedDRA
System Organ
Class
Very
Common
Common
Uncommon
Rare
Very Rare
Not known
Gastrointestinal disorders nausea vomiting, diarrhoea, abdominal pain, dysphagia, stomatitis, constipation, dyspepsia, anorexia, throat irritation abdominal enlargement gastro-intestinal perforation8 Skin and subcutaneous tissue disorders pruritis, rash, +alopecia urticaria, sweating, night sweats, +skin disorder severe bullous skin reactions, Stevens-Johns on Syndrome, toxic epidermal necrolysis (Lyell’s Syndrome)8 Musculoskeletal and connective tissue disorders hypertonia, myalgia, arthralgia, back pain, neck pain, pain Renal and urinary disorders renal failure5 General disorders and administration site conditions fever, chills, asthenia, headache tumour pain, flushing, malaise, cold syndrome, +fatigue, +shivering, +multi-organ failure5 infusion site pain Investigations decreased IgG levels For each term, the frequency count was based on reactions of all grades (from mild to severe), except for terms marked with "+" where the frequency count was based only on severe (≥ grade 3 NCI common toxicity criteria) reactions. Only the highest frequency observed in the trials is reported 1 includes reactivation and primary infections; frequency based on R-FC regimen in relapsed/refractory CLL 2 see also section infection below 3 observed during post-marketing surveillance 4 see also section haematologic adverse reactions below 5 see also section infusion-related reactions below. Rarely fatal cases reported 6 signs and symptoms of cranial neuropathy. Occurred at various times up to several months after completion of MabThera therapy 7 observed mainly in patients with prior cardiac condition and/or cardiotoxic chemotherapy and were mostly associated with infusion-related reactions 8 includes fatal cases

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

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

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

Description of selected adverse reactions

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

Localised candida infections as well as Herpes zoster were reported at a higher incidence in the MabThera-containing arm of randomised studies. Severe infections were reported in about 4% of patients treated with MabThera monotherapy. Higher frequencies of infections overall, including grade 3 or 4 infections, were observed during MabThera maintenance treatment up to 2 years when compared to observation. There was no cumulative toxicity in terms of infections reported over a 2-year treatment period. In addition, other serious viral infections either new, reactivated or exacerbated, some of which were fatal, have been reported with MabThera treatment. The majority of patients had received MabThera in combination with chemotherapy or as part of a haematopoietic stem cell transplant. Examples of these serious viral infections are infections caused by the herpes viruses (Cytomegalovirus, Varicella Zoster Virus and Herpes Simplex Virus), JC virus (PML), enterovirus (meningoencephalitis) and hepatitis C virus (see section 4.4.). Cases of fatal PML that occurred after disease progression and retreatment have also been reported in clinical trials. Cases of hepatitis B reactivation, have been reported, the majority of which were in patients receiving MabThera in combination with cytotoxic chemotherapy. Progression of Kaposi’s sarcoma has been observed in MabThera-exposed patients with pre-existing Kaposi’s sarcoma. These cases occurred in non-approved indications and the majority of patients were HIV positive.

Haematologic adverse reactions
In clinical trials with MabThera monotherapy given for 4 weeks, haematological abnormalities occurred in a minority of patients and were usually mild and reversible. Severe (grade 3/4) neutropenia was reported in 4.2%, anaemia in 1.1% and thrombocytopenia in 1.7% of the patients. During MabThera maintenance treatment for up to 2 years, leucopoenia (5% vs. 2%, grade 3/4) and neutropenia (10% vs. 4%, grade 3/4) were reported at a higher incidence when compared to observation. The incidence of thrombocytopenia was low (< 1%, grade 3/4) and was not different between treatment arms. During the treatment course in studies with MabThera in combination with chemotherapy, grade 3/4 leucopoenia (R-CHOP 88% vs. CHOP 79%), neutropenia (R-CVP 24% vs.
CVP 14%; R-CHOP 97% vs. CHOP 88%), were usually reported with higher frequencies when compared to chemotherapy alone. However, the higher incidence of neutropenia in patients treated with MabThera and chemotherapy was not associated with a higher incidence of infections and infestations compared to patients treated with chemotherapy alone. There were no differences reported for the incidence of anaemia. Some cases of late neutropenia occurring more than four weeks after the last infusion of MabThera were reported.

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

Cardiovascular adverse reactions
Cardiovascular reactions during clinical trials with MabThera monotherapy were reported in 18.8% of patients with the most frequently reported events being hypotension and hypertension. Cases of grade 3 or 4 arrhythmia (including ventricular and supraventricular tachycardia) and angina pectoris during infusion were reported. During maintenance treatment, the incidence of grade 3/4 cardiac disorders

was comparable between patients treated with MabThera and observation. Cardiac events were reported as serious adverse reactions (including atrial fibrillation, myocardial infarction, left ventricular failure, myocardial ischemia) in 3% of patients treated with MabThera compared to < 1% on observation. In studies evaluating MabThera in combination with chemotherapy, the incidence of grade 3 and 4 cardiac arrhythmias, predominantly supraventricular arrhythmias such as tachycardia and atrial flutter/fibrillation, was higher in the R-CHOP group (14 patients, 6.9%) as compared to the CHOP group (3 patients, 1.5%). All of these arrhythmias either occurred in the context of a MabThera infusion or were associated with predisposing conditions such as fever, infection, acute myocardial infarction or pre-existing respiratory and cardiovascular disease. No difference between the R-CHOP and CHOP group was observed in the incidence of other grade 3 and 4 cardiac events including heart failure, myocardial disease and manifestations of coronary artery disease.

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

Neurologic disorders
During the treatment period (induction treatment phase comprising of R-CHOP for at most eight cycles), four patients (2%) treated with R-CHOP, all with cardiovascular risk factors, experienced thromboembolic cerebrovascular accidents during the first treatment cycle. There was no difference between the treatment groups in the incidence of other thromboembolic events. In contrast, three patients (1.5%) had cerebrovascular events in the CHOP group, all of which occurred during the follow-up period.

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

Gastrointestinal disorders
Gastrointestinal perforation in some cases leading to death has been observed in patients receiving MabThera for treatment of non-Hodgkin’s lymphoma (NHL). In the majority of these cases, MabThera was administered with chemotherapy.

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

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

Patient subpopulations - MabThera monotherapy
Elderly (65 years and above):
The incidence of adverse reactions of all grades and grade 3/4 adverse reactions was similar in elderly patients compared to younger patients (below 65 years).

Bulky disease:
There was a higher incidence of grade 3/4 adverse reactions in patients with bulky disease than in patients without bulky disease (25.6% vs. 15.4%). The incidence of adverse reactions of any grade was similar in these two groups.

Re-treatment:
The percentage of patients reporting adverse reactions upon re-treatment with further courses of MabThera was similar to the percentage of patients reporting adverse reactions upon initial exposure (any grade and grade 3/4 adverse reactions).

Reporting of suspected adverse reactions

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

The information provided in this section pertains to the use of MabThera in oncology.
For information related to the autoimmune indications, please refer to the SmPC of MabThera intravenous formulation.

Summary of the safety profile

During the development programme, the safety profile of MabThera subcutaneous formulation was comparable to that of the intravenous formulation with the exception of local cutaneous reactions.
Local cutaneous reactions including injection site reactions were very common in patients receiving MabThera subcutaneous formulation. In the NHL phase 3 trial SABRINA (BO22334), local cutaneous reactions were reported in up to 20% of patients receiving subcutaneous MabThera. The most common local cutaneous reactions in the MabThera subcutaneous arm were injection site erythema (13%), injection site pain (7%), and injection site oedema (4%). Events seen following subcutaneous administration were mild or moderate, apart from one patient who reported a local cutaneous reaction

of Grade 3 intensity (injection site rash) following the first MabThera subcutaneous administration (Cycle 2). Local cutaneous reactions of any grade in the MabThera subcutaneous arm were most common during the first subcutaneous cycle (Cycle 2), followed by the second, and the incidence decreased with subsequent injections. Similar events were observed in the CLL SAWYER trial (BO25341) and were reported in up to 42% of patients in the MabThera subcutaneous arm. Most common local cutaneous reactions were injection site erythema (26%), injection site pain (16%), and injection site swelling (5%). Two patients in SAWYER trial who experienced Grade 3 local cutaneous reactions (injection site erythema, injection site pain and injection site swelling).

Adverse reactions reported in MabThera subcutaneous formulation usage

The risk of acute administration-related reactions associated with the subcutaneous formulation of MabThera was assessed in three clinical trials: SparkThera and SABRINA (the two trials in NHL) and SAWYER the CLL trial.
In trial SABRINA, severe administration-related reactions (grade≥ 3) were reported in two patients (2%) following administration of MabThera subcutaneous formulation. These events were Grade 3 injection site rash and dry mouth.
In trial SparkThera, no severe administration-related reactions were reported.
In SAWYER (BO25341), severe administration--related reactions (Grade ≥ 3) were reported in four patients (5%) following MabThera subcutaneous administration. These events were Grade 4 thrombocytopenia and Grade 3 anxiety, injection-site erythema and urticaria.

Adverse reactions reported in MabThera intravenous formulation usage

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

The overall safety profile of MabThera 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 MabThera monotherapy (as induction treatment or maintenance treatment following induction treatment) or in combination with chemotherapy.

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

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 trial in patients with CLL.

The most frequent reported or observed serious adverse reactions were:
●
Infusion-related reactions (including cytokine-release syndrome, tumour-lysis syndrome), see section 4.4.
●
Infections, see section 4.4.
●
Cardiovascular disorders, see section 4.4.

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

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

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

Tabulated list of adverse reactions

Table 1
Adverse reactions reported in clinical trials or during post-marketing surveillance in patients with NHL and CLL disease treated with MabThera 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, +bronchitis sepsis, +pneumonia, +febrile infection, +herpes zoster, +respiratory tract infection, fungal infections, infections of unknown aetiology, +acute bronchitis, +sinusitis, hepatitis B1 serious viral infection2, pneumocystis jirovecii pneumonia

progressive multifocal leukoencephalopathy enteroviral meningoenceph alitis2, 3
Blood and lymphatic system disorders neutropenia, leucopenia,
+febrile neutropenia,
+thrombocyto penia anaemia,
+pancytopenia,
+granulocytopenia coagulation disorders, aplastic anaemia, haemolytic anaemia, lymphadenopat hy transient increase in serum IgM levels4 late neutropenia4 Immune system disorders infusion- related reactions5, angioedema hypersensitivity anaphylaxis tumour lysis syndrome, cytokine release syndrome5, serum sickness infusion-related acute reversible thrombocytope nia5 Metabolism and nutrition disorders hyperglycaemia, weight decrease, oedema peripheral, face oedema, increased LDH, hypocalcaemia Psychiatric disorders depression, nervousness Nervous system disorders paraesthesia, hypoaesthesia, agitation, insomnia, vasodilatation, dizziness, anxiety dysgeusia peripheral neuropathy, facial nerve palsy6 cranial neuropathy, loss of other senses6

MedDRA
System Organ
Class
Very
Common
Common
Uncommon
Rare
Very Rare
Not known
Eye disorders lacrimation disorder, conjunctivitis severe vision loss 6
Ear and labyrinth disorders tinnitus, ear pain hearing loss6
Cardiac disorders
+myocardial infarction5, 7, arrhythmia,
+atrial fibrillation, tachycardia,
+cardiac disorder
+left ventricular failure,
+supraventricul ar tachycardia,
+ventricular tachycardia,
+angina,
+myocardial ischaemia, bradycardia severe cardiac disorders5, 7

heart failure5, 7
Vascular disorders hypertension, orthostatic hypotension, hypotension vasculitis (predominately cutaneous), leukocytoclastic vasculitis Respiratory, thoracic and mediastinal disorders bronchospasm5, respiratory disease, chest pain, dyspnoea, increased cough, rhinitis asthma, bronchiolitis obliterans, lung disorder, hypoxia interstitial lung disease8 respiratory failure 5 lung infiltration Gastrointestinal disorders nausea vomiting, diarrhoea, abdominal pain, dysphagia, stomatitis, constipation, dyspepsia, anorexia, throat irritation abdominal enlargement gastro-intestinal perforation8 Skin and subcutaneous tissue disorders pruritis, rash, +alopecia urticaria, sweating, night sweats, +skin disorder severe bullous skin reactions, Stevens-Johns on Syndrome, toxic epidermal necrolysis (Lyell’s Syndrome)8 Musculoskeletal and connective tissue disorders hypertonia, myalgia, arthralgia, back pain, neck pain, pain Renal and urinary disorders renal failure5 General disorders and administration site conditions fever, chills, asthenia, headache tumour pain, flushing, malaise, cold syndrome, +fatigue, +shivering, infusion site pain

MedDRA
System Organ
Class
Very
Common
Common
Uncommon
Rare
Very Rare
Not known
+multi-organ failure5
Investigations decreased IgG levels
For each term, the frequency count was based on reactions of all grades (from mild to severe), except for terms marked with "+" where the frequency count was based only on severe (≥ grade 3 NCI common toxicity criteria). 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 observed during post-marketing surveillance 4 see also section haematologic adverse reactions below 5 see also section infusion-related reactions below. Rarely fatal cases reported 6 signs and symptoms of cranial neuropathy. Occurred at various times up to several months after completion of MabThera therapy 7 observed mainly in patients with prior cardiac condition and/or cardiotoxic chemotherapy and were mostly associated with infusion-related reactions 8 includes fatal cases

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

Signs and symptoms suggestive of an infusion-related reaction were reported in more than 50% of patients in clinical trials involving MabThera intravenous formulation, and were predominantly seen during the first infusion, usually in the first one to two hours. These symptoms mainly comprised fever, chills and rigors. Other symptoms included flushing, angioedema, bronchospasm, vomiting, nausea, urticaria/rash, fatigue, headache, throat irritation, rhinitis, pruritus, pain, tachycardia, hypertension, hypotension, dyspnoea, dyspepsia, asthenia and features of tumour lysis syndrome.
Severe infusion-related reactions (such as bronchospasm, hypotension) occurred in up to 12% of the cases. Additional reactions reported in some cases were myocardial infarction, atrial fibrillation, pulmonary oedema and acute reversible thrombocytopenia. Exacerbations of pre-existing cardiac conditions such as angina pectoris or congestive heart failure or severe cardiac disorders (heart failure, myocardial infarction, atrial fibrillation), pulmonary oedema, multi-organ failure, tumour lysis syndrome, cytokine release syndrome, renal failure, and respiratory failure were reported at lower or unknown frequencies. The incidence of infusion-related symptoms decreased substantially with subsequent intravenous infusions and is < 1% of patients by the eighth cycle of MabThera (containing) treatment.

Description of selected adverse reactions

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

Localised candida infections as well as Herpes zoster were reported at a higher incidence in the MabThera-containing arm of randomised studies. Severe infections were reported in about 4% of patients treated with MabThera monotherapy. Higher frequencies of infections overall, including grade 3 or 4 infections, were observed during MabThera maintenance treatment up to 2 years when compared to observation. There was no cumulative toxicity in terms of infections reported over a 2-year treatment period. In addition, other serious viral infections either new, reactivated or exacerbated, some of which were fatal, have been reported with MabThera treatment. The majority of patients had received MabThera in combination with chemotherapy or as part of a haematopoietic stem cell transplant. Examples of these serious viral infections are infections caused by the herpes

viruses (Cytomegalovirus, Varicella Zoster Virus and Herpes Simplex Virus), JC virus (PML), enterovirus (meningoencephalitis) and hepatitis C virus (see section 4.4.). Cases of fatal PML that occurred after disease progression and retreatment have also been reported in clinical trials. Cases of hepatitis B reactivation, have been reported, the majority of which were in patients receiving MabThera in combination with cytotoxic chemotherapy. In patients with relapsed/refractory CLL, the incidence of grade 3/4 hepatitis B infection (reactivation and primary infection) was 2% in R-FC vs 0% in FC. Progression of Kaposi’s sarcoma has been observed in MabThera-exposed patients with pre-existing Kaposi’s sarcoma. These cases occurred in non-approved indications and the majority of patients were HIV positive.

Haematologic adverse reactions
In clinical trials with MabThera monotherapy given for 4 weeks, haematological abnormalities occurred in a minority of patients and were usually mild and reversible. Severe (grade 3/4) neutropenia was reported in 4.2%, anaemia in 1.1% and thrombocytopenia in 1.7% of the patients. During MabThera maintenance treatment for up to 2 years, leucopoenia (5% vs. 2%, grade 3/4) and neutropenia (10% vs.
4%, grade 3/4) were reported at a higher incidence when compared to observation. The incidence of thrombocytopenia was low (< 1%, grade 3/4) and was not different between treatment arms. During the treatment course in studies with MabThera in combination with chemotherapy, grade 3/4 leucopoenia (R-CHOP 88% vs. CHOP 79%, R-FC 23% vs. FC 12%), grade 3/4 neutropenia (R-CVP 24% vs. CVP 14%; R-CHOP 97% vs. CHOP 88%, R-FC 30% vs. FC 19% in previously untreated CLL), grade 3/4 pancytopenia (R-FC 3% vs. FC 1% in previously untreated CLL) were usually reported with higher frequencies when compared to chemotherapy alone. However, the higher incidence of neutropenia in patients treated with MabThera and chemotherapy was not associated with a higher incidence of infections and infestations compared to patients treated with chemotherapy alone. Studies with MabThera intravenous formulation in previously untreated and relapsed/refractory CLL have established that in up to 25% of patients treated with R-FC neutropenia was prolonged (defined as neutrophil count remaining below 1x109/L between Day 24 and 42 after the last dose) or occurred with a late onset (defined as neutrophil count below 1x109/L later than 42 days after last dose in patients with no previous prolonged neutropenia or who recovered prior to Day 42) following treatment with MabThera plus FC. There were no differences reported for the incidence of anaemia. Some cases of late neutropenia occurring more than four weeks after the last infusion of MabThera were reported. In the CLL first-line study, Binet stage C patients experienced more adverse events in the R-FC arm compared to the FC arm (R-FC 83% vs. FC 71%). In the relapsed/refractory CLL study grade 3/4 thrombocytopenia was reported in 11% of patients in the R-FC group compared to 9% of patients in the FC group.

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

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

3 or 4 cardiac disorders was low both in the first-line study (4% R-FC, 3% FC) and in the relapsed/refractory study (4% R-FC, 4% FC).

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

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

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

Gastrointestinal disorders
Gastrointestinal perforation in some cases leading to death has been observed in patients receiving MabThera for treatment of non-Hodgkin’s lymphoma (NHL). In the majority of these cases, MabThera was administered with chemotherapy.

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

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

Patient subpopulations - MabThera monotherapy
Elderly (65 years and above):
The incidence of adverse reactions of all grades and grade 3/4 adverse reactions was similar in elderly patients compared to younger patients (below 65 years).

Bulky disease:
There was a higher incidence of grade 3/4 adverse reactions in patients with bulky disease than in patients without bulky disease (25.6% vs. 15.4%). The incidence of adverse reactions of any grade was similar in these two groups.

Re-treatment:
The percentage of patients reporting adverse reactions upon re-treatment with further courses of MabThera was similar to the percentage of patients reporting adverse reactions upon initial exposure (any grade and grade 3/4 adverse reactions).

Patient subpopulations - MabThera combination therapy
Elderly (65 years and above)

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

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

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

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

Very rare cases of fatal PML have been reported following use of MabThera for the treatment of rheumatoid arthritis and autoimmune diseases [including Systemic Lupus Erythematosus (SLE) and vasculitis] and during post-marketing use of MabThera in NHL and CLL (where the majority of patients had received MabThera in combination with chemotherapy or as part of haematopoietic stem

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

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

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

Cardiac disorders
Angina pectoris, cardiac arrhythmias such as atrial flutter and fibrillation, heart failure and/or myocardial infarction have occurred in patients treated with MabThera. Therefore, patients with a history of cardiac disease and/or cardiotoxic chemotherapy should be monitored closely (see infusion-related reactions, below).

Infections
Based on the mechanism of action of MabThera and the knowledge that B-cells play an important role in maintaining normal immune response, patients have an increased risk of infection following MabThera therapy (see section 5.1). Serious infections, including fatalities, can occur during therapy with MabThera (see section 4.8). MabThera 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 MabThera 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 MabThera.

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

For information on progressive multifocal leukoencephalopathy (PML) please see PML section above.

Cases of enteroviral meningoencephalitis including fatalities have been reported following use of rituximab.

Hepatitis B Infections
Cases of hepatitis B reactivation, including those with a fatal outcome, have been reported in patients receiving MabThera. The majority of these patients were also exposed to cytotoxic chemotherapy.
Limited information from one study in relapsed/refractory CLL patients suggests that MabThera 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 MabThera. 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 MabThera. 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.

False negative serologic testing of infections
Due to the risk of false negative serologic testing of infections, alternative diagnostic tools should be considered in case of patients presenting with symptoms indicative of rare infectious disease e.g. West Nile virus and neuroborreliosis.

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 MabThera, treatment should be permanently discontinued.

Non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia

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

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 x 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 x 109/L.

Infusion-related adverse reactions of all kinds have been observed in 77% of patients treated with MabThera (including cytokine release syndrome accompanied by hypotension and bronchospasm in 10% of patients) see section 4.8. These symptoms are usually reversible with interruption of MabThera infusion and administration of an anti-pyretic, an antihistaminic and occasionally oxygen,

intravenous saline or bronchodilators, and glucocorticoids if required. Please see cytokine release syndrome above for severe reactions.

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 MabThera.
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 MabThera administration, consideration should be given to withholding anti-hypertensive medicines 12 hours prior to the MabThera infusion.

Haematological toxicities
Although MabThera is not myelosuppressive in monotherapy, caution should be exercised when considering treatment of patients with neutrophils < 1.5 x 109/L and/or platelet counts < 75 x 109/L as clinical experience in this population is limited. MabThera 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 MabThera therapy.

Immunisations
The safety of immunisation with live viral vaccines, following MabThera therapy has not been studied for NHL and CLL patients and vaccination with live virus vaccines is not recommended. Patients treated with MabThera 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 MabThera monotherapy when compared to healthy untreated controls had a lower rate of response to vaccination with tetanus recall antigen (16% vs. 81%) and Keyhole Limpet Haemocyanin (KLH) neoantigen (4% vs. 76% when assessed for > 2-fold increase in antibody titre). For CLL patients, similar results are assumable considering similarities between both diseases but that has not been investigated in clinical trials.

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

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

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

Methotrexate (MTX) naïve populations with rheumatoid arthritis
The use of MabThera is not recommended in MTX-naïve patients since a favourable benefit risk relationship has not been established.

Infusion-related reactions
MabThera 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 MabThera 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 MabThera. 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 MabThera.

There are no data on the safety of MabThera in patients with moderate heart failure (NYHA class III) or severe, uncontrolled cardiovascular disease. In patients treated with MabThera, 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 MabThera and patients closely monitored during administration. Since hypotension may occur during MabThera infusion, consideration should be given to withholding anti-hypertensive medications 12 hours prior to the MabThera 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).

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

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

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

Patients treated with MabThera 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 MabThera 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 MabThera as compared to patients only receiving methotrexate. Should non-live vaccinations be required whilst receiving MabThera therapy, these should be completed at least 4 weeks prior to commencing the next course of MabThera.

In the overall experience of MabThera 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 MabThera 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 MabThera (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 MabThera, however patients should be closely observed for signs of infection if biologic agents and/or DMARDs are used following MabThera therapy.

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

Excipients
This medicinal product contains 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.

This medicine contains 7.0 mg of polysorbate 80 in each 10 mL vial, which is equivalent to 0.7 mg/mL and 35.0 mg of polysorbate 80 in each 50 mL vial, which is equivalent to 0.7 mg/mL.
Polysorbates may cause allergic reactions.

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

The information provided in the section 4.4 pertains to the use of MabThera subcutaneous formulation in the approved indications Treatment of non-Hodgkin’s lymphoma (strength 1400 mg) and Treatment of chronic lymphocytic leukaemia (strength 1600 mg). For information related to the other indications, please refer to the SmPC of MabThera intravenous formulation.

The use of MabThera subcutaneous formulation as monotherapy in patients with stage III-IV follicular lymphoma who are chemoresistant or are in their second or subsequent relapse after chemotherapy

cannot be recommended as the safety of the once weekly subcutaneous administration has not been established.

Progressive multifocal leukoencephalopathy

Use of MabThera may be associated with an increased risk of progressive multifocal leukoencephalopathy (PML). 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 MabThera must be permanently discontinued. Following reconstitution of the immune system in immunocompromised patients with PML, stabilisation or improved outcome has been seen. It remains unknown if early detection of PML and suspension of MabThera therapy may lead to similar stabilisation or improved outcome.

Infusion/Administration-related reactions

MabThera is associated with infusion/administration-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. They are not specifically related to the route of administration of MabThera and can be observed with both formulations.

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

Severe cytokine release syndrome is characterised by severe dyspnea, 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, hyperphosphaetemia, 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 x 109/L) of circulating malignant cells, 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 x 109/L.

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 MabThera.
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 MabThera administration, consideration should be given to withholding anti-hypertensive medicines 12 hours prior to giving MabThera.

Infusion-related adverse reactions of all kinds have been observed in 77% of patients treated with MabThera intravenous formulation (including cytokine release syndrome accompanied by hypotension and bronchospasm in 10% of patients) see section 4.8. These symptoms are usually reversible with interruption of MabThera infusion and administration of an anti-pyretic, an antihistaminic, and, occasionally, oxygen, intravenous saline or bronchodilators, and glucocorticoids if required. Please see cytokine release syndrome above for severe reactions.

Administration related reactions have been observed in up to 50% of patients treated with MabThera subcutaneous formulation in clinical trials. The reactions occurring within 24 hours of the subcutaneous injection consisted primarily of erythema pruritus, rash and injections site reactions such as pain, swelling and redness and were generally of mild or moderate (grade 1 or 2) and transient nature (see section 4.8).

Local cutaneous reactions were very common in patients receiving MabThera subcutaneous in clinical trials. Symptoms included pain, swelling, induration, haemorrhage, erythema, pruritus and rash (see section 4.8). Some local cutaneous reactions occurred more than 24 hours after the MabThera subcutaneous administration. The majority of local cutaneous reactions seen following administration of MabThera subcutaneous formulation was mild or moderate and resolved without any specific treatment.

Before starting MabThera subcutaneous injections, all patients must always receive beforehand, a full dose of MabThera by intravenous infusion, using MabThera intravenous formulation. The highest risk of experiencing an administration related reaction is generally observed at cycle one. Beginning the therapy with MabThera intravenous infusion would allow a better handling of the administration reactions by slowing or stopping the intravenous infusion.

If patients were not able to receive one full MabThera intravenous infusion dose prior to the switch, they should continue the subsequent cycles with MabThera intravenous formulation until a full intravenous dose is successfully administered. Therefore, the switch to MabThera subcutaneous formulation can only occur at the second or subsequent cycles of treatment.

As with the intravenous formulation, MabThera subcutaneous formulation should be administered in an environment where full resuscitation facilities are immediately available and under the close supervision of an experienced healthcare professional. Premedication consisting of an analgesic/antipyretic and an antihistamine should always be administered before each dose of MabThera subcutaneous formulation. Premedication with glucocorticoids should also be considered.

Patients should be observed for at least 15 minutes following MabThera subcutaneous administration.
A longer period may be appropriate in patients with an increased risk of hypersensitivity reactions.

Patients should be instructed to contact their treating physician immediately if symptoms that are suggestive of severe hypersensitivity or cytokine release syndrome occur at any time after medicinal product administration.

Cardiac disorders

Angina pectoris, cardiac arrhythmias such as atrial flutter and fibrillation, heart failure and/or myocardial infarction have occurred in patients treated with MabThera. Therefore, patients with a history of cardiac disease and/or cardiotoxic chemotherapy should be monitored closely.

Haematological toxicities

Although MabThera is not myelosuppressive in monotherapy, caution should be exercised when considering treatment of patients with neutrophils < 1.5 x 109/L and/or platelet counts < 75 x 109/L as clinical experience in this population is limited. MabThera 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 MabThera therapy.

Infections

Serious infections, including fatalities, can occur during therapy with MabThera (see section 4.8).
MabThera 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 MabThera in patients with a history of recurring or chronic infections or with underlying conditions which may further predispose patients to serious infection (see section 4.8).

Cases of hepatitis B reactivation have been reported in patients receiving MabThera including fulminant hepatitis with fatal outcome. The majority of these patients were also exposed to cytotoxic chemotherapy. Hepatitis B virus (HBV) screening should be performed in all patients before initiation of treatment with MabThera. 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 MabThera. 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 PML have been reported during post-marketing use of MabThera in NHL (see section 4.8). The majority of patients had received rituximab in combination with chemotherapy or as part of a haematopoietic stem cell transplant.

Cases of enteroviral meningoencephalitis including fatalities have been reported following use of rituximab.

False negative serologic testing of infections

Due to the risk of false negative serologic testing of infections, alternative diagnostic tools should be considered in case of patients presenting with symptoms indicative of rare infectious disease e.g. West Nile virus and neuroborreliosis.

Immunisation

The safety of immunisation with live viral vaccines, following MabThera therapy has not been studied for NHL patients and vaccination with live virus vaccines is not recommended. Patients treated with MabThera may receive non-live vaccinations; however, with non-live vaccines response rates may be reduced. In a non-randomised study, patients with relapsed low-grade NHL who received the MabThera intravenous formulation as 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. 69% when assessed for > 2-fold increase in antibody titre).

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

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 suspected relationship to MabThera, treatment should be permanently discontinued.

Excipients

This medicine contains 7.02 mg of polysorbate 80 in each 15 mL vial, which is equivalent to 0.6 mg/mL. Polysorbates may cause allergic reactions.

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

The information provided in the section 4.4 pertains to the use of MabThera subcutaneous formulation in the approved indications Treatment of non-Hodgkin’s lymphoma (strength 1400 mg) and Treatment of CLL (strength 1600 mg). For information related to the other indications, please refer to the SmPC of MabThera intravenous formulation.

Progressive multifocal leukoencephalopathy

Use of MabThera may be associated with an increased risk of progressive multifocal leukoencephalopathy (PML). 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 MabThera must be permanently discontinued. Following reconstitution of the immune system in immunocompromised patients with PML, stabilisation or improved outcome has been seen. It remains unknown if early detection of PML and suspension of MabThera therapy may lead to similar stabilisation or improved outcome.

Infusion/Administration-related reactions

MabThera is associated with infusion/administration-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. They are not specifically related to the route of administration of MabThera and can be observed with both formulations.

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

Severe cytokine release syndrome is characterised by severe dyspnea, 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, hyperphosphaetemia, 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 x 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 x 109/L.

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 MabThera.
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 MabThera administration, consideration should be given to withholding anti-hypertensive medicines 12 hours prior to giving MabThera.

Infusion-related adverse reactions of all kinds have been observed in 77% of patients treated with MabThera intravenous formulation (including cytokine release syndrome accompanied by hypotension and bronchospasm in 10% of patients) see section 4.8. These symptoms are usually reversible with interruption of MabThera infusion and administration of an anti-pyretic, an antihistaminic, and, occasionally, oxygen, intravenous saline or bronchodilators, and glucocorticoids if required. Please see cytokine release syndrome above for severe reactions.

Administration related reactions have been observed in up to 50% of patients treated with MabThera subcutaneous formulation in clinical trials. The reactions occurring within 24 hours of the subcutaneous injection consisted primarily of erythema pruritus, rash and injections site reactions such as pain, swelling and redness and were generally of mild or moderate (grade 1 or 2) and transient nature (see section 4.8).

Local cutaneous reactions were very common in patients receiving MabThera subcutaneous in clinical trials. Symptoms included pain, swelling, induration, haemorrhage, erythema, pruritus and rash (see section 4.8). Some local cutaneous reactions occurred more than 24 hours after the MabThera subcutaneous administration. The majority of local cutaneous reactions seen following administration of MabThera subcutaneous formulation was mild or moderate and resolved without any specific treatment.

Before starting MabThera subcutaneous injections, all patients must always receive beforehand, a full dose of MabThera by intravenous infusion, using MabThera intravenous formulation. The highest risk of experiencing an administration related reaction is generally observed at cycle one. Beginning the therapy with MabThera intravenous infusion would allow a better handling of the administration reactions by slowing or stopping the intravenous infusion.

If patients were not able to receive one full MabThera intravenous infusion dose prior to the switch, they should continue the subsequent cycles with MabThera intravenous formulation until a full intravenous dose is successfully administered. Therefore, the switch to MabThera subcutaneous formulation can only occur at the second or subsequent cycles of treatment.

As with the intravenous formulation, MabThera subcutaneous formulation should be administered in an environment where full resuscitation facilities are immediately available and under the close supervision of an experienced healthcare professional. Premedication consisting of an analgesic/antipyretic and an antihistamine should always be administered before each dose of MabThera subcutaneous formulation. Premedication with glucocorticoids should also be considered.

Patients should be observed for at least 15 minutes following MabThera subcutaneous administration. A longer period may be appropriate in patients with an increased risk of hypersensitivity reactions.

Patients should be instructed to contact their treating physician immediately if symptoms that are suggestive of severe hypersensitivity or cytokine release syndrome occur at any time after medicinal product administration.

Cardiac disorders

Angina pectoris, cardiac arrhythmias such as atrial flutter and fibrillation, heart failure and/or myocardial infarction have occurred in patients treated with MabThera. Therefore, patients with a history of cardiac disease and/or cardiotoxic chemotherapy should be monitored closely.

Haematological toxicities

Although MabThera is not myelosuppressive in monotherapy, caution should be exercised when considering treatment of patients with neutrophils < 1.5 x 109/L and/or platelet counts < 75 x 109/L as clinical experience in this population is limited. MabThera 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 MabThera therapy.

Infections

Serious infections, including fatalities, can occur during therapy with MabThera (see section 4.8).
MabThera 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 MabThera in patients with a history of recurring or chronic infections or with underlying conditions which may further predispose patients to serious infection (see section 4.8).

Cases of hepatitis B reactivation have been reported in patients receiving MabThera including fulminant hepatitis with fatal outcome. The majority of these patients were also exposed to cytotoxic chemotherapy. Limited information from one study in relapsed/refractory CLL patients suggests that MabThera 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 MabThera. 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 MabThera. 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 PML have been reported during post-marketing use of MabThera in 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.

Cases of enteroviral meningoencephalitis including fatalities have been reported following use of rituximab.

False negative serologic testing of infections
Due to the risk of false negative serologic testing of infections, alternative diagnostic tools should be considered in case of patients presenting with symptoms indicative of rare infectious disease e.g. West Nile virus and neuroborreliosis.

Immunisation

The safety of immunisation with live viral vaccines, following MabThera therapy has not been studied for NHL and CLL patients and vaccination with live virus vaccines is not recommended. Patients treated with MabThera may receive non-live vaccinations; however, with non-live vaccines response rates may be reduced. In a non-randomised study, patients with relapsed low-grade NHL who received the MabThera intravenous formulation as 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. 69% when assessed for > 2-fold increase in antibody titre). For CLL patients, similar results are assumable considering similarities between both diseases, but this has not been investigated in clinical trials.

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

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 suspected relationship to MabThera, treatment should be permanently discontinued.

Excipients

This medicine contains 8.04 mg of polysorbate 80 in each 20 mL vial, which is equivalent to 0.6 mg/mL. Polysorbates may cause allergic reactions.

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

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

Co-administration with methotrexate had no effect on the pharmacokinetics of MabThera 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 MabThera. In these patients the rate of clinically relevant infection while on MabThera was 6.01 per 100 patient years compared to 4.97 per 100 patient years following treatment with the biologic DMARD.

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

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

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.

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

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

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.

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 MabThera.

Pregnancy

IgG immunoglobulins are known to cross the placental barrier.

B-cell levels in human neonates following maternal exposure to MabThera have not been studied in clinical trials. There are no adequate and well-controlled data from studies in pregnant women, however

transient B-cell depletion and lymphocytopenia have been reported in some infants born to mothers exposed to MabThera during pregnancy. Similar effects have been observed in animal studies (see section 5.3). For these reasons MabThera 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 rituximab concentrations in milk (relative infant dose less than 0.4%). Few cases of follow-up of breastfed infants describe normal growth and development up to 2 years. However, as these data are limited and the long-term outcomes of breastfed infants remain unknown, breast-feeding is not recommended while being treated with rituximab and optimally for 6 months following rituximab treatment.

Fertility

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

Contraception in males and females

Due to the long retention time of rituximab in B-cell depleted patients, women of childbearing potential must employ effective contraceptive methods during and for 12 months after treatment with MabThera.

Pregnancy

IgG immunoglobulins are known to cross the placental barrier.

B-cell levels in human neonates following maternal exposure to MabThera have not been studied in clinical trials. There are no adequate and well-controlled data from studies in pregnant women, however transient B-cell depletion and lymphocytopenia have been reported in some infants born to

mothers exposed to MabThera during pregnancy. Similar effects have been observed in animal studies (see section 5.3). For these reasons MabThera 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 rituximab concentrations in milk (relative infant dose less than 0.4%). Few cases of follow-up of breastfed infants describe normal growth and development up to 2 years. However, as these data are limited and the long-term outcomes of breastfed infants remain unknown, breast-feeding is not recommended while being treated with rituximab and optimally for 6 months following rituximab treatment.

Fertility

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

20%
38%*
† 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 MabThera in combination with methotrexate showed an enhanced response compared to patients negative to both.

Efficacy outcomes in MabThera 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*

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

Limited experience with doses higher than the approved dose of intravenous MabThera formulation is available from clinical trials in humans. The highest intravenous dose of MabThera 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 MabThera overdose have been reported. Three cases had no reported adverse event. The two adverse events that were reported were flu-like symptoms, with a dose of 1.8 g of rituximab and fatal respiratory failure, with a dose of 2 g of rituximab.

5.
PHARMACOLOGICAL PROPERTIES

Limited experience with doses higher than the approved dose of intravenous MabThera formulation is available from clinical trials in humans. The highest intravenous dose of MabThera 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.

Three patients in the MabThera subcutaneous formulation trial SABRINA (BO22334) were inadvertently administered subcutaneous formulation through the intravenous route up to a maximum rituximab dose of 2780 mg with no untoward effect.
Patients who experience overdose or medication error should be closely monitored.

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

5.
PHARMACOLOGICAL PROPERTIES

Limited experience with doses higher than the approved dose of intravenous MabThera formulation is available from clinical trials in humans. The highest intravenous dose of MabThera 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.

Three patients in the MabThera subcutaneous NHL formulation trial SABRINA (BO22334) were inadvertently administered subcutaneous formulation through the intravenous route up to a maximum rituximab dose of 2780 mg with no untoward effect.
Patients who experience overdose or medication error with MabThera should be closely monitored.

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

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: antineoplastic agents, monoclonal antibodies and antibody drug conjugates, ATC code: L01FA01

Mechanism of action

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 internalise 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 Fcγ 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.

Pharmacodynamic effects

Peripheral B-cell counts declined below normal following completion of the first dose of MabThera. 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 MabThera 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 MabThera 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 MabThera. In patients with GPA or MPA, the number of peripheral blood B-cells decreased to < 10 cells/μL after two weekly infusions of rituximab 375 mg/m2, and remained at that level in most patients up to the 6 month timepoint. The majority of patients (81%) showed signs of B-cell return, with counts > 10 cells/μL by Month 12, increasing to 87% of patients by Month 18.

Clinical efficacy and safety

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

Follicular lymphoma

Monotherapy

Initial treatment, weekly for 4 doses

Pharmacotherapeutic group: antineoplastic agents, monoclonal antibodies and antibody drug conjugates, ATC code: L01FA01

MabThera subcutaneous formulation contains recombinant human hyaluronidase (rHuPH20), an enzyme used to increase the dispersion and absorption of co-administered substances when administered subcutaneously.

Mechanism of action

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 internalise 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 Fcγ 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.

Pharmacodynamic effects

Peripheral B-cell counts declined below normal following completion of the first dose of MabThera.
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 MabThera 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 MabThera was administered as monotherapy or in combination with methotrexate.

Clinical efficacy and safety

Clinical efficacy and safety of MabThera subcutaneous formulation in non-Hodgkin’s lymphoma

The clinical efficacy and safety of MabThera subcutaneous formulation in non-Hodgkin’s lymphoma is based on data from a phase III clinical trial (SABRINA BO22334) in patients with follicular lymphoma (FL) and a phase Ib dose-finding/dose-confirmation trial (SparkThera BP22333) in patients with FL. Results from trial BP22333 are presented in section 5.2.

Trial BO22334 (SABRINA)

Pharmacotherapeutic group: antineoplastic agents, monoclonal antibodies and antibody drug conjugates, ATC code: L01FA01

MabThera subcutaneous formulation contains recombinant human hyaluronidase (rHuPH20), an enzyme used to increase the dispersion and absorption of co-administered substances when administered subcutaneously.

Mechanism of action

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 internalise 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 Fcγ 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.

Pharmacodynamic effects

Peripheral B-cell counts declined below normal following completion of the first dose of MabThera. 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 MabThera 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 MabThera was administered as monotherapy or in combination with methotrexate.

Clinical efficacy and safety

Clinical efficacy and safety of MabThera subcutaneous formulation in chronic lymphocytic leukaemia

A two-part phase Ib, multicentre, randomised, open-label, parallel-group trial (SAWYER BO25341) was conducted in patients with previously untreated CLL, to investigate the non-inferiority of the pharmacokinetic profile, together with efficacy and safety of MabThera subcutaneous formulation in combination with chemotherapy.

Adult non-Hodgkin’s lymphoma

Based on a population pharmacokinetic analysis in 298 NHL patients who received single or multiple infusions of MabThera as a single agent or in combination with CHOP therapy (applied MabThera 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 MabThera 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 MabThera 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 MabThera. This analysis suggests that dose adjustment of MabThera with any of the tested covariates is not expected to result in a meaningful reduction in its pharmacokinetic variability.

MabThera, 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 MabThera, yielded a mean Cmax following the fourth infusion of 486 µg/mL (range, 77.5 to 996.6 µg/mL). Rituximab was detectable in the serum of patients 3 – 6 months after completion of last treatment.

Absorption

Rituximab pharmacokinetics following single dose administration of MabThera subcutaneous 375 mg/m2, 625 mg/m2 and 800 mg/m2 were compared with MabThera intravenous 375 mg/m2 in FL patients. Following subcutaneous administration, the absorption of rituximab is slow, reaching maximal concentrations about 3 days after administration. Based on popPK analysis an absolute bioavailability of 64.6% was estimated. Rituximab exposure increased dose proportional over the 375 mg/m2 to 800 mg/m2 subcutaneous dose range. Pharmacokinetic parameters such as clearance, distribution volume, and elimination half-life were comparable for both formulations.

Trial BP22333 (SparkThera)
A two-stage phase Ib trial to investigate the pharmacokinetics, safety and tolerability of MabThera subcutaneous formulation in patients with follicular lymphoma (FL) as part of maintenance treatment.
In stage 2, MabThera subcutaneous formulation at a fixed dose of 1400 mg was administered as subcutaneous injection during maintenance treatment, after at least one cycle of MabThera intravenous formulation to FL patients who had previously responded to MabThera intravenous formulation in induction.

The comparison of predicted median Cmax data for MabThera subcutaneous formulation and intravenous formulation are summarised in Table 7.

Table 7:
Trial BP22333 (SparkThera): Absorption - Pharmacokinetic parameters of
MabThera SC compared to MabThera IV
MabThera subcutaneous
MabThera intravenous
Predicted median Cmax
(q2m) µg/mL
Predicted median Cmax
(q3m) µg/mL

The median Tmax in the MabThera subcutaneous formulation was approximately 3 days as compared to the Tmax occurring at or close to the end of the infusion for the intravenous formulation.

Trial BO22334 (SABRINA)

Absorption

MabThera at a fixed dose of 1600 mg was administered for 5 cycles subcutaneously at 4-weekly intervals, following the first cycle of MabThera intravenous formulation, in previously untreated CLL patients in combination with chemotherapy (fludarabine and cyclophosphamide (FC). The serum MabThera Cmax at Cycle 6 was lower in the subcutaneous arm than the intravenous, with geometric mean (CV%) values of 202 (36.1) μg/mL and 280 (24.6) μg/mL with the resulting geometric mean ratio (Cmax, SC/Cmax, IV) of 0.719 (90% CI: 0.653, 0.792). The geometric mean tmax in the MabThera subcutaneous group was approximately 3 days as compared to the tmax occurring at or close to the end of the infusion for the MabThera intravenous group. The geometric mean Ctrough (CV%) values at Cycle 5 (pre-dose Cycle 6) were higher among the MabThera subcutaneous group than the MabThera intravenous group; 97.5 µg/mL (42.6) versus 61.5 µg/mL (63.9) respectively with a resulting adjusted geometric mean ratio [90% CI] of 1.53 [1.27-1.85]. Similarly, the geometric mean AUC (CV%) values at Cycle 6 were higher among the subcutaneous group than the intravenous group; 4088 µg•day/mL (34.2) versus 3630 µg•day/mL (32.8) respectively) with a resulting adjusted geometric mean ratio [90% CI] of 1.10 [0.98-1.24].
Based on popPK analysis of study BO25341 (SAWYER) an absolute bioavailability of 68.4% was estimated.

Distribution/Elimination

The estimated half-life of MabThera subcutaneous formulation of 1600 mg is 30 days, the estimated clearance is 0.22 L/day and the volume of distribution of the central compartment is 4.65 L.

Special populations