Rituximab

Rituximab is a genetically engineered chimeric mouse/human monoclonal antibody of the IgG1 class, with human constant regions and murine variable regions, produced in Chinese hamster ovary cell culture. It binds CD20, an antigen on pre-B and mature B lymphocytes, and the coated cells are destroyed. Removing B cells treats B-cell cancers and reduces the part B cells play in several autoimmune diseases.

Mechanism of Action

• Target: CD20 is a transmembrane, non-glycosylated phosphoprotein found on normal and malignant B cells, including more than 95% of B-cell non-Hodgkin lymphomas. It is absent from haematopoietic stem cells, pro-B cells, normal plasma cells and other normal tissue. It does not internalise when the antibody binds, is not shed from the cell surface and does not circulate free in plasma, so there is no free antigen to compete for the antibody.
• Cell destruction: the Fab domain binds CD20, and the Fc domain recruits immune effector functions. Possible mechanisms are complement-dependent cytotoxicity (through C1q binding) and antibody-dependent cellular cytotoxicity (through Fcγ receptors on granulocytes, macrophages and NK cells). Binding to CD20 has also been shown to induce apoptosis.
• Rheumatoid arthritis: B cells are thought to contribute to joint inflammation through rheumatoid factor and other autoantibodies, antigen presentation, T-cell activation and pro-inflammatory cytokines.
• Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA): both are marked by circulating anti-neutrophil cytoplasmic antibodies and increased B-cell activity.
• B-cell depletion and recovery: peripheral B-cell counts fall below normal after the first dose. After treatment of haematological malignancies, recovery begins within 6 months and counts generally return to normal within 12 months, although in some patients it takes longer (a median of 23 months after induction therapy). In rheumatoid arthritis, B cells in the blood are depleted immediately after two 1,000 mg infusions given 14 days apart.
• Immunoglobulins: plasma cells lack CD20 and are not targeted directly, but immunoglobulin levels can still fall; in one study about 14% of lymphoma patients had IgM or IgG below the normal range. Immunoglobulin levels are therefore measured before treatment.

Pharmacokinetics

• Absorption: given intravenously, the whole dose reaches the circulation. In 203 patients with non-Hodgkin lymphoma (NHL) given 375 mg/m² weekly for 4 doses, the mean peak concentration after the fourth infusion was 486 µg/mL (range 77.5 to 996.6). With 8 weekly infusions in 37 patients, the mean peak rose from 243 µg/mL after the first infusion to 550 µg/mL after the eighth. Rituximab was still detectable in serum 3 to 6 months after the last treatment, and the profile with 6 infusions plus 6 cycles of CHOP was similar to that of rituximab alone. In rheumatoid arthritis, two doses of 500 mg gave peaks of about 157 and 183 µg/mL, and two doses of 1,000 mg about 318 and 381 µg/mL.
• Distribution: in a population analysis of 298 NHL patients the typical volume of the central compartment was 2.7 L. It varied with body surface area and with concurrent CHOP therapy, but the effect was relatively small. In rheumatoid arthritis the volume of distribution is about 3.1 L.
• Metabolism: as an antibody, rituximab is expected to be broken down by proteases throughout the body.
• Elimination: in NHL the typical non-specific clearance was 0.14 L/day, with an additional specific clearance of 0.59 L/day that is likely contributed by B cells or tumour burden. The median terminal half-life was 22 days (range 6.1 to 52 days). Patients with more CD19-positive cells or larger tumour lesions had a higher specific clearance. In 21 CLL patients the median terminal half-life was about 32 days (range 14 to 62 days).
• Special populations: in NHL, age, sex and WHO performance status did not affect pharmacokinetics, and adjusting the dose for these factors is not expected to reduce variability meaningfully. In paediatric patients aged 6 to 17 years with GPA or MPA, given 375 mg/m² weekly for 4 doses, exposure was similar to that in adults.

The indications below are those of the originator MabThera. The biosimilars (Ruxience, Riximyo, Rixathon, Truxima, Blitzima and Ituxredi) each have their own SmPC, which lists the indications that product is authorised for.

MabThera concentrate for intravenous infusion (100 mg and 500 mg vials)

• Follicular lymphoma: previously untreated adults with stage III–IV disease, in combination with chemotherapy; maintenance therapy in adults responding to induction therapy; and monotherapy in adults with stage III–IV disease who are chemoresistant or in their second or subsequent relapse after chemotherapy.
• Diffuse large B-cell lymphoma: adults with CD20-positive diffuse large B-cell non-Hodgkin lymphoma, in combination with CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisolone).
• Paediatric lymphoma: patients aged 6 months to under 18 years with previously untreated advanced-stage CD20-positive diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma (BL) or Burkitt leukaemia (mature B-cell acute leukaemia, BAL) or Burkitt-like lymphoma (BLL), in combination with chemotherapy.
• Chronic lymphocytic leukaemia (CLL): adults with previously untreated and relapsed or refractory CLL, in combination with chemotherapy. Only limited data are available on efficacy and safety in patients previously treated with monoclonal antibodies including MabThera, or refractory to previous MabThera plus chemotherapy.
• Rheumatoid arthritis: adults with severe active rheumatoid arthritis who had an inadequate response or intolerance to other disease-modifying anti-rheumatic drugs (DMARDs), including one or more tumour necrosis factor (TNF) inhibitors, in combination with methotrexate. With methotrexate, MabThera has been shown to reduce the rate of progression of joint damage on X-ray and to improve physical function.
• Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA): adults with severe, active disease, in combination with glucocorticoids; and induction of remission in paediatric patients aged 2 to under 18 years with severe, active GPA or MPA, in combination with glucocorticoids.
• Pemphigus vulgaris: adults with moderate to severe pemphigus vulgaris.

MabThera 1,400 mg solution for subcutaneous injection (adults, non-Hodgkin lymphoma only)

• Previously untreated stage III–IV follicular lymphoma, in combination with chemotherapy.
• Maintenance therapy in follicular lymphoma patients responding to induction therapy.
• CD20-positive diffuse large B-cell non-Hodgkin lymphoma, in combination with CHOP chemotherapy.

MabThera 1,600 mg solution for subcutaneous injection (adults, CLL only)

• Previously untreated and relapsed or refractory CLL, in combination with chemotherapy. The same limited-data caution applies to patients previously treated with monoclonal antibodies.

• Hypersensitivity to rituximab, to murine proteins or to any of the excipients. For the subcutaneous solutions this includes hyaluronidase.
• Active, severe infections.
• A severely immunocompromised state.
• Severe heart failure (New York Heart Association class IV) or severe, uncontrolled cardiac disease. This applies to use in rheumatoid arthritis, GPA, MPA and pemphigus vulgaris only.

In adults with NHL and CLL the most frequent reactions are infusion-related reactions (IRRs), which occur in most patients with the first infusion. Their incidence falls substantially with later infusions and is below 1% after eight doses. Infections, mostly bacterial and viral, occurred in about 30–55% of patients in lymphoma trials and in 30–50% in CLL trials. Infusion-related reactions of all kinds were seen in 77% of patients treated with MabThera, including cytokine release syndrome with hypotension and bronchospasm in 10%.

The groups below are for adults with NHL and CLL treated with MabThera alone, as maintenance or with chemotherapy, from clinical trials and after marketing. For some reactions (for example bronchitis, febrile neutropenia, pneumonia and fatigue) the SmPC counts only severe events (grade 3 or higher).

Very common (≥1/10): bacterial infections, viral infections, bronchitis; neutropenia, leucopenia, febrile neutropenia, thrombocytopenia; infusion-related reactions, angioedema; nausea; pruritus, rash, alopecia; fever, chills, asthenia, headache; decreased IgG levels.

Common (≥1/100 to <1/10): sepsis, pneumonia, febrile infection, herpes zoster, respiratory tract infection, fungal infection, infections of unknown cause, acute bronchitis, sinusitis, hepatitis B (including reactivation); anaemia, pancytopenia, granulocytopenia; hypersensitivity; hyperglycaemia, weight loss, peripheral oedema, face oedema, raised lactate dehydrogenase, hypocalcaemia; paraesthesia, hypoaesthesia, agitation, insomnia, vasodilatation, dizziness, anxiety; lacrimation disorder, conjunctivitis; tinnitus, ear pain; myocardial infarction, arrhythmia, atrial fibrillation, tachycardia, cardiac disorder; hypertension, orthostatic hypotension, hypotension; bronchospasm, respiratory disease, chest pain, dyspnoea, increased cough, rhinitis; vomiting, diarrhoea, abdominal pain, dysphagia, stomatitis, constipation, dyspepsia, anorexia, throat irritation; urticaria, sweating, night sweats, skin disorder; hypertonia, myalgia, arthralgia, back pain, neck pain, pain; tumour pain, flushing, malaise, cold syndrome, fatigue, tremor, multi-organ failure.

Uncommon (≥1/1,000 to <1/100): coagulation disorders, aplastic anaemia, haemolytic anaemia, lymphadenopathy; depression, nervousness; dysgeusia; left ventricular failure, supraventricular tachycardia, ventricular tachycardia, angina, myocardial ischaemia, bradycardia; asthma, bronchiolitis obliterans, lung disorder, hypoxia; abdominal enlargement; infusion site pain.

Rare (≥1/10,000 to <1/1,000): serious viral infection, Pneumocystis jirovecii pneumonia; anaphylaxis; serious cardiac disorders; interstitial lung disease.

Very rare (<1/10,000): progressive multifocal leukoencephalopathy; transient rise in serum IgM; tumour lysis syndrome, cytokine release syndrome, serum sickness; peripheral neuropathy with facial nerve palsy; severe vision loss; heart failure; vasculitis (mostly of the skin) including leucocytoclastic vasculitis; respiratory failure; gastrointestinal perforation; severe bullous skin reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell’s syndrome); renal failure.

Not known: enteroviral meningoencephalitis; late neutropenia; reversible severe thrombocytopenia related to the infusion; cranial neuropathy and loss of other senses; hearing loss; pulmonary infiltration.

Important serious reactions are infusion-related reactions (including cytokine release syndrome and tumour lysis syndrome), serious and sometimes fatal infections, hepatitis B reactivation, progressive multifocal leukoencephalopathy, cardiovascular events and severe skin reactions. In rheumatoid arthritis, GPA, MPA and pemphigus vulgaris, most infusion-related events in trials were mild to moderate; the commonest symptoms were headache, pruritus, throat irritation, flushing, rash, urticaria, hypertension and fever. Late neutropenia can occur in these indications. The SmPC gives the full side-effect profile for each indication.

Data on possible interactions with MabThera are limited.

• Chemotherapy in CLL: MabThera did not appear to change the pharmacokinetics of fludarabine or cyclophosphamide, nor did these medicines change those of MabThera.
• Methotrexate in rheumatoid arthritis: methotrexate had no effect on the pharmacokinetics of MabThera.
• Other monoclonal antibodies: patients with human anti-mouse antibodies (HAMA) or anti-drug antibodies (ADA) may have allergic or hypersensitivity reactions when given other diagnostic or therapeutic monoclonal antibodies.
• Biologic DMARDs after MabThera: in 283 rheumatoid arthritis patients who received a biologic DMARD after MabThera, the rate of clinically relevant infection was 6.01 per 100 patient-years while on MabThera and 4.97 per 100 patient-years after the biologic DMARD. Patients should be watched closely for infection when biologic agents or DMARDs follow MabThera, and anti-rheumatic therapy other than that specified in the indication is not recommended together with MabThera.
• Antihypertensive medicines: because blood pressure may fall during the infusion, withholding antihypertensive medicines for 12 hours before the infusion should be considered.
• Live vaccines: not recommended during MabThera treatment or while B cells are depleted (see Special Instructions).

MabThera must be given under the close supervision of an experienced healthcare professional, in an environment where full resuscitation facilities are immediately available. The label must be checked to make sure that the formulation (intravenous or subcutaneous) and strength prescribed are the ones given. No dose reductions of MabThera are recommended. When it is combined with chemotherapy, the standard dose reductions for the chemotherapy apply.

Premedication and Prophylaxis

• All indications: an antipyretic and an antihistamine (for example paracetamol and diphenhydramine) before every administration.
• Adult NHL and CLL: consider glucocorticoid premedication if MabThera is not given with glucocorticoid-containing chemotherapy.
• Paediatric NHL: paracetamol and an H1 antihistamine 30 to 60 minutes before the infusion, with prednisone as set out in the SmPC treatment plan.
• CLL: adequate hydration and a uricostatic starting 48 hours before treatment, to reduce the risk of tumour lysis syndrome. For patients whose lymphocyte count is above 25 × 10⁹/L, prednisone or prednisolone 100 mg intravenously shortly before the infusion reduces the rate and severity of acute infusion reactions and cytokine release syndrome.
• Rheumatoid arthritis, GPA, MPA and pemphigus vulgaris: methylprednisolone 100 mg intravenously, finished 30 minutes before each infusion, to reduce infusion-related reactions.
• Adult GPA or MPA: methylprednisolone 1,000 mg a day intravenously for 1 to 3 days before the first infusion, then oral prednisone 1 mg/kg/day (not above 80 mg/day, tapered as fast as clinical need allows) during and after the 4-week induction course.
• Paediatric GPA or MPA: methylprednisolone 30 mg/kg/day intravenously (not above 1 g/day) for three daily doses before the first infusion, with up to three more daily doses if needed, then oral prednisone 1 mg/kg/day (not above 60 mg/day), tapered as fast as clinical need allows.
• Pneumocystis jirovecii pneumonia prophylaxis is recommended in adults and children with GPA or MPA and in adults with pemphigus vulgaris, during and after treatment, following local guidelines.
• Medicines for treating hypersensitivity (adrenaline, antihistamines, glucocorticoids) must be available for immediate use.

Intravenous Dose by Indication

Follicular lymphoma

• Induction with chemotherapy (previously untreated or relapsed or refractory): 375 mg/m² body surface area per cycle, for up to 8 cycles, on Day 1 of each chemotherapy cycle after the intravenous glucocorticoid component of the chemotherapy, if there is one.
• Maintenance, previously untreated disease responding to induction: 375 mg/m² once every 2 months, starting 2 months after the last induction dose, until progression or for a maximum of two years (12 infusions).
• Maintenance, relapsed or refractory disease responding to induction: 375 mg/m² once every 3 months, starting 3 months after the last induction dose, until progression or for a maximum of two years (8 infusions).
• Monotherapy (chemoresistant, or second or later relapse): 375 mg/m² as an infusion once weekly for four weeks. The same four-week course can be repeated in patients who responded to a previous course of monotherapy.

Diffuse large B-cell lymphoma (adults)

• 375 mg/m² on Day 1 of each chemotherapy cycle, for 8 cycles, after the intravenous glucocorticoid component of CHOP. Safety and efficacy with other chemotherapy have not been established.

Paediatric lymphoma (6 months to under 18 years)

• 375 mg/m² body surface area as an infusion, with Lymphome Malin B (LMB) chemotherapy. In the SmPC treatment plan MabThera is given as six infusions: two in each of the two induction courses, 48 hours apart, and one in each of the two consolidation courses. None is given in the prephase or the maintenance courses. Prednisone is given before MabThera in the first induction course only. The dose changes only with body surface area.
• It should not be used in children from birth to 6 months of age with CD20-positive DLBCL.

Chronic lymphocytic leukaemia

• With chemotherapy, 375 mg/m² on Day 0 of the first cycle, then 500 mg/m² on Day 1 of each later cycle, for 6 cycles in total. The chemotherapy is given after the MabThera infusion.

Rheumatoid arthritis

• One course is two 1,000 mg infusions, the second two weeks after the first, given with methotrexate. The need for further courses is assessed 24 weeks after the previous course: retreat then if disease activity remains, otherwise delay until it returns. A response is usually reached within 16 to 24 weeks of the first course, and continued therapy should be reconsidered in patients with no benefit by then.

Granulomatosis with polyangiitis and microscopic polyangiitis

• Adult induction: 375 mg/m² once weekly for 4 weeks (four infusions).
• Adult maintenance: start no sooner than 16 weeks after the last induction infusion, or within the 4 weeks after remission when induction used other standard immunosuppressants. Give two 500 mg infusions two weeks apart, then 500 mg every 6 months. Treatment continues for at least 24 months after remission, and up to 5 years for patients at higher risk of relapse.
• Paediatric induction (2 to under 18 years): 375 mg/m² once weekly for 4 weeks. It should not be used under 2 years of age, because of the possibility of an inadequate immune response to childhood vaccinations.

Pemphigus vulgaris

• 1,000 mg as an infusion, followed two weeks later by a second 1,000 mg infusion, with a tapering course of glucocorticoids.
• Maintenance: 500 mg at months 12 and 18, then every 6 months if needed on clinical evaluation.
• Relapse: 1,000 mg, with the glucocorticoid dose resumed or increased as the clinical picture requires. Later infusions are given no sooner than 16 weeks after the previous one.

Infusion Rates (Intravenous)

• The prepared solution is given as an intravenous infusion through a dedicated line. It must not be given as an intravenous push or bolus.
• First infusion (adults, and children with GPA or MPA): start at 50 mg/h and, after the first 30 minutes, increase by 50 mg/h every 30 minutes to a maximum of 400 mg/h. Later infusions: start at 100 mg/h and increase by 100 mg/h every 30 minutes to a maximum of 400 mg/h.
• Paediatric lymphoma: the first infusion starts at 0.5 mg/kg/h (maximum 50 mg/h) and rises by 0.5 mg/kg/h every 30 minutes if there is no hypersensitivity or infusion-related reaction, to a maximum of 400 mg/h. Later infusions start at 1 mg/kg/h (maximum 50 mg/h) and rise by 1 mg/kg/h every 30 minutes to a maximum of 400 mg/h.
• Faster schedule in rheumatoid arthritis: if the first or later 1,000 mg infusions on the standard schedule caused no serious infusion-related reaction, later infusions can run at 250 mg/h for the first 30 minutes and then 600 mg/h for the next 90 minutes, at the same concentration (4 mg/mL in 250 mL). This must not be used in patients with clinically significant cardiovascular disease, including arrhythmias, or with previous serious infusion reactions to any biologic or to rituximab.
• Reactions during the infusion: mild or moderate reactions usually respond to a slower rate, which can be increased again when symptoms improve. With severe reactions, especially severe breathlessness, bronchospasm or hypoxia, stop the infusion at once. In lymphoma, check for tumour lysis syndrome, with laboratory tests and a chest X-ray for pulmonary infiltration. Do not restart until all symptoms have fully resolved and laboratory values and chest X-ray have normalised, and then at no more than half the previous rate. If the same severe reaction happens again, stopping treatment should be considered seriously.

Subcutaneous Formulations (MabThera 1,400 mg and 1,600 mg)

• Always start intravenously: before any subcutaneous injection, every patient must have received one full dose of the intravenous formulation. The switch can therefore only be made at the second or a later cycle. A patient who could not receive a full intravenous dose continues on the intravenous formulation until one has been given.
• Fixed dose: 1,400 mg (in 11.7 mL) for NHL only, or 1,600 mg (in 13.4 mL) for CLL only, irrespective of body surface area. They are for subcutaneous use only and must not be given intravenously.
• Follicular lymphoma, induction with chemotherapy: the first cycle uses the intravenous formulation, 375 mg/m², and later cycles use the 1,400 mg subcutaneous injection, up to 8 cycles in total, on Day 1 of each chemotherapy cycle after the glucocorticoid component. The SmPC also describes the maintenance and DLBCL regimens.
• CLL: after the first cycle with the intravenous formulation, later cycles use the 1,600 mg injection with chemotherapy. The same CLL prophylaxis applies: hydration and a uricostatic from 48 hours before treatment, and intravenous prednisone or prednisolone 100 mg shortly before administration if the lymphocyte count is above 25 × 10⁹/L. The cycle schedule is in the SmPC.
• Premedication: an antipyretic and an antihistamine before each administration, and consider glucocorticoids if MabThera is not combined with glucocorticoid-containing chemotherapy.
• Injection: per the 1,400 mg SmPC, inject over about 5 minutes into the abdominal wall, never into skin that is red, bruised, tender or hard or into moles or scars. No data exist for other body sites. Attach the injection needle to the syringe only immediately before use, to avoid clogging. Other subcutaneous medicines should preferably be given at different sites. An interrupted injection can be resumed at the same site, or another site can be used if appropriate.

Special Populations

• Elderly (65 years and over): no dose adjustment.
• Children and adolescents: MabThera is used in lymphoma from 6 months to under 18 years and in GPA or MPA from 2 to under 18 years, as above. Safety and efficacy in these age groups have not been established in other indications, and only limited data exist under 3 years of age. The safety and efficacy of the subcutaneous formulation under 18 years have not been established.

Infusion-Related Reactions and Cytokine Release Syndrome

• MabThera causes infusion-related reactions, which may be related to the release of cytokines and other chemical mediators. Cytokine release syndrome can look the same as an acute hypersensitivity reaction.
• Severe infusion-related reactions with fatal outcome have been reported after the intravenous formulation, starting between 30 minutes and 2 hours after the first infusion began. They involve lung events and sometimes rapid tumour lysis, with fever, chills, rigors, low blood pressure, urticaria and angioedema.
• Severe cytokine release syndrome shows as severe breathlessness, often with bronchospasm and hypoxia, plus fever, chills, rigors, urticaria and angioedema. It may include features of tumour lysis syndrome (high uric acid, potassium and phosphate, low calcium, acute kidney failure, raised lactate dehydrogenase) and can lead to acute respiratory failure and death. It usually appears within one or two hours of the first infusion.
• Patients with pulmonary insufficiency or lung tumour infiltration are at greater risk of a poor outcome. So are patients with a high tumour burden or many circulating malignant cells (25 × 10⁹/L or more), such as those with CLL. They need extreme caution and very close monitoring during the first infusion, and a reduced first infusion rate or split dosing over two days should be considered while the lymphocyte count stays above 25 × 10⁹/L.
• Patients with severe cytokine release syndrome must have the infusion stopped at once and receive intensive symptomatic treatment. Because early improvement may be followed by worsening, they are watched until tumour lysis syndrome and lung infiltration have resolved or been ruled out.
• The reactions are usually reversible when the infusion is paused and an antipyretic, an antihistamine, and sometimes oxygen, intravenous saline, bronchodilators or glucocorticoids are given.
• True hypersensitivity (anaphylactic) reactions typically occur within minutes of starting the infusion.
• Rheumatoid arthritis, GPA, MPA and pemphigus vulgaris: severe, sometimes fatal reactions have been reported after marketing. Most trial events were mild to moderate. The share of patients with a reaction was higher after the first infusion than after the second, and fell with later courses. Patients with heart disease or earlier cardiopulmonary reactions are watched closely. Depending on severity, MabThera is stopped temporarily or permanently; in most cases the infusion can restart at half the previous rate once symptoms have fully resolved. There are no safety data in moderate heart failure (NYHA class III) or severe, uncontrolled cardiovascular disease.

Hepatitis B Screening and Reactivation

• Hepatitis B virus (HBV) screening must be done in all patients before treatment starts. At minimum it includes HBsAg and HBcAb status, and may be supplemented by other markers following local guidelines.
• Hepatitis B reactivation, including fatal cases, has been reported in patients given MabThera, most of whom also had cytotoxic chemotherapy. In one study in relapsed or refractory CLL, MabThera may also have worsened the outcome of primary hepatitis B infection.
• Patients with active hepatitis B disease must not be treated with MabThera. Patients with positive serology (HBsAg or HBcAb) should see a liver specialist before treatment and be monitored and managed following local medical standards to prevent reactivation.

Infections

• B cells have an important role in normal immune responses, so the risk of infection rises. Serious infections, including fatal ones, can occur.
• MabThera must not be given to patients with an active, severe infection (for example tuberculosis, sepsis or opportunistic infections) or who are severely immunocompromised (for example with very low CD4 or CD8 levels).
• Caution is needed in patients with recurring or chronic infections or with conditions such as hypogammaglobulinaemia. Immunoglobulin levels should be measured before treatment, signs of infection should be assessed and treated promptly, and the risk of infection should be re-evaluated before each new course.
• Enteroviral meningoencephalitis, including fatal cases, has been reported. Because serological tests can be falsely negative, other diagnostic tools should be considered if a rare infection such as West Nile virus or neuroborreliosis is suspected.

Progressive Multifocal Leukoencephalopathy and the Patient Alert Card

• Very rare cases of fatal progressive multifocal leukoencephalopathy (PML) have been reported in rheumatoid arthritis, other autoimmune diseases (including systemic lupus erythematosus and vasculitis) and, after marketing, in NHL and CLL.
• Every patient treated for rheumatoid arthritis, GPA, MPA or pemphigus vulgaris must be given the patient alert card with each infusion. It carries safety information on the increased risk of infection, including PML.
• Patients are monitored regularly for new or worsening neurological symptoms, including cognitive or psychiatric changes that they may not notice, and they should tell a partner or carer about their treatment. If PML is suspected, dosing must be suspended until it has been excluded. If it is confirmed, MabThera is stopped permanently.

Cardiac Disorders

• Angina pectoris, cardiac arrhythmias such as atrial flutter and fibrillation, heart failure and myocardial infarction have occurred. Patients with a history of heart disease, or who have had cardiotoxic chemotherapy, should be monitored closely.

Severe Skin Reactions

• Toxic epidermal necrolysis (Lyell’s syndrome) and Stevens-Johnson syndrome, some fatal, have been reported. If a relationship to MabThera is suspected, treatment must be stopped permanently.

Blood Counts and Late Neutropenia

• NHL and CLL: MabThera alone is not myelosuppressive, but caution is advised when neutrophils are below 1.5 × 10⁹/L or platelets below 75 × 10⁹/L, because experience is limited. Full blood counts including neutrophils and platelets are done regularly during treatment.
• Rheumatoid arthritis, GPA, MPA and pemphigus vulgaris: neutrophils are measured before each course, regularly for up to 6 months after treatment ends, and whenever signs or symptoms of infection appear, because of late neutropenia.

Vaccinations

• Live viral vaccines are not recommended during MabThera treatment or while B cells are depleted, because their safety has not been studied.
• Non-live vaccines can be given, but responses may be reduced. In studies, responses to tetanus recall antigen and to a new antigen were lower in lymphoma patients given MabThera than in untreated controls, and responses to pneumococcal polysaccharide vaccine and a new antigen were lower in rheumatoid arthritis patients given MabThera with methotrexate.
• In rheumatoid arthritis, GPA, MPA and pemphigus vulgaris, vaccination status should be reviewed and brought up to date if possible, with vaccinations finished at least 4 weeks before the first MabThera dose. Non-live vaccines needed during treatment should be finished at least 4 weeks before the next course.

Rheumatoid Arthritis: Further Points

• MabThera is not recommended in patients who have not had methotrexate, because a favourable benefit–risk balance has not been established.
• The use of anti-rheumatic therapies other than those named in the indication is not recommended together with MabThera. Data on the sequential use of other DMARDs after MabThera are limited, and patients are watched for infection.
• Available data do not suggest an increased risk of malignancy beyond that of the underlying autoimmune disease.

Traceability and Biosimilars

• MabThera and its biosimilars are biological medicines. The trade name and batch number of the product given must be clearly recorded.

Pregnancy, Breastfeeding and Fertility

• Contraception: because rituximab stays in the body for a long time in B-cell-depleted patients, women of childbearing potential should use effective contraception during treatment and for 12 months afterwards.
• Pregnancy: IgG crosses the placenta. Transient B-cell depletion and lymphocytopenia have been reported in some infants born to mothers exposed to MabThera during pregnancy. It should not be given to pregnant women unless the possible benefit outweighs the potential risk.
• Breastfeeding: limited data suggest very low concentrations in milk (relative infant dose below 0.4%) and normal growth in breastfed infants followed for up to 2 years. Because the data are limited and long-term outcomes are unknown, breastfeeding is not recommended during treatment and, ideally, for 6 months afterwards.
• Fertility: animal studies did not show harmful effects on reproductive organs.

Sodium and Polysorbate 80

The intravenous vials contain 2.3 mmol (52.6 mg) sodium per 10 mL vial and 11.5 mmol (263.2 mg) per 50 mL vial, equal to 2.6% and 13.2% of the WHO recommended maximum daily intake of 2 g sodium for an adult. They also contain 7.0 mg (10 mL vial) and 35.0 mg (50 mL vial) of polysorbate 80, which may cause allergic reactions.

Effect on Driving

No studies have been done. The pharmacological activity and the reactions reported suggest that MabThera has no or negligible influence on the ability to drive and use machines.

Store MabThera in a refrigerator at 2–8 °C. Do not freeze. Keep the vial in the outer carton to protect it from light, out of the sight and reach of children. It is a cold-chain product: transport and hold it refrigerated until it is prepared for administration. For storage after dilution, or after the subcutaneous solution has been drawn into a syringe, see Shelf Life. The 100 mg vials are supplied in packs of 2 and the 500 mg vials in packs of 1; not all pack sizes may be marketed.

• Unopened vials: 3 years (MabThera 100 mg and 500 mg for infusion, and 1,400 mg for subcutaneous injection). The 1,600 mg solution has its own SmPC; check its section 6.3.
• Diluted infusion solution in 0.9% sodium chloride: physically and chemically stable for 30 days at 2–8 °C plus an additional 24 hours at up to 30 °C.
• Diluted infusion solution in 5% glucose: stable for 24 hours at 2–8 °C plus an additional 12 hours at room temperature.
• Subcutaneous solution once drawn into the syringe (1,400 mg SmPC): stable for 48 hours at 2–8 °C and then 8 hours at 30 °C in diffuse daylight.
• From a microbiological point of view, the prepared product should be used immediately. If it is not, preparation must take place under controlled and validated aseptic conditions, and in-use storage times and conditions are the responsibility of the user.

Prescription only (Rx), subject to restricted medical prescription (Annex II B). MabThera and its biosimilars are infusions and injections given under the close supervision of an experienced healthcare professional with full resuscitation facilities at hand, so they are supplied to the hospital or clinic that administers them, in cold-chain delivery at 2–8 °C. Hepatitis B screening must be completed before treatment starts. Each administration is recorded with the trade name and batch number, and in rheumatoid arthritis, GPA, MPA and pemphigus vulgaris the patient is given the alert card at every infusion.