MabThera 1400 mg solution for subcutaneous injection

Each mL contains 120 mg of rituximab.

Each vial contains 1400 mg/11.7 mL rituximab.

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

For the full list of excipients, see section 6.1.

Solution for injection.

Clear to opalescent, colourless to yellowish liquid.

MabThera subcutaneous formulation 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 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 for treatment of non-Hodgkin's lymphoma.

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) 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.

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 8cycles.

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.

• 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.

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 below 18 years has not been established. No data are available.

Elderly

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

Method of administration

Subcutaneous injections:

MabThera 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.

Intravenous infusion administration:

The Summary of Product Characteristics (SmPC) of MabThera100 mg and 500 mg concentrate for solution for infusion should be referred to for information on dosing instructions and method of administration.

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

Active, severe infections (see section 4.4).

Patients in a severely immunocompromised state.

In order to improve traceability of biological medicinal products, the tradename of the administered product should be clearly recorded (or stated) in the patient file.

The information provided in the section 4.4 pertains to the use of MabThera subcutaneous formulation in the approved indication Treatment of non Hodgkin lymphoma. 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 eva luate 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 eva luation, 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, tumuor 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 IV infusion. They were characterized 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, 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 only be treated with extreme caution. These patients should be very closely monitored throughout the first infusion. Consideration should be given to the use of a reduced infusion rate for the first infusion in these patients or a split dosing over two days during the first cycle and any subsequent cycles if the lymphocyte count is still >25 x 10⁹/L.

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.

Local cutaneous reactions were very common in patients receiving MabThera subcutaneous in clinical trials; reported in up to 50% of patients at some time during treatment. 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. The MabThera intravenous formulation 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 the MabThera intravenous formulation 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 the MabThera intravenous formulation in NHL (see section 4.8). The majority of patients had received rituximab in combination with chemotherapy or as part of a hematopoietic stem cell transplant.

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-randomized 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.

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.

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

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

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

Whether rituximab is excreted in human milk is not known. However, because maternal IgG is excreted in human milk, and rituximab was detectable in milk from lactating monkeys, women should not breastfeed while treated with MabThera and for 12 months following MabThera treatment.

Fertility

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

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