4.1. Therapeutic indications

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.

4.2. Posology and method of administration

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.

4.3. Contraindications

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.

4.4. Special warnings and precautions for use

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.

4.5. Interaction with other medicinal products and other forms of interaction

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.

4.6. Fertility, pregnancy and lactation

Contraception in males and females

Due to the long retention time of rituximab in B-cell depleted patients, women of childbearing potential 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.

4.7. Effects on ability to drive and use machines

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.

4.8. Undesirable effects

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 leukoencephalopathy

enteroviral meningoencephalitis2, 3

Blood and lymphatic system disorders

Neutronpenia, leucopenia, +febrile neutronpenia, +thrombocytopenia

anaemia, +pancytopenia, +granulocytopenia

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 thrombocytopenia 5

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

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‑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

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 stemcell 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 Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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.