Special Warning : אזהרת שימוש

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.

Progressive multifocal leukoencephalopathy (PML)

Very rare cases of fatal PML have been reported following use of MabThera for the treatment of rheumatoid arthritis and autoimmune diseases [including Systemic Lupus Erythematosus (SLE) and vasculitis] and during post-marketing use of MabThera in NHL and CLL (where the majority of patients had received MabThera in combination with chemotherapy or as part of haematopoietic stem cell transplant). Patients must be monitored at regular intervals for any new or worsening neurological symptoms or signs that may be suggestive of PML. If PML is suspected, further dosing must be suspended until PML has been excluded. The clinician should evaluate the patient to determine if the symptoms are indicative of neurological dysfunction, and if so, whether these symptoms are possibly suggestive of PML. Consultation with a Neurologist should be considered as clinically indicated.

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

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

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

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

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



Infections
Based on the mechanism of action of MabThera and the knowledge that B-cells play an important role in maintaining normal immune response, patients have an increased risk of infection following MabThera therapy (see section 5.1). Serious infections, including fatalities, can occur during therapy with MabThera (see section 4.8). MabThera should not be administered to patients with an active, severe infection (e.g. tuberculosis, sepsis and opportunistic infections, see section 4.3) or severely immunocompromised patients (e.g. where levels of CD4 or CD8 are very low). Physicians should exercise caution when considering the use of MabThera in patients with a history of recurring or chronic infections or with underlying conditions which may further predispose patients to serious infection e.g. hypogammaglobulinaemia (see section 4.8). It is recommended that immunoglobulin levels are determined prior to initiating treatment with MabThera.

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

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

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

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

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

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

Skin reactions
Severe skin reactions such as Toxic Epidermal Necrolysis (Lyell’s syndrome) and Stevens-Johnson syndrome, some with fatal outcome, have been reported (see section 4.8). In case of such an event, with a suspected relationship to MabThera, treatment should be permanently discontinued.

Non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia

Infusion related reactions
MabThera is associated with infusion related reactions, which may be related to release of cytokines and/or other chemical mediators. Cytokine release syndrome may be clinically indistinguishable from acute hypersensitivity reactions.

This set of reactions which includes syndrome of cytokine release, tumour lysis syndrome and anaphylactic and hypersensitivity reactions are described below.

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

Severe cytokine release syndrome is characterised by severe dyspnoea, often accompanied by bronchospasm and hypoxia, in addition to fever, chills, rigors, urticaria, and angioedema. This syndrome may be associated with some features of tumour lysis syndrome such as hyperuricaemia, hyperkalaemia, hypocalcaemia, hyperphosphataemia, acute renal failure, elevated lactate dehydrogenase (LDH) and may be associated with acute respiratory failure and death. The acute respiratory failure may be accompanied by events such as pulmonary interstitial infiltration or oedema, visible on a chest X-ray. The syndrome frequently manifests itself within one or two hours of initiating the first infusion. Patients with a history of pulmonary insufficiency or those with pulmonary tumour infiltration may be at greater risk of poor outcome and should be treated with increased caution.
Patients who develop severe cytokine release syndrome should have their infusion interrupted immediately (see section 4.2) and should receive aggressive symptomatic treatment. Since initial improvement of clinical symptoms may be followed by deterioration, these patients should be closely monitored until tumour lysis syndrome and pulmonary infiltration have been resolved or ruled out.
Further treatment of patients after complete resolution of signs and symptoms has rarely resulted in repeated severe cytokine release syndrome.

Patients with a high tumour burden or with a high number (≥25 x 109/L) of circulating malignant cells such as patients with CLL, who may be at higher risk of especially severe cytokine release syndrome, should be treated with extreme caution. These patients should be very closely monitored throughout the first infusion. Consideration should be given to the use of a reduced infusion rate for the first infusion in these patients or a split dosing over two days during the first cycle and any subsequent cycles if the lymphocyte count is still >25 x 109/L.

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

Anaphylactic and other hypersensitivity reactions have been reported following the intravenous administration of proteins to patients. In contrast to cytokine release syndrome, true hypersensitivity reactions typically occur within minutes after starting infusion. Medicinal products for the treatment of hypersensitivity reactions, e.g., epinephrine (adrenaline), antihistamines and glucocorticoids, should be available for immediate use in the event of an allergic reaction during administration of MabThera.
Clinical manifestations of anaphylaxis may appear similar to clinical manifestations of the cytokine release syndrome (described above). Reactions attributed to hypersensitivity have been reported less frequently than those attributed to cytokine release.

Additional reactions reported in some cases were myocardial infarction, atrial fibrillation, pulmonary oedema and acute reversible thrombocytopenia.

Since hypotension may occur during MabThera administration, consideration should be given to withholding anti-hypertensive medicines 12 hours prior to the MabThera infusion.

Haematological toxicities
Although MabThera is not myelosuppressive in monotherapy, caution should be exercised when considering treatment of patients with neutrophils < 1.5 x 109/L and/or platelet counts < 75 x 109/L as clinical experience in this population is limited. MabThera has been used in 21 patients who underwent autologous bone marrow transplantation and other risk groups with a presumable reduced bone marrow function without inducing myelotoxicity.

Regular full blood counts, including neutrophil and platelet counts, should be performed during MabThera therapy.

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

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

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

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

Infusion related reactions
MabThera is associated with infusion related reactions (IRRs), which may be related to release of cytokines and/or other chemical mediators.

Severe IRRs with fatal outcome have been reported in rheumatoid arthritis patients in the post- marketing setting. In rheumatoid arthritis most infusion-related events reported in clinical trials were mild to moderate in severity. The most common symptoms were allergic reactions like headache, pruritus, throat irritation, flushing, rash, urticaria, hypertension, and pyrexia. In general, the proportion of patients experiencing any infusion reaction was higher following the first infusion than following the second infusion of any treatment course. The incidence of IRR decreased with subsequent courses (see section 4.8). The reactions reported were usually reversible with a reduction in rate, or interruption, of MabThera infusion and administration of an anti-pyretic, an antihistamine, and, occasionally, oxygen, intravenous saline or bronchodilators, and glucocorticoids if required. Closely monitor patients with pre-existing cardiac conditions and those who experienced prior cardiopulmonary adverse reactions. Depending on the severity of the IRR and the required interventions, temporarily or permanently discontinue MabThera. In most cases, the infusion can be resumed at a 50 % reduction in rate (e.g. from 100 mg/h to 50 mg/h) when symptoms have completely resolved.

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

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

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


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


Immunisation
Physicians should review the patient’s vaccination status and patients should, if possible, be brought up-to-date with all immunisations in agreement with current immunisation guidelines prior to initiating MabThera therapy. Vaccination should be completed at least 4 weeks prior to first administration of MabThera.

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

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

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

Concomitant/sequential use of other DMARDs in rheumatoid arthritis
The concomitant use of MabThera and anti-rheumatic therapies other than those specified under the rheumatoid arthritis indication and posology is not recommended.

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

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


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

Effects on Driving

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.