Ruxience

/ Pfizer

This medicinal product should be administered under the close supervision of an experienced healthcare professional, and in an environment where full resuscitation facilities are immediately available.
Premedication and prophylactic medications:
Premedication consisting of an anti-pyretic and an antihistaminic, e.g. paracetamol and diphenhydramine, should always be given before each administration of rituximab.
Non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia
Premedication with glucocorticoids should be considered if rituximab is not given in combination with glucocorticoid-containing chemotherapy.
Prophylaxis with adequate hydration and administration of uricostatics starting 48 hours prior to start of therapy is recommended for CLL patients to reduce the risk of tumour lysis syndrome. For CLL patients whose lymphocyte counts are > 25 x 109/L, it is recommended to administer prednisone/prednisolone 100 mg intravenous shortly before infusion with rituximab to decrease the rate and severity of acute infusion reactions and/or cytokine release syndrome.
Rheumatoid arthritis, granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), and pemphigus vulgaris
Premedication with 100 mg intravenous methylprednisolone should be completed 30 minutes prior to rituximab infusion to decrease the incidence and severity of infusion-related reactions (IRRs).
In patients with GPA or MPA, methylprednisolone given intravenously for 1 to 3 days at a dose of 1000 mg per day is recommended prior to the first infusion of rituximab (the last dose of methylprednisolone may be given on the same day as the first infusion of rituximab). This should be followed by oral prednisone 1 mg/kg/day (not to exceed 80 mg/day, and tapered as rapidly as possible based on clinical need) during and after the 4 week induction course of rituximab treatment.
Pneumocystis jirovecii pneumonia (PJP) prophylaxis is recommended for patients with GPA/MPA or PV during and following rituximab treatment, as appropriate according to local clinical practice guidelines.
Non-Hodgkin’s lymphoma:
Follicular non-Hodgkin’s lymphoma: Combination therapy – The recommended dose of rituximab in combination with chemotherapy for induction treatment of previously untreated or relapsed/refractory patients with follicular lymphoma is: 375 mg/m2 body surface area per cycle, for up to 8 cycles. Rituximab should be administered on day 1 of each chemotherapy cycle, after intravenous administration of the glucocorticoid component of the chemotherapy if applicable.
Maintenance therapy:
• Previously untreated follicular lymphoma: 375 mg/m2 body surface area once every 2 months (starting 2 months after the last dose of induction therapy) until disease progression or for a maximum period of two years (12 infusions in total).
• Relapsed/refractory follicular lymphoma: 375 mg/m2 body surface area once every 3 months (starting 3 months after the last dose of induction therapy) until disease progression or for a maximum period of two years (8 infusions in total).
Monotherapy:
• Relapsed/refractory follicular lymphoma: The recommended dose of induction treatment for adult patients with stage III-IV follicular lymphoma who are chemoresistant or are in their second or subsequent relapse after chemotherapy is: 375 mg/m2 body surface area, administered as an intravenous infusion once weekly for four weeks.
For re-treatment with rituximab monotherapy for patients who have responded to previous treatment with rituximab monotherapy for relapsed/refractory follicular lymphoma, the recommended dose is: 375 mg/m2 body surface area, administered as an intravenous infusion once weekly for four weeks.
Diffuse large B cell non-Hodgkin’s lymphoma: Rituximab should be used in combination with CHOP chemotherapy. The recommended dosage is 375 mg/m2 body surface area, administered on day 1 of each chemotherapy cycle for 8 cycles after intravenous infusion of the glucocorticoid component of CHOP. Safety and efficacy of rituximab have not been established in combination with other chemotherapies in diffuse large B cell non-Hodgkin’s lymphoma.
Chronic lymphocytic leukaemia:
The recommended dosage of rituximab in combination with chemotherapy for previously untreated and relapsed/refractory patients is 375 mg/m2 body surface area administered on day 0 of the first treatment cycle followed by 500 mg/m2 body surface area administered on day 1 of each subsequent cycle for 6 cycles in total. The chemotherapy should be given after rituximab infusion.
Rheumatoid arthritis:
A course of rituximab consists of two 1000 mg intravenous infusions. The recommended dosage of rituximab is 1000 mg by intravenous infusion followed by a second 1000 mg intravenous infusion two weeks later.
Subsequent courses should be administrated every 24 weeks or based on clinical evaluation, but not sooner than every 16 weeks.
Available data suggest that clinical response is usually achieved within 16 – 24 weeks of an initial treatment course. Continued therapy should be carefully reconsidered in patients who show no evidence of therapeutic benefit within this time period.
Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA):
The recommended dosage for induction of remission therapy is 375 mg/m2 body surface area, administered as an intravenous infusion once weekly for 4 weeks (four infusions in total).
Pemphigus vulgaris:
The recommended dosage is 1000 mg administered as an IV infusion followed two weeks later by a second 1000 mg IV infusion in combination with a tapering course of glucocorticoids.
Maintenance treatment: A maintenance infusion of 500 mg IV should be administered at month 12 and then every 6 months thereafter based on clinical evaluation.
Treatment of relapse: In the event of relapse, patients may receive 1000 mg IV. The healthcare provider should also consider resuming or increasing the patient’s glucocorticoid dose based on clinical evaluation.
Subsequent infusions may be administered no sooner than 16 weeks following the previous infusion.
See prescribing information for full details.

Non-Hodgkin’s lymphoma (NHL):
-Treatment of patients with relapsed or refractory low-grade or follicular, B-cell non-hodgkin’s lymphoma.
-Treatment of previously untreated patients with low-grade or follicular lymphoma in combination with chemotherapy.
– Treatment of patients with CD20 positive diffuse large B- cell non-Hodgkin’s lymphoma in combination with CHOP chemotherapy.
– Rituximab maintenance therapy is indicated for the treatment of follicular lymphoma patients responding to induction therapy.
Chronic lymphocytic leukaemia (CLL):
Rituximab in combination with chemotherapy is indicated for the treatment of patients with previously untreated and relapsed/refractory chronic lymphocytic  leukaemia. Only limited data are available on efficacy and safety for patients previously treated with monoclonal antibodies including rituximab or patients refractory to previous rituximab plus chemotherapy.
Rheumatoid arthritis:
Rituximab is indicated, in combination with methotrexate, to reduce signs and symptoms in adult patients with moderately to severely active rheumatoid arthritis who had an inadequate response or intolerance to one or more TNF antagonist therapies.
Granulomatosis with polyangiitis and microscopic polyangiitis:
Rituximab, in combination with glucocorticoids, is indicated for the treatment of adult patients with granulomatosis with polyangiitis (GPA) (Wegener’s Granulomatosis (WG)) and microscopic polyangiitis (MPA).
Pemphigus vulgaris:
Treatment of adult patients with moderate to severe pemphigus vulgaris (PV).

* Hypersensitivity to the active substance or to murine proteins, or to any of the excipients.
* Active, severe infections.
* Patients in a severely immunocompromised state.
* Severe heart failure (New York Heart Association Class IV) or severe, uncontrolled cardiac disease for use in rheumatoid arthritis, granulomatosis with polyangiitis, microscopic polyangiitis and pemphigus vulgaris only.

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 rituximab. 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. If a patient develops PML, the dosing of rituximab 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 rituximab 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 rituximab. Therefore patients with a history of cardiac disease and/or cardiotoxic chemotherapy should be monitored closely.
Infections: Based on the mechanism of action of Ruxience and the knowledge that B-cells play an important role in maintaining normal immune response, patients have an increased risk of infection following Ruxience therapy. Serious infections, including fatalities, can occur during therapy with Ruxience. Ruxience should not be administered to patients with an active, severe infection (e.g. tuberculosis, sepsis and opportunistic infections) or severely immunocompromised patients (e.g. where levels of CD4 or CD8 are very low). Physicians should exercise caution when considering the use of Ruxience 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. It is recommended that immunoglobulin levels are determined prior to initiating treatment with Ruxience. Patients reporting signs and symptoms of infection following Ruxience therapy should be promptly evaluated and treated appropriately. Before giving a subsequent course of Ruxience treatment, patients should be re-evaluated for any potential risk for infections. Cases of enteroviral meningoencephalitis including fatalities have been reported following use of Ruxience.
Hepatitis B Infections: Cases of hepatitis B reactivation, including those with a fatal outcome, have been reported in patients receiving Ruxience. The majority of these patients were also exposed to cytotoxic chemotherapy. Limited information from one study in relapsed/refractory CLL patients suggests that Ruxience 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 Ruxience. At minimum this should include HBsAg-status and HBcAb-status. Patients with active hepatitis B disease should not be treated with Ruxience. 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. In case of such an event, with a suspected relationship to rituximab, treatment should be permanently discontinued.
Non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia:
Infusion-related reactions: Rituximab 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 includes syndrome of cytokine release, tumour lysis syndrome and anaphylactic and hypersensitivity reactions. See prescribing information for full details.
Haematological toxicities: Although rituximab 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. Regular full blood counts, including neutrophil and platelet counts, should be performed during Ruxience therapy.
Immunisations: The safety of immunisation with live viral vaccines, following rituximab therapy has not been studied for NHL and CLL patients and vaccination with live virus vaccines is not recommended. Patients treated with Ruxience may receive non-live vaccinations; however with non-live vaccines response rates may be reduced. 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 rituximab.
Rheumatoid arthritis, granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), and pemphigus vulgaris:
Methotrexate (MTX) naïve populations with rheumatoid arthritis: The use of rituximab is not recommended in MTX-naïve patients since a favourable benefit-risk relationship has not been established.
Infusion-related reactions: Rituximab 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. The reactions reported were usually reversible with a reduction in rate, or interruption, of rituximab 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 rituximab. 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 rituximab administration.
There are no data on the safety of rituximab in patients with moderate heart failure (NYHA class III) or severe, uncontrolled cardiovascular disease. In patients treated with rituximab, 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 rituximab and patients closely monitored during administration. Since hypotension may occur during rituximab infusion, consideration should be given to withholding anti-hypertensive medications 12 hours prior to the rituximab 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.
Late neutropenia: Measure blood neutrophils prior to each course of rituximab, and regularly up to 6-months after cessation of treatment, and upon signs or symptoms of infection.
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 rituximab therapy. Vaccination should be completed at least 4 weeks prior to first administration of rituximab.
The safety of immunisation with live viral vaccines following rituximab therapy has not been studied. Therefore vaccination with live virus vaccines is not recommended whilst on rituximab or whilst peripherally B cell depleted.
Patients treated with rituximab may receive non-live vaccinations; however, response rates to non-live vaccines may be reduced. Should non-live vaccinations be required whilst receiving rituximab therapy, these should be completed at least 4 weeks prior to commencing the next course of rituximab. See prescribing information for full details.
Concomitant/sequential use of other DMARDs in rheumatoid arthritis: The concomitant use of rituximab 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 rituximab. The available data indicate that the rate of clinically relevant infection is unchanged when such therapies are used in patients previously treated with rituximab, however patients should be closely observed for signs of infection if biologic agents and/or DMARDs are used following rituximab 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 underlying autoimmune condition.
See prescribing information for full details.

 See prescribing information for full details.

Currently, there are limited data on possible drug interactions with rituximab.
In CLL patients, co-administration with rituximab 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 rituximab.
Co-administration with methotrexate had no effect on the pharmacokinetics of rituximab in rheumatoid arthritis patients.
Patients with human anti-mouse antibody (HAMA) or anti-drug antibody (ADA) titres may have allergic or hypersensitivity reactions when treated with other diagnostic or therapeutic monoclonal antibodies.
In patients with rheumatoid arthritis, 283 patients received subsequent therapy with a biologic DMARD following rituximab. In these patients the rate of clinically relevant infection while on rituximab was 6.01 per 100 patient years compared to 4.97 per 100 patient years following treatment with the biologic DMARD.

Contraception in males and females:
Due to the long retention time of rituximab in B cell depleted patients, women of childbearing potential should use effective contraceptive methods during and for 12 months following treatment.
Pregnancy:
IgG immunoglobulins are known to cross the placental barrier.
B cell levels in human neonates following maternal exposure to rituximab 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 rituximab during pregnancy. Similar effects have been observed in animal studies. For these reasons, this medicinal product should not be administered to pregnant women unless the possible benefit outweighs the potential risk.
Breast-feeding:
Limited data on rituximab excretion into breast milk suggest very low rituximab concentrations in milk (relative infant dose less than 0.4%). Few cases of follow-up of breastfed infants describe normal growth and development up to 2 years. However, as these data are limited and the long-term outcomes of breastfed infants remain unknown, breast-feeding is not recommended while being treated with rituximab and optimally for 6 months following rituximab treatment.
Fertility:
Animal studies did not reveal deleterious effects of rituximab on reproductive organs.

Limited experience with doses higher than the approved dose of intravenous rituximab formulation is available from clinical trials in humans. The highest intravenous dose of rituximab tested in humans to date is 5000 mg (2250 mg/m2), tested in a dose escalation study in patients with CLL. No additional safety signals were identified.
Patients who experience overdose should have immediate interruption of their infusion and be closely monitored.
In the post-marketing setting five cases of rituximab 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.

Store in a refrigerator (2°C – 8°C).
Keep the vial in the outer carton in order to protect from light.