Redditux 100 mg/500 mg Solution

REDDITUX is indicated for:

• Non Hodgkin lymphoma (NHL):
• patients with relapsed or chemo-resistant low grade or follicular, CD20- positive, B-cell non Hodgkin lymphoma;
• previously untreated patients with stage III-IV follicular lymphoma in combination with chemotherapy;
• patients with follicular lymphoma as maintenance treatment, after response to induction therapy.
• patients with high grade CD20-positive diffuse large B cell non Hodgkin lymphoma in combination with CHOP (cyclophosphamide (C), doxorubicin (H), vincristine (O), prednisolone (P) chemotherapy.
• Chronic lymphocytic leukaemia (CLL):
• REDDITUX in combination with fludarabine and cyclophosphamide is indicated for the treatment of patients with previously untreated relapsed/refractory chronic lymphocytic leukaemia (CLL).
• Granulomatosis with polyangiitis and microscopic polyangiitis:
• REDDITUX, in combination with glucocorticoids, is indicated for the treatment of patients with severely active Granulomatosis with polyangiitis (GPA, also known as Wegeneru2019s granulomatosis) and microscopic polyangiitis (MPA).
• Pemphigus vulgaris:
• REDDITUX is indicated for the treatment of patients with moderate to severe pemphigus vulgaris (PV).

REDDITUX 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 and prophylactic medications

Premedication consisting of an anti-pyretic and an antihistaminic, e.g., paracetamol and diphenhydramine, should always be administered before each infusion of REDDITUX.

Premedication with glucocorticoids should be considered if REDDITUX is not given in combination with glucocorticoid-containing chemotherapy for treatment of non Hodgkin lymphoma and chronic lymphocytic leukaemia.

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 10 9 /u2113 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.

In patients with granulomatosis with polyangiitis (Wegeneru2019s) or microscopic polyangiitis in disease remission or pemphigus vulgaris, premedication with 100 mg intravenous methylprednisolone should be completed 30 minutes prior to REDDITUX infusions to decrease the incidence and severity of infusion related reactions (IRRs).

In patients with granulomatosis with polyangiitis (Wegener's) or microscopic polyangiitis, methylprednisolone given intravenously for 1 to 3 days at a dose of 1000 mg per day is recommended prior to the first infusion of REDDITUX (the last dose of methylprednisolone may be given on the same day as the first infusion of REDDITUX). 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 REDDITUX treatment.

Pneumocystis jirovecii pneumonia (PCP) prophylaxis is recommended for patients with GPA/MPA or PV during and following REDDITUX treatment.

Posology

Low-grade/CD20 positive or follicular B-cell non Hodgkin lymphoma:

Follicular non Hodgkin lymphoma

a) Initial treatment, weekly for 4 doses: The recommended dosage of REDDITUX used as a single agent/mono-therapy for adult patients is 375 mg/m 2 body surface area (BSA), administered as an intravenous infusion once weekly for four doses.

b) Initial treatment, bulky disease, weekly for 4 doses: The recommended dosage of REDDITUX used as a single agent/monotherapy for adult patients is 375 mg/m 2 body surface area (BSA), administered as an intravenous infusion once weekly for four doses.

c) Re-treatment following relapse, weekly for 4 doses: Patients who have responded to REDDITUX initially have been treated again with REDDITUX at a dose of 375 mg/m 2 body surface area, administered as an IV infusion once weekly for 4 weeks.

e) Combination therapy: The recommended dosage of REDDITUX in combination with chemotherapy for induction treatment of previously untreated or relapsed/refractory patients with follicular NHL is 375 mg/m 2 body surface area per cycle for 8 cycles (21 days/cycle). REDDITUX should be administered on day 1 of each chemotherapy cycle, after IV administration of the glucocorticoid component of the chemotherapy, if applicable.

f) Maintenance therapy: Previously untreated patients after response to induction treatment may receive maintenance therapy with REDDITUX given at 375 mg/m 2 body surface area once every 2 months until disease progression or for a maximum period of two years (12 infusions). Relapsed/refractory patients after response to induction treatment may receive maintenance therapy with REDDITUX given at 375 mg/m 2 body surface area once every 3 months until disease progression or for a maximum period of two years.

High grade/CD20 positive or diffuse large B-cell non-Hodgkin's lymphoma: REDDITUX should be used in combination with CHOP chemotherapy (R-CHOP). The recommended dosage is 375 mg/m 2 body surface area, administered on day 1 of each chemotherapy cycle for 8 cycles after IV administration of the glucocorticoid component of CHOP. The other components of CHOP should be given after the administration of REDDITUX.

First infusion: The recommended initial rate for infusion is 50 mg/hr; which can subsequently be escalated in 50 mg/hr increments every 30 minutes, to a maximum of 400 mg/hr.

Subsequent infusions: Subsequent doses of REDDITUX can be infused at an initial rate of 100 mg/hr, and increased by 100 mg/hr increments at 30-minute intervals, to a maximum of 400 mg/hr.

Dosage adjustments during treatment

No dose reductions of REDDITUX are recommended. When REDDITUX is given in combination with CHOP or CVP chemotherapy, standard dose reductions for the chemotherapeutic agents should be applied.

Chronic Lymphocytic Leukaemia (CLL) For CLL patients whose lymphocyte counts are > 25 x 10 9 /u2113 it is recommended to administer prednisone/prednisolone 100 mg IV shortly before infusion with REDDITUX to decrease the rate and severity of acute infusion reactions and/or cytokine release syndrome. The recommended dosage of REDDITUX in combination with chemotherapy for previously untreated and relapsed/refractory patients is 375 mg/m 2 body surface area administered on day 0 of the first treatment cycle (the day before chemotherapy) followed by 500 mg/m 2 body surface area administered on day 1 of each subsequent cycle for 6 cycles in total. The chemotherapy should be given after REDDITUX infusion.

Granulomatosis with polyangiitis and microscopic polyangiitis The recommended dosage of REDDITUX for treatment of GPA and MPA is 375 mg/m 2 body surface area, administered as an IV infusion once weekly for 4 weeks. Methylprednisolone 1 000 mg IV per day for 1 to 3 days is recommended in combination with REDDITUX to treat severe vasculitis symptoms, followed by oral prednisone 1 mg/kg/day (not to exceed 80 mg/day, and tapered as rapidly as possible per clinical need) during and after REDDITUX treatment.

First infusion: The recommended initial infusion rate for REDDITUX is 50 mg/h; subsequently, the rate can be escalated in 50 mg/h increments every 30 minutes to a maximum of 400 mg/h.

Subsequent infusions: Subsequent infusions of REDDITUX can be started at a rate of 100 mg/h and increased by 100 mg/h increments every 30 minutes to a maximum of 400 mg/h.

Pneumocystis jiroveci pneumonia (PCP) prophylaxis is recommended for patients with GPA and MPA during and following REDDITUX treatment, as appropriate.

Pemphigus vulgaris The recommended dosage of REDDITUX for the treatment of pemphigus vulgaris 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 months 12 and 18, and then every 6 months thereafter if needed, 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.

Special populations

Children and adolescents: The safety and efficacy of REDDITUX in children below 18 years has not yet been established.

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

Method of Administration

The prepared REDDITUX solution should be administered as an intravenous (IV) infusion through a dedicated line. It should not be administered as an intravenous injection or bolus infusion. REDDITUX infusions should be administered in an environment where full resuscitation facilities are immediately available and under the close supervision of an experienced physician. REDDITUX is compatible with 0,9 % sodium chloride (normal saline) or 5 % dextrose (D5W) solutions for infusion.

First infusion The recommended initial rate for infusion is 50 mg/hr; after the first 30 minutes, it can be escalated in 50 mg/hr increments every 30 minutes, to a maximum of 400 mg/hr.

Subsequent infusions Subsequent doses of REDDITUX can be infused at an initial rate of 100 mg/hr, and increased by 100 mg/hr increments at 30 minutes intervals, to a maximum of 400 mg/hr.

• Hypersensitivity to the active substance (rituximab) or to any of the excipients or to murine proteins.
• Active, severe infections (See Section 4.4).
• Patients in a severely immunocompromised state.
• Severe heart failure (New York Heart Association Class IV) or severe, uncontrolled cardiac disease. (See Section 4.4).

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. 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 REDDITUX 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 REDDITUX therapy may lead to similar stabilisation or improved outcome.

Non Hodgkin lymphoma (NHL) and chronic lymphocytic leukaemia (CLL)

Infusion related reactions (IRRs) 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 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 rituximab with an onset ranging within 30 minutes to 2 hours after starting the first rituximab 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 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 (u2265 25 x 10 9 /u2113) 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 10 9 / u2113.

Infusion-related adverse reactions of all kinds have been observed in 77 % of patients treated with rituximab (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 rituximab infusion and administration of an anti-pyretic, an antihistaminic and occasionally oxygen, intravenous saline or bronchodilators, and glucocorticoids if required.

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 REDDITUX. 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 rituximab administration, consideration should be given to withholding anti-hypertensive medicines 12 hours prior to the REDDITUX infusion.

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.

Haematological toxicities

Although REDDITUX is not myelosuppressive in monotherapy, caution should be exercised when considering treatment of patients with neutrophils < 1,5 x 10 9 /u2113 and/or platelet counts < 75 x 10 9 /u2113 as clinical experience in this population is limited. Rituximab has been used in 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 REDDITUX therapy.

Infections

Serious infections, including fatalities, can occur during therapy with rituximab. REDDITUX should not be administered to patients with an active, severe infection (e.g., tuberculosis, sepsis and opportunistic infections, see Section 4.3). Medical practitioners should exercise caution when considering the use of REDDITUX 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 and reports of fulminant hepatitis, some of which were fatal have been reported in patients receiving rituximab. The majority of these subjects were also exposed to cytotoxic chemotherapy. The reports were confounded by both the underlying disease state and the cytotoxic chemotherapy. Limited information from one study in relapsed/refractory CLL patients suggests that rituximab 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 REDDITUX. At minimum this should include HBsAg-status and HBcAb-status. Patients with active hepatitis B disease should not be treated with REDDITUX. 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 progressive multifocal leukoencephalopathy (PML) have been reported during post-marketing use of rituximab in NHL and CLL (see Section 4.8). The majority of patients had received rituximab in combination with chemotherapy or as part of a hematopoietic stem cell transplant.

Immunisations

The safety of immunisation with live viral vaccines, following rituximab therapy has not been studied for NHL and CLL patients. Vaccination with live virus vaccines is therefore not recommended. Patients treated with REDDITUX 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 rituximab 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, and varicella) were maintained for at least 6 months after treatment with rituximab.

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 REDDITUX, treatment should be permanently discontinued.

Paediatric population

See section u201c4.2 Posology and method of administration, Special populations.u201d

Limited data on possible drug interactions with rituximab is currently available. 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. 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.

Safety in pregnancy and lactation has not been established.

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. For these reasons REDDITUX should not be administered to pregnant women unless the possible benefit outweighs the potential risk.

Lactation

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

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 with REDDITUX.

Fertility

Animal studies did not reveal deleterious effects of rituximab on reproductive organs.

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

Experience from non Hodgkin lymphoma (NHL) and chronic lymphocytic leukaemia (CLL) in adults

Summary of the safety profile

The overall safety profile of rituximab in non Hodgkin lymphoma and chronic lymphocytic leukaemia is based on data from patients from clinical trials and from post-marketing surveillance. These patients were treated either with rituximab monotherapy (as induction treatment or maintenance treatment following induction treatment) or in combination with chemotherapy.

The most frequently observed adverse drug reactions (ADRs) in patients receiving rituximab 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 rituximab.

Infectious events (predominantly bacterial and viral) occurred in approximately 30 to 55 % of patients during clinical trials in patients with NHL and in 30 to 50 % of patients during clinical trial in patients with CLL.

The most frequent reported or observed serious adverse drug reactions were:

• Infusion-related reactions (including cytokine-release syndrome, tumour-lysis syndrome),
• Infections
• Cardiovascular events

Other serious ADRs reported include hepatitis B reactivation and PML (see Section 4.4).

Tabulated list of adverse reactions

The frequencies of ADRs reported with rituximab alone or in combination with chemotherapy are summarised in the tables below. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Frequencies are defined as very common (u2265 1/10), common (u2265 1/100 to < 1/10) uncommon (u2265 1/1,000 to < 1/100), rare (u2265 1/10,000 to < 1/1000) and very rare (<1/10,000). The ADRs identified only during post-marketing surveillance, and for which a frequency could not be estimated, are listed under u201cunknownu201d.

Limited experience with doses higher than the approved dose of intravenous rituximab is available from clinical trials in humans. The highest intravenous dose of rituximab tested in humans to date is 5000 mg (2250 mg/m 2), tested in a dose escalation study in patients with chronic lymphocytic leukaemia. 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.