Ristova Range 100 mg (in 10 m_) / 500 mg (in 50 m_) Infusion

RISTOVA is indicated for the treatment of:

• patients with relapsed or chemo-resistant low-grade or follicular, CD20-positive, B-cell non-Hodgkinu2019s 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-Hodgkinu2019s lymphoma in combination with CHOP (Cyclophosphamide - C, Doxorubicin - H, Vincristine - O, Prednisone - P) chemotherapy.

Chronic Lymphocytic Leukaemia

RISTOVA in combination with fludarabine and cyclophosphamide is indicated for the treatment of patients with relapsed/refractory chronic lymphocytic leukaemia (CLL).

Rheumatoid Arthritis

RISTOVA in combination with methotrexate is indicated for the treatment of adult patients with active rheumatoid arthritis who have had an inadequate response or intolerance to other disease-modifying anti-rheumatic drugs (DMARDs) including one or more tumour necrosis factor (TNF) inhibitor therapies.

ANCA-Associated Vasculitis (AAV):

RISTOVA in combination with glucocorticoids is indicated for the treatment of patients with severely active anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis.

The prepared RISTOVA solution should be administered as an IV infusion through a dedicated line. The prepared infusion solution must not be administered as an IV injection or bolus infusion. RISTOVA infusions should be administered in an environment where full resuscitation facilities are immediately available, and under the close supervision of an experienced physician.

RISTOVA is compatible with 0,9 % sodium chloride (normal saline) or 5 % dextrose (D5W) solutions for infusion. Pre-medication consisting of an anti-pyretic and an antihistaminic, e.g. paracetamol and diphenhydramine, should always be administered 30 to 60 minutes prior to each infusion of RISTOVA. Pre-medication with glucocorticoids should also be considered, particularly if RISTOVA is not given in combination with steroid-containing chemotherapy.

Patients should be closely monitored for the onset of cytokine release syndrome. In patients who develop evidence of severe reactions, especially severe dyspnoea, bronchospasm or hypoxia the infusion should immediately be interrupted. The patient should then be evaluated for evidence of tumour lysis syndrome including appropriate laboratory tests and, for pulmonary infiltration, with a chest X-ray. The infusion should not be restarted until complete resolution of all symptoms, and normalisation of laboratory values and chest X-ray findings. At this time, the infusion can be initially resumed at not more than one-half the previous rate. If the same severe adverse reactions occur for a second time the decision to stop the treatment should be seriously considered on a case by case basis. See WARNINGS.

Mild or moderate infusion-related reactions usually respond to a reduction in the rate of infusion. The infusion may be increased upon improvement of symptoms.

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

a) Initial treatment, weekly for 4 doses: The recommended dosage of RISTOVA used as a single agent/mono-therapy for adult patients is 375 mg/m2 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 RISTOVA used as a single agent/monotherapy for adult patients is 375 mg/m2 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 RISTOVA initially have been treated again with RISTOVA at a dose of 375 mg/m2 body surface area, administered as an IV infusion once weekly for 4 weeks.

d) Combination therapy: The recommended dosage of RISTOVA in combination with chemotherapy for induction treatment of previously untreated or relapsed/refractory patients with follicular NHL is 375 mg/m2 body surface area per cycle for 8 cycles (21 days/cycle). RISTOVA should be administered on day 1 of each chemotherapy cycle, after IV administration of the glucocorticoid component of the chemotherapy, if applicable.

e) Maintenance therapy: Previously untreated patients after response to induction treatment may receive maintenance therapy with RISTOVA given at 375 mg/m2 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 RISTOVA given at 375 mg/m2 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: RISTOVA should be used in combination with CHOP chemotherapy (R-CHOP). The recommended dosage is 375 mg/m2 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 RISTOVA.

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 RISTOVA 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.

Hypersensitivity to the active substance or to any of the excipients or to murine proteins. Active, severe infections. Patients in a severely immunocompromised state. Severe heart failure (New York Heart Association Class IV) or severe, uncontrolled cardiac disease. See WARNINGS and SIDE EFFECTS AND SPECIAL PRECAUTIONS.

Non-Hodgkinu2019s Lymphoma and Chronic Lymphocytic Leukaemia (CLL) Patients

Infusion-related adverse events: Patients with a high number (> 25 x 10 9 /u2113) of circulating malignant cells or high tumour burden such as patients with CLL and mantle cell lymphoma may be at higher risk of especially severe infusion-related reactions. These patients should be treated with extreme caution and only when other therapeutic alternatives have been exhausted. 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. (See SIDE EFFECTS AND SPECIAL PRECAUTIONS).

RISTOVA is associated in more than 77 % of patients with infusion-related reactions. These may be related to release of cytokine release syndrome and/or chemical mediators. Severe infusion-related reactions may be clinically indistinguishable from hypersensitivity reactions or cytokine release syndrome. Severe infusion-related reactions usually manifest within 30 minutes to 2 hours after starting the first RISTOVA infusion, and are characterised by pulmonary events and includes, in some cases, rapid tumour lysis and features of tumour lysis syndrome in addition to fever, chills, rigors. Other symptoms include flushing, angioedema, nausea, urticaria/rash, fatigue, headache, throat irritation, rhinitis, vomiting, and tumour pain. Hypotension and bronchospasm accompanied these symptoms in about 10 % of the cases.

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 DOSAGE AND DIRECTIONS FOR USE) 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.

Infusion reaction symptoms are usually reversible with interruption of the infusion. Treatment of infusion-related symptoms with an antihistaminic and a pain reliever is recommended. Additional treatment with bronchodilators or IV saline may be indicated. 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. Most patients who have experienced non-life threatening infusion-related reactions have been able to complete the full course of RISTOVA therapy. Further treatment of patients after complete resolution of signs and symptoms has rarely resulted in repeated severe infusion-related reactions. Anaphylactic and other hypersensitivity reactions have been reported following the intravenous administration of RISTOVA to patients. Epinephrine, antihistamines and glucocorticoids should be available for immediate use in the event of a hypersensitivity reaction to RISTOVA.

Regarding the management of infusion-related reactions:

• RISTOVA (rituximab) infusion should be discontinued in patients who develop clinically significant cardiopulmonary events and they should receive medical treatment.
• Patients with pre-existing cardiac and pulmonary conditions or those with prior clinically significant cardiopulmonary adverse events should be monitored during and after subsequent infusions of RISTOVA (rituximab). See SIDE-EFFECTS AND SPECIAL PRECAUTIONS.

In the reported cases, the following factors were more frequently associated with fatal outcomes: women, patients with pulmonary infiltrates, and patients with Chronic Lymphocytic Leukaemia (CLL) or mantle cell lymphoma.

Pulmonary events: Severe pulmonary infusion-related events that resulted in fatal outcomes have been reported during post-marketing use. Pulmonary events have included hypoxia, lung infiltration, and acute respiratory failure. Some of these events have been preceded by severe bronchospasm and dyspnoea. In some cases, symptoms worsened over time, while in others initial improvement was followed by clinical deterioration. Therefore, patients experiencing pulmonary events or other severe infusion-related symptoms should be closely monitored until complete resolution of their symptoms occur. 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. Acute respiratory failure may be accompanied by events such as pulmonary interstitial infiltration or oedema, visible on a chest x-ray. The syndrome usually manifests itself within one or two hours of initiating the first infusion. Patients who experience severe pulmonary events 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 the pulmonary event has resolved.

Rapid tumour lysis: RISTOVA mediates the rapid lysis of benign and malignant CD20-positive cells. Signs and symptoms (e.g., hyperuricaemia, hyperkalaemia, hypocalcaemia, hyperphosphataemia, acute renal failure, elevated LDH) consistent with tumour lysis syndrome (TLS) have been reported to occur within 30 minutes to 2 hours after the first RISTOVA infusion in patients with high numbers of circulating malignant lymphocytes. If these signs and symptoms develop, treatment should be stopped immediately. Prophylaxis for TLS should be considered for patients at risk of developing rapid tumour lysis (e.g. patients with a high tumour burden or with a high number (> 25 x 10 9 /u2113) of circulating malignant cells such as patients with CLL and mantle cell lymphoma). Patients at risk of developing rapid tumour lysis should be followed closely and appropriate laboratory monitoring performed. Appropriate medical therapy should be provided for patients who develop signs and symptoms consistent with rapid tumour lysis. Following treatment for and complete resolution of signs and symptoms, subsequent RISTOVA therapy has been administered in conjunction with prophylactic therapy for TLS in a limited number of cases. RISTOVA infusions should be administered in an environment where full resuscitation facilities are immediately available, and under the close supervision of an experienced oncologist/haematologist.

Cardiovascular: Since hypotension may occur during RISTOVA infusion, consideration should be given to withholding antihypertensive medications 12 hours prior to and throughout RISTOVA infusion. Angina pectoris or cardiac dysrhythmia, such as atrial flutter and fibrillation, heart failure or myocardial infarction have occurred in patients treated with RISTOVA. Therefore patients with a history of cardiac disease and/or cardiotoxic chemotherapy should be monitored closely. Less frequently, patients experienced an exacerbation of pre-existing cardiac conditions such as angina pectoris or congestive heart failure.

Hypersensitivity 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. Medications 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 RISTOVA. Clinical manifestations of anaphylaxis may appear similar to clinical manifestations of the cytokine release syndrome. Reactions attributed to hypersensitivity have been reported less frequently than those attributed to cytokine release.

Monitoring of blood counts: Although RISTOVA is not myelosuppressive in monotherapy, caution should be exercised when considering treatment of patients with neutrophil counts of < 1,5 x 10 9 /u2113 and/or platelet counts of < 75 x 10 9 /u2113, as clinical experience with such patients is limited. RISTOVA has been used in patients who underwent autologous bone marrow transplantation and in other risk groups with a presumable reduced bone marrow function without inducing myelotoxicity. Consideration should be given to the need for regular full blood counts, including platelet counts, during monotherapy with RISTOVA. When RISTOVA is given in combination with CHOP or CVP chemotherapy, regular full blood counts should be performed according to usual medical practice.

Infections: Serious infections, including fatalities, can occur during therapy with RISTOVA. RISTOVA treatment should not be administered to patients with active, severe infection (eg. tuberculosis, sepsis and opportunistic infections, see CONTRA-INDICATIONS). Physicians should exercise caution when considering the use of RISTOVA in patients with a history of recurring or chronic infections or with underlying conditions which may further predispose patients to serious infection (see SIDE EFFECTS AND SPECIAL PRECAUTIONS). Patients treated with RISTOVA should avoid exposure to patients with tuberculosis and should avoid contact with children and adults recently vaccinated with attenuated live vaccines.

Hepatitis B Infections: Cases of hepatitis B reactivation, including reports of fulminant hepatitis, some of which were fatal, have been reported in subjects receiving rituximab, although the majority of these subjects were also exposed to cytotoxic chemotherapy. The reports are confounded by both the underlying disease state and the cytotoxic chemotherapy. Hepatitis B virus (HBV) screening should be considered for high risk patients before initiation of treatment with RISTOVA. Carriers of hepatitis B and patients with a history of hepatitis B should be closely monitored for clinical and laboratory signs of active HBV infection during and for several months following RISTOVA therapy.

Progressive Multifocal Leuko-encephalopathy (PML): Cases of progressive multifocal leuko-encephalopathy (PML) have been reported during use of RISTOVA in NHL and CLL (See SIDE EFFECTS AND SPECIAL PRECAUTIONS). The majority of patients had received RISTOVA in combination with chemotherapy or as part of a haematopoietic stem cell transplant. Doctors treating patients with RISTOVA should consider PML in the differential diagnosis of patients reporting neurological symptoms and consultation with a neurologist should be considered as clinically indicated.

Immunisation: The safety of immunisation with live viral vaccines, following RISTOVA therapy has not been studied and vaccination with live virus vaccines is not recommended. Patients treated with RISTOVA 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 RISTOVA 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). 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 RISTOVA.

Rheumatoid Arthritis (RA) & ANCA-Associated Vasculitis (AAV) Patients

The efficacy and safety of RISTOVA for the treatment of autoimmune diseases other than rheumatoic arthritis and ANCA-associated vasculitis has not been established.

Infusion-related reactions: RISTOVA is associated with infusion-related reactions (IRRs), which may be related to release of cytokines and/or other chemical mediators. Pre-medication consisting of an analgesic/anti-pyretic and an anti-histaminic, should always be administered before each infusion of RISTOVA. For RA patients, pre-medication with glucocorticoids should also be administered before each infusion of RISTOVA, in order to reduce the frequency and severity of infusion-related reactions. See DOSAGE AND DIRECTIONS FOR USE, WARNINGS and SIDE EFFECTS AND SPECIAL PRECAUTIONS. For RA patients, most infusion-related events reported in clinical trials were mild to moderate in severity. Severe infusion-related reactions with fatal outcome have been reported in the post-marketing setting (see Post-Marketing, RA section). Closely monitor patients with pre-existing cardiac conditions and those who experienced prior cardiopulmonary adverse reactions. The most common symptoms were 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 of any treatment course than following the second infusion. Subsequent RISTOVA infusions were better tolerated by patients than the initial infusion. Fewer than 1 % of patients experienced serious IRRs, with most of these reported during the first infusion of the first course (see SIDE EFFECTS AND SPECIAL PRECAUTIONS). Most infusion events reported were mild to moderate in severity. The proportion of affected patients decreases with subsequent infusions. The reactions reported were usually reversible with a reduction in rate, or interruption, of RISTOVA infusion and administration of an anti-pyretic, an antihistamine, and, occasionally, oxygen, IV saline or bronchodilators, and glucocorticoids as required. Depending on the severity of the infusion-related reaction and the required interventions, temporarily or permanently discontinue RISTOVA. 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. Anaphylactic and other hypersensitivity reactions have been reported following the IV administration of proteins, including RISTOVA, to patients. Medicines 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 RISTOVA. In clinical studies 10/990 (1 %) patients with rheumatoid arthritis who received a first infusion of RISTOVA at any dose experienced a severe reaction during the infusion. RISTOVA infusions should be administered in an environment where full resuscitation facilities are immediately available, and under the close supervision of an experienced doctor. Infusion-related reactions for AAV patients were similar to those seen for RA patients in clinical trials (see SIDE EFFECTS AND SPECIAL PRECAUTIONS - ANCA-Associated Vasculitis). For AAV patients, RISTOVA was given in combination with high doses of glucocorticoids (see DOSAGE AND DIRECTIONS FOR USE), which may reduce the incidence and severity of these events (see information for RA indication above).

Currently, limited data are available on possible medicine interactions with RISTOVA. In CLL patients, co-administration with RISTOVA 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 RISTOVA in rheumatoid arthritis patients.

Safety in pregnancy and lactation has not been established.

Pregnancy: IgG immunoglobulins are known to cross the placental barrier. Developmental toxicity studies performed in 12 pregnant cynomolgus monkeys revealed no evidence of embryotoxicity in utero. Newborn offspring of maternal animals exposed to RISTOVA were noted to have depleted B cell populations during the post natal phase. Abortion occurred in 3 and foetal death in 2 dams. It is not known whether RISTOVA can cause foetal harm when administered to a pregnant woman or whether it can affect reproductive capacity. B cell levels in human neonates following maternal exposure to RISTOVA 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 RISTOVA should not be given to a pregnant woman unless the potential benefit outweighs the potential risk. Due to the long retention time of rituximab in B-cell depleted patients, women of childbearing potential should use effective contraceptive methods during treatment and up to 12 months following RISTOVA therapy.

Lactation: Whether rituximab is excreted in human milk is not known. However, because maternal IgG is excreted in human milk, RISTOVA should not be given to women who are breast-feeding.

The overall safety profile of RISTOVA in non-Hodgkinu2019s 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 RISTOVA 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 RISTOVA 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 RISTOVA. 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 trials 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 and cardiovascular events. Other serious ADRs reported include hepatitis B reactivation and PML (See WARNINGS).

There has been no experience of overdosage in human clinical trials. Single doses higher than 1 000 mg have not been tested in controlled clinical trials. The highest dose tested to date is 5 g in patients with chronic lymphocytic leukaemia. No additional safety signals were identified. Patients who experience overdose should have immediate interruption or reduction of their infusion and be closely supervised. Consideration should be given to the need for regular monitoring of blood cell count and for increased risk of infections while patients are B cell-depleted.