Adruxe Product Monograph

RECENT MAJOR LABEL CHANGES

TABLE OF CONTENTS

Certain sections or subsections that are not applicable at the time of the preparation of the most recent authorized product monograph are not listed.

RECENT MAJOR LABEL CHANGES ............................................................................................ 2

TABLE OF CONTENTS .............................................................................................................. 2

Part I: Health Professional Information .................................................................................. 4

1 Indications ........................................................................................................................... 4

1.1 Pediatrics ................................................................................................................... 5

1.2 Geriatrics .................................................................................................................... 5

2 Contraindications ................................................................................................................ 5

3 Serious Warnings and Precautions Box ................................................................................ 5

4 Dosage and Administration ................................................................................................. 6

4.1 Dosing Considerations................................................................................................ 6

4.2 Recommended Dose and Dosage Adjustment ........................................................... 6

4.3 Reconstitution ............................................................................................................ 9

4.4 Administration ........................................................................................................... 9

4.5 Missed Dose ............................................................................................................. 11

5 Overdosage ....................................................................................................................... 11

6 Dosage Forms, Strengths, Composition and Packaging ...................................................... 11

7 Warnings and Precautions ................................................................................................. 12

7.1 Special Populations .................................................................................................. 21

8 Adverse Reactions ............................................................................................................. 22

8.1 Adverse Reaction Overview ..................................................................................... 22

8.2 Clinical Trial Adverse Reactions ................................................................................ 22

8.3 Less Common Clinical Trial Adverse Reactions ......................................................... 60

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data ........................................................................................................... 61

8.5 Post-Market Adverse Reactions ............................................................................... 62

9 Drug Interactions ............................................................................................................... 64

9.1 Drug Interactions Overview ..................................................................................... 64

9.2 Drug-Drug Interactions ............................................................................................ 64

9.3 Drug-Food Interactions ............................................................................................ 65

9.4 Drug-Herb Interactions ............................................................................................ 65

9.5 Drug-Laboratory Test Interactions ........................................................................... 65

10 Clinical Pharmacology ...................................................................................................... 65

10.1 Mechanism of Action .......................................................................................... 65

10.2 Pharmacodynamics ............................................................................................ 66

10.3 Pharmacokinetics ............................................................................................... 66

11 Storage, Stability and Disposal ......................................................................................... 69

12 Special Handling Instructions ........................................................................................... 69

Part II: Scientific Information ................................................................................................ 69

13 Pharmaceutical Information ............................................................................................ 69

14 Clinical Trials .................................................................................................................... 70

14.1 Clinical Trials - Reference Biologic Drug ............................................................. 70

16 Non-Clinical Toxicology .................................................................................................... 97

17 Supporting Product Monographs ..................................................................................... 98

Patient Medication Information ........................................................................................... 99

Patient Medication Information ......................................................................................... 108

ADRUXE (rituximab for injection) is a biosimilar biologic drug (biosimilar) to Rituxan®. A biosimilar is a biologic drug that was granted authorization based on a demonstration of similarity to a version previously authorized in Canada, known as the reference biologic drug.

Part I: Health Professional Information

1 Indications

Non-Hodgkin’s Lymphoma (NHL)

ADRUXE (rituximab for injection) is indicated for:

• the treatment of patients with relapsed or refractory low-grade or follicular, CD20 positive, B-cell non-Hodgkin’s lymphoma.
• the treatment of patients with CD20 positive, diffuse large B-cell non-Hodgkin’s lymphoma (DLBCL) in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy.
• the treatment of patients with previously untreated Stage III/IV follicular, CD20 positive, B-cell non-Hodgkin's lymphoma in combination with CVP (cyclophosphamide, vincristine and prednisolone) chemotherapy.
• the maintenance treatment of patients with follicular non-Hodgkin’s lymphoma who have responded to induction therapy with either CHOP or CHOP plus ADRUXE.
• single-agent maintenance treatment of previously untreated patients with advanced follicular non-Hodgkin’s lymphoma with high tumour burden and who have responded to induction therapy with either CHOP plus ADRUXE or CVP plus ADRUXE.

Chronic Lymphocytic Leukemia (CLL)

ADRUXE (rituximab for injection) is indicated for:

• the treatment of patients with previously untreated or previously treated B-cell chronic lymphocytic leukemia (B-CLL), Binet Stage B or C, in combination with fludarabine and cyclophosphamide.

The use of rituximab in CLL is based on an improvement in progression-free survival. Overall survival benefit has not been demonstrated in patients with previous treatment for CLL. The efficacy of treatment with R-FC (ADRUXE-fludarabine and cyclophosphamide) in CLL patients who were previously treated with ADRUXE in combination with fludarabine and cyclophosphamide has not been studied (see 14 Clinical Trials for details).

Rheumatoid Arthritis (RA)

ADRUXE (rituximab for injection) in combination with methotrexate is indicated in adult patients:

• to reduce signs and symptoms in adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to one or more tumour necrosis factor (TNF) inhibitor therapies.

Rituximab in combination with methotrexate has been shown to reduce the rate of progression of joint damage as measured by x-ray.

Granulomatosis with Polyangiitis (GPA, also known as Wegener's Granulomatosis) and Microscopic Polyangiitis (MPA)

ADRUXE (rituximab for injection) in combination with glucocorticoids is indicated for

• the induction of remission in adult patients with severely active Granulomatosis with Polyangiitis (GPA, also known as Wegener's Granulomatosis) and Microscopic Polyangiitis (MPA).

Consideration should be given to current treatment guidelines for vasculitis.

1.1 Pediatrics

Pediatrics (< 18 years of age): The safety and effectiveness of ADRUXE in pediatric patients have not been established; therefore, Health Canada has not authorized an indication for pediatric use.

1.2 Geriatrics

Geriatrics (≥ 65 years of age): In the CLL setting, exploratory subgroup analysis indicates that use in the geriatric population is associated with differences in efficacy and safety. See 14.1 Clinical Trials - Reference Biologic Drug and for details.

2 Contraindications

• ADRUXE (rituximab) is contraindicated in patients with known Type I hypersensitivity or anaphylactic reactions to murine proteins, Chinese Hamster Ovary (CHO) cell proteins, (See), or to any component of this product. For a complete listing, see 6 Dosage Forms, Strengths, Composition and Packaging.
• ADRUXE is also contraindicated in patients who have or have had progressive multifocal leukoencephalopathy (PML).
• ADRUXE is not recommended for use in patients with severe, active infections.

3 Serious Warnings and Precautions Box

Serious Warnings and Precautions

• General: Rituximab is a potent drug. Several adverse reactions are associated with rituximab, some of which are severe and life-threatening (see 7 Warnings and Precautions). This drug should only be used by health professionals experienced in treating Non-Hodgkin’s Lymphoma (NHL), Chronic Lymphocytic Leukemia (CLL), Rheumatoid Arthritis (RA), Granulomatosis with Polyangiitis (GPA, also known as Wegener's Granulomatosis) and Microscopic Polyangiitis (MPA). Patients should be treated in a setting where full resuscitation facilities are immediately available, and where medications and supportive care measures for the treatment of hypersensitivity reactions (e.g., epinephrine, antihistamines, glucocorticoids) are immediately available in the event of an allergic reaction during administration (see 4 Dosage and Administration).
• Infusion Reactions: Deaths within 24 hours of rituximab infusion have occurred. Approximately 80% of fatal infusion reactions occurred in association with the first infusion. Carefully monitor patients during infusions. Discontinue rituximab infusion and provide medical treatment for Grade 3 or 4 infusion reactions (see , Infusion-Related Events).

• Progressive Multifocal Leukoencephalopathy (PML): Patients with RA, NHL and CLL who received treatment with rituximab may have an increased risk of PML. PML can cause disability or death. Healthcare professionals should monitor patients on rituximab for any new sign or

  • symptom that may be suggestive of PML. Further treatment with rituximab should be withheld immediately at the first sign or symptom suggestive of PML (see , Progressive Multifocal Leukoencephalopathy).
• Tumor Lysis Syndrome (TLS): Acute renal failure requiring dialysis with instances of fatal outcome has been reported in the setting of TLS following treatment of NHL patients with rituximab (see , Infusion-Related Events).
• Hepatitis B Virus (HBV) Reactivation: HBV reactivation has occurred in patients treated with rituximab, in some cases resulting in fulminant hepatitis, hepatic failure, and death. All patients should be screened for HBV infection before treatment initiation, and should be monitored during and after treatment with rituximab. In the event of HBV reactivation, rituximab and concomitant medications should be discontinued.
• Mucocutaneous Reactions: Severe, including fatal, mucocutaneous reactions including Toxic Epidermal Necrolysis (TEN) and Stevens Johnson Syndrome (SJS) have occurred in patients treated with rituximab. Patients experiencing a severe mucocutaneous reaction should discontinue treatment with rituximab and seek prompt medical evaluation (see 7 Warnings and Precautions, Skin).
• Infections: Serious, including fatal, bacterial, fungal, and new or reactivated viral infections can occur during or following the completion of rituximab-based therapy. rituximab treatment should not be initiated in patients with severe active infections. Patients should be screened for infectious disease history (see 7 Warnings and Precautions, Infections).
• Cardiovascular: Serious and potentially fatal cardiovascular events have been reported rarely following administration of rituximab (see 7 Warnings and Precautions).

4 Dosage and Administration

4.1 Dosing Considerations

• Hypersensitivity reactions and severe infusion-related reaction may occur with administration of ADRUXE (see 7 Warnings and Precautions). Since transient hypotension may occur during infusion with ADRUXE, consideration should be given to withholding anti-hypertensive medications 12 hours prior to and throughout infusion with ADRUXE.
• Patients who develop clinically significant arrhythmias should undergo cardiac monitoring during and after subsequent infusions of rituximab. Patients with pre-existing cardiac conditions such as angina and arrhythmias should be monitored during and after the infusion of ADRUXE.

4.2 Recommended Dose and Dosage Adjustment

Non-Hodgkin’s Lymphoma

Usual Dose

Low Grade or Follicular Non-Hodgkin’s Lymphoma

Premedication

Premedication consisting of an analgesic or anti-pyretic (e.g. acetaminophen) and an antihistaminic drug (e.g. diphenhydramine) should always be administered before each infusion of ADRUXE.

Premedication with glucocorticoids should also be considered, particularly if ADRUXE is not given in combination with steroid-containing chemotherapy (See 7 Warnings and Precautions: Non-Hodgkin’s Lymphoma and Chronic Lymphocytic Leukemia-Infusion- Related Events).

Initial treatment

The recommended dosage of ADRUXE as a single agent is 375 mg/m² given as an IV infusion once weekly for four doses (on days 1, 8, 15, and 22).

The recommended dosage of ADRUXE in combination with CVP chemotherapy is 375 mg/m² for 8 cycles (21 days/cycle), administered as an IV infusion on day 1 of each chemotherapy cycle after IV administration of the corticosteroid component of CVP.

Maintenance treatment

In previously untreated patients with advanced high-tumour burden follicular lymphoma, after complete or partial response to induction treatment the recommended dose of ADRUXE maintenance therapy is 375 mg/m² body surface area. ADRUXE maintenance therapy should be initiated eight weeks following completion of ADRUXE in combination with chemotherapy.

ADRUXE as a single agent should be administered every 8 weeks for a maximum of 12 doses (two years).

The recommended dose of ADRUXE for relapsed or refractory patients after response to induction treatment is 375 mg/m² every 3 months until disease progression or for a maximum period of two years.

Diffuse Large B-cell Non-Hodgkin’s Lymphoma

Premedication

Premedication consisting of an analgesic/anti-pyretic (e.g. acetaminophen) and an antihistaminic drug (e.g. diphenhydramine) should always be administered before each infusion of ADRUXE.

Premedication with glucocorticoids should also be considered, particularly if ADRUXE is not given in combination with steroid-containing chemotherapy (See 7 Warnings and Precautions/ Non-Hodgkin’s Lymphoma and Chronic Lymphocytic Leukemia/Infusion- Related Events).

ADRUXE should be used in combination with CHOP chemotherapy. The recommended dosage of ADRUXE is 375 mg/m² administered on day 1 of each chemotherapy cycle after IV administration of the glucocorticoid component of CHOP. The other components of CHOP (cyclophosphamide, doxorubicin, vincristine) should be given after the administration of ADRUXE.

Chronic Lymphocytic Leukemia

Premedication

Premedication consisting of an analgesic or anti-pyretic (e.g. acetaminophen) and an antihistaminic drug (e.g. diphenhydramine) should always be administered before each infusion of ADRUXE.

Premedication with glucocorticoids should also be considered, particularly if ADRUXE is not given in combination with steroid-containing chemotherapy (See 7 Warnings and Precautions: Non-Hodgkin’s Lymphoma and Chronic Lymphocytic Leukemia-Infusion- Related Events).

The recommended dosage of ADRUXE in combination with chemotherapy for previously untreated and previously treated patients is 375 mg/m² body surface area administered on day 1 of the first treatment cycle followed by 500mg/m² body surface area administered on day 1 of each subsequent cycle for 6 cycles in total. The chemotherapy should be given after ADRUXE infusion.

Prophylaxis with adequate hydration and administration of uricostatics (such as allopurinol) 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 x10⁹/L it is recommended to administer methylprednisolone IV shortly before infusion with ADRUXE to decrease the rate and severity of acute infusion reactions and/or cytokine release syndrome. In study ML17102 an equivalent of 80mg of methylprednisolone (100 mg prednisone IV) was given prior to infusions with rituximab for injection. Seventy-four percent (74%) of patients in the R-FC arms of study ML17102 received at least one dose of corticosteroids, with 27% receiving two or more doses.

Dosage Adjustments During Treatment

No dose reductions of ADRUXE are recommended but 47% of patients in the clinical trial ML17102 for CLL required a delayed and/or slowed infusion, and 17% required their first dose split over two days. When ADRUXE is given in combination with CHOP chemotherapy, standard dose reductions for the chemotherapeutic drugs should be applied. When ADRUXE is given as maintenance treatment, treatment should be delayed in case of significant clinical toxicity according to standard practice.

ADRUXE as a Component of ZEVALIN® (Ibritumomab Tiuxetan) Therapeutic Regimen

As a required component of the ZEVALIN therapeutic regimen, ADRUXE is administered twice. The first administration of ADRUXE is a single infusion of 250 mg/m² and should precede the second administration by 7-9 days. At the second administration, ADRUXE 250 mg/m² should be infused within 4 hours prior to the administration of 90Y-ibritumomab tiuxetan. Refer to the ZEVALIN product monograph for full prescribing information.

Rheumatoid Arthritis

Premedication

Premedication consisting of an analgesic or anti-pyretic (e.g. acetaminophen) and an antihistaminic drug (e.g. diphenhydramine) should always be administered before each infusion of rituximab. Premedication with glucocorticoids should also be administered in order to reduce the frequency and severity of infusion-related reactions. Patients should receive 100 mg IV methylprednisolone to be completed 30 minutes prior to each ADRUXE infusion (See 7 Warnings and Precautions: Rheumatoid Arthritis-Infusion-Related Events).

Usual Dose

A course of ADRUXE consists of two 1000 mg IV infusions. The recommended dosage of ADRUXE is 1000 mg by IV infusion followed two weeks later by the second 1000 mg IV infusion.

Retreatment in Patients with RA

The need for further courses should be evaluated 24 weeks following the previous course with retreatment given based on residual disease or disease activity returning to a level above a DAS28-ESR of 2.6 (treatment to remission). Patients may receive further courses no sooner than 16 weeks following the previous course.

Granulomatosis with Polyangiitis (GPA, also known as Wegener’s Granulomatosis) and Microscopic Polyangiitis (MPA)

The recommended dosage of ADRUXE for treatment of GPA/MPA is 375 mg/m² body surface area, administered as an IV infusion once weekly for 4 weeks.

Glucocorticoids administered as methylprednisolone 1000 mg intravenously per day for 1 to 3 days followed by oral prednisone 1 mg/kg/day (not to exceed 80 mg/day and tapered per clinical need) are recommended to treat severe vasculitis symptoms. This regimen should begin within 14 days prior to or with the initiation of ADRUXE and may continue during and after the 4 week course of ADRUXE treatment.

The efficacy and safety of subsequent courses of ADRUXE have not been established (see 7 Warnings and Precautions and 14 Clinical Trials).

4.3 Reconstitution

Parenteral Products:

Preparation for Administration:

Use appropriate aseptic technique. Use a sterile needle and syringe to prepare ADRUXE. ADRUXE does not contain any preservative or bacteriostatic agent. Withdraw the necessary amount of ADRUXE and dilute to a final concentration of 1 to 4 mg/mL into an infusion bag containing either 0.9% Sodium Chloride Injection USP or 5% Dextrose Injection USP. To avoid foaming, gently invert the bag to mix the solution. Discard any unused portion left in the vial. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. For in-use stability information refer to the 11 Storage, Stability and Disposal.

Incompatibilities

No incompatibilities between ADRUXE and polyvinylchloride or polyethylene bags have been observed.

4.4 Administration

ADRUXE infusions should be administered in a setting where full resuscitation facilities (see 3 Serious Warnings and Precautions Box) are immediately available, and under the close supervision of someone experienced and capable of dealing with severe infusion-related reactions. ADRUXE should be administered as an IV infusion through a dedicated line. Do not administer as an intravenous push or bolus.

Chronic Lymphocytic Leukemia

Do not administer as an intravenous push or bolus. Premedication with glucocorticoids should be considered, particularly if ADRUXE is not given in combination with steroid-containing chemotherapy. Premedication may attenuate infusion-related events. In the clinical trial ML17102 for CLL, the equivalent of 80 mg methylprednisolone (100 mg prednisone IV) was given to most patients prior to each infusion.

First Infusion

The ADRUXE solution for infusion should be administered intravenously at an initial rate of 50 mg/hr. ADRUXE should not be mixed or diluted with other drugs. If hypersensitivity or infusion-related events do not occur, escalate the infusion rate in 50 mg/hr increments every 30 minutes, to a maximum of 400 mg/hr. This rate corresponds to an administration time of 4.25 hours. If hypersensitivity or an infusion related event develops, the infusion should be temporarily slowed or interrupted (see 7 Warnings and

Precautions). The infusion can continue at one-half the previous rate upon improvement of patient symptoms.

Subsequent Infusions

Subsequent infusions of ADRUXE can be administered 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 as tolerated. This rate corresponds to an administration time of 3.25 hours.

Rheumatoid Arthritis

First infusion of each course

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. This rate corresponds to an administration time of 4.25 hours.

Second infusion of each course

Subsequent doses of ADRUXE 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. This rate corresponds to an administration time of 3.25 hours.

Alternative 120-minute subsequent infusions with the concentration of 4 mg/mL in a 250 mL volume (Rheumatoid Arthritis Only)

If patients did not experience a serious infusion-related adverse event during the previous infusion administered using the standard administration schedule, an alternative 120-minute infusion of a concentration at 4 mg/mL in a 250 mL volume can be administered for the second infusion. Initiate at a rate of 62.5 mL/hour (125 mg) given in the first 30 minutes and 150 mL/hour (875 mg) given over the next 90 minutes. If the 120-minute infusion is tolerated, the same alternative 120-minute infusion rate can be used when administering subsequent infusions and courses.

Patients who have clinically significant cardiovascular disease including arrhythmias or previous serious infusion reactions to any prior biologic therapy or to rituximab, should not be administered the alternative 120-minute infusion.

The Reddy2Assist program has been established to facilitate the administration of ADRUXE in RA and GPA/MPA. Information about the Reddy2Assist program can be obtained by calling 1-877-938-0670.

Granulomatosis with Polyangiitis (GPA, also known as Wegener’s Granulomatosis) and Microscopic Polyangiitis (MPA)

First infusion

The recommended initial infusion rate for ADRUXE 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. This rate corresponds to an administration time of 4.25 hours.

Subsequent infusions

Subsequent infusions of ADRUXE 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. This rate corresponds to an administration time of 3.25 hours.

Pneumocystis Jiroveci Pneumonia (PCP) prophylaxis is recommended for patients with GPA/MPA during and following treatment.

The Reddy2Assist program has been established to facilitate the administration of ADRUXE in RA and GPA/MPA. Information about the Reddy2Assist program can be obtained by calling 1-877-938-0670.

4.5 Missed Dose

Missed or delayed doses should not be omitted but administered at a later time point, based on professional judgment observing the total number of planned cycles and the planned interval between doses.

5 Overdosage

There has been no experience with overdosage in human clinical trials. Single doses higher than 1000 mg have not been tested in controlled clinical studies. The highest dose tested to date is 5g in patients with chronic lymphocytic leukemia. No additional safety signals were identified. Patients who experience overdose should have immediate interruption of their infusion and be closely monitored. 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.

For the most recent information in the management of a suspected drug overdose, contact your regional poison control centre or Health Canada’s toll-free number, 1-844-POISON-X (1-844-764-7669).

6 Dosage Forms, Strengths, Composition and Packaging

To help ensure the traceability of biologic products, including biosimilars, health professionals should recognise the importance of recording both the brand name and the non-proprietary (active ingredient) name as well as other product-specific identifiers such as the Drug Identification Number (DIN) and the batch/lot number of the product supplied.

Table 1 Dosage Forms, Strengths, Composition and Packaging

ADRUXE is a clear to opalescent, colorless to yellowish liquid for intravenous (IV) administration. ADRUXE is supplied at a concentration of 10 mg/mL in either 100 mg (10 mL) or 500 mg (50 mL) single-use vials.

100 mg: Each Carton contains one 100 mg/10 mL vial (10 mg/mL), with an orange flip-off cap.

500 mg: Each Carton contains one 500 mg/50 mL vial (10 mg/mL), with a purple flip-off cap.

The drug product is formulated as a sterile, preservative-free, concentrated aqueous solution for infusion composed of 10 mg/mL of the active ingredient in citrate buffer (7.17 mg/mL sodium citrate dihydrate, 0.164 mg/mL citric acid monohydrate), 9.0 mg/mL sodium chloride and 0.7 mg/mL polysorbate 80 and water for injection, pH 6.5.

7 Warnings and Precautions

Please see 3 Serious Warnings and Precautions Box

Carcinogenesis and Mutagenesis

No long-term animal studies have been performed to establish the carcinogenic or mutagenic potential of rituximab, or to determine its effects on fertility in males or females. Individuals of childbearing potential should use effective contraceptive methods during treatment and for up to 12 months following therapy with ADRUXE.

Cardiovascular

Non-Hodgkin’s Lymphoma and Chronic Lymphocytic Leukemia

Since transient hypotension may occur during infusion with rituximab, consideration should be given to withholding anti-hypertensive medications 12 hours prior to and throughout infusion with ADRUXE. Serious and potentially fatal cardiovascular events have been reported rarely following administration of rituximab. These events included: angina pectoris, cardiac arrhythmias such as atrial flutter and fibrillation, heart failure, myocardial infarction and cardiogenic shock. Infusions with ADRUXE should be discontinued in the event of serious or life threatening cardio-pulmonary events. Patients who develop clinically significant cardiovascular events should undergo cardiac monitoring during and after subsequent infusions of ADRUXE. Patients with pre-existing cardiac conditions including arrhythmias and angina have had recurrences of these events during therapy with rituximab and should be monitored throughout the infusion and immediate post-infusion period.

Rheumatoid Arthritis (RA) and Granulomatosis with Polyangiitis (GPA, also known as Wegener's Granulomatosis) and Microscopic Polyangiitis (MPA)

Since hypotension may occur during infusion with rituximab, consideration should be given to withholding anti-hypertensive medications 12 hours prior to the infusion of ADRUXE.

Angina pectoris, cardiac arrhythmias such as atrial flutter and fibrillation, heart failure or myocardial infarction have occurred in patients treated with rituximab. Patients who develop clinically significant arrhythmias should undergo cardiac monitoring during and after subsequent infusions of ADRUXE. Patients with a history of cardiac disease such as angina and arrhythmias should be monitored closely (see 4 Dosage and Administration).

Driving and Operating Machinery

It is not known whether ADRUXE has an effect on the ability to drive and operate machines, though the pharmacologic activity and adverse events reported to date do not indicate that such an effect is to be expected.

Endocrine and Metabolism

Non-Hodgkin’s Lymphoma and Chronic Lymphocytic Leukemia

Tumour Lysis Syndrome

Rituximab mediates the rapid lysis of benign and malignant CD20 positive cells. Signs and symptoms (e.g., hyperuricemia, hyperkalemia, hypocalcemia, hyperphosphatemia, acute renal failure, elevated LDH, high fevers) consistent with Tumour Lysis Syndrome (TLS) have been reported to occur within 1 to 2 hours though initial reports of TLS were not diagnosed until 12-24 hours after the first infusion in NHL patients with high numbers of circulating malignant lymphocytes. Acute renal failure requiring dialysis with instances of fatal outcome has been reported in the setting of TLS in NHL patients. 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 10⁹/L) of circulating malignant cells such as patients with CLL and mantle cell lymphoma). These patients 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 rituximab therapy has been administered in conjunction with prophylactic therapy for TLS in a limited number of cases.

Gastrointestinal

Non-Hodgkin’s Lymphoma and Chronic Lymphocytic Leukemia

Abdominal pain, bowel obstruction and perforation, in some cases leading to death, were observed in patients receiving rituximab in combination with chemotherapy for DLBCL. A causal association with rituximab has not been established.

In post-marketing reports, which include both patients with low-grade or follicular NHL and DLBCL, the mean time to onset of symptoms was 6 days (range 1-77) in patients with documented gastro-intestinal perforation. Complaints of abdominal pain, especially early in the course of treatment, should prompt a thorough diagnostic evaluation and appropriate treatment.

Hematologic

Non-Hodgkin’s Lymphoma and Chronic Lymphocytic Leukemia

Myelosuppression

Although rituximab is not myelosuppressive in monotherapy, caution should be exercised when considering treatment of patients with neutrophil counts < 1.5 x 10⁹/L and/or platelet counts of <75 x 10⁹/L, as clinical experience with such patients is limited. Rituximab 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.

Grade 3-4 neutropenia and decreased white blood cell counts were very common in ML17102 with combination therapy of rituximab with fludarabine and cyclophosphamide. Grade 4 lymphopenia was not captured. Neutropenia and febrile neutropenia occurred in higher frequencies in the R-FC arm. This increase did not result in a statistically significant increase in hospitalization rates.

Immune

Non-Hodgkin’s Lymphoma and Chronic Lymphocytic Leukemia

HAMA/HACA Formation

Human anti-murine antibody (HAMA) was not detected in 67 patients evaluated. Of 356 patients evaluated for human anti-chimeric antibody (HACA), 1.1% (4 patients) were positive. Patients who develop HAMA/HACA titers may have allergic or hypersensitivity reactions when treated with rituximab or other murine or chimeric monoclonal antibodies.

Immunization

The safety of immunization with live viral vaccines, following therapy with rituximab has not been studied. Therefore, vaccination with live virus vaccines is not recommended while receiving ADRUXE or during peripheral B-cell depletion.

Patients treated with ADRUXE may receive non-live vaccinations. However, with non-live vaccines response rates to the vaccination could be reduced. In a non-randomized study, patients with relapsed or refractory 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 titer.

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

Infections

Infections have been reported in some patients with prolonged hypogammaglobulinemia (defined as hypogammaglobulinemia >11 months after rituximab exposure).

Hepatitis B Reactivation with Related Fulminant Hepatitis

Cases of Hepatitis B virus (HBV) reactivation, occasionally with fulminant hepatitis, hepatic failure, and death has been reported in some patients with hematologic malignancies treated with rituximab. The majority of patients received rituximab in combination with chemotherapy. Isolated cases have been reported in patients who either had evidence of antibodies against Hepatitis B surface antigen before treatment or did not have any such antibodies. The median time to diagnosis of hepatitis was approximately 4 months after the initiation of rituximab and approximately one month after the last dose (see 8 Adverse Reactions).

Hepatitis B reactivation can occur in oncology patients even if Hepatitis B surface antigen status is normal. HBV screening should be performed in all patients before initiation of treatment with ADRUXE. At minimum, this should include HBsAg-status and HBcAb-status. These can be complemented with other appropriate markers as per local guidelines. Reactivation of HBV infection is a well-known complication in patients with chronic hepatitis B, especially in those receiving cytotoxic or immunosuppressive therapy. In addition, non-Hodgkin’s lymphoma of itself may be an independent risk factor for HBV reactivation. Patients with active hepatitis B disease should not be treated with ADRUXE. Patients with positive hepatitis B serology should consult liver disease experts before start of treatment and should be monitored and managed following local medical standards to prevent hepatitis B reactivation.

In patients who develop reactivation of viral hepatitis B, ADRUXE and any concomitant chemotherapy should be discontinued and appropriate treatment including antiviral therapy initiated. There are insufficient data regarding the safety of resuming therapy with rituximab in patients who develop hepatitis subsequent to HBV reactivation.

Additional Serious Viral Infections

The following additional serious viral infections, either new, reactivated or exacerbated, have been identified in clinical studies or post-marketing reports. The majority of patients were profoundly immune-suppressed. These viral infections included JC virus [progressive multifocal leukoencephalopathy (PML) (see 7 Warnings and Precautions: Non-Hodgkin’s Lymphoma and Chronic Lymphocytic Leukemia, Progressive Multifocal Leukoencephalopathy)], cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus, West Nile virus, and hepatitis C. In some cases, the viral infections occurred up to one year following discontinuation of rituximab and have resulted in death. ADRUXE treatment should not be initiated in patients with an active and/or severe infection or severely immunocompromised patients.

Tuberculosis Reactivation

In the CLL clinical trial ML17102, one patient treated with rituximab plus fludarabine and cyclophosphamide experienced reactivation of tuberculosis. Patients who develop reactivation of tuberculosis should be treated as per current medical practice and ADRUXE should be discontinued. There are no data regarding the safety of resuming therapy with ADRUXE in patients who develop tuberculosis reactivation.

Pneumocystis Jiroveci Pneumonia

Cases of Pneumocystis Jiroveci Pneumonia (PJP) have been reported in patients receiving rituximab in combination with chemotherapy. These cases included patients with multiple risk factors for PJP, including the underlying disease state and other immunosuppressive therapies. The use of PJP prophylaxis should be considered according to local guidelines.

Infusion-Related Events

Rituximab is associated with infusion-related reactions, which may be related to release of cytokines and/or other chemical mediators. Severe infusion-related reactions might be clinically indistinguishable from hypersensitivity reactions or cytokine release syndrome. Severe infusion-related reactions with fatal outcome have been reported during post-marketing use. Severe infusion-related reactions usually manifested within 30 minutes to 2 hours after starting the first infusion with rituximab. These reactions were characterized by pulmonary events, and included, in some cases, rapid tumour lysis and features of tumour lysis syndrome in addition to fever, chills, rigors, hypotension, urticaria, bronchospasm, acute respiratory distress syndrome, angioedema and other symptoms (see 8 Adverse Reactions: Experience From Clinical Trials in Hemato-Oncology).

Infusion related deaths (death within 24 hours of infusion) have been reported at a rate of approximately 0.04-0.07% (4-7 per 10,000 patients treated). Nearly all fatal events occurred in association with the first infusion.

Patients with a high number (> 25 X 10⁹/L) of circulating malignant cells or high tumour burden such as patients with CLL and mantle cell lymphoma, who may be at higher risk of especially severe cytokine release syndrome, should only be treated with extreme caution and 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 10⁹/L; in the CLL ML17102 trial, 47% of patients required a delayed and/or slowed infusion, and 17% of patients required split dosing.

Premedication consisting of an anti-pyretic and an antihistaminic (e.g. acetominophen and diphenhydramine) should always be administered before each infusion of ADRUXE. Premedication with glucocorticoids should also be considered, particularly if ADRUXE is not given in combination with steroid-containing chemotherapy (see 4 Dosage and Administration).

Medications for the treatment of hypersensitivity reactions, e.g., epinephrine, antihistamines and glucocorticoids should be available for immediate use in the event of a reaction during administration. In the CLL clinical trials, most patients received high-dose boluses intravenous corticosteroids [100 mg Prednisone IV] before each rituximab infusion.

Patients should be monitored closely throughout the infusion. Patients with a high tumour burden or with a high number (>25 x 10⁹/L) of circulating malignant cells such as patients with CLL and mantle cell lymphoma may be at higher risk of developing severe infusion-related reactions. If mild, the symptoms are usually reversible with interruption of ADRUXE infusion. Treatment of infusion-related symptoms with diphenhydramine and acetaminophen is recommended. Additional treatment with bronchodilators or IV saline or IV corticosteroids may be indicated and should be immediately available. In patients with severe reaction, the infusion should be interrupted immediately (see 4 Dosage and Administration) and they should receive aggressive symptomatic treatment. Since initial improvement may be followed by deterioration, these patients should be closely monitored until Tumour Lysis Syndrome (TLS) and pulmonary infiltration have been ruled out. In most cases, the infusion can be resumed at a 50% reduction in rate (e.g., from 100 mg/hr to 50 mg/hr) when symptoms have completely resolved. Most patients who have experienced non-life-threatening reactions have been able to complete the full course of therapy (see 4 Dosage and Administration). Further treatment of patients after complete resolution of signs and symptoms has rarely resulted in repeated severe infusion-related reactions. In the patients with a severe reaction, the decision to administer further infusions should be made by the treating physician on a case-by-case basis after assessing the risk versus benefit to the patient.

Anaphylaxis

Anaphylactic reactions, including fatalities, have been reported in patients treated with rituximab. These reactions may be clinically indistinguishable from severe infusion-related reactions, other hypersensitivity reactions or cytokine release syndrome. True hypersensitivity reactions typically occur after starting the second or subsequent infusion of rituximab. Epinephrine, antihistamines and glucocorticoids should be available for immediate use in the event of a hypersensitivity reaction to ADRUXE.

Rheumatoid Arthritis (RA) and Granulomatosis with Polyangiitis (GPA, also known as Wegener's Granulomatosis) and Microscopic Polyangiitis (MPA)

A total of 96/1039 (9.2%) patients with rheumatoid arthritis tested positive for HACA in clinical studies. The emergence of HACA was not associated with clinical deterioration or with an increased risk of reactions to subsequent infusions in the majority of patients. The presence of HACA could be associated with worsening of infusion or allergic reactions after the second infusion of subsequent courses. Such events could include hypersensitivity or anaphylactic reactions or anaphylactic shock. Failure to deplete B cells after receipt of further treatment courses has also been observed rarely.

A total of 23/99 (23%) rituximab-treated patients with GPA/MPA tested positive for HACA by 18 months. The clinical relevance of HACA formation in rituximab-treated patients is unclear.

Immunization

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

The safety of immunization with live viral vaccines following ADRUXE therapy has not been studied. Therefore, vaccination with live virus vaccines is not recommended while on ADRUXE or while peripherally B cell depleted.

Patients treated with ADRUXE may receive non-live vaccinations. However, response rates to non-live vaccines may be reduced. In a randomized study, patients with RA treated with rituximab 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 at least 6 months after rituximab as compared to patients only receiving methotrexate. Should non-live vaccinations be required while receiving ADRUXE therapy, these should be completed at least 4 weeks prior to commencing the next course of ADRUXE.

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

Infections

Infections have been reported in some patients with prolonged hypogammaglobulinemia (defined as hypogammaglobulinemia >11 months after rituximab exposure).

Serious infections can occur during therapy with rituximab. Based on the mechanism of action of rituximab and the knowledge that B cells play an important role in maintaining normal immune response, patients may have increased risk of infection following ADRUXE therapy (see 10 Clinical Pharmacology). ADRUXE should not be administered to patients with an active and/or severe infection or severely immuno-compromised patients (e.g. AIDS where levels of CD4 or CD8 are very low). Physicians should exercise caution when considering the use of ADRUXE in patients with a history of recurring or chronic infections or with underlying conditions which may further predispose patients to serious infection (see 8 Adverse Reactions: Rheumatoid Arthritis). Patients who develop infection following therapy with ADRUXE should be promptly evaluated and treated appropriately.

Hepatitis B Reactivation

Cases of hepatitis B reactivation including those with a fatal outcome, have been reported in RA and GPA/MPA patients receiving rituximab.

Hepatitis B virus (HBV) screening should be performed in all patients before initiation of treatment with ADRUXE. 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 ADRUXE. Patients with positive hepatitis B serology should consult liver disease experts before start of treatment and should be monitored and managed following local medical standards to prevent hepatitis B reactivation.

Infusion-Related Events

Rituximab is associated with infusion-related reactions, which may be related to release of cytokines and/or other chemical mediators. For RA patients premedication consisting of an anti-pyretic and an antihistaminic (e.g. acetaminophen and diphenhydramine) should always be administered before each infusion of ADRUXE. For RA patients, premedication with glucocorticoids should also be administered before each infusion of ADRUXE, in order to reduce the frequency and severity of infusion-related reactions (see 8 Adverse Reactions: Rheumatoid Arthritis and DOSAGE AND ADMINISTRATION: Rheumatoid Arthritis).

For GPA/MPA patients, rituximab was given in combination with higher doses of IV glucocorticoids (see 4 Dosage and Administration: GPA/MPA), which may reduce the incidence and severity of these events. Infusion related reactions (IRRs) in the GPA/MPA clinical study were defined as any adverse event occurring within 24 hours of an infusion and considered to be infusion-related by investigators in the safety population. Ninety nine patients were treated with rituximab and 12% experienced at least one

IRR. All IRRs were CTC Grade 1 or 2. The most common IRRs included cytokine release syndrome, flushing, throat irritation, and tremor.

Rituximab has caused severe infusion reactions. In spontaneous reports, fatal infusion reactions were reported very rarely in patients with autoimmune diseases and other co-morbidities (e.g. pulmonary fibrosis and Systemic Lupus Erythematosus (SLE)). The co-morbidities may have contributed to the fatal outcome (see 7 Warnings and Precautions: Non-Hodgkin’s Lymphoma and Chronic Lymphocytic Leukemia).

Severe infusion-related reactions with fatal outcome have been reported in the post-marketing setting (see 8 Adverse Reactions: Rheumatoid Arthritis, Post-Market Adverse Drug Reactions) and co- morbidities may have contributed to the fatal outcome. Closely monitor patients with pre-existing cardiac conditions and those who experienced prior cardiopulmonary adverse reactions.

In clinical studies, 10/990 (1%) patients with rheumatoid arthritis who received a first infusion of rituximab at any dose experienced a serious reaction during the infusion. Four out of ten patients that experienced serious infusion reactions did not receive premedication with IV steroids. No infusion reactions in the RA population were fatal. Most infusion events reported were mild to moderate in severity. 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 rituximab infusions were better tolerated by patients than the initial infusion. Less than 1% of patients experienced serious IRRs, with most of these reported during the first infusion of the first course. (See 8 Adverse Reactions: Rheumatoid Arthritis). The infusion-related reactions reported with rituximab were usually reversible with a reduction in rate, or interruption, of the infusion and administration of appropriate symptomatic treatment, if required. 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.

Depending on the severity of the infusion-related reaction and the required interventions, temporarily or permanently discontinue ADRUXE.

Anaphylaxis

Anaphylactic and other hypersensitivity reactions have been reported following the IV administration of proteins to patients. Medicinal products for the treatment of hypersensitivity reactions, e.g., epinephrine, antihistamines and glucocorticoids, should be available for immediate use in the event of an allergic reaction during administration of rituximab.

Concomitant use with Biologic Agents and Disease-Modifying Antirheumatic Drugs (DMARDs) other than Methotrexate in RA

Limited data are available on the safety of the use of biologic agents or DMARDs other than methotrexate in patients exhibiting peripheral B cell depletion following treatment with rituximab. Patients should be closely observed for signs of infection if biologic agents and/or DMARDs are used concomitantly.

Use in Patients with RA who had no Prior Inadequate Response to TNF Antagonists

A favourable benefit-risk relationship has not been established in patients with RA with prior inadequate responses to non-biologic DMARDs, and in MTX-naïve patients. The use of ADRUXE in patients with RA who have no prior inadequate response to one or more TNF antagonists is not recommended.

Retreatment in Patients with GPA and MPA

The safety and efficacy of retreatment with ADRUXE have not been established.

The efficacy and safety of ADRUXE for the treatment of autoimmune diseases other than rheumatoid arthritis and GPA/MPA has not been established.

Monitoring and Laboratory Tests

Non-Hodgkin’s Lymphoma and Chronic Lymphocytic Leukemia

Complete blood counts (CBC) and platelet counts should be obtained at regular intervals in patients with hematologic malignancies during therapy with ADRUXE and more frequently in patients who develop cytopenias (see 8 Adverse Reactions).

Neurologic

Non-Hodgkin’s Lymphoma and Chronic Lymphocytic Leukemia

Four cases of stroke or cerebral ischemia originated from a clinical study (GELA, LNH98-5) and concerned patients from 72 to 79 years of age, who had received rituximab in combination with CHOP chemotherapy, all with a history of cardiovascular disease or cardiovascular risk factors. In particular, lacunar lesions were seen in two patients, both of whom had a medical history of hypertension, the major risk factor of such small vessel disease. In 2 of these reports, the events were fatal and in the other two, the events were reported to have resolved. Furthermore, if the accepted definition of transient ischemic attack (TIA) (duration of signs/symptoms <24 hours) is applied, then one of the four patients with reported stroke experienced a TIA.

Progressive Multifocal Leukoencephalopathy

Cases of Progressive Multifocal Leukoencephalopathy have been reported during the use of rituximab in hematologic malignancies (NHL, CLL) (see 8 Adverse Reactions). The majority of patients had received rituximab in combination with chemotherapy or as part of a hematopoietic stem cell transplant.

Patients being treated with ADRUXE should be instructed to report any new neurological signs or symptoms to their physician. Physicians treating patients with non-Hodgkin’s lymphoma and chronic lymphocytic leukemia should be alert to any new signs or symptoms that may be suggestive of PML and consider PML in the differential diagnosis of patients reporting new-onset neurological symptoms.

Consultation with a neurologist should be considered as clinically indicated. Symptoms of PML are diverse, progress over days to weeks, and can include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory and orientation leading to confusion and personality changes. Further treatment with ADRUXE should be withheld immediately at the first sign or symptom suggestive of PML and an evaluation that includes a magnetic resonance imaging (MRI) scan without and, where clinically indicated, with gadolinium-enhancement of the brain should be performed. Cerebrospinal fluid analysis for JC viral DNA is recommended to confirm a diagnosis of PML. Discontinue ADRUXE and consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients with confirmed PML.

The absolute risk for PML in patients treated with ADRUXE cannot be precisely estimated and factors that might increase an individual patient's risk for PML have not been identified. There are no known interventions that can reliably prevent or adequately treat PML if it occurs. It is not known whether early detection of PML and discontinuation of ADRUXE will mitigate the disease. The relationship between the risk of PML and the duration of treatment is unknown.

Rheumatoid Arthritis (RA) and Granulomatosis with Polyangiitis (GPA, also known as Wegener's Granulomatosis) and Microscopic Polyangiitis (MPA)

Progressive Multifocal Leukoencephalopathy

Cases of fatal progressive multifocal leukoencephalopathy have been reported following use of rituximab for the treatment of autoimmune diseases (including RA). Several, but not all of the reported cases had potential risk factors for PML, including the underlying disease, long-term immunosuppressive therapy or chemotherapy. PML has also been reported in patients with autoimmune disease not treated with rituximab.

Patients being treated with ADRUXE should be instructed to report any new neurological signs or symptoms to their physician. Physicians treating patients with autoimmune diseases should be alert to any new signs or symptoms that may be suggestive of PML and consider PML in the differential diagnosis of patients reporting new-onset neurological symptoms. Consultation with a neurologist should be considered as clinically indicated. Symptoms of PML are diverse, progress over days to weeks, and can include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory and orientation leading to confusion and personality changes. Further treatment with ADRUXE should be withheld immediately at the first sign or symptom suggestive of PML and an evaluation that includes a magnetic resonance imaging (MRI) scan without and, where clinically indicated, with gadolinium-enhancement of the brain should be performed. Cerebrospinal fluid analysis for JC viral DNA is recommended to confirm a diagnosis of PML. Discontinue ADRUXE and consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients with confirmed PML.

The absolute risk for PML in patients treated with ADRUXE cannot be precisely estimated and factors that might increase an individual patient's risk for PML have not been identified. There are no known interventions that can reliably prevent or adequately treat PML if it occurs. It is not known whether early detection of PML and discontinuation of ADRUXE will mitigate the disease. The relationship between the risk of PML and the duration of treatment is unknown.

Respiratory

Non-Hodgkin’s Lymphoma and Chronic Lymphocytic Leukemia

Pulmonary Events

Pulmonary events have included hypoxia, lung infiltration and acute respiratory failure. Some of these events have been preceded by severe bronchospasm and dyspnea. 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 edema, 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 (see 4 Dosage and Administration) and should receive aggressive symptomatic treatment. 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.

Skin

Non-Hodgkin’s Lymphoma and Chronic Lymphocytic Leukemia

Severe mucocutaneous reactions including Stevens Johnson Syndrome (SJS), lichenoid dermatitis, vesiculobullous dermatitis, Toxic Epidermal Necrolysis (TEN) and paraneoplastic pemphigus have been reported rarely. Some of these cases were fatal. The onset varied from days to several months following exposure to rituximab. Patients experiencing a severe mucocutaneous reaction should discontinue treatment with ADRUXE and seek prompt medical evaluation. In case of such an event, with a suspected relationship to ADRUXE, treatment should be permanently discontinued. Skin biopsy may help to establish a diagnosis and guide subsequent treatment.

Rheumatoid Arthritis (RA) and Granulomatosis with Polyangiitis (GPA, also known as Wegener's Granulomatosis) and Microscopic Polyangiitis (MPA)

Severe skin reactions such as Toxic Epidermal Necrolysis (TEN) and Stevens-Johnson Syndrome (SJS), some with fatal outcome, have been reported. In case of such an event, with a suspected relationship to ADRUXE, treatment should be permanently discontinued.

7.1 Special Populations

7.1.1 Pregnancy

IgG immunoglobulins are known to pass the placental barrier. Developmental toxicity studies performed in cynomolgus monkeys revealed no evidence of embryotoxicity in utero. Newborn offspring of maternal animals exposed to rituximab were noted to have depleted B-cell populations during the postnatal phase. 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, ADRUXE should not be administered to pregnant women unless the possible benefit outweighs the potential risk.

Women of childbearing age should employ effective contraceptive methods during and for up to 12 months after treatment with ADRUXE.

The potential risk of transmissible maternal infections either recently acquired or reactivated through the use of ADRUXE should also be considered when prescribing ADRUXE to pregnant women.

7.1.2 Breastfeeding

There are limited data on the presence of rituximab in human milk and the effect on the breastfed child, and there are no data on the effect on milk production. Rituximab is detected in the milk of lactating cynomolgus monkeys, and maternal IgG is present in human breast milk. Rituximab has also been reported to be excreted at low concentrations in human breast milk. Given that the clinical significance of this finding for children is not known, advise women not to breastfeed during treatment with ADRUXE and for 6 months after the last dose due to the potential of serious adverse reactions in breastfed children.

7.1.3 Pediatrics

Pediatrics (< 18 years of age): The safety and effectiveness of ADRUXE in pediatric patients have not been established; therefore, Health Canada has not authorized an indication for pediatric use.

Hypogammaglobulinemia has been observed in pediatric patients treated with rituximab, in some cases severe and requiring long-term immunoglobulin substitution therapy.

7.1.4 Geriatrics

No dose adjustment is required in geriatric patients (aged > 65 years). In diffuse large B-cell lymphoma clinical studies, no overall differences in effectiveness were observed between elderly and younger subjects. However, geriatric patients were more likely to experience cardiac adverse events, mostly supraventricular arrhythmias. Serious pulmonary adverse events were also more common among the elderly, including pneumonia and pneumonitis.

In low-grade or follicular lymphoma clinical studies, no overall differences in safety or effectiveness were observed between geriatric and younger subjects.

In the trial of previously untreated CLL patients, patients over the age of 65 had, in general, more Grade 3/4 AEs with increasing age, and more AEs were recorded in the R-FC arm compared with FC alone.

Similar patterns were observed for SAEs (See 8 Adverse Reactions). The effect of rituximab when added to FC seems to be most pronounced with younger age. Due to the small size of the subgroup of patients over the age of 70 (FC n=25, R-FC n=33), no meaningful conclusion can be drawn for the effect rituximab might have in this age category (see 14 Clinical Trials).

Safety findings were similar in the BO17072 trial in previously treated CLL patients. Grade 3/4 AEs and SAEs generally increased with age in both arms of the study and were more frequently reported in the R-FC arm than the FC arm. However, the incidence of Grade 3/4 AEs was the same in R-FC and FC- treated patients over the age of 70 years (see 14 Clinical Trials).

In RA clinical studies, adverse reactions, including incidence, severity and type of adverse reaction were similar between older and younger patients.

8 Adverse Reactions

8.1 Adverse Reaction Overview

HEMATO-ONCOLOGY

Clinical trials have been conducted in patients with various malignancies and benign disorders in hematology treated with rituximab, predominantly in combination with chemotherapy. Across all hematologic indications, the most frequently observed serious adverse drug reactions were:

• bacterial infections, viral infections, bronchitis
• neutropenia, leucopenia, febrile neutropenia, thrombocytopenia
• infusion related reactions, angioedema

The majority of serious infusion-related reactions occurred during the first infusion of rituximab.

8.2 Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. Therefore, the frequencies of adverse reactions observed in the clinical trials may not reflect frequencies observed in clinical practice and should not be compared to frequencies reported in clinical trials of another drug.

Experience from Clinical Trials in Hemato-Oncology

The frequencies of adverse drug reactions (ADRs) reported with rituximab alone or in combination with chemotherapy are summarised in the tables below and are based on data from clinical trials. These

ADRs had either occurred in single-arm studies or had occurred with at least a 2% difference compared to the control-arm in at least one of the major randomized clinical trials. ADRs are added to the appropriate category in the tables below according to the highest incidence seen in any of the major clinical trials. Within each frequency grouping ADRs are listed in descending order of severity. Frequencies are defined as very common ≥1/10, common ≥1/100 to <1/10 and uncommon ≥1/1,000 to <1/100.

Rituximab Monotherapy/Maintenance Therapy

The ADRs in Table 2 are based on data from single-arm studies including 356 patients with low-grade or follicular lymphoma treated with rituximab weekly as single-agent for the treatment or re-treatment of non-Hodgkin’s lymphoma up to 4 weeks in most patients and from 25 patients who received doses other than 375 mg/m2 four doses and up to 500 mg/m2 single dose in the Phase I setting. The table also contains ADRs based on data from 671 patients with follicular lymphoma who received rituximab as maintenance therapy for up to 2 years following response to initial induction with CHOP or R-CHOP, R-CVP or R-FCM (see 14 Clinical Trials section for further details). The ADRs were reported up to 12 months after treatment with monotherapy and up to 1 month after treatment with rituximab maintenance.

Table 2 Summary of ADRs Reported in Patients with Low-Grade or Follicular Lymphoma Receiving Rituximab Monotherapy (N = 356) or Rituximab maintenance Treatment (N = 166) in Clinical Trials

Rituximab as Monotherapy

The adverse events listed below were considered by the investigator to be related or of unknown relationship to rituximab and were reported during or up to 12 months after treatment. Adverse events were graded according to the four scale National Cancer Institute (NCI) Common Toxicity Criteria.

Table 3 Summary of Adverse Events Reported in ≥ 1% of 356 NHL Patients Receiving Rituximab Monotherapy in Clinical Trials

Subpopulations

Elderly patients (≥ 65 years): The incidence of any adverse event and of Grade 3 and 4 adverse events was similar in elderly (N=94) and younger (N=237) patients (88.3% versus 92.0% for any adverse event and 16.0% versus 18.1% for Grade 3 and 4 adverse events).

Bulky disease: Patients with bulky disease (N=39) had a higher incidence of Grade 3 and 4 adverse events than patients without bulky disease (N=195; 25.6% versus 15.4%). The incidence of any adverse event was similar in these two groups (92.3% in bulky disease versus 89.2% in non-bulky disease).

Retreatment: The percentage of patients reporting any adverse event and Grade 3 and 4 adverse events upon re-treatment (N=60) with further courses of rituximab was similar to the percentage of patients reporting any adverse event and Grade 3 and 4 adverse events upon initial exposure (N=203; 95.0% versus 89.7% for any adverse event and 13.3% versus 14.8% for Grade 3 and 4 adverse events).

Rituximab Maintenance Treatment

Previously Untreated Follicular Non-Hodgkin's Lymphoma

In a study (MO18264) of patients with previously untreated Follicular non-Hodgkin's Lymphoma (see 14 Clinical Trials), detailed safety data collection was limited to Grade ≥ 2 infections, Grade ≥ 3 adverse events, and serious adverse events (see Table 4).

Table 4 Summary of Adverse Events Reported in ≥ 1% of Patients Receiving Rituximab Maintenance Therapy in MO18264

Table 5 Summary of Grade 3–5 AEs by Age Group (MSAP) in MO18264

MSAP: Maintenance Safety Analysis Population Percentages are based on the corresponding number (n).

* One patient died of fulminant hepatitis B (categorized as a hepatobiliary AE rather than an Infection & Infestation AE).

The results of rituximab maintenance treatment in patients older than 75 years of age should be interpreted with caution due to the small number of patients in this subgroup.

Relapsed/Refractory Follicular Non-Hodgkin's Lymphoma

The following data are from a Phase III clinical trial where patients with relapsed or refractory follicular non-Hodgkin’s lymphoma were randomized in a first phase to induction treatment with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or rituximab plus CHOP (R- CHOP). Patients who responded to induction treatment with CHOP or R-CHOP were randomized in a second phase to receive no further treatment (observation) or maintenance treatment with rituximab.

In the induction phase of the trial, a total of 462 patients (228 on CHOP, 234 on R-CHOP) contributed to the safety evaluation of the two induction regimens.

Table 6 Induction Phase: Summary of NCIC-CTC Grade 3 and 4 Adverse Events Reported in ≥ 1% of 462 Patients in Either Treatment Group (CHOP or R- CHOP)

*Adverse events that were reported at a higher incidence (≥ 2% difference) in the R-CHOP group compared to the CHOP group and, therefore, may be attributable to rituximab.

A total of 333 patients (167 observations, 166 rituximab) were included in the safety evaluation of the maintenance phase of the study. Maintenance treatment with rituximab consisted of a single infusion of rituximab at 375 mg/m2 body surface area administered every 3 months for a maximum period of 2 years or until disease progression.

Table 7 Maintenance Phase: Summary of NCIC-CTC Adverse Events (Grades 1–4 and Grades 3-4) Reported in ≥ 1% of 333 Patients in Either Treatment Group (Observation or Rituximab Maintenance)

*Adverse events (Grades 1-4) that were reported at a higher incidence (≥ 2% difference) in the rituximab maintenance group compared to observation and, therefore, may be attributable to rituximab.

#Adverse events (Grades 3-4) that were reported at a higher incidence (≥ 2% difference) in the rituximab maintenance group compared to observation and, therefore, may be attributable to rituximab.

Rituximab in Combination with Chemotherapy in NHL and CLL

The ADRs listed in the table below are based on rituximab-arm data from controlled clinical trials that occurred in addition to those seen with monotherapy/maintenance therapy and/or at a higher frequency grouping: 202 patients with diffuse large B-cell lymphoma (DLBCL) treated with R-CHOP, and from 234 and 162 patients with follicular lymphoma treated with R-CHOP or R-CVP, respectively, and from 397 previously untreated CLL patients and 274 previously treated CLL patients, treated with rituximab in combination with fludarabine and cyclophosphamide (R-FC) (see 14.1 Clinical Trials - Reference Biologic Drug for further details).

Table 8 Summary of Severe ADRs Reported in Patients Receiving R-CHOP in DLBCL (N = 202), R-CHOP in Follicular Lymphoma (N = 234) and R-CVP in Follicular Lymphoma (N = 162) and R-FC in Previously Untreated CLL (N = 397) or Previously Treated CLL (N = 274)

* includes reactivation and primary infections; frequency based on R-FC regimen in previously treated CLL Frequency count was based on only severe reactions defined in clinical trials as ≥ Grade 3 NCI common toxicity criteria

Only the highest frequency observed in any trial is reported

# prolonged and/or delayed onset neutropenia after completion of an R-FC course in previously untreated or relapsed/refractory CLL

Rituximab in Combination with CVP Chemotherapy

The following data are based on 321 patients from a randomized phase III clinical trial comparing rituximab plus CVP (R-CVP) to CVP alone (162 R-CVP, 159 CVP). Differences between the treatment groups with respect to the type and incidence of adverse event were mainly accounted for by typical adverse events associated with rituximab monotherapy.

Table 9 Summary of Adverse Events (all Intensities) Reported in ≥ 1% of 321 Patients in Either Treatment Group (CVP or R-CVP)

Rituximab in Combination with CHOP Chemotherapy

The following table shows all Grade 3 to 4 clinical adverse events, including Grade 2 infections, reported in ≥ 1% of patients in either treatment group (CHOP and rituximab plus CHOP [R- CHOP]) in a randomized phase III clinical trial in the total safety population (n=398). Adverse events were graded according to the four-scale National Cancer Institute of Canada (NCIC) Common Toxicity Criteria.

Table 10 Summary of Grade 3 and 4 Adverse Events (Including Grade 2 Infections) Reported in ≥ 1% of 398 Patients in Either Treatment Group (CHOP or R- CHOP)

* Adverse events that were reported at a higher incidence (≥ 2% difference) in the R-CHOP group as compared to the CHOP group and, therefore, may be attributable to R-CHOP.

# Febrile neutropenia as reported by investigators: Fever and neutropenia with or without documented infection (see below, subsection Infections).

The following terms have been reported as adverse events, however, were reported at a similar (< 2% difference between the groups) or lower incidence in the rituximab-arms compared to control arms: Hematotoxicity, neutropenic infection, urinary tract infection, septic shock, superinfection lung, implant infection, septicemia staphylococcal, lung infection, rhinorrhea, pulmonary edema, cardiac failure, sensory disturbance, venous thrombosis, mucosal inflammation NOS, influenza-like illness, edema lower limb, abnormal ejection fraction, pyrexia, general physical health deterioration, fall, multi-organ failure, venous thrombosis deep limb, abnormal ejection fraction, positive blood culture, anorexia, diabetes mellitus inadequate control.

The safety profile for rituximab in combination with other chemotherapies (e.g. MCP, CHVP- IFN) is comparable to the safety profile as described for the combination of rituximab and CVP, CHOP or FC in equivalent populations.

Rituximab in Combination with FC Chemotherapy

The following table shows all Grade 3 to 4 clinical adverse events and serious adverse events reported with a ≥ 2% difference in frequency between either treatment group (R-FC and FC) in ML17102 and BO17072. Grade 1 and 2 adverse events and Grade 4 lymphocytopenia were not captured in study ML17102. A total of 550 SAEs in 344 patients were reported across the two arms in the primary analysis of ML17102. Infections and infestations (15% in FC vs 18% in R- FC) and blood and lymphatic system disorders (11% in FC vs 17% in R-FC) were reported at higher frequencies, as expected, for the rituximab-containing arm. One case of tuberculosis was recorded as an adverse event in the R-FC arm. In the updated overall survival results (final analysis) of study ML17102 after a median of 66.4 months of observation (additional four years of follow-up data beyond that for the primary analysis), the safety profile of rituximab in combination with FC remained unchanged compared with that reported at the time of the primary analysis.

Table 11 Summary of Grade 3 & 4 Adverse Events and Serious Adverse Events that Occurred with a Difference in Incidence of ≥ 2% Between Either the R-FC Arm or the FC Arm

*Grade 1 and 2 adverse events and Grade 4 lymphocytopenia were not captured in ML17102.

**Primary analysis: 20.7 months median observation time.

Table 12 Summary of Grade 3 or 4 Adverse Events and Deaths by Binet Stage in ML17102 (Primary Analysis: 20.7 Months Median Observation Time)

In the subgroup analysis of Binet stage, in both arms of ML17102, the rate of Grade 3 or 4 AEs slightly increased from Binet stage B to Binet stage C. In the Binet stage A subgroup, there was no difference in the incidence of Grade 3 or 4 AEs between the FC and R-FC arms. In Binet stage B and C patients, the rates of Grade 3 or 4 AEs were higher in the R-FC arm compared to the FC arm. Similar patterns were observed for SAEs.

Table 13 Summary of Grade 3 or 4 Adverse Events and Fatal AEs by Binet Stage in BO17072

Table 14 Summary of Grade 3 or 4 Adverse Events and Deaths by Age in ML17102 (Primary Analysis: 20.7 Months Median Observation Time)

In the subgroup analysis of age in ML17102, Grade 3 or 4 AEs tended to increase with increasing age > 65 years, especially for > 70 years and more AEs were recorded in the R-FC arm compared with FC alone. Similar patterns were observed for SAEs.

Table 15 Summary of Grade 3 or 4 Adverse Events and Fatal AEs by Age in BO17072

Further Information on Selected, Serious Adverse Drug Reactions-- Non-Hodgkin’s Lymphoma and Chronic Lymphocytic Leukemia Patients

Infusion-Related Reactions

Monotherapy – 4 weeks treatment

Hypotension, fever, chills, rigors, urticaria, bronchospasm, sensation of tongue or throat swelling (angioedema), nausea, fatigue, headache, pruritus, dyspnea, rhinitis, vomiting, flushing, and pain at disease sites have occurred in association with rituximab infusion as part of an infusion- related symptom complex. Such infusion-related symptoms occurred in the majority of patients during the first infusion with rituximab. The incidence of infusion-related symptoms decreased from 77% (7% Grade 3/4) with the first infusion to approximately 30% (2% Grade 3/4) with the fourth infusion and to 14% (no Grade 3/4 events) with the eighth infusion. Some features of tumor lysis syndrome have also been observed (see 7 Warnings and Precautions: Tumor Lysis Syndrome).

Maintenance Treatment (NHL) up to 2 years

Non-serious signs and symptoms suggestive of an infusion-related reaction were reported in 41% of patients under general disorders (mainly asthenia, pyrexia, influenza-like illness, pain) and in 7% of patients for immune system disorders (hypersensitivity). Serious infusion-related reactions occurred in <1% of patients (see 7 Warnings and Precautions: Infusion -Related Events).

Combination Therapy (R-CVP in NHL; R-CHOP in DLBCL, R-FC in CLL)

Severe infusion-related reactions occurred in up to 12% of all patients at the time of the first treatment cycle with rituximab in combination with chemotherapy. The incidence of severe infusion-related reactions decreased to less than 1% by the eighth cycle of therapy. The signs and symptoms were consistent with those observed during monotherapy (see 7 Warnings and Precautions), but also included dyspepsia, rash, hypertension, tachycardia, features of tumour lysis syndrome. Additional reactions reported in isolated cases at the time of R-CHOP therapy were myocardial infarction, atrial fibrillation, pulmonary edema and acute reversible thrombocytopenia.

Infections

Monotherapy 4 weeks treatment

These were usually common, non-opportunistic and mild. Rituximab induced B-cell depletion in 70 to 80% of patients but was associated with decreased serum immunoglobulins in only a minority of patients. Infectious events, irrespective of causal assessment, occurred in 30.3% of 356 patients: 18.8% of patients had bacterial infections, 10.4% had viral infections, 1.4% had fungal infections, and 5.9% had infections of unknown etiology. Severe infectious events (grade 3 or 4), including sepsis occurred in 3.9% of patients; in 1.4% during the treatment period and in 2.5% during the follow up period.

Maintenance Treatment (NHL) up to 2 years

The proportion of patients with Grade 1 to 4 infections was 26% in the observation group and 47% in the rituximab group with severe (Grade 3/4) infections in 2% of patients on observation and 11% receiving rituximab maintenance treatment. Severe infections reported in ≥ 1% of patients in the rituximab arm were pneumonia (2%), respiratory tract infection (2%), febrile infection (1%), and herpes zoster (1%). In a large proportion of infections (all grades), the infectious agent was not specified or isolated, however, where an infectious agent was specified, the most frequently reported underlying agents were bacterial (observation 2%, rituximab 11%), viruses (observation 8%, rituximab 11 %) and fungi (observation 3%, rituximab 4%). There was no cumulative toxicity in terms of infections reported over the 2 -year maintenance period.

Data from a phase III clinical trial included two cases of fatal PML in NHL patients that occurred after disease progression and retreatment (see 7 Warnings and Precautions).

Combination Therapy (R-CVP in NHL; R-CHOP in DLBCL, R-FC in CLL)

In the R-CVP study the overall proportion of patients with infections or infestations during treatment and for 28 days after trial treatment end was comparable between the treatment groups (33% R-CVP, 32% CVP). The most common infections were upper respiratory tract infections which were reported for 12.3% patients on R-CVP and 16.4% patients receiving CVP; most of these infections were nasopharyngitis. Serious infections were reported in 4.3% of the patients receiving R-CVP and 4.4% of the patients receiving CVP. No life-threatening infections were reported during this study.

In the R-CHOP study the overall incidence of Grade 2 to 4 infections was 45.5% in the R-CHOP group and 42.3% in the CHOP group. Grade 2 to 4 fungal infections were more frequent in the R-CHOP group (4.5% vs 2.6% in the CHOP group); this difference was due to a higher incidence of localized Candida infections during the treatment period. The incidence of Grade 2 to 4 herpes zoster, including ophthalmic herpes zoster, was higher in the R-CHOP group (4.5%) than in the CHOP group (1.5%), with 7 of a total of 9 cases in the R-CHOP group occurring during the treatment phase [20, 61]. The proportion of patients with Grade 2 to 4 infections and/or febrile neutropenia was 55.4% in the R-CHOP group and 51.5% in the CHOP group.

Febrile neutropenia (i.e. no report of concomitant documented infection) was reported only during the treatment period, in 20.8% in the R-CHOP group and 15.3% in the CHOP group.

In patients with CLL, the overall incidence of Grade 3 or 4 infections during treatment and for 28 days after the end of trial treatment was comparable between the treatment groups both in the previously untreated (18% R-FC, 17% FC) and in the previously treated setting (19% R-FC, 18% FC). The incidence of Grade 3 or 4 hepatitis B infection (reactivation and primary infection) was 2% R-FC vs. 0% FC.

Hematologic Events

Monotherapy 4 weeks

Hematologic adverse events occur in a minority of patients and are usually mild and reversible. Severe neutropenia was reported in 4.2% of patients, severe anemia was reported in 1.1% of patients and severe thrombocytopenia was reported in 1.7% of patients. A single occurrence of transient aplastic anemia (pure red cell aplasia) and two occurrences of hemolytic anemia following therapy with rituximab were reported.

Maintenance Treatment (NHL) up to 2 years

Leucopenia (all grades) occurred in 26% of patients on observation vs 32% of patients in the rituximab arm, and neutropenia was reported in 14% of patients on observation and in 25% of patients on rituximab. There was a higher incidence of Grade 3-4 leucopenia (observation 2%, rituximab 5%) and neutropenia (observation 5%, rituximab 11%) in the rituximab arm compared to the observation arm. The incidence of Grade 3 to 4 thrombocytopenia (observation 1%, rituximab <1%) was low. In approximately half of the patients with available data on B-cell recovery after end of rituximab induction treatment, it took 12 months or more for their B-cell levels to return to normal values.

Combination Therapy (R-CVP in NHL; R-CHOP in DLBCL, R-FC in CLL)

Severe (Grade 3/4) Adverse Events Neutropenia: There was a higher incidence of Grade 3-4 neutropenia in the rituximab containing study arms compared to the chemotherapy arms. In the R-CVP study, the incidence of neutropenia was 24% in the R-CVP arm versus 14% in the CVP arm. These laboratory findings were reported as adverse events and resulted in medical intervention in 3.1% of patients on R-CVP and 0.6% of patients on CVP. The higher incidence of neutropenia in the R-CVP group was not associated with a higher incidence of infections and infestations. In the R-CHOP study, the incidence of severe neutropenia was 97% in the R- CHOP arm versus 88% in the CHOP arm. In previously untreated patients with CLL, Grade 3/ 4 neutropenia was reported as an adverse event in 30% of patients in the R-FC arm and in 19% of patients in the FC arm. In patients with previously treated CLL, the incidence of Grade 3/4 neutropenia adverse events was slightly higher in the R-FC arm (42% R-FC) compared to FC arm (40%).

Severe (Grade 3/4) Adverse Events Leucopenia: In the R-CHOP study, the incidence of severe leucopenia was 88% in the R-CHOP arm versus 79% in the CHOP arm. In previously untreated CLL, more patients receiving R-FC experienced Grade 3/ 4 adverse events of leucopenia (23%) compared with patients receiving FC (12%). In patients with previously treated CLL, the overall incidence of Grade 3/4 leucopenia adverse events was comparable between the treatment arms (4% R-FC, 3% FC).

Studies in previously untreated and relapsed refractory CLL have established that in some cases neutropenia was prolonged or with late onset following treatment in the rituximab plus FC group.

Severe (Grade 3/4) Adverse Events Anemia and Thrombocytopenia: No relevant difference between the treatment arms was observed with respect to Grade 3 and 4 anemia or thrombocytopenia. In the R-CVP study, the incidence of anemia was 0.6% in the R-CVP arm versus 1.9% in the CVP arm. The incidence of thrombocytopenia was 1.2% in the R-CVP arm versus 0% in the CVP arm. In the R-CHOP study, the incidence of anemia was 14% in the R- CHOP arm versus 19% in the CHOP arm. The incidence of thrombocytopenia was 15% in the R-CHOP arm versus 16% in the CHOP arm. The time to recovery from all hematological abnormalities was comparable in the two treatment groups. In the CLL first -line study, grade 3/4 anemia was reported by 4% of patients treated with R-FC compared to 7% of patients receiving FC, and Grade 3/ 4 thrombocytopenia was reported by 7% of patients in the R-FC group compared to 10% of patients in the FC group. In the previously treated CLL study, adverse events of Grade 3/4 anemia were reported in 12% of patients treated with R-FC compared to 13% of patients receiving FC and Grade 3/4 thrombocytopenia was reported by 11% of patients in the R-FC group compared to 9% of patients in the FC group.

Cardiovascular Events (see 7 Warnings and Precautions)

Monotherapy 4 weeks treatment

Cardiovascular events were reported in 18.8% of patients during the treatment period. The most frequently reported events were hypotension and hypertension. Two patients (0.6%) experienced grade 3 or 4 arrhythmia (including ventricular and supraventricular tachycardia) during an infusion with rituximab and one patient with a history of myocardial infarction experienced angina pectoris, evolving into myocardial infarction 4 days later.

Maintenance Treatment (NHL) up to 2 years

The incidence of Grade 3 to 4 cardiac disorders was comparable between the two treatment groups (5% in observation, 7% in rituximab). Cardiac events were reported as serious adverse event in <1% of patients on observation and in 3% of patients on rituximab: atrial fibrillation (1%), myocardial infarction (1%), left ventricular failure (<1%), myocardial ischemia (<1%).

Combination Therapy (R-CVP in NHL; R-CHOP in DLBCL, R-FC in CLL)

In the R-CVP study the overall incidence of cardiac disorders in the safety population was low (4% R-CVP, 5% CVP), with no relevant differences between the treatment groups.

In the R-CHOP study 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 rituximab infusion or were associated with predisposing conditions such as fever, infection, acute myocardial infarction or pre-existing respiratory and cardiovascular disease (see 7 Warnings and Precautions). 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.

In CLL, the overall incidence of Grade 3 or 4 cardiac disorders was low both in previously untreated patients (4% R-FC, 3% FC) and in previously treated patients (4% R-FC, 4% FC).

IgG Levels

Maintenance Treatment (NHL) up to 2 years

After induction treatment, median IgG levels were below the lower limit of normal (LLN) (<7 g/L) in both the observation and the rituximab groups. In the observation group, the median IgG level subsequently increased to above the LLN, but remained constant during rituximab treatment.

The proportion of patients with IgG levels below the LLN was about 60% in the rituximab group throughout the 2-year treatment period, while it decreased in the observation group (36% after 2 years).

Neurologic Events

Combination Therapy (R-CVP in NHL; R-CHOP in DLBCL, R-FC in CLL)

During the treatment period, (2% of patients) in the R-CHOP group, 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, (1.5% of patients) had cerebrovascular events in the CHOP group, all of which occurred during the follow-up period.

In CLL, the overall incidence of Grade 3 or 4 nervous system disorders was low both in previously untreated patients (4% R-FC, 4% FC) and in previously treated patients (3% R-FC, 3% FC).

Pulmonary Events (see 7 Warnings and Precautions)

Three pulmonary events have been reported in temporal association with rituximab infusion as a single agent: acute, infusion-related bronchospasm, an acute pneumonitis presenting 1-4 weeks post infusion with rituximab, and bronchiolitis obliterans. The bronchiolitis obliterans was associated with progressive pulmonary symptoms and culminated in death several months following the last infusion with rituximab. The safety of resumption or continued administration of rituximab in patients with pneumonitis or bronchiolitis obliterans is unknown.

Malignancy

Combination Therapy (R-CVP in NHL; R-CHOP in DLBCL, R-FC in CLL)

In the CLL previously untreated study, the incidence of malignancy following exposure to rituximab was 4.5% compared to 3.8% in patients not exposed to rituximab.

Rituximab in Combination with FC Chemotherapy

The following table shows all serious clinical adverse events reported in ≥ 1% of patients in either treatment group (R-FC and FC) in ML17102 and BO17072. In ML17102 Grade 1 and 2 adverse events and Grade 4 lymphocytopenia were not captured in the study.

Table 16 Summary of Serious Adverse Events that Occurred with an Incidence of ≥ 1%

*Grade 4 lymphocytopenia was not captured in ML17102.

** Onset in one patient before starting study medication.

*** (Primary analysis: 20.7 months median observation time)

# Grade 1 and 2 adverse events and Grade 4 lymphocytopenia were not captured in the study.

Combination Therapy

Elderly patients (≥ 65 years): The incidence of Grade 3/4 blood and lymphatic adverse events was higher in elderly patients (≥ 65 years of age) compared to younger patients, with previously untreated or previously treated CLL.

Experience from Clinical Trials in Rheumatoid Arthritis

The clinical efficacy of rituximab, given together with methotrexate was studied in three double- blind controlled clinical trials (one phase III trial and two phase II trials) in patients with rheumatoid arthritis. More than 1000 patients received at least one treatment course and were followed for periods ranging from 6 months to over 3 years; approximately 600 patients received two or more courses of treatment during the follow-up period.

Patients received 2 x 1000 mg of rituximab separated by an interval of two weeks; in addition to methotrexate (10-25 mg/week). Infusions of rituximab were administered after an IV infusion of 100 mg methylprednisolone; patients also received treatment with oral prednisolone for 15 days. Listed in

Table 17 are ADRs that occurred with at least a 2% difference compared to the control arm and more frequently by patients who had received at least one infusion of rituximab than among patients that had received placebo in the phase III trial and the combined population included in phase II studies. In these studies, adverse reactions were more frequent in patients treated with rituximab than in patients treated with placebo. Frequencies are defined as very common (≥1/10) and common (≥1/100 to <1/10).

The most frequent ADRs considered due to receipt of 2 x 1000 mg rituximab in phase II and III studies were acute infusion reactions. Infusion reactions occurred in 15% of patients following the first infusion of rituximab and 5% in placebo patients. Infusion reactions decrease d to 2% following the second infusion in both rituximab and placebo groups.

Table 17 Summary of Adverse Drug Reactions Occurring in Patients with Rheumatoid Arthritis Receiving Rituximab During Phase II and III Clinical Studies

Table 18 Adverse Reactions Occurring in at Least 1% of Patients and More Frequently in Rheumatoid Arthritis Patients Receiving Rituximab During Phase II and III Clinical Studies

* Reactions occurring within 24 hours of infusion

The following adverse events were reported at a frequency between 1% and 2% greater in the rituximab arms compared to the control arms: lower respiratory tract infections/pneumonia, abdominal pain upper, muscle spasms, asthenia, anxiety.

In addition to the events tabulated above, medically significant events reported rarely in the population treated with rituximab and considered potential reactions to treatment include the following:

General Disorders: Generalized edema

Immune system Disorders: Anaphylaxis, anaphylactoid reaction

Respiratory Disorders: Bronchospasm, wheezing, laryngeal edema

Skin and Subcutaneous Disorders: Angioneurotic edema, generalized pruritus.

The following serious adverse events were reported with an incidence rate of at least 1%:

Rheumatoid Arthritis and osteoarthritis (Pooled Phase II Study Population)

Rheumatoid Arthritis (Phase III Study Population).

Multiple Courses

Multiple courses of treatment are associated with a similar ADR profile to that observed following first exposure. The safety profile improved with subsequent courses due to a decrease in IRRs, RA exacerbation and infections, all of which were more frequent in the first 6 months of treatment.

In a study where all patients initially received rituximab followed by retreatment with either rituximab or placebo, the safety profile was similar to placebo. The proportion of patients who experienced any AEs, SAEs infections or serious infections was comparable between the placebo and rituximab retreatment arms.

Adverse Reactions Reported in RA Patients who had no Prior Inadequate Response to TNF Antagonists

Listed below are additional ADRs reported in Phase III placebo-controlled RA trials in either DMARD-IR or MTX Naive patients. These ADRs occurred with at least a 2% greater difference compared to control arm:

Very common (≥ 10%): headache

Common (≥ 1% to < 10%) (listed in decreasing order of frequency): diarrhea, dizziness, bronchitis, sinusitis, gastroenteritis, fatigue, alopecia, mouth ulceration, gastro-esophageal reflux, peripheral edema, erythema, depression anxiety, tinea pedis.

Further Information on Selected Adverse Drug Reactions- Rheumatoid Arthritis

Please note that the information presented below includes the all exposure population of more than 3000 RA patients who have received at least one treatment course and were followed for periods ranging from 6 months to over 5 years with an overall exposure equivalent to 7198 patient years. The patient populations receiving rituximab differed between studies, ranging from early active RA patients who were methotrexate (MTX) naïve, through MTX inadequate responders (MTX-IR) to patients who had inadequate response to anti-TNF therapies (TNF-IR).

Infusion-related reactions

The most frequent ADRs following receipt of rituximab in clinical studies were infusion-related reactions. Among the 3095 patients treated with rituximab, 1077 (35%) experienced at least one IRR. The vast majority of IRRs were CTC Grade 1 or 2. In clinical studies, fewer than 1% (14/3095 patients) of patients with RA who received an infusion of rituximab at any dose experienced a serious infusion-related reaction. There were no CTC Grade 4 IRRs and no deaths due to IRRs in the clinical studies. The proportion of CTC Grade 3 events and of IRRs leading to withdrawal decreased by course and were rare from course 3 onwards.

Signs and or symptoms suggesting an infusion-related reaction (nausea, pruritus, fever, urticaria/rash, chills, pyrexia, rigors, sneezing, angioneurotic oedema, throat irritation, cough and bronchospasm, with or without associated hypotension or hypertension) were observed in 720/3095 (23%) patients with rheumatoid arthritis following first infusion of the first exposure to rituximab. Premedication with IV glucocorticoid significantly reduced the incidence and severity of these events (see 7 Warnings and Precautions, Rheumatoid Arthritis).

In patients with moderate-to-severe active rheumatoid arthritis who did not experience a serious infusion-related reaction during or within 24 hours of their first infusion at the standard infusion regimen and received a 120-minute infusion of rituximab at the second infusion, the incidence of infusion-related reactions on Infusion 2 was 6.5% (95% CI [4.1%, 9.7%]). For the subsequent infusions

(Infusion 3 and Infusion 4) in the second course of treatment with rituximab, the incidence of infusion-related reactions during or within 24 hours of the 120 -minute infusion was 5.9% (95% CI [3.5%, 9.3%]) for Infusion 3 and 0.7% (95% CI [0.1%, 2.6%]) for Infusion 4, respectively (see 14 Clinical Trials- RHEUMATOID ARTHRITIS).

Infections

The overall rate of infection was approximately 97 per 100 patient years in patients treated with rituximab. The infections were predominately mild to moderate and consisted mostly of upper respiratory tract infections and urinary tract infections. In the all-exposure population the rate of serious infections, was approximately 4 per 100 patient years, some of which were fatal, including clostridium difficile colitis, pneumonia, progressive multifocal leukoencephalopathy (PML), neutropenic sepsis, septic shock and abdominal sepsis. In addition to the ADRs in Table 17, medically serious events reported also included pneumonia (including atypical pneumonia) at a frequency of 1.9%.

Malignancies

In RA clinical studies, the incidence of malignancy following exposure to rituximab is 0.8 per 100 patient years, which is within the range expected for an age- and gender- matched population. The rate of melanoma in RA clinical studies was 0.06 per 100 patient years (95% CI 0.02 -0.14 per 100 patient years), which is similar to the rate expected for an age and gender matched population. This overall rate includes 3 patients of 431 in the Study 2 extension.

On the basis of limited experience with rituximab in rheumatoid arthritis patients, a possible risk for the development of solid tumours cannot be excluded at this time, although present data do not seem to suggest any increased risk.

Experience from clinical trials Granulomatosis with Polyangiitis (GPA, also known as Wegener's Granulomatosis) and Microscopic Polyangiitis (MPA)

In the GPA/MPA clinical study, 99 patients were treated with rituximab (375 mg/m², once weekly for 4 weeks) and glucocorticoids (see 14.1 Clinical Trials - Reference Biologic Drug).

The adverse events listed in Table 19 occurred at an incidence of ≥ 1% in the rituximab-treated group.

Table 19 Adverse Events Occurring in at Least 1% of Rituximab-Treated GPA/MPA Patients in Clinical Study Up to Month 6*

*The study design allowed for crossover or treatment by best medical judgment, and 13 patients in each treatment group received a second therapy during the 6 month study period.

^aMost common infections in the rituximab group included upper respiratory tract infections, urinary tract infections, and herpes zoster.

^bMost common terms reported in the rituximab group included cytokine release syndrome, flushing, throat irritation, and tremor.

Further Information on Selected Adverse Drug Reactions-GPA and MPA

Infusion-related reactions

Infusion related reactions (IRRs) in the GPA/MPA clinical study were defined as any adverse event occurring within 24 hours of an infusion and considered to be infusion-related by investigators in the safety population. Ninety nine patients were treated with rituximab and 12% experienced at least one IRR. All IRRs were CTC Grade 1 or 2. The most common IRRs included cytokine release syndrome, flushing, throat irritation, and tremor. Rituximab was given in combination with intravenous glucocorticoids which may reduce the incidence and severity of these events.

Infections

In the RAVE study, 62% (61/99) of patients in the rituximab group experienced an infection of any type compared to 47% (46/98) of patients in the cyclophosphamide group by Month 6, infections were predominately mild to moderate and consisted mostly of upper respiratory tract infections, herpes zoster and urinary tract infections. The incidence of serious infections was 11% in the rituximab-treated patients and 10% in the cyclophosphamide treated patients. The most frequently reported serious infection in the rituximab group was pneumonia at a frequency of 4%.

Malignancies

In the RAVE study by Month 6, one malignancy was reported in each treatment arm. By the common close out date (the last patient's 18-month visit), 5 patients in the rituximab arm reported 6 malignancies and 2 patients in the cyclophosphamide arm reported 2 malignancies.

8.3 Less Common Clinical Trial Adverse Reactions

Rituximab as Monotherapy

The following adverse events were also reported (<1%): coagulation disorders, asthma, lung disorder, bronchiolitis obliterans, hypoxia, abdominal enlargement, pain at the infusion site, bradycardia, lymphadenopathy, nervousness, depression, dysgeusia.

Rituximab Maintenance Treatment

Uncommon (<1%) Adverse Events Reported in Clinical Trial MO18264 (not already listed in the Oncology Adverse Events Section)

Infections and infestations: escherichia urinary tract infection, herpes virus infection, cystitis, folliculitis, haemophilus infection, viral upper respiratory tract infection, skin infection, acute tonsillitis, catheter related infection, cellulitis, central line infection, paronychia, pyelonephritis, skin candida, staphylococcal infection, viral pharyngitis, abscess limb, appendicitis, ascariasis, broncopneumonia, campylobacter infection, campylobacter intestinal infection, cystitis escherichia, device related infection, endocarditis, fungal skin infection, gastric infection, gastrointestinal infection, helicobacter infection, herpes ophthalmic, impetigo, infective exacerbation of chronic obstructive airways disease, klebsiella infection, laryngitis, lower respiratory tract infection, lyme disease, meningitis, moraxella infection, mycobacterial infection, oral fungal infection, pertussis, postoperative abscess, postoperative wound infection, pulmonary tuberculosis, roseola, salmonellosis, serratia infection, skin bacterial infection, staphylococcal bacteraemia, staphylococcal skin infection, streptococcal bacteraemia, tinea cruris, tinea pedis, tracheitis, upper aerodigestive tract infection, vaginitis bacterial, vulvovaginal candidiasis, vulvovaginal mycotic infection

Neoplasms benign, malignant and unspecified (including cysts and polyps): colon cancer, bowen’s disease, breast cancer, dysplastic naevus syndrome, prostate cancer, acute myeloid leukaemia, adenocarcinoma, hypergammaglobulinaemia benign monoclonal, lipoma, lung adenocarcinoma, stage unspecified meningioma, neoplasm prostate, neuroendocrine carcinoma of the skin, skin cancer, skin papilloma, squamous cell carcinoma of skin

Nervous system disorders: carpal tunnel syndrome, convulsion, transient ischaemic attack, aphasia, facial palsy, Parkinson’s disease, subarachnoid hemorrhage

Cardiac disorders: aortic valve disease, cardiac arrest, congestive cardiomyopathy, ventricular extrasystoles

Respiratory, thoracic and mediastinal disorders: oropharyngeal pain, dyspnea, sleep apnea syndrome, pulmonary hemorrhage, rhinorrhea

Gastrointestinal disorders: intestinal obstruction, abdominal hernia, inguinal hernia, umbilical hernia, colonic polyp, gastrooesophagitis, jejunal perforation, parotid gland enlargement, sigmoiditis

Musculoskeletal and connective tissue disorders: artharalgia, intervertebral disc protrusion, crest syndrome

General Disorders and Administration Site Conditions: hyperthermia

Psychiatric disorders: depression, suicide attempt, anxiety disorder, panic attack

Eye disorders: conjunctivitis, glaucoma, maculopathy

Investigations: neutrophil count decreased, aspartate aminotransferase increased, gamma-glutamyltransferase increased

Vascular disorders: thrombophlebitis, vena cava thrombosis

Renal and urinary disorders: hydronephrosis

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data

Clinical Trial Findings

Rheumatoid Arthritis (RA) Patients

Hypogammaglobulinaemia (IgG or IgM below the lower limit of normal) has been observed in RA patients treated with rituximab. There was no increased rate in overall infections or serious infections after the development of low IgG or IgM.

Events of neutropenia associated with rituximab treatment, the majority of which were transient and mild or moderate in severity, were observed in clinical trials in RA patients after the first course of treatment. Neutropenia can occur several months after the administration of rituximab.

In placebo-controlled periods of clinical trials, 0.94% (13/1382) of rituximab treated patients and 0.27% (2/731) of placebo patients developed severe (Grade 3 or 4) neutropenia. In these studies, rates of severe neutropenia were 1.06 and 0.53/100 patient-years after the first treatment course, respectively, and 0.97 and 0.88/100 patient-years after multiple courses, respectively. Therefore, neutropenia can be considered an ADR for the first course only. Time to onset of neutropenia was variable. In clinical trials neutropenia was not associated with an observed increase in serious infection, and most patients continued to receive additional courses of rituximab after episodes of neutropenia.

Granulomatosis with Polyangiitis (GPA, also known as Wegener's Granulomatosis) and Microscopic Polyangiitis (MPA) Patients

Hypogammaglobulinemia (IgA, IgG or IgM below the lower limit of normal) has been observed in GPA and MPA patients treated with rituximab. At 6 months, in the rituximab group, 27% (21/79), 58% (40/69) and 51% (35/69) of patients with normal immunoglobulin levels at baseline, had low IgA, IgG and IgM levels, respectively compared to 25% (17/67), 50% (30/60) and 46% (31/68) in the cyclophosphamide group. There was no increased rate in overall infections or serious infections in patients with low IgA, IgG or IgM.

In the active-controlled, randomized, double-blind, multicenter, non-inferiority study of rituximab in GPA and MPA, 24% (20/83) of patients in the rituximab group (single course) and 23% (20/87) of patients in the cyclophosphamide group developed CTC Grade 3 or greater neutropenia. Neutropenia was not associated with an observed increase in serious infection in rituximab-treated patients. The effect of multiple rituximab courses on the development of neutropenia in GPA and MPA patients has not been studied in clinical trials.

8.5 Post-Market Adverse Reactions

Non-Hodgkin’s Lymphoma and Chronic Lymphocytic Leukemia Patients

The reporting frequencies in this section (rare, very rare) are based on estimated marketed exposures and largely data derived from spontaneous reports.

Additional cases of severe infusion-related reactions have been reported during post-marketing use of rituximab (see 7 Warnings and Precautions). As part of the continuing post- marketing surveillance of the safety of rituximab, the following serious adverse reactions have been observed:

Blood and Lymphatic System

Neutropenia: Rarely, the onset of neutropenia has occurred more than four weeks after the last infusion of rituximab. Cases of infusion-related acute reversible thrombocytopenia have been reported.

In post-marketing studies of rituximab in patients with Waldenstrom’s macroglobulinemia, 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 from the administration/start of rituximab treatment.

Body as a Whole

Anaphylaxis; mucositis and serum sickness-like reactions have been reported rarely.

Cardiovascular System

Severe cardiac events, including congestive heart failure and myocardial infarction have been observed, mainly in patients with prior cardiac condition and/or cardiotoxic chemotherapy and mostly associated with infusion-related reactions. Vasculitis, predominantly cutaneous, such as leukocytoclastic vasculitis and fatal cardiac failure have been reported very rarely.

Infections and Infestations

Cases of HBV reactivation, occasionally with fulminant hepatitis, hepatic failure, and death has been reported in some patients with hematologic malignancies treated with rituximab. The majority of patients received rituximab in combination with chemotherapy (see 7 Warnings and Precautions).

Other serious viral infections, either new, reactivation or exacerbation, some of which were fatal, have been reported with rituximab treatment. The majority of patients had received rituximab in combination with chemotherapy or as part of a haematopoietic stem cell transplant. Examples of these serious viral infections are infections caused by the herpes viruses (cytomegalovirus (CMV), Varicella zoster virus and Herpes simplex virus), JC virus (progressive multifocal leukoencephalopathy (PML) and Hepatitis C virus (see 7 Warnings and Precautions).

Progression of Kaposi’s sarcoma has been observed in rituximab-exposed patients with pre- existing Kaposi’s sarcoma. These cases occurred in non-approved indications and the majority of patients were HIV positive.

Increase in fatal infections in HIV lymphoma has been reported very rarely when rituximab is used with chemotherapy.

Immune Phenomena

Paraneoplastic neuropathy, encephalomyelitis, polymyositis, have been rarely reported. Other possible rare adverse events include: optic neuritis, uveitis, vasculitis, serum sickness or a lupus-like syndrome, pleuritis and arthritis. Systemic vasculitis has been reported very rarely.

Nervous System

Cases of cranial neuropathy with or without peripheral neuropathy have been rarely reported. Signs and symptoms of cranial neuropathy, such as severe vision loss, hearing loss, loss of other senses and facial nerve palsy, occurred at various times up to several months after completion of rituximab therapy.

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 recognized risk factors for PRES/RPLS, including the patients’ underlying disease, hypertension, immunosuppressive therapy and/or chemotherapy.

Respiratory System

Respiratory failure/insufficiency and lung infiltration in the context of infusion -related reactions (see 7 Warnings and Precautions). In addition to pulmonary events associated with infusions interstitial lung disease, some with fatal outcome, has been reported; pleural effusions, and pneumonia.

Skin and Appendages

Severe bullous skin reactions (including Toxic Epidermal Necrolysis and Stevens-Johnson Syndrome) and pemphigus, some with fatal outcome, have been reported rarely.

Urogenital System

Renal insufficiency/failure.

Rheumatoid Arthritis (RA), Granulomatosis with Polyangiitis (GPA, also known as Wegener's Granulomatosis) and Microscopic Polyangiitis (MPA) Patients

As part of the continuing post-marketing surveillance of rituximab safety, the following have been observed in the RA setting and are also expected, if not already observed, in GPA/MPA patients:

Infections and Infestations

Progressive multifocal leukoencephalopathy (PML) and reactivation of hepatitis B infection have been reported. Other serious viral infections, some of which were fatal, have been reported in patients treated with rituximab.

Body as a Whole

Serum sickness-like reaction has been reported.

Skin and Subcutaneous Tissue Disorders

Toxic Epidermal Necrolysis and Stevens-Johnson Syndrome some with fatal outcome have been reported very rarely.

Blood and Lymphatic System Disorders

Neutropenic events, including severe late onset and persistent neutropenia, have been reported rarely in the post-marketing setting, some of which were associated with fatal infections.

Nervous System

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 recognized risk factors for PRES/RPLS, including hypertension, immunosuppressive therapy and/or other concomitant therapies.

General Disorders and Administration Site Conditions

Severe infusion-related reactions with fatal outcome have been reported in the post-marketing setting (see 7 Warnings and Precautions).

9 Drug Interactions

9.1 Drug Interactions Overview

There have been no formal drug interaction studies performed with rituximab. However, the existing data suggest that rituximab does not affect the pharmacokinetics of drugs which are used in combination with rituximab.

9.2 Drug-Drug Interactions

There have been no formal drug interaction studies performed with rituximab. The tolerability of simultaneous or sequential combination of rituximab with chemotherapy other than CHOP and CVP or agents which are liable to cause depletion of normal B cells is not well defined.

Renal failure requiring dialysis has been observed in patients treated with the combination of rituximab and cisplatin. If this combination is used, extreme caution should be exercised and renal function should be monitored closely.

Based on information from the limited number of previously treated CLL patients in study BO17072, co-administration with rituximab did not appear to have an effect on the pharmacokinetics of fludarabine or cyclophosphamide.

Co-administration with methotrexate had no effect on the pharmacokinetics of rituximab in rheumatoid arthritis patients.

Concomitant use with Biologic Agents and DMARDs other than Methotrexate in RA

Limited data are available on the safety of the use of biologic agents or DMARDs other than methotrexate in patients exhibiting peripheral B cell depletion following treatment with rituximab. Patients should be closely observed for signs of infection if biologic agents and/or DMARDs are used concomitantly.

In the RA clinical trial program, 373 rituximab-treated patients received subsequent therapy with other DMARDs, of whom 240 received a biologic DMARD. In these patients the rate of serious infection while on rituximab (prior to receiving a biologic DMARD) was 6.1 per 100 patient years compared to 4.9 per 100 patient years following subsequent treatment with the biologic DMARD.

9.3 Drug-Food Interactions

Interactions with food have not been established.

9.4 Drug-Herb Interactions

Interactions with herbal products have not been established.

9.5 Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.

10 Clinical Pharmacology

10.1 Mechanism of Action

Rituximab binds specifically to the antigen CD20 (human B-lymphocyte-restricted differentiation antigen, Bp35), a hydrophobic transmembrane protein with a molecular weight of approximately 35 kDa located on pre-B and mature B lymphocytes. The antigen is also expressed on >90% of B-cell non-Hodgkin’s lymphomas (NHL) but is not found on hematopoietic stem cells, pro-B cells, normal plasma cells or other normal tissues. CD20 regulates an early step(s) in the activation process for cell cycle initiation and differentiation, and possibly functions as a calcium ion channel. CD20 is not shed from the cell surface and does not internalize upon antibody binding. Free CD20 antigen is not found in the circulation.

Type B lymphocytes are believed to play a central role in the pathogenesis of rheumatoid arthritis (RA) and associated chronic synovitis. In this setting, B cells may be acting at multiple sites in the autoimmune/inflammatory process, including through production of rheumatoid factor (RF) and other autoantibodies, antigen presentation, T cell activation, and/or pro-inflammatory cytokine production.

Depletion of CD 20 surface antigen positive B cells was associated with reduction of pro-inflammatory cytokines in rheumatoid synovial tissue.

The Fab domain of rituximab binds to the CD20 antigen on B-lymphocytes and the Fc domain recruits immune effector functions to mediate B-cell lysis in vitro. Possible mechanisms of cell lysis include complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC). The antibody has been shown to induce apoptosis in the DHL-4 human B-cell lymphoma line.

In patients with rheumatoid arthritis, the duration of peripheral B cell depletion was variable. The majority of patients received further treatment prior to full B cell repletion. Some patients had prolonged peripheral B cell depletion lasting 2 years or more after their last dose of rituximab.

In Vitro

The binding affinity of rituximab for the CD20 antigen is approximately 11x10^-9 M, by Scatchard analysis.

Rituximab antibody bound to CD20-positive cells also binds complement component C1q. The complement cascade is thereby activated, causing lysis of the CD20 target cell by complement dependent cellular cytotoxicity. The antibody also induces programmed cell death (apoptosis) in human B-cell lymphoma lines.

In vitro studies suggest that rituximab sensitizes drug-resistant human B-cell lymphoma lines to the cytotoxic effects of some chemotherapeutic agents. In human tissue, CD20 antigen binding with rituximab is highly restricted; binding to CD20 was found only on lymphoid cells in the thymus, the white pulp of the spleen, and a majority of peripheral blood and lymph node lymphocytes.

In Vivo

In macaque cynomolgus monkeys, doses of 269 mg/m² produced high plasma levels of rituximab (186 - 303 µg/mL) 24 hours after each of four infusions, which persisted at significant levels for two weeks after the last infusion. Weekly IV doses of 269 mg/m² of rituximab reduced B lymphocytes in both follicular and non-follicular areas of lymph nodes in 50% of monkeys treated for four weeks and in 67% of animals treated for eight weeks. CD20-antigen positive cells in the spleen were markedly reduced after eight weeks. In animals infused with lower doses of antibody, bone marrow and lymph node B cells were depleted by as much as 95%. In these animals the recovery of peripheral blood B cells usually started two weeks after treatment and was complete from 60 to greater than 90 days thereafter.

10.2 Pharmacodynamics

Normal Tissue Cross-reactivity: Rituximab binding was observed on lymphoid cells in the thymus, the white pulp of the spleen, and a majority of B-lymphocytes in peripheral blood and lymph nodes. Little or no binding was observed in non-lymphoid tissues examined.

10.3 Pharmacokinetics

Non-Hodgkin’s Lymphoma

In patients given single doses at 10, 50, 100, 250 or 500 mg/m² as an IV infusion, serum levels and the half-life of rituximab were proportional to dose. In 9 patients given 375 mg/m² as an IV infusion for four doses, the mean serum half-life was 59.8 hours (range 11.1 to 104.6 hours) after the first infusion and 174 hours (range 26 to 442 hours) after the fourth infusion. The wide range of half-lives may reflect the variable tumour burden among patients and the changes in CD20 positive (normal and malignant) B-cell populations upon repeated administrations.

Rituximab at a dose of 375 mg/m² was administered as an IV infusion at weekly intervals for four doses to 166 patients. The peak and trough serum levels of rituximab were inversely correlated with baseline values for the number of circulating CD20 positive B cells and measures of disease burden. Median steady-state serum levels were higher for responders compared to nonresponders; however, no difference was found in the rate of elimination as measured by serum half-life. Serum levels were higher in patients with International Working Formulation (IWF) subtypes B, C, and D as compared to those with subtype A. Rituximab was detectable in the serum of patients three to six months after completion of treatment.

The pharmacokinetic profile of rituximab when administered as six infusions of 375 mg/m² in combination with six cycles of CHOP chemotherapy was similar to that seen with rituximab alone.

Administration of rituximab resulted in a rapid and sustained depletion of circulating and tissue - based B cells. Lymph node biopsies performed 14 days after therapy showed a decrease in the percentage of B-cells in seven of eight patients who had received single doses of rituximab ≥ 100 mg/m². Among the 166 patients in the pivotal study, circulating B-cells (measured as CD19+ cells) were depleted within the first three doses with sustained depletion for up to 6 to 9 months post-treatment in 83% of patients. One of the responding patients (1%), failed to show significant depletion of CD19+ cells after the third infusion of rituximab as compared to 19% of the non-responding patients. B-cell recovery began at approximately six months following completion of treatment. Median B-cell levels returned to normal by twelve months following completion of treatment.

There were sustained and statistically significant reductions in both IgM and IgG serum levels observed from 5 through 11 months following rituximab administration. However, only 14 % of patients had reductions in IgG and/or IgM serum levels, resulting in values below the normal range.

Peripheral B-cell counts declined to levels below normal following the first dose of rituximab. In patients treated for hematological malignancies, B cell recovery began within 6 months of treatment and generally returning to normal levels within 12 months after completion of therapy, although in some patients this might take longer. In rheumatoid arthritis patients, immediate depletion of B cells in the peripheral blood was observed following two infusions of 1000 mg of rituximab separated by a 14 day interval. Peripheral blood B cell counts begin to increase from week 24 and evidence of repopulation is observed in the majority of patients by week 40, whether rituximab was administered as monotherapy or in combination with methotrexate.

Diffuse large B-cell non-Hodgkin’s lymphoma (DLBCL)

Elimination and distribution have not been extensively studied in patients with diffuse large B- cell non-Hodgkin´s lymphoma, but available data indicate that serum levels of rituximab in DLBCL patients are comparable to those in patients with low-grade or follicular NHL following treatment with similar doses.

Chronic Lymphocytic Leukemia (CLL)

No pharmacokinetic information in the untreated CLL population is available. Rituximab was administered as an IV infusion at a first-cycle dose of 375 mg/m² and increased to 500 mg/m² each cycle for 5 doses in combination with fludarabine and cyclophosphamide in the previously treated, low tumor burden CLL patients (absolute lymphocytes <25 x 10⁹ cells/L). The mean (± SD) Cmax and AUC0-τ was 175 ± 76 µg/ mL and 728 ± 488 µg∙d/mL, respectively, after the first-cycle dose (N = 21). The mean (± SD) Cmax and AUC0-τ was 408 ± 199 µg/mL and 4,080 ± 2,400 µg∙d/mL, respectively, after the fifth 500 mg/m² infusion (N=15).

Rheumatoid Arthritis

Following two intravenous infusions of rituximab at a dose of 1000 mg, two weeks apart, the mean terminal half-life was 20.8 days (range, 8.58 to 35.9 days), mean systemic clearance was 0.23 L/day (range, 0.091 to 0.67 L/day), and mean steady-state distribution volume was 4.6 L (range, 1.7 to 7.51 L). Population pharmacokinetic analysis of the same data gave similar mean values for systemic clearance and half-life, 0.26 L/day and 20.4 days, respectively. Population pharmacokinetic analysis revealed that BSA and gender were the most significant covariates to explain inter individual variability in pharmacokinetic parameters. After adjusting for BSA, male subjects had a larger volume of distribution and a faster clearance than female subjects. The gender-related pharmacokinetic differences are not considered to be clinically relevant and dose adjustment is not required.

The pharmacokinetics of rituximab were assessed following two IV doses of 500 mg and 1000 mg on Days 1 and 15 in four studies (WA17047, WA17045, WA17044, U3384G). In all these studies, rituximab pharmacokinetics were dose proportional over the limited dose range studied.

Table 20 Mean PK Parameters for Rituximab

Cfirst = post-infusion concentration after first infusion; Csecond = post-infusion concentration after second infusion

Values are mean ± SD (CV%)

ND = not determined

The PK parameters in the anti-TNF inadequate responder population, following the same dosage regimen (2 x 1000 mg, iv, 2 weeks apart), were similar with a mean maximum serum concentration of 369 µg/mL and a mean terminal half-life of 19.2 days.

Granulomatosis with Polyangiitis (GPA, also known as Wegener's Granulomatosis) and Microscopic Polyangiitis (MPA)

In GPA/MPA patients, peripheral blood CD19 B-cells depleted to less than 10 cells/μl following the first two infusions of rituximab and remained at that level in most patients through Month 6.

Rituximab mean clearance and volume of distribution were 0.313 L/day (range, 0.116 to 0.726 L/day) and 4.50 L (range, 2.25 to 7.39 L) respectively.

Special Populations and Conditions

• Pediatrics: Age had no effect on the pharmacokinetics of rituximab.
• Geriatrics: Age had no effect on the pharmacokinetics of rituximab.
• Gender: Gender had no effect on the pharmacokinetics of rituximab.
• Hepatic Insufficiency: No pharmacokinetic data are available in patients with hepatic impairment.
• Renal Insufficiency: No pharmacokinetic data are available in patients with renal impairment.

11 Storage, Stability and Disposal

Unopened vial

ADRUXE vials are stable at 2 – 8°C. Do not use beyond expiration date stamped on carton. Keep the vial in the outer carton to protect it from light.

Diluted medicinal product

Once prepared, administer the diluted solution immediately. If not administered immediately then:

• 0.9% Sodium Chloride solution

Aseptically prepared infusion solution of ADRUXE in 0.9% sodium chloride solution is may be stored for no more than 48 hours at 5 ± 3°C or at 25 ± 2°C, from the time of preparation to the end of infusion.

• 5% Dextrose solution

Aseptically prepared infusion solution of ADRUXE in 5% dextrose solution may be stored for no more than 48 hours at 5 ± 3°C or at 25 ± 2°C, from the time of preparation to the end of infusion.

As ADRUXE for infusion does not contain any antimicrobial preservative, it is essential to ensure that prepared solutions for infusion are not microbiologically compromised. The diluted product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user. Administration should take place as per standard practices after the aseptic preparation of intravenous admixtures.

12 Special Handling Instructions

Disposal of Unused/Expired Medicines

The release of pharmaceuticals in the environment should be minimized. Medicines should not be disposed of via wastewater, and disposal through household waste should be avoided. Use established ‘collection systems’ if available in your location.

Part II: Scientific Information

13 Pharmaceutical Information

Drug Substance

Proper name: Rituximab for injection

Chemical name: Recombinant anti-human CD20 monoclonal antibody

Molecular formula and molecular mass: The molecular formula of rituximab is C₆₄₁₆H₉₈₇₄N₁₆₈₈O₁₉₈₇S₄₄.

The molecular weight is calculated as 147 kDa from the primary sequence of the reduced, non-glycosylated form.

Structural formula: Rituximab is composed of two heavy chains of 451 amino acids and two light chains of 213 amino acids. The antibody is an IgG1 kappa immunoglobulin containing murine light and heavy chain variable region sequences and human constant region sequences.

Physicochemical properties: Clear to opalescent, colorless to pale yellowish solution, free of visible particles.

Product Characteristics:

ADRUXE (rituximab) is a genetically engineered chimeric murine/human monoclonal antibody that binds specifically to the transmembrane antigen CD20 found on the surface of normal and malignant B lymphocytes. Rituximab has a binding affinity for the CD20 antigen of approximately 11 nM by Scatchard analysis.

The chimeric anti-CD20 antibody is produced by mammalian cell (Chinese hamster ovary) suspension culture in a nutrient medium. The anti-CD20 antibody is purified by affinity and ion exchange chromatography. The purification process includes specific viral inactivation and removal procedures.

14 Clinical Trials

14.1 Clinical Trials - Reference Biologic Drug

Clinical Trials by Indication

*The median time of all clinical time-to event endpoints (e.g. progression free survival – PFS or overall survival – OS) was calculated by applying the Kaplan-Meier method (see table of trial results below).

Non-Hodgkin’s Lymphoma

Table 21 Follicular Non-Hodgkin’s Lymphoma, Monotherapy

Follicular Non-Hodgkin’s Lymphoma, Monotherapy

A multicenter, open-label, single-arm study was conducted in 166 patients with relapsed or refractory low-grade or follicular B-cell NHL who received 375 mg/m² of Rituximab given as an IV infusion weekly for four doses. Patients with tumour masses >10 cm or with > 5,000 lymphocytes/µL in the peripheral blood were excluded from the study. The results are presented in Table 21. The overall response rate (ORR) was 48% (80/166) with a 6% (10/166) complete response (CR) and a 42% (70/166) partial response (PR) rate. Disease-related signs and symptoms (including B-symptoms) were present in 23% (39/166) of patients at study entry and resolved in 64% (25/39) of those patients. The median time to onset of response was 50 days and the median duration of response is projected to be 10 to 12 months.

In a multivariate analysis, the ORR was higher in patients with IWF B, C, and D histologic subtypes as compared to IWF A subtype (58% vs. 12%), higher in patients whose largest lesion was <5 cm vs. >7 cm in greatest diameter (53% vs. 38%), and higher in patients with chemosensitive relapse as compared to chemoresistant (defined as duration of response <3 months) relapse (53% vs. 36%). ORR in patients previously treated with autologous bone marrow transplant was 78% (18/23). The following factors were not associated with a lower response rate: age ≥ 60 years, extranodal disease, prior anthracycline therapy, and bone marrow involvement.

In a second multicenter, multiple-dose study, 37 patients with relapsed or refractory B-cell NHL received 375 mg/m² of rituximab as an IV infusion once weekly for four doses. The ORR was 46% with a median duration of response of 8.6 months (range 2.6 to 26.2+). Single doses of up to 500 mg/m² were well-tolerated in a Phase I, dose escalation study.

Twenty one patients who have responded to rituximab initially have been treated again with rituximab. Response rate seems to be comparable in these retreated patients. Twenty patients have received two courses and one patient has received three courses of rituximab as 4-weekly infusions of 375 mg/m² per infusion. The percentage of patients reporting adverse events upon retreatment was similar to that reported following the first course, although the incidence of specific adverse events differed (see 8 Adverse Reactions). All patients had obtained an objective clinical response (CR or PR) to the first course of rituximab; upon retreatment, 6 of 12 patients evaluable for response obtained a complete or partial remission.

In another study with twenty-nine patients with relapsed or refractory, bulky (single lesion of >10 cm in diameter), low grade NHL received 375 mg/m² of rituximab as four weekly infusions. The overall incidence of adverse events and the incidence of Grade 3 and 4 adverse events was higher in patients with bulky disease than in patients with non-bulky disease (see 8 Adverse Reactions). Ten of 21 patients evaluable for response have obtained a complete or partial remission.

Table 22 Follicular Non-Hodgkin's Lymphoma, Initial Treatment in Combination with CVP

Follicular Non-Hodgkin's Lymphoma, Initial Treatment in Combination with CVP

In an open-label randomized trial, a total of 322 previously untreated low-grade or follicular B cell NHL patients were randomized to receive either CVP chemotherapy (cyclophosphamide 750 mg/m², vincristine 1.4 mg/m² up to a maximum of 2 mg on day 1, and prednisolone 40 mg/m²/day on days 1-5) every 3 weeks for 8 cycles or rituximab 375 mg/m² in combination with CVP (R-CVP). Rituximab was administered on the first day of each treatment cycle. The results are presented in Table 22. A total of 321 patients (162 R-CVP, 159 CVP) received therapy and were analyzed for efficacy. At the time of the analysis, the median observation time was 42 months. R-CVP led to a significant benefit over CVP for the primary endpoint, time to treatment failure (27 months vs. 6.6 months, p < 0.0001, log-rank test). The risk of experiencing a treatment failure event was reduced by 66% (95% CI: 55% - 74%) with R-CVP compared with CVP alone, using a Cox regression analysis. The Kaplan-Meier estimated event free rate at 36 months was 44% in the R-CVP group compared with 11% in the CVP group. The proportion of patients with a tumour response (CR, CRu, PR) was significantly higher (p < 0.0001 Chi-Square test) in the R-CVP group (81%) than the CVP group (57%). The median duration of response was 37.7 months in the R-CVP group and was 13.5 months in the CVP group (p < 0.0001, log-rank test). Amongst responding patients, Cox regression analysis showed that the risk of relapse was reduced by 65% (95% CI: 51% - 75%) in the R-CVP group compared to the CVP group.

The time to institution of new lymphoma treatment or death was significantly longer in the R-CVP group (not estimable), compared to the CVP group (12.3 months) (p < 0.0001, log-rank test). Treatment with R-CVP significantly prolonged the time to disease progression compared to CVP, 31.9 months and 14.5 months, respectively. At 36 months, 49% in the R-CVP group had not progressed, relapsed or died compared to 20% of patients receiving CVP.

A subsequent analysis of the primary and all secondary parameters, carried out with a median observation time of approximately 42 months, confirmed the benefit of R-CVP over CVP.

The rate of cause-specific deaths (death due to lymphoma) was significantly lower in the R-CVP arm when compared to the CVP arm (p=0.02 with stratification by center, log-rank test; 3-year event-free rate 93% for R-CVP versus 85% for CVP).

Treatment with R-CVP compared with CVP resulted in a consistent and positive treatment effect in the following subgroups: BNLI criteria, age, extra-nodal sites, bone marrow involvement, elevated LDH, elevated ß2 microglobulin, International Prognostic Index, B symptoms, bulky disease, nodal disease, and Follicular Lymphoma Prognostic Index.

Follicular Non-Hodgkin's Lymphoma, Maintenance Therapy (previously untreated and relapsed refractory patients)

Previously Untreated Advanced High-Tumor Burden Follicular Non-Hodgkin's Lymphoma

In a prospective open-label, international, multicenter, randomized Phase III trial (MO18264) 1193 patients with previously untreated advanced follicular lymphoma received induction therapy (phase one). During this phase, patients with advanced follicular lymphoma were evaluated for response to different rituximab plus chemotherapy induction regimens: R-CHOP (n=881), R-CVP (n=268) or R-FCM (n=44), according to the investigators’ choice. The benefit-risk profile of induction therapy with R-FCM could not be determined due to the small number of patients treated with this chemotherapy regimen. Patients who responded to induction treatment (i.e., achieved a confirmed or unconfirmed complete response [CR/CRu] or partial response [PR] at the end of induction), see Table 24, were randomized in the second phase to receive either rituximab maintenance therapy or no further treatment (observation).

All randomized patients were treated or observed for two years or until disease progression, whichever occurred first.

Table 23 Summary of Demographics and Characteristics

A total of 1078 patients responded to induction therapy, 35.5% had complete response, 28.3% had unconfirmed complete response and 26.5% had partial response. The table below provides responses for the R-CHOP and R-CVP regimens.

Table 24 Response at End of Induction Phase^*

R-CHOP (N=881)

R-CVP (N=268)

Responders

818 (92.8%)

227 (84.7%)

CR

326 (37.0%)

77 (28.7%)

CRu

267 (30.3%)

65 (24.3%)

PR

225 (25.5)

85 (31.7%)

Non-Responders¹

63 (7.2%)

41 (15.3%)

^* patients treated with R-FCM were not included in the table as the benefit/risk profile of this induction chemotherapy regimen could not be determined due to the small number of patients

¹ non-responders including stable disease, progressive disease, not evaluated and missing (i.e., no response assessment)

Following induction therapy, 1018 were randomized to rituximab maintenance therapy (n=505) or observation (n=513). The number of patients 65 years of age or older that were included within the maintenance therapy or observation arm were 123 and 124 respectively. The two treatment groups were well-balanced with regards to baseline characteristics and disease status. Rituximab was administered on Day 1 of each cycle of chemotherapy. Rituximab maintenance treatment consisted of a single infusion of rituximab at 375 mg/m² body surface area given every 2 months until disease progression or for a maximum of 12 infusions (2 years).

After a median observation time of 25 months from randomization, maintenance therapy with rituximab resulted in an improvement in the primary endpoint of progression-free survival (PFS) based on independent review assessment (stratified log-rank p-value < 0.0001; stratified by induction treatment and response to induction treatment), refer to Figure 1.

Figure 1 Kaplan–Meier Plot of Independent Review Assessed PFS

Rituximab maintenance treatment provided benefit in PFS in all subgroups tested: gender (male, female), age (<60 years, ≥ 60 years), FLIPI score (1, 2 or 3), induction therapy (R-CHOP, R-CVP) and regardless of the quality of response to induction treatment (CR or PR). The results of rituximab maintenance treatment in patients older than 75 years of age should be interpreted with caution due to the small number of patients in this subgroup.

The difference in overall survival between the two treatment arms was not conclusive. A longer follow-up is required to obtain mature overall survival results.

Relapsed/Refractory Follicular Non-Hodgkin's Lymphoma

Table 25 Relapsed/Refractory Follicular Non-Hodgkin's Lymphoma, Maintenance Therapy

1. 1. Estimates were calculated by hazard ratios
2. 2. Last tumour response as assessed by the investigator. The “primary” statistical test for “response” was the trend test of CR versus PR versus non-response (p < 0.0001)
3. 3. CHOP = cyclophosphamide (750 mg/m² i.v., day 1), doxorubicin (50 mg/m² i.v., day 1), vincristine (1.4 mg/m² i.v., (max. 2 mg) day 1) and prednisone (100 mg orally, days 1-5, every 21 days for 6 cycles).
4. 4. R-CHOP = Rituximab (375 mg/m² i.v. infusion, on day 1 of each cycle for 6 cycles) plus CHOP chemotherapy.

Abbreviations: RR, risk reduction; NA, not available; NR, not reached; mo, months; ORR, overall response rate; CR, complete response; PR, partial response; OS, overall survival; PFS, progression free survival

Follicular Non-Hodgkin's Lymphoma, Maintenance Therapy

In a prospective, open-label, international, multi-centre, Phase III trial, 465 patients with relapsed/refractory follicular NHL were randomized in a first step to induction therapy with either CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone; n=231) or rituximab plus CHOP (R-CHOP, n=234). The two treatment groups were well-balanced with regard to baseline characteristics and disease status. The results are presented in Table 25. A total of 334 patients achieving a complete or partial remission following induction therapy were randomized in a second step to maintenance therapy with rituximab (n=167) or observation (n=167). Maintenance treatment with rituximab consisted of a single infusion of rituximab at 375 mg/m² body surface area given every 3 months until disease progression or for a maximum period of two years.

The final efficacy analysis included all patients randomized to both parts of the study. After a median observation time of 50 months for patients randomized to the induction phase, R-CHOP significantly improved the outcome of patients with relapsed or refractory follicular NHL when compared to CHOP.

For patients randomized to the maintenance phase of the trial, the median observation time was 47.2 months from maintenance randomization. Maintenance treatment with rituximab led to a clinically relevant and statistically significant improvement in the primary endpoint, PFS, (time from maintenance randomization to relapse, disease progression or death) when compared to observation alone (p<0.0001 log-rank test). The median PFS was 42.9 months (range: 0.6 to 80.1 months) in the rituximab maintenance arm compared to 15.7 months (range: 0.6 to 79.4 months) in the observation arm. Using a cox regression analysis, the risk of experiencing progressive disease or death was reduced by 51% with maintenance treatment with rituximab when compared to observation (95% CI; 36 %-63 %). Kaplan-Meier estimated progression-free rates at 12 months were 78% in the rituximab maintenance group vs 59% in the observation group. An analysis of overall survival suggested a benefit of maintenance treatment with rituximab over observation (p=0.0229 log-rank test). The significance level for this analysis was set at 0.001.

The median time to new anti-lymphoma treatment was significantly longer with rituximab maintenance treatment than with observation (50.9 months (range 0.9 to 77.9 months) vs. 21.7 months (range 1.2 to 79.4 months), p=0.0003 log-rank test). The risk of starting a new treatment was reduced by 40% (95% CI; 20 %-54 %).

Table 26 Patients Starting New Lymphoma Treatment (NLT)/Reporting Disease Progression (PD)