Rituxan

>10%

NHL

• Angioedema (11%), hypotension (10%)
• Asthenia (26%), chills (33%), dizziness (10%), fever (53%), headache (19%)
• Pruritus (14%), rash (15%)
• Abdominal pain (14%), diarrhea (10%), nausea (23%), vomiting (10%)
• Leukopenia (14%), lymphopenia (48%), neutropenia (14%), thrombocytopenia (12%)
• Back pain (10%), myalgia (10%)
• Cough (13%), rhinitis (12%)
• Infection (31%), night sweats (15%)

1-10%

NHL

• Edema
• Flushing
• Hypertension
• Anxiety
• Anemia
• Elevated LDH
• Hyperglycemia
• Bronchospasm, dyspnea, sinusitis, throat irritation, urticaria

RA (Rituximab+Methotrexate vs Methotrexate Alone)

• Hypertension
• Anxiety, asthenia, chills, migraine, paresthesia, pyrexia
• Pruritus, urticaria
• Dyspepsia, nausea, upper abd pain
• Hypercholesterolemia
• Arthralgia
• Rhinitis, throat irritation, URI

Frequency Not Defined

Tumor lysis syndrome

Lymphoid malignancies

Hypogammaglobulinemia

Postmarketing Reports

Grade 3-4 prolonged or late-onset neutropenia

IV Preparation

Reconstitution: withdraw necessary amount of rituximab and dilute to a final concentration of 1-4 mg/mL into an infusion bag containing either NS or D5W

IV Administration

Consider premedication (ie, acetaminophen, diphenhydramine, and/or glucocorticoids for RA) before each infusion

Premedication with diphenhydramine and acetaminophen may attenuate infusion-related events

Because transient hypotension may occur during infusion, consider withholding antihypertensive medications 12 hr prior to infusion

Administer by slow IV infusion only; do not administer as an IV

First IV infusion rate: Start 50 mg/hr; increase by 50 mg/hr q30min, not to exceed 400 mg/hr

Drug is associated with hypersensitivity reactions which may respond to adjustments in infusion rate

Subsequent IV infusions (90 minutes)

• Standard IV infusions: Start 100 mg/hr, increase by 100 mg/hr q30min, not to exceed 400 mg/hr; institutional protocols may allow faster increments
• Previously untreated patients with follicular NHL or diffuse large B-cell lymphoma: If patients did not experience a Grade 3 or 4 infusion related adverse event during Cycle 1, a 90-minute infusion can be administered in Cycle 2 with a glucocorticoid-containing chemotherapy regimen
• Initiate at a rate of 20% of the total dose given in the first 30 minutes and the remaining 80% of the total dose given over the next 60 minutes
• If tolerated in Cycle 2, the same rate can be used when administering the remainder of the treatment regimen (through Cycle 6 or 8)
• Patients who have clinically significant cardiovascular disease or who have a circulating lymphocyte count ≥5000/mm³ before Cycle 2 should not be administered the 90-minute infusion

Infusion-related adverse effects

• Hypotension, bronchospasm, and angioedema have occurred as part of an infusion-related symptom complex
• Interrupt infusion for severe reactions and resume at a 50% reduction in rate (eg, from 100 to 50 mg/hr) when symptoms have completely resolved
• Treatment of these symptoms with diphenhydramine and acetaminophen is recommended
• Additional treatment with bronchodilators or IV saline may be indicated
• Discontinue infusions if serious or life-threatening cardiac arrhythmias

SC Preparation

Solution for SC is ready to use

SC Administration

Consider premedication (ie, acetaminophen, diphenhydramine, and/or glucocorticoids)

Premedication with acetaminophen and diphenhydramine may attenuate infusion-related reactions

Observe patients for 15 minutes after SC administration

If administration is interrupted, administer at the same site or at a different site along the abdomen

Avoid coadministering other SC medications at the same site

Avoid injections into areas where skin appears red, bruised, tender, or hard

Avoid injections in areas where there are moles or scars

No data available on other injection sites

Injection Rate

• Inject SC in abdomen
• 1400 mg/23,400 IU/vial (1400 mg rituximab and 23,400 Units hyaluronidase human): SC over ~5 minutes
• 1600 mg/26,800 Units vial (1600 mg rituximab and 26,800 Units hyaluronidase human): SC over ~7 minutes

Storage

IV

• Store under refrigeration
• Protect vials from direct sunlight
• Solutions for infusion are stable at 2-8°C (36-46°F) for 24 hr

SC

• Store unopened vials under refrigeration
• Protect vials from direct sunlight
• Solutions for SC injection are stable at 2-8°C (36-46°F) for 48 hr
• Solutions for SC injection in direct light are stable up to 30°C (86°F) for 8 hr

Yes

Common Side Effects of Rituxan

Tell your doctor if any of the following side effects become severe or don't go away:

• Back or joint pain
• Fatigue
• Headache
• Night sweats
• Flushing
• Diarrhea or nausea
• Runny nose or sneezing
• Feeling anxious or worried

Serious Side Effects of Rituxan

Tell your doctor right away if you experience any of the symptoms listed in the Warning section or any of the following serious side effects:

• Unusual bleeding or bruising
• Earache
• Fever, sore throat, chills, or other signs of infection
• An ongoing cough
• Sinus pain
• Ongoing diarrhea and weight loss
• Extreme fatigue
• Painful urination
• Chest tightness
• Tenderness, redness, warmth, or swelling of an area of the skin

Tell your doctor about all prescription, non-prescription, illegal, recreational, herbal, nutritional, or dietary drugs you're taking before taking Rituxan, especially:

• Cimzia (certolizumab)
• Drugs that suppress the immune system such as Imuran (azathioprine), Neoral or Sandimmune (cyclosporine), Prograf (tacrolimus), and Rapamune (sirolimus)
• Enbrel (etanercept)
• Humira (adalimumab)
• Medications for high blood pressure
• Other medications for rheumatoid arthritis
• Platinol (cisplatin)
• Remicade (infliximab)
• Simponi (golimumab)

Rituxan is given as a slow infusion through an IV.

The medicine is administered by a nurse or doctor in a medical facility or infusion center.

Your dose and treatment schedule will depend on your medical condition and your response to the therapy.

Rituxan Overdose

An overdose of Rituxan is unlikely since a trained doctor or nurse will be administering the medicine.

However, if you suspect an overdose, contact a poison control center or emergency room immediately.

You can get in touch with a poison control center at 800-222-1222.

Missed Dose of Rituxan

Call your doctor right away if you miss an appointment to receive your dose of Rituxan.

Non-Hodgkin's Lymphoma (NHL)

Rituxan® (rituximab) is indicated for the treatment of patients with:

• Relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL as a single agent
• Previously untreated follicular, CD20-positive, B-cell NHL in combination with first line chemotherapy and, in patients achieving a complete or partial response to Rituxan in combination with chemotherapy, as single-agent maintenance therapy.
• Non-progressing (including stable disease), low-grade, CD20-positive, B-cell NHL as a single agent after first-line CVP chemotherapy
• Previously untreated diffuse large B-cell, CD20-positive NHL in combination with CHOP or other anthracycline-based chemotherapy regimens

Chronic Lymphocytic Leukemia (CLL)

Rituxan® (rituximab) is indicated, in combination with fludarabine and cyclophosphamide (FC), for the treatment of patients with previously untreated and previously treated CD20-positive CLL.

Rheumatoid Arthritis (RA)

Rituxan® (rituximab) in combination with methotrexate is indicated for the treatment of adult patients with moderately- to severely- active rheumatoid arthritis who have had an inadequate response to one or more TNF antagonist therapies.

Granulomatos Is With Polyangiitis (GPA) (Wegener's Granulomatosis) And Microscopic Polyangiitis (MPA)

Rituxan® (rituximab), in combination with glucocorticoids, is indicated for the treatment of adult patients with Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis) and Microscopic Polyangiitis (MPA).

Limitations Of Use

Rituxan is not recommended for use in patients with severe, active infections.

Your doctor or pharmacist can provide more information about rituximab.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

Every effort has been made to ensure that the information provided by Cerner Multum, Inc. ('Multum') is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. Multum information has been compiled for use by healthcare practitioners and consumers in the United States and therefore Multum does not warrant that uses outside of the United States are appropriate, unless specifically indicated otherwise. Multum's drug information does not endorse drugs, diagnose patients or recommend therapy. Multum's drug information is an informational resource designed to assist licensed healthcare practitioners in caring for their patients and/or to serve consumers viewing this service as a supplement to, and not a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. Multum does not assume any responsibility for any aspect of healthcare administered with the aid of information Multum provides. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist.

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Rituxan is used to treat certain types of blood cancer. Rituxan is also used to treat rheumatoid arthritis and a certain disease that causes inflammation of the blood vessels. Rituxan is in a class of medications called monoclonal antibodies. It works by killing cancer cells. It treats rheumatoid arthritis by blocking the activity of the part of the immune system that may damage the joints, veins, and other blood vessels.

This medication comes in an injectable form that is given directly into a vein (IV) by a healthcare provider.

Common side effects include infections, chills, body aches, and tiredness.

Rituxan is part of the drug class:

• Monoclonal antibodies

Non-Hodgkin's Lymphoma (NHL)

The recommended dose is 375 mg/m2 as an intravenous (into the vein) infusion according to the following schedules:

• Relapsed or Refractory, Low-Grade or Follicular, CD20-Positive, B-Cell NHL: given once weekly for 4 or 8 doses.
• Retreatment for Relapsed or Refractory, Low-Grade or Follicular, CD20-Positive, B-Cell NHL: given once weekly for 4 doses.
• Previously Untreated, Follicular, CD20-Positive, B-Cell NHL: given on Day 1 of each cycle of chemotherapy, for up to 8 doses. With complete or partial response, Rituxan maintenance therapy is 8 weeks following completion of Rituxan in combination with chemotherapy. Rituxan is to be given as a single-agent every 8 weeks for 12 doses.
• Non-progressing, Low-Grade, CD20-Positive, B-cell NHL, after first-line CVP chemotherapy: following completion of 6–8 cycles of chemotherapy, Rituxan is to be given once weekly for 4 doses at 6-month intervals to a maximum of 16 doses.
• Diffuse Large B-Cell NHL: given on Day 1 of each cycle of chemotherapy for up to 8 infusions.

Chronic Lymphocytic Leukemia (CLL)

• The recommended dose is 375 mg/m2 the day prior to the initiation of chemotherapy, then 500 mg/m2 on Day 1 of cycles 2–6 (every 28 days).

In combination with Zevalin (Ibritumomab Tiuxetan)

• The dose of Rituxan is 250 mg/m2.
• Refer to the Zevalin package insert for full prescribing information regarding the Zevalin therapeutic regimen.

Rheumatoid Arthritis (RA)

• Two-1000 mg intravenous (into the vein) infusions separated by 2 weeks.
• Remaining courses should be given every 24 weeks but not sooner than every 16 weeks.

Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis) and Microscopic Polyangiitis (MPA)

• Rituxan 375 mg/m2 intravenous (into the vein) infusion once weekly for 4 weeks.

If this medication is administered by a healthcare provider in a medical setting, it is unlikely that an overdose will occur. However, if overdose is suspected, seek emergency medical attention.

Non-Hodgkin’s Lymphoma

Used as monotherapy for treatment of relapsed or refractory low-grade or follicular, antigen CD20-positive, B-cell non-Hodgkin’s lymphoma (NHL).1 2 7 9 12

Treatment of previously untreated follicular, antigen CD20-positive, B-cell NHL; used in combination with chemotherapy.1 9 14 56

Used as monotherapy for treatment of nonprogressing (e.g., stable disease), low-grade, antigen CD20-positive, B-cell NHL following first-line treatment with CVP chemotherapy.1

Treatment of previously untreated diffuse large B-cell, antigen CD20-positive, NHL; used in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or other anthracycline-based chemotherapy.1 9 14

Shown to offer benefit as maintenance therapy† in patients with relapsed or refractory indolent NHL following induction chemotherapy (with or without rituximab).29 30 31

Designated an orphan drug by FDA for the treatment of NHL.6

Used as a required component of a therapeutic regimen with ibritumomab tiuxetan (ibritumomab tiuxetan therapeutic regimen) for treatment of relapsed or refractory low-grade or follicular B-cell NHL, including follicular NHL that is refractory to rituximab therapy; also as part of the ibritumomab tiuxetan therapeutic regimen for consolidation treatment of newly diagnosed follicular NHL in patients who have achieved partial or complete response to first-line induction chemotherapy.18 55 Rituximab is used prior to ibritumomab to deplete peripheral B cells and to improve distribution of the radioimmunotherapeutic agent.1 18

Responses to rituximab have been observed in patients with recurrent aggressive antigen CD20-positive NHL†.9

Has been used in the treatment of lymphoplasmacytic lymphoma (Waldenstrom's macroglobulinemia)†.9

Use in combination with bendamustine† for treatment of previously untreated advanced-stage indolent NHL or for treatment of previously untreated advanced-stage mantle cell lymphoma† is a reasonable choice (accepted, with possible conditions); however, consider histologic subtype of NHL when selecting a combination chemotherapy regimen.10001 10018 10019

Use in combination with bendamustine† for treatment of relapsed or refractory indolent NHL or for treatment of relapsed or refractory mantle cell lymphoma† is recommended (accepted).10002 10003 10020

Has been used in the treatment of relapsed or refractory hairy cell leukemia.†32

Chronic Lymphocytic Leukemia

Used in combination with fludarabine and cyclophosphamide (FC) for treatment of previously untreated and previously treated antigen CD20-positive chronic lymphocytic leukemia (CLL).1

Designated an orphan drug by FDA for the treatment of CLL.6

Prolonged progression-free survival observed in previously untreated and previously treated patients with CLL.38 39 However, no benefit of adding rituximab to fludarabine/cyclophosphamide observed in previously untreated patients ≥70 years of age or in previously treated patients ≥65 years of age. 1 51

Rheumatoid Arthritis

Used in conjunction with methotrexate for treatment of moderately to severely active rheumatoid arthritis (RA) in adults with disease that has shown an inadequate response to ≥1 tumor necrosis factor (TNF; TNF-α) blocking agents.1 Manufacturer states that use in patients who have not demonstrated an inadequate response to ≥1 TNF blocking agents is not recommended.1

Although efficacy has been demonstrated in clinical studies in patients with prior inadequate response to nonbiologic disease-modifying antirheumatic drugs (DMARDs) and in methotrexate-naive patients, manufacturer states that favorable risk-to-benefit ratio has not been established in these populations.1

Idiopathic Thrombocytopenic Purpura

Has been used in adults with idiopathic thrombocytopenic purpura (ITP; also known as immune thrombocytopenic purpura)†.33 However, because efficacy compared with standard treatments cannot be determined (due to lack of controlled randomized studies), avoid indiscriminate use.33

Has been used in children with severe chronic ITP that is refractory to standard therapy†.34 However, because of low response rate (30–60%) and potentially serious adverse effects (including PML, some experts recommend use only in patients who have failed splenectomy.40

Pemphigus Vulgaris

Has been used in combination with immune globulin IV in the treatment of refractory pemphigus vulgaris†.36

General

• To minimize the risk of infusion-related events, premedication with acetaminophen and an antihistamine is recommended before each infusion.1 In patients receiving rituximab over 90 minutes, administer glucocorticoid component of the chemotherapy regimen prior to each rituximab infusion.56 64 (See Rate of Administration under Dosage and Administration.) Premedication with methylprednisolone 100 mg IV (or equivalent) is recommended 30 minutes prior to each infusion in patients with rheumatoid arthritis (given in conjunction with antihistamines and acetaminophen in clinical studies). 1 (See Infusion-related Effects under Cautions.)

• Monitor patients during infusion; appropriate diagnostic and treatment facilities, including medications for the treatment of severe adverse reactions (e.g., infusion-related reactions, cardiac arrhythmias) must be readily available.56 (See Infusion-related Effects and also Cardiac Effects under Cautions.)

• Prophylaxis against Pneumocystis jiroveci (formerly Pneumocystis carinii) pneumonia (PCP) and herpes virus infection recommended in patients with CLL during treatment and for up to 12 months after completion of therapy.1

Administration

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Administer by IV infusion;1 do not administer by rapid IV injection (e.g., IV push or bolus).1 11

Do not admix with other drugs or administer other drugs in the same IV line with rituximab infusion.1

Must be diluted prior to IV infusion.1 11

Use aseptic technique since drug product contains no preservative.1

Withdraw the appropriate dose of rituximab concentrate and dilute in an appropriate volume of 0.9% sodium chloride or 5% dextrose injection to yield a final rituximab concentration of 1–4 mg/mL;1 gently invert infusion bag several times to ensure complete mixing.1

Discard any unused solution remaining in the vial.1

Infuse initial dose at an initial rate of 50 mg/hour; if infusion-related events do not occur, infusion rate may be increased in increments of 50 mg/hour every 30 minutes to a maximum infusion rate of 400 mg/hour.1 11

If first infusion is tolerated well, administer subsequent infusions at an initial rate of 100 mg/hour; infusion rate may be increased in increments of 100 mg/hour every 30 minutes as tolerated to a maximum infusion rate of 400 mg/hour.1

Alternatively, an accelerated (90-minute) infusion may be used beginning with the second dose in patients with previously untreated follicular NHL or previously untreated diffuse large B-cell NHL who are receiving rituximab with a glucocorticoid-containing chemotherapy regimen if they tolerated the first dose (administered at the standard rate) without experiencing grade 3 or 4 infusion-related events.56 64 To administer dose over 90 minutes, administer 20% of total dose over 30 minutes and remaining 80% of dose over next 60 minutes.56 64 If infusion is tolerated, the same 90-minute infusion rate may be used for subsequent doses (through cycle 6 or 8).56 64

Do not administer over 90 minutes in patients with clinically important cardiovascular disease (i.e., uncontrolled hypertension, MI, unstable angina, NYHA class II or greater CHF, ventricular arrhythmia requiring medication within the past year, NYHA class II or greater peripheral vascular disease) or those with high circulating lymphocyte count (≥5000/mm3) before cycle 2.56 64 67

Decrease infusion rate or interrupt infusion if infusion-related events occur.1 Employ a slower infusion rate (i.e., at least 50% reduction in rate) when therapy is resumed following complete resolution of symptoms.1

Dosage

Adults

375 mg/m2 once weekly for 4 weeks1 7 12 or 8 weeks.1 16

If disease subsequently progresses following response to previous rituximab therapy, administer an additional course of 375 mg/m2 once weekly for 4 weeks.1

375 mg/m2 has been administered on day 1 of a 28-day cycle for a total of 4–6 cycles, in combination with bendamustine hydrochloride† (90 mg/m2 IV on days 2 and 3).10002 10003 An additional dose of rituximab has been administered one week prior to the first bendamustine-rituximab treatment cycle and repeated at 28 days following the last bendamustine-rituximab treatment cycle.10002 10003

375 mg/m2 on day 1 of each chemotherapy cycle for up to 8 doses.1 56

375 mg/m2 has been administered on day 1 of a 28-day cycle for up to 8 cycles, in combination with bendamustine hydrochloride† (90 mg/m2 IV on days 1 and 2).10001 10018

For patients with nonprogressing (including stable disease) who have received first-line therapy with 6–8 cycles of CVP chemotherapy, 375 mg/m2 once weekly for 4 weeks; repeat every 6 months for up to 16 doses.1

375 mg/m2 on day 1 of each chemotherapy cycle for up to 8 doses.1

Step 1 (day 1): Administer rituximab 250 mg/m2.18

Step 2 (day 7, 8, or 9): Administer rituximab 250 mg/m2, followed (within 4 hours) by a therapeutic dose of yttrium Y 90 ibritumomab tiuxetan.1 18

Cycle 1: 375 mg/m2 on day 0 (one day prior to FC chemotherapy).1 38

Cycles 2–6: 500 mg/m2 on day 1 of each FC chemotherapy cycle; repeat every 28 days for up to 5 doses.1 38

Cycle 1: 375 mg/m2 on day 0 (one day prior to FC chemotherapy).1 39

Cycles 2–6: 500 mg/m2 on day 1 of each FC chemotherapy cycle; repeat every 28 days for up to 5 doses.1 39

1 g administered 2 weeks apart, on days 1 and 15 (for a total of 2 doses).1 May repeat course every 24 weeks or based on clinical response, but no sooner than every 16 weeks between courses.1

Depending on the nature and severity of rituximab-related toxicities, slowing of the infusion rate, interruption of the infusion, or discontinuance of the drug may be required; provide appropriate treatment as indicated. 1 (See Cautions and see Rate of Administration under Dosage and Administration.)

Prescribing Limits

Adults

Maximum 8 infusions.1

Maximum 16 infusions.1

Maximum 8 infusions.1

Maximum 6 cycles of therapy (i.e., 6 rituximab infusions recommended).1 38

Maximum 6 cycles of therapy (i.e., 6 rituximab infusions recommended).1 39

Course of rituximab and methotrexate should not be repeated sooner than every 16 weeks.1

Special Populations

No special population dosage recommendations at this time.1

• It is used to treat a type of leukemia.
• It is used to treat a type of lymphoma.
• It is used to treat rheumatoid arthritis.
• It is used to treat Wegener's granulomatosis.
• It is used to treat microscopic polyangiitis.
• It may be given to you for other reasons. Talk with the doctor.

• Tell all of your health care providers that you take this medicine. This includes your doctors, nurses, pharmacists, and dentists.
• Have blood work checked as you have been told by the doctor. Talk with the doctor.
• You may have more of a chance of getting an infection. Wash hands often. Stay away from people with infections, colds, or flu. Some infections have been very bad and even deadly.
• Patients with cancer who take Rituxan may be at a greater risk of getting a bad health problem called tumor lysis syndrome (TLS). Sometimes, this has been deadly. Call your doctor right away if you have a fast heartbeat or a heartbeat that does not feel normal; any passing out; trouble passing urine; muscle weakness or cramps; upset stomach, throwing up, loose stools, or not able to eat; or feel sluggish.
• Talk with your doctor before getting any vaccines. Use with this medicine may either raise the chance of an infection or make the vaccine not work as well.
• If you are taking Rituxan for rheumatoid arthritis, make sure you are up to date with all your vaccines.
• People who took this medicine with some cancer drugs have had bowel block or tears in the bowel. Sometimes this has been deadly. Call your doctor right away if you have very bad belly pain; very hard stools (constipation); throwing up, throwing up blood, or throw up that looks like coffee grounds; or black, tarry, or bloody stools.
• If you are 65 or older, use Rituxan (rituximab) with care. You could have more side effects.
• Use birth control that you can trust to prevent pregnancy while taking this medicine and for up to 12 months after Rituxan.
• If you get pregnant while taking this medicine or within 12 months after your last dose, call your doctor right away.
• Tell your doctor if you are breast-feeding. You will need to talk about any risks to your baby.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Signs of infection like fever, chills, very bad sore throat, ear or sinus pain, cough, more sputum or change in color of sputum, pain with passing urine, mouth sores, or wound that will not heal.
• Signs of liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes.
• Chest pain or pressure or a fast heartbeat.
• A heartbeat that does not feel normal.
• Dizziness or passing out.
• Feeling very tired or weak.
• Very bad headache.
• Any unexplained bruising or bleeding.
• Kidney problems have happened with Rituxan in people with lymphoma. Sometimes, these have been deadly. Call your doctor right away if you are unable to pass urine or if you have blood in the urine or a change in the amount of urine passed.
• Heart failure has rarely happened in people taking this medicine. Sometimes, this has been deadly. Call your doctor right away if you have shortness of breath, a big weight gain, or swelling in the arms or legs.
• Very bad and sometimes deadly lung problems have happened with Rituxan. Call your doctor right away if you have lung or breathing problems like trouble breathing, shortness of breath, or a cough that is new or worse.

Administration

Administer only as an Intravenous Infusion [see Dosage and Administration (2.7)].

Do not administer as an intravenous push or bolus.

Premedicate before each infusion [see Dosage and Administration (2.7)].

Rituxan should only be administered by a healthcare professional with appropriate medical support to manage severe infusion reactions that can be fatal if they occur [see Warnings and Precautions (5.1)].

• First Infusion: Initiate infusion at a rate of 50 mg/hr. In the absence of infusion toxicity, increase infusion rate by 50 mg/hr increments every 30 minutes, to a maximum of 400 mg/hr.
• Subsequent Infusions:
  Standard Infusion: Initiate infusion at a rate of 100 mg/hr. In the absence of infusion toxicity, increase rate by 100 mg/hr increments at 30-minute intervals, to a maximum of 400 mg/hr.
  For previously untreated follicular NHL and DLBCL patients:
  If patients did not experience a Grade 3 or 4 infusion related adverse event during Cycle 1, a 90-minute infusion can be administered in Cycle 2 with a glucocorticoid-containing chemotherapy regimen.   Initiate at a rate of 20% of the total dose given in the first 30 minutes and the remaining 80% of the total dose given over the next 60 minutes. If the 90-minute infusion is tolerated in Cycle 2, the same rate can be used when administering the remainder of the treatment regimen (through Cycle 6 or 8). Patients who have clinically significant cardiovascular disease or who have a circulating lymphocyte count ≥5000/mm3 before Cycle 2 should not be administered the 90-minute infusion [see Clinical Studies (14.4)].
• Interrupt the infusion or slow the infusion rate for infusion reactions [see Boxed Warning, Warnings and Precautions (5.1)]. Continue the infusion at one-half the previous rate upon improvement of symptoms.

Recommended Dose for Non-Hodgkin's Lymphoma (NHL)

The recommended dose is 375 mg/m2 as an intravenous infusion according to the following schedules:

• Relapsed or Refractory, Low-Grade or Follicular, CD20-Positive, B-Cell NHL
  Administer once weekly for 4 or 8 doses.
• Retreatment for Relapsed or Refractory, Low-Grade or Follicular, CD20-Positive, B-Cell NHL
  Administer once weekly for 4 doses.
• Previously Untreated, Follicular, CD20-Positive, B-Cell NHL
  Administer on Day 1 of each cycle of chemotherapy, for up to 8 doses. In patients with complete or partial response, initiate Rituxan maintenance eight weeks following completion of Rituxan in combination with chemotherapy. Administer Rituxan as a single-agent every 8 weeks for 12 doses.
• Non-progressing, Low-Grade, CD20-Positive, B-cell NHL, after first-line CVP chemotherapy
  Following completion of 6–8 cycles of CVP chemotherapy, administer once weekly for 4 doses at 6-month intervals to a maximum of 16 doses.
• Diffuse Large B-Cell NHL
  Administer on Day 1 of each cycle of chemotherapy for up to 8 infusions.

Recommended Dose for Chronic Lymphocytic Leukemia (CLL)

The recommended dose is:

• 375 mg/m2 the day prior to the initiation of FC chemotherapy, then 500 mg/m2 on Day 1 of cycles 2–6 (every 28 days).

Recommended Dose as a Component of Zevalin® for treatment of NHL

• Infuse rituximab 250 mg/m2 within 4 hours prior to the administration of Indium-111-(In-111-) Zevalin and within 4 hours prior to the administration of Yttrium-90- (Y-90-) Zevalin.
• Administer Rituxan and In-111-Zevalin 7–9 days prior to Rituxan and Y-90- Zevalin.
• Refer to the Zevalin package insert for full prescribing information regarding the Zevalin therapeutic regimen.

Recommended Dose for Rheumatoid Arthritis (RA)

• Administer Rituxan as two-1000 mg intravenous infusions separated by 2 weeks.
• Glucocorticoids administered as methylprednisolone 100 mg intravenous or its equivalent 30 minutes prior to each infusion are recommended to reduce the incidence and severity of infusion reactions.
• Subsequent courses should be administered every 24 weeks or based on clinical evaluation, but not sooner than every 16 weeks.
• Rituxan is given in combination with methotrexate.

Recommended Dose for Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis) and Microscopic Polyangiitis (MPA)

• Administer Rituxan as a 375 mg/m2 intravenous 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 Rituxan and may continue during and after the 4 week course of Rituximab treatment.
• Safety and efficacy of treatment with subsequent courses of Rituxan have not been established [see Warnings and Precautions (5.14)].

Recommended Concomitant Medications

Premedicate before each infusion with acetaminophen and an antihistamine. For patients administered Rituxan according to the 90-minute infusion rate, the glucocorticoid component of their chemotherapy regimen should be administered prior to infusion [see Clinical Studies (14.4)].

For RA patients, methylprednisolone 100 mg intravenously or its equivalent is recommended 30 minutes prior to each infusion.

For GPA and MPA patients, glucocorticoids are given in combination with Rituxan [see Dosage and Administration (2.6)].

Pneumocystis jiroveci pneumonia (PCP) and anti-herpetic viral prophylaxis is recommended for patients with CLL during treatment and for up to 12 months following treatment as appropriate.

PCP prophylaxis is also recommended for patients with GPA and MPA during treatment and for at least 6 months following the last Rituxan infusion.

Preparation for Administration

Use appropriate aseptic technique. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Do not use vial if particulates or discoloration is present. Withdraw the necessary amount of Rituxan and dilute to a final concentration of 1 mg/mL to 4 mg/mL in an infusion bag containing either 0.9% Sodium Chloride, USP, or 5% Dextrose in Water, USP. Gently invert the bag to mix the solution. Do not mix or dilute with other drugs. Discard any unused portion left in the vial.

Rituxan solutions for infusion may be stored at 2°C–8°C (36°F–46°F) for 24 hours. Rituxan solutions for infusion have been shown to be stable for an additional 24 hours at room temperature. However, since Rituxan solutions do not contain a preservative, diluted solutions should be stored refrigerated (2°C–8°C). No incompatibilities between Rituxan and polyvinylchloride or polyethylene bags have been observed.

Relapsed or Refractory, Low-Grade or Follicular, CD20-Positive, B-Cell NHL

The safety and effectiveness of Rituxan in relapsed, refractory CD20+ NHL were demonstrated in 3 single-arm studies enrolling 296 patients.

Study 1

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 Rituxan given as an intravenous infusion weekly for 4 doses. Patients with tumor masses > 10 cm or with > 5000 lymphocytes/µL in the peripheral blood were excluded from the study.

Results are summarized in Table 4. The median time to onset of response was 50 days. Disease-related signs and symptoms (including B-symptoms) resolved in 64% (25/39) of those patients with such symptoms at study entry.

Study 2

In a multicenter, single-arm study, 37 patients with relapsed or refractory, low-grade NHL received 375 mg/m2 of Rituxan weekly for 8 doses. Results are summarized in Table 4.

Study 3

In a multicenter, single-arm study, 60 patients received 375 mg/m2 of Rituxan weekly for 4 doses. All patients had relapsed or refractory, low-grade or follicular, B-cell NHL and had achieved an objective clinical response to Rituxan administered 3.8–35.6 months (median 14.5 months) prior to retreatment with Rituxan. Of these 60 patients, 5 received more than one additional course of Rituxan. Results are summarized in Table 4.

Bulky Disease

In pooled data from studies 1 and 3, 39 patients with bulky (single lesion > 10 cm in diameter) and relapsed or refractory, low-grade NHL received Rituxan 375 mg/m2 weekly for 4 doses. Results are summarized in Table 4.

Previously Untreated, Low-Grade or Follicular, CD20-Positive, B-Cell NHL

The safety and effectiveness of Rituxan in previously untreated, low-grade or follicular, CD20+ NHL were demonstrated in 3 randomized, controlled trials enrolling 1,662 patients.

Study 4

A total of 322 patients with previously untreated follicular NHL were randomized (1:1) to receive up to eight 3-week cycles of CVP chemotherapy alone (CVP) or in combination with Rituxan 375 mg/m2 on Day 1 of each cycle (R-CVP) in an open-label, multicenter study. The main outcome measure of the study was progression-free survival (PFS) defined as the time from randomization to the first of progression, relapse, or death.

Twenty-six percent of the study population was >60 years of age, 99% had Stage III or IV disease, and 50% had an International Prognostic Index (IPI) score ≥2. The results for PFS as determined by a blinded, independent assessment of progression are presented in Table 5. The point estimates may be influenced by the presence of informative censoring. The PFS results based on investigator assessment of progression were similar to those obtained by the independent review assessment.

Study 5

An open-label, multicenter, randomized (1:1) study was conducted in 1,018 patients with previously untreated follicular NHL who achieved a response (CR or PR) to Rituxan in combination with chemotherapy. Patients were randomized to Rituxan as single-agent maintenance therapy, 375 mg/m2 every 8 weeks for up to 12 doses or to observation. Rituxan was initiated at 8 weeks following completion of chemotherapy. The main outcome measure of the study was progression-free survival (PFS), defined as the time from randomization in the maintenance/observation phase to progression, relapse, or death, as determined by independent review.

Of the randomized patients, 40% were ≥ 60 years of age, 70% had Stage IV disease, 96% had ECOG performance status (PS) 0–1, and 42% had FLIPI scores of 3–5. Prior to randomization to maintenance therapy, patients had received R-CHOP (75%), R-CVP (22%), or R-FCM (3%); 71% had a complete or unconfirmed complete response and 28% had a partial response.

PFS was longer in patients randomized to Rituxan as single agent maintenance therapy (HR: 0.54, 95% CI: 0.42, 0.70). The PFS results based on investigator assessment of progression were similar to those obtained by the independent review assessment.

Study 6

A total of 322 patients with previously untreated low-grade, B-cell NHL who did not progress after 6 or 8 cycles of CVP chemotherapy were enrolled in an open-label, multicenter, randomized trial. Patients were randomized (1:1) to receive Rituxan, 375 mg/m2 intravenous infusion, once weekly for 4 doses every 6 months for up to 16 doses or no further therapeutic intervention. The main outcome measure of the study was progression-free survival defined as the time from randomization to progression, relapse, or death. Thirty-seven percent of the study population was >60 years of age, 99% had Stage III or IV disease, and 63% had an IPI score ≥2.

There was a reduction in the risk of progression, relapse, or death (hazard ratio estimate in the range of 0.36 to 0.49) for patients randomized to Rituxan as compared to those who received no additional treatment.

Diffuse Large B-Cell NHL (DLBCL)

The safety and effectiveness of Rituxan were evaluated in three randomized, active-controlled, open-label, multicenter studies with a collective enrollment of 1854 patients. Patients with previously untreated diffuse large B-cell NHL received Rituxan in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or other anthracycline-based chemotherapy regimens.

Study 7

A total of 632 patients age ≥ 60 years with DLBCL (including primary mediastinal B-cell lymphoma) were randomized in a 1:1 ratio to treatment with CHOP or R-CHOP. Patients received 6 or 8 cycles of CHOP, each cycle lasting 21 days. All patients in the R-CHOP arm received 4 doses of Rituxan 375 mg/m2 on Days –7 and –3 (prior to Cycle 1) and 48–72 hours prior to Cycles 3 and 5. Patients who received 8 cycles of CHOP also received Rituxan prior to Cycle 7. The main outcome measure of the study was progression-free survival, defined as the time from randomization to the first of progression, relapse, or death. Responding patients underwent a second randomization to receive Rituxan or no further therapy.

Among all enrolled patients, 62% had centrally confirmed DLBCL histology, 73% had Stage III–IV disease, 56% had IPI scores ≥ 2, 86% had ECOG performance status of < 2, 57% had elevated LDH levels, and 30% had two or more extranodal disease sites involved. Efficacy results are presented in Table 6. These results reflect a statistical approach which allows for an evaluation of Rituxan administered in the induction setting that excludes any potential impact of Rituxan given after the second randomization.

Analysis of results after the second randomization in Study 7 demonstrates that for patients randomized to R-CHOP, additional Rituxan exposure beyond induction was not associated with further improvements in progression-free survival or overall survival.

Study 8

A total of 399 patients with DLBCL, age ≥ 60 years, were randomized in a 1:1 ratio to receive CHOP or R-CHOP. All patients received up to eight 3-week cycles of CHOP induction; patients in the R-CHOP arm received Rituxan 375 mg/m2 on Day 1 of each cycle. The main outcome measure of the study was event-free survival, defined as the time from randomization to relapse, progression, change in therapy, or death from any cause. Among all enrolled patients, 80% had Stage III or IV disease, 60% of patients had an age-adjusted IPI ≥ 2, 80% had ECOG performance status scores < 2, 66% had elevated LDH levels, and 52% had extranodal involvement in at least two sites. Efficacy results are presented in Table 6.

Study 9

A total of 823 patients with DLBCL, aged 18–60 years, were randomized in a 1:1 ratio to receive an anthracycline-containing chemotherapy regimen alone or in combination with Rituxan. The main outcome measure of the study was time to treatment failure, defined as time from randomization to the earliest of progressive disease, failure to achieve a complete response, relapse, or death. Among all enrolled patients, 28% had Stage III–IV disease, 100% had IPI scores of ≤ 1, 99% had ECOG performance status of < 2, 29% had elevated LDH levels, 49% had bulky disease, and 34% had extranodal involvement. Efficacy results are presented in Table 6.

In Study 8, overall survival estimates at 5 years were 58% vs. 46% for R-CHOP and CHOP, respectively.

Ninety-Minute Infusions in Previously Untreated Follicular NHL and DLBCL

In Study 10, a total of 363 patients with previously untreated follicular NHL (n=113) or DLBCL (n=250) were evaluated in a prospective, open-label, multi-center, single-arm trial for the safety of 90-minute rituximab infusions. Patients with follicular NHL received rituximab 375 mg/m2 plus CVP chemotherapy. Patients with DLBCL received rituximab 375 mg/m2 plus CHOP chemotherapy. Patients with clinically significant cardiovascular disease were excluded from the study. Patients were eligible for a 90-minute infusion at Cycle 2 if they did not experience a Grade 3-4 infusion-related adverse event with Cycle 1 and had a circulating lymphocyte count ≤ 5000/mm3 before Cycle 2. All patients were pre-medicated with acetaminophen and an antihistamine and received the glucocorticoid component of their chemotherapy prior to Rituxan infusion. The main outcome measure was the development of Grade 3-4 infusion-related reactions on the day of, or day after, the 90-minute infusion at Cycle 2 [See Adverse Reactions (6.1)].

Eligible patients received their Cycle 2 rituximab infusion over 90 minutes as follows: 20% of the total dose given in the first 30 minutes and the remaining 80% of the total dose given over the next 60 minutes [See Dosage and Administration (2.1)]. Patients who tolerated the 90-minute rituximab infusion at Cycle 2 continued to receive subsequent rituximab infusions at the 90-minute infusion rate for the remainder of the treatment regimen (through Cycle 6 or Cycle 8).

The incidence of Grade 3-4 infusion-related reactions at Cycle 2 was 1.1% (95% CI [0.3%, 2.8%]) among all patients, 3.5% (95% CI [1.0%, 8.8%]) for those patients treated with R-CVP, and 0.0% (95% CI [0.0%, 1.5%]) for those patients treated with R-CHOP. For Cycles 2-8, the incidence of Grade 3-4 infusion-related reactions was 2.8% (95% CI [1.3%, 5.0%]). No acute fatal infusion related reactions were observed.

Chronic Lymphocytic Leukemia (CLL)

The safety and effectiveness of Rituxan were evaluated in two randomized (1:1) multicenter open-label studies comparing FC alone or in combination with Rituxan for up to 6 cycles in patients with previously untreated CLL [Study 11 (n=817)] or previously treated CLL [Study 12 (n=552)]. Patients received fludarabine 25 mg/m2/day and cyclophosphamide 250 mg/m2/day on days 1, 2 and 3 of each cycle, with or without Rituxan. In both studies, seventy-one percent of CLL patients received 6 cycles and 90% received at least 3 cycles of Rituxan-based therapy.

In Study 11, 30% of patients were 65 years or older, 31% were Binet stage C, 45% had B symptoms, more than 99% had ECOG performance status (PS) 0–1, 74% were male, and 100% were White. In Study 12, 44% of patients were 65 years or older, 28% had B symptoms, 82% received a prior alkylating drug, 18% received prior fludarabine, 100% had ECOG PS 0–1, 67% were male and 98% were White.

The main outcome measure in both studies was progression-free survival (PFS), defined as the time from randomization to progression, relapse, or death, as determined by investigators (Study 11) or an independent review committee (Study 12). The investigator assessed results in Study 12 were supportive of those obtained by the independent review committee. Efficacy results are presented in Table 7.

Across both studies, 243 of 676 Rituxan-treated patients (36%) were 65 years of age or older and 100 Rituxan-treated patients (15%) were 70 years of age or older. The results of exploratory subset analyses in elderly patients are presented in Table 8.

Rheumatoid Arthritis (RA)

Reducing the Signs and Symptoms: Initial and Re-Treatment Courses

The efficacy and safety of Rituxan were evaluated in two randomized, double-blind, placebo-controlled studies of adult patients with moderately to severely active RA who had a prior inadequate response to at least one TNF inhibitor. Patients were 18 years of age or older, diagnosed with active RA according to American College of Rheumatology (ACR) criteria, and had at least 8 swollen and 8 tender joints.

In RA Study 1, patients were randomized to receive either Rituxan 2 × 1000 mg + MTX or placebo + MTX for 24 weeks. Further courses of Rituxan 2 × 1000 mg + MTX were administered in an open label extension study at a frequency determined by clinical evaluation, but no sooner than 16 weeks after the preceding course of Rituxan. In addition to the intravenous premedication, glucocorticoids were administered orally on a tapering schedule from baseline through Day 14. The proportions of patients achieving ACR 20, 50, and 70 responses at Week 24 of the placebo-controlled period are shown in Table 9.

In RA Study 2, all patients received the first course of Rituxan 2 × 1000 mg + MTX. Patients who experienced ongoing disease activity were randomized to receive a second course of either Rituxan 2 × 1000 mg + MTX or placebo + MTX, the majority between Weeks 24–28. The proportions of patients achieving ACR 20, 50, and 70 responses at Week 24, before the re-treatment course, and at Week 48, after retreatment, are shown in Table 9.

Improvement was also noted for all components of ACR response following treatment with Rituxan, as shown in Table 10.

The time course of ACR 20 response for Study 1 is shown in Figure 2. Although both treatment groups received a brief course of intravenous and oral glucocorticoids, resulting in similar benefits at Week 4, higher ACR 20 responses were observed for the Rituxan group by Week 8. A similar proportion of patients achieved these responses through Week 24 after a single course of treatment (2 infusions) with Rituxan. Similar patterns were demonstrated for ACR 50 and 70 responses.

Radiographic Response

In RA Study 1, structural joint damage was assessed radiographically and expressed as changes in Genant-modified Total Sharp Score (TSS) and its components, the erosion score (ES) and the joint space narrowing (JSN) score. Rituxan + MTX slowed the progression of structural damage compared to placebo + MTX after 1 year as shown in Table 11.

In RA Study 1 and its open-label extension, 70% of patients initially randomized to Rituxan + MTX and 72% of patients initially randomized to placebo + MTX were evaluated radiographically at Year 2. As shown in Table 11, progression of structural damage in Rituxan + MTX patients was further reduced in the second year of treatment.

Following 2 years of treatment with Rituxan + MTX, 57% of patients had no progression of structural damage. During the first year, 60% of Rituxan + MTX treated patients had no progression, defined as a change in TSS of zero or less compared to baseline, compared to 46% of placebo + MTX treated patients. In their second year of treatment with Rituxan + MTX, more patients had no progression than in the first year (68% vs. 60%), and 87% of the Rituxan + MTX treated patients who had no progression in the first year also had no progression in the second year.

Lesser Efficacy of 500 Vs. 1000 mg Treatment Courses for Radiographic Outcomes

RA Study 3 is a randomized, double-blind, placebo-controlled study which evaluated the effect of placebo + MTX compared to Rituxan 2 × 500 mg + MTX and Rituxan 2 × 1000 mg + MTX treatment courses in MTX-naïve RA patients with moderately to severely active disease. Patients received a first course of two infusions of rituximab or placebo on Days 1 and 15. MTX was initiated at 7.5 mg/week and escalated up to 20 mg/week by Week 8 in all three treatment arms. After a minimum of 24 weeks, patients with ongoing disease activity were eligible to receive re-treatment with additional courses of their assigned treatment. After one year of treatment, the proportion of patients achieving ACR 20/50/70 responses were similar in both Rituxan dose groups and were higher than in the placebo group. However, with respect to radiographic scores, only the Rituxan 1000 mg treatment group demonstrated a statistically significant reduction in TSS: a change of 0.36 units compared to 1.08 units for the placebo group, a 67% reduction.

Physical Function Response

RA Study 4 is a randomized, double-blind, placebo-controlled study in adult RA patients with moderately to severely active disease with inadequate response to MTX. Patients were randomized to receive an initial course of Rituxan 500 mg, Rituxan 1000 mg, or placebo in addition to background MTX.

Physical function was assessed at Weeks 24 and 48 using the Health Assessment Questionnaire Disability Index (HAQ-DI). From baseline to Week 24, a greater proportion of Rituxan-treated patients had an improvement in HAQ-DI of at least 0.22 (a minimal clinically important difference) and a greater mean HAQ-DI improvement compared to placebo, as shown in Table 12. HAQ-DI results for the Rituxan 500 mg treatment group were similar to the Rituxan 1000 mg treatment group; however radiographic responses were not assessed (see Dosing Precaution in the Radiographic Responses section above). These improvements were maintained at 48 weeks.

Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis) and Microscopic Polyangiitis (MPA)

A total of 197 patients with active, severe GPA and MPA (two forms of ANCA Associated Vasculidities) were treated in a randomized, double-blind, active-controlled multicenter, non-inferiority study, conducted in two phases – a 6 month remission induction phase and a 12 month remission maintenance phase. Patients were 15 years of age or older, diagnosed with GPA (75% of patients) or MPA (24% of patients) according to the Chapel Hill Consensus conference criteria (1% of the patients had unknown vasculitis type). All patients had active disease, with a Birmingham Vasculitis Activity Score for Granulomatosis with Polyangiitis (BVAS/GPA) ≥ 3, and their disease was severe, with at least one major item on the BVAS/GPA. Ninety-six (49%) of patients had new disease and 101 (51%) of patients had relapsing disease.

Patients in both arms received 1000 mg of pulse intravenous methylprednisolone per day for 1 to 3 days within 14 days prior to initial infusion. Patients were randomized in a 1:1 ratio to receive either Rituxan 375 mg/m2 once weekly for 4 weeks or oral cyclophosphamide 2 mg/kg daily for 3 to 6 months in the remission induction phase. Patients were pre-medicated with antihistamine and acetaminophen prior to Rituxan infusion. Following intravenous corticosteroid administration, all patients received oral prednisone (1 mg/kg/day, not exceeding 80 mg/day) with pre-specified tapering. Once remission was achieved or at the end of the 6 month remission induction period, the cyclophosphamide group received azathioprine to maintain remission. The Rituxan group did not receive additional therapy to maintain remission. The main outcome measure for both GPA and MPA patients was achievement of complete remission at 6 months defined as a BVAS/GPA of 0, and off glucocorticoid therapy. The pre-specified non-inferiority margin was a treatment difference of 20%. As shown in Table 13, the study demonstrated non-inferiority of Rituxan to cyclophosphamide for complete remission at 6 months.

Complete Remission (CR) at 12 and 18 months

In the Rituxan group, 44% of patients achieved CR at 6 and 12 months, and 38% of patients achieved CR at 6, 12, and 18 months. In patients treated with cyclophosphamide (followed by azathioprine for maintenance of CR), 38% of patients achieved CR at 6 and 12 months, and 31% of patients achieved CR at 6, 12, and 18 months.

Retreatment with Rituxan

Based upon investigator judgment, 15 patients received a second course of Rituxan therapy for treatment of relapse of disease activity which occurred between 8 and 17 months after the first course of Rituxan. The limited data preclude any conclusions regarding the efficacy of subsequent courses of Rituxan in patients with GPA and MPA [see Warnings and Precautions (5.14)].

Substance Name

Rituximab

CAS Registry Number

174722-31-7

Drug Class

Antibodies, Monoclonal

Antirheumatic Agents

Antineoplastic Agents

Dosage Forms & Strengths

solution for IV (Rituxan)

• 10mg/mL

solution for SC (Rituxan Hycela)

• Ready-to-use SC solution contains rituximab and hyaluronidase human
• (120mg/2000 units)/mL

Non-Hodgkin Lymphoma

Indications

• Relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL as a single agent
• Previously untreated follicular, CD20-positive, B-cell NHL in combination with first line chemotherapy and, in patients achieving a complete or partial response to rituximab in combination with chemotherapy, as single-agent maintenance therapy
• Nonprogressing (including stable disease), low-grade, CD20-positive, B-cell NHL as a single agent after first-line cyclophosphamide, vincristine, and prednisone (CVP) chemotherapy
• Previously untreated diffuse large B-cell, CD20-positive NHL in combination with CHOP or other anthracycline-based chemotherapy regimens

IV dose for NHL

• 375 mg/m² IV infusion according to the following schedules 
• Relapsed or refractory low-grade or follicular, CD20-positive, B-cell NHL: Once weekly x4-8 doses
• Retreatment for relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL: Once weekly x4 doses
• Previously untreated, follicular, CD20-positive, B-cell NHL: Administer on Day 1 of each chemotherapy cycle for up to 8 doses; with complete or partial response, initiate maintenance 8 weeks following completion of combination chemotherapy as a single-agent q8weeks for 12 doses
• Nonprogressing, low-grade, CD20-positive, B-cell NHL, after first-line CVP chemotherapy: Following completion of 6-8 cycles of CVP chemotherapy, administer once weekly for 4 doses at 6-month intervals to a maximum of 16 doses
• Diffuse large B-cell NHL: Administer on Day 1 of each cycle of chemotherapy for up to 8 infusions

SC dose (Rituxan Hycela) for follicular lymphoma

• Must receive at least 1 full dose of rituximab by IV infusion before starting SC administration to evaluate tolerability
• 1400 mg/23,400 units SC according to the following schedules
• Relapsed or refractory follicular lymphoma: Once weekly x 3 or 7 weeks following a full dose of rituximab IV at week 1 (ie, 4 or 8 weeks total)
• Retreatment for relapsed or refractory follicular lymphoma: Once weekly x 3 weeks following a full dose of rituximab IV at week 1 (ie, 4 weeks total)
• Nonprogressing, follicular lymphoma after first-line CVP chemotherapy: Following completion of 6–8 cycles of CVP chemotherapy and a full dose of a rituximab IV at week 1, administer once weekly for 3 weeks (ie, 4 weeks in total) at 6 month intervals to a maximum of 16 doses
• Previously untreated follicular lymphoma: Administer on Day 1 of Cycles 2–8 of chemotherapy (every 21 days), for up to 7 cycles following a full dose of a rituximab IV on Day 1 of Cycle 1 of chemotherapy (ie, up to 8 cycles in total)
• Previously untreated follicular lymphoma maintenance
  • In patients with complete or partial response, initiate maintenance SC treatment 8 weeks following completion rituximab SC in combination with chemotherapy
  • Administer as single-agent q8wk x 12 doses

SC dose (Rituxan Hycela) for diffuse large B-cell lymphoma

• Must receive at least 1 full dose of rituximab by IV infusion before starting SC administration to evaluate tolerability
• 1400 mg/23,400 units SC according to the following schedule
• Initiate on Day 1 of cycles 2-8 of CHOP chemotherapy for up to 7 cycles following a full dose of rituximab IV (Day 1, cycle 1) of CHOP (up to 6-8 cycles)

Chronic Lymphocytic Leukemia

Indicated for untreated and previously treated CD20-positive CLL; combined therapy with fludarabine and cyclophosphamide (FC)

375 mg/m² IV infusion on day 1 of 1st cycle (for 1st cycle, administer 1 day before chemotherapy with FC), THEN  

500 mg/m² IV on day 1 of subsequent cycles (administer on same day as chemotherapy with FC)

Repeat q28 days x6 cycles

Fludarabine & cyclophosphamide dosage

• Fludarabine: 25 mg/m² IV qDay x 3 days
• Cyclophosphamide: 250 mg/m² IV qDay x3 days
• Repeat q28 days x 6 cycles

SC administration (Rituxan Hycela) for CLL

• Must receive at least 1 full dose of rituximab by IV infusion before starting SC administration to evaluate tolerability
• 1600 mg/26,800 units SC according to the following schedule
• Initiate on Day 1 of cycles 2-6 (every 28 days) of FC chemotherapy for a total of 5 cycles following a full dose of rituximab IV (Day 1, cycle 1) up to 6 cycles in total

Rheumatoid Arthritis

1000 mg IV infusion, repeat after 2 week (2 infusions separated by 2 week is 1 course)

Repeat course q24weeks or based on clinical evaluation (but no sooner than 16 weeks)

Used in combo with methotrexate

Premedicate with glucocorticoids 30 minutes before infusion to reduce infusion rxn

Not to exceed 1000 mg/dose

Wegener Granulomatosis

375 mg/m² IV qWeek x4 weeks 

Administration

• Premedicate with acetaminophen and antihistamine before rituximab infusion
• Administer methylprednisolone 1 g IV/day x1-3 days, then prednisone 1 mg/kg/day PO; not to exceed 80 mg/day and taper as clinically needed
• Initiate glucocorticoids within 14 days prior to or with initiation or rituximab; may continue during and after the 4-week rituximab treatment course
• Concomitant use of immunosuppressants other than corticosteroids has not been studied in Wegener granulomatosis
• Safety and efficacy of subsequent courses of rituximab not established

Microscopic Polyangiitis

375 mg/m² IV qWeek x4 weeks 

Administration

• Premedicate with acetaminophen and antihistamine before rituximab infusion
• Administer methylprednisolone 1 g IV/day x1-3 days, then prednisone 1 mg/kg/day PO; not to exceed 80 mg/day and taper as clinically needed
• Initiate glucocorticoids within 14 days prior to or with initiation or rituximab; may continue during and after the 4-week rituximab treatment course
• Concomitant use of immunosuppressants other than corticosteroids has not been studied in microscopic polyangiitis
• Safety and efficacy of subsequent courses of rituximab not established

Orphan Designations

Treatment of immune thrombocytopenic purpura (ITP)

Treatment of pemphigus vulgaris

Sponsor

• Genentech, Inc; 1 DNA Way; South San Francisco, CA 94080-4990

Rasmussen Encephalitis (Orphan)

Orphan designation for treatment of Rasmussen encephalitis

Sponsor

• Keck Graduate Institute of Applied Life Sciences; 535 Watson Drive; Claremont, California 91711

Safety and efficacy not established

Rheumatoid Arthritis: Safety and effectiveness not established; FDA has not required pediatric studies in polyarticular juvenile idiopathic arthritis (PJIA) patients <16 years due to concerns regarding the potential for prolonged immunosuppression as a result of B-cell depletion in the developing juvenile immune system

Wegener Granulomatosis: Safety and effectiveness not established

Black Box Warnings

Fatal infusion reaction

• Can result in serious, including fatal reactions
• Deaths within 24 hours of infusion have occurred
• Approximately 80% of fatal infusion reactions occurred in association with the first infusion
• Carefully monitor patients during infusion
• In patients with Non-Hodgkin’s Lymphoma (NHL) receiving rituximab monotherapy, NCI-CTC Grade 3 and 4 cytopenias reported; reactions included lymphopenia, neutropenia, leukopenia, anemia, and thrombocytopenia; discontinue infusion and provide medical treatment for grade 3 or 4 reactions

Mucocutaneous reactions (severe)

• Severe, including fatal, mucocutaneous reactions reported including paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis

Progressive multifocal leukoencephalopathy

• John Cunningham virus infection resulting in progressive multifocal leukoencephalopathy and death has been reported in patients treated with rituximab

Reactivation of hepatitis B

• Reactivation of hepatitis B virus (HBV) infection reported, including deaths
• Screen all patients for HBV infection before initiating drug by measuring hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc)
• Consult with hepatitis experts regarding monitoring and use of HBV antiviral therapy when screening identifies patients at risk of HBV reactivation due to evidence of prior HBV infection
• Monitor patients with evidence of prior HBV infection for clinical and laboratory signs of hepatitis B or HBV reactivation during therapy and for several months thereafter, since reactivations have occurred several months following completion of therapy
• In patients who develop reactivation of HBV, immediately discontinue the drug and start appropriate HBV treatment, also discontinue any chemotherapy until the HBV infection is controlled or resolved
• Because of insufficient data, no recommendation can be made regarding the resumption of the drug in patients who develop HBV reactivation hepatitis

Contraindications

Hypersensitivity to any component, murine proteins

Cautions

Cardiac arrhythmia, angina, high tumor burden, concomitant cisplatin

Infusion reactions may occur and are potentially fatal; reactions may resolve with slowing or suspending infusion; risk diminishes with subsequent infusions

Risk of potentially fatal mucocutaneous reactions

Risk of potentially fatal tumor lysis syndrome

Increased risk of potentially fatal hepatitis B virus reactivation

Potential risk of progressive multifocal leukoencephalopathy

IV Preparation

Reconstitution: withdraw necessary amount of rituximab and dilute to a final concentration of 1-4 mg/mL into an infusion bag containing either NS or D5W

IV Administration

Consider premedication (ie, acetaminophen, diphenhydramine, and/or glucocorticoids for RA) before each infusion

Premedication with diphenhydramine and acetaminophen may attenuate infusion-related events

Because transient hypotension may occur during infusion, consider withholding antihypertensive medications 12 hr prior to infusion

Administer by slow IV infusion only; do not administer as an IV

First IV infusion rate: Start 50 mg/hr; increase by 50 mg/hr q30min, not to exceed 400 mg/hr

Drug is associated with hypersensitivity reactions which may respond to adjustments in infusion rate

Subsequent IV infusions (90 minutes)

• Standard IV infusions: Start 100 mg/hr, increase by 100 mg/hr q30min, not to exceed 400 mg/hr; institutional protocols may allow faster increments
• Previously untreated patients with follicular NHL or diffuse large B-cell lymphoma: If patients did not experience a Grade 3 or 4 infusion related adverse event during Cycle 1, a 90-minute infusion can be administered in Cycle 2 with a glucocorticoid-containing chemotherapy regimen
• Initiate at a rate of 20% of the total dose given in the first 30 minutes and the remaining 80% of the total dose given over the next 60 minutes
• If tolerated in Cycle 2, the same rate can be used when administering the remainder of the treatment regimen (through Cycle 6 or 8)
• Patients who have clinically significant cardiovascular disease or who have a circulating lymphocyte count ≥5000/mm³ before Cycle 2 should not be administered the 90-minute infusion

Infusion-related adverse effects

• Hypotension, bronchospasm, and angioedema have occurred as part of an infusion-related symptom complex
• Interrupt infusion for severe reactions and resume at a 50% reduction in rate (eg, from 100 to 50 mg/hr) when symptoms have completely resolved
• Treatment of these symptoms with diphenhydramine and acetaminophen is recommended
• Additional treatment with bronchodilators or IV saline may be indicated
• Discontinue infusions if serious or life-threatening cardiac arrhythmias

SC Preparation

Solution for SC is ready to use

SC Administration

Consider premedication (ie, acetaminophen, diphenhydramine, and/or glucocorticoids)

Premedication with acetaminophen and diphenhydramine may attenuate infusion-related reactions

Observe patients for 15 minutes after SC administration

If administration is interrupted, administer at the same site or at a different site along the abdomen

Avoid coadministering other SC medications at the same site

Avoid injections into areas where skin appears red, bruised, tender, or hard

Avoid injections in areas where there are moles or scars

No data available on other injection sites

Injection Rate

• Inject SC in abdomen
• 1400 mg/23,400 IU/vial (1400 mg rituximab and 23,400 Units hyaluronidase human): SC over ~5 minutes
• 1600 mg/26,800 Units vial (1600 mg rituximab and 26,800 Units hyaluronidase human): SC over ~7 minutes

Storage

IV

• Store under refrigeration
• Protect vials from direct sunlight
• Solutions for infusion are stable at 2-8°C (36-46°F) for 24 hr

SC

• Store unopened vials under refrigeration
• Protect vials from direct sunlight
• Solutions for SC injection are stable at 2-8°C (36-46°F) for 48 hr
• Solutions for SC injection in direct light are stable up to 30°C (86°F) for 8 hr