Full Prescribing Information for the U.S

Product on the Market: Rituxan®
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First Monoclonal Antibody Cancer Treatment Approved in US
Rituxan® (Rituximab) is the first monoclonal antibody found to be effective and safe for the treatment of cancer in the United States. Rituxan is indicated for the treatment of patients with relapsed or refractory, low grade or follicular, CD20-positive, B-cell non-Hodgkin’s lymphoma (NHL), which is cancer of the lymphatic system. It’s a disease that’s fatal in the large majority of patients. Rituxan is genetically engineered from portions of mouse and human antibodies and is produced through recombinant DNA technology.

IDEC co-promotes Rituxan in the U.S. with Genentech, Inc. Outside the U.S. Rituxan is marketed by F. Hoffmann LaRoche under the tradename MabThera(r). In Japan Rituxan is marketed by Zenyaku Kogyo, Ltd. and Nippon Roche.

Rituxan’s Clinical Trial Data
In the pivotal trial preceding product approval by the FDA in November 1997, Rituxan was evaluated using strict criteria. Complete response (CR) was defined as no evidence of disease for at least 28 days, with all lymph nodes shrinking to less than 1 cm x 1 cm in diameter. Partial response (PR) was defined as equal to or greater than a 50 percent decrease in tumor diameter with no evidence of progressive disease for at least 28 days. An independent panel of lymphoma experts verified all responses.

An Overall Response Rate of 48 Percent
During the pivotal, multi-center study, Rituxan achieved an overall response rate of 48 percent (80/166). Six percent (10/166) of patients had complete responses, as determined by the trial’s strict criteria. Forty-two percent (70/166) of patients had partial responses. The median duration of responses is projected to be 10 to 12 months.

Rituxan Activates B-Cell Death
Monoclonal antibodies such as Rituxan are derived from a single clone of antibody-producing cells and bind only to one antigen. Rituxan binds specifically to the CD20 antigen, a molecule present on the surface of the normal and abnormal pre-B and mature B cells. More than 90 percent of B-cell NHL express CD20.

Once bound to B cells, Rituxan induces lysis (dissolution or destruction of the cell) through several proposed mechanisms, based on in vitro data. Rituxan is believed to work with elements of the human immune system to kill CD20+ B cells through antibody-dependent toxicity (ADCC) and complement-dependent cytotoxicity (CDC). Through in-vitro experiments Rituxan’s binding has also been shown to induce apoptosis (programmed cell death). B cell recovery begins at approximately six months following completion of treatment, and median B-cell levels return to normal by 12 months.

One way researchers determine the efficacy of a new cancer agent, like Rituxan, is by determining during clinical trials its Overall Response Rate (ORR), which combines both Complete Responses (CR) with Partial Responses (PR). Thus, ORR equals CR plus PR. Although the definitions of what constitute a CR or PR may vary from study to study, a CR in NHL typically means tumor bulk has been reduced to the point that it is virtually undetectable by conventional means. A PR means that tumor bulk has been reduced by 50%.

The most common adverse events associated with Rituxan, based on our clinical trial experience, are infusion-related, consisting mainly of mild to moderate flu-like symptoms (e.g., fever, chills, rigors) that occur in the majority of patients during the first infusion. Other events which occur with less frequency include nausea, rashes, fatigue and headaches. More serious events include hypotension, wheezing, sensation of tongue or throat swelling and recurrence of cardiac events in patients with a history of angina or arrhythmia. These symptoms were usually limited in duration to the period of infusion and decrease with subsequent infusions. These adverse events are generally milder and of a shorter duration than the adverse events associated with chemotherapy.

In April 2001 the FDA approved expanded usage of Rituxan to include times-8 dosing, retreatment and bulky disease (tumors greater than 10 centimeters). The expanded label for Rituxan was approved on the basis of the following clinical trials results.

    • Initial Treatment with Eight Weekly Infusions
      In an investigational Phase II multi-center, single-arm, multiple-dose study, 37 patients with relapsed or refractory, low grade NHL received 375 mg/m2) of Rituxan once a week for a total of eight weekly infusions. Overall response rates were 57 percent (21/37 patients) with 14 percent of patients experiencing complete responses and 43 percent partial responses. The projected median duration of response is 13.4 months.


  • Retreatment
    In another investigational Phase II multi-center, single-arm study, 60 patients with relapsed or refractory, low grade or follicular NHL were retreated when they relapsed after obtaining an objective clinical response with their initial four-week course of Rituxan. These patients received 375 mg/m2 once weekly dose of Rituxan for an additional four weeks. Of the 60 patients, 58 received a second course and two received a third course of Rituxan. The overall response rate was 38 percent (23/60 patients) with 10 percent achieving complete responses and 28 percent partial responses. The projected median duration of response is 15 months.
  • Bulky Disease
    Results also were submitted from multiple Rituxan studies of 39 low-grade NHL patients with relapsed or refractory bulky disease, which is especially difficult to treat successfully due to the increased tumor size. In 39 patients, an overall response rate of 36 percent (14/39) was observed, with three percent achieving complete responses and 33 percent achieving partial responses. The median duration of response was 6.9 months. Each patient received 375 mg/m2) of Rituxan in four weekly infusions.

Safety Information
A Dear Healthcare Provider letter was sent to physicians to enhance their understanding of adverse events that may be associated with Rituxan use. The new labeling includes information on 20 post-marketing reports of rare severe mucocutaneous reactions that have been seen in patients treated with Rituxan. Eight of these resulted in a fatal outcome. Patients experiencing these reactions have highly compromised immune systems related to their disease.
Currently there has been no direct link made between these types of reactions and Rituxan, however, until more is known, it is important that physicians understand that Rituxan could have contributed to some of these events and manage their patients accordingly.

These reactions have been described as paraneoplastic pemphigus (PNP), lichenoid dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, or vesiculobullous dermititis. Most of these reactions were PNP which is known to be associated with various B-cell lymphomas, particularly NHL and chronic lymphocytic leukemia (CLL). Patients experiencing these types of reactions should have their Rituxan infusion discontinued and receive appropriate medical therapy which includes a skin biopsy to help guide treatment.

The majority of patients experience infusion-related symptoms with their first Rituxan infusion. These symptoms include, but are not limited to, flu-like fever, chills/rigors, nausea, urticaria, headache, bronchospasm, angioedema and hypotension. These symptoms vary in severity and generally are reversible with medical intervention. Administration of Rituxan weekly for eight doses or retreatment was associated with higher rates of grade 3 and 4 adverse events overall compared with the original four dose schedule. In rare instances, severe and fatal infusion-related reactions have occurred, nearly all of which have been associated with the first Rituxan infusion. These events appear as manifestations of an infusion-related complex and include hypoxia, pulmonary infiltrates, adult respiratory distress syndrome, myocardial infarction, ventricular fibrillation, cardiogenic shock and tumor lysis syndrome. Patients who develop clinically significant infusion-related cardiopulmonary events should have Rituxan infusion discontinued and receive medical treatment.

Additionally, clinical trials have been initiated in other B-cell malignancies such as chronic lymphocytic leukemia (CLL) and multiple myeloma, as well as non-malignant conditions such as rheumatoid arthritis and lymphoproliferative disorders associated with solid organ transplant therapies.