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Rituxan |
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Access to Drug
Background on Use
Who is Rituxan for?
See Indications below
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Scheduling Rituxan (under construction)
About CD20 -- the target of Rituxan
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How is it made?
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What should I expect, and how should I
prepare for my first
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 | Review and print out the Dosage
and Administration Guide for details Rituxan.com This will help familiarize yourself with the details of the procedure and allow you to ask informed questions. |
| Do not be shy about asking questions of
your doctor about
your specific risk factors in advance of the treatment. (... " pre-existing cardiac and pulmonary conditions, those with prior clinically significant cardiopulmonary adverse events, and those with high numbers of circulating malignant cells (  25,000/mm³)
with or without evidence of high tumor burden." Rituxan.com |
| You should plan to stay the day for the first infusion -- which
should be given very slowly to minimize infusion-related risks. If you
tolerate the first infusion well, you may be done in as little as
three hours after that. |
| Prepare a thank-you-in-advance gift, such as baked
goods, for the nursing staff. They work very hard and appreciate
being appreciated. |
| Arrange to have a friend or relative accompany you, if at all
possible. The therapy can make you drowsy and impact
your ability to drive. |
| Bring your favorite reading material, or a portable audiotape/CD
player with headphones to help pass the time. |
| Bring some favorite snacks, bottled water, and a pillow as well.
Many centers will have snacks and drink available. |
| Be positive! Most patients have little problem at all. It's common to experience fatigue for the remainder of the day, and the next day as well. |
Monitoring your reactions
| Talk to the nurse and your doctor about treatment risks and what
they will do to monitor you. Indicate that you are in no hurry
to complete the infusion and that you will appreciate being monitored
closely, especially the first time. |
| Ask the nurse or doctor about sensations that are to be expected and
what to report immediately. Also refer to the Dosage and Administration
Guide for details. |
| Just before treatment, you will also receive Tylenol
in pill form. |
| You will receive Benadryl to help you tolerate the infusion better.
This will make you drowsy. The same IV used to administer the Benadryl will
be used to administer the Rituxan. The Benadryl may cause a temporary
burning sensation. |
| The rate of administering the Rituxan is very slow at the start; it
may be increased when it's determined you are tolerating it well. |
| Your vitals (temperature and blood pressure) will be taken and monitored throughout the treatment
session, as often as every 30 minutes. Use this time to report
unusual sensations. |
| Notify the nurse when you have any unusual sensations. |
The above Rituxan checklist - Print
version
Rituxan circulates in the lymphatic system and tissue. It binds specifically to the CD20 antigen, a molecule present on the surface of the normal and malignant pre-B and mature B cells. This binding can be imagined as a lock fitting a key. More than 90 percent of B-cell NHL express CD20. Once bound to B-cells, Rituxan induces lysis (destruction of the cell) through several possible mechanisms:
| Apoptosis: The Rituxan antibody induces cells to which it is
bound to initiate programmed cell death. The activation of this
program by the cell results in the death of the cell (a kind of
suicide). |
| Antibody-dependent Cell-mediated Cytotoxicity (ADCC) - An immune response triggered by the presence of antibody coating the target cell. Upon binding its antigen, the Antibody's Fc region is exposed and will bind its receptor on the NK cell (or other effector cells) to form a bridge. Once the bridge is formed, a poorly understood lytic (killing) signal is delivered to the target cell by the effector cell, resulting in its demise. |
Click image to enlarge.
| Complement-dependent cytotoxicity
(CDC): A mechanism in which antibody
bound to the target cell surface fixes complement, which results in
assembly of the membrane attack complex that punches holes in the
target cell membrane resulting in subsequent cell lysis. Dr
David J. Flavell | ||
| Inhibition of proliferation: The Rituxan antibody sends
signals to the cell that stops the cell from dividing further. | ||
| Vaccinal effect - when a therapy leads to recognition of
tumor antigens (abnormal proteins) as foreign leading to an attack of the
remaining tumors by effector cells in the immune system. | ||
| Synergistic effects with
chemotherapy: The Rituxan antibody
sends signals to the cell that sensitizes it to killing mechanisms of
chemotherapy agents. Shifts it towards apoptosis, perhaps.
|
Types | Common | Incidence of | Serious infusion-related | Other Risks: Rare, Viral, Immune deficiency
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TYPES:
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COMMON:
|
"Incidence
of Side Effects (Adverse Events) in > 5% of Patients
with Relapsed or Refractory, Low-Grade or Follicular
NHL, Receiving Single-agent Rituxan (N=356)a,b
NOTE: AE rates
in this one study (non-random sample; probably younger patients)
may not predict the incidence of AEs in the general population (of patients who
use Rituxan to treat disease).
|
TYPE |
All
Grades (%) |
Grade
3 and 4 (%) |
|
Any Adverse Events |
99% |
57% |
|
Body as a Whole |
86% |
10% |
|
Fever |
53% |
1% |
|
Chills |
33% |
3% |
|
Infection |
31% |
4% |
|
Asthenia |
26% |
1% |
|
Headache |
19% |
1% |
|
Abdominal Pain |
14% |
1% |
|
Pain |
12% |
1% |
|
Back Pain |
10% |
1% |
|
Throat Irritation |
9% |
0 |
|
Flushing |
5% |
0 |
|
Cardiovascular |
25% |
3% |
|
Hypotension (low blood pressure) |
10% |
1% |
|
Hypertension (high blood
pressure) |
6% |
1% |
|
Digestive |
37% |
2% |
|
Nausea |
23% |
1% |
|
Diarrhea |
10% |
1% |
|
Vomiting |
10% |
1% |
|
Hemic and Lymphatic System |
67% |
48% |
|
Lymphopenia |
48% |
40% |
|
Leukopenia |
14% |
4% |
|
Neutropenia |
14% |
6% |
|
Thrombocytopenia |
12% |
2% |
|
Anemia |
8% |
3% |
|
Metabolic and Nutritional Disorders |
38% |
3% |
|
Angioedema |
11% |
1% |
|
Hyperglycemia (high
blood sugar) |
9% |
1% |
|
Peripheral Edema (swelling
of tissues) |
8% |
0 |
|
LDH Increase (blood test marker) |
7% |
0 |
|
Musculoskeletal System |
26% |
3% |
|
Myalgia (muscle
pain) |
10% |
1% |
Arthralgia (pain
in the joints) |
10% |
1% |
|
Nervous System |
32% |
1% |
|
Dizziness |
10% |
1% |
|
Anxiety |
5% |
1% |
|
Respiratory System |
38% |
4% |
|
Increased Cough |
13% |
1% |
|
Rhinitis (irritation
and |
12% |
1% |
|
Bronchospasm (difficulty
in breathing |
8% |
1% |
|
Dyspnea (shortness
of breath) |
7% |
1% |
|
Sinusitis |
6% |
0% |
|
Skin and Appendages |
44% |
2% |
|
Night Sweats |
15% |
1% |
|
Rash |
15% |
1% |
|
Pruritus (itching) |
14% |
1% |
|
Urticaria |
8% |
1% |
Despite profound B-cell depletion, the incidence of infection did not appear to be increased. During treatment in the large multicenter trial of single-agent RITUXAN, 68 infectious events occurred. Of these, 7 were Grade 3 and none were Grade 4.5" http://www.rituxan.com/lymphoma/HCP/Files/PDFs/HCP_Q&A_Guide.pdfAdapted from: Full Prescribing Information gene.com
* Infection when Rituxan is used as monotherapy: "There were sustained reductions in serum levels of both IgM and IgG observed from 5 through 11 months following single agent RITUXAN administration, which were statistically significant. It is important to note that only 14% of patients had reductions in serum IgM and/ or IgG to values below the normal range.1
Because of its specificity of action (it targets specific cells), Rituxan is generally less toxic than chemotherapies. However, it's not uncommon for patients to experience transient side effects -- mainly mild to moderate flu-like symptoms (fever, chills, rigors).
However, some patients may experience significant side effects. Most commonly, these adverse events occur during the first infusion. Severe and fatal reactions are uncommon but have occurred. See box warning below.
| Some patients taking Rituxan may experience bowel obstruction aol.mediresource.com
|
| Box warning for possible severe side effects IDEC
|
| Serum sickness (uncommon) : "shivering fever (38.5°C) and
polyarthralgias presented.
|
| Tumor lysis syndrome (uncommon) : "Rituximab-induced ATLS
has been reported in
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Results. Severe hypersensitivity reactions are rare, with an incidence of
5%, provided patients receive proper premedication, close monitoring, and prompt intervention when symptoms occur.
Reactions to taxanes and monoclonal antibodies produce similar symptoms, but are generally immediate, occurring during the first few minutes of the first or second infusion. However, 10%–30% of reactions to monoclonal antibodies are delayed, and may occur in later infusions, indicating the importance of close observation of the patient following administration.
Mild-to-moderate reactions can be managed by temporary infusion interruption, reduction of the infusion rate, and symptom management. Rechallenge should be considered after complete resolution of all symptoms.
Severe reactions may require treatment discontinuation.
Conclusion. Hypersensitivity or infusion reactions to platinum compounds are acquired; reactions to taxanes and monoclonal antibodies are immediate and typically occur during the first few minutes of the first infusion. The different time of onset should be considered when developing strategies for preventing and managing hypersensitivity reactions. The decision to rechallenge or discontinue treatment after a reaction occurs depends on the severity of the reaction and other clinical factors.
Factors that may influence risks of adverse reactions
"Patients requiring close monitoring during first and all subsequent infusions include those with pre-existing cardiac and pulmonary conditions, those with prior clinically significant cardiopulmonary adverse events and those with high numbers of circulating malignant cells (> 25,000/mm3) with or without evidence of high tumor burden. IDEC
"Major risk factors include high numbers of circulating malignant lymphoma cells, pulmonary infiltrates or lymphoma involvement, and prior cardiovascular disease. This report updates the safety experience of Rituximab therapy with data from clinical trials and postmarketing safety experience, and examines how this information can be used to optimize therapy." See Optimizing the use of rituximab for treatment of B-cell non-Hodgkin's lymphoma: a benefit-risk update. Kunkel
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Complement activation plays a key role in
the side-effects of rituximab treatment.
|
Other Risks: Rare, Viral, Immune deficiency
| Rare / Uncommon: |
| NEW Progressive
multifocal leukoencephalopathy [PML] after Rituxan therapy in
|
| "Hypoglycemia is a very rare toxicity of rituximab. The
exact mechanism of rituximab
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| Viral:
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| Immune deficiency:
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Effect of prior rituximab on high-dose therapy and autologous
stem cell transplantation in follicular lymphoma. Bone
Marrow Transplant. 2007 Sep 17; PMID:
17873917
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How long does it take to respond?
How long it takes for Rituxan to work can be very different from one person to the next. Rituxan works gradually, so don't' be discouraged if it takes a while to work for you. When Rituxan was tested, it often took several months after the completion of Rituxan treatment for the tumor to shrink.
Time to First Tumor Response in Efficacy Studies
Adapted from table in http://www.emea.europa.eu/humandocs/PDFs/EPAR/Mabthera/025998en6.pdf
Monotherapy
Studies (follicular NHL)Responders Average Time (Days) Median Time (Days) Min Time (Days) Max Time (Days) 102-02 -II
102-0517 of 37
80 of 16658.2
65.350
507
21112
288Total 97 of 203 64 50 7 288
What is the expected response rate?
The expected response rate is just an average (a statistic calculated for a large group) which cannot predict individual outcomes. Some factors that may influence individual outcomes are: treatment history, tumor burden, type of lymphoma, the number of infusions, serum levels that you obtain, other treatments you are receiving with Rituxan, and perhaps variable molecular characteristics of the malignant cells.
What is the expected time to initial response?
It can vary by lymphoma subtype. In one study in follicular lymphoma the median time to
initial onset of response was 50 days. (Rituxan® full Prescribing Information, April 2001)In a pivotal, multi-center study, Rituxan achieved an overall response rate of 48 percent (80/166).
Complete Responses (CR): Six percent (10/166) of patients had complete responses.
Partial Responses (PR): Forty-two percent (70/166) of patients.
Median Duration of Response: Projected to be 10 to 12 months.
Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients
respond to a four-dose treatment program. J Clin Oncol. 1998 Aug;16(8):2825-33. PMID: 9704735 PubMedOf interest is that median duration of responses can be longer than "the medians achieved in the patients' prior course of rituximab." This is not the rule for cancer treatments, and speaks to the potential of Rituxan and treatments with targeted mechanisms to better manage lymphomas.
Rituximab anti-CD20 monoclonal antibody therapy in non-Hodgkin's lymphoma: safety and efficacy of
re-treatment. J Clin Oncol. 2000 Sep;18(17):3135-43. PMID: 10963642 PubMedReports on factors associated with response to Rituxan
Absolute lymphocyte count (ALC) predicts therapeutic efficacy of rituximab therapy in follicular lymphomas.
Br J Haematol. 2007 Apr 13 PMID: 17433025
This study supports our hypothesis that a higher ALC predicts longer TTP following rituximab therapy.Genetic characteristics (FCGR3A genotype) predict response to Rituxan? Blood 2002 Feb 1 | PubMed
Rituxan review article Medscape (free login req.)
CLL/SLL: Rituximab using a thrice weekly dosing schedule in B-cell chronic lymphocytic leukemia and small
lymphocytic lymphoma demonstrates clinical activity and acceptable toxicity.
J Clin Oncol. 2001 Apr 15;19(8):2153-64. PMID: 11304767 PubMedPrognostic factors for non-Hodgkin's lymphoma patients treated with chemotherapy
may not predict outcome in patients treated with rituximab.
Leuk Lymphoma. 2006 Sep;47(9):1830-40 PMID: 17064996Serum levels of Rituxan may influence efficacy Berinstein
Extended Rituximab (anti-CD20 monoclonal antibody) therapy for relapsed or refractory low-grade or follicular non-Hodgkin's lymphoma. PubMed abstract
Rituxan as frontline treatment "With further follow-up and repeat courses of rituximab, the major response
rate increased from 47% to 65% and the complete response rate increased from 7% to 27%."
Semin Oncol 2002 Feb;29(1 Suppl 2):25-9 abstract 4-09-02
TOPIC
SEARCH PubMed
Rituxan kills both normal and malignant b-cells that express CD20. Precursor cells from which new b-cells are generated do not express CD20 and are not affected. B-cell recovery begins at approximately six months following completion of treatment, and median B-cell levels return to normal by 12 months.
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B cell reconstitution after rituximab treatment of lymphoma recapitulates B cell ontogeny.Clin Immunol. 2007 Feb;122(2):139-45. Epub 2006 Sep
27 PMID: 17008130
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Immunophenotypic changes and clinical outcome in B-cell lymphomas treated with rituximab.
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