Re: Attn: Smita Therapeutic utility of Monoclonal antibodies

[Guest guest]

Dear Smita, I was agog over such a reply from any young PG student. It is a reflection of your assiduous toil for detailed net search and I am certainly sure that it will be a godsend posting for all PG students to increase their knowledge about monoclonal antibodies. I am supplementing it

with the warnings issued by US FDA regarding monoclonal antibodies. This is a compilation of safety information on monoclonal antibody drugs already approved by the US FDA (Food and Drug Administration), most of them posted on the FDA website. The URLs are included at the time of compilation. [From Jan 2006- Feb 2008] [Copied from www.ibiblio.org and www.fda.gov] Muromonab CD3(Orthoclone OKT 3) mouse monoclonal antibody, Transplant anti-rejection Safety information: Anaphylactic or anaphylactoid reactions may occur following administration of any dose or course of ORTHOCLONE OKT3. In addition, serious, occasionally life-threatening or lethal, systemic, cardiovascular, and central nervous system reactions have been reported following administration of ORTHOCLONE OKT3. These have included: pulmonary edema, especially in patients with volume overload; shock, cardiovascular collapse, cardiac or respiratory arrest, seizures, coma, cerebral edema, cerebral herniation, blindness and paralysis.

http://www.orthobiotech.com/orthoclone.html Abciximab (reopro) humanized mouse monoclonal antibody prevents blood clotting Side effects: Acid or sour stomach; belching; burning, crawling, itching, numbness, prickling, “pins and needles”, or tingling feelings; changes in vision; delusions; dementia; fear; heartburn; indigestion or stomach discomfort, upset or pain; mood or mental changes; nausea; nervousness; vomiting.

http://www.drugs.com/cons/ReoPro.html Rituxan (Rituximab) humanized mouse monoclonal antibody, treatment of Non-Hodgkins lymphoma Warning: Fatal Infusion Reactions: Deaths within 24 hours of RITUXAN infusion have been reported. These fatal reactions followed an infusion reaction complex which included hypoxia, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrilation

orcardiogenic shock. Approximately 80% of fatal infusion reactions occurred in association with the first infusion. http://www.fda.gov/medwatch/SAFETY/2005/Jan_PI/Rituxan_PI.pdf Zenapax (daclizumab) humanized mouse monoclonal antibody, , transplant immune suppression Warning: Severe, acute (onset within 24 hours) hypersensitivity reactions including anaphylaxis have been observed

both on initial exposure to ZENAPAX and following re-exposure. These reactions may include hypotension, bronchospasms, wheezing, laryngeal edema, pulmonary edema, cyanosis, hypoxia, respiratory arrest, cardiac arrhythmia, cardiac arrest, peripheral edema, loss of consciousness, fever, rash, urticaria, diaphoresis, pruritus, and/or injection site reactions. http://www.fda.gov/medwatch/SAFETY/2003/zenapax.htm Basiliximab(Simulect) humanized mouse monoclonal antibody, transplant ant-rejection Warning: severe acute (onset within 24 hours) hypersensitivity reactions including anaphylaxis have been observed both on initial exposure to Simulect® and/or following re-exposure after several months. These reactions may include hypotension, tachycardia, cardiac failure, dyspnea, wheezing, bronchospasm, pulmonary edema, respiratory failure, urticaria, rash, pruritus, and/or sneezing. If a severe hypersensitivity reaction occurs, therapy with Simulect® should be permanently discontinued. Medications for the treatment of severe hypersensitivity reactions including anaphylaxis should be available for immediate use. Patients previously administered Simulect® should only be re-exposed to a subsequent course of therapy with extreme caution. http://www.fda.gov/medwatch/safety/2000/simule.htm Palivizumab(Synagis) humanized mouse monoclonal antibody, anti-respiratory syncytial virus Warning: Very rare cases of anaphylaxis (<1 case per 100,000 patients) have been reported following re-exposure to Synagis (palivizumab. Rare severe acute hypersensitivity reactions have also been reported on initial exposure or re-exposure to palivizumab. http://www.fda.gov/medwatch/SAFETY/2002/Synagis_PI.pdf Infliximab (Remicade), humanized mouse monoclonal antibody, anti-arthritis Warning; tuberculosis infection some fatal http://www.fda.gov/medwatch/safety/2005/Sep_PI/Remicade_PI.pdf Trastuzumab (Herceptin) humanized mouse monoclonal antibody, cancer therapy Warning: CARDIOMYOPATHY: HERCEPTIN administration can result in the development of ventricular dysfunction and congestive heart failure. http://www.accessdata.fda.gov/scripts/cder/onctools/labels.cfm?GN=Trastuzumab Gemtuzumab (Mylotarg) humanized mouse monoclonal antibody, cancer therapy

Warning: Mylotarg administration can result in severe hypersensitivity reactions (including anaphylaxis), and other infusion-related reactions which may include severe pulmonary events. Infrequently, hypersensitivity reactions and pulmonary events have been fatal http://www.fda.gov/medwatch/SAFETY/2004/apr_PI/Mylotarg_PI.pdf Alemtuzumab (Campath-1H) humanized mouse monoclonal antibody, leukemia cancer treatment Warning: Campath may lower the ability of the bone marrow to make blood cells. Some of these effects can be severe and lead to death. Three patients in a clinical study of the drug Campath for the treatment of Multiple Sclerosis (MS) developed severe idiopathic thrombocytopenic purpura (ITP). http://www.fda.gov/cder/drug/InfoSheets/patient/alemtuzumabPIS.pdf 90 ibritumomab tiuxetan (Zevalin) Mouse monoclonal antibody, cancer therapy (Yttrium radio therapy associated) Warning: Deaths have occurred within 24 hours of Rituximab infusion, an essential component of the ZEVALIN therapeutic regimen. These fatalities were associated with an infusion reaction symptom complex that included hypoxia, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, or cardiogenic shock.

http://www.accessdata.fda.gov/scripts/cder/onctools/labels.cfm?GN=Ibritumomab%20Tiuxetan Adalimumab, Human monoclonal antibody, arthritis treatment Warning: TUBERCULOSIS (FREQUENTLY DISSEMINATED OR EXTRAPULMONARY AT CLINICAL PRESENTATION), INVASIVE FUNGAL INFECTIONS, AND OTHER OPPORTUNISTIC INFECTIONS, HAVE BEEN OBSERVED IN PATIENTS RECEIVING HUMIRA. SOME OF THESE INFECTIONS HAVE BEEN FATAL

http://www.fda.gov/medwatch/safety/2005/Oct_PI/Humira_PI.pdf Omalizumab (Xolair) humanized mouse monoclonal antibody, treatment of allergic asthma Warning: [uPDATE 07/02/2007] Genetech and FDA informed healthcare professionals and asthmatic patients that the prescribing information for Xolair was revised to include a new BOXED WARNING, and updated WARNINGS, PRECAUTIONS, and

ADVERSE REACTIONS sections that address the risk of anaphylaxis (the onset of action can be delayed for 24 hours or more) when taking this medication. In addition, a new MEDICATION GUIDE was developed and will be provided to patients when a prescription for Xolair is filled or refilled at the pharmacy. Due to the risk of anaphylaxis, Xolair should only be administered to patients in a healthcare setting under direct medical supervision. Patients should be observed for an appropriate period of time following each Xolair injection. [Posted 02/21/2007] FDA notified asthmatic patients and healthcare professionals of new reports of

serious and life-threatening allergic reactions (anaphylaxis) in patients after treatment with Xolair (omalizumab). Usually these reactions occur within two hours of receiving a Xolair subcutaneous injection. However, these new reports include patients who had delayed anaphylaxis—with onset two to 24 hours or even longer—after receiving Xolair treatment. Anaphylaxis may occur after any dose of Xolair (including the first dose), even if the patient had no allergic reaction to the first dose. Health care professionals who administer Xolair should be prepared to manage life-threatening anaphylaxis and should observe their Xolair-treated patients for at least two hours after Xolair is given. Patients under treatment with Xolair should be fully informed about the signs and symptoms of anaphylaxis, their chance of developing delayed anaphylaxis following Xolair treatment, and how to treat it when it occurs. FDA has requested Genentech add a boxed warning to the product label and

to revise the Xolair label and provide a MEDICATION GUIDE for patients to strengthen the existing warning for anaphylaxis. Tositumomab and Iodine I 131 (Bexxar) mouse monoclonal antibody, cancer therapy Warning: Hypersensitivity reactions, including anaphylaxis. http://www.fda.gov/cder/foi/label/2003/tosicor062703LB.pdf Efalizumab (Raptiva) humanized mouse monoclonal antibody, treatment of psoriasis Warning: Hemolytic anemia; serious infections has been updated to include rare postmarketing reports of necrotizing fasciitis, tuberculous pneumonia, bacterial sepsis with seeding of distant sites, severe pneumonia with neutropenia, and worsening of infection (e.g. cellulitis,pneumonia) despite antimicrobial treatment. http://www.fda.gov/medwatch/safety/2005/raptiva_deardoc_071205.pdf Cetuximab (Erbitux) humanized mouse monoclonal antibody, , cancer therapy Warning: Severe infusion reactions occurred with the administration of ERBITUX in approximately 3% of patients, rarely with fatal outcome (<1 in 1000). Severe infusion reactions are characterized by rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), urticaria, and hypotension. http://www.fda.gov/medwatch/safety/2005/Sep_PI/Erbitux_PI.pdf Bevacizumab (Avastin) humanized mouse monoclonal antibody, cancer therapy Warning: Posted 04/21/2007] Genentech and FDA notified healthcare professionals of important new safety information regarding tracheoesophageal (TE) fistula formation in a recent

clinical study in patients with limited-stage small cell lung cancer (SCLC). This multicenter, non-randomized, single-arm phase II clinical trial study combined chemotherapy and radiation plus Avastin. There have been two confirmed serious adverse events of TE fistula (one fatal) reported in the first 29 patients enrolled in this study. A third, fatal event (upper aerodigestive tract hemorrhage and death of unknown cause), was also reported, in which TE fistula was suspected but not confirmed. All three events occurred during the Avastin maintenance phase of the study in the context of persistent esophagitis. Additionally, six other cases of TE fistula have also been reported in other lung and esophageal cancer studies using Avastin and chemotherapy alone or with concurrent radiation treatment. Avastin is not approved for the treatment of SCLC. The current prescribing information includes a description of gastrointestinal tract fistula formation in patients with colorectal cancer and other types of cancer treated with Avastin Natalizumab (Tsabri) humanized mouse monoclonal antibody, treatment of multiple sclerosis (MS) Posted 02/27/2008] Biogen Idec, Elan and FDA notified healthcare professionals of reports of clinically significant liver injury, including markedly elevated serum hepatic enzymes and elevated total bilirubin, occurred as early as six days after the first dose of Tysabri. The combination of transaminase elevations and elevated bilirubin without evidence of obstruction is recognized as an important predictor of severe liver injury that may lead to death or the need for a liver transplant in some patients. Tysabri should be discontinued in patients with jaundice or other evidence of significant liver injury. Physicians should inform patients that Tysabri may cause liver injury. Suspended Marketing of Tysabri (natalizumab) 2005: FDA is issuing this public health advisory to inform patients and health care providers about the suspended marketing of Tysabri (natalizumab) due to two serious adverse events reported with its use. FDA has received a report from Biogen Idec, the manufacturer of Tysabri, of one confirmed, fatal case and one additional case of progressive multifocal leukoencephalopathy (PML) in patients receiving Tysabri for multiple sclerosis (MS). Both patients were enrolled in a long-term clinical trial and had been taking Tysabri for more than two years. http://www.fda.gov/cder/drug/advisory/natalizumab.htm Ranizumab (Lucentis) Warning : Posted 02/01/2007] Genentech informed healthcare professionals of preliminary safety information from a planned interim analysis in an ongoing study (SAILOR) which confirmed the higher incidence of stroke in the 0.5 mg dose group compared to the 0.3 mg dose group (1.2% versus 0.3%, respectively; P=0.02) of patients with neovascular (wet) age-related macular degeneration who received intravitreal Lucentis. The rates of stroke for both dose groups are lower than the rates seen in the controlled clinical trials and included in the approved labeling. The planned

frequency of dosing was not the same as that described in the approved labeling. This comparison was one of many made during this interim analysis. Regards Mangesh Bankar"Dr. Smita Mali" <smt_mali@...> wrote: Hello all, Monoclonal antibody therapy is a form of passive immunotherapy. The combination of a mouse B cell that can recognize a particular antigen and a long-lived mouse myeloma cell makes the hybridoma cell, a kind of perpetual antibody-making factory. Because the antibodies are all identical clones made from a single (mono)

hybridoma cell, they are called monoclonal antibodies. One problem with this is that the human immune system can see these antibodies as foreign and can mount a response against them. In the short term, this can sometimes cause allergic-type reactions. In the long term, it means that the antibodies may only be effective the first time they are given; after that, the body's immune system destroys them before they can be helpful. To tackle this problem replace some parts of these mouse antibody proteins with human parts. Depending on how much of the MAb is human, these are called chimeric or humanized antibodies. Some MAbs are now fully human, which means they are likely to be safer and may be more effective. Newer approach uses fragments of antibodies instead of whole ones, which may make them more effective. Two types of monoclonal antibodies are used in cancer treatments: Naked monoclonal antibodies are those without any drug or radioactive material attached to them. Conjugated monoclonal antibodies are those joined to a chemotherapy drug, radioactive particle, or a toxin (a substance that poisons cells). Naked Monoclonal Antibodies:

Naked MAbs are the most commonly used MAbs at this time. Some naked MAbs attach to cancer cells to act as a marker for the body's immune system to destroy them. Antibodies now in use in this group include: · Rituximab: To treat B cell non-Hodgkin lymphoma and (off label) ITP, MAB against the CD20 antigen, found on B cells. · Alemtuzumab: To treat B-CLL, MAB against the CD52 antigen, present on both B cells and T cells. Some naked MAbs attach to the specific antigens, which are functional parts of cancer cells or other cells that help cancer cells grow. Examples of FDA approved MAbs of this type include: Trastuzumab: antibody against the HER2/neu protein. This protein is present in large numbers on tumor cells in some cancers. When HER2/neu is activated, it helps these

cells grow. Trastuzumab stops these proteins from becoming active. It is used to treat breast cancers that have large amounts of this protein. Cetuximab: Cetuximab is an antibody against the EGFR protein, which is present in high amounts on some tumor cells and helps them grow and divide. Cetuximab blocks the activation of EGFR. It is used to treat some advanced colorectal cancers as well as some head and neck cancers. Panitumumab: This MAb also targets the EGFR antigen. It is used to treat some cases of advanced colorectal cancer. Bevacizumab: Bevacizumab targets the VEGF protein, which is normally made by tumor cells to attract new blood vessels to feed their growth. Bevacizumab attaches to VEGF, which blocks it from signaling for new blood vessels to form. This MAb is used along with chemotherapy to treat some colorectal, lung, and breast cancers, and is being studied for use against other cancers. Conjugated Monoclonal Antibodies: Conjugated MAbs are joined to drugs, toxins, or radioactive substances. The MAb acts as a homing device, circulating in the body until it finds the target antigen. It then delivers the toxic substance to

where it is needed most, which lessens damage to normal cells in other parts of the body. Conjugated MAbs are also sometimes referred to as "tagged", "labeled" or "loaded" antibodies. They can be divided into groups depending on what they are linked to. MAbs with radioactive particles attached are referred to as radiolabeled, and this type of therapy is known as radioimmunotherapy (RIT). · Ibritumomab tiuxetan: is used to treat B cell non-Hodgkin

lymphoma · Tositumomab: is used to treat certain types of non-Hodgkin lymphoma MAbs with chemotherapy drugs attached are often referred to as chemolabeled. MAbs attached to toxins are called immunotoxins. · Gemtuzumab ozogamicin: It contains a toxin called calicheamicin, attached to an antibody against the CD33 antigen treat some people with acute myelogenous leukemia (AML). Scientists are also studying toxins linked to hormone-like substances called growth factors. But because the growth factor/toxin drugs do not contain antibodies, they are not classified as immunotoxins. The only growth factor/toxin approved by the FDA thus far is denileukin diftitox (Ontak). It

consists of a growth factor (IL-2) + diphtheria toxin, used to treat a rare type of skin lymphoma (cutaneous T cell lymphoma). Regards, Dr Smita Mali, JRII, GMC, Nagpur.

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[Guest guest]

Dear All,

Its good to know that young PG students are researching thorugh the internet to find out so many safety issues that we in the West already know about in detail. Anyone scanning the FDA, MHRA, EMEA websites will be able to get an uptodate safety issue profiles of the drug. However, my problem is, how many PG students and medics in India do this researching and how many actually practice it in their day to day practice to report these ADE to the authoritities. Also, another big question is do the people woring in India;s Drug Regulatory Deoartment have this knowledge and if yes, then what have they done or are doing, and if not then why not? As already discussed several times before, India's Pharmacovigilance Status is so poor that it is a big shame even to talk about it and no one seems to do anything about it. This is very wrong and everyone in India should start asking questions to the DCGI and Ministry of Health, rather

than write here and forget.

Any questions to this effect will be most welcome. Vijay, please take the lead.

Regards

Pipasha

Re: Attn: Smita Therapeutic utility of Monoclonal antibodies

Dear Smita,

I was agog over such a reply from any young PG student. It is a reflection of your assiduous toil for detailed net search and I am certainly sure that it will be a godsend posting for all PG students to increase their knowledge about monoclonal antibodies. I am supplementing it with the warnings issued by US FDA regarding monoclonal antibodies.

This is a compilation of safety information on monoclonal antibody drugs already approved by the US FDA (Food and Drug Administration) , most of them posted on the FDA website. The URLs are included at the time of compilation. [From Jan 2006- Feb 2008]

[Copied from www.ibiblio. org and www.fda.gov]

Muromonab CD3(Orthoclone OKT 3) mouse monoclonal antibody, Transplant anti-rejection

Safety information: Anaphylactic or anaphylactoid reactions may occur following administration of any dose or course of ORTHOCLONE OKT3. In addition, serious, occasionally life-threatening or lethal, systemic, cardiovascular, and central nervous system reactions have been reported following administration of ORTHOCLONE OKT3. These have included: pulmonary edema, especially in patients with volume overload; shock, cardiovascular collapse, cardiac or respiratory arrest, seizures, coma, cerebral edema, cerebral herniation, blindness and paralysis. http://www.orthobio tech.com/ orthoclone. html

Abciximab (reopro) humanized mouse monoclonal antibody prevents blood clotting

Side effects: Acid or sour stomach; belching; burning, crawling, itching, numbness, prickling, “pins and needlesâ€, or tingling feelings; changes in vision; delusions; dementia; fear; heartburn; indigestion or stomach discomfort, upset or pain; mood or mental changes; nausea; nervousness; vomiting. http://www.drugs. com/cons/ ReoPro.html

Rituxan (Rituximab) humanized mouse monoclonal antibody, treatment of Non-Hodgkins lymphoma

Warning: Fatal Infusion Reactions: Deaths within 24 hours of RITUXAN infusion have been reported. These fatal reactions followed an infusion reaction complex which included hypoxia, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrilation orcardiogenic shock. Approximately 80% of fatal infusion reactions occurred in association with the first infusion. http://www.fda. gov/medwatch/ SAFETY/2005/ Jan_PI/Rituxan_ PI.pdf

Zenapax (daclizumab) humanized mouse monoclonal antibody, , transplant immune suppression

Warning: Severe, acute (onset within 24 hours) hypersensitivity reactions including anaphylaxis have been observed both on initial exposure to ZENAPAX and following re-exposure. These reactions may include hypotension, bronchospasms, wheezing, laryngeal edema, pulmonary edema, cyanosis, hypoxia, respiratory arrest, cardiac arrhythmia, cardiac arrest, peripheral edema, loss of consciousness, fever, rash, urticaria, diaphoresis, pruritus, and/or injection site reactions. http://www.fda. gov/medwatch/ SAFETY/2003/ zenapax.htm

Basiliximab( Simulect) humanized mouse monoclonal antibody, transplant ant-rejection

Warning: severe acute (onset within 24 hours) hypersensitivity reactions including anaphylaxis have been observed both on initial exposure to Simulect® and/or following re-exposure after several months. These reactions may include hypotension, tachycardia, cardiac failure, dyspnea, wheezing, bronchospasm, pulmonary edema, respiratory failure, urticaria, rash, pruritus, and/or sneezing. If a severe hypersensitivity reaction occurs, therapy with Simulect® should be permanently discontinued. Medications for the treatment of severe hypersensitivity reactions including anaphylaxis should be available for immediate use. Patients previously administered Simulect® should only be re-exposed to a subsequent course of therapy with extreme caution. http://www.fda. gov/medwatch/ safety/2000/ simule.htm

Palivizumab( Synagis) humanized mouse monoclonal antibody, anti-respiratory syncytial virus

Warning: Very rare cases of anaphylaxis (<1 case per 100,000 patients) have been reported following re-exposure to Synagis (palivizumab. Rare severe acute hypersensitivity reactions have also been reported on initial exposure or re-exposure to palivizumab. http://www.fda. gov/medwatch/ SAFETY/2002/ Synagis_PI. pdf

Infliximab (Remicade), humanized mouse monoclonal antibody, anti-arthritis

Warning; tuberculosis infection some fatal http://www.fda. gov/medwatch/ safety/2005/ Sep_PI/Remicade_ PI.pdf

Trastuzumab (Herceptin) humanized mouse monoclonal antibody, cancer therapy

Warning: CARDIOMYOPATHY: HERCEPTIN administration can result in the development of ventricular dysfunction and congestive heart failure. http://www.accessda ta.fda.gov/ scripts/cder/ onctools/ labels.cfm? GN=Trastuzumab

Gemtuzumab (Mylotarg) humanized mouse monoclonal antibody, cancer therapy

Warning: Mylotarg administration can result in severe hypersensitivity reactions (including anaphylaxis) , and other infusion-related reactions which may include severe pulmonary events. Infrequently, hypersensitivity reactions and pulmonary events have been fatal http://www.fda. gov/medwatch/ SAFETY/2004/ apr_PI/Mylotarg_ PI.pdf

Alemtuzumab (Campath-1H) humanized mouse monoclonal antibody, leukemia cancer treatment

Warning: Campath may lower the ability of the bone marrow to make blood cells. Some of these effects can be severe and lead to death. Three patients in a clinical study of the drug Campath for the treatment of Multiple Sclerosis (MS) developed severe idiopathic thrombocytopenic purpura (ITP). http://www.fda. gov/cder/ drug/InfoSheets/ patient/alemtuzu mabPIS.pdf

90 ibritumomab tiuxetan (Zevalin) Mouse monoclonal antibody, cancer therapy (Yttrium radio therapy associated)

Warning: Deaths have occurred within 24 hours of Rituximab infusion, an essential component of the ZEVALIN therapeutic regimen. These fatalities were associated with an infusion reaction symptom complex that included hypoxia, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, or cardiogenic shock. http://www.accessda ta.fda.gov/ scripts/cder/ onctools/ labels.cfm? GN=Ibritumomab% 20Tiuxetan

Adalimumab, Human monoclonal antibody, arthritis treatment

Warning: TUBERCULOSIS (FREQUENTLY DISSEMINATED OR EXTRAPULMONARY AT CLINICAL PRESENTATION) , INVASIVE FUNGAL INFECTIONS, AND OTHER OPPORTUNISTIC INFECTIONS, HAVE BEEN OBSERVED IN PATIENTS RECEIVING HUMIRA. SOME OF THESE INFECTIONS HAVE BEEN FATAL http://www.fda. gov/medwatch/ safety/2005/ Oct_PI/Humira_ PI.pdf

Omalizumab (Xolair) humanized mouse monoclonal antibody, treatment of allergic asthma

Warning: [uPDATE 07/02/2007] Genetech and FDA informed healthcare professionals and asthmatic patients that the prescribing information for Xolair was revised to include a new BOXED WARNING, and updated WARNINGS, PRECAUTIONS, and ADVERSE REACTIONS sections that address the risk of anaphylaxis (the onset of action can be delayed for 24 hours or more) when taking this medication. In addition, a new MEDICATION GUIDE was developed and will be provided to patients when a prescription for Xolair is filled or refilled at the pharmacy. Due to the risk of anaphylaxis, Xolair should only be administered to patients in a healthcare setting under direct medical supervision. Patients should be observed for an appropriate period of time following each Xolair injection.

[Posted 02/21/2007] FDA notified asthmatic patients and healthcare professionals of new reports of serious and life-threatening allergic reactions (anaphylaxis) in patients after treatment with Xolair (omalizumab) . Usually these reactions occur within two hours of receiving a Xolair subcutaneous injection. However, these new reports include patients who had delayed anaphylaxis—with onset two to 24 hours or even longer—after receiving Xolair treatment. Anaphylaxis may occur after any dose of Xolair (including the first dose), even if the patient had no allergic reaction to the first dose. Health care professionals who administer Xolair should be prepared to manage life-threatening anaphylaxis and should observe their Xolair-treated patients for at least two hours after Xolair is given. Patients under treatment with Xolair should be fully informed about the signs

and symptoms of anaphylaxis, their chance of developing delayed anaphylaxis following Xolair treatment, and how to treat it when it occurs. FDA has requested Genentech add a boxed warning to the product label and to revise the Xolair label and provide a MEDICATION GUIDE for patients to strengthen the existing warning for anaphylaxis.

Tositumomab and Iodine I 131 (Bexxar) mouse monoclonal antibody, cancer therapy

Warning: Hypersensitivity reactions, including anaphylaxis. http://www.fda. gov/cder/ foi/label/ 2003/tosicor0627 03LB.pdf

Efalizumab (Raptiva) humanized mouse monoclonal antibody, treatment of psoriasis

Warning: Hemolytic anemia; serious infections has been updated to include rare postmarketing reports of necrotizing fasciitis, tuberculous pneumonia, bacterial sepsis with seeding of distant sites, severe pneumonia with neutropenia, and worsening of infection (e.g. cellulitis,pneumoni a) despite antimicrobial treatment. http://www.fda. gov/medwatch/ safety/2005/ raptiva_deardoc_ 071205.pdf

Cetuximab (Erbitux) humanized mouse monoclonal antibody, , cancer therapy

Warning: Severe infusion reactions occurred with the administration of ERBITUX in approximately 3% of patients, rarely with fatal outcome (<1 in 1000). Severe infusion reactions are characterized by rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), urticaria, and hypotension. http://www.fda. gov/medwatch/ safety/2005/ Sep_PI/Erbitux_ PI.pdf

Bevacizumab (Avastin) humanized mouse monoclonal antibody, cancer therapy

Warning:

Posted 04/21/2007] Genentech and FDA notified healthcare professionals of important new safety information regarding tracheoesophageal (TE) fistula formation in a recent clinical study in patients with limited-stage small cell lung cancer (SCLC).. This multicenter, non-randomized, single-arm phase II clinical trial study combined chemotherapy and radiation plus Avastin. There have been two confirmed serious adverse events of TE fistula (one fatal) reported in the first 29 patients enrolled in this study. A third, fatal event (upper aerodigestive tract hemorrhage and death of unknown cause), was also reported, in which TE fistula was suspected but not confirmed. All three events occurred during the Avastin maintenance phase of the study in the context of persistent esophagitis. Additionally, six other cases of TE fistula have also been reported in other lung and

esophageal cancer studies using Avastin and chemotherapy alone or with concurrent radiation treatment.

Avastin is not approved for the treatment of SCLC. The current prescribing information includes a description of gastrointestinal tract fistula formation in patients with colorectal cancer and other types of cancer treated with Avastin

Natalizumab (Tsabri) humanized mouse monoclonal antibody, treatment of multiple sclerosis (MS)

Posted 02/27/2008] Biogen Idec, Elan and FDA notified healthcare professionals of reports of clinically significant liver injury, including markedly elevated serum hepatic enzymes and elevated total bilirubin, occurred as early as six days after the first dose of Tysabri. The combination of transaminase elevations and elevated bilirubin without evidence of obstruction is recognized as an important predictor of severe liver injury that may lead to death or the need for a liver transplant in some patients. Tysabri should be discontinued in patients with jaundice or other evidence of significant liver injury. Physicians should inform patients that Tysabri may cause liver injury.

Suspended Marketing of Tysabri (natalizumab) 2005: FDA is issuing this public health advisory to inform patients and health care providers about the suspended marketing of Tysabri (natalizumab) due to two serious adverse events reported with its use. FDA has received a report from Biogen Idec, the manufacturer of Tysabri, of one confirmed, fatal case and one additional case of progressive multifocal leukoencephalopathy (PML) in patients receiving Tysabri for multiple sclerosis (MS). Both patients were enrolled in a long-term clinical trial and had been taking Tysabri for more than two years. http://www.fda.. gov/cder/ drug/advisory/ natalizumab. htm

Ranizumab (Lucentis)

Warning : Posted 02/01/2007] Genentech informed healthcare professionals of preliminary safety information from a planned interim analysis in an ongoing study (SAILOR) which confirmed the higher incidence of stroke in the 0.5 mg dose group compared to the 0.3 mg dose group (1.2% versus 0.3%, respectively; P=0..02) of patients with neovascular (wet) age-related macular degeneration who received intravitreal Lucentis. The rates of stroke for both dose groups are lower than the rates seen in the controlled clinical trials and included in the approved labeling. The planned frequency of dosing was not the same as that described in the approved labeling. This comparison was one of many made during this interim analysis.

Regards

Mangesh Bankar"Dr. Smita Mali" <smt_mali (DOT) co.in> wrote:

Hello all,

Monoclonal antibody therapy is a form of passive immunotherapy. The combination of a mouse B cell that can recognize a particular antigen and a long-lived mouse myeloma cell makes the hybridoma cell, a kind of perpetual antibody-making factory. Because the antibodies are all identical clones made from a single (mono) hybridoma cell, they are called monoclonal antibodies.

One problem with this is that the human immune system can see these antibodies as foreign and can mount a response against them. In the short term, this can sometimes cause allergic-type reactions. In the long term, it means that the antibodies may only be effective the first time they are given; after that, the body's immune system destroys them before they can be helpful. To tackle this problem replace some parts of these mouse antibody proteins with human parts. Depending on how much of the MAb is human, these are called chimeric or humanized antibodies. Some MAbs are now fully human, which means they are likely to be safer and may be more effective. Newer approach uses fragments of antibodies instead of whole ones, which may make them more effective.

Two types of monoclonal antibodies are used in cancer treatments:

Naked monoclonal antibodies are those without any drug or radioactive material attached to them.

Conjugated monoclonal antibodies are those joined to a chemotherapy drug, radioactive particle, or a toxin (a substance that poisons cells).

Naked Monoclonal Antibodies:

Naked MAbs are the most commonly used MAbs at this time.

Some naked MAbs attach to cancer cells to act as a marker for the body's immune system to destroy them. Antibodies now in use in this group include:

· Rituximab: To treat B cell non-Hodgkin lymphoma and (off label) ITP, MAB against the CD20 antigen, found on B cells.

· Alemtuzumab: To treat B-CLL, MAB against the CD52 antigen, present on both B cells and T cells.

Some naked MAbs attach to the specific antigens, which are functional parts of cancer cells or other cells that help cancer cells grow. Examples of FDA approved MAbs of this type include:

Trastuzumab: antibody against the HER2/neu protein. This protein is present in large numbers on tumor cells in some cancers. When HER2/neu is activated, it helps these cells grow. Trastuzumab stops these proteins from becoming active. It is used to treat breast cancers that have large amounts of this protein.

Cetuximab: Cetuximab is an antibody against the EGFR protein, which is present in high amounts on some tumor cells and helps them grow and divide. Cetuximab blocks the activation of EGFR. It is used to treat some advanced colorectal cancers as well as some head and neck cancers.

Panitumumab: This MAb also targets the EGFR antigen. It is used to treat some cases of advanced colorectal cancer.

Bevacizumab: Bevacizumab targets the VEGF protein, which is normally made by tumor cells to attract new blood vessels to feed their growth. Bevacizumab attaches to VEGF, which blocks it from signaling for new blood vessels to form. This MAb is used along with chemotherapy to treat some colorectal, lung, and breast cancers, and is being studied for use against other cancers.

Conjugated Monoclonal Antibodies:

Conjugated MAbs are joined to drugs, toxins, or radioactive substances. The MAb acts as a homing device, circulating in the body until it finds the target antigen. It then delivers the toxic substance to where it is needed most, which lessens damage to normal cells in other parts of the body.

Conjugated MAbs are also sometimes referred to as "tagged", "labeled" or "loaded" antibodies. They can be divided into groups depending on what they are linked to.

MAbs with radioactive particles attached are referred to as radiolabeled, and this type of therapy is known as radioimmunotherapy (RIT).

· Ibritumomab tiuxetan: is used to treat B cell non-Hodgkin lymphoma

· Tositumomab: is used to treat certain types of non-Hodgkin lymphoma

MAbs with chemotherapy drugs attached are often referred to as chemolabeled.

MAbs attached to toxins are called immunotoxins.

· Gemtuzumab ozogamicin: It contains a toxin called calicheamicin, attached to an antibody against the CD33 antigen treat some people with acute myelogenous leukemia (AML).

Scientists are also studying toxins linked to hormone-like substances called growth factors. But because the growth factor/toxin drugs do not contain antibodies, they are not classified as immunotoxins.

The only growth factor/toxin approved by the FDA thus far is denileukin diftitox (Ontak). It consists of a growth factor (IL-2) + diphtheria toxin, used to treat a rare type of skin lymphoma (cutaneous T cell lymphoma).

Regards,

Dr Smita Mali ,

JRII, GMC,

Nagpur.

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