Bexxar7

Integrated Safety of BEXXAR^®

Acute safety events were analyzed from the data from 230 patients in the 5 clinical studies
Delayed and serious adverse events were analyzed from the data from the entire 230 patients in the 5 clinical studies and 765 patients in the Expanded Access Program (EAP)
Safety was evaluated in a total of 995 patients

Infusional Toxicity
(N=230)

29% of patients reported fever, rigors/chills, or sweating within 14 days following the dosimetric dose
Adjustment of the rate of infusion to control adverse reactions, occurred in 7% of patients and included temporary interruption of the infusion and reducing the rate by 50%
The infusion was permanently discontinued in 2 patients
Pretreatment with acetaminophen and antihistamine
Benefit of premedication in preventing infusion-related toxicity has not been evaluated

Hypersensitivity Reactions
(N=230)

In the post-marketing reports severe hypersensitivity reactions, including fatal anaphylaxis have been reported
14 patients (6%) experienced one or more the following adverse events: allergic reaction, face edema, injection site hypersensitivity, anaphylactic reaction, laryngismus, and serum sickness
Medications for the treatment of severe hypersensitivity should be available for immediate use in the event of allergic reactions (e.g., epinephrine, antihistamines, corticosteroids)
The BEXXAR^® therapeutic regimen is contraindicated in patients with known hypersensitivity to murine proteins or any other component of the BEXXAR^® therapeutic regimen
Patients who have received murine proteins should be screened for HAMA prior to receiving BEXXAR^®

Hematologic Toxicity
(N=230)

The most common hematologic adverse events were severe or life-threatening Grade 3 and 4 cytopenias, which occurred in 71% of patients
Monitor blood counts weekly for 10-12 weeks following treatment

More frequent monitoring may be required for patients with moderate or more severe cytopenias until resolution

	Platelets	ANC	Hemoglobin
Grade 3/4*	53%	63%	29%
Median Duration Grade 3/4**	32 days	31 days	23 days
Grade 4***	21%	25%	5%
Median nadir	43,000/mm³	690 cells/mm³	10gm/dL
Median time to nadir	34 days	43 days	47 days
Grade 3/4 without recovery to Grade 2	7%	7%	5%
* Grade 3/4 toxicity was assumed if patient was missing 2 or more weeks of hematology data between Weeks 5 and 9. Duration of Grade 3/4 of 1000+ days (censored) was assumed for those patients with undocumented Grade 3/4 and no hematologic data on or after Week 9 Grade 4 toxicity was assumed if patient had documented Grade 3 toxicity and was missing 2 or more weeks of hematology data between Week 5 and Week 9. Data on File: GlaxoSmithKline*

Non-Hematologic Adverse Events
(N=230)

Non-hematologic AEs were predominantly Grade 1 or 2
The most common non-hematologic AEs (all grades):
- Asthenia (46%)
- Fever (37%)
- Nausea (36%)
- Increased Cough (21%)
- Infection (21%)
The most common Grade 3/4 non-hematologic AEs:
- Abdominal pain (3%)
- Nausea (3%)
- Dyspnea (3%)

Delayed Adverse Events:
Myelodysplasia/Acute Leukemia

Study	N	Investigator- Reported New Cases (Crude Incidence)	Cumulative Incidence	Median Follow-Up Months	Median Time to Development of MDS/Acute Leukemia (months)
Clinical Studies	230	24(10%)	4.7% at 2 years 15% at 5 years	39	34
Expanded Access Program	765	20(3%)	1.6% at 2 years 6% at 5 years	27	31
Total	995	44%		29	31
Relative risk vs. background rate cannot be determined due to absence of controlled studies. BEXXAR® PI.

Other Delayed Adverse Events (N=995)
Secondary Malignancies

Additional non-hematological malignancies were reported in 54 of the 995 patients
There were 65 reports of secondary malignancies in these 54 patients, and the most common included:
- Non-melanomatous skin cancers (26)
- Colorectal cancer (7)
- Head and neck cancer (6)
- Breast cancer (5)
- Lung cancer (4)
- Bladder cancer (4)
- Melanoma (3)
- Gastric cancer (2)
Some of these events included recurrence of an earlier diagnosis of cancer
The relative risk of developing secondary cancers in patients receiving the BEXXAR^®therapeutic regimen over the background rate in this population cannot be determined due to the absence of controlled studies

Human Anti-Mouse Antibody (HAMA)

Study Population	*Evaluable Patients (n)**	Median Follow-up	Incidence of HAMA Positivity	Median Time to Positivity	6,12,18 month cumulative incidence
5 Clinical Trials n=230	219	6 months	23(11%)	6 months	6%,17% and 21%
EAP N=765	569	7 months	57(10%)	5 months	7%,12% and 13%
*Evaluable Patients= patients who are seronegative prior to BEXXAR and had post-BEXXAR HAMA levels available
Potential Implications of HAMA Presence of HAMA may affect the results and toxicity of therapeutic agents produced by murine antibody technology *HAMA positively may affect the results of in vitro* and in vivo diagnostic tests , as well as murine-based therapies. Patients who are HAMA positive may be at increased risk for serious allergic reactions if they are treated with murine antibodies Patients who have received murine proteins should be screened for HAMA**

Hypothyroidism

Study Population	*Evaluable Patients (n)**	Median Follow-up	Incidence of Hypothyroidism**	Median Time to Hypothyroidism**	2 and 5 year cumulative incidence
5 Clinical Trials n=230	137	46 months	18%	16 months	11%,19%
EAP N=765	455	33 months	13%	15 months	9%,17%
Evaluable Patients= patients without increase in TSH prior to BEXXAR, not on thyroid medications, and had at least one post-BEXXAR TSH level *Hypothyroidism was based on elevated TSH or initiation of thyroid replacement medications
Potential Implications of Hypothyroidism TSH levels should be measured baseline and monitored annually All patients must receive thyroid blocking agents Patients unable to tolerate blocking agents should not receive BEXXAR^®

Safety Summary

Serious hypersensitivity reactions, including one with fatal outcome, have been reported in the post-marketing setting
Hypersensitivity, including anaphylaxis, occurred in 6% of patients during clinical trials
Adjustments in the rate of infusion due to toxicity occurred in 7% of patients, including discontinuation in 2 patients

Hematologic AEs - Dose Limiting (N=230)
- Primarily Grade 3 or 4 thrombocytopenia (53%) and Grade 3 or 4 neutropenia (63%), with a median duration of 1 month
- Supportive care was administered in 27% of patients
- Incidence of serious infections: 9%
- Non-hematologic AEs predominantly Grade 1 and 2
- Severe nausea and vomiting, alopecia and mucositis: <5%
  - Delayed AEs (N=995)
  - MDS/AML: 4% of the patients
  - Additional secondary malignancies: 5.4% of the patients (65 cases)
  - HAMA: 10% in 788 patients
  - Hypothyroidism: 14% in 592 patients

Assessment of Patients for Receiving the
BEXXAR^® Therapeutic Regimen

No known hypersensitivity to any component of BEXXAR

Not pregnant and not breast-feeding

< 25% intratrabecular marrow space involvement

Adequate renal function

Platelets ³ 100,000/mm³

Neutrophils ³ 1500 cells/mm³

Adequate bone marrow reserve