Appendix 5: Summary of Fatal Outcomes Associated with Clozaril Use and the Development of Agranulocytosis
Events Under Initial Monitoring System

	MCN ¹	Age (years) / Sex	Duration of Therapy (weeks)	dose (mg/day)	use of CSF ²	Days after Clozaril discontiuation event occured	Cause
1	90-1069	76/F	11	400	unknown	54	Autopsy confirmed the cause of death to be acute peritonitis, respiratory failure, and renal failure due to septic shock.
2	90-1250	45/M	12	400	unknown	3	Shortly after agranutocytosis occurred, pneumonia and sepsis developed and then patient died 3 days later. Tegretol and Klonopin use were also considered as a possible contributory factor.
3	91-2835	72/F	9	300	yes	6	WBC dropped from 9000 to 400 with no granulocytes in 12 days, then patient developed bronchopneumonia and pseudomonal sepsis, and then she died 2 days later despite treatment with antibiotics.
4	91-3697	49/M	10	800-900	unknown	6	Clozaril was d/c'd when WBC was 3000. Five days later WBC was 1000, then patient died the next day; per autopsy, death was due to E. coll sepsis secondary to agranulocytosis.
5	91-3773	59/F	4	300	unknown	9	Clozarill was d/c'd when WBC fell to 500 with fever, eight days later WBC was up to 4700, but then patient died from "massive sepsis" despite treatment in ICU and antibiotics.
6	92-0785	40/M	5	500	unknown	5	WBC fell from 5600 to 500 with no granulocytes detected and then patient died four days later despite antiblotics / isolation; death was due to aspiration pneumonia and sepsis per autopsy.
7	93-3053	64/M	4	300	yes	54	Low WBCs and neutrophils persisted for two months. He was reported to have died due to agranulocytosls. A bone marrow aspirate revealed a myelold maturation arrest.
8	93-3616	70/F	6	37.5	unknown	12	The last WBC on Clozaril was 11 ,000 and then patient switched to Stelazine. Nine days later, WBC was 500. Patient was admitted and in three days had died from sepsis.
9	93-3792	38/M	8	600	yes	20	Patient was admitted after WBC fell from 8100 to 2000. WBC continued to fall. He died from sepsis despite treatment. A side effect of amphotericin B may have contributed.
10	93-4619	41/M	16 to 26	600	yes	30	Patient was admitted with pneumonia and no neutrophils. WBC eventually responded and Increased to 34, 600. Despite treatment, patient died from septic shock 4 days later.
11	94-0453	62/M	3	400	unknown	9	WBC was 700 after 3 weeks of Clozaril. The patient was admitted and died 9 days later. He had a history of COPD, CHF and NIDDM.
12	95-0713	52/F	4	200	yes	33	Developed leukocytosis of 18,000 and then a week later developed agranulocytosis. WBC increased to 34,000 with treatment, but patient died a week later due to cryptococcal pneumonia.
13	95-1359	39/M	9	600	yes	12	WBC fell from 7100 to 1700 in ten days and then to 300 with no granulocytes. Despite treatment, patient died possibly from complications of pneumonia.
14	95-1503	58/M	4	500	yes	18	WBC fell from 3500 to 1500 in three days at which point Clozaril was discontinued. Then WBC dropped to 400 despite neupogen treatment. Patient died following development of pneumonia, sepsis, and renal failure.
15	95-2494	55/M	9	250	unknown	9	Patient was admitted when his WBC was noted to be 400 after 9 weeks of Clozaril. He died from pneumonia.
16	96-2302	52/F	unknown	375	unknown	14	Patient was admitted when her WBC was noted to be 500. There was no improvement after 2 weeks and she died of septic shock secondary to agranulocylosls.
17	97-0061	66/M	9 to 13	200	yes	8	WBC fell from 7300 to 200 in 4 days and the patient was admitted with pneumonia. There was no improvement with neupogen and he died within a week from pneumonia.
18	91-3775 #	60/M	8	500	no	33	Patient admitted with a WBC of 2000 and treated for an Infection. After treatment, WBC Increased to >25K. Subsequently he had a pulmonary arrest, then died 9 days later.
19	96-0745 ##	53/F	32	400	yes	27	Patient admitted with a WBC of 1500, infection, gallstones, and jaundice. Clozaril was d/c'd. WBC decreased to 200 and then responded to treatment. Later on she devefoped pneumonia with recurrence of agranulocytosis and died.
20	97-0764	54/M	4	unknown	yes	16	Hospitalized with agranulocytosis. Neupogen was started after discovery of WBC of 1100 and ANC of 18%. Within 17 days WBC went back up to 6500. Patient, who had Huntington’s Chorea, died of cardiac arrest on the day he was supposed to be discharged from the hospital.

	Events Under Current Monitoring System

	MCN ¹	Age (years) / Sex	Duration of Therapy (weeks)	dose (mg/day)	use of CSF ²	Days after Clozaril discontiuation event occured	Cause

21	98-3018	35/F	5 to 300	300	yes	6	Treatment was intermitent for extended periods of time between 1993-1998 with WBC levels within normal limits and never below 4100 On 10/15/98 her WBC was 4300 on and dropped to 3100 on 10/28/98 and 1200 on 11/12/98 when Clozaril was discontinued. At the time agranulocytosis developed she was also on Seroquel.
22	99-0993	70/M	8	250	Yes	20	Hospitalized with agranulocytosis – WBC 600 on 5/13/99. Clozail stopped, Neupogen started. Bone marrow aspirate showed no WBC precursors. Patient died of sepsis.



	¹ MCN = Manufacturers Control Number; first part of number Indicates year that case was reported.
	² CSF = Colony Stimulating Factor
	^#The cause of death for these two patients may actually have been due to other complicating factors othe
	^## This patient's initial agranulocytosis occurred after 8 months of treatment with Clozaril.