Analysis of Spontaneous Adverse Event Reports

Page 19
3. Analysis of Spontaneous Adverse Event Reports

Potentially Suggestive of Glucose Dysregulation in
Lilly Clintrace Database
Using the methods described in Section 2.1, a total of 945 adverse event reports were
identified in the comprehensive review of spontaneous adverse event reports in the Lilly
Clintrace database. Figure 3.1 shows the report flow algorithm by which these case
reports were evaluated. As shown in this figure, of these 945 reports:
*
716 reports did not meet criteria as severe cases of glucose

dysregulation, and were therefore not included in this review
38 reports did not meet other criteria for inclusion in this review ie,
the patient was not receiving olanzapine, peak glucose <126 mg/dL, or
no glucose-related MedDRA Preferred Term was contained in adverse
event report; brief case summaries are provided for these 38 reports in
Section 3.1
48 were cases of death in which glucose dysregulation was reported

and the patient was on olanzapine at event onset; cases were assessed
for potential etiology and contribution of olanzapine to glucose
dysregulation; brief case summaries appear in Section 3.2.1, and full
case narratives in Appendix C
47 were cases of nonfatal coma, or nonfatal coma and acidosis, in

which glucose dysregulation was reported and the patient was on
olanzapine at event onset; cases were assessed for potential etiology
and contribution of olanzapine to glucose dysregulation; brief case
summaries appear in Section 3.2.2, and full case narratives in
Appendix C
96 were cases of acidosis non-coma, nonfatal in which glucose

dysregulation was reported and the patient was on olanzapine at event
onset; cases were assessed for potential etiology and contribution of
olanzapine to glucose dysregulation; brief summaries appear in
Section 3.2.3, and full case narratives in Appendix C
ZY 4076 362
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Eli Lilly Zyprexa Products Liability Litigation

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Zyprexa MDL Plaintiffs' Exhibit No.00379
Glucose 4 Update
26 March 2003
Confidential and Subject to Protective Order
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Summary of Report Categorization and Clinical Assessment of Etiologic Classification of Glucose Dysregulation
Spontaneous Adverse Event Reports through 31 Mar 02
Does report ha dkfinttiveividne of glucose

dysregulation i.e., definitive MedDRA term,
glucose peak > 126 mg/dl, and/or Clintrace text
ìder,tifiifier?
Yes
.,
cases with verified hyperglycemia I diabetes

mellitus definitive MedDRA Preferred tern, or
spportive data in Clintrace report
LWas
there rePort of de:t coma and/J
No
Potentially severe cases with report of death, coma and/or acidosis
Clinical Assessment of I
Classification of Glucose DysregulationL
Indeterminable IN
15
Other Apparent Etiology OE
14
21
14
Possible Other Etiology POE
16
16
30
Other Etiology & Olanzapine Possible

OE+OP
29
6
16
Possible Other Etiology & Olanzapine

Possible POEOP
0
47
Olanzapine Possible OP
No Other Apparent Etiology NOAE
48
Figure 3.1.
20
Mar 2003
96
Summary of report categorization and clinical assessment of etiologic contributors.

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Page 21
3.1. Adverse Event Reports Not Meeting Inclusion Criteria
Of the 945 adverse event reports evaluated for this review, 716 reports were identified as
nonsevere ie, not involving death, coma, andlor acidosis, and thus did not meet criteria
for inclusion in this review of severe adverse events. Additional information about the
716 cases that were outside the scope of this review is available upon request.
Of the 945 adverse event reports evaluated for this review, another 38 reports failed to
meet the criteria for a glucose dysregulation adverse event for at least one of the
following reasons:
*
The patient was found not to be receiving olanzapine at the onset of

the reported adverse event;
The patient was reported to have a peak glucose <126 mg/dL;
The report did not have a definitive MedDRA Preferred Term

identifier listed in the adverse event report or in the report narrative
from the Lilly Clintrace system, and did not contain a reference to
laboratory values for glucose dysregulation.
Of these 38 adverse event reports, 22 reports were nonsevere not involving death, coma,
andlor acidosis. Table 3.1 summarizes these 22 reports designated as Category 0-a.
Additional information about these 22 nonsevere reports is available upon request.
The remaining 16 of these 38 reports were severe adverse events that involved death,
coma, and/or acidosis, but did not meet inclusion criteria for this review ie, the report
lacked definitive MedDRA Preferred Term potentially suggestive of glucose
dysregulation, and any data suggesting hyperglycemia or diabetes mellitus; and/or the
patient was not on olanzapine at the onset of the adverse event. These 16 reports
designated as Category 0-b are summarized in Table 3.2; Appendix C provides full
narratives of these 16 reports.
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Table 3.1.
E
I
NA
Case ID
EWC000606915
NA
NA
Category 0-a: Not a Case Nonsevere Adverse Event Report That Did Not Meet Inclusion Criteria for
Glucose Dysregulation n=22
-
Death
Reported as
Glucose
Metabolism
Related?
MedDRA Preferred Terms
Concomitant Drugs
Temporally Associated
with Glucose
Dysregulation, Acidosis,
Pancreatitis and/or
Weight Gain
Reported Pre.
Existing
Glucose
Dysregulation
Gestational diabetes
NA
EWCOI 0527027
Blood glucose increased,

Extrapyramidal disorder NEC
NA
Risperidone 3,8,
Fluoxetine 2,3,5,7,8,9
EWC020230150
Hyperglycaemia NOS
NA
Clorazepate dipotassium
2,5,8,9,
Lithium 2,8,9,
Lormetazepam 8,9,
Mianserin 2,8,9,
Venlafaxine 2,5,7,8,9
NA
GB9701285 IA

Hypertension NOS
NA
Droperidol 2,9,
Lorazepam 8,9
NA
GBS99I 104697
Diabetes mellitus NOS,

Weight increased
NA
Acamprosate,
Buspirone 8,9,
Ethinylestradiol/
levonorgestrel 2,5,8,9,
Nitrazepam 8,9,
Quetiapine 2,7,8,
Sertraline 2,5,7,8,9,
Zopiclone 9
Comments
Peak glucose unknown. Weight not reported.

Gestational diabetes mellitus diagnosed after being off
olanzapine approximately 5 months. Diabetes
successfully controlled with dietary measures.
Resolved - off olanzapine -5 months at onset. Pre
existing glucose regulation status unknown.
Peak glucose 115 mg/dl F; baseline not reported.
Resolved on olanzapine, fluoxetine and risperidone;
discontinued due to EPS. Pre-existing glucose
regulation status unknown.
Peak glucose Ill mg/dl F on 4 day of olanzapine
therapy. Pre-existing hypercholesterolemia,
hypertriglyceridemia cholesterol 498 mg/dl,
triglycerides 1242 mg/dl, and possible obesity with
weight 95 kg pre-olanzapine. Smoked 2 ppd of
cigarettes. Pre-existing glucose regulation status
unknown.
Peak glucose 198 mg/dl prior to start of olanzapine.
Hypertension and hyperglycemia preceded start of
olanzapine, diagnosed by treating physician after
olanzapine begun. Outcome unknown on olanzapine.
Peak glucose unknown. Weight gain began with onset
of diabetes mellitus which occurred 6.5 m after
olanzapine discontinuation. History of hypertension.
Pre-existing glucose regulation status unknown.
Outcome of event unknown off olanzapine.
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Table 3.1.
NA
Case ID
GBS010208276
Glucose 4 Update
26 March 2003
Glucose Dysregulation n=22 continued
-

Death
Reported as
Glucose
Metabolism
Related?
NA
Glycosylated haemoglobin increased
Concomitant Drugs
with Glucose
Pancreatitis and/or
Weight Gain
Rispendone 3,8,
Reported Pre
Existing
Glucose
Dysregulation
U
NA
US97083850A
Glycosuria present,
Haematuria
NA
NA
US97094765A
Hyperglycaemia NOS
NA
Valproate 1,7,8,9,
AN
US98022098A

Polydipsia,
Polyuria
NA
Thiothixenc 2,9,
Valproate 1,7,8,9,
Paroxetine 2,5,6,7,8,9
Comments
Peak glucose unknown. Elevated blood glucose and
HbAlc occurred -3.5 m after olanzapine was

discontinued; on nsperidone -3.5 months at onset. Has
family history of diabetes mellitus. Status of pre
existing glucose regulation unknown. Event not
resolved off olanzapine.
Patient with history of VonHippcl-Lindau disease,
resected renal cortex tumors and partial nephrectomy.
Peak glucose 116 mg/dl with 2+ glycosuria and
hematuria approximately 6 weeks after starting
olanzapine. Previous urinalysis for glucose and blood
negative 5 and 8 months before event. Pre-existing
glucose regulation status is unknown. Patient was not
known to have diabetes mellitus at time of event.
Weight 56.0 kg. Outcome is unknown, off olanzapine.
Peak glucose reported 120 mg/dl at time of event.
Glucose 134 mg/dl 2.5 months before olanzapine
started. Unknown if patient had diabetes mellitusat
time of event. HbAlc not reported. Pre-existing
glucose dysrcgulation reported as hyperglycemia.
Weight and BMI not reported. Event resolved on
olanzapine.
Peak glucose 800 mg/dl after off olanzapine 14 days;
polydipsia and polyuria onset at unreported time. It
was unknown if patient had pre-existing glucose
dysregulation. Weight and HMt not reported. Patient
hospitalized at 2 weeks following olanzapine cessation
treated with insulin for 3 weeks. Outcome is improved
off olanzapine and controlled with diet.
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Table 3.1.
-
Death
Reported as
Glucose
Metabolism
Related?
NA
Concomitant Drugs
with Glucose
Pancreatitis and/or
Weight Gain
Reported Pre
Existing
Glucose
Dysregulation
Y
10
NA
Case ID
US980707664

Aggression,
Hyperglycaemia NOS,
Weight increased
11
NA
US981 112911

Lactation disorder NOS,
Weight increased
NA
Benztropine 8,
Chlorpromazine 2,9,
Fluphenazine 2,9,
Lorazepam 8,9,
Valproate 1,7,8,9
12
NA
US000949426

Weight increased
NA
NA
USOOI 152687
Blood pressure increased,

Fluid retention,
Glucose tolerance impaired,
Weight increased
NA
Benztropine 8,
Carbamazepine 2,5,7,
Clonazepam 8,9,
Glibenclamide,
Magnesium oxide,
Multivitamin,
Phenytoin2,4,8
Amlodipine 9,
Desipramine 2,8,9,
Haloperidol 2,9,
Haloperidol decanoate 2,
Lithium 2,8,9
13
Comments
Peak glucose 400 mg/dl at 11 days after olanzapine
stopped because psychiatrist thought she did not need
it; became more aggressive after olanzapine stopped.
Pre-existing glucose dysregulation reported with
glucose levels 134 to 149 mg/dl approximately 3
months before peak glucose measured. Weight and
height were not reported. It is unknown if the patient
had diabetes at the time of event. Eleven days after
olanzapine was discontinued had a blood glucose level
400 mg/dl. Insulin therapy was started. Patient had
weight gain at unspeci lied time. Outcome of event is
unknown off olanzapine.
Peak random glucose was 202 rng/dl after being off
olanzapine for approximately 3 months. Weight gain
and lactation disorder began during olanzapine therapy;
BMJ 35 kg/rn2. Glycosylated hemoglobin level was
8.0% on unspecified date. Pre-existing glucose
regulation status unknown, although glipizide was
listed as a concomitant medication start date not
reported. Outcome was unknown; patient remained
off olanz.apine.
Peak glucose 149 mg/dl on olanzapine. Pre-existing
Type II diabetes mellitus with glucose 188 mg/dl and
HbAlc 6.7% one day prior to beginning olanzapine.
Glucose levels decreased after olanzapine started.
Outcome was improved on olanzapine; glucose
increase preceded oJanzapine initiation.
Peak glucose unknown. "Borderline" diabetes
diagnosed 17m after olanzapine cessation. History of
hypertension, possible obesity 104 kg. Outcome
unknown off olanzapine.
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Table 3.1.
-
Concomitant Drugs
Death
.
Reported as
Glucose
with Glucose
Metabolism
Pancreatitis and/or
Gain
Reported Pre
Existing
Glucose
Body mass index increased,

Hormone level NOS abnormal,
Hyperlipidaemia N OS,
Flypoglycaemia NOS
Body mass index increased,
1-Iyperlipidaemia NOS,
Hypoglycaemia NOS
NA
Lysregulation
U
NA
USO 10362476

Feeling jittery,
Liver function tests NOS abnormal,
Porphyrinuria
NA
Diazepam 8,9
NA
USOI 0565404
NA
Captopril /
hydrochiorothiazide
2,5,7,8,
Norlriptyline 8,9
NA
US010769408
Alanine aminotransferase increased,

Aspartate aminotransferase increased,
Blood lactate dehydrogenase increased,
Gamma-glutamyltransferase increased,
Serum fenitin increased,
Weight_increased
Confusion,
Peripheral swelling
NA
Divalproex 1,7,8,9,
Metformin 1,
Risperidone 3,8,
Humulin insulin
Case ID
14
NA
US001254605
15
NA
LJSOO 1254607
16
NA
17
18
Related?
Weight
Comments
mg/dl. Concurrent hyperinsulinemia,
increased leptin, hyperlipidemia cholesterol 320 mg/dl
and triglycerides 373 mgIdl. No baseline values
reported. Outcome and status of olanzapine use
unknown. History of obesity.
Peak glucose reprinted to be an "average" of 124
mgldl. Concurrent hypennsulinemia, increased leptin,
hyperlipidemia cholesterol 273 nig/dI and triglycerides
361 mg/dl. Baseline values not reported. Outcome
and status of olanzapine use were unknown.
Peak glucose unknown. Prior USC of olanzapine,
glucose levels not reported. Blood glucose elevation
occurred 14 days prior to re-introduction of olanzapine.
Urine positive for porphynns. Outcome on olanzapine
unknown.
Peak glucose 124 mgldl F. HbA1 chad normalized on
olanzapine prior to dietary treatment. History of
hypertension. Peak weight 96.8 kg but reportedly not
obese. Outcome resolved on olanzapine.
Peak glucose 119
Patient began taking insulin 8 days prior to olanzapine

for blood glucose of 500 mgldl. Patient had a history
of glucose dysregulation and diabetes mellitus. Patient
was obese, weight 170 kg. Had confusion and
peripheral swelling. Blood glucose levels decreased to
105 to 400 mg/dl range 10 days after starting
olanzapine and 19 days after starting insulin. Event
resolved on olanzapine; subsequent status of olanzapinc
use is unknown.
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Table 3.1.
19
NA
Case H
US010973487
20
21
NA
USOI 1075433
Glucose 4 Update
26 March 2003
Glucose Dysregu lation n=22 continued
-
Death
Reported as
Glucose
Metabolism
Related?
NA

Blood alkaline phosphatase NOS
increased,
Blood chloride abnormal NOS,
Blood cholesterol increased,
Blood sodium abnormal NOS,
Blood triglycerides increased,
Choiclithiasis,
Gamma-glutamyltransferase increased,
Hyperglycaemia NOS,
Platelet count abnormal,
White blood cell Count abnormal NOS
Blood glucose increased
Concomitant Drugs
with Glucose
Pancreatitis and/or
Weight Gain
Bipenden,
Flunitrazepam 8,9,
Haloperidol 2,9,
Haloxazolam 8,9,
Trihexyphenidyl,
Zopiclone 9
Reported Pre
Existing
Glucose
Dysregulation
U
tA
NA
Flunitrazepani 8,9,
Ursodeoxycholic acid
NA
USOH 176856
Diabetes mcllitus NOS,

Hepatic function abnormal NOS
Comments
Patient with elevated GGT 6 weeks before starting
olanzapine had blood glucose 202 mg/dl one month
after his first and only dose of olanzapinc.
Cholelithiasis diagnosed 2 days after his single
olanzapine dose. Pre-existing glucose dysregulation
and history of diabetes mellitus were unknown.
Weight was 76kg and BMI 25 mg/kg2. Patient had
elevated blood alkaline phosphatase, cholesterol,
triglycerides, GGT, abnormal NOS blood chloride,
sodium, platelet count, WBC and one month after a
single olanzapine dose. Event resolved off olanzapine.
Patient had fasting glucose 116 mg/dl after having
taken olanzapine for 3 years. Prior status of glucose
regulation unknown. Unknown outcome on
olanzapinc.
Patient with prior history of hyperglycemia and drug
induced impaired liver function reportedly due to
halopendol; had worsening hepatic function after
having taken olanzapine for 22 days. Fifty days after
olanzapine and bipenden were stopped, 35 days after
rispendone was stopped and 70 days after
chlorpromazinel phenobarbital/ promethazine was
stopped, she had glycosuria and elevated blood glucose
level. Peak blood glucose level was 153 mgldl and
HbAlc 8.2%. Patient had no family history of diabetes
meflitus; weight was unknown. Event resolved off
olanzapine.
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Glucose Dysregulation n=22 concluded
Table 3.1.
E
Case ID
22
NA
US020382306

Blood calcium decreased,
Blood urea decreased,
Glycosylated haernoglobin increased,
Haematocrit decreased,
Haemoglobin decreased,
Lymphocytosis,
Neutrophil count abnormal NOS,
Red blood cell count decreased,
Thrombocytopenia,
White blood cell Count decreased,
White blood cell count increased
Death
Reported as
Glucose
Metabolism
Related?
NA
Concomitant Drugs
with Glucose
Pancreatitis and/or
Weight Gain
Reported Pre
Existing
Glucose
Dysregulation
Amfebutainone 2,9,
Levothyroxine 2,
Montelukast
Comments
Patient with history of hypothyroidism, obesity BMI

48 kg/rn2, diabetes mellitus and glucose dysregulation
developed severe thrombocytopenia, decreased blood
calcium, urea nitrogen, hematocrit, RI3C, WBC,
lymphocytosis, and random glucose 115 mg/dl after
having taken olanzapinc for more than 2 years. Had
spontaneous nasopharyngeal bleed platelet nadir 1K,
atypical lymphocytosis and required 9 transfusions of
blood bank platelets in 5 days between olanzapine
cessation and hyperglycemia; unknown if
corticosteroids administered with platelets. Peak
glucose 448 mgldl occurred 7 days after olansapine
was discontinued. His HbAIC was 6.6%.
Hematologic events continue. Outcome of clevated
blood glucose is not resolved and elevated HbAlc is
unknown off olanzapine for 5 days at event onset.
Abbreviations:
1
Concomitant Drugs Temporally Associated with Possible Adverse Events:
Hyperglycemia, Insulin requirement changes; 3

8
Weight loss; 9
Weight gain; NA
Diabetic Ketoacidosis; 4
Acidosis, Lactic acidosis, Metabolic acidosis; 2
Hyperosmolar non-ketotic coma; 5
Diabetes mellitus, Glucose tolerance decreased, Glycosuria,
Hyperlipidemia, Hypcrtriglyceridemia; 6
Concomitants lacked temporal association with glucose dysregulation, acidosis, pancreatitis and/or weight gain; N
Ketonuria, Ketosis; 7
Pancreatitis;
No concomitants being taken;
U = Unknown/not reported if Concomitants being taken.

Death Reported as Glucose Metabolism Related? Y
Yes, death reported as glucose metabolism related; N
No, death reported as due to cause other than glucose metabolism; U
Unknown cause
of death; NA = Death not reported.

Reported Pre-Existing Glucose Dysregulation Hyperglycemia and/or Diabetes mellitus: Y
Yes, glucose dysregulation preceded olanzapine use; N
No, glucose dysregulation did not precede
olanzapine use; U = Unknown if glucose dysregulation preceded olanzapine use.
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Table 3.2.
Glucose 4 Update
26 March 2003
Category 0-b: Not a Case Severe Adverse Event Report That Did Not Meet
Inclusion Criteria for Glucose Dysregulation n=16
-
Death
Reported as
Glucose
Metabolism
Related?
NA
Concomitant Drugs
with Glucose
Pancreatitis and/or
Weight Gain
Clonazepam 8,9,
Paroxetine 2,5,6,7,8,9,
Risperidone 3,8,
Valproate 1,7,8,9
Reported Pre
Existing
Glucose
Dysregulation
U
2.08
Case ID
US961 10727A

Convulsions NOS,
Kctoacidosis,
Pulmonary oedema NOS
5.03
US97035185A
Metabolic acidosisNOS,
Respiratory distress
NA
Diphenhydramine 9,
Erythromycin 7
4.01
US9709051 IA
Alanine aminotransferase increased,

Blood creatine phosphokinase increased,
Body temperature increased,
Ketonuna present,
Muscle rigidity,
Protein urine
NA
Chlorpromazinc 2,9,
Erythromycin 7,
Lorazepam 8,9
9.01
US9SOIOI42A
Abdominal pain NOS,

Acidosis NOS,
Cardio-respiratory arrest,
Nausea,
Vomiting NOS
Lamivudine 1,2,7,
Stavudine 1,7,
Promethazine 2,9
Comments
Peak glucose unknown. Neither hyperglycemia nor
diabetes mellitus reported; not a case of glucose
dysregulation. Ketoacidosis reportedly thought to be
related to primary event of seizures of unspecified
etiology. Outcome unknown off olanzapine.
dysregulation. Admitted to the hospital with metabolic
acidosis and acute respiratory distress; probable URI
based on concomitant medications. No clinical
information or laboratory values reported. Outcome
and status of olanzapine use unknown.
diabetes mellitus reported; off olanzapine I day at
onset. Not a case of glucose dysregulation.
Concurrently had possible viral infection with fever
peak 39 .2C, trace ketonuria, proteinuria,
cogwhceling and SGPT elevation; arterial pH and
HCO3 not reported. Resolved off olanzapine,
chiorpromazine and lorazepam.
dysregulation. Marked obesity BMI 47.0 kg/rn2; HIV
positive in stable condition; had 2 week history of
abdominal pain with increasing nausea and vomiting
over 2 to 3 days. Diagnosed with refractory
unspecified metabolic acidosis pH <7.0; HCO3 6.4
and possible sepsis on fiuconazole, lamivudine and
stavudine. Death due to cardiorespiratory arrest.
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Category 0-b: Not a Case Severe Adverse Event Report That Did Not Meet Inclusion Criteria for
Glucose Dysregulation n=1 6 continued
Table 3.2.
c.
Glucose 4 Update
26 March 2003
-
6.02
Case II
US980707656

Lactic acidosis
5.05
US99OI 15843
Coma NEC,
Disseminated intravascular coagulation,
Hyperkalaemia,
Hypotension NOS,
Leucocytosis NOS,
Metabolic acidosis NOS,
Pyrexia,
Rhabdomyolysis,
Status epilepticus,
Tachycardia NOS
5.06
US990420528
Convulsions NOS,
Depressed level of consciousness,
Flyponatraemia,
Pleural effusion,
Pneumonia NOS,
Proteinuria present,
Respiratory acidosis,
Respiratory failure exc neonatal
Death
Reported as
Glucose
Metabolism
Related?
NA
NA
Concomitant Drugs
with Glucose
Pancreatitis and/or
Weight Gain
U
Reported Pre
Existing
Glucose
Dysregulation
U
Clonazepam 8,9,
Levothyroxine 2,
Propranolol 2
Albuterol 2
Comments
dysregulation. Reported only as having lactic acidosis.
No laboratory values or clinical history were reported.
Patient reportedly not hospitalized. Lactic acidosis
improved off olanzapine.
dysregulation. History of alcohol abuse with 5 months
of sobriety, and obesity. Metabolic acidosis pH 6.94
secondary to seizure of 80 minutes duration. Cause of
death was DIC due to metabolic acidosis,
rhabdomyolysis and br hyperthermia due to seizure.
Seizure reported as possibly due to possible abrupt
clonazepam withdrawal; following status epilcpticus
had dilated pupils and left lateral gaze deviation.
Autopsy reportedly free of cerebral hemorrhages and
devoid of reason for seizures; microscopic cardiac
exam showed areas of myocardial necrosis. On
olanzapine, propranolol, levothyroxine and possibly
clonazepam at death.
dysregulation. Had respiratory failure with respiratory
and non-anion gap metabolic acidosis. Concurrent
polysubstance and alcohol abuse, obtundation,
pneumonia with pleural effusion and seizure; history of
COPD and asthma. Taking phenobarbital; drug level
not reported. Seizure reportedly was èxpected given
his history' which included excessive water intake;
serum sodium 115 meqfL and 113 meq/L. Event
resolved off olanzapine and concomitants.
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Table 3.2.
Glucose 4 Update
26 March 2003
Glucose Dysregulation n=1 6 continued
-
Death
Reported as
Glucose
Metabolism
8
2.17
Case ID
US990623621
9.02
US990827170
10
2.21
US000540965
5.07
USOO1 154063
Related?
Concomitant Drugs
iith Glucose
Pancreatitis and/or
Weight Gain
Bupropion 2,8,9,
Reported Pre
Existing
Glucose
Dysregulation
Ketoacidosis,
Movement disorder NOS,
Neuroleptic malignant syndrome,
Weight decreased
NA
Acidosis NOS,
Depressed level of consciousness,
Dysarthria,
Miosis,
Mucous membrane disorder NOS,
Overdose NOS,
Pressure sore,
Suicide attempt,
Tachycardia NOS
Ketoacidosis
NA
NA
NA
Apnoea,
Coma NEC,
Encephalopathy NOS,
Hemiplegia,
Hypotension NOS,
Pneumonia NOS
NA
Ranitidine 7
Lcvothyroxine 2
11
Comments
Neither hyperglycemia nor diabetes mellitus reported;

not a case of glucose dysregulation. Diagnosed with
NMS and ketosis reportedly due to starvation; arterial
pH and HCO3 not reported. BMI 16.9 kg/rn2 following
45 lbs 20.5 kg weight loss while on olanzapine.
Improved off olanzapine.
diabetes mellitus reported. Intentional acute overdose
with trihexyphenidyl and olanzapine amount
unknown. Metabolic acidosis with HCO3 15 and
anion gap 30. Had decubiti and CPK elevation at
presentation; had mucous membrane disorder NOS
concurrently. Unknown outcome and status of
olanzapine use.
dysregulation. MedDRA Preferred Term reported only
as ketoacidosis. Medical history, concomitant
medication and outcome off olanzapine are unknown.
dysregulation. Hospitalized with respiratory failure of
unspecified etiology, and metabolic acidosis. No pH or
HCO3 reported. Presented with healing toe paronychia
without cellulitis, respiratory distress with initially
clear lungs and subsequent pneumonia, dehydration
and unresponsiveness. Had fever, diagnosed with
NMS with labile blood pressure. lntubated, developed
lateralizing findings without pathology on brain MRI;
cultures blood, urine, CSF negative. Developed
pneumonia and left herniplegia before event resolution.
Improved off olanzapine.
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Table 3.2.
E
12
4.06
Case ID
US010666926
13
5.08
USOI 0871462

Acidosis NOS,
Blood creatinine increased,
Blood urea increased,
Electrolyte imbalance,
Haematuria,
Ketonuria present,
Polyuna,
Proteinuria present
Hepatic failure,
Leukocytosis NOS,
Pneumonia staphylococcal,
Renal failure NOS,
Respiratory failure cxc neonatal,
Rhabdomyolysis
Death
Reported as
Glucose
Metabolism
Related?
NA
Concomitant Drugs
with Glucose
Pancreatitis and/or
Weight Gain
N
Reported Pre
Existing
Glucose
Dregulation
U
Comments
diabetes mcllitus reported; not a case of glucose
dysregulation. Hospitalization with diagnoses of
concurrent NMS and fever. Five days after midazolam
stopped, found to have labile blood pressure, acidosis,
tachycardia, fever, CPK elevation, incontinence and
tremor; also had proteinuna, ketonuria, and polyuria.
The presence or absence of glycosuria was not
specified. Outcome unknown off olanzapine.
dysregulation. Had metabolic and respiratory acidosis
pH 7.14. Had rhabdomyolysis, respiratory, liver, and
renal failure; presented in month of August with fever,
diaphoresis and unresponsiveness on day of planned
discharge from a group home; CXR showed bibasilar
infiltrates on admission; sputum culture at intubation
grew Staphylococcus aureus. Death due to NMS,
Staphylococcus aureus pneumonia, respiratory, renal
and hepatic failure.
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Table 3.2.
-
Concomitant Drugs
Death
Reported as
Glucose
Metabolism
Case ID
Related?
with Glucose
Pancreatitis and/or
Weight Gain
Reported Pre
Existing
Glucose
Dysregulation
Comments
14
5.09
USOI 1074903
Multi-organ
failure, Cardiac arrest,

Renal failure NOS, Hyperpyrexia,
Agitation, Suicidal ideation, Hostility,
Anxiety NEC, Judgment impaired,
Abdominal pain NOS, Constipation,
Difficulty in mictuntion, Insomnia,
Blood pressure increased, Tachycardia
NOS, Lethargy, Tachypnoea, Coma,
Dry skin, Intentional self-injury,
White blood cell Count increased, Blood
sodium increased, Blood potassium
increased, Blood chloride increased,
Blood bicarbonate decreased, Blood urea
increased, Blood creatinine
phosphokinase increased, B'ood calcium
increased, Blood phosphorus increased,
Blood creatine phosphokinase increased,
Aspartate aminotransferase increased,
Blood albumin increased, Blood urine
present, Protein urine,
Lung infiltration NOS, Prothrombin
time prolonged, Metabolic acidosis,
Respiratory acidosis
Buspirone 8,9,
Clomipramine 2,5,9,
Clonazepam 8,9,
Fluoxetine hydrochloride
2,3,5,7,8,9,
Gabapentin 2,8,
Haloperidol 2,9,
Nortriptyline 8,9,
Zolpidem 2,8
Peak glucose unknown; neither hyperglycemia nor

diabetes mellitus reported, therefore not a case of
glucose dysregulaon. Height, weight, 13M1, personal
and family history of diabetes, baseline laboratory
values not reported. Patient's death due to multiorgan
failure following fever 4 .4C, possible NMS CPK
46,040 U/L; subsequently 89,000 U/L, muscle
rigidity and pneumonia present after discontinuation of
aB psychotropic medications; had respiratory and
metabolic acidosis pH 7.26. Diagnosis of pneumonia
and fever followed treatment with a polypharmacy of
psychotropic medications combined with an
unspecified form and duration of physical restraint.
Laboratory values at time of fever were compatible
with dehydration sodium 156 meq/L, potassium 5.0
meq/L, chloride 116 meq/L, BUN 49 mg/L, crcatinine
2.9 mgfL; fluid intake during restraint not reported.
Unknown if hematuna was trauma related. Death 24
hours after detection of hyperthermia reportedly due to
multi-organ failure possibly related to dehydration and
metabolic derangements due to possible NMS and/or
pneumonia. Unknown if autopsy performed.
15
1.79
USO 11074993
Diabetic ketoacidosis
Mirtazapine 2,8,
Perphenazine 2,9
Peak glucose unknown. No history of olanzapine use.

Patient was not taking olanzapine; was in postmarketing study and taking perphenazinc. Height,
weight, BMI, personal and family history, baseline
laboratory values not reported. Patient found dcad at
home in bed; cause of death reported as diabetic
ketoacidosis. Blood glucose level, vitreous humor
glucose level, pH, HCO3, toxicology report and
detailed autopsy results not reported.
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Glucose Dysregulation n=1 6 concluded
Table 3.2.
E
16
1.84
Case ID
US020382427

Blood triglycerides increased,
Diabetic ketoacidosis,
Pancreatitis acute
Death
Reported as
Glucose
Metabolism
Related?
NA
Concomitant Drugs
with Glucose
Pancreatitis and/or
Weight Gain
Bromperidol 2,9,
Ethyl loflazepate 8,9,
Flunitrazeparn 8,9
Reported Pre
Existing
Glucose
Dysregulation
U
Comments
Peak glucose 778 mg/dl. Patient off olanzapine 17 to
24 days at event onset; therefore, this is not a case of
glucose dysregulation on olanzapinc. Risk factors for
development of diabetes mellitus included race, family
history of diabetes, obesity BMl 35.9 kg/rn2, pre
olanzapine dyslipidemia and past history of pancreatitis
unreported etiology. Concomitants started and
stopped same dates as olanzapine. Elevated
triglycerides 514 mg/dl documented after two weeks
of olanzapine. Diagnosed with diabetic ketoacidosis
and acute pancreatitis with arterial pH 6.96, 3+ ketones
in unspecified body fluid, blood pressure 90/60 rnmHg,
respiratory rate 42/mm, amylase 1575 IU/L or 2015
lU/L, lipase 3095 IU/L and HbAlc 13.5%. A CT scan
indicated acute pancreatitis. Abdominal pain occurred
17 days after last olanzapine dose; DKA diagnosed 24
days after olanzapine cessation. Treatment included
intubation, dopamine hydrochloride, insulin and
antibiotics directly into pancreatoduodenal artery.
Triglycerides not reported at time of presentation with
DKA. Presence or absence of infection as part of acute
presentation was not specified although treated with
antibiotics. Events resolved.
Abbreviations:
8
Weight loss; 9
Weight gain; NA
I
=
Hyperlipidemia, Hypertriglyceridemia; 6
=
=
Pancreatitis;
Unknown/not reported if concomitants being taken.
Unknown cause

No, glucose dysrcgulation did not precede
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3.2. Severe Glucose Dysregulation Adverse Event Reports

Of the 945 adverse event reports initially identified in the comprehensive review of
spontaneous adverse event reports in the Lilly Clintrace database, 191 reports were
identified through clinical review as severe adverse event cases potentially suggestive of
glucose dysregulation and involving death, coma, andlor acidosis. Cases of paricreatitis
with or without reported glucose dysregulation are also presented. These cases are
briefly summarized in a tabular format in the following sections, with detailed summaries
for each case presented in Appendix C.
The adverse event reports in the following sections are presented in a hierarchical order
ie, all death cases in Section 3.2.1; all nonfatal coma cases in Section 3.2.2; all nonfatal,
non-coma cases involving acidosis in Section 3.2.3. A case appears in only one of the
three sections according to the priority assigned to the event death > coma> acidosis.
For example, a fatal case involving acidosis is found in Section 3.2.1, but is not repeated
in Section 3.2.3.
3.2.1. Deaths Category 1

3.2.1.1. Case Tables
A total of 48 cases involved death, and met the criteria for inclusion as a severe adverse
event potentially suggestive of glucose dysregulation temporally associated with
commercially-marketed olanzapine. This number represents all known cases of death
with a data cutoff of 31 March 2002. Table 3.3 summarizes these 48 cases designated as
Category 1. Appendix C provides full narratives of these cases.
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Category 1: Cases of Death in Which Glucose Dysregulation was Reported and the Patient Was on
Olanzapine at Event Onset n=48
Table 3.3.
10.01
Case H
CA010503671
12.03
CAOI 0603802
MedDRA Preferred
Terms
Nonketotic
hypcrglycaemichyperosmolar coma
Diabetic coma NOS
Etiology of
Glucose
Dysregulation
POE
Death
Reported as
Glucose
Metabolism
Related?
Y
POE & OP
Concomitant Drugs
with Glucose
Dysrcgulation, Acidosis,
Pancreatitis and/or
Weight Gain
U
Topiramate 1,2,5,6,7,8,
Valproate 1,7,8,9
Reported Pre
Existing
Glucose
Dysregulation
Y
Comments
Peak glucose 951 mgldl post-mortem, peripheral blood;
881 mg/dI post mortem vitreous humor. Prior to
olanzapine, obesity and fasting hyperglycemia 130
mg/dl present. After 6 days olanzapine use and
approximately 2.5 months of prescribed but uncertain
olanzapine use, glucose level increased further but was
not assessed until after death. Reported cause of death
was hypcrosmolar diabetic coma and terminal
dehydration. Had a history of street drug and alcohol
abuse but autopsy toxicology negative for ethanol or
other volatile alcohols, cocaine, marijuana, opiates, or
benzodiazepincs and olanzapine present 45 nglml
from unspecified sample site; patient was reportedly
difficult and noncompliant. ` Elevated post-mortem
beta-hydroxybutyrate levels may have resulted from
dehydration. Neither details of his `feeling unwell" for
a few days prior to death nor of concomitant
medications were provided.
Peak glucose unknown. Baseline glucose and medical
details surrounding onset of diabetic coma not reported.
Had multiple risk factors for diabetes mellitus family
history, race, obesity. Sixteen-year-old male with pie
olanzapine BMI 30.5 kg/rn2 developed polyuna,
diabetic coma and died; unknown if autopsy performed.
Patient weighed 250 lb 113.6kg prior to starting
olanzaprne; gained 4.5 kg in 3 months during
olanzapine treatment. Six months prior to olanzapine
use was hospitalized and placed on a "cocktail of
drugs" including "typical antipsychotics."
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Olanzapine at Event Onset n=48 continued
Table 3.3.
;
a
3
2.03
Case ID
EWC980400445
5.02
EWC990202785
MedDRA Preferred
Terms
Cardiac arrest,
Cardiac failure
NOS,
Hyperglycaemia
NOS,
Ketoacidosis
Cardiac arrest,
Cyanosis NOS,
Dyspnoea NOS,
Hyperglycaemia
NOS,
Hyperkalaemia,
Hypotension NOS,
Metabolic acidosis
NOS,
Neuroleptic malignant
syndrome,
Respiratory failure
cxc neonatal,
Ventricular
tachycardia
Etiology of
Glucose
.
Dysregulation
OE
Death
Reported as
Glucose
Metabolism
Related?
N
POE
Concomitant Drugs
with Glucose
Pancreatitis and/or
.
Weight Gain
Haloperidol 2,9,
Lorazepam 8,9
Clomipramine 2,5,9,
Lithium 2,8,9
Reported Pre
Existing
Glucose
.
Dysregulation
Y
Comments
Peak glucose 500 mg/dL. History of codeine and
diazepam addictions causing prior hospitalizations.
Prior to olanzapine patient had elevated glucose 141
mg/dl pp and had received haloperidol. Prcsentcd
with nausea and leg weakness followed by rigid
abdomen, absent bowel sounds and erysipelas without
cultures of site or blood, or treatment reported; pH 7.08
with base deficit 23; dehydrated and hypotensive;
treated with dopanline and dobutamine. Exam showed
responsive, over-mid size pupils and focal findings
right-sided Babinski with absent oculocephalic
reflexes. Death reported due to cardiac failure and
electromechanical dissociation; iatrogenic
pneumothorax during central line placement treated
with chest tube. Olanzapine last given on day before
death; unknown status of original concomitant use.
Peak glucose 1499 mg/dL. The patient presented with
hyperglycemia glucose 363 mg/dl; serum glucose
rose to 1499 mg/dl following glucose administration,
despite insulin, during resuscitative attempts to treat
significant hyperkalemia due to acidosis pH 7.08
resulting from shock. Type of acidosis was not
reported. Etiology of pre-olanzapine weight loss,
lymphadenopathy and hepatosplenomegaly not
reported. Presentation with dyspnea, cyanosis and
hypotension. Pulmonary emboli not reported at
autopsy after extensive resuscitation, nor was sepsis, or
Addisons disease. Death due to NMS, hyperkalemia,
rhythm disturbances; on olanzapine, clomipramine and
carbamazepine.
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Table 3.3.
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26 March 2003
29.01
Case ID
EWC000506738
29.02
EWC010526873
MedDRA Preferred
Terms
Duodenal
haemorrhage,
Hyperglycaemia
NOS
Death NOS,
Dizziness exc
vertigo,
Drug level NOS
changed,
Hyperglycaemia
NOS,
Hypotension NOS,
Loss of consciousness
NEC
Etiology of
Glucose
Dysregulation
OE
Death
Reported as
Glucose
Metabolism
Related?
N
POE
Concomitant Drugs
with Glucose
Pancreatitis and/or
Weight Gain
Ciprofloxacin 1,2,
Citalopram 7,8,9,
Insulin injection,
Isophane,
Nitrazepam 8,9
Clothiapine 7,
Levomepromazine 2,9,
Lorazepam 8.9
Reported Pre
Existing
Glucose
Dysregulation
Y
Comments
Peak glucose 585 mg/dL. Had poorly controlled, pre
olanzapine diabetes mellitus HbAIc 9.1% and
concurrent urinary tract infection with antibiotic
treatment and insulin begun concurrent with
olanzapine. Urinary tract infection, age, concomitant
medications ciprofloxacin and citalopram, and
uncontrolled preexisting diabetes are etiologies for
worsening hyperglycemia. Death was due to duodenal
hemorrhage after off olanzapine and all concomitants
for two days; hyperglyccmia had resolved.
Peak glucose 223 mg/dL. Detection of hyperglycemia
without glycosuria or ketonuria ùrine test normal"
occurred in context of acute hypotension and loss of
consciousness. Known pre-olanzapine cardiac disease
NOS and baseline hyperglycemia. Treated at nursing
home with intravenous fluids for hypotension,
subsequently developed dizziness and lost
consciousness; died on way to hospital. Death on
olanzapine, levomepromazine, clothiapine and
lorazepam; reported as possibly a suicide attempt with
possible excess ingestion of olanzapine or excessive
administration or accumulation in body; autopsy
toxicology showed "abnormally high olanzapine
elevation" 540 ng/mI blood - unspecified site; other
drug levels reportedly not elevated, although
levomepromazine 630 ng/ml.
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Table 3.3.
29.03
Case ID
EWC020230016
29.04
FRO2O 100595
MedDRA Preferred
Terms
Completed suicide,
Hypergycaemia
NOS,
Non-accidental
overdose
Agitation,
Death NOS,
Hyperglycaemia
NOS,
Weight increased
Etiology of
Glucose
Dysregulation
IN
OE
Death
Reported as
Glucose
Metabolism
Related?
N
Concomitant Drugs
with Glucose
Pancreatitis and/or
Weight Gain
Propiomazine maleate
2,9,
Zopiclone 9
Reported Pre
Existing
Glucose
Dysregulation
U
Comments
Peak glucose 303 mg/dl, femoral blood post-mortem;
results obtained post-mortem, five days after she had
last been seen. Death was reported as suicide by
intentional overdose of olanzapine only; olanzapine
level 0.2 meg/gm, lactate 55.2 mmolIL sample site not
reported. Blood was `screened for other substances
but only olanzapine was detectable." Risk factors for
developing diabetes mellitus including height, weight,
personal and family history, baseline laboratory values
were not reported. In absence of autopsy information,
past medical history and ante-mortem evidence of
hyperglycemia, unable to confirm glucose
dysregulation as an ante-mortem condition.
Peak glucose 400 mg/dl. Klinefelters syndrome was a
known risk factor for diabetes; not obese BMI 20.3
kglm2, but gained weight amount, timing not
reported. Personal and family history of diabetes not
reported; positive personal and family history of
phlebitis. Thirteen months after starting olanzapine,
patient reported fatigue, and oral candidiasis was found
on exam, HbAlc 9.8%; Ireatment of candidiasis and
hyperglycemia not reported. Approximately 3 weeks
later, glucose remained 400 mg/dl and acetone present
in urine; no treatment reported. Olanzapine
discontinued three weeks later and 10 days after last
olanzapine dose, patient found dead. No autopsy;
cause of death unexplained but suicide or alcohol
ingestion reportedly not suspected. Hyperglycemia
detected in context of an oral infection in patient with
Klinefelters syndrome.
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Table 3.3.
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MedDRA Preferred
Terms
Arrhythmia NOS,
Aspartatc
aminotransferase
increased, Blood
crcatinine increased,
Coma NEC,
Diabetes mellitus
NOS, Diarrhoea
NOS, Ketoacidosis,
Left ventricular
failure,
Left ventricular
hypertrophy,
Lethargy, Listless
2.06
Case ID
GBS9909041 38
10
11.03
G8S010508789
Diabetic
hyperglycaemic coma
11
2.09
US97022578A
Blood glucose
increased,
Coma NEC,
Death NOS,
Ketoacidosis,
Pyrexia
Concomitant Drugs
with Glucose
Pancreatitis and/or
Weight Gain
Alprazolam 8,9,
Clonazepam 8,9,
Lithium 2,8,9,
Etiology of
Glucose
Dysregulation
OE
Death
Reported as
Glucose
Metabolism
Related?
N
IN
Metformin I,
Sertraline 2.5,7,8,9
POE
Chlorpromazine 2,9,
Lithium 2,8,9,
Lorazepam 8,9
Reported Pre
Existing
Glucose
Dysregulation
U
Comments
Peak glucose 1645 mg/dL. Prior to presentation had 3
week history of polydipsia, 4 days of lethargy, and
diarrhea for 2 days; Consumed -4.5 L soft drinks per
day in week prior to death. Cloudy hematuria at
autopsy; culture not reported. Death on olanzapine,
paroxetine, lithium, clonazepam and alprazolarn;
autopsy findings included massive hepatomegaly, left
ventricular hypertrophy with focal myocardial fibrosis,
left ventricular failure, and blood alcohol 432 mg%.
Normokalemia in presence of marked acidosis pH
7.1, left ventricular hypertrophy with focal myocardial
fibrosis and alcohol intoxication were significant
contributors to cardiac arrest and death. Obesity,
dietary non-compliance, sedentary lifestyle, weight
gain and acute alcohol abuse were contributors to
hyperglycemia and acidosis. Pancreatic autolysis
present at autopsy.
Peak glucose unknown. Pre-olanzapine Type II
diabetes mellitus and probable obesity female
weighing 99.3 kg reportedly died at home in diabetic
coma. Corroborating data, e.g.. vitreous humor glucose
levels and negative findings on toxicology and
anatomy, were not reported. Patient's premorbid
medical status, including history of adherence to
medications, was not reported.
The case lacked details about the clinical context in
which DKA peak glucose 900 mg/dl manifested and
about intrinsic risk factors e.g., habitus, race, past
medical history and concurrent diagnoses. The
etiology of high fever and coma following resolution of
DKA is not determinable from the reported data
beyond the reporting physician's suspicion of NMS or
brainstem emboli as cause of death.
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Table 3.3.
Category 1: Cases of Death in Which Glucose Dysregulation vw

12
29.05
Case ID
US97 112521 A
13
6.01
US97121726A
Glucose 4 Update
26 March 2003
MedDRA Preferred
Ternis
Hyperglycaemia
NOS
Blood creatine
phosphokinase
increased,
Blood glucose
increased,
Body temperature
increased,
Coma NEC,
Hepatic failure,
Hypotension NOS,
Lactic acidosis,
Nausea,
syndrome,
Renal failure NOS,
Respiratory failure
cxc neonatal,
Vomiting NOS
Etiology of
Glucose
Dysregulation
POE
Death
Reported as
Glucose
Metabolism
Related?
Y
POE
Concomitant Drugs
with Glucose
Pancreatitis and/or
Weight Gain
U
Diphenhydramine 9,
Haloperidol 2,9,
Naproxen 2,7,8,
Temazepam 8,9
Reported Pre
Existing
Glucose
Dysregulation
Ii
--
Comments
Peak glucose unknown. Case lacks details of acute
clinical events; patient had an intrinsic risk factor
obesity and reportedly undiagnosed diabetes mellitus
which was exacerbated. Treating physician did not
believe olanzapine was responsible for events.
Obesity, undiagnosed diabetes and treating physician
assessment suggest a possible etiology, other than
olanzapine exacerbated the underlying disease.
Autopsy not performed; peak glucose not reported;
death reportedly due to hyperglycemia.
Peak glucose 1700 mgldL. Etiology of sudden onset of
marked hyperglycemia with lactic acidosis, fever
42.6C, coma, probable rhabdomyolysis CK 60,000,
and multiple organ failure in previously stable patient
not evident in data. Although NMS was considered as
a diagnosis, she did not have reported rigidity or EPS
findings. Seizure activity was not witnessed. Initial
symptoms of nausea and vomiting may have been a
primary event or a response to hyperglycemia and
lactic acidosis. Glycosylated hemoglobin not reported.
Blood, urine and CSF cultures were negative; extrinsic
toxins were not discussed. Toxicology studies for
prescribed medications, drugs of abuse, or toxins were
not reported. Had a long term seemingly asymptomatic
interval on a complex drug regimen and cataclysmic
decline; autopsy not performed. On olanzapine and
concomitants at death.
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Table 3.3.
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Etiology of
Glucose
Dysregulation
POE
Death
Reported as
Glucose
Metabolism
Related?
U
IN
i:;.
14
2.13
Case ID
US98024165A
15
1.33
US98 1012271
MedDRA Preferred
Terms
Gastrointestinal upset,
Ketoacidosis,
Pancreatitis
haemorrhagic,
Pyrexia
Dry mouth,
Speech disorder
NEC,
Thirst,
Vision blurred,
Weight increased
Concomitant Drugs
with Glucose
Pancreatitis and/or
Weight Gain
Lithium 2,8,9,
Lorazepam 8,9,
Valproate 1,7,8,9
Buspirone 8,9,
Lithium 2,8,9,
Reported Pre
Existing
Glucose
Dysregulation
U
Comments
Peak glucose unknown. Presented with fever 39.4C,
flu-like symptoms, and gastrointestinal symptoms
NOS; she was not hospitalized. Post-mortem
diagnosis of acute hemorrhagic pancreatitis; there was
no history of alcohol use. Although probable that the
patient developed hyperglycemia during the
pancreatitis, neither glucose levels nor specific report
of hyperglycemia or diabetes mellitus was provided,
but conservatively assessed as instance of glucose
dysregulation. It is unknown from the reported data
why the patient was not hospitalized or further
evaluated in the 5 days between onset of symptoms and
death. Status of gall bladder function and presence or
absence of cholelithiasis at autopsy were not specified;
toxicology was not reported.
Peak glucose 867 mg/dL post-mortem vitreous humor.
Risk factors for development of diabetes mellitus
including obesity BMI 31.9 kg/rn2 and pre-olanzapine
weight gain with continued gain on olanzapine. Past
history regarding alcohol use not reported. Toxicology
results are compatible with the diagnosis of acute
diabetic ketoacidosis. Baseline serum glucose levels
and clinical information about possible diagnoses
concurrent with acute deterioration were not reported.
Death occurred on olanzapine, paroxetine, trazodone,
lithium, and buspirone; autopsy showed hepatomegaly
with fatty metamorphosis, cerebral and pulmonary
vascular congestion; vitreous humor and blood acetone
levels = 19 mg/dL and II mg/dL respectively. Cause
of death was diabetic ketoacidosis.
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385
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Table 3.3.
Etiology of
Glucose
Dysregulation
POE
OE
Levothyroxinc 2,
Metformin I
POE
Valproate 1,7,8,9
.9
MedDRA Preferred
Terms
Death NOS,
Diabetic coma NOS,
Hyperglycaemia
NOS,
Hyperphagia,
Malaise,
Polydipsia,
Polyuria
16
12.09
Case ID
US990420242
17
1.36
US9906234 11
Diabetes mellitus
NOS,
Mental Status
changes,
Pancreatitis NOS,
Thromboembolism
NOS,
Vomiting NOS
18
30.06
US990623659
Blood glucose
increased,
Pancreatitis acute
Concomitant Drugs
with Glucose
Pancreatitis and/or
Weight Gain
Multiple psychiatric
medications NOS
Death
Reported as
Glucose
Metabolism
Related?
N
Reported Pre
Existing
Glucose
Dysregulation
U
Comments
Peak glucose unknown. Death was reported due to
"complications" unrelated to diabetes mellitus.
Reported risk factors for development of diabetes
mellitus were age and obesity. She presented with
acute loss of bladder control and "felt ill." The patients
pre-admission symptoms include polyuria, polydipsia
and polyphagia for `some time." Data regarding the
"unrelated complication" which caused death were not
reported.
Peak glucose >400 mg/dl fasting. Hashimotos
thyroiditis, cholelithiasis and obesity by history.
Developed vomiting, pancreatitis and heparin-induced
thrombocytopenia during terminal events. Had
cholclithiasis and suspected panereatitis on first
admission after 2 years on olanzapine; when off
olanzapine, and on risperidone glucose increased.
Switched back to olanzapine and glucose managed with
metformin. Developed confirmed episode of
pancreatitis with DKA pH 6.9; status of cholelithiasis
not reported. Unknown status of olanzapine and
concomitant use with resolved pancreatitis at time of
death. Developed antibodies to hepann followed by
diffuse clotting after recovery from the reported
episode of pancreatitis and DKA.
Peak glucose unknown. Only reported medical data
were that patient was black and had acute pancreatitis
diagnosed at autopsy, associated with antemortem
elevated glucose levels, and that panereatitis was the
cause of death. Valproate was begun the same month
pancreatitis was diagnosed. The case lacked clinical
details necessary for fully assessing the patient's risk
factors and acute medical events. Duration of
olanzapine use at onset not reported.
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Table 3.3.
Glucose 4 Update
26 March 2003
Etiology of
Glucose
Dysregulation
OE
Death
Reported as
Glucose
Metabolism
Related?
N
MedDRA Preferred
Terms
Diabetes mcllitus
NOS,
Loss of
consciousness,
syndrome,
Renal failure
Concomitant Drugs
with Glucose
Pancreatitis and/or
Weight Gain
Reported Pre
Existing
Glucose
Dysregulation
U
19
18.05
Case ID
US990725729
20
28.01
US991233059
Agitation,
Depression,
Diabetic complication
NOS,
Hyperphagia,
Insomnia NEC,
Restlessness,
Urinary incontinence
IN
Clonazepam 8,9,
Diphenhydramine 9,
Fluoxctine 2,3,5,7,8,9,
Glibenclamide,
Metforrnin 1,
Risperidone 3,8
21
30.07
US000337604
Blood glucose
increased,
Pulmonary embolism
POE
Levothyroxine 2
22
1.46
U5000338270
Death NOS,
Renal failure NOS
IN
Comments
Peak glucose unknown. Presented in July, admitted to
hospital and diagnosed with diabetes mellitus after 18
months of olanzapine use and 2 years of fluoxetine use;
glucose levels and p1-I not reported. Three days later
diagnosed with NMS fever 41.7C, rigidity, coma,
CPK peak 400,000 IU. Treated with dantrolene and
bromocriptine, CPK and rigidity improved but died due
to renal failure. Autopsy was not performed; death
reported due to renal failure due to probable
rhabdomyolysis.
Peak glucose unknown. Concurrent insomnia,
restlessness and hyperphagia; diabetes treated with
metformin preceded olanzapine use. Patient's glycemic
control at baseline, and during her 3-week
hospitalization, were not reported. Obesity BMI 34.2
kg/rn2 and age were risk factors for diabetes mellitus.
Specific cause of death unknown from available data;
death reportedly due to unspecified "diabetic
complications.' Patient was `found dead" at home;
autopsy was not performed. Risperidone and
diphenhydramine re-started 2 weeks before death.
Peak glucose unknown. The patient's excessive weight
and age are possible etiologies for her hyperglycemic
measurements of unreported severity. Death was due
to pulmonary embolus at autopsy, not related to
olanzapine administration.
Peak glucose 1299 mg/dL. Concurrent renal failure;
patient incarcerated at onset. Absence of climeal
details, past or concurrent history in an incarcerated
patient. Death from unknown cause; unknown status of
olanzapine use at death.
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Table 3.3.
.8
-
23
18.06
Glucose 4 Update
26 March 2003
Case ID
US000542556
MedDRA Preferred
Terms
Blood cholesterol
increased,
Diabetes mellitus
Concomitant Drugs
with Glucose
Pancreatitis and/or
Weight Gain
Valproate 1,7,8,9
Etiology of
Glucose
Dysregulation
POE
Death
Reported as
Glucose
Metabolism
Related?
N
OE
Quetiapine 2,7,8
OE
Diclofenac 7,8,
Insulin human injection
isophane
Reported Pre
Existing
Glucose
Dysregulation
U
NOS,
Pancreatitis
necrotizing
24
29.07
US000744983
Death NOS,
Dizziness cxc
vertigo,
Hyperglycaemia
NOS,
Vomiting NOS
25
29.08
US000948765
Confusion,
Dyspnoea NOS,
Hyperglycaemia
NOS,
Lung cancer stage
unspecified cxc
metastatic tumours to
lung,
Respiratory arrest
exc neonatal
Comments
Peak glucose unknown. Concomitant medications
were begun concurrently with olanzapinc. Status of
olanzapine and concomitant use, when necrotizing
pancrcatitis was found I month after diabetes was
diagnosed, is unknown; it is unknown if patient
hospitalized or if autopsy performed. From reported
data, it is possible olanzapine, paroxetine and valproate
were being administered when necrotizing pancreatitis
began.
Peak glucose 175 mg/dL. Risk factors were race and
alcoholism history. This case lacked clinical data
necessary for precise assessment. Non-fasting glucose
had been 175 mg/dl without concurrent DKA on
olanzapine approximately 10 months prior to reported
DKA. The acute terminal episode of nausea and
vomiting while on only quctiapine may have caused or
been the consequence of ketoacidosis, or, have
originated with a primary gastrointestinal process.
Patients reported terminal diagnosis of `diabetic
ketoacidosis' was made after he had been off
olanzapine for 23 days and on quctiapinc for 11 days;
glucose reportedly was 175 mg/dl when diagnosed with
DKA at terminal admission. Died at unknown interval
after admission due to unreported cause; unknown if
toxicology and autopsy performed.
Peak glucose >800 mg/dl. Post-marketing study
participant with exacerbation of diabetes mellitus 2
months after starting olan7.apine. Concurrent
metastatic lung cancer, probable hyperlipidemia, and
obesity are etiologies for exacerbation of diabetes
mellitus. Presented 4 months later with dyspnea and
confusion attributed by investigator to metastatic lung
cancer. Respiratory arrest and death were reportedly
due to metastatic lung cancer; on olan7.apinc,
diclofenac and insulin at death.
Page 44
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Page 26
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Table 3.3.
p
a
26
1.54
Case ID
US000948999
27
1.60
USO 10158524
Glucose 4 Update
26 March 2003
MedDRA Preferred
Terms
Abdominal pain
NOS,
Lethargy,
Overdose NOS
Etiology of
Glucose
.
Dysregulation
POE
IN
Death
Reported as
Glucose
Metabolism
Related?
Y
Concomitant Drugs
with Glucose
Pancreatitis and/or
.
.
Weight Gain
U
Clonazepam 8,9,
Valproate 1,7,8,9
Reported Pre
Existing
Glucose
.
Dysregulation
Y
Comments
Peak glucose 843 mg/dL post-mortem. Autopsy
revealed triple vessel coronary artery atherosclerosis,
macrovesicular steatosis of liver and perimortem
fracture of left 6th rib. Patient's diagnosis of
`borderline' diabetes mellitus was made only 3 days
before death. Post-mortem diagnosis of ketoacidosis
with reported value for acetone of 0.029 W/V by gas
chromatography. Potassium of 16 meq/L from
unspecified sample. Post-mortem bicarbonate of<5
meq/L. Sampling confounders not discussed in report.
Reported increased daytime somnolence was related by
his sister to nocturnal insomnia. Absence of details
about the patient's medical status during the 2 months
prior to terminal events despite participation in postmarketing trial sponsored by Abbott Laboratories;
known risk factors for glucose dysregulation were age,
hyperlipidemia, hypertension, alcohol and substance
abuse; had past history of anemia and reflux
esophagiti s.
Peak glucose unknown. Diagnosis of DKA made post
mortem. Vitreous humor studies not reported, and
could have been informative. Presented with acute
abdominal pain, lethargy while incarcerated; paramedic
determined at the jail she did not require emergency
treatment. Glycosylated hemoglobin of 13% at autopsy
with acetone in blood and urine. Facts from autopsy
and the minimal clinical history are compatible with
development of DKA or diabetes with metabolic
acidosis likely causing metabolic abnormalities PH,
electrolyte leading to arrhythmia and death.
Concomitants begun same date as olanzapine.
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Table 3.3.
aB
Glucose 4 Update
26 March 2003
28
c.J
30.10
Case ID
US010259319
29
30.11
US010361601
30
30.12
US010361653
MedDRA Preferred
Terms
Blood glucose
increased,
NEC,
Overdose NOS,
Pulmonary embolism,
Thirst,
Urinary frequency
Bloodglucose
increased,
Body temperature
increased,
Cardiac arrest,
Death NOS,
Dizziness cxc
vertigo,
Fall,
Sepsis NOS
Blood glucose
increased,
Death NOS
Concomitant Drugs
th Glucose
Pancreatitis and/or
.
Weight
Gain
Lithium 2,8,9
Etiology of
Glucose
.
Dysregulation
POE
Death
Reported as
Glucose
Metabolism
Related?
N
OE
IN
Reported Pre.
Existing
Glucose
.
Dysregulation
U
Comments
Peak glucose 1300 mg/dL. Family history, obesity and
age were risk factors. Presented at outpatient clinic
with complaints of thirst and urinary frequency of
unreported durations; evaluation for urinary tract
infection not reported. Treatment intervention not
reported as having occurred. Three days after
presenting with thirst and urinary frequency, patient
hospitalized in coma and died from pulmonary
embolus. Progression of presenting events to coma and
death due to pulmonary embolism may have resulted
from dehydration, stasis and/or acute coagulopathy;
unknown if autopsy performed. Details about
laboratory data other than a single glucose were not
reported.
Peakglucose2lOomgldL. Organismcausingsepsis
was not reported. Presented with dizziness, fell and hit
head; diagnosed with sepsis with fever to 42.2C, had
cardiopulmonary arrest and died on day of presentation.
Interpreted as having probable coma in course of
events. Cause of death reported as unknown but
contributed to by sepsis, cardiac arrest and
hyperglycemia. Autopsy not performed.
Peak glucose 220 mg/dL. Past medical and family

history, habitus and baseline laboratory values not
reported. It was unknown if patient had prior episodes
of hyperglycemia or diabetes mellitus. Clinical details
surrounding the death were not reported. Cause of
death not reported; unknown if autopsy performed.
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Glucose 4 Update
26 March 2003
Table 3.3.
E
31
10.06
Case ID
USO 10361657
32
18.07
US010362485
MedDRA Preferred
Terms
Death NOS,
Influenza like illness,
Nonketotic
hyperglycaemichyperosmolar coma,
Pneumonia NOS,
Pulmonary embolism,
Renal failure NOS,
Respiratory failure
exc neonatal,
Upper gastrointestinal
haemorrhage,
Weight increased
Death NOS,
Diabetes mellitus
NOS,
Overdose NOS
Etiology of
Glucose
Dsregulation
OE
Death
Reported as
Glucose
Metabolism
Related?
N
POE
Concomitant Drugs
with Glucose
Pancreatitis and/or
Weight Gain
Isoniazid 1,2
Ciprofioxacin 1,2,
Clonazepam 8,9,
Levothyroxine 2,
Topiramate 1,2,5,6,7,8
Reported Pre
Existing
Glucose
Dysregulation
U
Comments
Peak glucose 2000 mg/dL. Risk factors were age, race,
obesity, weight gain. After 11 months of olanzapine
use, 45-year-old patient with chronic obstructive
disease and unspecified pulmonary problems, living in
an extended care residence, developed acute flu-like
illness and hyperglycemia, hyperosmolar non-ketotic
coma associated with pneumonia, respiratory and renal
failure; taking isoniazid. Death occurred reportedly
due to probable pulmonary embolism and respiratory
failure during the second hospital admission, after
patient off olanzapine approximately 6 weeks and with
unknown status of concomitant use. Glucose
metabolism at the terminal admission not reported.
Peak glucose unknown. Concomitant use of
ciprofloxacin for unspecified infection at the time of
diabetes mellitus diagnosis. Death - I m after glucose
dysregulation diagnosed and controlled by diet. Found
dead in bed at home. Autopsy revealed coronary artery
disease and old myocardial infarction; cause of death
not reported.
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Table 3.3.
Glucose 4 Update
26 March 2003
33
1.65
Case ID
USO 10564728
34
1.66
USO 10565220
MedDRA Preferred
Terms
Chest pain NEC,
Dizziness exc
vertigo,
Death
Death NOS,
Vision blurred,
Dry mouth
Etiology of
Glucose
Dsregu1ation
OE
Death
Reported as
Glucose
Metabolism
Related?
N
POE
Concomitant Drugs
with Glucose
Pancreatitis and/or
Weight Gain
Carbarnazepine 2,5,7,
Diltiazern 2,9,
Diphenhydramine 9,
Enalapril 7,
Fluoxetine 2,3,5,7,8,9,
Glipizide.
Hydroxyzine pamoate
2,9,
Insulin,
Torsernide 2
Albuterol 2,
Amitriptyline 2,8,9,
Chlorpromazine 2,9,
Clonidine 2,9,
Reported Pre
Existing
Glucose
Dsregu1ation
Y
Comments
Peak glucose 461 mg/dL. Post-marketing study
participant; pre-olanzapinc Type I diabetes mellitus,
obesity BMI 30.2 kg/rn2, pulmonary and systemic
hypertension, end-stage liver disease, drug and alcohol
abuse, severe noncompliance with follow-up, and
concomitant medications are all risk factors.
Diagnosed with diabetic ketoacidosis, HCO3 8 meq/L,
urine ketones 150 mgldl; pH not reported. Had coffee
ground emesis, weakness, nausea and 11gb 7.4 g/dl;
DKA at that time reportedly due to alcohol abuse and
"gross' noncompliance. Had chest pain and dizziness
after 3 days of study drug olanzapine. Death reported
4 months after DKA, and was "natural." Patient had
been drinking heavily and possibly noncompliant with
medieations. Autopsy revealed cardiomegaly, right
ventricular hyperirophy with dysplasia on posterior
wall, hcpatic micronodular cirrhosis, splenomegaly,
intact gastroesophageal varices, nephrosclerosis, post
cholecystectomy and appendectomy. DKA improved
on 01 an zapine
and insulin; unknown status of olanzapine use at time
of death.
Peak glucose 1600 mgldL. Autopsy results and
toxicology not reported for legal reasons. Patient
taking methadone for polysubstance abuse. Concurrent
diagnoses of asthma and hepatitis C; Presented the day
before death with blurred vision and dry mouth, and
was diagnosed as having an allergic reaction; glucose
level not reported as performed. Day of death
presented to ER with unreported symptoms, diagnosed
with DKA, transferred to ICU and died. Status of
medication compliance was unknown. Medical
examiner was unable to provide a copy of autopsy or
other records.
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Table 3.3.
Glucose 4 Update
26 March 2003
Etiology of
Glucose
Dysregulation
IN
POE
Lithium 2,8,9
MedDRA Preferred
Terms
Muscle twitching
Concomitant Drugs
with Glucose
Dysrcgulation, Acidosis,
Pancreatitis and/or
Weight Gain
Lithium 2,8,9
Death
Reported as
Glucose
Metabolism
Related?
Y
Reported Pre
Existing
Glucose
Dysregulation
U
-j
r
1.67
Case ID
US010565235
3.01
USO 10565250
Diabetes mellitus
NOS,
Ketosis
.70
US010768802
IN
Lithium 2,8,9
2.28
US010769550
Death NOS,
Ketoacidosis
IN
Comments
Peak glucose 610 mg/dl post-mortem; sample site not
reported. Diagnosis of diabetic ketoacidosis made
post-mortem. BMI not reported; weight 102.7 kg; race
only reported risk factor. Toxicology confirming
presence of olanzapine and concomitant lithium at the
time of death not reported. Two days before he died at
home, patient was seen in ER for hand twitching;
lithium level was `normal.' No other labs reported.
Case report of probable diabetic ketoacidosis lacks
baseline glucose, habitus. personal and family medical
history, clinical context of death, and, start dates or
durations of olanzapinc and lithium use.
Peak glucose 1185 mg/dL post-mortem. Autopsy and
toxicology not reported for legal reasons. Found dead
at home. Diagnosis of hyperglycemia and ketosis due
to diabetes mellitus made post-mortem. Site of
samplings vitreous humor vs. blood and post-mortem
interval to sampling not reported. Toxicology, to
confirm the presence of olanzapine, lithium, and the
presence or absence of ethanol, was not reported.
Patient had history of alcohol dependence, cocaine
abuse, hypertension and hepatitis C.
Peak glucose unknown. No baseline laboratory values
were reported. Past medical and family history, habitus
and clinical events surrounding the death were not
reported. Developed diabetic ketoacidosis and died; on
olanzapine and lithium at time of death; cause of death
diabetic ketoacidosis; unknown if autopsy was
performed.
Peak glucose 800 mg/dL. Past medical and family
history, and habitus not reported. Patient developed
ketoacidosis and died. Unknown if autopsy performed.
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Confidential
Table 3.3.
Glucose 4 Update
26 March 2003
MedORA Preferred
Terms
Convulsions NOS,
Death NOS,
Diabetic coma NOS,
Hyperglycaemia
NOS
Etiology of
Glucose
Dysregulation
POE
Death
Reported as
Glucose
Metabolism
Related?
U
Concomitant Drugs
with Glucose
Pancreatitis and/or
Weight Gain
Chloi-propamide
Reported Pre
Existing
Glucose
Dysregulation
Y
39
12.11
Case ID
USOI 0871705
40
1.77
US010973861
IN
41
1.78
US010974040
Diabetic
hyperosniolar coma,
Renal failure NOS,
Metabolic acidosis,
Convulsions NOS,
Tonsillitis acute
NOS,
Hyponatremia,
Hyperuricemia,
C-reactive protein
increased,
Hypokalemia,
Blood creatinine
increased
OE
Flunitrazepani 8,9,
Risperidone 3,8,
Triazolam 8,9,
Mefenamic acid 2,7,8,9,
Hydrocortisone 2,9
Comments
Peak glucose 488 mg/dL. Patient with pre-olanzapine
stable, controlled diabetes mellitus treated with oral
hypoglycemic agent, had a seizure, was found to have
hyperglycemia and reportedly a diabetic coma and
died. Cause of death reported as unknown. No
description of surrounding clinical events was
provided. Seizure etiology was not reported. Timing
of glucose measurement relative to seizure was not
reported.
Peak glucose unknown. Past medical history, baseline
laboratory values, family history and habitus not
reported. Race was only reported risk factor for
diabetes. After a several-year history of olanzapine
administration, patient apparently abruptly developed
diabetic ketoacidosis and died within 24 hours
following hospital admission. Because of paucity of
reported clinical data, the case cannot be assessed with
respect to causation of DKA.
Peak glucose 1655 mg/dl. Pre-olanzapine glucose of
80 mg/dl was measured approximately 20 months
before starting olanzapine, and, prior to treatment with
risperidone. Patient with risk factors of race, obesity, a
strongly positive family history for diabetes had known
diabetes mellitus before infectious prodrome of
pharyngitis began. Infectious pharyngitis exacerbated
diabetes that appears not to have been treated with
hypoglycemic agents at hospital admission when
glucose was 600 mgldl. Intravenous glucose,
antibiotics, hydrocortisone and large volume of juice
were followed by peak glucose, hyperglycemic coma,
electrolyte imbalance, pH 7.25 and death. Cause of
death reported to be hyperglycemia, diabetic coma and
dehydration.
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Table 33.
Glucose 4 Update
26 March 2003
42
2.30
Case II
USO1 1075155
13.02
USOI 1075562
MedDRA Preferred
Terms
Ketoacidosis
Etiology of
Glucose
Dysregulation
IN
Death
Reported as
Glucose
Metabolism
Related?
Y
Concomitant Drugs
with Glucose
Pancreatitis and/or
Weight Gain
Paroxetine hydrochloride
2,5,6,7,8,9
Reported Pre
Existing
Glucose
Dysregulation
U
43
Cardiac arrest,
Convulsions NOS,
Diabetes mellitus
insulin-dependent,
Lung infiltration
NOS,
Pyrexia,
Ventricular
fibrillation
POE
Comments
Peak glucose unknown. Past medical history, weight,
habitus, and family history not reported; duration of
olanzapine use, baseline glucose and HbAlc not
reported. Race was a risk factor for diabetes mellitus.
Reportedly developed slight elevation of post-prandial
blood glucose levels following initiation of olanzapine,
but no values reported, and no treatment of
hyperglycemia reported. Patient died following
ingestion of à lot of candy" and before seeing
physician. Cause of death reported as secondary to
ketoacidosis; glucose, pH, ketones, and bicarbonate
levels not reported. Unknown if autopsy was
performed.
Peak glucose >1000 mg/dl. Past medical history
reportedly negative for diabetes mellitus, cardiac
problems or seizures; unknown regarding prior
hyperglycemia. Risk factors include family history of
diabetes. Reported as not on any concomitant
medications; weight, habitus not reported. No baseline
laboratory values reported. Hospitalized for seizures
after taking olanzapine 5 years. Hyperglycemia
occurred in context of seizures, fever, pneumonia with
subsequent sepsis during hospitalization. Concurrent
pulmonary infiltrates, cardiomyopathy EF 30% by
echocardiogram, positive CIA antibody, elevated
glycosylated hemoglobin no value reported;
developed bacteremia from enterobacter; treated with
levofloxacin, ceftriaxone, insulin, ramipril, metoprolol,
diuretics, aspirin. Olanzapine held for 6 days; restarted
2 days prior to ventricular fibrillation and cardiac
arrest. Unknown if autopsy performed. Cause of death
reported as ventricular fibrillation and cardiac arrest.
Pneumonic infiltrates and cardiomyopathy etiologies
not specified.
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Table 3.3.
.E
p
a
rjj
44
10.08
Glucose 4 Update
26 March 2003
Case ID
USOI 1178209
MedDRA Preferred
Terms
Appetite increased
NOS,
Cardio-respiratory
arrest,
Hepatocellular
damage,
Hyperglycaemia
NOS,
Hyperlipidaemia
NOS,
Nonketotic
hyperglycaemichyperosmolar coma
Etiology of
Glucose
.
Dysregulation
OE
Death
Reported as
Glucose
Metabolism
Related?
Y
Concomitant Drugs
with Glucose
Pancreatitis and/or
.
.
Weight Gain
Bromperidol 2,9,
Cloxazolam 8,9,
Haloperidol 2,9,
Quetiapine 2,7,8,
Timiperone 2,9
Reported Pre
Existing
Glucose
.
Dysregulation
Y
Comments
Peak glucose 854 mg/dl. No history of diabetes
mellitus although FBS 137 mg/dl 14 weeks pre
olanzapine; no history of acute pancrcatitis or
dehydration. Past medical history positive for elevated
liver functions tests and pre-existing hyperlipidernia
triglycerides 547 mg/dl, cholesterol 278 mg/dl, drug
induced parkinsonism, and treatment with Ed. Risk
factors include pre-olanzapine obesity 13M1 34.6
kg/rn2, dyslipidemia, race, dietary excess and
noncompliance. Hyperglycemia and hyperlipidemia
increased after taking olanzapine for 2 weeks. One
month later, 6kg weight loss, polydipsia, and reported
high intake of soft drinks and juice; HbAlc 10.0% to
15.4%, serum glucose 723 mg/dI several hours post
prandial, triglycerides 960 mg/dl, cholesterol 362
mg/dl, urine glucose 1000 mgldl and 3+ ketones; pH
not reported. No treatment when glucose 723 rng/dl
was reported. Liver function tests improved. Two days
later, patient had cardiopulmonary arrest, taken to ER.
CPR included epinephrine, vasopressin, DC shock.
Drug toxicology screen negative. Patient arrested a
second time followed by encephalopathy. Diagnosed
with hyperglycemia NOS, hyperlipidemia NOS,
nonketotic hypcrglycemic-hyperosrnolar coma and
hepatocellular damage. Unspecified treatments of postresuscitation encephalopathy and hyperglycemia
continued. Head CT scan indicated severe damage due
to hypoxia. Death off olanzapine, fenofibrate,
timiperone and cloxazolam for 5 days.
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Table 3.3.
Glucose 4 Update
26 March 2003
45
29.10
Case ID
USOI 1278839
46
11 .06
US020382774
MedDRA Preferred
Terms
Hypcrglycaemia
NOS
Diabetic
hyperglycaemic
coma,
Disseminated
intravascular
coagulation,
syndrome,
Prescribed overdose,
Shock,
Vegetative state
chronic,
Weight increased,
Anorexia,
Polydipsia,
Thirst,
Methicillin-resistant
staphylococcal aureus
infection,
Respiratory tract
infection NOS,
Urinary tract infection
NOS
Etiology of
Glucose
.
Dysregulation
IN
OE
Death
Reported as
Glucose
Metabolism
Related?
Y
Concomitant Drugs
with Glucose
Pancreatitis and/or
.
Weight Gain
2,5,6,7,8,9
Dosulepin 2,8,9,
Flunitrazepam 8,9,
Lithium carbonate 2,8,9,
Triazolam 8,9
Reported Pre
Existing
Glucose
.
Dysregulation
U
Comments
Peak glucose unknown. Risk factors for development
of diabetes mellitus included age, being overweight and
race; BMI, personal and family history of diabetes and
baseline laboratory values not reported. Thirteen days
after starting olanzapine, patient was found dead in his
apartment. Estimated to have been dead for 3 days at
discovery. Autopsy negative for stroke or myocardial
infarction. Vitreous humor glucose reported to be
àbnormally high."
Peak glucose 1309 mg/dl. Reported to have a
"tendency" toward obesity but peak l3MI 21.4 kglm2.
Had race, weight gain and positive family history of
diabetes as risk factors; no personal history of diabetes,
pancreatitis or alcohol abuse. Reportedly consumed 5
to 8 liters of juice per day with normal glucose levels;
unknown if this continued to time of event when
hyperglycemia was detected and abruptly deteriorated.
Diabetic hyperglycemic coma, possible NMS and
disseminated intravascular coagulation DIC with
CPK 1739 lUlL, myoglobinuna 2500 ng/dl and
elevated WBC value not reported. Although
diagnosed with NMS, rigidity and EPS findings were
not reported as present or absent; response to
dantrolene and other measures was one of transient
improvement. MRSA diagnosed. Renal failure
requiring dialysis with creatinine clearance of 2.7
mi/mm. Diabetic coma reported as resolved without
supporting data provided. Had lack of EEG activity
following pharyngeal edema with attempted re
intubation; tracheotomy was required. Data supporting
diagnosis of DIC not provided. Death reported due to
DIC and shock; off olanzapine and concomitants
approximately 24 days prior to death.
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26 March 2003

Confidential
Olanzapine at Event Onset n=48 concluded
Table 3.3.
E
47
18.08
Case ID
USAO2OI 10463
48
30.15
USA020313247
MedDRA Preferred
Terms
Death NOS,
Diabetes mellitus
NOS,
Weight increased
Blood glucose
increased,
Death NOS,
Ncuroleptic malignant
syndrome,
Prescribed overdose
Etiology of
Glucose
Dysregulation
IN
IN
Death
Reported as
Glucose
Metabolism
Related?
U
Concomitant Drugs
with Glucose
Pancreatitis and/or
Weight Gain
U
Lithium 2,8,9
Reported Pre
Existing
Glucose
Dysregulation
U
Comments
Peak glucose unknown. Race, concomitant
medications, baseline laboratory values, personal and
family history, and habitus not reported. Developed
diabetes after gaining 45.5 kg over an unreported
interval. Duration of olanzapine use at time of event
and treatment not reported. Patient died at an
unreported interval after DM diagnosed; cause of death
not reported and unknown if autopsy was performed.
Peak glucose 1400 mgldl. Hypertension, possibly
untreated, risk factor for development of diabetes
mellitus. No personal history of diabetes mellitus;
hyperglycemia unknown. Baseline laboratory values,
weight, BMI, family history of diabetes mellitus not
reported. Diagnosed with neuroleptic malignant
syndrome NMS, hyperglycemia and died less than 26
days after starting olanzapine. Temperature, muscle
rigidity, CPK levels, pH or whether comatose not
reported. Treatment, cause of death, whether autopsy
performed and clinical details about events leading to
death not reported.
Abbreviations:
8
Weight loss; 9
I
=
Weight gain; NA = Concomitants lacked temporal association with glucose dysregulation, acidosis, pancreatitis and/or weight gain; N
Pancreatitis;
U = Unknown/not reported if concomitants being taken.

of death; NA
Unknown cause
Death not reported.
Etiology of Glucose Dysregulation: NOAE = No other apparent etiology; POE
Possible other etiology; OE = Other etiology; OP= olanzapine possible etiology; NA
Not applicable; IN
Indeterminable from reported data.

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3.2.1.2. Summary
Of the 191 severe adverse event cases potentially suggestive of glucose dysregulation
identified for this review, 48 cases involved death occurring in temporal association
with olanzapine administration. The reported cause of death in 32 of 48 66.7% cases
was either not related to glucose dysregulation 19 of 48, or the cause was unknown
13 of 48. In 16 of 48 cases 33.3%, the reported cause of death was reported as related
to glucose metabolism.
In 35 of 48 cases 72.9%, at least one concomitant drug temporally associated with
glucose dysregulation, pancreatitis, acidosis, and/or weight gain was reported. Of these
35 cases, the reported cause of death was related to glucose dysregulation or diabetes in
12 of 35 cases 34.3%, and was unknown or related to other causes in 23 of 35 cases
65.7%. In 4 of 35 death cases 11.4%, patients were also receiving valproic acid or
derivatives. Table 3.4 shows actual drug classes for concomitant drug use in these cases.
Table 3.4.
Breakdown of Reported Cause of Death

with Concomitant Drug Use by Drug Class n=35
Cause of Death
Diabetes
Mellitus
n=12
Other than
Diabetes
Mellitus
n=17
Phenothiazine Class
Atypical antipsychotics risperidone, quetiapirie
Paroxetine
Corticosteroid
Lithium
Thyroid preparation
Vaiproic acid arid derivatives
Unknown
n=6
Concomitant Medications Temporally Associated with

Glucose Dysregulation, Pancreatitis, Acidosis, and/or
Weight Gain in Deaths with Reported Evidence of Glucose
Dysregulation and on Olanzapine n=35
1
4
Carbamazepine
0
6
0
Cases having concomitant drugs, other than agents or classes
3
specified above, that are temporally associated with
hyperglycemia, diabetes mellitus, pancreatitis, acidosis and/or
weight gain i.e., none of the specified classes or agents
Note: Numbers of drugs for each cause of death exceeds the `n" for the cause of death because some
patients were taking more than one of the specified agents.
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Page 56
All 48 death cases were confounded by the presence of definite or possible other etiologic
contributing factors known to affect glucose homeostasis including preexisting risk
factors for diabetes, weight gain, medical conditions or concomitant treatment with drugs
known be associated with glucose dysregulation or weight gain, or by a lack of
information in the adverse event report that precluded clear assessment of etiologic
factors.
In 33 of 48 68.8% death cases, patients had medical conditions or diagnoses other than
concurrent acute pancreatitis that were, or could be, a contributor to or exacerbant of
glucose dysregulation. In 15 of 48 31.3% death cases, the presence or absence of a
contributing diagnosis or medical condition was not specifically reported and made
assessment of glucose dysregulation etiology indeterminable. In I of 48 cases 2.1%,
other or possible other etiologies for glucose dysregulation were present, with olanzapine
as a potential contributing factor via weight gain possibly occurring during treatment
with olanzapine or when treatment with olanzapine could not be definitively ruled out as
an additional contributor, as described in Section 2.1.2.2. There were no cases in which
olanzapine was the only apparent etiology for glucose dysregulation.
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Page 57
3.2.2. Nonfatal Coma, or Nonfatal Coma and Acidosis

Category 2
3.2.2.1. Case Tables
A total of 47 cases involved nonfatal coma, or nonfatal coma and acidosis, and met the
criteria for inclusion as a severe adverse event potentially suggestive of glucose
dysregulation temporally associated with commercially-marketed olanzapine. This
number represents all known cases of nonfatal coma or nonfatal coma and acidosis with
a data cutoff of 31 March 2002. Table 3.5 summarizes these 47 cases designated as
Category 2; Appendix C provides full narratives of these cases.
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Table 3.5.
Glucose 4 Update
26 March 2003
Category 2: Cases of Nonfatal Coma, or Nonfatal Coma and Acidosis, in Which

Glucose Dysregulation was Reported and the Patient Was on Olanzapine at Event Onset n=47
Etiology of
Glucose
.
Dysregulation
OE
12.01
Case ID
CA0004O 1405

Diabetic coma NOS,
Gastric erosions,
Peripheral neuropathy
NEC,
Renal failure acute,
Upper gastrointestinal
haemorrhage
12.02
CA010403514
Diabetic coma NOS,

Hyperglycaemia NOS,
Polyneuropathy NOS
IN
12.04
DE981 100634
Abdominal pain NOS,

Diabetic coma NOS,
Hyperglycaemia NOS,
Nausea
POE
Concomitant Drugs
Temporally Associated with
Glucose Dysregulation,
Acidosis, Pancreatitis and/or
.
Weight Gain
Ciprofloxacin 1,2,
Clonazepam 8,9,
Reported Pre
Existing
Glucose
.
Dysregulation
U
Aliopunnol 1,2,
Lithium 2,8,9,
Valproate 1,7,8,9
Chlorprothixene 2,9,
Haloperidol 2,9
Comments
Peak glucose 492 mgldL. Risk factors include
marked obesity' BMI not reported, and pieolanzapine infection NOS. Began ciprofloxacin for
unspecified infection 16 days before glucose-related
events; off antibiotic 3 days at detection of
hyperglycemia. Hospitalized with a diabetic coma,
peripheral neuropathy, acute renal failure, seizures,
erosive gastritis unreported etiology and massive
upper GI bleed. Resolution of abnormal glucose
metabolism occuned after discontinuation of
olanzapine and concomitant drugs.
Peak glucose 1153 mg/dL. Risk factor of age.
Hospitalized with diabetic coma 19 days after first
glucose elevation 463 mgldl on olanzapine and after
38 days total of olanzapine use. Resolution of
hyperglycemia occurred off lithium and olanzapine.
Peak glucose 800 mg/dL. Status of drug abuse history
and possible scquclac were not reported. De novo
presentation of Type! diabetes mellitus with acidosis.
Hospitalized in coma with pH 6.8, severe dehydration;
treated with insulin.
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Glucose 4 Update
26 March 2003
Etiology of
Glucose
.
Dysregulation
POE & OP
.E
4
15.01
Case II
DE991 201851
12.05
Reported Pre
Existing
Glucose
.
Dysregulation
Y
Comments
Peak glucose 739 mg/dL. Risk factors for
development of diabetes mellitus included age, latent
Type II diabetes mellitus reportedly without treatment
although blood glucose 180 mg/dl, and obesity BMI
33.2 kg/rn2; had elevated hepatic enzymes while
taking vaiproate and olanzapine. Family history and
baseline laboratory not reported. Seemingly stable
glucose metabolism for approximately 29 months
during the first use of olanzapine. O1anapine and
valproate discontinued due to elevated hepatic
enzymes; olanzapine re-introduced after-I month.
Diagnosed with `beginning' diabetic coma and
hospitalized. Treated initially with insulin and diet.
Resolution of diabetes occurred off olanzapinc without
insulin or special diet after initial acute therapy with
insulin.

Glucose Dysregulation was Reported, Patient Was on Olanzapine at Event Onset n=47 continued
Table 3.5.

Diabetes mellitus non
insulin-dependent,
Hyperglycaemia NOS,
Liver function tests NOS
abnormal,
Somnolence
Concomitant Drugs
.
Weight Gain
Lithium 2,8,9
Case II
DE000802838
Etiology of
Glucose
Dysregulation
OE

Diabetic coma NOS,
Mental disorder NOS due
to a general medical
condition,
Rhabdomyolysis
Concomitant Drugs
Weight Gain
Clomipramine 2,5,9,
Lithium 2,8,9
Reported Pre
Existing
Glucose
Dysregulation
Y
Comments
Peak glucose 1972 mg/ilL. Risk factors for
development of diabetes mellitus included age, obesity
BMI 29.0 kg/rn2, family history and prior
hyperglycemia. Had concurrent pneumonia, acute
renal failure, rhabdomyolysis and increased
consumption of glucose drinks with presentation in
month of July. Acidosis likely was due to dehydration
and/or renal failure and/or possibic hypotension.
Improved off olanzapine and clomipramine.
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Tabte 3.5.
Glucose 4 Update
26 March 2003

Etiology of
Glucose
Dysregulation
IN
Concomitant Drugs
Weight Gain
N
Reported Pre
Existing
Glucose
Dysregulation
U
Case ID
DEO 10906747

Diabetic hyperglycaemic
coma,
Impotence,
Loss of libido
12.06
EWC00060685
6
Diabetic coma NOS
OE
Alimemazinc 2,9,
Cyamemazine 2,9,
Lorazepam 8,9,
Milnacipran 9
11.02
EWC02012969
2
Bronchopneumonia NOS,
coma
OE
Haloperidol 2,9,
Salbutamol 2,3
11.01
Comments
Peak glucose 600 mgldL. Reportedly did not have
"predisposing factors" for developing diabetes mellitus.
No details reported concerning family history, past
medical history, habitus, baseline laboratory values or
clinical details surrounding acute events. Hospitalized
with diabetic coma and new onset diabetes mellitus.
Age 48 yrs was only reported risk factor. Reportedly
frilly recovered but with sequelae of diabetes mellitus,
off olanzapine.
Peak glucose 2060 mg/dL. Risk factors included age,
positive family history, obesity BMI 39.1 kg/m2 and
history of 3 children weighing 4.0 to 4.5 kg at birth.
Seven months prior to olanzapine initiation was
diagnosed with `latent diabetes.' Had dry mouth and
consumed 4 to 6 liters of glucose-rich drinks per day.
Acute lactic acidosis and ketoacidosis p1-I 7.24 with
coma. Glucose control improved on olanzapine and
off cyamemazine; did not resolve off olanzapine with
weight loss and insulin.
Peak glucose> 800 mg/dl. Risk factors for diabetes
included a positive family history and weight gain.
History of prior hyperglycemia when taking olanzapine
during an acute exacerbation of asthma; unknown if
asthma treated with corticosteroids. Flu-like illness
with fever in week preceding ketoacidosis pH 6.9 and
coma; concurrent bronchopneumonia at time of event.
Diagnosed with Type I diabetes mellitus with antiGAD antibodies titer 1:64 and negative anti-insulin
and anti-ICA antibodies. Intrinsic risk factors and antiGAD antibodies are etiologies for Type I diabetes
mellitus.
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Table 3.5.
Glucose 4 Update
26 March 2003

1.12
Case tD
US97021057A
10
26.08
US9703138IA
Il
1.13
US97054048A

Blood crcatinine increased,
Dehydration,
Diabetic coma NOS,
Hyperglycaemia NOS,
Hypotension NOS,
syndrome,
Pyrexia,
Weakness
Blood amylase increased,
Depressed level of
consciousness,
Pancreatitis acute,
Pyrexia,
Sedation,
Sepsis NOS
Cerebral oedema,
Coma NEC,
Renal tubular necrosis
Etiology of
Glucose
Dysregulation
OE
Concomitant Drugs
Weight Gain
Alprazolam 8,9,
Atenolol 2,
Levothyroxine 2,
Lithium 2,8,9,
Spironolactone I
hydrochlorothiazide 2,5,7,8
Reported Pre
Existing
Glucose
Dysregulation
Y
OE
Clonazepam 8,9,
Thiothixene 2,9.
Vaiproate 1,7,8,9
IN
Doxycycline 7,
Levothyroxine 2,
Lithium 2,8,9
Comments
Peak glucose 1400 mg/dL. Hospitalized in ICU with
previously undiagnosed, untreated diabetes mellitus,
NMS, hyperosmolar coma, sepsis and diabetic
ketoacidosis following seizure at home. Treated with
dantrolene, broad spectrum antibiotics, bromocriptinc,
intravenous insulin and bicarbonate. HbAlc 12.3% at
presentation after 20 days on olanzapine. Improved
following discontinuation of olanzapine and all
concomitants except carbamazepine.
Peak glucose 1672 mg/dL. Patient developed marked
hyperglycemia with diagnosed hyperosmolar,
hyperglycemic coma attributed to acute pancreatitis
and sepsis; amylase 900 lUlL. Sedation, nausea and
vomiting without reported abdominal pain preceded
DM and pancreatitis diagnoses by an unknown interval
and were treated by dose reduction of all medications.
Improved following simultaneous discontinuation of
vaiproate, clonazepam and olanzapine without
rechallenge.
Peak glucose >800 mg/dL. Patient with
hypothyroidism found unresponsive. Hospitalized
with diabetic ketoacidosis, acute tubular necrosis,
cerebral edema and coma with CPK >12.000 after
being found unresponsive. No other laboratory values
or clinical history reported; Not resolved; unknown
status of olanzapine use.
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Table 3.5.
Glucose 4 Update
26 March 2003

Etiology of
Glucose
.
Dysregulation
POE
Concomitant Drugs
.
Weight Gain
Amfebutamone 2,9,
Reported Pre.
Existing
Glucose
.
Dysregulation
U
12
1.16
Case II
US97072944A

Cerebral oedema,
Metabolic acidosis NOS
13
12.08
US97091735A
Abnormal behaviour NOS,

Diabetic coma NOS,
Hypersomnia,
Mania,
Polydipsia
POE
Clonazepam 8,9,
Lorazepam 8,9,
14
1.22
US98015059A
Abdominal pain NOS,

Depressed level of
consciousness,
Diabetes mellitus insulindependent,
Hyperglycaemia NOS,
Lethargy,
Nausea,
Polydipsia,
Polyuria,
Tachycardia NOS,
Vomiting NOS
POE
Buspirone 8.9,
Valproate 1,7,8,9
Comments
Peak glucose 1178 mg/dL. Severe, prolonged lactic
and ketoacidosis pH 7.06; HCO3 <5. Cultures and
presence or absence of sepsis not reported. In context
of prolonged acidosis and cerebral edema, case
conservatively interpreted as coma probably present.
No baseline laboratory values reported. `Normal'
serum glucose 4 to 6 weeks prior to onset of events;
unknown if this was a baseline measurement or if
occurred during olanzapine therapy. Event resolved
with insulin use; insulin continued but status of
olanzapine use unknown.
development of diabetes mellitus included age and
possible hypertension. Ingestion of large quantities of
malted beverages occurred during medication noncompliance and benzodiazepine abuse. Had
hypersomnia, polydipsia and lost consciousness; taken
to ER and diagnosed with diabetic coma. Negative
olanzapine rechallenge at reduced dose.
Peak glucose 404 mg/dL. Duration of olanzapine use,
baseline glucose and HbAlc not reported. Presented
with acute abdominal pain, nausea, vomiting and
depressed level of consciousness; diagnosed with
diabetic ketoacidosis pH 6.83, HCO3 7.7 and pCO2 9
mmHg, anion gap 30.2, and ketonuria present.
Amylase, lipase, diagnostic tests not reported.
Reportedly patient may have had undiagnosed pre
olanzapine diabetes mellitus; mother died at age 24
from DKA. Depressed level of consciousness
conservatively assessed as possible coma.
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Table 35.
Glucose 4 Update
26 March 2003

Glucose Dysregulation was Reported, Patient Was on Otanzapine at Event Onset n=47 continued
15
cu
1.28
Case ID
US980503939

Cough,
Pancreatitis N OS,
Somnolence,
Weight increased
16
18.28
US980910808
Abdominal distension,
Abdominal pain NOS,
Coma NEC,
Hyperglycaemia NOS,
Muscle rigidity,
syndrome,
Pyrexia
Etiology of
Glucose
Dysregulation
OE
OE
Concomitant Drugs
Weight Gain
NA
Paroxetine2,5,6,7,8,9
Reported Pre
Existing
Glucose
Dysregulation
U
Comments
Peak glucose 1160 mg/dl. Tolerated olanzapine for 17
months without hyperglycemia reported. Obesity
BMI 27.4 kg/rn2 and weight gain 4.5 06.8 kg.
Week-long prodrome of sore throat and cough treated
with elixir; became increasingly somnolent; flu-like
illness with R LL pneumonia, pancreatitis, and
poorly arousable" at presentation; Urine positive for
RBC and WBC; diagnosed with diabetic ketoacidosis,
pH 6.82, anion gap 21 and positive serum acetone test.
Concurrent pancreatitis, pneumonia and possible UT!
were precipitating factors. OTC cough medicine may
have contained alcohol or glucose. Event resolved
with insulin, off olanzapine; insulin then discontinued.
Peak glucose 2600 mg/dL. Baseline blood glucose,
personal and family history, height and habitus not
reported. Abdominal pain which preceded event by 2
days was not further described. Intra-abdominal
infection, cholelithiasis or pancreatitis of unknown
etiology or secondary to the marked hyperglycemia
and likely dehydration were not reported ruled-out.
Event included coma and profound hyperglycemia with
blood glucose 2600 mg/dl. Diagnosed with NMS by
some physicians; reporting physician thought NMS
was erroneous diagnosis. Concurrent fever, renal and
pulmonary failure, and possible infection.
Improvement inferred based on transfer from ICU to
rehabilitation; unknown status of olanzapine use.
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Table 3.5.
Glucose 4 Update
26 March 2003

17
1.34
Case ID
US981012355

Aggression,
Appetite increased NOS,
Coma NEC,
Convulsions NOS,
Depressed level of
consciousness,
Fatigue,
syndrome,
Pneumonia aspiration,
Respiratory failure exc
neonatal
18
10.02
US98 1112856

Nonketotic hypcrglycaemichyperosmolar coma,
Respiratory distress
Etiology of
Glucose
Dysregulation
POE
OE
Concomitant Drugs
Weight Gain
Fluoxetine2,3,5,7,8,9
Atenolol/chlorthalidone 2,
Reported Pre
Existing
Glucose
Dysregulation
U
Comments
Peak glucose 1305 mg/dL. Race, obesity BMI 40.3
kg/rn2, and family history of diabetes are risk factors
for diabetes. Baseline mild elevation of CPK, GGT
and alkaline phosphatase. Presented in coma; CSF and
"other' unspecified cultures negative. Differential
diagnosis of acute event included NMS 42.2C,
rigidity, CPK 15,000 tilL vs. DKA vs. meningitis.
Diagnosed with diabetic ketoacidosis; pH, HCO3, urine
and serum ketones not reported. Event treated with
bromocystine and dantrolene for possible NMS, and
insulin and hydration for DKA. Seizures were treated
with diphenylhydantoin. Treated with antibiotics and
anti-virals for possible meningitis. Treated with
metromidazole for aspiration pneumonia.
Peak glucose 1676 mg/dL. Risk factors for diabetes
mellitus included hypertension and morbid obesity
weight 146.8 kg; family history and baseline
laboratory values not reported. Nonkctotic
hyperglycemic hyperosmolar serum osmolality 416
mosm/kg coma and acute pansinusitis at presentation.
Other laboratories included glycosuria 4+, HbAI C
21.7%, peak BUN/creatinine 87 mg/dl /5.2 mg/dl.
Reported to have respiratory acidosis and ventilatory
failure. Treatment included insulin, dopamine,
intravenous hydration and furosemide. Required
intubation, artificial ventilation and intravenous
ciprofloxacin and ceftriaxone for pansinusitis. Possible
Cushing's syndrome suspected. Resolved off
olanzapine, chlorthalidone and concomitants.
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Table 3.5.
Glucose 4 Update
26 March 2003

Etiology of
Glucose
.
Dysregulation
POE
Concomitant Drugs
.
Weight Gain
Lithium 2,8,9,
Valproate 1,7,8,9
Reported Pre
Existing
Glucose
.
Dysregulation
U
19
18.30
Case ID
US9901 15337

Depressed level of
consciousness,
Pyrexia
20
18.31
US9901 16671
Agitation,
Confusion,
Dehydration,
Intubation N OS,
Mental status changes,
Pancreatitis NOS,
Weakness
POE
Diphenhydramine 9
21
4.02
US9903 19151
Coma NEC,
Convulsions NOS,
Electrocardiogram abnormal
NOS,
Hyperglycaemia NOS,
Hypertension NOS,
Ketonuria present,
Muscle rigidity,
Respiratory rate increased,
Salivary hypersecretion,
Tachycardia NOS,
White blood cell increased
OE
Sertraline 2,5,7,8,9
U rI
Comments
Peak glucose 900 mg/dL. Age was on'y reported risk
factor. Baseline blood glucose, personal and family
history, height and weight were not reported.
Diagnosed with diabetes mellitus and possible coma
`depressed level of consciousness'; hospitalized in
ICU with temperature peak 41 .1C rectally, was not
rigid; CPK level not reported. Outcome unknown off
olanzapine, lithium and vaiproate.
Peak glucose 1400 mgldL. Baseline blood glucose,
personal and family history, particularly lipid
metabolism and alcohol history, height and weight not
reported; reported to be a `poor historian." Race only
reported risk factor for diabetes. Hospitalized in ICU
for treatment of nonketotic, hyperglycemic state `close
to coma; trace serum ketones and serum osmolarity>
400 mosm/L; pH and bicarbonate not reported.
Diagnosed with concurrent pancreatitis with serum
lipase 5000 U/L; amylase not reported. Symptoms and
signs of pancrcatitis not reported. Improved off
olanzapine and diphenhydramine; continued to require
insulin following olanzapine cessation. Conservatively
catcgorized as coma.
Peak glucose 204 mgldL. Age only reported risk factor
for diabetes mdllitus. Weight, BMI, baseline
laboratory values, personal and family history not
reported. Hospitalized with hyperglycemia and coma
occumng in Context of seizure activity of unknown
etiology; one day following dose incrcases of sertraline
to 100 mg daily and olanzapinc from 15 mg to 20mg.
Decorticate posturing and rigidity noted in post-ictal
period; EEG normal. HCO3 21 meq/L and trace
ketonuria. Arterial pH not reported. No diagnosis of
diabetes or treatment reported. Negative rechallenge
on reduced olanzapinc dose with sertralinc
discontinued.
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Confidential

Table 3.5.
-
P
a
22
11.04
Case ID
US990522556

coma,
Hyperglycaemia NOS
23
25.30
US990522804
Agitation,
Blood alkaline phosphatase
NOS increased,
Blood urea decreased,
Bronchitis NOS,
Coma NEC,
Dermatitis NOS,
Dysarthria,
Hyperglycaemia NOS,
Non-accidental overdose,
Pyrexia,
neonatal,
Sinus tachycardia
Etiology of
Glucose
Dysregulatlon
POE
OE
Concomitant Drugs
.
.
Weight Gain
Haloperidol decanoate 2,9,
Hydrochlorothiazide 2,5,7,8,
Propranolol 2
Vaiproic acid 1,7,8,9
Reported Pre
Existing
Glucose
*
Dysregulation
U
Comments
mellitus were race and hypertension. Hospitalized with
diabetic coma. No clinical details about the acute
event were reported. No follow up data reported about
status of olanzapine or concomitant medication use;
continued on insulin.
Peak glucose was 299 mg/dl. This was exacerbation of
pre-existing diabetes mellitus in morbidly obese BMI
40.7 kg/rn2 male following ingestion of alcohol, fever
with bronchitis, and overdose of olanzapine 520 mg
and beer followed by coma. His ùsual" blood
pressure was 140/90 mmHg. Rash during cefuroxime
therapy for bronchitis was treated with
methyiprednisolone, Oral hypoglycemic agent
continued after discharge, off olanzapine.
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Olanzapine LYI 70053

Confidential

Table 3.5.
24
4.03
Case II
US990725071

Ammonia increased,
Blood triglycerides
increased,
Dehydration,
Drooling,
Fungaemia,
Glyeosuria present,
Flyperglycaemia NOS,
Ketonuria present,
Lethargy,
Nonketotic hyperglycaemichyperosmolar coma,
Pneumonia NOS,
25
10.03
US991232959
Aortic thrombosis,
Coagulation time NOS
shortened,
Dehydration,
Drug level NOS changed,
Gangrene NOS,
Hyperglycaemia NOS,
Nephrogenic diabetes
insipidus,
syndrome,
Nonlcetotic hyperglycaemichyperosmolar coma,
Pain in limb,
Peripheral ischaemia NOS,
Renal impairment NOS,
Weight increased
Note: Case
information also
appeared under
duplicate case
II
US000134310;
all data moved
to this ease ID
US99I 232959
Etiology of
Glucose
Lysregulation
OE
OE
Concomitant Drugs
Temporally Associated ith
Weight Gain
Haloperidol 2,9,
Lorazepam 8,9,
Loxapine 2,8,9,
Valproate 1,7,8,9
Clonazepam 8,9,
Enalapril 7,
Lithium 2,8,9,
Nicotinic acid 2,9,
Valproic acid 1,7,8,9
Reported Pre
Existing
Glucose
Dysregulation
Y
Comments
Peak glucose 800 mg/dl. Race and obesity BMI 28.9
kg/rn2 were intrinsic risk factors for developing
diabetes. Prior episodes of insulin-requiring
hyperglycemia on clozapine. First episode of diabetes
occurred after 9 months on olanzapine in context of
hypertriglyceridemia and probable significant hepatic
dysfunction demonstrated by blood ammonia elevation.
Resolution of hyperglycemia with trace ketonuria
occurred with continued olanapine. Second episode
described as nonketotic, hyperglycemic. hyperosmolar
coma. Patient had concurrent renal failure, sepsis due
to fungus unspecified primary site, acute bacteremia
and pneumonia. Required extensive treatment of
infection, discontinuation of olanzapine and all
concomitants; on insulin after discharge; negative
olanzapine rechallenge after second hyperglycemic
event.
Peak glucose 942 mg/dL. Very complex patient with
multiple diagnoses. Intrinsic risk factors for diabetes
mellitus included age, hypertension, dyslipidemia,
obesity BMI 34.6 kg/rn2 and positive family history.
Had pre-existing peripheral vascular disease and
developed gangrenous left foot with subsequent
amputation. Diagnosed with non -ketotic
hyperglycemic hyperosmolar coma. Had toxic lithium
levels and manifested nephrogenic diabetes insipidus
with subsequent hyperosmolar, hypercoagulable state
with aortic thrombosis. Also developed a
pseudomonas infection at unspecified site; required
cholecystectomy during acute hospitalization.
Improved off olanzapine and lithium and on insulin
followed by oral hypoglycemic.
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Confidential

Table 3.5.
Etiology of
Glucose
Dysregulation
OE
Concomitant Drugs
Weight Gain
Albuterol 2,
Atorvastatin 2,7,9,
Clonazepam 8,9,
Fluphenazine 2,9,
Gabapentin 2,8,
Glipizide,
Losartan / hydrochiorothiazide
2,5,7,8,
Terazosin 9,
Theophylline 2,
Torsernide 2,
Valproate 1,7,8,9
Reported Pre
Existing
Glucose
Dysregulation
U
26
U
1.40
Case ID
US99 1233035

Blood alkaline phosphatase
NOS increased,
coma,
Overdose NOS,
Pancreatitis acute,
Psychotic disorder NOS
27
10.04
US0001 34612
Hyperglycaernia NOS,
Pneumonia NOS
OE
Gabapentin 2,8,
Lansoprazole 2,8,
Metoprolol 2,
28
1.43
US000235232
Diabetic coma NOS,

POE
Valproate 1,7,8,9
Comments
Peak glucose 400 mg/dl. Obesity BMI 31.3 kg/rn2,
age, family history of diabetes, hypertension and
dyslipidemia were risk factors for diabetes. Diagnosed
with diabetic ketoacidosis with coma and pancreatitis.
Anion gap, pH, HCO, urine and serum ketones,
amylase, lipase and treatment of event not reported.
Second episode of pancreatitis diagnosed after off
olanzapine 2 months and on fluphenazine with normal
lipase, amylase. elevated BUN and creatinine. First
episode resolved on olanzapine and off valproate;
olanzapine then discontinued and fluphenazine begun
for control of psychosis. Following resolution of 2nd
episode of pancreatitis there was a negative olanzapine
rechallenge.
mellitus were age, overweight BMI 26.3 kg/rn2,
dyslipidemia, hypertension and alcohol abuse.
Concurrent pneumonia treated with clindarnycin and
ofloxacin. Pre-olanzapine esophageal stricture was
risk for aspiration. Patient developed hyperosmolar.
hyperglycemic, non-ketotic coma lasting less than 24
hours. Resolved off olanzapine with pneumonia
treated.
Peak glucose 1300 rng/dL. Presented with nausea,
polydipsia and polyuria after 15 months on olanzapine;
hospitalized with diabetic ketoacidosis and diabetic
coma. Intrinsic risk factors included ethnicity,
overweight with BMI 25.6 kg/rn2 and familial diabetes.
Treated with insulin and continued to require insulin 5
months after olanzapine was stopped.
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Table 3.5.
Concomitant Drugs
Weight Gain
Fluvoxamine 2,5,8,9,
Mirtazapine 2,8
Etiology of
Glucose
Dysregulation
POE
Reported Pre
Existing
Glucose
Dysregulation
U
29
r r,
12. 07
Case ID
US000236390
McdDRA Preferred Terms

Diabetic coma NOS
30
10.05
US000338309

Nonketotic hyperglycaemichyperosmolar coma
POE
Amfebutamone 2,9,
Valproate 1,7,8,9
31
1.50
US000642765
Blood creatinine increased,

Blood triglycerides
increased,
Pancreatitis NOS,
Weight decreased,
Weight increased
OE
Atenolol 2,
Diltiazern 2,9,
Oxazepam 8,9,
Comments
Peak glucose 1300 mg/dL. Personal and family
history, weight and baseline blood glucose levels not
reported. Had glucose "spikes" during 2-year period
while taking olanzapine, carbamazepine, fiuvoxamine
and mirtazapine. Developed diabetic coma in month
following transition from mirtazapine to fluvoxamine.
Hospitalized; treatment not reported. Resolved off
olanzapine, fluvoxamine and carbamazepine.
development of diabetes mellitus included age, obesity,
hypertension, alcoholism and family history. Had
mental changes described as probable hyperosmolar
coma. Concomitant drugs begun same date as
olanzapine.
Peak glucose 1069 mg/dL. Had multiple intrinsic risk
factors: age, race, obesity, BMI 32.8 kg/rn2, family
history, hypertension, possible hyperlipidemia, history
of pancreatitis. Also had coronary insufficiency,
seizure disorder, and chronic renal insufficiency. Lost
16.4 kg over 2 years then regained 5.5 kg in 2-5
months prior to DKA. Hospitalized with DKA and
possible coma altered mental state' and `mild"
pancreatitis amylase 263 lUlL, lipase 1509 lU/L;
gastrointestinal symptoms and signs were not reported.
Treated with insulin which still was required after
olanzapine stopped. Triglycerides 773 mg/dl on
admission. Conservatively assessed as coma being
present.
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Table 3.5.
Glucose 4 Update
26 March 2003

32
26.26
Case ID
USD00846904

Depressed level of
consciousness,
Polydipsia,
Polyuria,
Weight increased
33
26.30
US001051222

NEC
34
2.25
USD01152751
Blood potassium increased,

Ketoacidosis,
Overdose NOS,
Sedation,
Vomiting NOS
Etiology of
Glucose
Dysregulation
POE & OP
IN
POE
Concomitant Drugs
Weight Gain
Halopcridol 2.9
Reported Pre
Existing
Glucose
Dysregulation
U
NA
Clonazepam 8,9,
Zaleplon 2,5,6,8,9
Comments
Peak glucose 700 mgldL. Risk factors included race
and weight gain of 13.6 to 18.2 kg during olanzapine
therapy; habitus and BMI were not reported.
Hospitalized with possible coma òut of it".
Reported data also lacked baseline laboratory values,
habitus, personal and family medical history. Event
resolved off olanzapine; acute treatment of
hyperglycemia was reported to be unknown.
Conservatively assessed as coma being present.
Peak glucose> 1500 mg/dL. Found unconscious in his
room at a boarding house. Although hyperglycemia
and coma reportedly resolved off olanzapine, the case
lacked clinical data about baseline laboratory values,
concurrent medical diagnoses, premorbid state, and
family history for assessment of possible role of
olanzapine.
Peak glucose 771 mg/dL. Race, positive family history
were intrinsic risk factors for developing diabetes.
Concurrent abdominal pain, nausea, vomiting,
impaired consciousness, polyuna and polydipsia;
diagnosed with diabetic ketoacidosis, with potassium
6.0 mg/dl; pH, HCO3, serum and urine ketones not
reported. Unknown if abdominal pain, nausea,
vomiting represented primary event such as
cholecystitis or pancreatitis, or were secondary to
diabetic ketoacidosis. Conservatively assessed as
coma being present.
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Table 3.5.
35
1.61
Case ID
US010259819

Abdominal pain NOS,
Aspartate aminotransferase
increased,
Cerebrovascular accident
NOS,
Diabetic coma NOS,
Encephalopathy NOS,
Pancreatitis NOS
36
26.41
USOI 0361819
Abdominal pain NOS,

Confusion,
Headache NOS,
Vomiting NOS,
Weakness
37
12. 10
US010463302
Diabetic coma NOS
Etiology of
Glucose
Dysregulation
OE
Concomitant Drugs
Weight Gain
N
Reported Pre.
Existing
Glucose
Dysregulation
N
POE & OP
IN
Conunents
Peak glucose 600 mg/dL. Being overweight BMI 25.3
kg/rn2 was risk factor for diabetes. No past history of
hyperglycemia. Had been stable for 2 years on
olanzapinc with one-time hyperglycemia, a few months
prior to DKA. Diagnosis of DKA preceded by 24-hour
prodrome of flu-like illness, abdominal pain, and
normal glucose and amylase on 2 occasions on the day
of onset. Diagnosed with pancreatitis, diabetic
ketoacidosis, coma, CVA at an unspecified time and
encephalopathy. History positive for substance and
alcohol abuse. Improved off olanzapine; treatment
unknown. Cholclithiasis not reported as present or
absent.
Peak glucose 1300 mg/dL. Age was only reported risk
factor for diabetes mellitus. Had elevated blood
glucose 3 to 6 months after starting olanzapine; refused
further levels, missed appointments, and lost to follow
up until `being near diabetic coma' and went to
emergency room. Concurrent events after 6 to 9
months of olanzapine included 5 day history of
vomiting, abdominal pain, headache, and confusion.
Improved and "stabilized' on olanzapine and insulin.
Information about concomitant medications, habitus
and past and concurrent medical histories not reported.
Conservatively assessed as coma being plesenL
Peak glucose unknown. Personal history of
"borderline" diabetes mellitus, age, race, family
history, height, weight, baseline laboratory values and
concomitant medications not reported. Diagnosed with
diabetic coma, unknown if hospitalized. Clinical
context of events, treatment, Outcome and laboratory
values not reported.
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Table 3.5.
.9
38
10.07
Case ID
US010566463
MedORA Preferred Terms

Dehydration,
Pancreatitis acute,
Pneumonia NOS,
Pyrexia,
Venous thrombosis NOS.
White blood cell increased
39
1.73
US010770537
Diabetic kctoacidosis
Etiology of
Glucose
.
Dregu1ation
POE
POE
Concomitant Drugs
.
Weight Gain
N
Reported Pre
Existing
Glucose
.
Dysregulation
Li
Comments
Peak glucose 1626 mgldL. Risk factors for
history and weight gain preceding olanzapine
initiation. Presented with fever, 2 to 3 days of
abdominal pain and nausea, fatigue, increasing
polyuria and polydipsia for 7 days, and weight loss.
Hospitalized with nonketotic, hyperosmolar,
hyperglycemic coma, DVT, pneumonia, pancreatitis
and acidosis with bicarbonate 16 meqlL, venous pH
7.21, BUN 59 mg/dl, creatinine 4.1 mgldl, amylase 449
U/L, lipase 953 U/L, cholesterol 276 mgldl and
triglycerides 460 mgldl; treated with insulin.
Concurrent DVT treated with anticoagulants and left
lower lobe pneumonia treated with antibiotics; fever to
104.0F. Required renal dialysis. Radiologic study of
pancreas not reported. Hyperglycemia recurred 14
months subsequent to olanzapine discontinuation after
additional weight gain.
Peak glucose 512 mg/dL. Hyperglyccmia181 mg/dl
6 months prior Lo olanzapinc. Risk factors for diabetes
included race, obesity BMI 31.5 kg/rn2, and pre
olanzapine hyperglyccmia. Diagnosed with diabetic
ketoacidosis, hospitalized with pH 7.06, ketonuna,
glycosuna, and Kussmaul respirations. Consciousness
level was TCS of 20/100. Improved off olanzapinc and
on insulin; continued to require insulin, off olanzapine.
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Table 3.5.

40
26.46
Case ID
US011074916

Apnoea,
Coma,
Hypothermia,
41
11.05
USOI 1076561
coma,
Pressure sore
Etiology of
Glucose
Dysregulation
OE
OE
Concomitant Drugs
Weight Gain
Brotizolam 8,9,
Diazepam 8,9,
Haloperidol 2,9,
Quazepam 8,9,
Quetiapine 2,7,8
Donepezil hydrochloride 2,8,9,

Flunitrazepam 8,9,
Promethazinc hydrochloride
2,9
Reported Pre
Existing
Glucose
Dsregulation
U
Comments
Peak glucose 340 mg/dl at presentation in coma.
Weight, BMI, personal and family history of diabetes,
baseline laboratory values not reported. Incontinent of
urine 3 days after starting olanzapine; no glucose levels
reported. Coma and hyperglycemia occurred I day
after olanzapine discontinued. Patient hypothermic
35C, heart rate 90 bpm, blood pressure 100/52
mmHg, oxygen saturation 93%, no response to pain,
pupils dilated and unresponsive. Apnea reported on
way to hospital; resolved with cardiac massage. Past
medical history not reported, "no abnormalities found"
by blood test NOS or on MRI NOS or computed
tomography NOS. No toxicology specified as
performed. Outcome was resolved off olanzapine and
all concomitants and unknown during rechallenge of
òriginal medications."
Peak glucose 748 mgldl. Patient with medical history
alcoholic dementia and hepatopathy, insomnia, druginduced parkinsonism. "severe" diabetes mellitus with
gangrene NOS, non-compliance with oral
hypoglycemic agents. Family history and habitus
unknown. Baseline glucose 194 mg/dl. Discontinued
glibenclamide on her own. Concurrent pressure ulcers;
treated with IV fluids, antibiotics NOS. Diagnosed
with varicella NOS. Developed somnolence,
decreased level of consciousness. Hospitalized,
diagnosed with hyperglycemic coma; pH, HCO3,
serum and urine ketones not reported. Treated with IV
fluids and insulin; outcome resolved off olanzapine;
negative olanzapine rechallenge.
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Table 35.
42
15.07
Case ID
IJSOI 1176945

Coma,
insulin-dependent,
Non-accidental overdose,
Pneumonia aspiration,
Prescribed overdose,
Rhabdomyolysis
43
12.12
USQI 1278836
Diabetic coma NOS,

Weight increased
Etiology of
Glucose
Dysregulation
POE
POE & OP
Concomitant Drugs
Glucose Lysregulation,
Weight Gain
Alprazolain 8,9,
Amfebutamone hydrochloride
2,9,
Levothyroxinc sodium 2,
Lorazepam 8,9,
Sertraline hydrochloride
2,5,7,8,9,
Oral hypoglycemic agent
NOS
Vaiproate sodium 1,7,8,9
Reported Pre
Existing
Glucose
Dysregulation
U
Comments
Peak glucoses unknown. Past medical history of
Graves disease post thyroidectomy with iatrogenic
hypothyroidism; hypertension, horse-shoe shaped
kidney, nicotine use, and obesity BMI 43.0 kg/rn2; no
family history of diabetes reported. Patient with
prescribed overdose developed non-insulin dependent
diabetes mellitus; baseline glucose not reported.
Reportedly began oral hypoglycemic agent NOS.
Ten months later, intentionally overdosed on 1500mg
olanzapine and 30 mg alprazolarn; taken to ER, treated
with activated charcoal, ventilatory support.
Hyperglycemia during coma was not specified.
Diagnosed with coma, aspiration pneumonia,
rhabdomyolysis CPK not reported; pH, HCO1, serum
and urine ketones not reported. Overdose improved off
olanrapine but with residual weakness, neuritic
numbness and extremity pain; unknown outcome of
NIDDM. Continued olanzapine use following NIDDM
diagnosis with unknown outcome; olanzapine and
alprazolam discontinued after intentional overdose.
Peak glucose 800 mg/dl. Risk factors for developing
diabetes mellitus included positive family history, race
and weight gain while taking olanzapinc and valproate;
height, BMI and baseline laboratory values not
reported. Diagnosed with diabetic coma, unknown if
hospitalized. Concurrent weight gain 9.5 kg.
Treatment included insulin and diabetic diet. Outcome
was improved, off olanzapine; status of valproate use
unknown.
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Table 3.5.
Glucose 4 Update
26 March 2003

,,$,
44
c
10.09
Case II
USD1 1279411

Nonketotic hyperglycacmichyperosmolar coma
Etiology of
Glucose
Dysregulation
OE
Concomitant Drugs
Temporally Associated th
Weight Gain
Aminoleban 2,4,
Flunitrazepain 8,9,
Lorazepam 8,9
Reported Pre
Existing
Glucose
Dysregulation
Y
Comments
Peak glucose 668 mg/dl. Known to be diabetic,
treatment not reported. Had an inability to eat with
need for parenteral and gavage alimentation due to
hanging by a hose in pre-olanzapine suicide attempt.
Additionally, she had an unspecified infection, pre
olanzapine possibly pneumonia, which required
systemic antibiotics. Diagnosed with nonketotic
hyperglycemic, hyperosmolar coma with glycosuria
3+, polyuria and hypernatremic sodium 177 mcqlL,
glycosuria 149 gmiday, urine sodium 46 meq/L,
ammonia 324 mo units reported], osmotic pressure 410
mmHg. Treatment included intravenous fluid and
insulin drip. The reporter considered dehydration and
infection the principal causes of increased blood
glucose levels. Event resolved off olanzapine.
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Table 35.
ss
a
45
12.13
Case ID
US020383076

Diabetic coma NOS,
Glycosylated
haenioglobin increased,
Weakness,
Gait abnormal NOS,
Tremor,
Dysphagia
46
23.02
USAOI 1210215

Depressed level of
consciousness,
Lethargy,
Hypertension NOS,
Heart rate increased,
Glycosylated haemoglobin
increased
Etiology of
Glucose
.
Dysregulation
OE
POE
Concomitant Drugs
.
Weight Gain
Delapril hydrochloride 7,
Flunitrazepam 8,9,
Haloperidol 2,9,
Human insulin RDNA origin
Nateglinide,
Promethazine hydrochloride
2,9,
Chlorpromazinelpromethazine/
phenobarbital 2, 9,
Donepezil hydrochloride 2,8,9,
Gabapentin 2,8,
Loratadine 9,
Mirtazapine 2,8
Reported Pre
Existing
Glucose
.
Dysregulation
Y
Comments
Peak glucose 389 mg/dl on olanzapine and 819 mg/dl,
15 days after olanzapine discontinued. Risk factors for
glucose dysregulation included Type I diabetes
mellitus, hypertension, arteriosclerosis and inferred
dyslipidemia. Baseline glucose 191 mg/dl; no baseline
HbAlc. Reported `coma' had purposeful response to
noxious stimuli compatible with obtundation rather
than coma. Sensorium cleared after discontinuation of
pharmacopoeia of neuroleptic medications and after
fluid replacement.
Peak glucose 1053 mg/dl. Past medical history
included Alzheimer's disease. No BMI reported; no
other relevant history reported, including diabetes.
Family history not reported. Risk factor for diabetes
mellitus was age. After taking olanzapine for
approximately 19 months, diagnosed with
hyperglycemia and elevated blood pressure NOS. No
baseline laboratory data were reported. No urine or
serum ketones, pH, HCO, nor clinical status was
reported other than "impaired consciousness."
Olanzapine and all concomitant medications stopped
the day of presentation. The next day, blood glucose
was mid-300s mg/dl. Approximately I month later,
glucose was 123 mg/dl and ilbAic 9.1%. Outcome
was resolved, off olanzapine and all concomitant
medications.
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Glucose Dysregulation was Reported, Patient Was on Olanzapine at Event Onset n=47 concluded
Table 3.5.
cs
,.
-
47
1214
Case ID
USAO2OI 10503
MedURA Preferred Terms

Diabetic coma NOS.
Rhabdomyolysis,
Weight increased
Etiology of
Glucose
.
Dysregulation
POE & OP
Concomitant Drugs
Glucose Dysrcgulation,
.
.
Weight Gain
Allopurinol 1,2,
Atenolol 2,
Furosemide 2,5,7,
Gabapentin 2,8,
Levothyroxine sodium 2,
Loxapine suecinatc 2,8,9,
Nifedipine 9
Reported Pre
Existing
Glucose
.
Dysregulation
U
Comments
Peak glucose 1501 mg/dl. Age, race, hypertension,
positive family history of diabetes, history of alcohol
abuse and weight gain 14.5 kg during the course of
olanzapine were risk factors for developing diabetes
mellitus. Dates of introduction and durations of
cnocmitnat medication use were not reported. Found
comatose and diagnosed with diabetic coma and was
acidotic p1-I 7.2 with concurrent rhabdomyolysis
CPK not reported; suspected of being in diabetic
coma for several days based on presence of
rhabdomyolysis. Fluid status not reported. Treatment
not reported. Improved off olanzapine. Unknown if
concomitant medications continued.
Abbreviations:
8
Weight loss; 9 = Weight gain; NA =
I
=
Acidosis, Lactic acidosis, Metabolic acidosis; 2 = Diabetes mellitus, Glucose tolerance decreased, Glycosuria,
I-typcrosmolar non-kctotic coma; 5
Hyperlipidcmia, Hypertriglyceridemia; 6
=
=
Pancreatitis;

Etiology of Glucose Dysregulation: NOAE = No other apparent etiology; POE
Possible other etiology; OE
Other etiology; OP= olani.apine possible etiology; NA
Not applicable; IN

Reported Pre-Existing Glucose Dysregulation Hyperglycemia and/or Diabetes metlitus: Y
olanzapine use; U
Unknown if glucose dysregulation preceded olanzapine use.
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3.2.2.2. Summary
identified for this review, 47 cases involved nonfatal coma or coma and acidosis
occurring in temporal association with olanzapine administration.
Of these 47 cases, 39 83.0% were receiving concomitant medications known to be
temporally associated with glucose dysregulation, pancreatitis, acidosis, and/or weight
gain. In 12 of these 39 cases 30.8%, patients were receiving concomitant vaiproic acid
or derivatives. The actual drug classes for concomitant drug use in these 39 cases is
presented in Table 3.6.
Table 3.6.
Use of Concomitant Medications in Non-Fatal Cases of

Coma or Coma and Acidosis n=39
Use of Concomitant
Medications in Non-Fatal
Cases of Coma or Coma and
Acidosis
n49

Glucose Dysregulation, Acidosis, Pancreatitis, and/or
Weight gain in Patients with Reported Evidence of
Glucose Dysregulation, on Olanzapine, in Non-fatal
cases
Phenothiazines
Atypical anti-psychotics Risperidone, Quetiapine, Clozapine
Paroxetine
Corticosteroid
Lithium
Thyroid preparation
Vaiproic acid and derivatives
12
Carbamazepine
Cases having concomitant drugs that are temporally
associated with hyperglycemia, diabetes mellitus, pancreatitis,
acidosis and/or weight gain and none of the agents or classes
specified above.
11
Note: Numbers of drugs for each category of pathology exceeds the `n' for that pathology because some
patients were taking more than 1 of the specified agents.
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Forty-two of these 47 cases 89.4% had other or possible other etiologic factors for
glucose dysregulation including preexisting risk factors for diabetes, weight gain,
concurrent medical conditions or concomitant treatment with drugs known be associated
with glucose dysregulation, or pancreatitis. In 5 of 47 cases 10.6%, a lack of
information in the adverse event report precluded clear assessment of etiologic factors.
In 5 of 47 cases 10.6%, other or possible other etiologies for glucose dysregulation were
present, with olanzapine as a potential contributing factor via weight gain possibly
occurring during treatment with olanzapine or when treatment with olanzapine could not
be definitively ruled out as an additional contributor, as described in Section 2.1.2.2.
There were no cases in which olanzapine was the only possible etiology for glucose
dysregulation.
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3.2.3. Acidosis, Non-Coma, Nonfatal Category 3

32.3.1. Case Tables
A total of 96 cases involved non-coma, nonfatal acidosis and met the criteria for
inclusion as a severe adverse event potentially suggestive of glucose dysregulation
temporally associated with commercially-marketed olanzapine. This represents all
known cases of nonfatal, non-coma acidosis with a data cutoff of 31 March 2002.
Table 3.7 summarizes these 96 cases designated as Category 3; Appendix C provides
full narratives of these cases.
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Category 3: Cases of Acidosis Non-Coma, Nonfatal in Which Glucose Dysregulation was Reported
and the Patient Was on Olanzapine at Event Onset n=96
Table 3.7.
MedDRA Preferred
Terms
Pancreatitis NOS
Etiology of
Glucose
.
Dysregulation
POE
Concomitant Drugs
Temporally Associated iith
.
Weight Gain
N
Reported Pre
Existing
Glucose
.
Dysregulation
Y
1.01
Case ID
CA990600604
1.02
CA010403555

Weight increased
OE & OP
Chlorpromazine 2,9
1.03
DE990200873

insulin-dependent,
Weight increased
POE & OP
NA
18.01
DE0003021 18
Diabetes mellitus
NOS,
Hypercholesterolaemia,
Hyperlipidaemia NOS,
Liver function tests
NOS abnormal,
Pancreatitis NOS
OE
Comments
Peak glucose unknown. Hospitalized with acute
pancreatitis Grade D or E on CT scan and diabetic
ketoacidosis ten days after olanzapine started; HbAlc
èlevated' at time of diagnosis. No reported laboratory
values. Reported as "probably' undiagnosed and untreated
diabetes mellitus for `some time." Paroxetine and
tritluopcrazine discontinued 17 days before presentation
with IJKA; known concurrent alcohol use. Improved off
olanzapine.
Peak glucose 676 mg/dL. Long history of substance abuse
including dimenhydrinate; adult height of 1.16 m 3 It, 10
in. Had a 9 kg weight gain during concurrent
chiorprornazine and olanzapine use; peak BMI 51.6 kg/rn2.
Hospitalized with diabetic ketoacidosis pH 7.05; HbAl c
19.7%. Positive olanzapine dechallenge, rechallenge,
dechallenge; status of insulin use not reported.
Peak glucose 550 mg/dL. Had a 50kg gain to peak weight
150 kg BMI 41.6kg/rn2 at onset. Hospitalized with
diabetic ketoacidosis venous pH 7.19; treated with
insulin. Possible concurrent alcohol intake; positive family
history; treated with unspecified diuretic. Improved on
olanzapine with insulin use.
Peak glucose 784 mg/dL. Participating in a post-marketing
study. Risk factors of baseline obesity and alcohol abuse
history; no prior history of pancreatitis or concurrent
alcohol use. Baseline elevated GGT of unreported
etiology. Previous antipsychotic medications fluphenazine
and levornepromazine have temporal association with
glucose dysregulation and weight gain; no concomitant
medication. Metabolic acidosis pH 7.15.
Hypertnglyceridemia present concurrently. Glucose
dysregulation improved and pancreatitis resolved on
olanzapine, diet and insulin.
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and the Patient Was on Olanzapine at Event Onset n=96 continued
Table 3.7.
MedORA Preferred
Terms
Cardiogenic shock,
Hyperglycaemia NOS,
Metabolic acidosis
NOS
5.01
Case ID
DE000502386
2.01
DE010706337
Diabetes mellitus
insulin-dependent,
Hyperglycaemia NOS,
Ketoacidosis,
Myalgia,
syndrome,
Polydipsia,
Polyuria,
Pyrexia,
Tachycardia NOS
2.02
DEOI 1207548
Diabetes mellitus
NOS,
Ketoacidosis,
Prescribed overdose
Etiology of
Glucose
Dysregulation
OE
POE
IN
Concomitant Drugs
Weight Gain
Clomethiazole edisilatc I
Reported Pre
Existing
Glucose
Dysregulation
U
NA
Comments
Peak glucose 200 mg/dL. Chronic aErial fibrillation and
cardiomyopathy prior to olanzapine. Concurrent acute
decompensation of atrial fibrillation with DVI and
cardiogcnic shock; not on warfarin. Flypcrglycemia
detected in context of marked physiologic Stress and
treatment of shock with catecholamines. Nonketotic
metabolic acidosis was not diabetic in origin. Events
resolved prior to dose reduction of olanzapine.
Peak glucose >800 mg/dL. Personal and family history,
weight, and height not reported. Tolerated olanzapine for
22 months with àverage" blood glucose 78 mg/dl. Events
preceding polyuria, polydipsia and thigh pain were
unreported. These symptoms were prodrome to
presentation 8 days later with rhabdomyolysis, diabetes
mellitus and ketoacidosis; events occurred in July;
rhabdomyolysis and heat stress could have contributed to
diabetes. Diagnosed with NMS despite low grade fever
38C, normal sensorium and no reported extrapyramidal
symptoms or rigors; renal insufficiency creatinine 1.9
mg/dl present. Diabetes had not resolved after off
olanzapine 6 weeks.
Peak glucose unknown. Age, personal and family history,
height, weight and baseline laboratory values not reported.
Diagnosed with "severe" diabetes mellitus and
ketoacidosis, hospitalized; pH, HCO1, serum and urine
ketones, treatment of the event, outcome and status of
olanzapine use not reported.
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Table 3.7.
Case ID
EWC99060373
4
MedDRA Preferred
Terms
Weight decreased
etiology of
Glucose
Dysregulation
POE & OP
1.04
2.04
EWC99060374
0
Ketoacidosis,
Weight decreased
10
1.05
EWC00070723
3
IN
11
1.06
EWC01062742
5
Blood creatine
phosphokinase
increased,
Diabetes mellitus
NOS,
Weight increased
POE & OP
POE & OP
Concomitant Drugs
Glucose flysregulation,
Weight Gain
Neuroleptics NOS
Reported Pre
Existing
Glucose
Dysregulation
N
Alprazolarn 8,9,
Meprobamate,
Clorazepate / acepromazine /
aceprometazine 8,9,
11
Zopiclone 9
Comments
Peak glucose 649 mgldL. Obese with BMI 40 kg/rn2.
HbAlc 14.7% after 3 months on olanzapine. Hospitalized
with diabetic ketoacidosis pH 7.11; HCO3 5. Islet cell
and GAD antibodies negative; C-reactive protein present.
Treated with insulin and diet initially. Resolved off
olanzapine; insulin stopped and managed only with diet
due to hypoglycemia on insulin after olanzapinc
discontinued..
Peak glucose 648 rng/dL. Alcohol addiction and hepatitis
C positive pre-olanzapine; obese BMI 32.3 kg/rn2,
HgAI c 14.7%; pH and HCO3 not reported. Lost weight,
presented in ketoacidosis, olanzapine discontinued and
insulin requirements resolved 15 days after olanzapine
cessation. Glycemic control remained normal 1 year after
olanzapine discontinued despite regaining 16kg.
Peak glucose unknown. Hospitalized in ICU with diabetic
ketoacidosis. Medical history, concomitant medications
and event treatment not specified. Laboratory values not
reported.
Peak glucose 600 mg/dL. Had 10kg weight gain and peak
BM! 28.0 kg/rn2 on olanzapine and zopiclone. Concurrent
polyuria, polydipsia and anorexia; hospitalized with
increased CPK and ketoacidosis pH 7.3 and ketonuria;
HbAlc 10.7% after -4 months on olanzapine. Peptide C
was "low." Had "major social difficulty and irregular
situation" NOS which contributed to peripheral
neuropathy. Treated with insulin initially, then with oral
hypoglycemic agent. Resolved off olanzapine and
zopiclone.
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Table 3.7.
-
12
13.01
13
2.05
Case Li
EWC01072773
3
EWCO 1092830
3
MedDRA Preferred
Terms
Alanine
aminotransferasc
increased,
Aspartate
aminotransferase
increased,
Diabetes mellitus
insulin-dependent,
Gammaglutamyltransferase
increased,
Liver fatty,
Renal impairment
NOS,
Thrombocythaemia,
Weight increased
Diabetes mellitus
NOS,
Ketoacidosis,
Weight increased
Etiology of
Glucose
Dysregutation
POE & OP
POE & OP
Concomitant Drugs
Acidosis, Pancreatitis andlor
Weight Gain
2,5,6,7,8,9
Reported Prc
Existing
Glucose
Dysregulation
U
Comments
Peak glucose 627 mg/dl. Past medical history included
"several years" of untreated hypertonia, tachycardic
rhythm without chest pain, nicotine abuse, cannabis abuse,
and alcohol use; reportedly stopped drinking after starting
olanzapine. No known family history of diabetes. Risk
factors include obesity BMI 33.9 kg/rn2 peak, alcohol
use, and concomitant paroxetine. During first four weeks
of paroxetine use had nausea and vomiting; glucose level
not reported. After taking olanzapine approximately 16
months, had elevated liver enzymes SGOT 61, SGPT 98,
GGT 66 and thrombocylosis PLT 352 g/L. After taking
olanzapine for more than 2 years BMI increased to 37.1
kg/rn2 and paroxetine at least 5 months, had vomiting,
polydipsia, polyuria, complaints of tiredness/weakness,
and inability to eat due to nausea; 2 days later developed
shallow, rapid breathing and was hospitalized. Urine
positive for glucose, albumin, hemoglobin and RBC;
culture not reported. Diagnosed with insulin-dependent
diabetes mellitus and ketoacidosis pH 7.0 with renal
insufficiency. WBC 33.3 K at presentation. No baseline
laboratory data reported. Had increased liver enzymes,
HbAlc 8.1%, cholesterol 297 mg/dl, triglycerides 982
mg/dl, LDH 640 U/L, sodium 126 meqlL, chloride 84
meq/L, phosphorus 2.4 mmolIL. Treated with insulin and
within one week laboratory values were improved and he
was discharged. Outcome is improved on olanzapine and
paroxetine.
Peak glucose 1333 mg/dL. Took olanzapine for 3 years
without reported glucose dysregulation; obese with weight
gain on olanzapine; no concomitant medications; pH 7.15
with elevated blood ketones; had 2 week prodrome of
polyuria and polydipsia and concurrent diarrhea and
vomiting. No baseline laboratory values or past medical
history reported. Event treated with insulin and resolved
with continued insulin treatment off olanzapine.
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Table 3.7.
14
[
1.07
Case ID
EWC02033021
7
15
1.08
GB970822 I 8A
16
1.09
G8S01020820
6
17
2.07
GBSOIO7O92I
2
MedDRA Preferred
Terms
Body temperature
increased,
Muscle rigidity,
White blood cell
increased
t-Iyperglycaemia NOS,
Ketoacidosis
Etiology of
Glucose
Dysregulation
POE
Concomitant Drugs
Weight Gain
Reported Pre
Existing
Glucose
Dysregulation
U
POE
IN
EN
Comments
Peak glucose 787 mg/dl fasting. Age was risk factors for
diabetes; weight and height not reported. No personal or
family history of diabetes, no history of pancreatitis and
reportedly blood glucose and urinalysis indicated patient
was not diabetic. Diagnosed with diabetic ketoacidosis;
pH, HCO3, urine and serum ketones not reported.
Resolution of ketoacidosis after treatment with unspecified
anti-diabetic medication and after discontinuation of
olanzapine and paroxetine. Olanzapine rechallenge on an
intermittent basis without reported recurrence of
hyperglycemia. Hypoglycemic agent discontinued due to
normoglycemia 3.5 months after acute event.
Peak glucose unknown. Admitted in August to hospital
with fever 40C, rigidity and increased WBC NOS. No
evidence of infection; CPK 800 lUlL. Diagnosed with
diabetic ketoacidosis. No laboratory values reported.
Treatment of event not reported. Outcome unknown off
olanzapine.
Peak glucose unknown. Hospitalized in July with diabetic
ketoacidosis; treated with insulin; pH and HCO3 not
reported; no concomitant medications. Past and concurrent
medical history not reported; age 55 years only reported
intrinsic risk factor. Glucose levels returned to normal on
olanzapine and insulin after 6 months, following which
normalization, both olanzapine and insulin were
discontinued. HCO3
Peak glucose unknown. Hospitalized with hyperglycemia
and ketoacidosis; pH, bicarbonate, not reported. Treatment
not reported. Reportedly had "not had any previous
problems' conservatively inferred to be with
hyperglycemia or ketoacidosis although that was not
specified. Family history, personal history regarding
dyslipidcmia, hypertension, alcohol use, and baseline
laboratory values not reported. Positive olanzapine
dechallenge without reported hypoglycemic agent therapy.
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Table 3.7.
Case II
GBSOI 080933
8
MedLJRA Preferred
Terms
Diabetes mellitus
insulin-dependent,
Etiology of
Glucose
Dysregulation
IN
18
1.10
19
1.11
GBSO2O2IOIO
5
Hyperglycacrnia NOS
IN
20
2.10
US97060070A
Diabetes mellitus
NOS,
Hyperglycaemia NOS,
Ketoacidosis,
Paraesthesia NEC,
Thirst,
Urinary frequency,
Vomiting NOS
21
1.14
US97062497A
22
2.11
US97065620A
Concomitant Drugs
Weight Gain
U
Reported Pre
Existing
Glucose
Dysregulation
U
POE
Clozapine 2,6,7,8,9,
Valproate 1,7,8,9
Diabetes mellitus
insulin-dependent,
Hyperglycaemia NOS
POE
Diabetes mellitus
NOS,
I-iyperglycaemia NOS,
Ketoacidosis
POE & OP
Comments
Peak glucose unknown. Hospitalized with new onset Type
I diabetes mellitus and "mild" diabetic ketoacidosis.
Treatment of event not reported. Medical history,
concomitant medications, pH and HCO3 not reported;
outcome and olanzapine use status unknown.
Peak glucose unknown. Positive family history of diabetes
was only reported risk factor for diabetes mellitus; past
medical history, habitus, prior episodes of hyperglycemia
and baseline laboratory values not reported. Reported to
have a normal blood glucose level prior to olanzapine use.
Reported as "pre-acidosis" and "nearly" demonstrating
diabetic ketoacidosis, hospitalized. Glucose, pH, HCO3,
urine and serum ketones, glycosylated hemoglobin not
reported. Treatment of event not reported. Reportedly not
resolved on olanzapine; treatment unknown.
Peak glucose 1050 mg/dL. Had very rapid onset of
symptoms 2 days after olanzapine initiation; BMI 28.7
kg/m2. Baseline metabolic data and HbAI c at onset not
reported. Nausea and vomiting concurrent with event
onset preceded by paresthesia, thirst and urinary frequency;
pH 7.39, pCO2 36 mmHg, p0271 mmHg, FICO3 17 and
ketoacidosis reported. Etiology of hypoxemia not
reported. Improved off olanzapine and treated with
insulin.
Peak glucose 700 mg/dL. Obesity with peak BMI 35.1
kg/rn2, race and positive family history are risk factors.
Hospitalized and diagnosed with insulin-dependent
diabetes mellitus and ketoacidosis after 10 weeks or less of
olanzapine. No laboratory values were reported. Outcome
unknown on olanzapine.
Peak glucose 1600 mg/dL. Obesity with sleep apnea was
risk factor; weight, BMI, baseline glucose levels not
reported; reportedly "normal' glucose 4 weeks prior to
event. Diagnosed with diabetic ketoacidosis; pH, flC03,
serum and urine ketones not reported. Insulin requirement
decreased off olanzapine.
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Table 3.7.
,
B
23
1.15
Case ID
US97070604A
MedORA Preferred
Terms
Diabetes mellitus
NOS,
Glaucoma NOS
Etiology of
Glucose
Dysregulation
POE & OP
Concomitant Drugs
Weight Gain
Levothyroxine 2,
Lithium 2,8,9,
Ranitidine 7
Reported Pre
Existing
Glucose
Dysregulation
U
Comments
Peak glucose 877 mg/dI. Age and obesity with peak BMI
36.5 kg/rn2 are risk factors for diabetes. Hospitalized with
diabetic ketoacidosis; initial treatment not reported. Later
was treated with glibenclamide which was discontinued
following olanzapine cessation and her diabetes "remained
controlled" off oral hypoglycemic agent.
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Table 3.7.
g
24
5.04
Case ID
US97074243A
MedDRA Preferred
Terms
Balance impaired
NOS,
Blood calcium
increased,
Blood creatine
phosphokinase
increased,
Blood creatinine
increased,
Blood lactate
dehydrogenase
increased,
Blood uric acid
increased,
Dehydration,
Glycosuria present,
Haematocnt abnormal,
Heat stroke,
Hypcrphosphataemia,
Joint stiffness,
Lethargy,
Malaise,
Metabolic acidosis
NOS,
syndrome,
Tachypnoea,
Vomiting NOS,
White blood cell
increased
Etiology of
Glucose
Dysregulation
OE
Concomitant Drugs
Weight Gain
Captopril 7,8,
Indaparnide 2,5,8
Reported Pre
Existing
Glucose
Dysregulation
Y
Comments
Peak glucose 1600 mgldL. Hypertension and obesity
BMI 40.4 kg/rn2, age, and race are risk factors. History
of prior hyperglycemic episodes NOS but no baseline
values reported. Hospitalized in ICU in July with
vomiting, malaise, impaired balance; diagnosed with
possible NMS vs. heat stroke 41.3C; responded well to
fluids; no air conditioning in home. Patient slightly stiff
without rigidity; BUN 58 mg/dl, creatinine 4.5 mg/dI.
Respiratory acidosis pCO2 45 to 50 mmHg; oriented and
responsive. Reported to have lactic acidosis with
bicarbonate 21 meqlL. All medication discontinued and
outcome unknown; treatment unreported.
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Category 3: Cases ot Acidosis Non-Coma, Nonfatal in Which Glucose Dysregulation was Reported
Table 3.7.
,$
MedDRA Preferred
Terms
Hyperglycaemia NOS,
Ketoacidosis,
Overdose NOS,
Polydipsia,
Polyuria
Etiology of
Glucose
Dysregulation
POE
Concomitant Drugs
Weight Gain
Clonazepam 8,9,
Valproate 1,7,8,9
Reported Pre
Existing
Glucose
Dysregulation
Y
2.12
Case ID
US97084135A
1.17
US97094222A
Diabetes mellitus
inadequate control,
Mental disorder NEC
POE
Flaloperidol 2,9,
Levothyroxine 2
1.18
US97102155A
OE & OP
Valproate 1,7,8,9
1.19
US97 I 05545A
Abdominal pain NOS,

Diabetes mellitus
NOS,
Fungal infection NOS,
Weight increased
Sertraline 2,5,7,8,9,
Valproate 1,7,8,9
.20
US971 13046A

Eating disorder NEC,
Nausea,
Polydipsia,
Urinary frequency,
Vomiting NOS
POE
IN
Comments
Peak glucose 1400 mg/dL. Risk factors included positive
family history and pre-olanzapine borderline increased
fasting glucose levels values not reported; height, weight
not reported. Diabetic ketoacidosis, hospitalized; pH,
J-1C03, serum and urine ketones not reported. Tolerated a
reduced olanzapine dose rechallenge off clonazcpam and
on concomitants valproate and risperidone, with insulin.
Peak glucose 1100 mgldL. Had episode of diabetic
ketoacidosis 7 months prior to olanzapinc initiation. Had
diagnosis of `borderline' diabetes mellitus.' Obese with
peak [3M! 33.0 kg/rn2, hypertensive and hypothyroid,
anemia. Patient adherence to dietary constraints for
diabetes mellitus, given her residence in a homeless
shelter, was not reported. Patient improved; unknown
status of olanzapinc use.
Peak glucose 1274 rng/dL. Had 32.3 kg weight gain with
peak [3M! 37.1 kg/rn2. Patient had concurrent oral and
vaginal candidiasis and family history of diabetes mellitus;
diagnosed with diabetic ketoacidosis HCO3 15.
Infections treated, olanzapine tapered off over two months
and insulin requirements declined.
Peak glucose unknown. Past medical and concurrent
history, personal and family history of diabetes not
reported; BMI 21.4 kg/rn2. Not hospitalized for diabetic
ketoacidosis; pH, HCO3, treatment and outcome not
reported. Remained on olanzapine.
mellitus included race, family history and obesity.
Duration on olanzapine and HbAlc not reported. Off
olanzapine, she improved only slightly. Acetone elevation
associated with nausea, acute vomiting and probable poor
oral intake. Urine cultures not reported. Glycemic and
acetone control worsened, off olanzapine, requiring
increased insulin for reported possible insulin resistance.
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Table 3.7.
Glucose 4 Update
26 March 2003
30
21.01
Case ID
USO1 1177261
31
1.21
U597 11 3076A
MedDRA Preferred
Terms
Myositis,
Respiratory failure cxc
neonatal,
Encephalopathy NOS,
Dehydration,
Diabetes mellitus
inadequate control,
Oesophageal ulcer,
Diverticulum NOS,
Iron deficiency anaemia,
Venous stasis,
Psoriasis,
Haemorrhoids,
Hypertension NOS
Etiology of
Glucose
Dysregulation
OE
IN
Concomitant Drugs
Weight Gain
Fluticasone propionate 2,5,7,8,9,
Furosemide 2,5,7,
Omeprazole 2,7,
Rosiglitazone maleate 2,9,
Fluoxetine hydrochloride
2,3,5,7,8,9
Reported Pre
Existing
Glucose
Dysregulation
Y
Comments
Peak glucose 129 mg/dl; acidosis respiratory in origin.
Past medical history of COPD, CHF, chronic renal
insufficiency, obstructive sleep apnea, increased CPK,
Type II diabetes mellitus, and noncompliance with
medications. Height, weight, BMI, and family history not
reported. After taking olanzapine for over 1 year, patient
presented to ER with generalized muscle weakness,
shortness of breath, and ulcerations on calves; HR 90, RR
20, temperature 36.4C, and CPK 3678 with negative
troponin. Hospitalized; treated with hydration; peak
glucose 129 mg/dl. CPK continued to rise, EMG
performed; diagnosed with myositis and treated with
corticosteroids. After muscle biopsy indicating no clear
etiology of muscle weakness, required 100% oxygen via
rebreather mask; pH 7.19, pCO2 85 mmHg, p02 326
mmHg. Transferred to ICU; required ventilatory support.
Colonoscopy and EGD performed; diagnosed with
diverticulosis. Patient had "marked' hypertension; no
tumors found; CPK 910; diabetes reportedly "very
unstable while on steroids for myositis. Steroids tapered.
Patient required tracheostomy. CT scan of chest was
negative. Transferred to long-term care unit. Remained on
ventilator, received feedings via PEG tube. Final reported
CPK was 19. Diabetes improved off olanzapine and
fluoxetine, with cessation of corticosteroids and continued
insulin.
Peak glucose unknown. Past medical history, personal and
family history of diabetes, weight, l3Ml, concomitant
medications not reported. Reportedly not hospitalized for
diabetic ketoacidosis. Treatment, pH, HCO3 and outcome
were not reported.
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Table 3.7.
Glucose 4 Update
26 March 2003
s.
a
32
1.23
Case ID
US98025323A
33
2.14
US980300059
34
1.24
US980300072
MedDRA Preferred
Terms
Abdominal pain upper,
Amnesia NEC,
Diabetes mellitus
insulin-dependent,
Feeling jittery,
Hypoaesthesia,
Polyuria,
Renal impairment
NOS,
Urinary incontinence,
Vision blurred,
Vomiting NOS,
Weakness
Diabetes mellitus
insulin-dependent,
Ketoacidosis,
Nausea,
Overdose NOS,
Polydipsia,
Polyuna,
Vomiting NOS
Diabetes mellitus
NOS,
Drug ineffective,
Drug level NOS below
therapeutic,
Hyperglycaemia NOS,
Polydipsia,
Polyuria,
Weight increased
Etiology of
Glucose
.
Dysregulation
OE
POE
POE & OP
Concomitant Drugs
.
.
Weight Gain
Lithium 2,8,9,
Valproate 1,7,8,9
Reported Pre
Existing
Glucose
.
Dysregulation
Y
Comments
Peak glucose 1825 mg/dL. Risk factors included possible
history of "borderline diabetes,' race, obesity BMI 36.6
kg/rn2, cocaine and alcohol abuse, and possible family
history of diabetes. Diagnosed with diabetic ketoacidosis
HCO3 15, anion gap 29 after presenting with acute
nausea, vomiting and abdominal pain. Other etiologies for
decompensation of "borderline diabetes" include alcohol
abuse, suspected Klinefelter's syndrome evaluation in
process at time of report, medication non-compliance and
pancreatitis. Improved off olanzapine and on insulin.
Valproate 1,7,8,9,
Peak glucose 851 mg/dL. Obesity with 14.5 kg weight

loss in month prior to events. Concurrent polydipsia,
polyuria, nausea and vomiting. Risk factors included
obesity BMI 38.0 kg/rn2 and "borderline" non-fasting
blood glucose level, possibly prior to olanzapine.
Diagnosed with diabetic ketoacidosis, hospitalized; p1-I,
HCO3, serum and urine ketones not reported. Continued to
require insulin, off all medications.
Buspirone 8,9,
Estrogens conjugated 2,8,
Temazepam 8,9,
Valproate 1,7,8,9
Peak glucose 400 mg/dL. Probable obesity female

weighing 136kg; height not reported, age, weight gain on
olan7.apine 20.4kg, and race are risk factors for reported
DKA; pH, HCO3 and ketones not reported. May have had
pre-olanzapine glucose intolerance which worsened
baseline glucose 122 mg/dl. Improved off olanzapine
and on insulin.
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Table 3.7.
35
1.25
Case ID
US980401894
36
1.26
US9 80402030
37
1.27
US980502976
38
2.15
US980503031
Glucose 4 Update
26 March 2003
MedDRA Preferred
Terms
Abdominal pain NOS,
Hypotension NOS,
Ketosis,
Polydipsia,
Polyuria,
Vomiting NOS
Blood glucose abnormal,
Etiology of
Glucose
Dysregulation
POE
Concomitant Drugs
Weight Gain
Haloperidol decanoate 2,9
Reported Pre
Existing
Glucose
Dysregulation
U
POE
POE
Lamotrigine 2,7,8,9,
Levothyroxine 2,
Lisinopnl 2,8,9,
Nifcdipine 9
POE
Disorientation,
Hyponatraemia,
Lethargy,
Polydipsia,
Polyuria,
Tachycardia NOS
Diabetes mellitus
insulin-dependent,
Hyperglycaemia NOS,
Ketoacidosis
Comments
Peak glucose 478 mgldL; HbAlc 11.2%. Diabetic
ketoacidosis with polyuna, polydipsia, abdominal pain,
nausea, vomiting, hypotension 90/53 mmHg, pH 7.2 and
ketonuria. Race and family history are risk factors for
developing Type II diabetes. Not obese BMI 21.1 kg/rn2;
C-peptide normal and islet cell antibodies negative.
Outcome, treatment and status of concomitant and
Peak glucose 1000 mg/dL. Diabetic ketoacidosis with
HCO3 9 meq/L after tolerating olanzapine well for 18
months. Concurrent history not reported. Obese BMI
29.6 kg/rn2; no reported weight gain. Improved off
olanzapine; reporter thought insulin continued after off
olanzapine.
Peak glucose 1356 mg/dL. Diabetic ketoacidosis with pH
7.17 and HCO3 13 meq/L. History of hypertension and
seizure disorder. Obesity BMI 33.3 kg/rn2 is risk factor.
Improved off olanzapine and levothyroxine, and with
insulin therapy.
Peak glucose 860 mg/dL. Intrinsic risk factor of positive

family history of diabetes. Diagnosed with diabetic
ketoacidosis, hospitalized with pH 7.15; HCO3 and serum
and urine ketones not reported. Treatment of acute event
not reported; improved off olanzapine and sertraline and on
insulin.
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Table 3.7.
.E
39
8.01
Case ID
US980503937
40
1.29
US9806061 34
41
1.30
US980807835
MedDRA Preferred
Terms
Acetone abnormal
NOS,
Dehydration,
Dysuria,
Fatigue,
Glycosuna present,
Hyperglycaemia NOS,
Hyponatraemia,
Ocdcma peripheral,
Polydipsia,
Polyuria,
Somnolence,
Urinary tract infection
NOS,
Weight decreased
Diabetes mellitus
insulin-dependent,
Dysarthria,
Overdose NOS,
Orthostatic hypotension,
Sinus tachycardia,
Somnolence,
Tongue disorder NOS,
Weight decreased,
Weight increased
Etiology of
Glucose
Dysregulation
OE
IN
POE & OP
Concomitant Drugs
Weight Gain
Medroxyprogesterone 2,9,
Nitrofurantoin 7,
Thiothixene 2,9,
Reported Pre.
Existing
Glucose
Dysregulation
U
Fluphenazine 2,9,
Nifedipine 9,
Valproate 1,7,8,9
Comments
Peak glucose 766 mg/dL. Off olanzapinc 2 weeks at
diagnosis of glucose-related events but patient reported
polyuria, polydipsia, dysuria and weight loss for "several
weeks" prior to diagnosis of UT! and DM. Ketonemia 1:2
dilution in presence of dehydration, without evidence of
acidosis HCO3 27; pre-olanzapine obesity, amenorrhea
and hyperprolactinemia. Olanzapine had been
discontinued after 6 months use due to fatigue and sedation
which persisted until UT! treated with nitrofurantoin and
DM diagnosed and treated. Resolved with insulin, oral
hypoglycemic agent and treatment of UT!. Conservatively
assessed as possible acidosis with glucose-dysregulation
onset prior to olanzapine discontinuation or at same time as
discontinued.
Peak glucose unknown. Past medical history,
personallfamily history of diabetes mcli itus, baseline blood
glucose, weight and BMI were not reported. Hospitalized
with "significant" diabetic acidosis; pH, HCO3 not
reported. No concomitant medications. Outcome
unknown off olanzapine, and treated with insulin. Treating
physician did not know if glucose dysregulation began on
olanzapinc or preceded its use.
Peak glucose 1200 mg/dL. Race, age, hypertension, pre
o!anzapine obesity BMI 34.5 kg/m2, probable
hyperlipidemia inferred from history of myocardial
infarction, weight gain 9.5 kg are risk factors for
diabetes. Diabetic ketoacidosis diagnosed and treated with
insulin; pH, HCO3, ketones not reported. Tolerated
oianzapine well for four months prior to fluphenazine
addition; no weight or glucose value immediately prior to
starting fluphenazine. Resolved off olanzapine and off
insulin.
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Confidential
Table 3.7.
MedDRA Preferred
Terms
Etiology of
Glucose
Dysregulation
OE & OP
42
1.31
Case II
US980910146
43
1.32
US98 1011107

Diabetes mellitus
NOS,
POE
44
2.16
US98IOI 1749
Abdominal pain NOS,

Diabetes mellitus
NOS,
Hyperventilation,
Ketoacidosis,
Weight increased
POE & OP
Concomitant Drugs
Weight Gain
Valproate 1,7,8,9,
Insulin
Reported Pre
Existing
Glucose
Dregulaflon
Y
Valproate 1,7,8,9
Psychiatric medications NOS
Comments
Peak glucose 516 mg/dL. Elevated blood glucose 156
mg/dl at 6 months pre-olanzapine, family history of
diabetes, personal history of gestational diabetes,
cholelithiasis and probable obesity female with weight
114.5 kg are risk factors for diabetes. Required insulin
from onset of olanzapine therapy. Diabetic ketoacidosis
with pH 7.18, HCO3 9 and urine ketones> 80 units not
reported. Resolved off olanzapinc and on insulin. Insulin
requirements decreased following olanzapine cessation.
Peak glucose 551 mgldL. Race and possible obesity
weight 107.7 kg, height not reported possible
contributing factors. Started olanzapine and vaiproate
simultaneously and seemingly tolerated for 15 months.
Diagnosed with diabetic ketoacidosis; urine and serum
ketones, arterial pH and serum HCO3 not reported;
required oral hypoglycernics after olanzapine and valproate
discontinued.
Peak glucose 900 mg/dL. Obesity BMI 27.0 kg/rn2 and
weight gain were risk factors for diabetes. Not clear in
report if weight was baseline. Diagnosed with diabetie
ketoacidosis at presentation with abdominal pain and
hyperventilation; hospitalized; pH, HCO1, urine and serum
ketones not reported. Ketogenie diet may have referred to
an intentional effort to lose weight. Tolerated rechallenge
of reduced dose olanzapine, off insulin and unknown if
still taking oral hypoglycemic agent.
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Confidential
Table 3.7.
45
1.35
Case ID
US98 1214405
46
1.37
US990725399
47
1.38
U5991029836
MedDRA Preferred
Terms
Diabetes mellitus
NOS,
Overdose NOS,
Pancreatitis NOS
Alanine
aminotransferase
increased,
Aspartate
aminolransferase
increased,
Pancreatitis NOS,
Tachycardia NOS,
Weight increased
Weight increased,
White blood cell count
increased
Etiology of
Glucose
Dysregulation
OE
OE
POE & OP
Concomitant Drugs
Weight Gain
Valproate 1,7,8,9
Reported Pre.
Existing
Glucose
Dysregulation
U
Buspirone 8,9,
Propranolol 2,
Comments
Peak glucose 553 mg/dL. Race, age, obesity, history of
alcohol abuse with subsequent cirrhotic and fatty liver due
to alcoholism, hyperlipidemia and nicotine abuse were risk
factors for diabetes. No reported adverse events on
olanzapine for 14 months prior to paroxetine introduction.
Pancreatitis, diabetic ketoacidosis developed I to 2 months
after paroxetine added. Amylase 490 lU/L, lipase 1298
lU/L, HbAI c 11.5%, pH 7.29, pCO2 31 mmHg, anion gap
19, urine ketones > 80, triglycerides 375 mg/dl and
transaminases mildly elevated. Improved off olanzapine
and paroxetine on oral hypoglycemic; negative olanzapine
rechallenge.
Peak glucose 713 mg/dl, random. Obesity BMI 27.2
kg/m2, alcohol abuse with possible continued ingestion,
race, weight gain are risk factors for diabetes. Diagnosed
with diabetic ketoacidosis, anion gap 25, urinary ketones
40, ilbAic 18%, alcohol not detected. Equivocal
diagnosis of pancreatitis with mildly elevated enzymes
peak amylase 148 U/L; peak lipase 79 UIL, but benign
abdominal exam with abdominal pain, nausea and
vomiting. Still required insulin after olanzapine,
buspirone, sertraline and propranolol discontinued.
Peak glucose 1210 mg/dl. Baseline glucose, family history
not reported; patient obese. Gained 20.5 kg time frame
not reported; BMI 31.8 kg/m2 at presentation. Presented
with polydipsia, polyuna, lethargy and somnolence;
diagnosed as diabetic ketoacidosis, but reported pH 7.3
was venous and no anion gap < 3 at time of event.
Resolved off olanzapine and on insulin. Intramuscular
fluphenazine was tapered and discontinued after
olanzapine started, -33 days prior to event.
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Confidential
Table 3.7.
MedDRA Preferred
Terms
Etiology of
Glucose
Dysregulation
IN
Concomitant Drugs
Weight Gain
Albuterol 2,
Clonazepam 8,9,
Haloperidol 2,9,
Omeprazole 2,7
Reported Pre
Existing
Glucose
Dysregulation
U
48
1.39
Case ID
US991030278
49
4.04
US99 1232628

Impaired gastric
emptying,
Ketonuria present,
Pain in limb
OE
Albuterol 2,
Clonazepam 8,9,
Dihydroergotamine 2,6,
Metoclopramide,
Lispro,
Human extended zinc insulin
RDNA origin
50
1.41
US0001 33815
OE
51
1.42
US0001 34052
Diabetes mellitus
NOS,
Weight increased
POE
Fluphenazine decanoate 2,9
Comments
Peak glucose 498 mg/dl. Risk factors and concurrent
history not reported. History of asthma; unknown if
corticosteroids used. Diagnosed with diabetic
ketoacidosis; pH, HCO1, urine and serum ketones and
concurrent medical history not reported. Treatment and
outcome of event not reported after olanzapine
discontinued.
Peak glucose>300 mg/dl. Five year history of pre
olanzapine insulin-dependent diabetes mellitus. Family
history, BMI, glycemic control not reported. Teenager
with one month history of gastric paresis prior to
exacerbation. Improved glycemic control while
hospitalized. Hospitalized with worsened glycemic control
and "small' amount of ketonuria; pH not reported.
Outcome improved, on olanzapine and insulin. Reporter
suspected insulin resistance; insulin antibodies were
pending.
Peak glucose unknown. Past medical history, habitus and
family history not reported. Unknown if hospitalized for
diabetic ketoacidosis; treated with insulin. Off olanzapine
6 weeks following diagnosis with no change in insulin
requirements. Negative olanzapinc rechallenge. Possible
de novo Type I diabetes mellitus in 12.5 year old male.
Not resolved off olanzapine on insulin; negative
olanzapine rechallenge with reduced insulin requirements
with normalization of glucose and HbAlc levels with
declining insulin requirements over 6 months.
Peak glucose unknown. Risk factors included positive
family history and age. No baseline laboratory values
reported. Events immediately preceding hospitalization for
diabetic ketoacidosis not reported; improvement occurred
on olanzapine and oral hyperglycemic agent.
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Table 3.7.
Glucose 4 Update
26 March 2003
MedDRA Preferred
Terms
Ketoacidosis,
Weight increased
Etiology of
Glucose
.
Dysregulation
POE & OP
Concomitant Drugs
.
.
Weight Gain
Reported Pre
Existing
Glucose
.
Dysregulation
U
52
2.18
Case ID
US000134444
53
1.44
US000235653
Overdose NOS
POE
Amlodipine 9,
Buspirone 8,9,
Fluticasone 2,5,7,8,9,
Omeprazole 2,7
54
2.19
US0003 36807
Blood triglycerides
increased,
Ketoacidosis
POE
Amfebutamone 2,9,
Doxepin 2,8,9,
Gabapentin 2,8
55
1.45
US000338253
IN
Comments
Peak glucose 1400 mg/dL. Positive family history of
diabetes and weight gain were risk factors for diabetes.
Baseline weight 59.1 kg; height not reported. Baseline
laboratory values not reported. Gained 40.9 kg while
taking olanzapine and venlafaxine. Diagnosed with
diabetic ketoacidosis, hospitalized and treated with insulin;
pH, HCO3, urine and serum ketones not reported.
Hyperglycemia resolved, off olanzapinc, and after 4.5 kg
weight loss; insulin then was discontinued.
Peak glucose unknown. Hospitalized with diabetic
ketoacidosis. Risk factors included race, obesity and
probable hypertension. History of asthma treated with
fluticasone. Outcome and treatment unknown off
olanzapine.
Peak glucose 479 F mg/dL. Risk factors of age, family
history, probable dyslipidemia and obesity BMI 35.3
kg/m2. Concomitant medications started I day prior to
olanzapine. Diagnosed with diabetic ketoacidosis with pH
7.21, HbAI c 17%, ketonemia 1:8, ketonuria >80,
triglycerides 7,320 mg/dI. Treated with unspecified
hypoglycemic agents. Continued need for hypoglycemic
agent, off olanzapinc. Continued hyperlipidemia 1 month
after discontinuing olanzapine.
Peak glucose 1600 mg/dL. Patient incarcerated at event
onset; concurrent renal failure. Hospitalized with diabetic
ketoacidosis in an unreported medical context. No family
or past medical history reported. Events immediately
preceding the event of diabetic ketoacidosis were not
reported. No age or race reported. Resolved with
unknown status of olanzapine use or treatment.
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Confidential
Table 3.7.
56
c
1.47
Case ID
US000439362
57
1.48
US000440152
58
1.49
US000440162
59
2.20
US000540963
60
2.22
tJS000542007
MedDRA Preferred
Terms
Convulsions NOS,
Diabetes mcllitus non
insulin-dependent,
Hallucination NOS,
Renal failure NOS,
Renal tubular necrosis,
Thrombocytopenia,
Weight increased
Diabetes mellitus
NOS,
Weight increased
Diabetes mellitus
NOS,
Etiology of
Glucose
Dysregulation
OE & OP
Concomitant Drugs
Weight Gain
Imipramine 2,8.9,
Rispendone 3,8,
Reported Pre
Existing
Glucose
Dysregulation
U
POE & OP
POE
Diabetes rnellitus
NOS,
Ketoacidosis
IN
Diabetes mellitus
NOS,
Ketoacidosis
IN
Comments
Peak glucose 669 mgldL. Initially took olanzapine and
had no reported glucose dysregulation, but had a 13.6 kg
weight gain. DiGeorge syndrome; patient had a history of
weight gain during previous olanzapine use. Olanzapine
was discontinued, hallucinations worsened, olanzapine
restarted and risperidone and imiprarnine initiated. Nausea
and vomiting at onset of acute events. Had diabetic
ketoacidosis, seizures, renal failure and thrombocytopenia;
treated with insulin. Had a family history of diabetes
mellitus. Hospitalized with diabetic ketoacidosis pH 6.9,
HCO 2. Resolved off olanzapine and imipramine and on
reduced venlafaxine and risperidone doses; one month later
diagnosed with Type II diabetes mellitus requiring oral
hypoglycemic.
Peak glucose 1161 mgldL. Intrinsic risk factors included
race, age and hyperlipidernia; positive PPD. Had diabetic
ketoacidosis treated with insulin; eventually only dietary
control was required with patient off olanzapine.
Peak glucose 550 mg/dL. Risk factors included race and
pre-olanzapine obesity BMI 31.2 kg/rn2. Patient with
sickle cell trait diagnosed with new onset diabetes mellitus
and diabetic ketoacidosis treated acutely and longer term
with insulin and diet; olanzapine was continued.
Peak glucose unknown. A risk factor for developing
diabetes was being "overweight'; BMI, personal and
family history not reported. Diagnosed with diabetic
ketoacidosis; glucose, pH, HCO3, urine and serum ketones,
treatment and outcome off olanzapine not reported.
Peak glucose unknown. Age and race were risk factors for
developing diabetes; BMI, personal and family history, and
concomitant medications not reported. Diabetic
ketoacidosis not requiring hospitalization; pH, glucose,
HCO1, urine and serum ketones, treatment and outcome
not reported. Olanzapine was continued.
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Table
Glucose 4 Update
26 March 2003
3: Cases of Acidosis Non-Coma, Nonfatal in Which Glucose Dysregulation was Reported

37.
Category
MedDRA Preferred
Terms
Nausea,
Vomiting NOS
Etiology of
Glucose
Dysregulation
IN
61
1.51
Case ID
US000746032
62
1.52
US000847003
POE
63
1.53
US0008477 16
Hyperventilation,
Nausea,
Polydipsia,
Polyuria,
Weight increased
POE & OP
64
1.55
1JS000950632
IN
Concomitant Drugs
Weight Gain
U
Reported Pre
Existing
Glucose
Dysregulation
U
Gemfibrozil 7,8,
Levothyroxine 2
Fluphenazine decanoate 2,9,

Gabapentin 2,8
Comments
Peak glucose 639 mg/dL. Presented with 3 to 4 day
history of nausea and vomiting and diagnosed with
diabetic ketoacidosis; venous pH 7.13, moderate serum
ketones, and normal C-peptide level. Required oral
hypoglycemic agent after olanzapine discontinued;
outcome not reported. Past medical history, family history,
baseline laboratory values, height, weight and concomitant
medications not reported.
Peak glucose unknown. Obesity BMI 35.5 kg/rn2 and
hyperlipidemia are risk factors for diabetes. Diabetic
ketoacidosis, hospitalization in ICU; no reported pH,
HCO3, serum or urine ketones, or treatment of the event;
patient improved on olanzapine.
Peak glucose 850 mg/dL. Diabetic ketoacidosis treated in
ICU with insulin; pH, HCO, urine and serum ketones not
reported. Risk factors included family history, chronic
hepatitis C from IV drug abuse, cocaine, alcohol and
marijuana abuse, although patient denied use in past
several months. Weight gain 4.5 to 6.8 kg on olanzapine.
Outcome unknown off olanzapine.
Peak glucose unknown. Past medical history, height,
weight, family history and concomitant medications not
reported. Diagnosed with diabetic ketoacidosis and
hospitalized. No reported pH, HCO3, serum and urine
ketones, treatment or Outcome. Unknown outcome and
Status of olanzapine use.
Page

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Zyprexa
442
4076
MDL Plaintiffs' Exhibit No.00379
99

Page
81
ZY 4076 443
Confidential
Table 3.7.
Glucose 4 Update
26 March 2003
MedDRA Preferred
Terms
Blood alcohol excessive,
Hyperglycaemia NOS,
Weight decreased
as
65
1.56
Case ID
US000950662
66
2.23
USOOIO5 1188
Blood creatinine
increased,
Depressed level of
consciousness,
Ketoacidosis,
Overdose NOS
67
2.24
USOO 1052076
Blood potassium
increased,
Blood sodium decreased,
Ketoacidosis,
Overdose NOS
68
1.57
USOI 0157535
Etiology of
Glucose
*
DsreguIation
OE
OE
Concomitant Drugs
*
Weight Gain
Haloperidol decanoate 2
Reported Pre
Existing
Glucose
*
Dysregulation
Y
Goserelin 9,
Nilutamide 2,8
POE & OP
IN
Comments
Peak glucose> 800 mg/dL. Age, race, obesity BMI 38.1
kg/rn2 and acute alcohol use are risk factors for diabetes;
family history not reported. Also had progressive increase
in blood glucose for 5 years; on olanzapine only 18
months; lost 15.9 kg on olanzapine. Diagnosed with
diabetic ketoacidosis; had a history of noncompliance with
medications, including olanzapine; unknown if taking
olanzapine at onset. Alcohol level elevated 26 hours after
admission; no alcohol level done in ER at presentation.
Diagnosed with diabetic ketoacidosis; pH, HCO1, serum
and urine ketones not reported. Outcome and status of
olanzapine use unknown.
Peak glucose 1113 mg/dL Age, history of alcohol abuse,
race, obesity, and family history of diabetes were risk
factors for developing diabetes. Also has hepatitis C and
prostate cancer with spinal metastases resulting in
paraplegia. Presented complaining of abdominal pain,
nausea, drowsiness and disorientation; diagnosed with
diabetic ketoacidosis, hospitalized with pH 7.07, BUN 70
mg/dl, creatinine 2.8, potassium 6.0 meq/L and sodium
141 meg/L. Improved off olanzapine and on insulin.
Peak glucose 1243 rng/dL. Age, race, positive family
history and obesity 13M1 27.3 kg/rn2 were risk factors for
developing diabetes. Had cardiomyopathy secondary to
cocaine abuse. Diabetic ketoacidosis, hospitalized with
sodium 121 meq/L, potassium 8.4 meq/L; pH, HCO3 and
urine and serum ketones not reported. Blood glucose
progressively declined and insulin dose decreased, off
olanzapine.
Peak glucose 361 mg/dL. Age and race were risk factors
for diabetes mellitus; height, weight, past medical history
and baseline laboratory values not reported. Concurrent
excessive thirst, polyuria and confusion; diagnosed with
diabetic ketoacidosis, but not hospitalized; pH, HCO3,
serum and urine ketones not reported. Event treated with
insulin. Resolved on olanzapine and insulin.
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Table 3.7.
Glucose 4 Update
26 March 2003
69
a
L r,
1.58
Case ID
US010157572
MedDRA Preferred
Terms
70
1.59
US010157580
71
2.26
US010158719
Ketoacidosis
72
1.62
US010260062
neonatal
Etiology of
Glucose
.
Dysregulation
IN
POE
IN
OE & OP
Concomitant Drugs
.
Weight Gain
N
Reported Pre.
Existing
Glucose
.
Dysregulation
U
Clozapine 2,6,7,8,9
Haloperidol decanoate 2,9
Comments
Peak glucose 578 mg/dL. Risk factors for diabetes include
race and history of alcohol abuse unknown if active or
historical; pancreatic function, baseline laboratory values,
height, weight not reported. Diagnosed with diabetic
ketoacidosis, transferred to ICU for intravenous fluids and
insulin; pH, HCO5, serum and urine ketones not reported.
Patient improved on insulin and diet; unknown status of
olanzapine use on diet and insulin, with insulin gradually
withdrawn over several months.
Peak glucose 317 mg/dL. Race was an intrinsic risk factor;
in 2 months preceding events, had received 4 psychotropic
medications perphenazine, lithium, valproic acid and
clozapine. No baseline blood glucose reported.
Diagnosed with diabetic ketoacidosis; pH, HCO3, urine
serum ketones, treatment not reported. Improved with
unknown status of olanzapine use or treatment.
Peak glucose unknown. Race was only reported risk
factor. Weight, BMI, and personal history of diabetes or
hyperglycemia not reported. Blood glucose reportedly
normalized no values specified after off olanzapine 10
days following diagnosis of "ketoacidosis"; glucose, PH,
HCO1, serum and urine ketones not reported. No
information about immediate premorbid status or acute and
long-term therapy.
Peak glucose unknown. Race, age, pre-olanzapine obesity
BMI 27.4 kg/rn2, and weight gain 6.8 kg to BMI 30.4
kg/rn2 on olanzapine were risk factors for diabetes
mellitus. No baseline glucose reported. Concurrent
respiratory failure of unreported etiology; diabetic
ketoacidosis reported; pH, HCO3, serum and urine ketones
not reported. Unknown outcome off olanzapine and on
insulin.
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Table 3.7.
Glucose 4 Update
26 March 2003
MedDRA Preferred
Terms
Hyperglycacmia NOS,
Ketonuria present,
Polydipsia,
Polyuria
Etiology of
Glucose
Dysregulation
IN
Concomitant Drugs
Weight Gain
Bupropion 2,8,9,
Gabapentin 2,8
Reported Pre
Existing
Glucose
Dysregulation
U
73
4.05
Case ID
USO 10361992
74
1.63
USO 10362247
IN
Mirtazapine 2,8
75
2.27
USO 10362340
Ketoacidosis
IN
76
1.64
USO 10362903
IN
NA
77
1.68
USO 10768797

IN
Comments
Peak glucose 350 mg/dL. Weight, baseline laboratory
values, personal and family history were not reported.
History of cocaine abuse with mania. Hospitalized with
blood glucose 350 mg/dl and ketonuria; pH, HCO3 and
serum ketones not reported. Polyuria and polydipsia
present for I month prior to hospitalization. Unknown
Outcome off olanzapine and on insulin.
Peak glucose unknown. Age, race, personal and family
history, weight, baseline laboratory values not reported.
Diagnosed with diabetic kctoacidosis, hospitalized; pH,
HCO3, serum and urine ketones, treatment of event not
reported. Outcome, status of olanzapine use and treatment
unknown.
Peak glucose unknown. Hyperglycemia not reported but
patient reported as having `no previous history of
hyperglycemia." Age only reported risk factor for diabetes
mellitus. MedDRA Preferred Term was only reported
reference to ketoacidosis; concurrent and past medical
history and concomitant medications not reported.
Outcome and treatment unknown off olanzapine.
history, height, weight and baseline laboratory values not
reported. Diagnosed with diabetic ketoacidosis,
hospitalized; pH, HCO1, serum and urine ketones,
treatment of the event and outcome off olanzapine not
reported.
Peak glucose 600 mg/dL. Age was only reported risk
factor for diabetes; race, weight, concomitant medications,
personal and family history not reported. Diagnosed with
diabetic ketoacidosis; pH, HCO3, urine and serum ketones,
treatment not reported. Resolved off olanzapine. Longterm therapy not reported.
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Table 3.7.
Glucose 4 Update
26 March 2003
MedDRA Preferred
Terms
Etiology of
Glucose
.
Dysregulation
IN
Concomitant Drugs
Glucose Dysregulatiun,
.
.
Weight Gam
U
Reported Pre
Existing
Glucose
*
Dysregulation
U
78
1.69
Case LI
USOI 0768800
79
1.71
US010769382
Hyperglycaemia NOS
POE
80
1.72
USO 10769385
Hyperglycaemia NOS
POE
Lithium 2,8,9,
Valproate 1,7,8,9
81
2.29
US01087155I

Ketoacidosis
POE
82
1.74
USO 10872076
Headache NOS,
Insulin-requiring type II
diabetes mellitus,
Upper respiratory tract
infection NOS,
Weight increased
OE & OP
Atenolol 2,
Chlorpromazine 2,9,
Cloni dine 2,9,
Gabapentin 2,8,
Atorvastatin 2,7,9,
Ibuprofen 9,
Propranolol 2,
Valproic acid 1,7,8,9,
Venlafaxine 2,5,7,8,9,
Metformin 1
Comments
Peak glucose unknown. Race, weight, personal and family
history, baseline laboratory values, concomitant
medications not reported. Diabetic ketoacidosis,
hospitalized in ICU; pH, HCO3, glucose, urine and serum
ketones, treatment not reported. Resolved off olanzapine.
Long-term therapy not reported.
Peak glucose unknown. Being òverweight" was only
reported risk factor for diabetes. Diagnosed with diabetic
ketoacidosis, hospitalized; glucose, pH, HCO3, urine and
serum ketones not reported. Improved with continued
need for insulin after olanzapine discontinued.
Peak glucose 550 mg/dl. Known Type II diabetes, diet
controlled and being "overweight" were risk factors for
diabetes. Weight, baseline laboratory values including
HbAlc, family and personal history not reported.
Diagnosed with diabetic ketoacidosis, hospitalized; pH,
HCO3, urine and serum ketones and treatment not reported.
Unknown outcome off olanzapine; long term treatment
unknown.
Peak glucose 523 rng/dL. Age, race, obesity BMI 27.5
kg/rn2 and hypertension were risk factors for diabetes.
Diagnosed with ketoacidosis; pH, ketones and HCO1 not
reported. Resolved with continued insulin requirement off
olanzapine.
Peak glucose 765 mg/dL. Intrinsic risk factors included
obesity and weight gain BMI 31.1 kg/rn2 prior to
olanzapine, probable family history of diabetes, probable
hypertension, and glucose intolerance prior to olanzapine.
History of hepatitis A, IV methamphetamine abuse, rare
alcohol use, further weight gain BMI 35.4 kglm2 by time
of event. History of URI, onychomycosis and tobacco
abuse; diagnosed with diabetic ketoacidosis with HCO3 15
mcq/L; serum and urine ketones positive. Ketoacidosis
began - 5 days after metformin begun. Required insulin 2
months after event, but able to halve the dose on continued
olanzapine. Negative for islet cell and GAD antibodies.
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Table 3.7.
Glucose 4 Update
26 March 2003
MedDRA Preferred
Terms
Blood creatinine
increased,
Blood triglycerides
increased,
Etiology of
Glucose
Dysregulation
IN
4
83
1.75
Case ID
USO 10973033
84
1.76
USO 10973240
OE
85
1.80
USOI 1076560
POE
86
1.81
USOI 1177745
IN
Concomitant Drugs
Acidosis, Pancreatitis andlor
Weight Gain
N
Reported Pre
Existing
Glucose
Dysregulation
U
Clonazepam 8,9,
Lamivudine/zidovudine 1,2,7,
Docusate,
Ketoconazole 5,
Lopinavir 2,3,5,7,
Megestrol acetate 2,9,
Naproxen 2,7,8,
Omeprazole 2,7,
Phenytoin 2,4,8,
Valproate 1,7,8,9
U
Comments
Peak glucose unknown. Race and dyslipidemia only
reported risk factors for diabetes; weight, BMI, personal,
family history, baseline values not reported. Reportedly
had `no relevant history." Diagnosed with diabetic
ketoacidosis, hypertriglyceridemia, renal insufficiency; pH,
HCO3, treatment and outcome not reported. Outcome and
treatment unknown off olanzapine.
Peak glucose unknown. Age and chronic infection were
reported risk factors for developing diabetes. Also on
multiple anti-viral agents and conventional antibiotics
compatible with treatment of HIV, if not active AIDS
complex and complications; marijuana prescribed.
Diagnosed with diabetic ketoacidosis; pH, HCO3, ketones
and treatment not reported. Outcome and treatment off
olanzapine not reported.
Peak glucose 800 mgldl. No personal history of diabetes

had risk factors of strongly positive family history and
obesity BMI 38.7 kg/rn2; glucose 92 mg/dl seven months
prior to olanzapine use. Developed polyuria, polydipsia,
fever temperature not reported, nausea, and vomiting.
Diagnosed with diabetic ketoacidosis; hospitalization
unknown. No pH, HCO3, unne and serum ketones
reported. Treated with unspecified medications and diet;
improved off olanzapine but with continued hyperglycemia
3 months after olanzapine cessation.
Peak glucose unknown. Past medical history, family
history and concomitants not reported. Risk factors
include race. Weight, habitus, baseline glucose levels not
reported. Developed diabetic ketoacidosis treated with
insulin after taking olanzapine for 6 months. Serum
glucose level, pH, HCO1, serum and ketone urine levels
not reported. Outcome and treatment unknown off
olanzapine.
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Table 3.7.
87
4.07
Case ID
USOI 1278580
MedDRA Preferred
Terms
Acidosis NOS,
Aggression,
Agitation,
Blood potassium
increased,
Diabetes mellitus
NOS,
Folliculitis,
Hyperglycaemia NOS,
Hypoglycemia NOS,
Incontinence NOS,
Ketonuna,
Thrombocytopenia
Etiology of
Glucose
Dysregulation
OE
Concomitant Drugs
Weight Gain
Fluphenazine 2,9,
Reported Pre
Existing
Glucose
Dysregulation
U
Comments
Peak glucose 1240 mg/dl. Past medical history of
developmental disability, questionable seizure disorder,
dystonic reactions with fluphenazine and benztropinc; no
family or personal history of diabetes mellitus reported.
Risk factors include obesity BMI 27.5 kg/rn2 and race.
After taking olanzapine for 29 months, presented to ER
with agitation, frequent incontinence, polydipsia,
polyphagia, nausea, vomiting and reported significant
weight loss BMI 22.0 kg/m2. Ketonuna detected, history
of vomiting for 2 weeks and ensuing dehydration.
Diagnosed with ketoacidosis, diabetes mellitus,
hyperglycemia, ketonuria; HbAlc 7.5%, pH 7.3, HCO3 11
meq/L, pCO2 24 mmHg, 3+ ketonuria, sodium 146 meqlL,
potassium 6.0 meq/L, BUN 27 mgldl; plasma osmolarity,
serum kctones, beta-hydroxybutyrate levels not reported.
Treated with IV hydration, insulin, haloperidol, lorazepam.
Also started on cephalexin for folliculitis. Vaiproic acid
discontinued due to thrombocytopenia; improved on
olanzapine at increased dose. Changed to pioglitazone and
metformin, subsequently developed hypoglycemia-like
symptoms NOS; metformin stopped. Improved on
increased olanzapine dose, oral hypoglycemic, and off
valproate.
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Table 3.7.
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26 March 2003
B
88
1.82
Case ID
USOI 1279180
89
2.31
USO1 1279464
MedDRA Preferred
Terms
Diabetic kctoacidosis
Dehydration,
Diabetes mellitus
insulin-dependent,
Ketoacidosis
Etiology of
Glucose
Dysregulation
POE
POE
Concomitant Drugs
Weight Gain
U
Promethazine 2,9,
Quetiapine 2,7,8
Reported Pre
Existing
Glucose
Lysregulation
U
Comments
Peak glucose 876 mg/dl. No reported risk factors for
diabetes mellitus. Acute presentation in diabetic
ketoacidosis was in context of vague abdominal pain and
vomiting. Over the 27 days or less of olanzapine use in the
hospital, he lost 3 kg but had no reported symptoms of
polyuria or polydipsia. At time of glucose-related event
patient had Kussmaul respirations and was tachycardic
heart rate not reported, anion gap 28, potassium 5.7
meq/L, WBC 17.2K and ketonemia present. Treatment
included intravenous hydration with sodium bicarbonate
and insulin drip. One day later FIbAIc was 18.6%; HbAlc
not reported from baseline. Outcome was improved, off
olanzapine, but requiring diet and insulin; unknown if
receiving concomitant medications.
Peak glucose 1250 mg/dl; reported to have ketoacidosis
and insulin dependent diabetes mellitus but pH not
reported, and HCO 29 meq/L with anion gap 9. Risk
factors for development of diabetes mellitus included prior
hyperglycemia and obesity HMI 29.5 kg/rn2. Had
possible history of seizures. Reportedly had tolerated
olanzapine for `many years' without evidence of diabetes
mellitus. Diagnosed with diabetes mellitus, hospitalized;
trace ketones in urine and glycosuna 3+, sodium 112
meq/L, potassium 5.6 meqlL, chloride 78 meq/L,
bicarbonate 29 meq/L and creatinine 2.0 rng/dl after
nausea, vomiting, polyuna and polydipsia. Improved off
olanzapine after resolution of nausea and vomiting,
treatment with insulin and rehydration; insulin therapy
continued.
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Table 3.7.
.9
`
Case ID
USO2O1 81053
MedDRA Preferred
Terms
Pancreatitis acute
Etiology of
Glucose
Dysregulation
POE
Concomitant Drugs
Weight Gain
Estrogens conjugated 2,8,
Hydrochlorothiazidef
triamterene 2,5,7,8,
Reported Pre
Existing
Glucose
Dysregulation
N
90
1.83
91
1.85
USAOI 121024
6
IN
92
1.86
USAO2OIIO74
0
IN
Comments
Peak glucose 957 mg/dI. Risk factors for diabetes mellitus
included hypertension, obesity BMI 39.0 kg/rn2, age, race
and positive family history of diabetes; baseline laboratory
values not reported. Presented with abdominal pain and
diagnosed with diabetic ketoacidosis and acute pancrcatitis
with ketonernia, anion gap 3!, bicarbonate 11.0 meqlL, pH
7.3, HbAlc 11.7%, amylase 373 UIL, lipase 1035 U/L.
Concurrent acute pancreatitis reportedly thought to be
secondary to estrogen, hydrochiorothiazide or valproate.
No evidence of chronic pancreatitis or scarnng on CT.
Lipase and amylase declined on olanzapine and insulin.
Event resolved off olanzapine and valproic acid, and on
continued treatment with insulin and oral hypoglycemic
agent.
Peak glucose unknown. Race was only reported risk factor
for diabetes; personal and family history, weight, BMI and
concomitant medications not reported. Diabetic
ketoacidosis diagnosed and patient hospitalized; PH,
HCO3, urine and serum ketones, treatment, outcome and
status of olanzapinc use not reported.
history, weight. RMI, baseline laboratory values not
reported. Reportedly not taking concomitant medications.
Took olanzapine for 5 years; developed diabetic
ketoacidosis requiring hospitalization at an unknown date.
Glucose level, pH, HCO1, urine and serum ketones,
treatment, outcome, and status of olanzapine use not
reported.
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Contidenhal
Table 3.7.
93
2.32
94
1.87
Case ID
USAO2O2I 098
8
USAO2O2I 140
I
MedDRA Preferred
Terms
Diabetes mellitus
NOS,
Ketoacidosis,
syndrome
Pancreatitis NOS,
Schizophrenia NOS
Etiology of
Glucose
Dysregulation
POE
NOAE
Concomitant Drugs
Weight Gain
U
Reported Pre
Existing
Glucose
flysregulation
U
Comments
Peak glucose unknown. Obesity only reported risk factor
for diabetes mellitus; personal and family history, BMI,
baseline laboratory values and concomitant medications
not reported. Diagnosed with ketoacidosis, diabetes
mellitus and "a bit of NMS" neuroleptic malignant
syndrome after taking olanzapine for one week. Blood
glucose level, FIbAI c, pH, HCO3, urine and serum ketoncs,
temperature, CPK levels and whether rigidity present were
not reported. Treatment, outcome and status of olanzapine
not reported.
Peak glucose 517 mg/dl. Risk factors for development of
diabetes mellitus included race and dyslipidemia; height,
weight and BMI not reported. Reportedly had no
significant medical history, no personal or family history
of diabetes mellitus. Noncompliant with olanzapinc
dosing with subsequent relapse of schizophrenia. Had
random glucose 133 mg/dl two months before acute
events. Diagnosed with diabetic ketoacidosis and
pancreatitis. and hospitalized; admitting glucose 517
mg/dl, serum amylase 577 U/L, lipase 2399 UIL,
triglycerides 1441 nig/dl after 3 day history of nausea,
vomiting and abdominal pain. Abdominal CT scan
revealed large, edematous pancreas; pH, HCO3 levels not
reported. Treatment other than discontinuation of
olanzapine not reported; hyperglycemia resolved after
olanzapine cessation.
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Table 3.7.
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and the Patient Was on Olanzapine at Event Onset n=96 concluded
95
z
1.88
Case ID
USAO2O2I 179
4
96
1.89
USAO2O2I 191
9
MedDRA Preferred
Terms
Concomitant Drugs
Glucose flysregulation,
Weight Gain
U
Etiology of
Glucose
Dysregulation
IN
POE
Reported Pre
Existing
Glucose
Dysregulation
U
Comments
history, height, weight, BMI, baseline laboratory values
and concomitant medications not reported. Diabetic
ketoacidosis diagnosed, hospitalized after taking
olanzapine; dose, duration not reported. It was unknown if
coma was present. Blood glucose level, pH, HCO1, urine
and serum ketones, treatment of the event not reported.
Outcome was improved, off olanrapine.
Peak glucose unknown. Race and obesity l3Ml 27.6
kg/rn2 were risk factors for development of diabetes
mellitus; personal and family history of diabetes and
possible prior episodes of hyperglycemia were not
reported. Reportedly taking no concomitant medications.
Diabetic ketoacidosis diagnosed, hospitalized and treated
with insulin. Blood glucose level, pH, HCO3, serum and
urine ketones and clinical events surrounding presentation
of diabetic ketoacidosis not reported. Outcome was not
resolved on olanzapinc and treated with insulin; reported
information was provided only 4 days after acute event.
Abbreviations:
8
U
Weight loss; 9
Weight gain; NA
1
=
=
=
Pancreatitis;
Unknown/not reported if concomitants being taken.
Etiology of Glucose Dysrcgulation: NOAE = No other apparent etiology; POE
Not applicable; IN =

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3.2.3.2. Summary
identified for this review, a total of 96 cases were identified involving non-coma, nonfatal
acidosis and meeting the criteria for inclusion as a severe adverse event potentially
suggestive of glucose dysregulation temporally associated with commercially-marketed
olanzapine.
Of these 96 cases, 50 patients 52.1% were receiving concomitant medications known to
be temporally associated with glucose dysregulation, pancreatitis, acidosis, andlor weight
gain. In 17 of these 50 cases 34%, patients were receiving concomitant vaiproic acid or
derivatives. The actual drug classes for concomitant drug use in these 50 cases is
presented in Table 3.8.
Table 3.8.
Use of Concomitant Medications in Cases of Acidosis

Nonfatal, Non-Coma n=50
Use of Concomitant Medications
Cases of Acidosis
Non-Coma, Nonfatal
n=50

Glucose Dysregulation, Acidosis, Pancreatitis, and/or
Weight Gain in Patients with Reported Evidence of
Glucose Dysregulation, on Olanzapine, in Non-Fatal
cases
Phenothiazines
Atypical anti-psychotics Risperidone, Quetiapine, Clozapine
Paroxetine
Corticosteroid
Lithium
Thyroid preparation
Valproic acid and derivatives
17
Carbamazepine
Cases having concomitant drugs that are temporally
associated with hyperglycemia, diabetes mellitus, pancreatitis,
acidosis and/or weight gain and none of the agents or classes
specified above.
14
Note: Numbers of drugs for each category of pathology exceeds the `n' for that pathology because some
patients were taking more than 1 of the specified agents.
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A majority of these severe spontaneous adverse event reports 66 of 96; 68.8% were
confounded by the presence of other etiologic factors 20/96 or possible other etiologic
contributing factors 46/96 known to affect glucose homeostasis including risk factors
for diabetes, weight gain, concurrent medical conditions that have been established to
affect glucose homeostasis, or concomitant treatment with drugs known be associated
with glucose dysregulation. In 29 of these 96 cases 30.2%, a lack of critical clinical
information in the adverse event report precluded clear assessment of possible etiologic
contributors, and the cases were classified as indeterminable. In 22 of 96 cases 22.9%,
other or possible other etiologies for glucose dysregulation were present, with olanzapine
as a potential contributing factor via weight gain possibly occurring during treatment
with olanzapine or when treatment with olanzapine could not be definitively ruled out as
an additional contributor, as described in Section 2.1.2.2.
In 1 of these 96 cases, no apparent etiology for glucose dysregulation other than
treatment with olanzapine was identified. This case was nonfatal and resolved after
discontinuation of olanzapine: Case USAO2O21 1401 was reported to have pancreatitis
NOS and diabetic ketoacidosis. The patient was reported to have no significant medical
history, nor personal or family history of diabetes mellitus, nor use of concomitant
medications. He presented with a 3-day history of abdominal pain, nausea, and vomiting.
An abdominal CT scan revealed a large edematous pancreas; the status of the gallbladder
was not discussed in the reported data. Laboratory values on hospital admission were:
lipase 2399 UIL, amylase 577 UIL, triglycerides 1441 mg/dL, peak glucose 517 mg/dL.
The patient had risk factors for diabetes non-Caucasian ethnicity and dyslipidemia, and
was reported as noncompliant with olanzapine use. Hyperglycemia was reportedly
resolved after hospitalization and discontinuation of olanzapine without report of
therapeutic interventions or hospital course. The clinical course of pancreatitis was not
discussed in the report, nor were long-term treatment and status of diabetes mellitus.
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3.2.4. Reports Involving Pancreatitis

3.2.4.1. Report Tables
Table 3.9 shows reports of pancreatitis acute and/or historical, with or without reported
glucose dysregulation, in which olanzapine was prescribed at some time in clinical
course, but not necessarily at event onset. Full narratives for these patients appear in
Appendix C.
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Reports of Pancreatitis Acute and/or Historical With or Without Reported Glucose Dysregulation;
Olanzapine Prescribed at Some Time in Clinical Course, Not Necessarily at Event Onset n=29
Table 3.9.
t
1.01
Case ID
CA990600604
18.01
DE0003021 18
MedDRA Preferred
Terms
Pancreatitis NOS
Diabetes mellitus
NOS,
Hypercholesterolaemia,
Hyperlipidaemia
NOS,
Liver function tests
NOS abnormal,
Pancreatitis NOS
Etiology of
Glucose
Dysregulation
POE
Death
Reported
as Glucose
Metabolism
Related?
NA
OE
NA
Concomitant Drugs
Temporally
Associated with
Glucose
Dysregulation,
Acidosis, Pancreatitis
and/or Weight Gain
N
Reported Pre
Existing
Glucose
Dysregulation
Y
Comments
Peak glucose unknown. Hospitalized with acute
pancreatitis Grade D or Eon CT scan and diabetic
ketoacidosis ten days after olanzapine started; HbAlc
"elevated" at time of diagnosis. No reported laboratory
values. Reported as `probably' undiagnosed and
untreated diabetes mellitus for "some time."
Paroxetine and trifluoperazine discontinued 17 days
before presentation with DKA; known concurrent
alcohol use. Improved off olanzapine.
Peak glucose 784 mg/dL. Participating in a post
marketing study. Risk factors of baseline obesity and
alcohol abuse history; no prior history of pancreatitis
or concurrent alcohol use. Baseline elevated GGT
compatible with alcohol related hepatic damage.
Previous antipsychotic medications fluphenazine and
levomepromazine have temporal association with
glucose dysregulation and weight gain; no concomitant
medication. Metabolic acidosis pH 7.15.
Hypertriglyceridemia present concurrently. Glucose
dysregulation improved and pancreatitis resolved on
olanzapine, diet and insulin.
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continued
Table 3.9.
r,
r.,
15.03
Case ID
DE010104555
MedDRA Preferred
Terms
insulin-dependent,
Drug interaction
NOS,
Hyperlipidaemia
NOS,
Pancreatitis NOS
Etiology of
Glucose
Dysregulation
POE
Death
Reported
as Glucose
Metabolism
Related?
NA
Concomitant Drugs
Temporally
Associated with
Glucose
Dysregulation,
and/or Weight Gain
Clozapine 2,6,7,8,9,
Reported Pre
Existing
Glucose
Dysregulation
U
Comments
Peak glucose 372 mg/dl. Medical history of clozapine
use for 11 years but no other reported personal or
family history; use of alcohol not discussed.
Diagnosed with hypertriglyceridemia no value
reported around time olanzapine begun. Risk factors
include obesity weight 114kg; BMI not reported.
After taking olanzapinc 1 year and paroxetine and
pirenzepine for 3 months, was hospitalized due to
epigastric eramping and vomiting. Pancreatitis, Type
II diabetes mellitus, hyperlipidemia and drug
interaction diagnosed; HbAI c 11%. No pH, HCO3, or
serum/urine ketones reported; serum lipase 70 U/L and
amylase "within normal limits." Triglycerides 1147
mg/dl, cholesterol 387 mgldl. No report of abdominal
ultrasound or CT being performed. Liver function
studies, CPK, LDH, and TSH reported within normal
limits. Treatment included total fasting, omeprazole,
mcironidazole, clarithromycin indication not
specified, and insulin therapy. Olanzapine and all
concomitants were stopped. Approximately 2 weeks
after event, triglycerides were 596 mg/dl, cholesterol
237 mg/dI, HDL 39 mgldl, and LDL 79 mg/dl. No
further glucose or other laboratory data reported.
Outcome resolved off olanzapine, clozapine,
paroxetine, and pirenzepine. Long term therapy not
reported. Reporter thought pancreatitis possibly
caused by hypeririglyceridemia.
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continued
Table 3.9.
20.01
Case 11
FRO1 1000322
29.12
US97031177A
MedDRA Preferred
Terms
Diabetes mellitus
aggravated
Hyperglycaemia
NOS,
Pancreatic enzymes
NOS increased
Etiology of
Glucose
Dysregulation
POE
Death
Reported
as Glucose
Metabolism
Related?
NA
IN
NA
Concomitant Drugs
Temporally
Associated with
Glucose
Dysregulation,
and/or Weight Gain
Insulin human,
Lithium carbonate
2,8,9,
Propranolol 2
Reported Pre
Existing
Glucose
Dysregulation
Y
Conunents
Peak glucose 300 mg/dl. Pre-olan7.apine glycemic
control not reported. Current status of alcohol use,
dietary habits and concurrent medical status not
provided, had pre-olanzapine insulin-dependent
diabetes. Data deficits preclude assessment of severity
of exacerbation and complete determination of possible
causes. Glycemic control did not improve off
olanzapine with continued insulin. Although the
patient had a history of pancreatitis due to alcoholism,
acute pancreatitis was unlikely given the normal
tomodensitometry of abdomen and absence of reported
symptoms.
Peak glucose unknown. Patient without specific
clinical information reported, and no medical or family
history reported. No height, weight or BMI reported.
No baseline laboratory values were reported nor risk
factor information. After taking olanzapinc for
unknown duration, reportedly was hospitalized
reasons unknown and found to have elevated
pancreatic enzymes and hyperglycemia. Laboratory
data not reported. Unknown if patient had acute
pancreatitis. Neither treatment nor details of
hospitalization were reported. Outcome and status of
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continued
Table 3.9.
c
26.08
Case ID
US97031381A
MedDRA Preferred
Terms
Blood amylase
increased,
Blood glucose
increased,
Depressed level of
consciousness,
Pancreatitis acute,
Pyrexia,
Sedation,
Sepsis NOS
Etiology of
Glucose
Dysregulation
OE
Death
Reported
as Glucose
Metabolism
Related?
NA
Concomitant Drugs
Temporally
Associated with
Glucose
Dysregulation,
and/or Weight Gain
Clonazepam 8,9,
Thiothixene 2,9,
Valproate 1,7,8,9
Reported Pre
Existing
Glucose
Dysregulation
U
Comments
Peak glucose 1672 mgldL. Patient developed marked
hyperglycemia with diagnosed hyperosmolar,
hyperglycemic coma attributed to acute pancreatitis
and sepsis; amylase 900 lUlL. Sedation, nausea and
vomiting without reported abdominal pain preceded
DM and pancreatitis diagnoses by an unknown interval
and were treated by dose reduction of all medications.
Improved following simultaneous discontinuation of
valproate, clonazepam and olanzapine without
rechallenge.
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Table 3.9.
continued
T
`
jj
18.09
Case ID
US97106181A
MedDRA Preferred
Terms
Agitation,
Confusion,
Diabetes mellitus
NOS,
Hepatomegaly,
Insomnia NEC,
Memory impairment,
Pancreatic disorder
NOS,
Renal disorder NOS,
Thirst,
Urinary frequency,
Vision blurred,
Weight decreased
Etiology of
Glucose
Dysregulation
POE
Death
Reported
as Glucose
Metabolism
Related?
NA
Concomitant Drugs
Temporally
Associated with
Glucose
Dysregulation,
and/or Weight Gain
Valproate 1,7.8.9,
Lcvothyroxine 2
Reported Pre
Existing
Glucose
Dysregutation
U
Comments
Peak glucose 1291 mg/dl. No reported medical history
except "working with hazardous chemicals" NOS.
No reported family history. Risk factors include age
and obesity BMI 29.7 kg/m2; alcohol use history not
reported. After taking olanzapine for 3 days,
developed extreme thirst, blurred vision and confusion.
Diagnosed with hypothyroidism and started on
levothyroxine. Presented to hospital approximately
one month later and found to have elevated glucose.
Diagnosed with diabetes mellitus, admitted to ICU and
started on insulin. Reportedly discontinued all his
medications one day prior to the event. Also noted to
have polyuria, "loss of eyesight" NOS, "swollen"
kidneys and liver, "pancreas shutdown," "loss of
hearing," sleeplessness, and 13.6kg weight loss. No
laboratory data other than peak glucose reported.
Neither symptoms, signs nor diagnosis of acute
pancreatitis reported. Olanzapine and concomitants
remained stopped. Follow-up glucose 2 weeks after
event, after patient returned home, was 287 mg/dl with
HbAlc 13.6%. Two weeks later, glucose 109 mgldl.
Outcome improved; patient off olanzapine, vaiproate
and presumably levothyroxine, and on insulin 2
months after olanzapine cessation. Reported follow-up
information from nurse: patient may have been an
undiagnosed diabetic, continues with diabetes mellitus,
fatigue, painful warts, leukocytosis from UTI,
decreased vision, proteinuna but no blindness or
deafness.
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Table 3.9.
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continued
,,
2.13
Case ID
US98024165A
1.28
US980503939
MedDRA Preferred
Terms
Gastrointestinal upset,
Ketoacidosis,
Pancreatitis
haemorrhagic,
Pyrexia
Cough,
Pancreatitis NOS,
Somnolence,
Weight increased
Etiology of
Glucose
Dysregulation
POE
Death
Reported
as Glucose
Metabolism
Related?
U
OE
NA
Concomitant Drugs
Temporally
Associated with
Glucose
Dysregulation,
and/or Weight Gain
Lithium 2,8,9,
Lorazepam 8,9,
Valproate 1,7,8,9
NA
Reported Pre
Existing
Glucose
Dysregulation
U
Comments
Peak glucose unknown. Presented with fever 39.4C,
flu-like symptoms, and gastrointestinal symptoms
NOS; she was not hospitalized. Post-mortem
diagnosis of acute hemorrhagic pancreatitis; there was
no history of alcohol use. Although probable that the
patient developed hyperglycemia during the
pancreatitis, neither glucose levels nor specific report
of hyperglycemia or diabetes mellitus was provided,
but conservatively assessed as instance of glucose
dysregulation. It is unknown from the reported data
why the patient was not hospitalized or further
evaluated in the 5 days between onset of symptoms
and death. Status of gall bladder function and presence
or absence of cholelithiasis at autopsy were not
specified; toxicology was not reported.
Peak glucose 1160 mg/dl. Tolerated olanzapine for 17
months without hyperglycemia reported. Obesity
BMI 27.4 kg/m2 and weight gain 4.5 to 6.8 kg.
Week-long prodrome of sore throat and cough treated
with elixir; became increasingly somnolent; flu-like
illness with R LL pneumonia, pancrcatitis, and
`poorly arousable" at presentation; Urine positive for
RBC and WBC; diagnosed with diabetic ketoacidosis,
pH 6.82, anion gap 21 and positive serum acetone test.
Concurrent pancreatitis, pneumonia and possible UT!
were precipitating factors. OTC cough medicine may
have contained alcohol or glucose. Event resolved
with insulin, off olanzapine; insulin then discontinued.
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Table 3.9.
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continued
10
1.35
Case ID
US981 214405
11
18.31
US9901 16671
MedDRA Preferred
Terms
Diabetes mellitus
NOS.
Overdose NOS,
Pancreatitis NOS
Agitation,
Confusion,
Dehydration,
Diabetes mellitus
NOS,
lntubation NOS,
Pancreatitis NOS,
Weakness
Etiology of
Glucose
Dysregulation
OE
Death
Reported
as Glucose
Metabolism
Related?
NA
POE
NA
Concomitant Drugs
Temporally
Associated with
Glucose
Dysregulation,
and/or Weight Gain
Valproate 1,7,8,9
Diphenhydramine9
Reported Pre.
Existing
Glucose
Dsregulation
U
Comments
Peak glucose 553 mgldL. Race, age, obesity, history
of alcohol abuse with subsequent cirrhotic and fatty
liver due to alcoholism, hyperlipidemia and nicotine
abuse were risk factors for diabetes. No reported
adverse events on olanzapine for 14 months prior to
paroxetine introduction. Pancreatitis, diabetic
ketoacidosis developed 1 to 2 months after paroxetine
added. Amylase 490 lUlL, lipase 1298 lUlL, HbAlc
11.5%, pH 7.29, pCO2 31 mmHg, anion gap 19, urine
ketones> 80, triglycerides 375 mgldl and
transaminases mildly elevated. Improved off
olanzapine and paroxetine on oral hypoglycemic;
negative olanzapine rechallenge.
Peak glucose 1400 mg/dL. Baseline blood glucose,
personal and family history, particularly lipid
metabolism and alcohol history, height and weight not
reported; reported to be a `poor historian.' Race only
reported risk factor for diabetes. Hospitalized in ICU
for treatment of nonketotic, hyperglycemic state `close
to coma'; trace serum ketones and serum osmolanty>
400 mosmlL; pH and bicarbonate not reported.
Diagnosed with concurrent pancreatitis with serum
lipase 5000 U/L; amylase not reported. Symptoms and
signs of pancreatitis not reported. Improved off
olanzapine and diphenhydramine; continued to require
insulin following olanzapine cessation. Conservatively
categorized as coma.
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Reports of Pancreatitis Acute andlor Historical With or Without Reported Glucose Dysregulation;
continued
Table 3.9.
is
12
1.36
Case ID
US99062341 1
13
26.15
US990623659
MedDRA Preferred
Terms
Diabetes mellitus
NOS,
Pancreatitis NOS,
Thromboembolism
NOS,
Vomiting NOS
Blood glucose
increased,
Pancreatitis acute
Etiology of
Glucose
Dysregulation
OE
Death
Reported
as Glucose
Metabolism
Related?
N
POE
Concomitant Drugs
Temporally
Associated with
Glucose
Dysregulation,
and/or Weight Gain
Levothyroxine 2,
Metformin I
Valproate 1,7,8,9
Reported Pre
Existing
Glucose
Dysregulation
U
Comments
Peak glucose >400 mg/dl fasting. Hashimotos
thyroiditis, cholelithiasis and obesity by history.
Developed vomiting, pancreatitis and heparin-induced
thrombocytopenia during terminal events. Had
cholelithiasis and suspected pancreatitis on first
admission after 2 years on olanzapinc; when off
olanzapine, and on risperidone glucose increased.
Switched back to olanzapine and glucose managed
with metformin. Developed confirmed episode of
pancreatitis with DKA pH 6.9; status of cholelithiasis
not reported. Unknown status of olanzapine and
concomitant use with resolved pancreatitis at time of
death. Developed antibodies to heparin followed by
diffuse clotting after recovery from the reported
episode of pancreatitis and DKA.
Peak glucose unknown. Only reported medical data
were that patient was black and had acute pancreatitis
diagnosed at autopsy, associated with antemortem
elevated glucose levels, and that pancreatitis was the
cause of death. Valproate was begun the same month
pancreatitis was diagnosed. The case lacked clinical
details necessary for fully assessing the patient's risk
factors and acute medical events. Duration of
olanzapine use at onset not reported.
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Olanzapine LY170053
Confidential
Glucose 4 Update
26 March 2003
continued
Table 3.9.
14
1.37
Case ID
US990725399
15
18.10
US991 131653
MedDRA Preferred
Terms
Alanine
aniinotransferase
increased,
Aspartate
aminotransferase
increased,
Pancreatitis NOS,
Tachycardia NOS,
Weight increased
Diabetes mellitus
NOS,
Pancreatitis NOS,
Weight increased
Etiology of
Glucose
Dysregulation
OE
Death
Reported
as Glucose
Metabolism
Related?
NA
OE
NA
Concomitant Drugs
Temporally
Associated with
Glucose
Dysregulation,
and/or Weight Gain
Buspirone 8,9,
Propranolol 2,
Valproate 1,7,8,9
Reported Pre
Existing
Glucose
Dysregulation
U
Comments
Peak glucose 713 mgldl, random. Obesity BMI 27.2
kg/m2, alcohol abuse with possible continued
ingestion, race, weight gain are risk factors for
diabetes. Diagnosed with diabetic ketoacidosis, anion
gap 25, urinary ketones 40, HbAlc 18%, alcohol not
detected. Equivocal diagnosis of pancreatitis with
mildly elevated enzymes peak amylase 148 U/L; peak
lipase 79 UIL, but benign abdominal exam with
abdominal pain, nausea and vomiting. Still required
insulin after olanzapine, buspirone, serlraline and
propranolol discontinued.
Peak glucose unknown. Neither medical nor family
history reported. Risk factors include age, obesity, and
45.5 kg weight gain over 2 years 1 year on combined
olanzapine and valproate. After taking olanzapine for
approximately 1 year, she was diagnosed with diabetes
mellitus and pancreatitis. Hospitalized, treated with
insulin, then switched to an oral hypoglycemic agent
NOS, diet, exercise and weight loss program. No
laboratory values, baseline or otherwise, were reported.
Reportedly the glucose level normalized off valproate.
Outcome was resolved on olanzapine and off valproate
with continued diet, oral hypoglycemic, weight loss
and exercise.
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Table 3.9.
16
r.
1.40
Glucose 4 Update
26 March 2003
continued
Case ID
US99 1233035
MedDRA Preferred
Terms
Blood alkaline
phosphatase NOS
increased,
Diabetic
hyperglycaemic coma,
Overdose NOS,
Pancreatitis acute,
Psychotic disorder
Etiology of
Glucose
Dysregulation
OE
Death
Reported
as Glucose
Metabolism
Related?
NA
POE
NOS
17
18.41
US000542556
Blood cholesterol
increased,
Diabetes mellitus
NOS,
Pancreatitis
necrotizing
Concomitant Drugs
Temporally
Associated with
Glucose
Dysregulation,
and/or Weight Gain
Albuterol 2,
Atorvastatin 2,7,9,
Clonazeparn 8,9,
Fluphenazine 2,9,
Gabapentin 2,8,
Glipizide,
Losartan I
hydrochlorothiazide
2,5,7,8,
Terazosin 9,
Theophylline 2,
Torsemide 2,
Valproate 1,7,8,9
Valproate 1,7,8,9
Reported Pre
Existing
Glucose
Dysregulation
U
Comments
Peak glucose 400 mg/dl. Obesity BMI 31.3 kg/rn2,
age, family history of diabetes, hypertension and
dyslipidemia were risk factors for diabetes. Diagnosed
with diabetic ketoacidosis with coma and pancreatitis.
Anion gap, pH, HCO3, urine and serum ketones,
amylase, lipase and treatment of event not reported.
Second episode of pancreatitis diagnosed after off
olanzapine 2 months and on fluphenazine with normal
lipase, amylase, elevated BUN and creatinine. First
episode resolved on olanzapine and off valproate;
olanzapine then discontinued and fluphenazinc begun
for control of psychosis. Following resolution of 2nd
episode of panereatitis there was a negative olanzapine
rechallenge.
Peak glucose unknown. Concomitant medications
were begun concurrently with olanzapine. Status of
olanzapine and concomitant use, when necrotizing
pancreatitis was found I month after diabetes was
diagnosed, is unknown; it is unknown if patient
hospitalized or if autopsy performed. From reported
data, it is possible olanzapine, paroxetine and valproate
were being administered when necrotizing pancreatitis
began.
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continued
Table 3.9.
18
1.50
Case ID
US000642765
19
18.11
US000744760
MedDRA Preferred
Terms
Blood creatinine
increased,
Blood triglycerides
increased,
Pancreatitis NOS,
Weight decreased,
Weight increased
Alopecia,
Diabetes mellitus
NOS,
Pancreatitis acute,
Serum ferritin
increased
Etiology of
Glucose
Dysregulation
OE
Death
Reported
as Glucose
Metabolism
Related?
NA
POE
NA
Concomitant Drugs
Temporally
Associated with
Glucose
Dysregulation,
and/or Weight Gain
Atenolol 2,
Diltiazem 2,9,
Hydrochlorothiazide
2,5,7,8,
Oxazepam 8,9,
Clomipramine 2,5,9
Reported Pre
Existing
Glucose
Dysregulation
U
Comments
Peak glucose 1069 mgldL. Had multiple intrinsic risk
factors: age, race, obesity, BMI 32.8 kg/rn2, family
history, hypertension, possible hyperlipidernia, history
of pancreatitis. Also had coronary insufficiency,
seizure disorder, and chronic renal insufficiency. Lost
16.4 kg over 2 years then regained 5.5 kg in 2-5
months prior to DKA. Hospitalized with DKA and
possible coma "altered mental state" and "mild"
pancreatitis arnylase 263 lUlL, lipase 1509 lUlL;
gastrointestinal symptoms and signs were not reported.
Treated with insulin which still was required after
olanzapine stopped. Triglycerides 773 mg/dl on
admission. Conservatively assessed as coma being
present.
Peak glucose unknown. No reported past medical or
family history. Risk factors include obesity BMI 27.3
kg/m2 and dyslipidemia. After taking olanzapine
approximately 6 months, developed abdominal pain
and was hospitalized. Diagnosed with acute
pancreatitis with diabetes mellitus; amylase and lipase
not reported. Concurrently developed alopecia and
increased serum ferritin level NOS. No baseline or
current laboratory values reported. Olanzapine
stopped; halopendol begun. Approximately 3 months
after event and post-olanzapine, glucose was 78 mg/dl,
HbAlc 3.5%, total cholesterol 266 mgldl, HDL 31
mg/dl, VLDL 70.8 mg/dl, LDL 164.2 mgldl, AST 18
UIL, and serum ferritin 389 nglml. Outcome is
resolved off olanzapine; long term therapy not
reported.
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continued
Table 3.9.
20
30.16
Case ID
US010159008
21
26.41
US010259819
MedDRA Preferred
Terms
Abnormal behaviour
NOS,
Blood glucose
increased,
Hallucination NOS,
Hypovolaemic shock,
Pancreatitis acute
Abdominal pain
NOS,
Aspartate
aminotransferase
increased,
Blood glucose
increased,
Cerebrovascular
accident NOS,
Diabetic coma NOS,
Encephalopathy
NOS,
Pancreatitis NOS
Etiology of
Glucose
Dysregulation
POE
Death
Reported
as Glucose
Metabolism
Related?
NA
OE
NA
Concomitant Drugs
Temporally
Associated with
Glucose
Dysregulation,
and/or Weight Gain
Ranitidine 7
Reported Pre
Existing
Glucose
Dysregulation
U
Comments
Peak glucose in 700s mg/dl range. History of acid
reflux and mental retardation. No family history
reported. Risk factors include ethnicity, being
overweight BMl 25.6 kg/m2, and age. After taking
olanzapine 1 year, developed nausea, vomiting,
abdominal pain and was taken to ER. Diagnosed with
hypovolemic shock, blood glucose increased, and acute
pancreatitis. No laboratory data other than glucose
reported; no radiologic study of pancreas reported.
Olanzapine was stopped; treatment other than glipizide
not reported. Reportedly pancreatitis symptoms
resolved after discharge, which was 4 days after event
and post-olanzapine.
Peak glucose 600 mg/dL. Being overweight BMl
25.3 kg/rn2 was risk factor for diabetes. No past
history of hyperglycemia. Had been stable for 2 years
on olanzapine with one-time hyperglycemia, a few
months prior to DKA. Diagnosis of DKA preceded by
24-hour prodrome of flu-like illness, abdominal pain,
and normal glucose and amylase on 2 occasions on the
day of Onset. Diagnosed with pancreatitis, diabetic
ketoacidosis, coma, CVA at an unspecified time and
encephalopathy. History positive for substance and
alcohol abuse. Improved off olanzapine; treatment
unknown. Cholelithiasis not reported as present or
absent.
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Table 3.9.
Glucose 4 Update
26 March 2003
continued
22
30.17
Case ID
US010362248
23
18.12
US010464632
MedDRA Preferred
Terms
Blood amylase
increased,
Blood glucose
increased,
Lipase increased
Confusion,
Diabetes mellitus
NOS,
Pyrexia,
Renal failure NOS
Etiology of
Glucose
Dysregulation
POE
Death
Reported
as Glucose
Metabolism
Related?
NA
POE
NA
Concomitant Drugs
Temporally
Associated with
Glucose
Dysregulation,
and/or Weight Gain
Hydrochiorothiazide
2,5,7,8,
Lithium 2.8,9
Reported Pre
Existing
Glucose
Dysregulation
U
Comments
Peak glucose 1100 mgldl. Past medical history of
hypertension; no reported family history. Risk factors
include race, age, hypertension. No information
regarding habitus. After taking olanzapine for
unknown duration, developed increased glucose and
elevated amylase and lipase 600 U/L and 700 U/L
respectively; gastrointestinal symptoms and signs not
reported. Neither baseline nor follow-up laboratory
values reported. Olanzapine stopped; outcome and
treatment unknown.
Peak glucose 1600 mg/dl. Past medical history of
hematuria, acute pancreatitis, dehydration,
hyperglycemia 5 years prior to starting olanzapinc, and
long history of taking trifluoperazine stop date
unknown. No family history reported. BMI 25.8
kg/m2. Risk factors included being overweight, prior
hyperglycemia, non-compliance with follow-up, acute
pancreatitis, and race. No baseline laboratory values
reported. After taking olanzapine approximately 1
month, developed polyuna, polydipsia, abdominal
pain, nausea, vomiting, fever temperature not
reported, and mental confusion. Fever source not
specified; cultures not reported. Hospitalized with
diagnosis of diabetes mellitus and renal failure; acute
recurrent pancreatitis not diagnosed; amylase and
lipase not reported. No pH, HCO3, HbAI c, pancreatic
enzymes, serum or urine ketones were reported. No
treatment reported; no renal biopsy performed.
Olanzapine stopped. Patient recovered; ongoing
treatment of event not required.
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EU LUly-Zyprexa Products Liabflity Litigation
Page 107
ZY

Confidential
Table 3.9.
24
10.07
469
Glucose 4 Update
26 March 2003
continued
4076
Case ID
US010566463
MedDRA Preferred
Terms
DehydraLion,
Diabetes mellitus
NOS,
Nonketotic
hypcrglycaemichyperosmolar coma,
Pancreatitis acute,
Pneumonia NOS,
Pyrexia,
Venous thrombosis
NOS,
White blood cell
increased
Etiology of
Glucose
Dysregulation
POE
Death
Reported
as Glucose
Metabolism
Related?
NA
Concomitant Drugs
Temporally
Associated with
Glucose
Dysregulation,
and/or Weight Gain
N
Reported Pre
Existing
Glucose
Dregulation
U
Comments
history and weight gain preceding olanzapine
initiation. Presented with fever, 2 to 3 days of
abdominal pain and nausea, fatigue, increasing
polyuna and polydipsia for 7 days and weight loss.
Hospitalized with nonketotic, hyperosmolar,
hyperglycemic coma, DVT, pneumonia, pancreatitis
and acidosis with bicarbonate 16 meq/L, venous pH
7.21, BUN 59 mg/dl, creatinine 4.1 mg/dl, amylase
449 U/L, lipase 953 U/L. cholesterol 276 mgldl and
triglycerides 460 mg/dl; treated with insulin.
Concurrent DVI treated with anticoagulants and left
lower lobe pneumonia treated with antibiotics; fever to
104.0F. Required renal dialysis. Radiologic study of
pancreas not reported. Hyperglycemia recurred 14
months subsequent to olanzapine discontinuation after
additional weight gain.
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Table 3.9.
Glucose 4 Update
26 March 2003
continued
,j
25
25.01
Case ID
US010768955
MedDRA Preferred
Terms
Glycosuria present,
Polyuria,
Weight increased
Etiology of
Glucose
Dysregulation
POE
Death
Reported
as Glucose
Metabolism
Related?
NA
Concomitant Drugs
Temporally
Associated with
Glucose
Dysregulation,
and/or Weight Gain
Allopurinol 1,2,
Atorvastatin 2,7,9,
Bupropion 2,8,9,
Buspirone 8,9,
Citalopram 7,8,9,
Clomdine 2,9,
Estrogens conjugated
2,8,
Gabapentin 2,8,
Gemfibrozil 7,8,
Hydrochlorothiazide
2,5,7,8,
Naproxen 2,7,8,
Pantoprazole 8,9,
Salmeterol xinafoate
2,7
Reported Pre
Existing
Glucose
Dysregulation
U
Comments
Peak glucose unknown. Reportedly urine glucose 223
mg/dl. Past medical history included alcoholism,
pancreatitis, asthma, hypertension, nicotine addiction,
proteinuria, fatty liver, possible obesity female
weighing 90kg; no BMI reported; strongly positive
family history of diabetes mellitus and weight gain
were additional risk factors. After taking olanzapine
for approximately 1 year, was found to have
glycosuria, polyuria, and increased weight. Acute
pancreatitis not described. No baseline laboratory
values reported. Olanzapine was discontinued; treated
with glyburide, diet modifications; outcome unknown.
No follow-up data reported.
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Glucose 4 Update
26 March 2003
continued
Table 3.9.
`
.,
26
t
29.13
Case ID
US010872482
MedDRA Preferred
Terms
Hyperglycaemia
NOS,
Hyperlipidsemia
NOS
Etiology of
Glucose
Dysregulation
POE
Death
Reported
as Glucose
Metabolism
Related?
NA
Concomitant Drugs
Temporally
Associated with
Glucose
Lysregulation,
and/or Weight Gain
Brotizolam 8,9,
Haloperidol 2,9
Reported Pre
Existing
Glucose
Dysregulation
Y
Comments
Peak glucose 521 mgldl. Had past medical history of
drug-induced parkinsonism, constipation, "obesity"
BMI 26.8 kg/m2, two episodes of acute pancreatitis,
17 and 22 years prior to present event. No family
history reported. Fasting blood glucose 126 mgldl four
months prior to event. Risk factors include race, age,
obesity and prior pancreatitis. After taking olanzapinc
7 weeks, stopping haloperidol for 5 weeks, developed
polydipsia and polyuria; advised to decrease food
intake and stop between meal snacks; reporter thought
hyperglycemia possibly pre-existing; diagnosed with
hyperglycemia and hyperlipidemia cholesterol 507
mgldl. No other baseline laboratory values reported.
Treatment included diet therapy. Blood glucose
dropped to 241 mg/dl. Olanzapine was stopped;
risperidone started. Blood glucose increased to 302
mg/dl; cholesterol decreased to 186 mgldl.
Glibcnclamidc and voglibose were started. Glucose
decreased to 226 mg/dl, cholesterol to 112 mg/dl.
Outcome worsened then improved off olanzapine, and
brotizolam and with addition of oral agents.
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Table 3.9.
Glucose 4 Update
26 March 2003
continued
rd
27
1.83
Case II
US02018 1053
MedDRA Preferred
Terms
Pancreatitis acute
Etiology of
Glucose
Dysregulation
POE
Death
Reported
as Glucose
Metabolism
Related?
NA
Concomitant Drugs
Temporally
Associated with
Glucose
Dysregulation,
and/or Weight Gam
Carbarnazepine 2,5,7,
Estrogens conjugated
2,8,
HydrochlorothiazidcJ
triamterene 2,5,7,8,
Reported Pre
Existing
Glucose
Dysregulation
N
Comments
Peak glucose 957 mgldl. Risk factors for diabetes
mellitus included hypertension, obesity BMI 39.0
kg/rn2, age, race and positive family history of
diabetes; baseline laboratory values not reported.
Presented with abdominal pain and diagnosed with
diabetic ketoacidosis and acute pancreatitis with
ketonernia, anion gap 31, bicarbonate 11.0 rneq/L, pH
7.3, 1-IbAl c 11.7%, amylase 373 UIL, lipase 1035 U/L.
Concurrent acute pancreatitis reportedly thought to be
secondary to estrogen, hydrochlorothiazide or
valproate. No evidence of chronic pancreatitis or
scarring on CT. Lipase and amylase declined on
olanzapinc and insulin. Event resolved off olanzapine
and vaiproic acid, and on continued treatment with
insulin and oral hypoglycemic agent.
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continued
Table 3.9.
28
r
1.84
Case ID
US020382427
MedDRA Preferred
Terms
Blood triglycendes
increased,
Pancreatitis acute
Etiology of
Glucose
Dysregulation
NA
Death
Reported
as Glucose
Metabolism
Related?
NA
Concomitant Drugs
Temporally
Associated with
Glucose
Dysregulation,
and/or Weight Gain
Bromperidol 2,9,
Ethyl loflazepate 8,9,
Flunitrazepam 8,9
Reported Pre
Existing
Glucose
Dysregulation
U
Comments
Peak glucose 778 mg/dl. Patient off olanzapinc 17 to
24 days at event onset; therefore, this is not a case of
glucose dysregulation on olanzapine. Risk factors for
history of diabetes, obesity BMI 35.9 kg/rn2, pre
olanzapine dyslipidemia and past history of
pancreatitis unreported etiology. Concomitants
started and stopped same dates as olanzapine. Elevated
triglycerides 514 mgldl documented after two weeks
of olanzapine. Diagnosed with diabetic ketoacidosis
and acute pancreatitis with arterial pH 6.96, 3+ kctones
in unspecified body fluid, blood pressure 90/60 mmHg,
respiratory rate 42/mm, amylase 1575 IU/L or 2015
lU/L, lipase 3095 llJ/L and HbAI c 13.5%. A CT scan
indicated acute pancreatitis. Abdominal pain occurred
17 days after last olanzapine dose; DKA diagnosed 24
days after olanzapinc cessation. Treatment included
intubation, doparnine hydrochloride, insulin and
antibiotics directly into pancreatoduodenal artery.
Triglycerides not reported at time of presentation with
DKA. Presence or absence of infection as part of acute
presentation was not specified although treated with
antibiotics. Events resolved.
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concluded
Table 3.9.
`,
29
1.87
Case ID
USAO2O2I 1401
Death
Reported
as Glucose
Metabolism
Related?
NA
Etiology of
Glucose
Dysregulation
NOAE
MedDRA Preferred
Terms
Pancreatitis NOS,
Schizophrenia NOS
Concomitant Drugs
Temporally
Associated with
Glucose
Dysregulation,
and/or Weight Gain
N
Reported Pre
Existing
Glucose
Dysregulation
U
Comments
Peak glucose 517 mgldl. Risk factors for development
of diabetes mellitus included race and dyslipidernia;
height, weight and BMI not reported. Reportedly had
no significant medical history, no personal or family
history of diabetes mellitus. Noncompliant with
olanzapine dosing with subsequent relapse of
schizophrenia. Had random glucose 133 mg/dl two
months before acute events. Diagnosed with diabetic
ketoacidosis and pancreatitis, and hospitalized;
admitting glucose 517 mgldl, serum amylase 577 U/L.,
lipase 2399 UIL, triglycerides 1441 mgldl after 3 day
history of nausea, vomiting and abdominal pain.
Abdominal CT scan revealed large, edematous
pancreas; pH, HCO3 levels not reported. Treatment
other than discontinuation of olanzapine not reported;
hyperglycemia resolved after olanzapine cessation.
Abbreviations:
8
Weight loss; 9
Weight gain; NA
I
=
Hyperlipidemia, Hypcrtriglyceridemia; 6
Ketonuna, Ketosis; 7
Pancreatitis;

Unknown cause

Etiology of Glucose flysregulation: NOAE = No other apparent etiology; POE
Not applicable; IN

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Page 132
3.2.4.2. Summary
Estimates of worldwide incidence of acute pancreatitis range from 73 to 750 per million
population per year Steinberg and Tenner 1994; Coruield et al. 1985; Baron and Morgan
1999. In the United States alone, it is estimated that 50,000 to 80,000 cases of acute
pancreatitis are diagnosed annually Pancreas.org [WWW]. Among the factors known
to precipitate acute pancreatitis, alcohol abuse and gallstones account for the majority
70% to 80% of cases. The role of hyperlipidemia has been estimated to account for
acute pancreatitis in 3% to 38% of cases Toskes 1990. Only about 2% of cases of
pancreatitis are drug-induced Cerulli 1999, with associated agents including
azathioprine, estrogens, thiazide, and loop diuretics. Of psychotropic agents, the greatest
evidence for contribution to pancreatitis exists for vaiproic acid Yazdani et al. 2002. In
up to 30% of patients with acute pancreatitis, the etiology is idiopathic WebMD
[WWW].
Pancreatitis has been identified as one of the possible precipitating factors in the
development of diabetic ketoacidosis DKA and hyperosmolar hyperglycemia other
precipitating factors in the development of DKA include infection, cerebrovascular
accident, alcohol abuse, myocardial infarction, trauma [ADA 2003]. Acute pancreatitis
is likely to be associated with severe episodes of DKA with marked acidosis and
hyperglycemia, and DKA may mask coexisting acute pancreatitis Nair et al. 2000.
Of the 945 reports potentially suggestive of glucose dysregulation identified for this
review, 28 reports 3.0% involved pancreatitis acute and/or historical reported in
temporal association with glucose dysregulation, with olanzapine being prescribed at
some time in clinical course, though not necessarily at event onset. Table 3.9 includes a
summary of one additional case [US0203 82427]; although a case of pancreatitis reported
with glucose dysregulation, this patient was off olanzapine 17 to 24 days at event onset,
and was therefore classified as not a case of glucose dysregulation on olanzapine.
Of the 28 cases of pancreatitis where glucose dysregulation was reported, 10 patients
35.7% were receiving vaiproate concomitantly. Four of 28 cases resulted in death.
In 3 of 4 of these fatal cases, vaiproate was administered as a concomitant medication. In
one case US000542556, the patient was concomitantly treated with vaiproate,
paroxetine, and carbamazepine, all of which have been temporally associated with
pancreatitis. In the only case resulting in death where vaiproate was not a concomitant
medication, other medical conditions were potential etiological factors for the episode of
pancreatitis.
Of the 28 reports of pancreatitis reported with glucose dysregulation, 27 of the 28 reports
96.4% were confounded by the presence of intrinsic risk factors for diabetes; medical
conditions known to affect glucose regulation; weight gain; were receiving concomitant
medications known to be temporally associated with glucose dysregulation, pancreatitis,
acidosis, and/or weight gain; or the etiology was indeterminable.
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Of all 191 cases of potentially severe glucose dysregulation, only 1 case had no other
apparent etiology for glucose dysregulation than possibly olanzapine. This case
USAO2O2I 1401, which is the same patient described in the preceding Acidosis section
was reported to have pancreatitis NOS and diabetic ketoacidosis. The patient was
reported to have no significant medical history, nor personal or family history of diabetes
mellitus, nor use of concomitant medications. He presented with a 3-day history of
abdominal pain, nausea, and vomiting. An abdominal CT scan revealed a large
edematous pancreas; the status of the gallbladder was not discussed in the reported data.
Laboratory values on hospital admission were: lipase 2399 UIL, amylase 577 U/L,
triglycerides 1441 mg/dL, peak glucose 517 mg/dL.
The patient had risk factors for diabetes non-Caucasian ethnicity and dyslipidemia, and
was reported as noncompliant with olanzapine use. Hyperglycemia was reportedly
resolved after hospitalization and discontinuation of olanzapine without report of
therapeutic interventions or hospital course. The clinical course of pancreatitis was not
discussed in the report, nor were long-term treatment and status of diabetes mellitus.
While pancreatitis can be a precipitating factor in the development of DKA or
hyperosmolar hyperglycemic states via impairment of pancreatic insulin secretory
function, DKA is frequently associated with a number of metabolic disturbances,
including transient elevation of exocrine pancreatic enzymes amylase or lipase in the
absence of clinical symptoms, signs, or radiographic evidence of acute pancreatitis.
Vantyghem et al. 1999. Although the mechanism for the observed high frequency of
pancreatic enzyme elevation in DKA remains unclear, it has been hypothesized that DKA
may lead to functional damage of the pancreas via ischemia or oxidative stress mediated
by acute metabolic disturbances associated with DKA eg, at the level of glucose, plasma
osmolality, BUN or bicarbonate Vantyghem et al. 1999; Kjaergaard et al. 1984.
Along with this increase in pancreatic enzymes, the fact that clinical presentation of DKA
can overlap with symptoms of acute pancreatitis such as nausea, vomiting, and
abdominal pain may lead to difficulties in differentiating DKA from acute pancreatitis in
a clinical setting Hughes 1961; Gumaste et al. 1993.
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32.5. Dechallenge-Rechallenge Sequences and Outcomes

In this review, a total of 945 adverse event reports were identified for evaluation of the
presence of potential glucose dysregulation during treatment with olanzapine methods
described in Section 2.1. These 945 reports were also reviewed for changes in
symptoms or signs of glucose dysregulation following olanzapine dechallenge drug
discontinuation and rechallenge drug reintroduction. Figure 3.2 shows the report
algorithm used to identify cases for assessment of olanzapine dechallenge.
As shown in Figure 3.2, a total of 38 reports did not meet criteria for inclusion in the
assessment of changes in glucose andlor clinical status following olanzapine
discontinuation 13 reports devoid of reference to hyperglycemia by MedDRA Preferred
Term, report text, or laboratory values; 8 having peak random glucoses <126 mg/dL; and
17 reports of patients not on olanzapine at onset of event.
Of the remaining 907 cases with definite glucose dysregulation on olanzapine at event
onset, olanzapine was continued in 367 cases, and were thus classified as "Not
Applicable" for assessment of dechallenge-rechallenge. Cases in which the status of
olanzapine use was either not reported or unknown 125 cases were classified as
"Unevaluable" with respect to evaluation of dechallenge-rechallenge. Olanzapine was
definitely dechallenged discontinued in 415 cases.
The 415 cases of glucose dysregulation in which definite olanzapine discontinuation
occurred were further evaluated to identify use of a hypoglycemic agent or regimen
during or following the acute event. If a hypoglycemic/antidiabetic agent or regimen was
used, the case was determined to be "Uncertain" 268 cases with respect to the possible
influence of olanzapine cessation on outcome of hyperglycemic events.
There were 37 cases in which the patient had concurrent treatments or medical
conditions, some of which were treated during discontinuation of olanzapine eg,
infection, noncompliance with diet or drugs, cancer, pancreatitis, active alcohol or drug
abuse, myocardial infarction, CHF, asthma, surgery, etc. These conditions confounded
the interpretation of olanzapine dechallenge in these 37 cases, which were therefore
categorized as "Uncertain" for assessability of dechallenge-rechallenge.
The remaining 110 cases were evaluated for other confounders of interpretation of
dechallenge-rechallenge data. Olanzapine discontinuation in 8 cases was
contemporaneous with discontinuation of a concomitant medication temporally
associated with glucose dysregulation, pancreatitis, acidosis, and/or weight gain. These
8 cases were categorized as "Uncertain" for assessability of olanzapine discontinuation.
There was one additional case of a patient diagnosed with diabetic ketoacidosis DKA
after being off olanzapine for 23 days and on quetiapine for 11 days; that patient died
approximately 3 days after DKA was diagnosed US000744983.
Following this assessment, a total of 101 cases were found to meet criteria for assessment
of outcome of olanzapine dechallenge-rechallenge.
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Dechal enqe
Reports identified by MedDRA Preferred terms 1
not on olanzapine at event onset Class 0
reports with peak glucose <126 mg/dl
Classi
reports with neither definitive MedDRA term identifier nor
Clintrace text reference to, or, laboratory values for glucose
dysregulation hyperglycemia or diabetes mellitus Class 2
Cases with verified hyperglycemia/diabetes mellitus

definitive MedDRA Preferred Terms or supportive data in
Clintrace reports 2
367
415
Cases in which olanzapine was discontinued

268
37
110
cases in which a hypoglycemic/antidiabetic agent or specified treatment

regimen for hyperglycemia was used during dechallerige making
interpretation of the dechallenge phase uncertain Class 5
cases with concurrent specific illness or diagnosis or treatment of
concurrent medical condition confounding interpretation of the
dechallenge phase and making its classification uncertain Class 6 e.g.,
infection, noncompliance with diet or drugs, cancer, surgery,
pancreatitis, active alcohol or drug abuse, Klinefelters syndrome,
myocardial infarction, etc.
Cases in which a hypoglycemiclantidiabetic agent or specific

treatment regimen for hyperglycemia was not used, or, in which it
was unknown or unreported if a hypoglycemic/antidiabetic agent or
treatment regimen was used
8
101
cases in which it is unknown or unreported if olanzapine was

discontinued Class 3
cases in which olanzapine was continued not dechallenged
Class 4
cases with concomitant medication known to be associated

with glucose dysregulation or weight gain discontinued
contemporaneously with olanzapine cessation and/or with
onset of acute event Class 7
death occurring
Class 8
5 days after discontinuation of olanzapine
Cases meeting criteria for assessment of dechallenge Class 9
I MedDRA Preferred Terms definitive for, or suggestive of, hyperglycemia/diabetes mellitus.

2 MedDRA Preferred Terms definitive for hyperglycemia/diabetes mellitus.
Figure 3.2.
Assessment of reports for inclusion as a case of

dechallenge.

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A total of 101 cases were found to meet criteria for assessment of outcome of olanzapine
dechallenge-rechallenge shown in Figure 3.3. The outcome of dechallenge was
unknown for 49 cases, negative for 9 cases olanzapine discontinuation had no effect on
symptoms or signs of hyperglycemia, and positive in 43 cases symptoms or signs of
hyperglycemia abated with olanzapine discontinuation. Thus, the outcome of
dechallenge was unknown or negative in 58 of 101 cases 57.4%.
Those 101 cases of reported dechallenge were further evaluated for the presence or
absence of rechallenge. Of the 49 cases with an unknown dechallenge outcome, 2 cases
were rechallenged: 1 patient US9801 171 IA was rechallenged with an unknown
olanzapine dose and had an unknown response to rechallenge; 1 patient US010157699
was rechallenged with reduced olanzapine dose and had a negative response symptoms
or signs of hyperglycemia did not return with olanzapine reintroduction.
None of the 9 patients having negative dechallenge responses were rechallenged.
Of the 43 patients having a positive dechallenge response hyperglycemic symptoms or
signs abated with olanzapine discontinuation, 4 patients were rechallenged. The
responses of those 4 were:
*
Unknown for 2 on reduced olanzapine dose AU97104762A and

USAO2O1 10562
Negative no recurrence of glucose dysregulation for 1 case on

reduced olanzapine dose DE00070268 1
Positive recurrence of glucose dysregulation for 1 case with an

unknown olanzapine rechallenge dose AU0008O 1766
In case AU0008O 1766 which involved both positive dechallenge and rechallenge, the
patient had diagnosed pre-olanzapine diabetes mellitus without reported treatment or
level of glycemic control. The patient's glucose regulation was reported to have
improved with olanzapine discontinuation and worsened with resumption of olanzapine
therapy. Although he was taking four concomitant medications atorvastin, citalopram,
ramipril and levothyroxine having known temporal association with diabetes,
pancreatitis, and/or weight gain, their doses and durations of administration were not
reported. It was inferred from available data that these medications were continued
during the time of olanzapine dechallenge, rechallenge, dechallenge phases, all of which
were reported to be positive. Although there were no baseline data, nor medical history
concurrent with exacerbation of diabetes, a very conservative assessment of the limited
positive dechallenge-rechallenge-dechallenge information suggests there was no other
apparent contributor than olanzapine identifiable from the limited available data, despite
the reported confounders for events.
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KEY:
a Rechallenged with reduced olanzapine dose

b Rechallenged with unknown olanzapine dose
c Rechallenged with onginal and reduced dose
Figure 3.3.
Assessment of outcome of dechallenge/rechaHenge.
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3.2.5.1. Summary
In a dechallenge/rechallenge assessment of 945 reports reviewed in detail, 101 cases met
criteria for assessment of dechallenge. Of those 101 cases with evaluable dechallenge
data, 6 were reported to have had an olanzapine rechallenge. Of those cases, only 1 case
AU0008O 1766 showed a positive response to both phases. This patient had known
preexisting diabetes mellitus, where glucose regulation was reported to have improved
with olanzapine discontinuation and worsened with resumption of olanzapine therapy.
The rechallenge for this patient was performed with an unknown dose of olanzapine and
unknown status of concomitant drug use, which included use of medications temporally
associated with glucose dysregulation, pancreatitis, acidosis, and/or weight gain
atorvastin, citalopram, levothyroxine, and ramipril.
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3.2.6. Conclusions Lilly Clintrace Database

-
Of the 945 adverse event reports potentially suggestive of glucose dysregulation

identified in a search of the Lilly Clmtrace database, 907 cases involved definite glucose
dysregulation occurring with temporal association with olanzapine treatment at event
onset. A total of 191 of these cases were identified to be severe adverse events
potentially suggestive of glucose dysregulation and involving death, coma, and/or
acidosis.
As of 31 March 2002, approximately 9,070,000 patients had been treated with
commercially marketed olanzapine. Thus, the reporting rate for the total of all adverse
event categories potentially suggestive of glucose dysregulation 907 reports observed in
temporal association with commercially marketed olanzapine was 0.01% 907 of
9,070,000. The reporting rate for all cases of severe adverse events potentially
suggestive of glucose dysregulation involving death, coma, and/or acidosis 191 cases
was <0.01%.
Of these 191 potentially severe adverse events potentially suggestive of glucose
dysregulation, nearly all 190 of 191 were confounded by other or possible other
etiologies 141 of 191, or had a lack of information in the adverse event report which
precluded clear assessment of etiologic factors 49 of 191. Of these 191 cases, only
1 case was identified as involving no apparent etiology other than treatment with
olanzapine. This case involved nonfatal, non-coma acidosis, and resolved after
discontinuation of olanzapine.
In this review of 945 reports potentially suggestive of glucose dysregulation, a total of
28 reports of pancreatitis involving glucose dysregulation were identified, 27 of which
were confounded by intrinsic risk factors for diabetes mellitus; medical conditions known
to affect glucose regulation; weight gain; were receiving concomitant medications known
to be temporally associated with glucose dysregulation, pancreatitis, acidosis, and/or
weight gain; or the etiology was indeterminable. In 1 case mentioned also in the
preceding paragraph, no apparent etiology for the glucose dysregulation other than
olanzapine was identified. In 10 of 28 cases 35.7% of pancreatitis where glucose
dysregulation was reported, patients were receiving vaiproate concomitantly.
Any evaluation of a pancreatic dysfunction within the context of diabetic ketoacidosis
must take into consideration the complexities of endocrine and exocrine pancreatic
function. Pancreatitis can be a precipitating factor in the development of DKA or
hyperosmolar hyperglycemic states via impairment of pancreatic insulin secretory
function. Conversely, DKA is frequently associated with a number of metabolic
disturbances, including transient elevation of exocrine pancreatic enzymes amylase or
lipase in the absence of clinical symptoms, signs or radiographic evidence of acute
pancreatitis. Vantyghem et al 1999. The limitations of postmarketing adverse event
data do not allow for definitive conclusions to be made regarding a potential causal
relationship between pancreatitis and DKA in the cases included in this review.
Olanzapine LY170053
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In an assessment of olanzapine dechallenge and rechallenge in these 945 patients,
101 cases had evaluable dechallenge data, 6 of which were reported to have had an
olanzapine rechallenge. Of the evaluable cases, only 1 case showed a positive response
to both phases ie, glucose dysregulation resolved with olanzapine discontinuation and
returned with olanzapine resumption. This patient was concomitantly receiving
medications temporally associated with glucose dysregulation, pancreatitis, acidosis,
andlor weight gain, which were not reported to have been dechallenged.
Of the potentially severe adverse events potentially suggestive of glucose dysregulation,
nearly all were confounded by intrinsic risk factors for diabetes mellitus, other or possible
other etiologies, or had a lack of information in the adverse event report which precluded
clear assessment of etiologic factors. Given the limitations of spontaneous adverse event
data eg, incomplete reporting of essential information; selective reporting based on
literature or competitive marketplace activities; or approximation of drug exposure
calculations, definitive conclusions regarding actual incidence or causality of olanzapine
in cases of glucose dysregulation cannot be made on the basis of spontaneous adverse
event reports.
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Analysis of Spontaneous Adverse Event Reports

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Analysis of Spontaneous Adverse Event Reports

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3. Analysis of Spontaneous Adverse Event Reports

716 reports did not meet criteria as severe cases of glucose

48 were cases of death in which glucose dysregulation was reported

47 were cases of nonfatal coma, or nonfatal coma and acidosis, in

96 were cases of acidosis non-coma, nonfatal in which glucose

Eli Lilly Zyprexa Products Liability Litigation

Zyprexa MDL Plaintiffs' Exhibit No.00379

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Olanzapine LY1 70053

Does report ha dkfinttiveividne of glucose

cases with verified hyperglycemia I diabetes

there rePort of de:t coma and/J

Potentially severe cases with report of death, coma and/or acidosis

Other Apparent Etiology OE

Possible Other Etiology POE

Other Etiology & Olanzapine Possible

Possible Other Etiology & Olanzapine

Summary of report categorization and clinical assessment of etiologic contributors.

Eli Lilly Zyprexa Products Liability Litigation

Zyprexa MDL Plaintiffs' Exhibit No.00379

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The patient was found not to be receiving olanzapine at the onset of

The patient was reported to have a peak glucose <126 mg/dL;

The report did not have a definitive MedDRA Preferred Term

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Zyprexa MDL Plaintiffs' Exhibit No.00379

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Olanzapine LY1 70053

MedDRA Preferred Terms

Blood glucose increased,

Blood glucose increased,

Diabetes mellitus NOS,

Peak glucose unknown. Weight not reported.

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Zyprexa MDL Plaintiffs' Exhibit No.00379

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Olanzapine LY1 70053

MedDRA Preferred Terms

Glycosylated haemoglobin increased

Blood glucose increased,

HbAlc occurred -3.5 m after olanzapine was

Eli Lilly Zyprexa Products Liability Litigation

Zyprexa MDL Plaintiffs' Exhibit No.00379

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Olanzapine LY1 70053

MedDRA Preferred Terms

Blood glucose increased,

Blood glucose increased,

Blood pressure increased,

Eli Lilly Zyprexa Products Liability Litigation

Zyprexa MDL Plaintiffs' Exhibit No.00379

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Olanzapine LY1 70053

Body mass index increased,

Blood glucose increased,

Alanine aminotransferase increased,

MedDRA Preferred Terms

Patient began taking insulin 8 days prior to olanzapine

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Zyprexa MDL Plaintiffs' Exhibit No.00379

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Olanzapine LY1 70053

MedDRA Preferred Terms