FDA Clinical Review of Olanzapine Pamoate Depot in the Treatment of Schizophrenia

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FDA Clinical Review of Olanzapine Pamoate Depot
in the Treatment of Schizophrenia

• Jing Zhang, M.D., Ph.D.
• Division of Psychiatry Products
• Food and Drug Administration

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Topics to be Covered

• Overview of Clinical Program
• Brief Summary of Efficacy
• Brief Summary of General Safety
• Focus on the Excessive Sedation (ES) Events

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Olanzapine Pamoate (OP) Depot

• Monohydrate crystalline salt, practically
  insoluble in aqueous medium and more soluble in
  plasma
• Administration by deep gluteal muscular injection
• Indication schizophrenia

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Clinical Review of OP Depot Data

• Efficacy Two controlled clinical studies
• HGJZ (short-term, placebo-controlled)
• HGKA (longer-term, controlled)
• Safety All 8 OP Depot studies
• 2 randomized, double-blind, controlled trials
• 6 open label studies

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Acute Efficacy EvaluationStudy HGJZ

• 8-week, inpatient out patient, multi-center,
  double-blind, randomized, placebo-controlled
  trial
• Four treatment groups randomized 1111
• 300mg OP Depot /2wks
• 405mg OP Depot /4wks
• 210mg OP Depot /2wks
• Placebo

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Acute Efficacy Evaluation (Continued)

• 406 patients enrolled
• 404 randomized (100 patients/group)
• Overall completion rate was 66 (267/404)
• 300mg/2wks (67, )
• 210mg/2wks (67.9)
• 405/4wks (72 )
• Placebo (57.1 )

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Acute Efficacy Evaluation(Continued)

• Primary Analysis
• Mean change from baseline to 8-week endpoint on
  Positive and Negative Syndrome Scale for
  Schizophrenia (PANSS) Total Score
• Results
• All OP Depot treatment groups were superior to
  placebo
• P-values were lt0.001 for all three OP Depot arms
  vs. placebo

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Longer-Term Efficacy Evaluation Study HGKA

• 24-week, multi-center, double-blind, controlled,
  parallel group study of clinically stable
  schizophrenia patients
• Five treatment groups randomized 21112
• (2) OP Depot 405 mg/4wks
• (1) OP Depot 300 mg/2wks
• (1) OP Depot 150 mg/2wks
• (1) OP Depot 45 mg/4wks
• (2) Oral olanzapine (10, 15, 20 mg/d)

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Longer-term Efficacy Evaluation (Continued)

• 1065 randomized
• 300 in 405 mg/4wk and oral OLZ
• 150 in 300 mg/2wk, 150 mg/2wk and 45 mg/2wk
• Overall study completion 70.7
• OP Depot 405mg/4wk 69.8
• OP Depot 300mg/2wks 75.9
• OP Depot 150mg/2wks 64.3
• OP Depot 45mg/4wks 52.8
• Oral olanzapine 80.1

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Longer-Term Efficacy Evaluation (Continued)

• Primary Analysis
• Time to exacerbation of symptoms (relapse)
• Results
• All higher OP Depot dose groups superior to the
  low OP Depot (45mg /4Wk) dose
• 300mg/ 2Wk p lt0.001
• 405mg/4Wk p lt0.001
• 150mg/2Wk p0.006

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Safety Evaluation 3 OP Depot Databases

• Placebo-Controlled Database
• Data from HGJZ, 3 OP Depot arms
• 306 exposed to OP Depot for up to 8 weeks
• Olanzapine-Controlled Database
• Data from HGKA, 3 higher OP Depot arms
• 599 were exposed to OP Depot for up to 24 weeks
• Overall Integrated Database
• All patients (n1778, June 06) treated with OP
  Depot in 2 controlled studies and in 6 open-label
  studies

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OP Depot Patient Exposure

• Review data cut off date June 2006
• 936 exposed for at least 24 weeks
• 445 exposed for at least 48 weeks
• Total 1778 patients, 1039 patient-years

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Discontinuations Due to AEs

• lt 6 in all 3 databases
• Common reasons for discontinuations
• Worsening of the underlying disease (e.g.,
  psychotic disorder, agitation, acute psychosis)
• Other events similar to those observed in oral
  olanzapine treatment (weight gain,
  sedation/somnolence, and increased hepatic
  enzymes).

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Serious Adverse EventsDeaths

• 3 deaths of OP depot-treated patients
• Cardiomyopathy
• Leptospirosis
• Essential hypertension
• 1 death in oral olanzapine-treated patient
• Sepsis
• None of these deaths were considered as study
  drug related

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Other Serious Adverse Events HGJZ 8-week
Placebo-Controlled Trial

• 14 of 19 of patients who reported at least 1 SAE
  were OP Depot-treated
• psychotic disorder/schizophrenia (n6)
• anxiety/agitation (n2)
• depressed level of consciousness (n1)
• cholecystitis (n1)
• SAEs in the placebo group included schizophrenia,
  chest pain, asthenia, convulsion, and hip
  fracture
• The most commonly reported SAEs were consistent
  with underlying disease in all 3 databases

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Common Treatment Emergent Adverse Events (TEAEs)

• HGJZ TEAEs 5 in at least one of OP Depot arms
  and at least twice that of placebo
• Headache, sedation, nausea, dry mouth, increased
  appetite, nasopharyngitis, and vomiting.
• HGKA profile similar to oral olanzapine

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Injection-Site-Related AEs

• Reporting rate Overall 8.5
• Injection-site-pain was most commonly reported
• 4 patients discontinued due to injection site
  related AEs

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Metabolic Syndrome Safety Data

• Weight
• Lipids
• Blood Glucose

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Weight Gain 7 Baseline Weight to Endpoint
8-Week Study HGJZ
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Triglyceride Change from Normal to High 8-week
Study HGJZ (any time)
Normal to high lt150 to gt200 mg/dL
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Mean Change From Baseline to Endpoint in Weight
24-Week Study HGKA
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Mean Change from Baseline in Fasting Glucose
24-Week Study HGKA
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Fasting Triglycerides Change from Normal to
High24-Week Study HGKA
Normal to high lt150 to gt 200 mg/dL
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Metabolic Syndrome Safety Summary

• OP Depot is associated with weight gain, lipid
  and glucose dysregulation
• Profile similar to oral olanzapine

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Primary Safety Issue The Excessive Sedation (ES)
Events

• The ES events characterized by severe sedation
  and temporally associated with OP Depot injection
• Clinical signs and symptoms consistent with those
  observed in oral olanzapine overdoseprofound
  sedation, seizure, dizziness, confusion,
  disorientation, slurred speech, altered gait, and
  weakness.

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Case 1

• 31 year old man, 2nd injection of 300 mg/4wks. 45
  min after injection, he experienced severe
  sedation, moderate akathisia, dizziness, and
  feelings of weakness. After more than 6 hours,
  patient was still sedated but was reported to
  feel better. Recovered after approximately 48 hr
  and continued in study.

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Case 1
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Case 2

• 32 year old man, 1st injection of 405mg/4wks. 10
  min after injection, he experienced dizziness.
  Speech progressively altered and somnolence
  appeared. After 1.5 hr, no response to verbal
  stimuli. After 2 hr, profound sedation, bilateral
  miosis with no photomotor reflex, automatic
  movements, Babinski sign on left side, and no
  response to pain. Hospitalized. Brain CT neg.
  Able to speak with difficulty next morning.
  Recovered approximately 60 hr later. Discontinued
  study.

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Case 3

• 63 year old man, 2nd injection of 405 mg/4wks.
  15-20 min post injection, appeared pale, with
  unsteady gait and confusion. 30 min post
  injection, he became disoriented with seizures in
  hands and legs. Walked into wall, suffered
  superficial injuries. Hospitalized with diagnosis
  of tonic clonic convulsions and partial
  consciousness. Intubated. ECG, brain CT and
  lumbar puncture were normal. Recovered in
  approximately 60 hr. Discontinued study.

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Case 6

• 51 year old man, 24th injection of 300 mg/2wks,
  10 min post injection left site without
  complaint. 50 min post injection, he was found
  unconscious at bus stop. Hospitalized. Remained
  in coma for 12 hr. Vital signs and ECG were
  reported to be normal. Recovered approximately
  after 24 hr. He continued in the study.

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Case 17

• 59 year old woman, 27th injection of 300 mg/2wks.
  2 hr 45 min post injection, experienced
  significant somnolence. 20 min later, experienced
  difficulty with speech, motor restlessness, and
  anxiety. 6 hr 15 min post injection, progressed
  to profound sedation, unarousable for 8 hr.
  Responsive to pain. Vital signs reported as
  normal. Hospitalized. Recovered after
  approximately 12 hr. Continued in study.

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Olanzapine Plasma Concentrations in a Single
Patient with 2 Events
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Summary of ES Events

• As of 30 September 2007, 25 ES events reported in
  24 patients. 34,825 injections given to 2054
  patients.
• 1.2 of patients
• 0.07 of injections
• Symptoms consistent with those reported in cases
  of oral olanzapine overdose
• 2 additional cases reported after 30 Sept. 2007

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Summary of Severity of ES Events

• Severity of sedation ranged from drowsiness to
  deep coma
• 20/24 patients were hospitalized
• Two cases of coma
• Two patients were intubated
• Delirium reported in 2 cases
• Tonic-clonic convulsions in 2 cases
• High blood pressure in 1 case (190/110 mmHg 60
  min post injection)

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Summary of Timing of ES Events

• Time from injection to onset of initial symptoms
  
• Majority have occurred within 1 hr of injection
  (21/25 84)
• Range from immediately post injection to up to 3
  hrs after injection.
• Timing with regard to number of injections
• Most events occurred after patient had received
  several months of injection
• Ranged from 1st injection to 40th injection
• One patient experienced two events of ES

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Summary of Clinical Outcome

• All patients who experienced ES events were
  reported to have recovered within 3-72 hrs.
• The majority of these patients (17/24 68)
  remained in the studies and continued to receive
  OP Depot therapy

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Potential Causality of ES Events

• Causality remains unknown
• an excessive amount of olanzapine entered the
  systemic circulation more rapidly than intended
• The large bore (19-gauge) needle may play some
  role in causing local tissue or vascular injury
• The opacity and thickness of the product may make
  it difficult to detect aspirated blood in the
  needle

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Potential Causality of ES Events (continued)

• The incidence and pattern of the ES events
  remained unchanged after systematic retraining of
  study personnel in proper injection technique in
  July 2006.
• 10 additional cases were reported following
  training.

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OP Depot Solubility Investigations

• In vitro solubility experiment 35 to 68 of OP
  monohydrate dissolved in human blood within
  roughly ½ hr, much higher than anticipated for an
  insoluble OP Monohydrate salt.
• Equilibrium solubility experiment the solubility
  of OP Monohydrate in plasma is 167 times higher
  (0.5 mg/ml in plasma, 0.003 mg/ml in aqueous
  buffer) than that in an aqueous medium.

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Conclusions

• The incidence is relatively common
• 1.2 of patients
• 0.07 of injections
• Unpredictable pattern of occurrence
• Unchanged by systematic re-training of RNs
• Sedation symptoms tended to be severe
• 5 altered consciousness
• 2 in coma
• 2 intubated
• 20/24 hospitalized

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Back-Up Slides
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Plasma Olanzapine Concentration in 7 ES Events
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Histogram for Number of Injections (for All 2054
Patients)
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Histogram for Number of Injections (for Patients
without ES Event)
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Histogram for Number of Injections (for 24
Patients with ES Events)
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Histogram for Number of Injections up to First ES
Event (for 24 Patients with ES Events)
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Expected Number of ES Events(provided by Lilly)
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Histogram for Accumulated Dose per Patient(for
All 2054 Patients)
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Histogram for Accumulated Dose per Patient(for
Patients without ES Events)
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Histogram for Accumulated Dose per Patient(for
Patients with ES Events)