# Presentation: 928897

## 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

## Topics to be Covered

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

**Notes:**
-I was asked to address 2 topics: 
-critical pathways
-pathologic domains as targets for drug development
-Most focus on critical pathways, because not a lot to say about pathologic domains

## 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

**Notes:**
-I was asked to address 2 topics: 
-critical pathways
-pathologic domains as targets for drug development
-Most focus on critical pathways, because not a lot to say about pathologic domains

## 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

## Acute Efficacy EvaluationStudy HGJZ

- 8-week, inpatient & out patient, multi-center, double-blind, randomized, placebo-controlled trial
- Four treatment groups randomized 1:1:1:1
- 300mg OP Depot /2wks
- 405mg OP Depot /4wks
- 210mg OP Depot /2wks
- Placebo

## 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% )

## 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 <0.001 for all three OP Depot arms vs. placebo

## 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 2:1:1:1:2
- (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)

## 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%

## 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 <0.001
- 405mg/4Wk: p <0.001
- 150mg/2Wk: p=0.006

## 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 (n=1778, June 06) treated with OP Depot in 2 controlled studies and in 6 open-label studies

## 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

| N=1778 |  |  |  |  |  |
| --- | --- | --- | --- | --- | --- |
|   | Min | Med | Mean | Max | Total |
| Number of injections | 1 | 7 | 11.31 | 52 | 20,102 |
| Days of OP Depot exposure | 14 | 168 | 213.41 | 735 | 379,437 |
| Total patient-years of exposure:             1038.84 |  |  |  |  |  |

## Discontinuations Due to AEs

- < 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).

## Serious Adverse EventsDeaths

- 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

## 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 (n=6)
- anxiety/agitation (n=2)
- depressed level of consciousness (n=1)
- cholecystitis (n=1)
- 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

## 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

## 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

## Metabolic Syndrome Safety Data	

- Weight
- Lipids
- Blood Glucose

## Weight Gain ≥ 7% Baseline Weight to Endpoint  8-Week Study HGJZ

| Treatment Group | N | % |
| --- | --- | --- |
| Placebo | 97 | 12.4 |
| 210Q2W | 106 | 23.6 |
| 405Q4W | 100 | 27.0 |
| 300Q2W | 99 | 35.4 |

## Triglyceride Change from Normal to High 8-week Study HGJZ (any time)

| Treatment Group | N | % |
| --- | --- | --- |
| Placebo | 88 | 3.4 |
| 210Q2W | 94 | 12.8 |
| 405Q4W | 96 | 6.3 |
| 300Q2W | 91 | 14.3 |

- Normal to high: <150 to >200 mg/dL

## Mean Change From Baseline to Endpoint in Weight 24-Week Study HGKA

| 
Treatment  | 
N | Mean  
Change (kg) |
| --- | --- | --- |
| 45Q4W | 144 | -0.95 |
| 150Q2W | 140 | 0.67 |
| 405Q4W | 315 | 0.89 |
| 300Q2W | 140 | 1.70 |
| Oral OLZ | 322 | 1.30 |

## Mean Change from Baseline in Fasting Glucose 24-Week Study HGKA

| 
Treatment  | 
N | Mean 
Change
(mmol/L) |
| --- | --- | --- |
| 45Q4W | 111 | -0.01 |
| 150Q2W | 110 | 0.14 |
| 405Q4W | 257 | 0.17 |
| 300Q2W | 114 | 0.22 |
| Oral OLZ | 322 | 0.07 |

## Fasting Triglycerides % Change from Normal to High24-Week Study HGKA

| Treatment  | N | % |
| --- | --- | --- |
| 45Q4W | 111 | 3.4 |
| 150Q2W | 110 | 6.5 |
| 405Q4W | 257 | 9.8 |
| 300Q2W | 114 | 24.5 |
| Oral OLZ | 322 | 13.8 |

- Normal to high: <150 to > 200 mg/dL

## Metabolic Syndrome Safety Summary

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

## 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 overdose—profound sedation, seizure, dizziness, confusion, disorientation, slurred speech, altered gait, and weakness.

## 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.

## Case #1

## 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.

## 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.

## 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.

## 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.

## Olanzapine Plasma Concentrations in a Single Patient with 2 Events

##  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

## 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)

## 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

## 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

## 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

## 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.

## OP Depot Solubility Investigations

*In vitro* solubility experiment: ~35 to 68% of OP monohydrate dissolved in human blood within roughly 1⁄2 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.

## 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

## Back-Up Slides

## Plasma Olanzapine Concentration in 7 ES Events

## Histogram for Number of Injections (for All 2054 Patients)

- Histogram for Number of Injections (for All 2054 Patients)

## Histogram for Number of Injections (for Patients without ES Event)

## Histogram for Number of Injections (for 24 Patients with ES Events)

## Histogram for Number of Injections up to First ES Event  (for 24 Patients with ES Events)

## Expected Number of ES Events(provided by Lilly) 

## Histogram for Accumulated Dose per Patient(for All 2054 Patients)

## Histogram for Accumulated Dose per Patient(for Patients without ES Events)

## Histogram for Accumulated Dose per Patient(for Patients with ES Events)