Clozaril^®^ (clozapine) Tablets

Briefing Book for Psychopharmacological Drugs Advisory Committee Meeting
(June 16, 2003)

  -------------------- --------------------------------------------------
  Document status:     Final

  Release date:        May 19, 2003

  Number of pages:     40
  -------------------- --------------------------------------------------

Available for public disclosure without redaction

Table of contents

1 Introduction [5](#introduction)

2 Monitoring Systems [7](#monitoring-systems)

2.1 Policy and Objectives [7](#policy-and-objectives)

2.2 Limitations [7](#limitations)

2.3 Differences [7](#differences)

2.3.1 Historical background [7](#historical-background)

2.3.2 Definitions of Leukopenia and Agranulocytosis used in analysis
[9](#definitions-of-leukopenia-and-agranulocytosis-used-in-analysis)

2.4 Criteria for Action [9](#criteria-for-action)

3 United States [10](#united-states)

3.1 Methods for Analysis [10](#methods-for-analysis)

3.1.1 Patient population [10](#patient-population)

3.1.2 Demographics [14](#demographics)

3.1.3 Incidence rates and life table analyses of severe leukopenia and
agranulocytosis
[14](#incidence-rates-and-life-table-analyses-of-severe-leukopenia-and-agranulocytosis)

3.1.4 WBC at Time of Discontinuation
[15](#wbc-at-time-of-discontinuation)

3.1.5 Projected rates of severe leukopenia and agranulocytosis
[15](#projected-rates-of-severe-leukopenia-and-agranulocytosis)

3.2 Results from United States [18](#results-from-united-states)

3.2.1 Demographics of patients in the initial monitoring system and the
current monitoring system
[18](#demographics-of-patients-in-the-initial-monitoring-system-and-the-current-monitoring-system)

3.2.2 Incidence of leukopenia and agranulocytosis
[21](#incidence-of-leukopenia-and-agranulocytosis)

3.2.3 Risk of moderate leukopenia and agranulocytosis over time
[23](#risk-of-moderate-leukopenia-and-agranulocytosis-over-time)

3.2.4 White Blood Cell Count at Time of Discontinuation
[24](#white-blood-cell-count-at-time-of-discontinuation)

3.2.5 Fatal Outcomes Related to Agranulocytosis
[26](#fatal-outcomes-related-to-agranulocytosis)

3.2.6 Analysis of Prodrome Period [27](#analysis-of-prodrome-period)

3.2.7 Projected Rates [27](#projected-rates)

3.3 Discussion and Conclusion (United States)
[29](#discussion-and-conclusion-united-states)

4 United Kingdom [30](#united-kingdom)

4.1 Methods for Analysis [30](#methods-for-analysis-1)

4.1.1 Patient Population [30](#patient-population-1)

4.1.2 Cohorts [30](#cohorts)

4.1.3 Statistics [30](#statistics)

4.2 Results from United Kingdom [31](#results-from-united-kingdom)

4.2.1 Demographics [31](#demographics-1)

4.2.2 Incidence of leukopenia and agranulocytosis
[32](#incidence-of-leukopenia-and-agranulocytosis-1)

4.3 Discussion and Conclusion (United Kingdom)
[34](#discussion-and-conclusion-united-kingdom)

5 Australia [35](#australia)

5.1 Methods for Analysis [35](#methods-for-analysis-2)

5.2 Results from Australia [36](#results-from-australia)

5.3 Discussion and Conclusion (Australian)
[36](#discussion-and-conclusion-australian)

6 Overall Discussion [37](#overall-discussion)

7 Overall Conclusion [40](#overall-conclusion)

List of In-text tables

Table 1 Definitions of leukopenia and agranulocytosis used in analysis
by monitoring system
[9](#table-1-definitions-of-leukopenia-and-agranulocytosis-used-in-analysis-by-monitoring-system)

Table 2 Registry Criteria for Action
[10](#table-2-registry-criteria-for-action)

Table 3: Description of patients treated with Clozaril since
introduction of generic clozapine.
[11](#table-3-description-of-patients-treated-with-clozaril-since-introduction-of-generic-clozapine.)

Table 4: Patient disposition [14](#table-4-patient-disposition)

Table 5: Estimation of the number of severe leukopenia and
agranulocytosis cases for patients in Cohort 3 after weekly monitoring
for six months and monthly thereafter
[18](#table-5-estimation-of-the-number-of-severe-leukopenia-and-agranulocytosis-cases-for-patients-in-cohort-3-after-weekly-monitoring-for-six-months-and-monthly-thereafter)

Table 6: Demographics of all patients in Initial system and Current
system
[19](#table-6-demographics-of-all-patients-in-initial-system-and-current-system)

Table 7: Demographics of patients in Initial system and Current system
who developed agranulocytosis
[20](#table-7-demographics-of-patients-in-initial-system-and-current-system-who-developed-agranulocytosis)

Table 8: White Blood Cell Count (WBC) at time of discontinuation by
duration for patients with WBC value between 3000 and 6000 at time of
discontinuation by system cohort
[26](#table-8-white-blood-cell-count-wbc-at-time-of-discontinuation-by-duration-for-patients-with-wbc-value-between-3000-and-6000-at-time-of-discontinuation-by-system-cohort)

Table 9: Stratified White Blood Cell Count (WBC) at time of
discontinuation by duration for patients with WBC value at time of
discontinuation by system cohort
[26](#table-9-stratified-white-blood-cell-count-wbc-at-time-of-discontinuation-by-duration-for-patients-with-wbc-value-at-time-of-discontinuation-by-system-cohort)

Table 10: Median Slope for Patients Who Developed Moderate Leukopenia
and Did or Did Not Develop Agranulocytosis
[27](#table-10-median-slope-for-patients-who-developed-moderate-leukopenia-and-did-or-did-not-develop-agranulocytosis)

Table 11: Actual and projected number of cases of severe leukopenia and
agranulocytosis after weekly monitoring during the first six months of
therapy followed by bi-weekly monitoring (Current system cohort)
[28](#table-11-actual-and-projected-number-of-cases-of-severe-leukopenia-and-agranulocytosis-after-weekly-monitoring-during-the-first-six-months-of-therapy-followed-by-bi-weekly-monitoring-current-system-cohort)

Table 12: Demographics of all patients in Initial system and Current
system
[31](#table-12-demographics-of-all-patients-in-initial-system-and-current-system)

Table 13: Demographics of all patients with agranulocytosis in Initial
system and Current system
[32](#table-13-demographics-of-all-patients-with-agranulocytosis-in-initial-system-and-current-system)

Table 14 Summary of Results [34](#table-14-summary-of-results)

Table 15: Summary of Results [36](#table-15-summary-of-results)

Table 16: Incidence of agranulocytosis in US, UK and Australia
[40](#table-16-incidence-of-agranulocytosis-in-us-uk-and-australia)

List of figures

Figure 1: US changes in CNR monitoring frequency.
[8](#figure-1-us-changes-in-cnr-monitoring-frequency.)

Figure 2: UK and Ireland, changes in CPMS monitoring frequency
[8](#figure-2-uk-and-ireland-changes-in-cpms-monitoring-frequency)

Figure 3: Australian CPMS monitoring frequency
[8](#figure-3-australian-cpms-monitoring-frequency)

Figure 4: Overview of Cohorts [12](#figure-4-overview-of-cohorts)

Figure 5: Algorithm for Probabilities
[17](#figure-5-algorithm-for-probabilities)

Figure 6: Trend of Agranulocytosis Rate
[21](#figure-6-trend-of-agranulocytosis-rate)

Figure 7: Incidence of moderate leukopenia, severe leukopenia and
agranulocytosis during the first 6 months of treatment by monitoring
system cohort
[22](#figure-7-incidence-of-moderate-leukopenia-severe-leukopenia-and-agranulocytosis-during-the-first-6-months-of-treatment-by-monitoring-system-cohort)

Figure 8: Incidence of moderate leukopenia, severe leukopenia and
agranulocytosis after the first 6 months of treatment by monitoring
system cohort
[23](#figure-8-incidence-of-moderate-leukopenia-severe-leukopenia-and-agranulocytosis-after-the-first-6-months-of-treatment-by-monitoring-system-cohort)

Figure 9: Hazard rate for moderate leukopenia and agranulocytosis over
8.5 years
[24](#figure-9-hazard-rate-for-moderate-leukopenia-and-agranulocytosis-over-8.5-years)

Figure 10: Time to first discontinuation
[25](#figure-10-time-to-first-discontinuation)

Figure 11: Trend of Agranulocytosis Rate
[33](#figure-11-trend-of-agranulocytosis-rate)

List of Appendices

Appendix 1: Post-text Tables regarding data from the United States

Appendix 2: Post-text Tables regarding data from the United Kingdom

Appendix 3: Post-text Tables regarding data from Australia

Appendix 4: Method for Estimating the Rates of Agranulocytosis and
Severe Leukopenia if the Current Bi-weekly Monitoring Option of WBC
Counts After Six Months of Treatment with Clozaril is Changed to a Less
Frequent Monitoring Option

Appendix 5: Narratives of fatal outcomes associated with Clozaril use
and the development of agranulocytosis

Appendix 6:Algorithm for criteria for changes in monitoring frequency in
the United States, United Kingdom and Australia.

# 1 Introduction

Clozaril^®^ (clozapine) is an antipsychotic drug that was approved in
the United States in 1989. It is chemically classified as a tricyclic
dibenzodiazepine derivative and is considered the first in the class of
drugs known as 'atypical' antipsychotics. It was classified as an
'atypical' antipsychotic because of its unique dopamine receptor binding
profile, its effects on various dopamine mediated behaviors, and the
paucity of extrapyramidal side effect, which differentiated it from the
'typical' antipsychotic drugs initially developed to treat schizophrenia
(e.g., chlorpromazine and haloperidol).

As previously mentioned, the initial indication for Clozaril was for the
treatment of patients with treatment-resistant schizophrenia. This
restricted indication was primarily based on the risk/benefit profile
considered at the time of approval. The efficacy of Clozaril in the
treatment of patients with schizophrenia was well established; however,
the risk of developing agranulocytosis that was associated with its use
during clinical trials and foreign marketing experience was also well
established. Agranulocytosis is clinically defined as the absence of
granulocytes, which may lead to serious infections and fatal outcomes.
The potential risk to Clozaril-treated patients of developing such a
serious complication (i.e., agranulocytosis) was considered high enough
compared not only to other antipsychotic drugs but to other drugs on the
market at the time to warrant a restricted indication.

The lack of known predictors for patients who will develop
agranulocytosis and the overall morbidity and mortality associated with
agranulocytosis were the leading reasons why the Food and Drug
Administration (FDA) and Novartis Pharmaceuticals Corporation (Novartis)
mutually agreed to implement a hematological monitoring system to reduce
the risk of agranulocytosis and its serious sequale. The rationale for
the frequency of monitoring was based on the premise that a relationship
existed between the frequency of monitoring and the probability of early
detection of leukopenia. Early detection is considered important because
the development of agranulocytosis could be minimized if patients were
identified at a point prior to agranulocytosis (e.g., moderate
leukopenia; WBC between 2000 and 3000 cells/mm^3^). Monitoring on a
daily basis was thought to be impractical, but a schedule of weekly
monitoring seemed practical and safe. Thus, Novartis developed the
Clozaril National Registry (CNR) to ensure weekly monitoring of White
Blood Cell (WBC) counts for Clorzaril-treated patients throughout their
duration of therapy.

In 1997, following nearly eight years of safe and effective use of
Clozaril in the United States, the risk of agranulocytosis associated
with Clozaril-therapy was becoming better understood. Importantly, two
characteristics were identified:

1.  The risk of agranulocytosis was greatest during the first six months
    of therapy and gradually declines thereafter, but never reaches
    zero.

2.  The number of fatal outcomes was lower than expected.

Given these observations, the possibility of reducing the frequency of
monitoring was considered at the 48th meeting (July 14, 1997) of the
Psychopharmacological Drugs Advisory Committee (PDAC). Specifically, the
following questions were posed to the PDAC:

1.  Should the frequency of monitoring be reduced at some time point
    after initiation of therapy? If so, when and to what frequency?

2.  Should monitoring be discontinued at some time point? If so, when?

3.  Should monitoring become voluntary?

The PDAC provided the following recommendations to the questions posed
at the meeting:

-   Monitoring frequency should be reduced after six months to every two
    weeks.

-   Mandatory monitoring should be continued.

-   After implementation of the current monitoring system, an evaluation
    of the impact this frequency of monitoring had on the rate of
    agranulocytosis should be conducted.

In 1998, Novartis implemented the current monitoring system that was
recommended by the PDAC members (i.e., weekly for the first 26 weeks of
treatment and every two weeks thereafter). Also, shortly thereafter the
first generic version of Clozaril became available in US (note: brand
clozapine is referred to as "Clozaril" and generic as "generic
clozapine" throughout this document) and patients treated with generic
clozapine became subject to the current monitoring system. Manufacturers
of generic clozapine are responsible for ensuring adherence to the
current monitoring frequency schedule by maintaining a registry database
with functionality identical to the CNR. Novartis, however, is
responsible for maintaining a database of patients who should not be
rechallenged with clozapine ("Non-rechallengable database") and generic
manufacturers are responsible for:

1.  contacting Novartis prior to initiating patients to cross-check them
    against the "Non-rechallengable database" and

2.  informing Novartis of patients who should be added to this database.

In 2001, the FDA contacted Novartis to follow up on the 1997 PDAC
recommendation to evaluate the impact of the current monitoring system
on the rate of agranulocytosis and whether further reductions were
warranted based on the new data from the CNR.

There were a series of meetings that occurred with the FDA over the next
several months regarding the methods of analyses that were eventually
agreed upon between the FDA and Novartis and the data from those
analyses were summarized and submitted to the FDA in 2002 and 2003. One
important milestone that also occurred in late 2002 was the approval of
Clozaril for the treatment of recurrent suicidal behavior. Consequently,
the number of patients who will be exposed to Clozaril is expected to
increase since this new indication allows for the use of Clozaril in
patients who are not treatment-resistant, which is a considerably
broader group of patients who were not previously exposed to Clozaril.

Following their review of the updated registry data, the FDA informed
Novartis that these data should be reviewed by the PDAC, where once
again the question of whether to reduce the frequency of monitoring
would be discussed.

The data summarized herein were prepared as background information for
review and discussion at the PDAC meeting scheduled for June 16, 2003.

# 2 Monitoring Systems

## 3 Policy and Objectives

The Novartis policy of "No Blood No Drug" is applied globally to all
Clozaril-treated patients through national centralized monitoring
services, or institutional/physician oversight. Monitoring systems vary
somewhat from country to country, however the US, UK and Australian
national registries described in this briefing document are
representative of Novartis' global monitoring practices.

These 3 registries are identified as follows:

United States: Clozaril National Registry (CNR)

United Kingdom and Ireland: Clozaril Patients Monitoring Service (CPMS)

Australia: Clozaril Patient Monitoring Service (CPMS)

The objective of all monitoring systems is the early detection of
[moderate leukopenia]{.underline} in order to reduce or prevent the
occurrence of [severe leukopenia]{.underline},
[agranulocytosis]{.underline} and [death]{.underline}.

## 4 Limitations

The registry databases were designed for monitoring and not for
explanatory assessment. The data for analyses are based on single data
entry and are not validated.

Section 2.3 describes important differences between the three monitoring
systems under discussion. These differences limit the ability to compare
the results of data analyses between the systems.

## 5 Differences

### 6 Historical background

Mandatory hematological monitoring accompanied commercial introduction
of Clozaril in the US, UK, and Ireland in 1990 and in Australia in 1992.
The initial monitoring frequency and subsequent changes leading to the
current systems are summarized in Figures 1-3 below

####### Figure 1: US changes in CNR monitoring frequency. 

In the US, the initial monitoring system required weekly monitoring for
the duration of treatment. In 1998, this requirement was changed to
monitoring every 2 weeks after the first 6 months of treatment

####### Figure 2: UK and Ireland, changes in CPMS monitoring frequency

In the UK and Ireland, the initial monitoring system required weekly
monitoring for 18 weeks and then every 2 weeks thereafter. This
requirement was changed to monthly monitoring after 52 weeks of
treatment in the UK in 1995 and in Ireland in 1999.

####### Figure 3: Australian CPMS monitoring frequency

In Australia, the monitoring system remains unchanged since its
establishment in 1992. Weekly monitoring is required for the first 18
weeks with the option of monthly monitoring thereafter.

### 7 Definitions of Leukopenia and Agranulocytosis used in analysis 

The terms moderate leukopenia, severe leukopenia and agranulocytosis
have been used in the analysis of data from all 3 monitoring systems.
Table 1 below shows the definitions of these terms by monitoring system.

###### Table 1 Definitions of leukopenia and agranulocytosis used in analysis by monitoring system 

+------------------+----------------+----------------+----------------+
|                  | **US (CNR)**   | **UK(CPMS)**   | **Australia    |
|                  |                |                | (CPMS)**       |
+==================+================+================+================+
| **Moderate       | WBC ≤ 3000     | WBC ≤ 3000     | WBC ≤ 3000     |
| leukopenia**     |                |                |                |
| cells/mm^3^      |                | or ANC \< 2000 |                |
+------------------+----------------+----------------+----------------+
| **Severe         | WBC \< 2000    | WBC \<2000     | WBC \< 2000    |
| leukopenia**     |                |                |                |
|                  |                | or ANC \<1000  |                |
| cells/mm^3^      |                |                |                |
+------------------+----------------+----------------+----------------+
| **A              | WBC ≤ 1000 or  | WBC ≤ 1000     | WBC ≤ 1000 or  |
| granulocytosis** |                |                |                |
|                  | ANC ≤ 500      | or ANC \<500   | ANC ≤ 500      |
| cells/mm^3^      |                |                |                |
+------------------+----------------+----------------+----------------+

The US CNR collects only WBC counts systematically. However,
agranulocytosis was defined by absolute neutrophil count (ANC) in 80% of
the cases included in the analysis of US data. These cases were
identified through Medwatch and other reports received by Novartis
Clinical Safety and Epidemiology and eventually entered in to the CNR.
The UK and Australian registries routinely collect absolute neutrophil
counts and the determination of moderate leukopenia, severe leukopenia
and agranulocytosis are often based on these counts.

## 8 Criteria for Action

The three monitoring systems also differ in the action taken at
different values for WBC and ANC (Table 2). Most of these differences
are subtle but there is one major difference: in the UK and Australia,
if the WBC falls below 3000 and/or the ANC is [\<]{.underline} 1500,
Clozaril is permanently discontinued and the patient must never be
rechallenged. However in the US, Clozaril is only temporarily
discontinued at this level (WBC below 3000) and/or an ANC between 1000
and 1500. Furthermore in the US, patients are not permanently
discontinued until the WBC falls below 2000 or the ANC falls below 1500.

Across all three countries, patients must meet certain criteria before
moving to the next phase of monitoring frequency (e.g., from weekly to
bi-weekly monitoring in the US). The qualifying criteria vary somewhat
among the three countries and an algorithm showing these criteria is
presented in Appendix 6.

###### Table 2 Registry Criteria for Action

+------------------+----------------+----------------+----------------+
| **Action**       | **US (CNR)**   | **UK (CPMS)**  | **Australia    |
|                  |                |                | (CPMS)**       |
+==================+================+================+================+
| **Initiation of  | WBC ≥3500      | WBC ≥3500      | WBC ≥3500      |
| treatment**      |                |                |                |
|                  |                | and ANC \>2000 | and ANC \>2000 |
| cells/mm^3^      |                |                |                |
+------------------+----------------+----------------+----------------+
| **Twice weekly   | WBC 3000-3500  | WBC 3000-3500  | WBC ≤3500      |
| monitoring**     | and ANC \>1500 | and/or         |                |
|                  |                |                | and/or         |
| cells/mm^3^      |                | ANC1500-2000   |                |
|                  |                |                | ANC1500-2000   |
+------------------+----------------+----------------+----------------+
| **Temporary      | WBC 2000-3000  | N/A            | N/A            |
| d                |                |                |                |
| iscontinuation** | and/or         |                |                |
|                  |                |                |                |
| cells/mm^3^      | ANC 1000-1500  |                |                |
+------------------+----------------+----------------+----------------+
| **Permanent      | WBC \<2000     | WBC \<3000     | WBC \<3000     |
| di               |                |                |                |
| scontinuation.** | and/or         | and/or         | and/or         |
|                  |                |                |                |
| cells/mm^3^      | ANC \<1000     | ANC ≤1500      | ANC ≤1500      |
+------------------+----------------+----------------+----------------+

Source: US, UK and Australia Clozaril prescribing information

# 9 United States

## 10 Methods for Analysis 

### 11 Patient population

As of September 1, 2001 there were 203,818 patients enrolled in the CNR
who provided more than 21 million laboratory records for possible
analysis. Given the availability of generic clozapine in the US,
Novartis is no longer the sole source of WBC counts for
clozapine-treated patients because the CNR was established only for
patients treated with Clozaril. Therefore, it was not possible to
calculate total patient exposure to clozapine.

In these analyses all patients were classified into nine classes based
on their treatment with Clozaril or generic clozapine as described in
the following Table 3:

###### Table 3: Description of patients treated with Clozaril since introduction of generic clozapine.

+------+-----------+-----------+-----------+--------------------------+
| *    | **        | **Tr      | **        | #                        |
| *Pat | Treatment | eatment** | Treatment |                          |
| ient | initiated |           | ended     | ######### Comments       |
| Ty   | with**    | **        | with**    |                          |
| pe** |           | continued |           |                          |
|      |           | with**    |           |                          |
+------+-----------+-----------+-----------+--------------------------+
| 1    | Clozaril  | Clozaril  | Clozaril  | CNR has complete record  |
|      |           |           |           | of their WBC.            |
+------+-----------+-----------+-----------+--------------------------+
| 2    | Clozaril  | Generic   | Generic   | CNR does not have        |
|      |           | clozapine | clozapine | records of WBC since     |
|      |           |           |           | their switch to Generic  |
|      |           |           |           | clozapine. Total         |
|      |           |           |           | exposure of these        |
|      |           |           |           | patients can not be      |
|      |           |           |           | computed using CNR data. |
+------+-----------+-----------+-----------+--------------------------+
| 3    | Clozaril  | Both      | Clozaril  | CNR does not have        |
|      |           | Generic   |           | complete records of WBC  |
|      |           | clozapine |           | since their switch to    |
|      |           | and       |           | Generic clozapine.       |
|      |           | Clozaril  |           |                          |
+------+-----------+-----------+-----------+--------------------------+
| 4    | Clozaril  | Both      | Generic   | CNR does not have        |
|      |           | Generic   | clozapine | complete records of WBC  |
|      |           | clozapine |           | since their switch to    |
|      |           | and       |           | Generic clozapine. Total |
|      |           | Clozaril  |           | exposure of these        |
|      |           |           |           | patients cannot be       |
|      |           |           |           | computed using CNR data. |
+------+-----------+-----------+-----------+--------------------------+
| 5    | Generic   | Generic   | Generic   | CNR does not have        |
|      | clozapine | clozapine | clozapine | records of WBC for these |
|      |           |           |           | patients. Total exposure |
|      |           |           |           | of these patients cannot |
|      |           |           |           | be computed using CNR    |
|      |           |           |           | data.                    |
+------+-----------+-----------+-----------+--------------------------+
| 6    | Generic   | Clozaril  | Clozaril  | CNR does not have        |
|      | clozapine |           |           | complete records of WBC  |
|      |           |           |           | since they started with  |
|      |           |           |           | Generic clozapine. Total |
|      |           |           |           | exposure of these        |
|      |           |           |           | patients cannot be       |
|      |           |           |           | computed using CNR data. |
+------+-----------+-----------+-----------+--------------------------+
| 7    | Generic   | Both      | Generic   | CNR does not have        |
|      | clozapine | Generic   | clozapine | complete records of WBC. |
|      |           | clozapine |           | Total exposure of these  |
|      |           | and       |           | patients cannot be       |
|      |           | Clozaril  |           | computed using CNR data. |
+------+-----------+-----------+-----------+--------------------------+
| 8    | Generic   | Both      | Clozaril  | CNR does not have        |
|      | clozapine | Generic   |           | complete records of WBC. |
|      |           | clozapine |           | Total exposure of these  |
|      |           | and       |           | patients cannot be       |
|      |           | Clozaril  |           | computed using CNR data. |
+------+-----------+-----------+-----------+--------------------------+
| 9    | \         | \         | \         | Patients enrolled in     |
|      | _\_\_\_\_ | _\_\_\_\_ | _\_\_\_\_ | CNR, but never treated   |
|      |           |           |           | with Clozaril or had     |
|      |           |           |           | only one WBC entry.      |
|      |           |           |           | Total exposure of these  |
|      |           |           |           | patients cannot be       |
|      |           |           |           | computed using CNR data. |
+------+-----------+-----------+-----------+--------------------------+

#### 12 Inclusion Criteria

The sole source of data for the data from the US analyses comes from the
CNR, subject to the data exclusion criteria mentioned in the following
section.

#### 13 Exclusion Criteria

The exclusion criteria for the United States data were as follows:

1.  Patients who were enrolled in the CNR, but never started treatment
    with Clozaril or had only one WBC entry in the database (Table 3:
    Patient type 9). Approximately 22,000 patients were excluded based
    on this criterion.

2.  Patients who were believed to have started treatment with generic
    clozapine before any treatment with Clozaril (Table 3: Patient types
    5, 6, 7 and 8). Approximately 4,000 patients were excluded based on
    this criterion.

3.  Patients who started Clozaril treatment bit switched to generic
    clozapine at some point in time(Table 3: Patient types 5, 6, 7 and
    8). Data for these patients after treatment with generic clozapine
    were excluded. Some data from approximately 19,000 patients were
    excluded based on this criterion.

#### 14 Cohort Definitions

As shown in Figure 4 below, the patients in the CNR were divided into 3
cohorts and are described as follows:

####### Figure 4: Overview of Cohorts

**[Cohort 1 (Initial system):]{.underline}**

Cohort 1 includes data from approximately 97,000 patients. This cohort
represents the group of patients who were included in the briefing book
submitted to FDA on May 30, 1997, which was prepared for the
Psychopharmacological Drugs Advisory Committee (PDAC) Meeting held on
July 14, 1997. This cohort includes all patients who started Clozaril
between Feb 5, 1990 and April 30, 1995 (the cut-off date for the 1997
briefing book).

**[Cohort 2 (Initial system):]{.underline}**

Cohort 2 includes data from approximately 41,000 patients. This cohort
represents all patients who initiated Clozaril therapy after the April
30, 1995 cut-off mentioned above but before the implementation of the
current monitoring system. Therefore, it includes all patients who
started Clozaril between April 30, 1995 and October 1, 1997 (six months
prior to the introduction of the current monitoring system).

**[Cohort 3 (Current system):]{.underline}**

Cohort 3 includes data from approximately 39,000 patients. This cohort
represents patients who have been monitored according to the current
monitoring system. It includes all patients who started Clozaril (global
change) after October 1, 1997 (six months before the introduction of
biweekly monitoring option).

For purposes of comparing the initial system with the current system
patients were dichotomized into Cohorts 1 and 2 (combined). All relevant
data, subject to exclusion criteria 1, 2 and 3 and collected by April 1,
1998 (introduction of bi-weekly monitoring) were used to compute
relevant rates and ratios for Cohorts 1 and 2 (combined); all relevant
data, subject to exclusion criteria 1, 2 and 3 and collected between
April 1, 1998 and September 1, 2001 were used to compute relevant rates
and ratios for Cohort 3. Therefore, combined data from Cohorts 1 and 2,
also referred to as the "initial monitoring system" cohort, contain
information on patients who were subject to weekly monitoring of WBC
under the previous monitoring system effective until April 1, 1998. In
contrast data from Cohort 3, also referred to as the "current system"
cohort contains information on patients who effectively enrolled after
October 1, 1997 and follow the current monitoring system in USA with an
option to have bi-weekly monitoring after six months of Clozaril
treatment.

Estimation of rates under monthly and no-monitoring options were
performed for patients in Cohort 3 only.

Table 4 summarizes the disposition of patients described above with the
application of the exclusion criteria explained in Section 3.1.1.2

###### 

###### Table 4: Patient disposition

+------------------------------+----------+----------------------------+
|                              | **Number |                            |
|                              | of       |                            |
|                              | Pa       |                            |
|                              | tients** |                            |
+------------------------------+----------+----------------------------+
| ##### **Enrolled in CNR**^¶^ | 203,818  |                            |
+------------------------------+----------+----------------------------+
| **Excluded from analysis due |          |                            |
| to:**                        |          |                            |
+------------------------------+----------+----------------------------+
| Exclusion Criterion 1        | 21,743   |                            |
+------------------------------+----------+----------------------------+
| Exclusion Criterion 2        | 3,971    |                            |
+------------------------------+----------+----------------------------+
|                              |          | **Number of patients for   |
|                              |          | whom part of data were     |
|                              |          | excluded due to**          |
|                              |          |                            |
|                              |          | **Exclusion Criterion 3**  |
+------------------------------+----------+----------------------------+
|                              |          |                            |
+------------------------------+----------+----------------------------+
| **Included in Analysis:**    |          |                            |
+------------------------------+----------+----------------------------+
| All Cohorts                  | 178,104  | 19,318                     |
+------------------------------+----------+----------------------------+
| Cohort 1                     | 97,485   | 10,791                     |
+------------------------------+----------+----------------------------+
| Cohort 2                     | 41,359   | 4,175                      |
+------------------------------+----------+----------------------------+
| Cohort 3                     | 39,260   | 4,352                      |
+------------------------------+----------+----------------------------+

**Exclusion Citerion** **1:** Exclude patients who were enrolled in CNR,
but never started treatment with clozapine or had only one record of WBC
in the database

**Exclusion Citerion 2**: Exclude patient who started treatment with
generic clozapine before any treatment with Clozaril (Patient types 5,
6, 7 and 8)

**Exclusion Citerion 3**: Patients started on Clozaril, but switched to
generic clozapine at some point of time (Patient types 2, 3, and 4)
after December 1, 1997. For these patients, exclude all data collected
after the first treatment with generic clozapine.

### 15 Demographics

Summary statistics of the demographics variables (i.e., age, sex, and
race) are provided by cohort and for patients with agranulocytosis,
moderate leukopenia and severe leukopenia.

### 16 Incidence rates and life table analyses of severe leukopenia and agranulocytosis

Number of cases, total exposure and incidence rates of moderate
leukopenia, severe leukopenia and agranulocytosis by cohort, and by
treatment duration with Clozaril are provided.

In order to study the trend of agranulocytosis, severe leukopenia and
moderate leukopenia over the years, the percent of new patients by
calendar year were tabulated along with the corresponding incidence
rates of agranulocytosis, severe leukopenia and moderate leukopenia.

Life table analysis method was used for estimating cumulative
probability of event incidence rates and hazard rates of
agranulocytosis, severe leukopenia and moderate leukopenia by cohort.
Yearly conditional risks were tabulated separately for the initial
monitoring system (Cohorts 1 and 2) and the current monitoring system
(Cohort 3) for the incidence of agranulocytosis and severe leukopenia.

### 17 WBC at Time of Discontinuation

The WBC at the time of discontinuation (or interruption of treatment)
for each patient was determined as follows:

> For patients in Cohorts 1 and 2, if the time elapsed (gap) between two
> consecutive WBC counts was greater than 15 days during the entire
> study period then the patient was considered discontinued
> (interrupted) Clozaril treatment.
>
> For patients in Cohort 3, if the time elapsed (gap) between two
> consecutive WBC counts was greater than 15 days during the first six
> months of therapy or if the gap between WBC counts was greater than 30
> days after 6 months of therapy then the patient in Cohort 3 was
> considered discontinued (interrupted) Clozaril treatment.

The WBC count on the date of first discontinuation was summarized and
the time to first discontinuation from baseline was used in computing
Kaplan-Meier estimates of probability of discontinuation and presented
in a graph.

In addition, patients who discontinued (as defined above) with a WBC
value between 3,000 to 6,000 cells/mm^3^ were identified and median WBC
values were compared for patients in Cohorts 1 and 2 (combined) and
Cohort 3.

### 18 Projected rates of severe leukopenia and agranulocytosis 

Estimation of rates under monthly and no-monitoring options was
performed for patients in Cohort 3 only. These rates reflect the
estimated of risk for patients in Cohort 3 if they were monitored on a
monthly basis or not monitored after their first six months, one year,
or two years of treatment with Clozaril. These rates are also referred
as projected rates under a less frequent monitoring option in this
document.

The method of estimation of these rates of severe leukopenia and
agranulocytosis after 6 months (one year and two years) of treatment
with Clozaril was similar to the method of estimation of these rates for
less frequent monitoring used in the 1997 briefing book submitted to FDA
(Appendix 4: Attachment 3).

The duration of prodrome and the rate of decrease in WBC counts (slope)
during prodrome were calculated for each patient. The onset of prodrome
to moderate leukopenia (WBC 3000/mm3) was determined by examining data
for WBC counts and determining the date from which the count showed a
continual decline until moderate leukopenia developed, allowing for one
possible increase in the count during that interval but only to a level
that did not exceed the baseline count. The duration of the prodrome was
defined as the time from onset to the date of moderate leukopenia (the
first day with WBC 3000/mm3). This definition of the onset of prodrome
was adapted from Alvir, et. al. and was used in the briefing document
submitted to FDA for the 1997 PDAC meeting regarding Clozaril. The
number of patients that would be "caught" or "missed" to detect at
moderate leukopenia under less frequent monitoring were estimated by
calculating the number of days it would have taken the patient to reach
severe leukopenia from the date of the last WBC count and the rate of
decrease (slope) of WBC during prodrome.

The projection of rates of severe leukopenia and agranulocytosis under
less frequent monitoring depends on the following four quantities
estimated from data collected after six months of treatment:

1.  P1 = Probability that a patient will develop severe leukopenia given
    that the patient was detected ("caught") at moderate leukopenia
    (2000/mm^3^ \<WBC3000/mm^3^).

2.  P2 = Probability that a patient will develop agranulocytosis given
    that the patient was detected ("caught") at moderate leukopenia
    (2000/mm^3^ \<WBC3000/mm^3^).

3.  P3 = Probability that a patient will develop agranulocytosis given
    that the patient was not detected ("missed") at moderate leukopenia
    (i.e. severe leukopenia, WBC \< 2000/mm^3^ by the time of
    detection).

4.  P4 = Incidence rate (per person-year) of agranulocytosis among
    patients who did not have a WBC 3000/mm^3^ before developing
    agranulocytosis. These are the patients who developed
    agranulocytosis before they met the criteria for moderately
    leukopenic.

The estimates of these four quantities based on data from Cohort 3 were
deemed unreliable since the number of occurrences of agranulocytosis or
severe leukopenia in Cohort 3 after six months of treatment was less
than 10. These four quantities were estimated using data from Cohorts 1
and 2 during their weekly monitoring of WBC. Estimation of these
quantities is demonstrated in Figure 5.

####### Figure 5: Algorithm for Probabilities

####### 

In Cohort 3, the total number of cases of agranulocytosis occurred after
six months from start of Clozaril treatment was 10. Three of these cases
occurred with less than six months of Clozaril treatment (e.g., a
patient was treated for five months with Clozaril and developed
agranulocytosis at month 7). These three cases were excluded from the
analysis. The total number of severe leukopenia cases observed after six
months of treatment under the current monitoring was 9. Finally, the
estimation of the rates of agranulocytosis and severe leukopenia
utilizing P1-P4 is illustrated in Table 5.

###### Table 5: Estimation of the number of severe leukopenia and agranulocytosis cases for patients in Cohort 3 after weekly monitoring for six months and monthly thereafter

+-----------------+-----------+-------------+-------------+----------+
|                 | **Number  | **Agra      | **Estimated | **E      |
|                 | of        | nulocytosis | number of   | stimated |
|                 | Patients  | rate**      | agranu      | number   |
|                 | with      |             | locytosis** | of       |
|                 | [\>]{.un  |             |             | severe   |
|                 | derline}6 |             | **cases**   | leuk     |
|                 | months of |             |             | openia** |
|                 | treatment |             |             |          |
|                 | in Cohort |             |             | *        |
|                 | 3**       |             |             | *cases** |
+-----------------+-----------+-------------+-------------+----------+
| Moderate under  | 230       |             |             |          |
| the current     |           |             |             |          |
| monitoring      |           |             |             |          |
+-----------------+-----------+-------------+-------------+----------+
| > "Caught" at   | 134       | P2=0.021    | 1           | 134      |
| > moderate      |           |             | 34\*P2=2.83 | \*P1=3.5 |
| > under monthly |           |             |             |          |
| > monitoring    |           |             |             |          |
+-----------------+-----------+-------------+-------------+----------+
| > "Missed" at   | 96        | P3=0.413    | 9           | 96       |
| > moderate      |           |             | 6\*P3=39.68 |          |
| > under monthly |           |             |             |          |
| > monitoring    |           |             |             |          |
+-----------------+-----------+-------------+-------------+----------+
| Never moderate  | 21974^\#^ | P4=0.000104 | 266         |          |
| under the       |           |             | 96\*P4=2.78 |          |
| current         |           |             |             |          |
| monitoring      |           |             |             |          |
+-----------------+-----------+-------------+-------------+----------+
| Total           | 22204     |             | 45.29       | 99.5     |
+-----------------+-----------+-------------+-------------+----------+

^\#^These patients were treated for 26696 person-years

As seen in Table 5, there were 230 patients within Cohort 3 who
developed moderate leukopenia under the current monitoring system. If
there were no monitoring of WBC after six months of treatment then all
those 230 patients would have continued taking Clozaril even after
developing moderate leukopenia. It is expected these patients' WBC
counts would continue to decrease at a median rate of 126/mm3 per day
(see Post-text Table 3.6-3). Ultimately, all these patients would have
developed severe leukopenia. These patients would have considerably
higher probability of developing agranulocytosis due to late detection
in the absence of monitoring. As mentioned in the 1997 briefing book,
67% of these patients would develop agranulocytosis. Hence under no
monitoring option of WBC, the total number of agranulocytosis cases is
estimated as 230\*.67 + 26696\*P4 = 154.1 + 2.8 = 156.9.

## 19 Results from United States

### 20 Demographics of patients in the initial monitoring system and the current monitoring system

Within the initial and current monitoring systems, the demographics of
all patients, patients with moderate leukopenia, severe leukopenia or
agranulocytosis are comparable with respect to sex, age, and race. The
percentage of patients with missing information was also similar between
these groups. The demographic data for all patients and patients with
agranulocytosis are shown in Tables 6 and 7 below. Demographics for
patients with moderate or severe leukopenia are presented in Appendix 1
Post-text Tables 3.1-2 and 3.1-3

###### Table 6: Demographics of all patients in Initial system and Current system 

+-----------------+-----------------+-----------------+-----------------+
| **Demographic** | **Category**    | **Initial       | **Current       |
|                 |                 | system**        | system**        |
|                 |                 |                 |                 |
|                 |                 | **N (%)**       | **N (%)**       |
+-----------------+-----------------+-----------------+-----------------+
| **Sex**         | Male            | 79256 (57.1)    | 22287 (56.8)    |
+-----------------+-----------------+-----------------+-----------------+
|                 | Female          | 56430 (40.6)    | 16149 (41.1)    |
+-----------------+-----------------+-----------------+-----------------+
|                 | Missing         | 3158 ( 2.3)     | 824 ( 2.1)      |
+-----------------+-----------------+-----------------+-----------------+
|                 | Total           | 138844 (100)    | 39260 (100)     |
+-----------------+-----------------+-----------------+-----------------+
|                 |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| **Age (years)** | \<= 35          | 50124 (36.1)    | 12794 (32.6)    |
+-----------------+-----------------+-----------------+-----------------+
|                 | 36 - 50         | 53225 (38.3)    | 14808 (37.7)    |
+-----------------+-----------------+-----------------+-----------------+
|                 | 51 - 65         | 17474 (12.6)    | 6073 (15.5)     |
+-----------------+-----------------+-----------------+-----------------+
|                 | \> 65           | 14863 (10.7)    | 4761 (12.1)     |
+-----------------+-----------------+-----------------+-----------------+
|                 | Missing         | 3158 ( 2.3)     | 824 ( 2.1)      |
+-----------------+-----------------+-----------------+-----------------+
|                 | Total           | 138844 (100)    | 39260 (100)     |
+-----------------+-----------------+-----------------+-----------------+
|                 | Mean            | 42.1            | 43.0            |
+-----------------+-----------------+-----------------+-----------------+
|                 |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| **Race**        | White           | 95958 (69.1)    | 24528 (62.5)    |
+-----------------+-----------------+-----------------+-----------------+
|                 | Black           | 17367 (12.5)    | 6058 (15.4)     |
+-----------------+-----------------+-----------------+-----------------+
|                 | Hispanic        | 5819 ( 4.2)     | 2014 ( 5.1)     |
+-----------------+-----------------+-----------------+-----------------+
|                 | Oriental        | 1725 ( 1.2)     | 460 ( 1.2)      |
+-----------------+-----------------+-----------------+-----------------+
|                 | Other           | 1578 ( 1.1)     | 724 ( 1.8)      |
+-----------------+-----------------+-----------------+-----------------+
|                 | Missing         | 16397 (11.8)    | 5476 (13.9)     |
+-----------------+-----------------+-----------------+-----------------+
|                 | Total           | 138844 (100)    | 39260 (100)     |
+-----------------+-----------------+-----------------+-----------------+

Source: Appendix 1, Post-text Table 3.1-1

###### Table 7: Demographics of patients in Initial system and Current system who developed agranulocytosis

+-----------------+-----------------+-----------------+-----------------+
| **Demographic** | **Category**    | **Initial       | **Current       |
|                 |                 | system**        | system**        |
|                 |                 |                 |                 |
|                 |                 | **N (%)**       | **N (%)**       |
+-----------------+-----------------+-----------------+-----------------+
| **Sex**         | Male            | 283 ( 54.7%)    | 31 ( 55.4%)     |
+-----------------+-----------------+-----------------+-----------------+
|                 | Female          | 234 ( 45.3%)    | 25 ( 44.6%)     |
+-----------------+-----------------+-----------------+-----------------+
|                 | Total           |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
|                 |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| **Age**         | \<= 35          | 109 ( 21.1%)    | 13 ( 23.2%)     |
+-----------------+-----------------+-----------------+-----------------+
|                 | 36 - 50         | 200 ( 38.7%)    | 18 ( 32.1%)     |
+-----------------+-----------------+-----------------+-----------------+
|                 | 51 - 65         | 159 ( 30.8%)    | 17 ( 30.4%)     |
+-----------------+-----------------+-----------------+-----------------+
|                 | \> 65           | 49 ( 9.5%)      | 8 ( 14.3%)      |
+-----------------+-----------------+-----------------+-----------------+
|                 | Total           | 517 (100.0%)    | 56 (100.0%)     |
+-----------------+-----------------+-----------------+-----------------+
|                 | Mean            | 46.8            | 47.7            |
+-----------------+-----------------+-----------------+-----------------+
|                 | SD              | 13.4            | 15.4            |
+-----------------+-----------------+-----------------+-----------------+
|                 |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| **Race**        | White           | 349 ( 67.5%)    | 37 ( 66.1%)     |
+-----------------+-----------------+-----------------+-----------------+
|                 | Black           | 15 ( 2.9%)      | 3 ( 5.4%)       |
+-----------------+-----------------+-----------------+-----------------+
|                 | Hispanic        | 24 ( 4.6%)      | 4 ( 7.1%)       |
+-----------------+-----------------+-----------------+-----------------+
|                 | Oriental        | 3 ( 0.6%)       | 0 ( 0.0%)       |
+-----------------+-----------------+-----------------+-----------------+
|                 | Other           | 7 ( 1.4%)       | 0 ( 0.0%)       |
+-----------------+-----------------+-----------------+-----------------+
|                 | Missing         | 119 ( 23.0%)    | 12 ( 21.4%)     |
+-----------------+-----------------+-----------------+-----------------+
|                 |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+

Source: Appendix 1, Post-text Table 3.1-4

###  

### 21 Incidence of leukopenia and agranulocytosis 

Figure 6 below shows that the overall rate of agranulocytosis decreased
consistently by calendar year. This decrease may be explained to some
extent by the similarly consistent decrease in the proportion of new
patients entering the registry overtime.

####### Figure 6: Trend of Agranulocytosis Rate

![](media/image2.wmf){width="6.122916666666667in" height="5.51875in"}

During the first six months the monitoring frequency was weekly for both
the initial and current monitoring systems. The rates of moderate
leukopenia was similar for both systems; however, severe leukopenia and
agranulocytosis were less under the current monitoring system compared
to the initial monitoring system (Figure 7).

####### Figure 7: Incidence of moderate leukopenia, severe leukopenia and agranulocytosis during the first 6 months of treatment by monitoring system cohort

![](media/image3.wmf){width="5.879133858267717in"
height="3.5811023622047244in"}

After the first 6 months of treatment, the frequency of monitoring
remained weekly under the initial system and changed to bi-weekly under
the current system. The rates of moderate leukopenia severe leukopenia
and agranulocytosis were less compared to the first six months but
similar between the systems (Figure 8).

####### 

####### Figure 8: Incidence of moderate leukopenia, severe leukopenia and agranulocytosis after the first 6 months of treatment by monitoring system cohort

![](media/image4.wmf){width="5.966535433070866in"
height="3.5125984251968503in"}

### 22 Risk of moderate leukopenia and agranulocytosis over time

The hazard rate for developing moderate leukopenia or agranulocytosis is
greatest during the first 6 months of Clozaril treatment (up to
approximately 45/1000 patient-years and 15/1000 patient-years
respectively) after which the risk diminishes significantly. The hazard
rate begins to stabilize after about 18 months of treatment at
approximately 9 per thousand patient-years for moderate leukopenia and
approximately 0.3 per thousand patient-years for agranulocytosis (Figure
9).

####### Figure 9: Hazard rate for moderate leukopenia and agranulocytosis over 8.5 years

![](media/image5.wmf){width="6.307086614173229in"
height="3.395669291338583in"}

### 23 White Blood Cell Count at Time of Discontinuation

There were 110,659 patients defined as patients who discontinued therapy
(see Section 3.1.4 for definition). Of these patients, there were 67,883
who discontinued during the first 6 months of therapy and 42,776 who
discontinued after 6 months of therapy.

The median white blood cell count at the time of discontinuation for
patients in the initial system and current system were 7800 and 7400
cells/mm^3^, respectively for patients on therapy for less than or equal
to 6 months and 7900 and 7600 cells/mm^3^, respectively for patients on
therapy for more than 6 months (Appendix 1, Post-text Table 3.5-1).
Additionally, there is no clinically meaningful difference between the
groups with regard to the distribution (i.e., 5^th^, 25^th^, 75^th^,
95^th^ percentiles) of WBC values at the time of discontinuation. These
WBC counts may be high because patients may have been discontinued for
any reason (e.g., lost to follow-up) and not for reasons related to
abnormal lab values.

Figure 10 shows that 58% of the patients within the current system
discontinued therapy within 6 months after initiating therapy. In
comparison, 40% of the patients within the initial system discontinued
therapy within 6 months after initiating therapy.

####### Figure 10: Time to first discontinuation

![](media/image6.png){width="6.896456692913386in"
height="4.795669291338583in"}

The WBC values for patients who were discontinued with a WBC value
between 3000 and 6000 cells/mm^3^ were also evaluated. The value of 3000
cells/mm^3^ was chosen because this is the level of WBC counts where
patients discontinue from Clozaril treatment and are considered to have
developed moderate leukopenia. The upper limit of 6000 cells/mm^3^ was
chosen because patients who were discontinued with a value above this
level would be less likely to have been discontinued for a reason
related to an abnormal WBC value and more likely for other reasons
(e.g., availability of alternative treatment).

As seen in Table 8 below, the median and mean WBC at the time of
discontinuation for patients with a WBC value between 3000 and 6000 in
the initial system and the current system were similar for patients on
therapy for less than or equal to 6 months and greater than 6 months.

###### Table 8: White Blood Cell Count (WBC) at time of discontinuation by duration for patients with WBC value between 3000 and 6000 at time of discontinuation by system cohort

+---------+---------+---------+---------+---------+-----------+-------+
| **WBC** | **[\<   |         | **\>6   |         | **Total   |       |
|         | ]{.unde |         | m       |         | duration  |       |
| *       | rline}6 |         | onths** |         | of        |       |
| *(cells | m       |         |         |         | therapy** |       |
| /mm3)** | onths** |         |         |         |           |       |
+---------+---------+---------+---------+---------+-----------+-------+
|         | **In    | **Cu    | **In    | **Cu    | **        | *     |
|         | itial** | rrent** | itial** | rrent** | Initial** | *Curr |
|         |         |         |         |         |           | ent** |
+---------+---------+---------+---------+---------+-----------+-------+
| **N**   | 9837    | 4396    | 7084    | 712     | 16921     | 5108  |
+---------+---------+---------+---------+---------+-----------+-------+
| *       | 5300    | 5300    | 5400    | 5300    | 5300      | 5300  |
| *Median |         |         |         |         |           |       |
| WBC**   |         |         |         |         |           |       |
+---------+---------+---------+---------+---------+-----------+-------+
| **Mean  | 5183    | 5165    | 5236    | 5185    | 5205      | 5168  |
| WBC**   |         |         |         |         |           |       |
+---------+---------+---------+---------+---------+-----------+-------+

Source: Appendix 1, Post-text Table 3.5-2

The proportion of patients who discontinued with values between 3000 and
6000 cells/mm^3^ and within each stratum was similar between the groups
(Table 9). Over 60% of the patients in both groups discontinued with a
WBC value \>5000-6000 cells/mm^3^ regardless of duration of therapy.

###### Table 9: Stratified White Blood Cell Count (WBC) at time of discontinuation by duration for patients with WBC value at time of discontinuation by system cohort

+---------+----------+--------+---------+--------+---------+---------+
| **WBC   | **Median |        |         |        |         |         |
| (cells  | WBC**    |        |         |        |         |         |
| /mm3)** |          |        |         |        |         |         |
|         | **N      |        |         |        |         |         |
|         | (%)**    |        |         |        |         |         |
+---------+----------+--------+---------+--------+---------+---------+
|         | **[      |        | **\>6   |        | **Total |         |
|         | \<]{.und |        | m       |        | d       |         |
|         | erline}6 |        | onths** |        | uration |         |
|         | months** |        |         |        | of      |         |
|         |          |        |         |        | th      |         |
|         |          |        |         |        | erapy** |         |
+---------+----------+--------+---------+--------+---------+---------+
|         | **I      | **Cur  | **In    | **Cur  | **In    | **Cu    |
|         | nitial** | rent** | itial** | rent** | itial** | rrent** |
+---------+----------+--------+---------+--------+---------+---------+
| *       | 3800     | 3800   | 3800    | 3800   | 3800    | 3800    |
| *[\>]{. |          |        |         |        |         |         |
| underli | 649 (7%) | 2      | 376     | 50     | 1025    | 334     |
| ne}3000 |          | 84(6%) | (5%)    | (7%)   | (6%)    | (7%)    |
| -4000** |          |        |         |        |         |         |
+---------+----------+--------+---------+--------+---------+---------+
| *       | 4700     | 4700   | 4700    | 4700   | 4700    | 4700    |
| *\>4000 |          |        |         |        |         |         |
| -5000** | 2955     | 138    | 1935    | 216    | 4890    | 16      |
|         | (30%)    | 7(32%) | (27%)   | (30%)  | (29%)   | 03(31%) |
+---------+----------+--------+---------+--------+---------+---------+
| *       | 5600     | 5600   | 5600    | 5600   | 5600    | 5600    |
| *\>5000 |          |        |         |        |         |         |
| -6000** | 6233     | 2725   | 4773    | 446    | 11006   | 3171    |
|         | (63%)    | (62%)  | (68%)   | (63%)  | (65%)   | (62%)   |
+---------+----------+--------+---------+--------+---------+---------+

Source: Appendix 1, Post-text Table 3.5-3a, 3.5-3b, 3.5-3c

#### 

### 24 Fatal Outcomes Related to Agranulocytosis

Overall, there were 22 (4%) fatalities among the 620 patients who
developed agranulocytosis. Of these 22 fatalities, 20 (91%) occurred
within the first six months of treatment. Two (9%) of the 22 fatalities
occurred in patients in the current system cohort and 1 of the 2
occurred during the first 6 months of treatment (see Appendix 5 for
narratives regarding these fatal outcomes).

### 25 Analysis of Prodrome Period

The rate of decline in WBC from normal to moderate leukopenia was
analyzed in patients who subsequently did or did not develop
agranulocytosis.

In Appendix 1, Post-text Tables 3.6-1 to 3.6-3 provide summary
statistics on the duration of prodrome and the rate of decrease (i.e.,
slope) of WBC counts during prodrome. The median duration of prodrome
for all patients who developed moderate leukopenia in the initial system
and the current system appears to be independent of the duration of
Clozaril therapy. The median duration of prodrome ranged from 21-25 days
and 26-29 days for patients in the initial system cohort and current
system cohort, respectively (Appendix 1, Post-text Table 3.6-1) who were
treated with Clozaril from \>6 months to \>2 years of therapy.

Table 10 provides the median slope for patients with moderate leukopenia
who did or did not develop agranulocytosis. Patients who developed
agranulocytosis during the first 6 months declined faster across both
groups than those who did not develop agranulocytosis. Also, patients
who did develop agranulocytosis during the first 6 months of therapy in
the initial system had a much steeper slope in WBC counts than those in
the current system.

###### Table 10: Median Slope for Patients Who Developed Moderate Leukopenia and Did or Did Not Develop Agranulocytosis

+-----------+--------------+--------------+-------------+--------------+
| *         | **Initial    |              | **Current   |              |
| *Duration | system**     |              | system**    |              |
| of        |              |              |             |              |
| Therapy** | **Median     |              | **Median    |              |
|           | Slope {WBC   |              | Slope {WBC  |              |
|           | cells/mm^3^  |              | cells/mm^3^ |              |
|           | (n)}**       |              | (n)}**      |              |
+-----------+--------------+--------------+-------------+--------------+
|           | **Did not    | **Developed  | **Did not   | **Developed  |
|           | Develop      | Agr          | Develop     | Agr          |
|           | Agranul      | anulocytosis | Agra        | anulocytosis |
|           | ocytosis\*** | \*\***       | nulocytosis | \*\***       |
|           |              |              | \***        |              |
+-----------+--------------+--------------+-------------+--------------+
| [\<]{.un  | 150 (1444)   | 241 (334)    | 144 (366)   | 161 (28)     |
| derline}6 |              |              |             |              |
| mos.      |              |              |             |              |
+-----------+--------------+--------------+-------------+--------------+
| 6 mos. -- | 135 (563)    | 244 (19)     | 126 (87)    | 71 (1)       |
| 1 year    |              |              |             |              |
+-----------+--------------+--------------+-------------+--------------+
| 1-2 years | 161 (743)    | 150 (32)     | 121 (77)    | None         |
+-----------+--------------+--------------+-------------+--------------+
| \>2 years | 142 (2175)   | 156 (48)     | 167 (49)    | \-           |
+-----------+--------------+--------------+-------------+--------------+

Slope = decrease in WBC/day; \*Source: Appendix 1, Post-text Table
3.6-3; \*\*Source: Appendix 1, Post-text Table 3.6-2

### **26** Projected Rates

The actual and projected number of cases of severe leukopenia and
agranulocytosis under various monitoring frequencies are provided in
Table 11 below.

###### Table 11: Actual and projected number of cases of severe leukopenia and agranulocytosis after weekly monitoring during the first six months of therapy followed by bi-weekly monitoring (Current system cohort)

  --------------------- ------------------------- ---------- ----------------- -----------------
                        **Change to               **Actual   **Projected       **Projected
                        [bi-weekly]{.underline}   Cases      Additional Cases  Additional Cases
                        monitoring after          Observed   with Monthly      with No
                        [weekly]{.underline}      under      Monitoring**      monitoring**
                        monitoring for:**         current                      
                                                  system**                     

  **Severe Leukopenia** Six months                9          91                221

                        One year                  5\*        56                123

                        Two years                 4\*        16                46

                                                                               

  **Agranulocytosis**   Six months                7          38                150

                        One year                  2\*        26                86

                        Two years                 0\*        9                 34
  --------------------- ------------------------- ---------- ----------------- -----------------

\*Bi-weekly monitoring still occurs (i.e., no change from current
monitoring system)

Source: Appendix 1, Post-text Tables 3.6-4 and 3.6-6

Note: The number of severe leukopenia and agranulocytosis cases provided
in Table 11 are based, in part, on the calculations shown in Table 5.

As seen in Table 11, if the current monitoring was changed to "monthly
monitoring" **after six months** then we would have observed 91
additional cases of severe leukopenia and 38 additional cases of
agranulocytosis after **six months of treatment** and 221 and 150
additional, respectively if "no monitoring" was in place. After six
months of therapy, bi-weekly monitoring is currently required and the
actual observed rate of agranulocytosis is 0.26/1000 person-years. Based
on the projections in Table 5, the rate of agranulocytosis would
increase to 1.68/1000 person-year if the monitoring frequency after six
months of therapy was decreased to monthly intervals and increased to
5.81/1000 person-year if monitoring was discontinued after six months of
therapy (Apendix 1, Post-Text Table 3.6-5).

If the current monitoring was changed to "monthly monitoring" **after
one year** then we would have observed 56 additional cases of severe
leukopenia and 26 additional cases of agranulocytosis after **one year
of treatment** and 123 and 86 additional, respectively if "no
monitoring" was in place. After six months of therapy, bi-weekly
monitoring is currently required and the actual observed rate of
agranulocytosis is 0.26/1000 person-years. Based on the projections in
Table 5, the rate of agranulocytosis would increase to 1.21/1000
person-year if the monitoring frequency after six months of therapy was
decreased to monthly intervals and increased to 3.43/1000 person-year if
monitoring was discontinued after one year of therapy (Appendix 1,
Post-Text Table 3.6-5).

If the current monitoring was changed to "monthly monitoring" **after
two years** then we would have observed 16 additional cases of severe
leukopenia and 9 additional cases of agranulocytosis after **two years
of treatment** and 46 and 34 additional cases, respectively if "no
monitoring" was in place. After six months of therapy, bi-weekly
monitoring is currently required and the actual observed rate of
agranulocytosis is 0.26/1000 person-years. Based on the projections in
Table 11, the rate of agranulocytosis would increase to 0.6/1000
person-year if the monitoring frequency after six months of therapy was
decreased to monthly intervals and increased to 1.52/1000 person-year if
monitoring was discontinued after two years of therapy (Appendix 1,
Post-Text Table 3.6-5).

## 27 Discussion and Conclusion (United States)

Results of the analyses of US data showed that:

-   the rate of agranulocytosis decreased consistently overtime (Figure
    9). This decrease may be explained to some extent by the similarly
    consistent decrease in the percentage of new patients entering the
    registry by calendar year.

-   the demographic characteristics of patients in the initial and
    current monitoring systems were comparable.

-   the rate of moderate leukopenia during and after the first six
    months of treatment was similar in both monitoring systems

-   during the first six months of treatment, the rates of severe
    leukopenia and agranulocytosis were less in the current monitoring
    system than in the initial system

-   after the first six months of treatment, the rates of severe
    leukopenia and agranulocytosis were similar in both monitoring
    systems

The factors responsible for the unexpected decrease in the observed
rates of severe leukopenia and agranulocytosis during the first 6 months
are unclear. These findings were unexpected because the frequency of
monitoring (i.e. weekly) was identical during the first six months for
both the initial and current systems. Possible explanations for these
unexpected findings are as follows:

-   Patients who received generic clozapine were not considered in these
    analyses when exposure to more than six months of clozapine
    treatment was known (Section 3.1.1.2; Exclusion Criteria 3). This
    resulted in an exclusion of data during the period of highest risk
    for agranulocytosis i.e. the first six months.

-   Patients switching to alternative atypical antipsychotics treatments
    prior to developing severe leukopenia or agranulocytosis.

-   The greater proportion of patients who discontinued (Figure 10)
    during the first six months of therapy under the current monitoring
    system (58%) compared to the initial monitoring system (40%). This
    resulted in an exclusion of data during the period of highest risk
    for agranulocytosis i.e., the first six months.

Overall, the United States data showed that the CNR effectively detects
moderate leukopenia, and reduces the occurrence of severe leukopenia,
agranulocytosis and death.

The change in monitoring frequency from weekly to every two weeks was
not associated with an increase in the rates of moderate leukopenia,
severe leukopenia or agranulocytosis.

# 28 United Kingdom

## 29 Methods for Analysis

### 30 Patient Population

Data collected by the Clozaril Patient Monitoring Service (CPMS) from
the UK and Ireland between the inception of the registry and April 2002
were used.

#### 31 Inclusion and exclusion criteria.

All patients who received Clozaril in the UK and Ireland were eligible
for inclusion in the analysis. As of April 2002, there were 29,298
patients registered and 1,828,832 laboratory records collected in the
CPMS.

Consistent with the US analysis, patients who were enrolled in the CPMS,
but never started treatment with Clozaril or had only one WBC entry in
the database were excluded. It is important to note that generic
clozapine is not available in the UK and therefore the exclusion
criteria applied in the US (section 3.1.1.2)were not applicable.

Ultimately, 27,894 CPMS registry participants and 1,814,848 laboratory
records were included in the analysis.

### 32 Cohorts

Patients were divided into the following three cohorts:

-   **Initial system:** Included patients enrolled before implementation
    of the change to monthly monitoring in 1995 (see figure 2). Data
    beyond the implementation date were excluded.

-   **Current system, new patients:** Included patients enrolled one
    year prior to the implementation of monthly monitoring; therefore
    being eligible for monthly monitoring at the time of implementation.

-   **Current system, old patients:** Included patients from the initial
    system cohort plus the data that were excluded for these patients as
    described in bullet 1 above.

For purposes of assessing the impact of the change in the monitoring
system that occurred in 1995, data from patients in the "initial system
cohort" and "current system, new patients cohort" were compared. The
data from the "current system, old patient cohort" helps to distinguish
the contribution of change in monitoring schedule protocol and other
time related factors to the differences in the incidence rates.

### 33 Statistics

Stratified analysis by variables suspected to have an influence in the
incidence rate values was conducted i.e. calendar year, treatment
duration, and cohort as defined above.

In order to compute confidence intervals for the incidence rates based
on person-years, the numerator of the rate was assumed to be a Poisson
variable. Since the rates observed are low, this is a reasonable
assumption. Exact Poisson limits for counts ≤ 20 and the normal
approximation for counts \> 20 were used. Tables and Figures present 95%
Confidence Intervals. Ninety-five percent confidence intervals for
incidence rates were computed using poison approximation (Anders Ahlbom,
1993).

##  34 Results from United Kingdom

### 35 Demographics

Within the initial and current monitoring systems, the demographics of
all patients, patients with moderate leukopenia, severe leukopenia or
agranulocytosis are comparable with respect to sex, age, and race with
the exception of patients over 65 years of age who developed severe
leukopenia.. The percentage of missing information was also similar
between these groups. The demographic data for all patients and patients
with agranulocytosis are shown in Tables 12 and 13 below. Demographics
for other subgroups are presented in Appendix 2, Post-text Table 4.22.

###### Table 12: Demographics of all patients in Initial system and Current system

+-----------------+-----------------+-----------------+-----------------+
| **Demographic** | **Category**    | **Initial       | **Current       |
|                 |                 | system**        | System**        |
|                 |                 |                 |                 |
|                 |                 | **N (%)**       | **N (%)**       |
+-----------------+-----------------+-----------------+-----------------+
| Gender          | Male            | 4201 (65.0)     | 14583 (67.9)    |
|                 |                 |                 |                 |
|                 | Female          | 2174 (34.1)     | 6890 (32.1)     |
+-----------------+-----------------+-----------------+-----------------+
| Age at          | [               | 3220 (50.5)     | 11236 (52.3)    |
| initiation      | \<]{.underline} |                 |                 |
|                 | 35              | 2208 (34.6)     | 7053 (32.8)     |
| of treatment    |                 |                 |                 |
|                 | 36-50           | 767(12.0)       | 2627 (12.2)     |
|                 |                 |                 |                 |
|                 | 51-65           | 180 (2.8)       | 557 ( 2.5)      |
|                 |                 |                 |                 |
|                 | \>65            |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| Race            | Caucasian       | 5755 (90.3)     | 18652 (86.7)    |
|                 |                 |                 |                 |
|                 | Afro-Carib      | 278 ( 4.3)      | 1389 ( 6.5)     |
|                 |                 |                 |                 |
|                 | Mixed           | 112 ( 1.7)      | 345 ( 1.6)      |
|                 |                 |                 |                 |
|                 | Oriental        | 24 ( 0.4)       | 90 ( 0 .4)      |
|                 |                 |                 |                 |
|                 | Asian           | 206 ( 3.2)      | 997( 4.6)       |
+-----------------+-----------------+-----------------+-----------------+

Source: Appendix 2, Post Text Table 4.22

###### Table 13: Demographics of all patients with agranulocytosis in Initial system and Current system

+-----------------+-----------------+-----------------+-----------------+
| **Demographic** | **Category**    | **Initial       | **Current       |
|                 |                 | system**        | System**        |
|                 |                 |                 |                 |
|                 |                 | **N (%)**       | **N (%)**       |
+-----------------+-----------------+-----------------+-----------------+
| Gender          | Male            | 28 (58.3)       | 92 (61.3)       |
|                 |                 |                 |                 |
|                 | Female          | 20 (41.7)       | 58 (38.7)       |
+-----------------+-----------------+-----------------+-----------------+
| Age at          | [               | 12 (25.0)       | 35 (23.3)       |
| initiation      | \<]{.underline} |                 |                 |
|                 | 35              | 25 (52.1)       | 54 (35.0))      |
| of treatment    |                 |                 |                 |
|                 | 36-50           | 11 (22.9)       | 52 (34.7)       |
|                 |                 |                 |                 |
|                 | 51-65           | 0 (0.00)        | 9 (6.0)         |
|                 |                 |                 |                 |
|                 | \>65            |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| Race            | Caucasian       | 45 (93.7)       | 138 (92.0)      |
|                 |                 |                 |                 |
|                 | Afro-Carib      | 1 ( 2.1)        | 1 ( 0.7)        |
|                 |                 |                 |                 |
|                 | Mixed           | 0 (0.0)         | 2 ( 1.3)        |
|                 |                 |                 |                 |
|                 | Oriental        | 0 ( 0.0)        | 0 ( 0 .0)       |
|                 |                 |                 |                 |
|                 | Asian           | 2 (4.2)         | 9 (6.0)         |
+-----------------+-----------------+-----------------+-----------------+

Source: Appendix 2, Post Text Table 4.22

### 

### 36 Incidence of leukopenia and agranulocytosis 

Figure 11 below shows that the rate of agranulocytosis decreased by
calendar year. This decrease may be explained to some extent by the
similarly consistent decrease in the percentage of new patients entering
the registry by calendar year.

####### Figure 11: Trend of Agranulocytosis Rate

![](media/image7.wmf){width="6.0152777777777775in"
height="5.139583333333333in"}

The rates of moderate leukopenia, severe leukopenia and agranulocytosis
observed between weeks 0 and 18 decreased significantly between weeks 19
to 52 and again after 52 weeks under both the initial and current
systems. Patients in the current system cohort had a higher incidence of
agranulocytosis during monthly monitoring after week 52 than did
patients in the initial system cohort during bi-weekly monitoring after
week 52, however, this difference was not statistically significant
(Table 14).

###### Table 14 Summary of Results

+----------------+----------------+----------------+-------+--------+
|                | **Weeks 0-18** | **Weeks        | **    |        |
|                |                | 19-52**        | Weeks |        |
|                | **Weekly**     |                | \     |        |
|                |                | **bi-weekly**  | >52** |        |
|                |                |                |       |        |
|                |                |                | *     |        |
|                |                |                | *bi-w |        |
|                |                |                | eekly |        |
|                |                |                | /     |        |
|                |                |                | mont  |        |
|                |                |                | hly** |        |
+================+================+================+=======+========+
| **Moderate     |                |                |       |        |
| Leukopenia**   |                |                |       |        |
|                |                |                |       |        |
| {per 1,000 pt. |                |                |       |        |
| yrs. (N)}      |                |                |       |        |
+----------------+----------------+----------------+-------+--------+
| **Incidence:** | 105.1 (182)    | 30.5 (79)      | 11.8  |        |
| pre-1995       |                |                | (77)  |        |
| (initial       |                |                |       |        |
| system)        |                |                |       |        |
+----------------+----------------+----------------+-------+--------+
| **Incidence:** | 82.5 (482)     | 20.7 (177)     |       | 7.4    |
| patients       |                |                |       | (228)  |
| enrolled       |                |                |       |        |
| post-1995      |                |                |       |        |
| (current       |                |                |       |        |
| system)        |                |                |       |        |
+----------------+----------------+----------------+-------+--------+
| **Severe       |                |                |       |        |
| Leukopenia**   |                |                |       |        |
|                |                |                |       |        |
| {per 1,000 pt. |                |                |       |        |
| yrs. (N)}      |                |                |       |        |
+----------------+----------------+----------------+-------+--------+
| **Incidence**: | 33.5 (58)      | 4.3 (11)       | 2.6   |        |
| pre-1995       |                |                | (17)  |        |
| (initial       |                |                |       |        |
| system)        |                |                |       |        |
+----------------+----------------+----------------+-------+--------+
| **Incidence:** | 31.9 (186)     | 4.0 (34)       |       | 1.9    |
| patients       |                |                |       | (58)   |
| enrolled       |                |                |       |        |
| post-1995      |                |                |       |        |
| (current       |                |                |       |        |
| system)        |                |                |       |        |
+----------------+----------------+----------------+-------+--------+
| **Agr          |                |                |       |        |
| anulocytosis** |                |                |       |        |
|                |                |                |       |        |
| {per 1,000 pt. |                |                |       |        |
| yrs. (N)}      |                |                |       |        |
+----------------+----------------+----------------+-------+--------+
| **Incidence**: | 24.8 (43)      | 1.2 (3)        | **0.3 |        |
| pre-1995       |                |                | (2)** |        |
| (initial       |                |                |       |        |
| system)        |                |                |       |        |
+----------------+----------------+----------------+-------+--------+
| **Incidence:** | 20.4 (119)     | 1.5 (13)       |       | **0.6  |
| patients       |                |                |       | (18)** |
| enrolled       |                |                |       |        |
| post-1995      |                |                |       |        |
| (current       |                |                |       |        |
| system)        |                |                |       |        |
+----------------+----------------+----------------+-------+--------+

Source: Appendix 2, Post-text tables 4.5, 4.11 and 4.18

## 37 Discussion and Conclusion (United Kingdom)

The change in monitoring frequency from weekly to bi-weekly monitoring
is not associated with an increase in the rates of moderate leukopenia,
severe leukopenia or agranulocytosis. Although the change from bi-weekly
to monthly monitoring was associated with an increase in the incidence
of agranulocytosis, it was not statistically significant.

# 38 Australia

## 39 Methods for Analysis

From December 1992 to the data cut-off date of April 28, 2003, more than
13,000 patients received Clozaril. If a patient temporarily discontinued
Clozaril treatment and then later rechallenged with Clozaril again then
that patient's initial enrolment date (entry date) in the database is
replaced with the new entry date in the system.

In addition, the start and end date of Clozaril treatment for more than
3,000 patients could not be extracted from the Australian database due
to database incompatibility issues. Therefore, these patients were not
included in the analysis. Thus, it was not possible to calculate the
total exposure time of Clozaril based on the CPMS database in Australia.
The exposure time presented in this document is an underestimate of the
actual value. Consequently, it was not possible to obtain the exact
number of patients with moderate leukopenia, severe leukopenia or
agranulocytosis. As a result, all event rates presented in this document
should be considered over estimates of the actual rate.

Demographic data are not provided because Australian regulations
prohibit the release of information on patients' sex, race or age.

Due to the above mentioned limitations of data from Australia very
limited analyses were performed on Australian data. Incidences rate per
1000 person years were computed for 0-18 weeks, 19 to 52 weeks, and
greater than 52 weeks (Appendix 3, Post-text Tables 5.1-1, 5.1-2, 5.2-1,
5.2-2, 5.3-1, 5.3-2 ). No other analyses were performed with Australian
data.

## 40 Results from Australia

The rates of moderate leukopenia, severe leukopenia and agranulocytosis
observed between weeks 0 and 18 decreased significantly between weeks 19
to 52 and again after 52 weeks.

###### Table 15: Summary of Results 

+--------------------+---------------+---------------+---------------+
|                    | **Weeks       | **Weeks       | **Weeks       |
|                    | 0-18**        | 19-52**       | \>52**        |
|                    |               |               |               |
|                    | **Weekly**    | **monthly**   | **monthly**   |
+====================+===============+===============+===============+
| **Moderate         | 52.5 (165)    | 11.8 (60)     | 6.1 (165)     |
| Leukopenia**       |               |               |               |
|                    |               |               |               |
| {per 1,000 pt.     |               |               |               |
| yrs. (N)}          |               |               |               |
+--------------------+---------------+---------------+---------------+
| **Severe           | 12.7 (40)     | 1.6 (8)       | 0.7 (19)      |
| Leukopenia**       |               |               |               |
|                    |               |               |               |
| {per 1,000 pt.     |               |               |               |
| yrs. (N)}          |               |               |               |
+--------------------+---------------+---------------+---------------+
| *                  | 8.3 (26)      | 2.2 (11)      | 0.5 (14)      |
| *Agranulocytosis** |               |               |               |
|                    |               |               |               |
| {per 1,000 pt.     |               |               |               |
| yrs. (N)}          |               |               |               |
+--------------------+---------------+---------------+---------------+

Source: Appendix 3, Post-text Tables 5.1-2, 5.2-2, 5.3-2

## 41 Discussion and Conclusion (Australian)

The rate of agranulocytosis in Australia after 52 weeks of treatment is
similar to the rate observed in the United Kingdom after 52 weeks of
treatment.

# 42 Overall Discussion

Clozaril is recognized, during its long history, as one of the most
efficacious anti-psychotics offered to the patients. Today it remains
the only drug approved for the treatment of treatment resistant
schizophrenia patients as well as for the treatment of recurrent
suicidal behavior in patients with schizophrenia and schizoaffective
disorder. Since its first introduction in Austria in 1969, it has been
marketed in more than 80 countries throughout the world.

Despite such benefits, Clozaril has been associated with a serious risk
of agranulocytosis. The incidence rate of agranulocytosis in Europe
prior to monitoring was observed to be 1-2% per year. During clinical
trials completed prior to approval in the US the rate was 1.3% at 1 year
of treatment. Hematological monitoring systems were put in place
throughout the world by Novartis to ensure its safe use. The general
guidelines of monitoring systems have been:

1)  Weekly, biweekly or monthly- monitoring of white blood cell count
    for early detection of moderate or severe leukopenia or
    agranulocytosis,

2)  Immediate discontinuation of clozapine if severe leukopenia or
    agranulocytosis is observed,

3)  Maintenance of non-rechallengable patient database to ensure
    exclusion of patients who developed leukopenia or agranulocytosis
    from re-exposure to clozapine,

4)  Adherence to "no blood no drug" policy. These guidelines were
    developed in cooperation with local health authorities.

Over the years, health authorities have re-evaluated the level of risk
based on data from Clozaril national registries and made adjustments to
the monitoring frequencies. In the US, such a review took place in 1997
the outcome of which was a change in monitoring frequency from weekly
intervals for the entire duration of treatment to weekly monitoring for
the first 6 months of treatment followed by monitoring every two weeks
thereafter. This new monitoring schedule was initiated in April 1998.
The outcome of a similar review of registry data in the UK in 1995 was a
change from bi-weekly to monthly monitoring after 52 weeks of Clozaril
treatment.

This briefing document is provided to facilitate the PDAC's and FDA's
re-evaluation of the current clozapine monitoring guidelines in the US.
It contains a summary of the results of analyses submitted to FDA on
September, 2002, October, 2002, and February 2003 as well as analyses of
data from the UK and Australian registries.

Results of the analyses of US data showed that:

-   the rate of agranulocytosis decreased consistently overtime (Figure
    9). This decrease may be explained to some extent by the similarly
    consistent decrease in the percentage of new patients entering the
    registry by calendar year.

-   the demographic characteristics of patients in the initial and
    current monitoring systems were comparable.

-   the rate of moderate leukopenia during and after the first six
    months of treatment was similar in both monitoring systems

-   during the first six months of treatment, the rates of severe
    leukopenia and agranulocytosis were less in the current monitoring
    system than in the initial system

-   after the first six months of treatment, the rates of severe
    leukopenia and agranulocytosis were similar in both monitoring
    systems.

The factors responsible for the unexpected decrease in the observed
rates of severe leukopenia and agranulocytosis during the first 6 months
are unclear. These findings were unexpected because the frequency of
monitoring (i.e. weekly) was identical during the first six months for
both the initial and current systems. Possible explanations for these
unexpected findings are as follows:

-   Patients who received generic clozapine were not considered in these
    analyses when exposure to more than six months of clozapine
    treatment was known (Section 3.1.1.2; Exclusion Criteria 3). This
    resulted in an exclusion of data during the period of highest risk
    for agranulocytosis i.e. the first six months.

-   Patients switching to alternative atypical antipsychotics treatments
    prior to developing severe leukopenia or agranulocytosis.

-   The greater proportion of patients who discontinued (Figure 10)
    during the first six months of therapy under the current monitoring
    system (58%) compared to the initial monitoring system (40%). This
    resulted in an exclusion of data during the period of highest risk
    for agranulocytosis i.e. the first six months.

The change in the frequency of monitoring in the US was not associated
with an increase in fatal outcomes related to agranulocytosis because
only one of the fatalities occurred after the first six months of
treatment.

Results of the analyses of UK data showed that:

-   The rate of agranulocytosis decreased consistently by calendar year
    (Figure 11). This decrease may be explained to some extent by the
    similarly consistent decrease in the percentage of new patients
    entering the registry by calendar year.

-   The change from bi-weekly monitoring to at least monthly monitoring
    after 52 weeks of treatment may have contributed to the observed
    increase in the rate of agranulocytosis. However, this increased
    rate does not only reflect the contribution of patients being
    monitored on a monthly monitoring schedule because some patients
    continued to be monitored on a weekly or bi-weekly basis. In fact,
    the incidence rate of agranulocytosis in the group of patients who
    continued to be monitored on a weekly (4.6/1,000 patient-years) or
    bi-weekly (0.9/1,000 patient-years) basis after 52 weeks was greater
    than that of those who were actually monitored on a monthly
    (0.35/1,000 patient-years) basis (Appendix 2; Post-text table 4.6).

Results of the analyses of Australian data showed that:

-   the rates of moderate leukopenia, severe leukopenia and
    agranulocytosis observed between weeks 0 and 18 decreased
    significantly between weeks 19 to 52 and again after 52 weeks.

Results of the analyses of data from over 200,000 patients from the US,
UK and Australian registries representing over 1 million patient years
show that the incidence rates for moderate leukopenia, severe leukopenia
and agranulocytosis due to exposure to Clozaril have consistently
declined in all 3 countries during the duration of treatment (Table 18)
and by calendar year (Figures 6 and 11).

The rates of these dyscrasias appear to be higher in the UK and
Australia than in the US, which maybe due to differences in: registry
procedures, definitions of events, practice of medicine, availability of
generics or other atypical antipsychotics in the market.

###### Table 16: Incidence of agranulocytosis in US, UK and Australia 

+-------------------+--------------+-----------------+-----------------+
|                   | **Weeks      | **Weeks 19-52** | **Weeks \>52**  |
|                   | 0-18**       |                 |                 |
|                   |              | **1000 pt/yr    | **1000 pt/yr    |
|                   | **1000 pt/yr | (n)**           | (n)**           |
|                   | (n)**        |                 |                 |
+===================+==============+=================+=================+
| **United States** |              |                 |                 |
+-------------------+--------------+-----------------+-----------------+
| Pre-1998          | 8.8 (366)    | 0.8 (50)        | 0.4 (101)       |
|                   |              |                 |                 |
| (monitoring       | weekly       | weekly          | weekly          |
| frequency)        |              |                 |                 |
+-------------------+--------------+-----------------+-----------------+
| Post-1998         | 3.8 (40)     | 1.0 (14)        | 0.1 (2)         |
|                   |              |                 |                 |
| (monitoring       | weekly       | w               | bi-weekly       |
| frequency)        |              | eekly/bi-weekly |                 |
+-------------------+--------------+-----------------+-----------------+
| **United          |              |                 |                 |
| Kingdom**         |              |                 |                 |
+-------------------+--------------+-----------------+-----------------+
| Pre-1995          | 24.8 (43)    | 1.2 (3)         | 0.3 (2)         |
|                   |              |                 |                 |
| (monitoring       | weekly       | bi-weekly       | bi-weekly       |
| frequency)        |              |                 |                 |
+-------------------+--------------+-----------------+-----------------+
| Post-1995         | 20.4 (119)   | 1.5 (13)        | 0.6 (18)        |
|                   |              |                 |                 |
| (monitoring       | weekly       | bi-weekly       | monthly         |
| frequency)        |              |                 |                 |
+-------------------+--------------+-----------------+-----------------+
| **Australia**     |              |                 |                 |
+-------------------+--------------+-----------------+-----------------+
| Agranulocytosis   | 8.3 (26)     | 2.2 (11)        | 0.5 (14)        |
|                   |              |                 |                 |
| (monitoring       | weekly       | monthly         | monthly         |
| frequency)        |              |                 |                 |
+-------------------+--------------+-----------------+-----------------+

Source: Appendix 1, Post-text Table 3.2-1c.; Appendix 2, Post-text Table
4.4; Appendix 3, Post-text Table 5.2-2

# 43 Overall Conclusion

The results of the analyses show that the current monitoring systems in
the US, UK and Australia are associated with a very low rate of
agranulocytosis and death due to agranulocytosis. Based on these data it
may be reasonable to consider a less frequent monitoring schedule in the
United States; however, these data do not rule out the possibility that
less frequent monitoring may result in an increase in the rate of
agranulocytosis. Therefore, it is just as reasonable to consider
maintaining the current monitoring system.