Clozaril® (clozapine) Tablets
Briefing
Document for Psychopharmacological Drugs Advisory Committee Meeting (
Appendix
1: Post-text tables (
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Document status: |
Final |
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Release date: |
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Number of pages: |
90 |
Available for public disclosure without redaction
Post-text table 3.1-1 Summary of demographic information by cohort for all patients
Post-text table 3.1-2 Summary of demographic information by cohort for patients with moderate leukopenia
Post-text table 3.1-3 Summary of demographic information by cohort for patients with severe leukopenia
Post-text table 3.1-4 Summary of demographic information by cohort for patients with agranulocytosis
Post-text table 3.1-5 Summary of demographic information by cohort for patients discontinued
Post-text table 3.1-6a Summary of demographic information for cohort 3 patients who switched to bi-weekly monitoring after 6 months of treatment
Post-text table 3.1-6b Summary of demographic information for cohort 3 patients who remained on weekly monitoring after 6 months of treatment
Post-text table 3.2-1a Summary statistics for incidence of agranulocytosis
Post-text
table 3.2-1b Summary statistics for
incidence of agranulocytosis before and after six months of treatment
Post-text
table 3.2-1c Summary statistics for
incidence of agranulocytosis by treatment duration of 0-18, 19-52, and > 52
weeks
Post-text
table 3.2-1d Number of patients with WBC
<= 1000 at the time of agranulocytosis
Post-text table 3.2-2 Life table for incidence of agranulocytosis for cohorts 1 and 2
Post-text table 3.2-3 Life table for incidence of agranulocytosis for cohort 3
Post-text table 3.2-4 Life table for incidence of agranulocytosis for all three cohorts
Post-text table 3.2-5 Distribution of patients and agranulocytosis cases by calendar year
Post-text table 3.2-6 Distribution of patients and agranulocytosis cases by calendar year after six months of treatment with clozapine
Post-text
table 3.2-7 Yearly conditional risk of
agranulocytosis and severe leukopenia per 1000 patients for cohorts 1 and 2
Post-text
table 3.2-8 Yearly conditional risk agranulocytosis
and severe leukopenia per 1000 patients for cohort 3
Post-text table 3.3-1a Summary statistics for incidence of severe leukopenia
Post-text
table 3.3-1b Summary statistics for
incidence of severe leukopenia before and after six months of treatment
Post-text
table 3.3-1c Summary statistics for
incidence of severe leukopenia by treatment duration of 0-18, 19-52, and >
52 weeks
Post-text table 3.3-2 Life table for incidence of severe leukopenia for cohorts 1 and 2
Post-text table 3.3-3 Life table for incidence of severe leukopenia for cohort 3
Post-text table 3.3-4 Life table for incidence of severe leukopenia for all three
cohorts
Post-text table 3.3-5 Distribution of patients and severe leukopenia cases by calendar year
Post-text table 3.3-6 Distribution of patients and severe leukopenia cases by calendar year after six months of treatment with clozapine
Post-text
table 3.4-1a Summary statistics for
incidence of moderate leukopenia
Post-text table 3.4-1b Summary statistics for incidence of moderate
leukopenia before and after six months of treatment
Post-text table 3.4-1c Summary statistics for incidence of moderate
leukopenia by treatment duration of 0-18, 19-52, and > 52 weeks
Post-text
table 3.4-2 Life table for incidence of
moderate leukopenia for cohorts 1 and 2
Post-text
table 3.4-3 Life table for incidence of
moderate leukopenia for cohort 3
Post-text
table 3.4-4 Life table for incidence of
moderate leukopenia for all three cohorts
Post-text table 3.4-5 Distribution of patients and moderate leukopenia cases by calendar year
Post-text table 3.4-6 Distribution of patients and moderate leukopenia cases by calendar year after six months of treatment with clozapine
Post-text
table 3.5-1 Summary statistics of WBC counts at
discontinuation by cohort with patients discontinued before
Post-text
table 3.5-2 Summary statistics of WBC counts at
discontinuation by cohort for patients with WBC value between 3000 and 6000 at
time of discontinuation
Post-text
table 3.5-3 Summary statistics of WBC counts at
discontinuation by cohort for patients with WBC value between 3000 and
6000 by 1000 at time of discontinuation
Post-text
table 3.5-4 Kaplan-Meier estimate of probability of
discontinuation by cohort
Post-text table 3.6-1 Summary statistics on duration of prodrome and slope during prodrome for patients who developed moderate leukopenia by Cohort
Post-text table 3.6-2 Summary statistics on duration of prodrome and slope during prodrome for moderate leukopenia patients who also developed agranulocytosis by Cohort
Post-text table 3.6-3 Summary statistics on duration of prodrome and slope during prodrome for moderate leukopenia patients who did not develop agranulocytosis by Cohort
Post-text table 3.6-4 Number of agranulocytosis and severe leukopenia cases projected to occur after change from bi-weekly monitoring for Cohort 3
Post-text table 3.6-5 Cumulative number of agranulocytosis and severe leukopenia cases projected to occur beginning 6 months after initiation of Clozaril therapy, by timing of reduction in frequency of WBC monitoring for Cohort 3
Post-text table 3.6-6 Additional cases of agranulocytosis and severe leukopenia projected to occur as a result of switching from bi-weekly monitoring to less-frequent monitoring for Cohort 3
Post-text table 3.6-7 Projection of total number of deaths under different monitoring systems for Cohort 3
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Clozaril (clozapine)
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Post-text table 3.1-1
Summary of demographic information by cohort
All patients
(Excluding patient's data met criteria 1, 2, and 3) [1]
____________________________________________________________________________________________________________________________
----------------------------------------- Cohort
-----------------------------------------
Cohort
1 Cohort 2 Cohort 3 Cohorts 1 and 2 p-value [2]
____________________________________________________________________________________________________________________________
Age <=35 37453 ( 38.4%) 12671 ( 30.6%) 12794 ( 32.6%) 50124 ( 36.1%) <0.0001
36-50 37812 ( 38.8%) 15413 ( 37.3%) 14808 ( 37.7%) 53225 ( 38.3%)
51-65 11517 ( 11.8%) 5957 ( 14.4%) 6073 ( 15.5%) 17474 ( 12.6%)
>65 8015 ( 8.2%)
6848 ( 16.6%) 4761 (
12.1%) 14863 ( 10.7%)
Missing 2688 ( 2.8%)
470 ( 1.1%) 824 (
2.1%) 3158 ( 2.3%)
Total 97485 (100.0%) 41359 (100.0%) 39260 (100.0%) 138844 (100.0%)
Mean 40.8 45.0 43.0 42.1
STD 14.2 17.3 16.7 15.3
Gender N (%) Male 56156 ( 57.6%) 23100 ( 55.9%) 22287 ( 56.8%) 79256 ( 57.1%) 0.1342
Female 38641 ( 39.6%) 17789 ( 43.0%) 16149 ( 41.1%) 56430 ( 40.6%)
Missing 2688 ( 2.8%)
470 ( 1.1%) 824 (
2.1%) 3158 ( 2.3%)
____________________________________________________________________________________________________________________________
[1] Criteria 1: Excluded patients with
only one record of WBC;
Criteria 2: Excluded patients
suspected of starting with generic clozapine before Clozaril;
Criteria 3: Patients started on Clozaril,
but switched to generic after
after the first generic
clozapine.
[2] From Pearson Chi-square test
(excluding missing values) to compare Cohorts 1 and 2 with Cohort 3
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Post-text table 3.1-1 (Continued)
Summary of demographic information by cohort
All patients
(Excluding patient's data met criteria 1, 2, and 3) [1]
____________________________________________________________________________________________________________________________
----------------------------------------- Cohort
-----------------------------------------
Cohort
1 Cohort 2 Cohort 3 Cohorts 1 and 2 p-value [2]
____________________________________________________________________________________________________________________________
Race N (%) White 67380 ( 69.1%) 28578 ( 69.1%) 24528 ( 62.5%) 95958 ( 69.1%) <0.0001
Black 11533 ( 11.8%) 5834 ( 14.1%) 6058 ( 15.4%) 17367 ( 12.5%)
Hispanic 3914 (
4.0%) 1905 ( 4.6%)
2014 ( 5.1%) 5819 (
4.2%)
Oriental 1246 (
1.3%) 479 ( 1.2%)
460 ( 1.2%) 1725 (
1.2%)
Other 1012 ( 1.0%)
566 ( 1.4%) 724 (
1.8%) 1578 ( 1.1%)
Missing 12400 ( 12.7%) 3997 (
9.7%) 5476 ( 13.9%) 16397 ( 11.8%)
____________________________________________________________________________________________________________________________
[1] Criteria 1: Excluded patients with
only one record of WBC;
Criteria 2: Excluded patients
suspected of starting with generic clozapine before Clozaril;
Criteria 3: Patients started on Clozaril,
but switched to generic after
after the first generic
clozapine.
[2] From Pearson Chi-square test
(excluding missing values) to compare Cohorts 1 and 2 with Cohort 3
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Post-text table 3.1-2
Summary of demographic information by cohort
Patients with moderate leukopenia [1]
With data
cut-off date of
____________________________________________________________________________________________________________________________
----------------------------------------- Cohort
-----------------------------------------
Cohort
1 Cohort 2 Cohort 3 Cohorts 1 and 2 p-value [3]
____________________________________________________________________________________________________________________________
Age <=35 1288 ( 35.1%) 191 ( 23.6%) 176 ( 28.9%) 1479 ( 33.0%) 0.0002
36-50 1459 ( 39.7%) 267 ( 32.9%) 206 ( 33.9%) 1726 ( 38.5%)
51-65 546 ( 14.9%) 160 ( 19.7%) 116 ( 19.1%) 706 ( 15.7%)
>65 365 ( 9.9%)
184 ( 22.7%) 104 (
17.1%) 549 ( 12.2%)
Missing 15 ( 0.4%)
9 ( 1.1%) 6 (
1.0%) 24 ( 0.5%)
Total 3673 (100.0%) 811 (100.0%) 608 (100.0%) 4484 (100.0%)
Mean 42.2 49.3 46.0 43.5
STD 14.8 17.6 18.0 15.6
Gender N (%) Male 1968 ( 53.6%) 409 ( 50.4%) 319 ( 52.5%) 2377 ( 53.0%) 0.8877
Female 1690 ( 46.0%) 393 ( 48.5%) 283 ( 46.5%) 2083 ( 46.5%)
Missing 15 ( 0.4%)
9 ( 1.1%) 6 (
1.0%) 24 ( 0.5%)
____________________________________________________________________________________________________________________________
[1] Moderate leukopenia is defined as WBC
counts <= 3000/mm^3.
[2] Criteria 1: Excluded patients with
only one record of WBC;
Criteria 2: Excluded patients
suspected of starting with generic clozapine before Clozaril;
Criteria 3: Patients started on Clozaril,
but switched to generic after
after the first generic
clozapine.
[3] From Pearson Chi-square test
(excluding missing values) to compare Cohorts 1 and 2 with Cohort 3
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Post-text table 3.1-2 (Continued)
Summary
of demographic information by cohort
Patients with moderate leukopenia [1]
With data
cut-off date of
____________________________________________________________________________________________________________________________
----------------------------------------- Cohort
-----------------------------------------
Cohort
1 Cohort 2 Cohort 3 Cohorts 1 and 2 p-value [3]
____________________________________________________________________________________________________________________________
Race N (%) White 2559 ( 69.7%) 560 ( 69.1%) 376 ( 61.8%) 3119 ( 69.6%) <0.0001
Black 382 ( 10.4%) 111 ( 13.7%) 107 ( 17.6%) 493 ( 11.0%)
Hispanic 133 (
3.6%) 41 ( 5.1%)
30 ( 4.9%) 174 (
3.9%)
Oriental 49 (
1.3%) 5 ( 0.6%)
5 ( 0.8%) 54 (
1.2%)
Other 42 ( 1.1%)
7 ( 0.9%)
9 ( 1.5%) 49 (
1.1%)
Missing 508 ( 13.8%) 87 ( 10.7%) 81 ( 13.3%) 595 ( 13.3%)
____________________________________________________________________________________________________________________________
[1] Moderate leukopenia is defined as WBC
counts <= 3000/mm^3.
[2] Criteria 1: Excluded patients with
only one record of WBC;
Criteria 2: Excluded patients
suspected of starting with generic clozapine before Clozaril;
Criteria 3: Patients started on Clozaril,
but switched to generic after
after the first generic
clozapine.
[3] From Pearson Chi-square test
(excluding missing values) to compare Cohorts 1 and 2 with Cohort 3
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Clozaril (clozapine)
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Post-text table 3.1-3
Summary of demographic information by cohort
Patients with severe leukopenia [1]
With data
cut-off date of
____________________________________________________________________________________________________________________________
----------------------------------------- Cohort
-----------------------------------------
Cohort
1 Cohort 2 Cohort 3 Cohorts 1 and 2 p-value [3]
____________________________________________________________________________________________________________________________
Age <=35 74 ( 16.2%) 21 ( 22.3%) 9 ( 15.8%) 95 ( 17.2%) 0.9643
36-50 204 ( 44.5%) 28 ( 29.8%) 23 ( 40.4%) 232 ( 42.0%)
51-65 117 ( 25.5%) 31 ( 33.0%) 16 ( 28.1%) 148 ( 26.8%)
>65 62 ( 13.5%) 14 ( 14.9%) 9 ( 15.8%) 76 ( 13.8%)
Missing 1 ( 0.2%)
0 ( 0.0%) 0 (
0.0%) 1 ( 0.2%)
Total 458 (100.0%) 94 (100.0%) 57 (100.0%) 552 (100.0%)
Mean 48.1 48.3 50.0 48.1
STD 13.8 14.7 16.0 14.0
Gender N (%) Male 241 ( 52.6%) 55 ( 58.5%) 30 ( 52.6%) 296 ( 53.6%) 0.8753
Female 216 ( 47.2%) 39 ( 41.5%) 27 ( 47.4%) 255 ( 46.2%)
Missing 1 ( 0.2%)
0 ( 0.0%) 0 (
0.0%) 1 ( 0.2%)
____________________________________________________________________________________________________________________________
[1] Severe leukopenia is defined as WBC
counts < 2000/mm^3.
[2] Criteria 1: Excluded patients with
only one record of WBC;
Criteria 2: Excluded patients suspected
of starting with generic clozapine before Clozaril;
Criteria 3: Patients started on Clozaril,
but switched to generic after
after the first generic
clozapine.
[3] From Pearson Chi-square test
(excluding missing values) to compare Cohorts 1 and 2 with Cohort 3
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Post-text table 3.1-3 (Continued)
Summary of demographic information by cohort
Patients with severe leukopenia [1]
With data
cut-off date of
____________________________________________________________________________________________________________________________
----------------------------------------- Cohort
-----------------------------------------
Cohort
1 Cohort 2 Cohort 3 Cohorts 1 and 2 p-value [3]
____________________________________________________________________________________________________________________________
Race N (%) White 309 ( 67.5%) 79 ( 84.0%) 40 ( 70.2%) 388 ( 70.3%) 0.2158
Black 9 ( 2.0%)
3 ( 3.2%) 4 (
7.0%) 12 ( 2.2%)
Hispanic 19 (
4.1%) 5 ( 5.3%)
4 ( 7.0%) 24 (
4.3%)
Oriental 2 (
0.4%) 0 ( 0.0%)
0 ( 0.0%) 2 (
0.4%)
Other 6 ( 1.3%)
1 ( 1.1%) 0 (
0.0%) 7 ( 1.3%)
Missing 113 ( 24.7%) 6 (
6.4%) 9 ( 15.8%) 119 ( 21.6%)
____________________________________________________________________________________________________________________________
[1] Severe leukopenia is defined as WBC
counts < 2000/mm^3.
[2] Criteria 1: Excluded patients with
only one record of WBC;
Criteria 2: Excluded patients
suspected of starting with generic clozapine before Clozaril;
Criteria 3: Patients started on Clozaril,
but switched to generic after
after the first generic
clozapine.
[3] From Pearson Chi-square test
(excluding missing values) to compare Cohorts 1 and 2 with Cohort 3
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Post-text table 3.1-4
Summary of demographic information by cohort
Patients
with agranulocytosis
With data
cut-off date of
____________________________________________________________________________________________________________________________
----------------------------------------- Cohort
-----------------------------------------
Cohort
1 Cohort 2 Cohort 3 Cohorts 1 and 2 p-value [2]
____________________________________________________________________________________________________________________________
Age <=35 93 ( 21.5%) 16 ( 18.8%) 13 ( 23.2%) 109 ( 21.1%) 0.6035
36-50 174 ( 40.3%) 26 ( 30.6%) 18 ( 32.1%) 200 ( 38.7%)
51-65 124 ( 28.7%) 35 ( 41.2%) 17 ( 30.4%) 159 ( 30.8%)
>65 41 ( 9.5%)
8 ( 9.4%) 8 ( 14.3%) 49 (
9.5%)
Total 432 (100.0%) 85 (100.0%) 56 (100.0%) 517 (100.0%)
Mean 46.5 48.2 47.7 46.8
STD 13.4 13.1 15.4 13.4
Gender N (%) Male 232 ( 53.7%) 51 ( 60.0%) 31 ( 55.4%) 283 ( 54.7%) 0.9296
Female 200 ( 46.3%) 34 ( 40.0%) 25 ( 44.6%) 234 ( 45.3%)
____________________________________________________________________________________________________________________________
[1] Criteria 1: Excluded patients with
only one record of WBC;
Criteria 2: Excluded patients
suspected of starting with generic clozapine before Clozaril;
Criteria 3: Patients started on Clozaril,
but switched to generic after
after the first generic
clozapine.
[2] From Pearson Chi-square test
(excluding missing values) to compare Cohorts 1 and 2 with Cohort 3
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Post-text table 3.1-4 (Continued)
Summary of demographic information by
cohort
Patients with agranulocytosis
With data
cut-off date of
____________________________________________________________________________________________________________________________
----------------------------------------- Cohort
-----------------------------------------
Cohort 1 Cohort 2 Cohort 3 Cohorts 1 and 2 p-value [2]
____________________________________________________________________________________________________________________________
Race N (%) White 277 ( 64.1%) 72 ( 84.7%) 37 ( 66.1%) 349 ( 67.5%) 0.6171
Black 13 ( 3.0%)
2 ( 2.4%) 3 (
5.4%) 15 ( 2.9%)
Hispanic 22 (
5.1%) 2 ( 2.4%)
4 ( 7.1%) 24 (
4.6%)
Oriental 3 (
0.7%) 0 ( 0.0%)
0 ( 0.0%) 3 (
0.6%)
Other 6 ( 1.4%)
1 ( 1.2%) 0 (
0.0%) 7 ( 1.4%)
Missing 111 ( 25.7%) 8 (
9.4%) 12 ( 21.4%) 119 ( 23.0%)
____________________________________________________________________________________________________________________________
[1] Criteria 1: Excluded patients with
only one record of WBC;
Criteria 2: Excluded patients
suspected of starting with generic clozapine before Clozaril;
Criteria 3: Patients started on Clozaril,
but switched to generic after
after the first generic
clozapine.
[2] From Pearson Chi-square test
(excluding missing values) to compare Cohorts 1 and 2 with Cohort 3
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Post-text table 3.1-5
Summary of demographic information by cohort
Patients who discontinued [1]
With data
cut-off date of
____________________________________________________________________________________________________________________________
----------------------------------------- Cohort
-----------------------------------------
Cohort
1 Cohort 2 Cohort 3 Cohorts 1 and 2 p-value [3]
____________________________________________________________________________________________________________________________
Age <=35 27291 ( 41.4%) 7483 ( 32.7%) 7440 ( 34.0%) 34774 ( 39.2%) <0.0001
36-50 25990 ( 39.4%) 8349 ( 36.5%) 8259 ( 37.7%) 34339 ( 38.7%)
51-65 7111 ( 10.8%) 3169 ( 13.9%) 3281 ( 15.0%) 10280 ( 11.6%)
>65 4699 ( 7.1%)
3729 ( 16.3%) 2644 (
12.1%) 8428 ( 9.5%)
Missing 823 ( 1.2%)
122 ( 0.5%) 269 (
1.2%) 945 ( 1.1%)
Total 65914 (100.0%) 22852 (100.0%) 21893 (100.0%) 88766 (100.0%)
Mean 39.8 44.4 42.6 41.0
STD 13.6 17.4 16.7 14.8
Gender N (%) Male 38876 ( 59.0%) 12743 ( 55.8%) 12518 ( 57.2%) 51619 ( 58.2%) 0.0175
Female 26215 ( 39.8%) 9987 ( 43.7%) 9106 ( 41.6%) 36202 ( 40.8%)
Missing 823 ( 1.2%)
122 ( 0.5%) 269 (
1.2%) 945 ( 1.1%)
____________________________________________________________________________________________________________________________
[1] Discontinuation is defined as follows:
If a patient had a gap between WBC
counts greater than 15 days during weekly monitoring or a gap between WBC
counts
greater than 30 days during bi-weekly
monitoring then start date of the gap is defined as the date of
discontinuation.
For patients who discontinued on
multiple occurrences then only the first point of discontinuation is utilized.
[2] Criteria 1: Excluded patients with
only one record of WBC;
Criteria 2: Excluded patients suspected of
starting with generic clozapine before Clozaril;
Criteria 3: Patients started on Clozaril,
but switched to generic after
after the first generic
clozapine.
[3] From Pearson Chi-square test
(excluding missing values) to compare Cohorts 1 and 2 with Cohort 3
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Post-text table 3.1-5 (Continued)
Summary of demographic information by cohort
Patients who discontinued [1]
With data
cut-off date of
____________________________________________________________________________________________________________________________
----------------------------------------- Cohort
-----------------------------------------
Cohort
1 Cohort 2 Cohort 3 Cohorts 1 and 2 p-value [3]
____________________________________________________________________________________________________________________________
Race N (%) White 48081 ( 72.9%) 15869 ( 69.4%) 13847 ( 63.2%) 63950 ( 72.0%) <0.0001
Black 8150 ( 12.4%) 3290 ( 14.4%) 3402 ( 15.5%) 11440 ( 12.9%)
Hispanic 2913 (
4.4%) 1190 ( 5.2%)
1261 ( 5.8%) 4103 (
4.6%)
Oriental 958 (
1.5%) 285 ( 1.2%)
273 ( 1.2%) 1243 (
1.4%)
Other 726 ( 1.1%)
335 ( 1.5%) 379 (
1.7%) 1061 ( 1.2%)
Missing 5086 ( 7.7%)
1883 ( 8.2%) 2731 ( 12.5%) 6969 (
7.9%)
____________________________________________________________________________________________________________________________
[1] Discontinuation is defined as follows:
If a patient had a gap between WBC
counts greater than 15 days during weekly monitoring or a gap between WBC
counts
greater than 30 days during bi-weekly
monitoring then start date of the gap is defined as the date of
discontinuation.
For patients who discontinued on
multiple occurrences then only the first point of discontinuation is utilized.
[2] Criteria 1: Excluded patients with
only one record of WBC;
Criteria 2: Excluded patients
suspected of starting with generic clozapine before Clozaril;
Criteria 3: Patients started on Clozaril,
but switched to generic after
after the first generic
clozapine.
[3] From Pearson Chi-square test
(excluding missing values) to compare Cohorts 1 and 2 with Cohort 3
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Clozaril (clozapine)
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Post-text table 3.1-6a
Summary of demographic information in cohort 3
Patients who
switched to bi-weekly monitoring after 6 months treatment
(Excluding patient's data meeting criteria 1, 2, and 3) [1]
____________________________________________________________________________________________________________________________
Cohort 3
____________________________________________________________________________________________________________________________
Age <=35
6294 ( 35.1%)
36-50
7160 ( 39.9%)
51-65
2590 ( 14.4%)
>65 1797 ( 10.0%)
Missing
115 ( 0.6%)
Total
17956 (100.0%)
Mean
41.7
STD
15.8
Gender N (%) Male
10530 ( 58.6%)
Female
7311 ( 40.7%)
Missing
115 ( 0.6%)
____________________________________________________________________________________________________________________________
[1] Criteria 1: Excluded patients with
only one record of WBC;
Criteria 2: Excluded patients
suspected of starting with generic clozapine before Clozaril;
Criteria 3: Patients started on Clozaril,
but switched to generic after
after the first generic
clozapine.
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Clozaril (clozapine)
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Post-text table 3.1-6a (Continued)
Summary of demographic information for cohort 3
Patients who
switched to bi-weekly monitoring after 6 months treatment
(Excluding patient's data meeting criteria 1, 2, and 3) [1]
____________________________________________________________________________________________________________________________
Cohort 3
____________________________________________________________________________________________________________________________
Race N (%) White
11626 ( 64.7%)
Black
2679 ( 14.9%)
Hispanic
983 ( 5.5%)
Oriental
228 ( 1.3%)
Other 306
( 1.7%)
Missing
2134 ( 11.9%)
____________________________________________________________________________________________________________________________
[1] Criteria 1: Excluded patients with
only one record of WBC;
Criteria 2: Excluded patients
suspected of starting with generic clozapine before Clozaril;
Criteria 3: Patients started on Clozaril,
but switched to generic after
after the first generic
clozapine.
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Clozaril (clozapine)
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Post-text table 3.1-6b
Summary of demographic information in cohort 3
Patients on weekly monitor after
6 months treatment
(Excluding patient's data met criteria 1, 2, and 3) [1]
____________________________________________________________________________________________________________________________
Cohort 3
____________________________________________________________________________________________________________________________
Age <=35
1392 ( 32.7%)
36-50
1628 ( 38.3%)
51-65 665 (
15.6%)
>65
519 ( 12.2%)
Missing
49 ( 1.2%)
Total
4253 (100.0%)
Mean
43.0
STD 16.8
Gender N (%) Male
2493 ( 58.6%)
Female
1711 ( 40.2%)
Missing
49 ( 1.2%)
____________________________________________________________________________________________________________________________
[1] Criteria 1: Excluded patients with
only one record of WBC;
Criteria 2: Excluded patients
suspected of starting with generic clozapine before Clozaril;
Criteria 3: Patients started on Clozaril,
but switched to generic after
after the first generic
clozapine.
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Clozaril (clozapine)
____________________________________________________________________________________________________________________________
Post-text table 3.1-6b
(Continued)
Summary of demographic information in cohort 3
Patients on weekly monitor after 6 months treatment
(Excluding patient's
data met criteria 1, 2, and 3) [1]
____________________________________________________________________________________________________________________________
Cohort
3
____________________________________________________________________________________________________________________________
Race N (%) White 2567 ( 60.4%)
Black
760 ( 17.9%)
Hispanic
196 ( 4.6%)
Oriental
35 ( 0.8%)
Other
78 ( 1.8%)
Missing
617 ( 14.5%)
____________________________________________________________________________________________________________________________
[1] Criteria 1: Excluded patients with
only one record of WBC;
Criteria 2: Excluded patients
suspected of starting with generic clozapine before Clozaril;
Criteria 3: Patients started on Clozaril,
but switched to generic after
after the first generic
clozapine.
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Page 1 of 2
Clozaril (clozapine)
____________________________________________________________________________________________________________________________
Post-text table 3.2-1a
Summary statistics
for incidence of agranulocytosis
All duration
With data
cut-off date of
(Excluding
patient's data met criteria 1, 2, and 3) [1]
____________________________________________________________________________________________________________________________
Cohort Category
All Duration
____________________________________________________________________________________________________________________________
Cohort 1 Incidence/1000 patient year 1.350
Number of incidence 432
Number of patient 97485
Total patient year 319972
Cohort 2
Incidence/1000 patient year 1.778
Number of incidence 85
Number of patient 41359
Total patient
year
47818
Cohort 3
Incidence/1000 patient year 1.360
Number of incidence 56
Number of patient 39260
Total patient year 41172
____________________________________________________________________________________________________________________________
[1] Criteria 1: Excluded patients with
only one record of WBC;
Criteria 2: Excluded patients
suspected of starting with generic clozapine before Clozaril;
Criteria 3: Patients started on Clozaril,
but switched to generic after
will be excluded after the
first generic clozapine.
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Novartis Pharmaceuticals Corporation
Page 2 of 2
Clozaril (clozapine)
____________________________________________________________________________________________________________________________
Post-text table 3.2-1a (Continued)
Summary
statistics for incidence of agranulocytosis
All duration
With data
cut-off date of
(Excluding patient's data met criteria 1, 2, and 3) [1]
____________________________________________________________________________________________________________________________
Cohort Category
All Duration
____________________________________________________________________________________________________________________________
Cohorts 1 and 2 Incidence/1000 patient
year
1.406
Number of incidence 517
Number of patient 138844
Total patient year 367790
Cohorts 1, 2, and 3 Incidence/1000
patient year 1.401
Number of incidence 573
Number of patient 178104
Total
patient year
408962
____________________________________________________________________________________________________________________________
[1] Criteria 1: Excluded patients with
only one record of WBC;
Criteria 2: Excluded patients
suspected of starting with generic clozapine before Clozaril;
Criteria 3: Patients started on Clozaril,
but switched to generic after
will be excluded after the
first generic clozapine.
C:\NOVARTIS\CLOZARIL\STAT\PROGRAM\TABLES\APPEND_3\DRAFT14\AG_USA.SAS 08MAY03:
Novartis Pharmaceuticals Corporation Page
1 of 2
Clozaril (clozapine)
____________________________________________________________________________________________________________________________
Post-text
table 3.2-1b
Summary statistics for incidence of agranulocytosis
By duration of 1 - 6 months and > 6 months
With data
cut-off date of
(Excluding patient's data met criteria 1, 2, and 3) [1]
____________________________________________________________________________________________________________________________
------------- Duration -------------
Cohort Category (1 - 6] Months > 6 Months
____________________________________________________________________________________________________________________________
Cohort 1 Incidence/1000
patient year
7.563 0.420
Number
of incidence
315 117
Number
of patient 97485 75635
Total
patient year
41649 278324
Cohort 2 Incidence/1000
patient year 4.724 0.224
Number
of incidence
78 7
Number
of patient
41359 28673
Total
patient year
16513 31305
Cohort 3 Incidence/1000
patient year
3.250 0.370
Number
of incidence
46 10
Number
of patient
39260 22209
Total
patient year
14152 27020
____________________________________________________________________________________________________________________________
[1] Criteria 1: Excluded patients with
only one record of WBC;
Criteria 2: Excluded patients
suspected of starting with generic clozapine before Clozaril;
Criteria 3: Patients started on Clozaril,
but switched to generic after
will be excluded after the
first generic clozapine.
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Novartis Pharmaceuticals Corporation
Page 2 of 2
Clozaril (clozapine)
____________________________________________________________________________________________________________________________
Post-text table 3.2-1b (Continued)
Summary statistics for incidence of agranulocytosis
By duration of 1 - 6 months and > 6 months
With data
cut-off date of
(Excluding patient's data met criteria 1, 2, and 3) [1]
____________________________________________________________________________________________________________________________
------------- Duration -------------
Cohort Category (1 -
6] Months > 6 Months
____________________________________________________________________________________________________________________________
Cohorts 1 and 2 Incidence/1000 patient
year
6.757 0.400
Number
of incidence
393 124
Number
of patient
138844 104308
Total
patient year
58162 309628
Cohorts 1, 2, and 3 Incidence/1000 patient
year
6.071 0.398
Number
of incidence
439 134
Number
of patient 178104 126517
Total
patient year
72314 336648
____________________________________________________________________________________________________________________________
[1] Criteria 1: Excluded patients with
only one record of WBC;
Criteria 2: Excluded patients
suspected of starting with generic clozapine before Clozaril;
Criteria 3: Patients started on Clozaril,
but switched to generic after
will be excluded after the
first generic clozapine.
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Novartis Pharmaceuticals Corporation
Page 1 of 2
Clozaril (clozapine)
____________________________________________________________________________________________________________________________
Post-text table 3.2-1c
Summary statistics for incidence of agranulocytosis
By duration of treatment (1 -
18, 19 - 52, and > 52 weeks)
With data
cut-off date of
(Excluding patient's data meeting criteria 1, 2, and 3) [1]
____________________________________________________________________________________________________________________________
-------------------------- Duration --------------------------
Cohort Category (0-18] Weeks (18-52] Weeks >52 Weeks
____________________________________________________________________________________________________________________________
Cohort 1 Incidence/1000 patient
year 9.833 0.882 0.400
Number of
incidence 293 42 97
Number of
patient 97485 79038 68534
Total patient
year 29797 47599 242576
Cohort 2 Incidence/1000 patient
year 6.099 0.479 0.209
Number of
incidence 73 8 4
Number of
patient 41359 30675 20846
Total patient
year 11969 16717 19132
Cohort 3 Incidence/1000 patient
year 3.797 1.077 0.113
Number of
incidence 40 14 2
Number of
patient 39260 25093 15936
Total patient
year 10535 12997 17640
____________________________________________________________________________________________________________________________
[1] Criteria 1: Excluded patients with
only one record of WBC;
Criteria 2: Excluded patients
suspected of starting with generic clozapine before Clozaril;
Criteria 3: Patients started on Clozaril,
but switched to generic after
will be excluded after the
first generic clozapine.
C:\NOVARTIS\CLOZARIL\STAT\PROGRAM\TABLES\APPEND_3\DRAFT5\AG_18_52.SAS 21APR
Novartis Pharmaceuticals Corporation
Page 2 of 2
Clozaril (clozapine)
____________________________________________________________________________________________________________________________
Post-text table 3.2-1c (Continued)
Summary statistics for incidence of agranulocytosis
By
duration of treatment (1 - 18, 19 - 52, and > 52 weeks)
With data
cut-off date of
(Excluding patient's
data meeting criteria 1, 2, and 3) [1]
____________________________________________________________________________________________________________________________
--------------------------
Duration --------------------------
Cohort Category (0-18] Weeks (18-52] Weeks >52 Weeks
____________________________________________________________________________________________________________________________
Cohorts 1 and 2 Incidence/1000 patient year 8.763 0.777 0.386
Number of
incidence 366 50 101
Number of
patient 138844 109713 89380
Total patient
year 41766 64315 261708
Cohorts 1, 2, and 3 Incidence/1000 patient year 7.763 0.828 0.369
Number of incidence 406 64 103
Number of
patient 178104 134806 105316
Total patient
year 52301 77312 279348
____________________________________________________________________________________________________________________________
[1] Criteria 1: Excluded patients with
only one record of WBC;
Criteria 2: Excluded patients
suspected of starting with generic clozapine before Clozaril;
Criteria 3: Patients started on Clozaril,
but switched to generic after
will be excluded after the
first generic clozapine.
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Clozaril (clozapine)
____________________________________________________________________________________________________________________________
Post-text table 3.2-1d
Number of
patients with WBC <= 1000 at the time of agranulocytosis [1]
With data
cut-off date of
(Excluding patient's data met
criteria 1, 2, and 3) [2]
____________________________________________________________________________________________________________________________
--------------------------------- Cohort
----------------------------------
Cohort 1 Cohort 2 Cohort 3 Cohorts 1 and 2
____________________________________________________________________________________________________________________________
WBC <= 1000/mm^3 Yes 122 ( 28.2%) 24 ( 28.2%) 11 ( 19.6%) 146 ( 28.2%)
No 310 ( 71.8%) 61 ( 71.8%) 45 ( 80.4%) 371 ( 71.8%)
Total 432 (100.0%) 85 (100.0%) 56 (100.0%) 517 (100.0%)
____________________________________________________________________________________________________________________________
[1] Within 30 days before or 5 days after
date of agranulocytosis, as reported in CNR
[2] Criteria 1: Excluded patients with
only one record of WBC;
Criteria 2: Excluded patients
suspected of starting with generic clozapine before Clozaril;
Criteria 3: Patients started on Clozaril,
but switched to generic after
after the first generic
clozapine.
C:\NOVARTIS\CLOZARIL\STAT\PROGRAM\TABLES\APPEND_3\DRAFT19\AG_1000.SAS 13MAY03:
Post-text table 3.2-2: Life
table for incidence of agranulocytosis for Cohorts 1 & 2
with
data cut-off date of
(Excluded
patients data meeting criteria 1, 2, 3)
______________________________________________________________________________________________________________________
Cumulative # of
Cumulative Cum. rate Cum. rate
Hazard Hazard/ Hazard/
Time
# of # of patients
rate /1000 pat. /1000 pat.
rate/ 1000 pt-yr 1000 pt-yr
interval
occurrences occurrences left
/1000 pat. 95% L.C.L. 95% U.C.L.
1000 pt-yr 95% L.C.L. 95% L.C.L.
______________________________________________________________________________________________________________________
Yr.
0-0.5 393 393 138844
0.0000 0.0000 0.0000 6.4651 5.8259 7.1043
0.5-1 23 416 104308
3.2273 2.9088 3.5459 0.4750 0.2809 0.6691
1-2 33 449 89380
3.4640 3.1312 3.7969 0.4140 0.2728 0.5553
2-3
25 474 70022
3.8766 3.5153 4.2378 0.4012 0.2439 0.5585
3-4 15 489 54597
4.2761 3.8825 4.6697 0.3102 0.1532 0.4672
4-5 11 500
42117 4.5850 4.1616 5.0083 0.3113 0.1273 0.4952
5-6 14 514 28565
4.8947 4.4336 5.3559 0.6266 0.2984 0.9548
6-7 2 516 16120
5.5181 4.9534 6.0828 0.1731 0.0000 0.4131
7-8 1 517 6983
5.6903 5.0773 6.3032 0.2328 0.0000 0.6892
8-9 0 517 1607
5.9217 5.1593
6.6842 0.0000 - -
_______________________________________________________________________________________________________________________
Note: L.C.L = Lower Confidence Limit; U.C.L = Upper Confidence Limit
Post-text table 3.2-3: Life
table for incidence of agranulocytosis for Cohort 3
'
(Excluded
patients data meeting criteria 1, 2, 3)
______________________________________________________________________________________________________________________
Cumulative # of
Cumulative Cum. rate Cum. rate
Hazard Hazard/ Hazard/
Time
# of # of patients
rate /1000 pat. /1000 pat.
rate/ 1000 pt-yr 1000 pt-yr
interval
occurrences occurrences left
/1000 pat. 95% L.C.L. 95% U.C.L.
1000 pt-yr 95% L.C.L. 95% L.C.L.
______________________________________________________________________________________________________________________
Yr.
0-0.5 46 46 39260
0.0000 0.0000 0.0000 2.9934 2.1284 3.8584
0.5-1 8 54 22209
1.4956 1.0637 1.9274 0.8389 0.2576 1.4202
1-2 2 56 15936
1.9143 1.3942 2.4344 0.1678 0.0000 0.4003
2-3 0 56 7903
2.0818 1.5123 2.6512
0.0000 - -
3-4 0 56 2638
2.0818 1.5123 2.6512 0.0000 - -
_______________________________________________________________________________________________________________________
Note: L.C.L = Lower Confidence Limit; U.C.L = Upper Confidence Limit
Post-text table 3.2-4: Life
table for incidence of agranulocytosis for all 3 Cohorts
with data
cut-off date of
(Excluded
patients data meeting criteria 1, 2, 3)
______________________________________________________________________________________________________________________
Cumulative # of
Cumulative Cum. rate Cum. rate
Hazard Hazard/ Hazard/
Time
# of # of patients
rate /1000 pat. /1000 pat.
rate/ 1000 pt-yr 1000 pt-yr
interval
occurrences occurrences left
/1000 pat. 95% L.C.L. 95% U.C.L.
1000 pt-yr 95% L.C.L. 95% L.C.L.
______________________________________________________________________________________________________________________
Yr.
0-0.5 439 439 178104
0.0000 0.0000 0.0000 5.7645 5.2253 6.3038
0.5-1 31 470 126517
2.8781 2.6093 3.1470 0.5349 0.3466 0.7232
1-2 35 505 105316
3.1448 2.8601 3.4294 0.3820 0.2555 0.5086
2-3 25 530 77925
3.5255 3.2142 3.8368 0.3699 0.2249 0.5149
3-4 15 545 57235
3.8940 3.5510 4.2371
0.3020 0.1491 0.4548
4-5 11 556 42117
4.1948 3.8196 4.5700 0.3113 0.1273 0.4952
5-6 14 570 28565
4.5047 4.0873 4.9221 0.6266 0.2984 0.9548
6-7 2 572 16120
5.1283 4.5985 5.6580 0.1731 0.0000 0.4131
7-8 1 573 6983
5.3005 4.7196 5.8814 0.2328 0.0000 0.6892
8-9 0 573 1607
5.5321 4.7950 6.2691 0.0000 - -
_______________________________________________________________________________________________________________________
Note: L.C.L = Lower Confidence Limit; U.C.L = Upper Confidence Limit
Post-text table 3.2-5
Summary statistics for incidence of agranulocytosis
By calendar year
With data
cut-off date of
(Excluding
patient's data met criteria 1, 2, and 3) [1]
Cohort: Cohorts 1 and 2
___________________________________________________________________________________________________
Category 1990 1991
1992 1993 1994
1995 1996 1997
1998
___________________________________________________________________________________________________
Number of new 9639.0
13763.0 22024.0 25444.0
19750.0 19603.0 19195.0
9426.0 0.0
patients started
Clozaril
% of new patients 100.0
61.7 53.8 41.7
27.3 24.9 22.1
11.5 0.0
[3]
Number of patients 9639.0
22293.0 40931.0 61004.0
72336.0 78749.0 86812.0
81877.0 68131.0
taking drug during
the year
Patient year 4463.0
13078.8 27365.2 44148.1
55726.7 63485.8 72111.1
70886.6 16524.7
Number of 42.0 68.0
91.0 88.0 55.0
67.0 78.0 23.0
5.0
agranulocytosis
Rate
of 4.4 3.1
2.2 1.4 0.8
0.9 0.9 0.3
0.1
agranulocytosis /
1000 patients
Incidence / 1000 9.4
5.2 3.3 2.0
1.0 1.1 1.1
0.3 0.3
patient year
___________________________________________________________________________________________________
[1] Criteria 1: Excluded patients with only
one record of WBC;
Criteria 2: Excluded patients suspected
of starting with generic clozapine before Clozaril;
Criteria 3: Patients started on Clozaril,
but switched to generic after
will be excluded after the
first generic clozapine.
C:\NOVARTIS\CLOZARIL\STAT\PROGRAM\TABLES\APPEND_3\DRAFT19\AG_CALYR.SAS 13MAY03:
Post-text table 3.2-5 (Continued)
Summary statistics for incidence of agranulocytosis
By calendar year
With data
cut-off date of
(Excluding patient's data met criteria 1, 2, and 3) [1]
Cohort: Cohort 3
________________________________________________________________
Category 1997 1998
1999 2000 2001
________________________________________________________________
Number of new 3206.0
12602.0 11786.0 8186.0
3480.0
patients started
Clozaril
% of new patients 100.0
82.3 53.2 36.8
21.0
[3]
Number of patients 3206.0
15313.0 22156.0 22265.0
16573.0
taking drug during
the year
Patient year 386.7 6853.1
13053.3 13967.2 6911.6
Number of 1.0 20.0
14.0 17.0 4.0
agranulocytosis
Rate of 0.3 1.3
0.6 0.8 0.2
agranulocytosis /
1000 patients
Incidence / 1000 2.6 2.9
1.1 1.2 0.6
patient year
________________________________________________________________
[1] Criteria 1: Excluded patients with only
one record of WBC;
Criteria 2: Excluded patients suspected
of starting with generic clozapine before Clozaril;
Criteria 3: Patients started on Clozaril,
but switched to generic after
will be excluded after the
first generic clozapine.
C:\NOVARTIS\CLOZARIL\STAT\PROGRAM\TABLES\APPEND_3\DRAFT19\AG_CALYR.SAS 13MAY03:
Post-text table 3.2-6
Summary statistics
for incidence of agranulocytosis
After 6 months treatment
By calendar year
With data cut-off date of
Cohort: Cohorts 1 and 2
___________________________________________________________________________________________________
Category 1990 1991
1992 1993 1994
1995 1996 1997
1998
___________________________________________________________________________________________________
Number of patients 4273.0
12842.0 27239.0 44500.0
58026.0 65234.0 74632.0
75798.0 67986.0
taking drug during
the year
Patient year 1074.2 7662.5
18182.5 33514.5 47178.0
55554.0 63953.6 66276.6
16232.3
Number of 2.0 4.0
12.0 16.0 18.0
23.0 35.0 10.0
4.0
agranulocytosis
Rate of 0.5 0.3
0.4 0.4 0.3
0.4 0.5 0.1
0.1
agranulocytosis /
1000 patients
Incidence / 1000 1.9
0.5 0.7 0.5
0.4 0.4 0.5
0.2 0.2
patient year
___________________________________________________________________________________________________
[1] Criteria 1: Excluded patients with only
one record of WBC;
Criteria 2: Excluded patients suspected
of starting with generic clozapine before Clozaril;
Criteria 3: Patients started on Clozaril,
but switched to generic after
will be excluded after the
first generic clozapine.
C:\NOVARTIS\CLOZARIL\STAT\PROGRAM\TABLES\APPEND_3\DRAFT19\AG6CALYR.SAS 13MAY03:
Post-text table 3.2-6 (Continued)
Summary statistics for incidence of agranulocytosis
After 6 months treatment
By calendar year
With data
cut-off date of
Cohort: Cohort 3
_______________________________________________________
Category 1998 1999
2000 2001
_______________________________________________________
Number of patients 6329.0
13766.0 15830.0 12750.0
taking drug during
the year
Patient year 2201.7 8322.2
10838.0 5658.1
Number of 1.0 3.0
2.0 4.0
agranulocytosis
Rate of 0.2 0.2
0.1 0.3
agranulocytosis /
1000 patients
Incidence / 1000 0.5 0.4
0.2 0.7
patient year
_______________________________________________________
[1] Criteria 1: Excluded patients with only
one record of WBC;
Criteria 2: Excluded patients suspected
of starting with generic clozapine before Clozaril;
Criteria 3: Patients started on Clozaril,
but switched to generic after
will be excluded after the
first generic clozapine.
C:\NOVARTIS\CLOZARIL\STAT\PROGRAM\TABLES\APPEND_3\DRAFT19\AG6CALYR.SAS 13MAY03:
Post-text table 3.2-7: Yearly
conditional risk per 1000 patients for Cohorts 1 & 2
with
data cut-off date of
(Excluded
patients data meeting criteria 1, 2, 3)
________________Agranulocytosis_________________ _______________Severe
Leukopenia________________
Time # of
Cond. Std. Lower
Upper # of Cond.
Std. Lower Upper
interval occur.
risk Error 95% C.L.
95% C.L. occur. risk
Error 95% C.L. 95% C.L.
_______________________________________________________________________________________________________________
Yr.
0-1 416 3.639
0.178 3.290 3.988 435
3.805 0.182 3.448
4.162
0.5-1.5 41
0.446 0.070 0.309
0.582 54 0.587
0.080 0.431 0.744
1-2 33
0.414 0.072 0.273
0.555 36 0.452
0.075 0.304 0.599
2-3 25
0.401 0.080 0.244
0.558 26 0.417
0.082 0.257 0.578
3-4 15
0.310 0.080 0.153
0.467 20 0.414
0.092 0.232 0.595
4-5 11
0.311 0.094 0.127
0.495 15 0.424
0.110 0.210 0.639
5-6 14
0.626 0.167 0.298
0.954 11 0.492
0.148 0.201 0.783
6-7 2
0.173 0.122 0.000
0.413 5 0.433
0.194 0.054 0.813
7-8 1
0.233 0.233 0.000
0.689 4 0.932
0.466 0.019 1.844
8-9 0
0.000 0.000 0.000
0.000 0 0.000
0.000 0.000 0.000
_______________________________________________________________________________________________________________________
Post-text table 3.2-8: Yearly
conditional risk per 1000 patients for Cohort 3
(Excluded
patients data meeting criteria 1, 2, 3)
________________Agranulocytosis_________________ _______________Severe
Leukopenia________________
Time # of
Cond. Std. Lower
Upper # of Cond.
Std. Lower Upper
interval occur.
risk Error 95% C.L.
95% C.L. occur. risk
Error 95% C.L. 95% C.L.
_______________________________________________________________________________________________________________
Yr.
0-1 54 1.955
0.266 1.434 2.476 52
1.882 0.261 1.371
2.394
0.5-1.5 9
0.534 0.178 0.185
0.883 5 0.297
0.133 0.037 0.557
1-2 2
0.168 0.119 0.000
0.400 1 0.084
0.084 0.000 0.248
2-3 0
0.000 0.000 0.000
0.000 4 0.759
0.379 0.015 1.502
3-4 0
0.000 0.000 0.000
0.000 0 0.000
0.000 0.000 0.000
_______________________________________________________________________________________________________________________
Novartis Pharmaceuticals Corporation Page
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Clozaril (clozapine)
____________________________________________________________________________________________________________________________
Post-text table
3.3-1a
Summary
statistics for incidence of severe leukopenia [1]
All duration
With data cut-off date of
(Excluding patient's data met criteria 1, 2, and 3) [2]
____________________________________________________________________________________________________________________________
Cohort
Category
All Duration
____________________________________________________________________________________________________________________________
Cohort 1
Incidence/1000 patient year 1.432
Number of incidence 458
Number of patient 97485
Total patient year 319909
Cohort 2 Incidence/1000 patient
year
1.966
Number of incidence 94
Number of patient 41359
Total patient year 47815
Cohort 3
Incidence/1000 patient year
1.385
Number of incidence 57
Number of patient 39260
Total
patient year 41167
____________________________________________________________________________________________________________________________
[1] Severe leukopenia is defined as WBC
counts < 2000/mm^3.
[2] Criteria 1: Excluded patients with
only one record of WBC;
Criteria 2: Excluded patients
suspected of starting with generic clozapine before Clozaril;
Criteria 3: Patients started on Clozaril,
but switched to generic after
will be excluded after the
first generic clozapine.
C:\NOVARTIS\CLOZARIL\STAT\PROGRAM\TABLES\APPEND_3\DRAFT14\SL_USA.SAS 08MAY03:
Novartis Pharmaceuticals Corporation
Page 2 of 2
Clozaril (clozapine)
____________________________________________________________________________________________________________________________
Post-text table 3.3-1a (Continued)
Summary
statistics for incidence of severe leukopenia [1]
All duration
With data
cut-off date of
(Excluding patient's data met criteria 1, 2, and 3) [2]
____________________________________________________________________________________________________________________________
Cohort
Category
All Duration
____________________________________________________________________________________________________________________________
Cohorts 1 and 2 Incidence/1000
patient year
1.501
Number of incidence 552
Number of patient 138844
Total patient year 367724
Cohorts 1, 2, and 3 Incidence/1000
patient year
1.489
Number of incidence
609
Number of patient 178104
Total patient year 408891
____________________________________________________________________________________________________________________________
[1] Severe leukopenia is defined as WBC
counts < 2000/mm^3.
[2] Criteria 1: Excluded patients with
only one record of WBC;
Criteria 2: Excluded patients suspected
of starting with generic clozapine before Clozaril;
Criteria 3: Patients started on Clozaril,
but switched to generic after
will be excluded after the
first generic clozapine.
C:\NOVARTIS\CLOZARIL\STAT\PROGRAM\TABLES\APPEND_3\DRAFT14\SL_USA.SAS 08MAY03:
Novartis Pharmaceuticals Corporation
Page 1 of 2
Clozaril (clozapine)
____________________________________________________________________________________________________________________________
Post-text table 3.3-1b
Summary
statistics for incidence of severe leukopenia [1]
By duration of 1 - 6 months and > 6 months
With data
cut-off date of
(Excluding patient's data met criteria 1, 2, and 3) [2]
____________________________________________________________________________________________________________________________
------------- Duration -------------
Cohort Category (1 -
6] Months > 6 Months
____________________________________________________________________________________________________________________________
Cohort 1 Incidence/1000
patient year
7.708 0.492
Number
of incidence
321 137
Number
of patient
97485 75630
Total
patient year
41644 278265
Cohort 2 Incidence/1000
patient year
4.966 0.383
Number of
incidence
82 12
Number
of patient
41359 28670
Total patient year 16512 31304
Cohort 3 Incidence/1000
patient year
3.392 0.333
Number of incidence 48 9
Number
of patient
39260 22204
Total
patient year
14149 27017
____________________________________________________________________________________________________________________________
[1] Severe leukopenia is defined as WBC counts
< 2000/mm^3.
[2] Criteria 1: Excluded patients with
only one record of WBC;
Criteria 2: Excluded patients
suspected of starting with generic clozapine before Clozaril;
Criteria 3: Patients started on Clozaril,
but switched to generic after
will be excluded after the
first generic clozapine.
C:\NOVARTIS\CLOZARIL\STAT\PROGRAM\TABLES\APPEND_3\DRAFT14\SL_6MON.SAS 08MAY03:
Novartis Pharmaceuticals Corporation
Page 2 of 2
Clozaril (clozapine)
____________________________________________________________________________________________________________________________
Post-text table 3.3-1b (Continued)
Summary
statistics for incidence of severe leukopenia [1]
By duration of 1 - 6 months and > 6 months
With data
cut-off date of
(Excluding patient's data met criteria 1, 2, and 3) [2]
____________________________________________________________________________________________________________________________
------------- Duration -------------
Cohort Category (1 -
6] Months > 6 Months
____________________________________________________________________________________________________________________________
Cohorts 1 and 2 Incidence/1000 patient year 6.930 0.481
Number
of incidence
403 149
Number of patient 138844 104300
Total
patient year
58156 309569
Cohorts 1, 2, and 3 Incidence/1000 patient
year
6.237 0.469
Number
of incidence
451 158
Number
of patient
178104 126504
Total
patient year
72305 336586
____________________________________________________________________________________________________________________________
[1] Severe leukopenia is defined as WBC
counts < 2000/mm^3.
[2] Criteria 1: Excluded patients with
only one record of WBC;
Criteria 2: Excluded patients
suspected of starting with generic clozapine before Clozaril;
Criteria 3: Patients started on Clozaril,
but switched to generic after
will be excluded after the
first generic clozapine.
C:\NOVARTIS\CLOZARIL\STAT\PROGRAM\TABLES\APPEND_3\DRAFT14\SL_6MON.SAS 08MAY03:
Novartis Pharmaceuticals Corporation
Page 1 of 2
Clozaril (clozapine)
____________________________________________________________________________________________________________________________
Post-text table 3.3-1c
Summary
statistics for incidence of severe leukopenia [1]
By
duration of 1 - 18, 19 - 52, and > 52 weeks
With data
cut-off date of
(Excluding patient's
data meeting criteria 1, 2, and 3) [2]
____________________________________________________________________________________________________________________________
--------------------------
Duration --------------------------
Cohort Category (0-18] Weeks (18-52] Weeks >52 Weeks
____________________________________________________________________________________________________________________________
Cohort 1 Incidence/1000 patient
year 9.801 1.156 0.458
Number of
incidence 292 55 111
Number of
patient 97485 79023 68527
Total patient
year 29794 47595 242519
Cohort 2 Incidence/1000 patient
year 6.434 0.658 0.314
Number of incidence 77 11 6
Number of
patient 41359 30673 20847
Total patient
year 11968 16715 19132
Cohort 3 Incidence/1000 patient
year 4.082 0.693 0.283
Number of
incidence 43 9 5
Number of
patient 39260 25085 15935
Total patient
year 10534 12994 17639
____________________________________________________________________________________________________________________________
[1] Severe Leukopenia is defined as WBC
counts < 2000/mm2.
[2]
Criteria 1: Excluded patients with only one record of WBC;
Criteria 2: Excluded patients
suspected of starting with generic clozapine before Clozaril;
Criteria 3: Patients started on Clozaril,
but switched to generic after
will be excluded after the
first generic clozapine.
C:\NOVARTIS\CLOZARIL\STAT\PROGRAM\TABLES\APPEND_3\DRAFT12\SL_18_52.SAS 05MAY03:
Novartis Pharmaceuticals Corporation
Page 2 of 2
Clozaril (clozapine)
____________________________________________________________________________________________________________________________
Post-text table 3.3-1c (Continued)
Summary
statistics for incidence of severe leukopenia [1]
By
duration of 1 - 18, 19 - 52, and > 52 weeks
With data
cut-off date of
(Excluding patient's data meeting criteria 1, 2, and 3) [2]
____________________________________________________________________________________________________________________________
-------------------------- Duration --------------------------
Cohort Category (0-18] Weeks (18-52] Weeks >52 Weeks
____________________________________________________________________________________________________________________________
Cohorts 1 and 2 Incidence/1000 patient year 8.836 1.026 0.447
Number of
incidence 369 66 117
Number of
patient 138844 109696 89374
Total patient
year 41762 64311 261651
Cohorts 1, 2, and 3 Incidence/1000 patient year 7.878 0.970 0.437
Number of
incidence 412 75 122
Number of
patient 178104 134781 105309
Total patient
year 52296 77305 279290
____________________________________________________________________________________________________________________________
[1] Severe Leukopenia is defined as WBC
counts < 2000/mm2.
[2] Criteria 1: Excluded patients with
only one record of WBC;
Criteria 2: Excluded patients
suspected of starting with generic clozapine before Clozaril;
Criteria 3: Patients started on Clozaril,
but switched to generic after
will be excluded after the
first generic clozapine.
C:\NOVARTIS\CLOZARIL\STAT\PROGRAM\TABLES\APPEND_3\DRAFT12\SL_18_52.SAS 05MAY03:
Post-text table 3.3-2: Life
table for incidence of severe leukopenia for Cohorts 1 & 2
with
data cut-off date of
(Excluded
patients data meeting criteria 1, 2, 3)
______________________________________________________________________________________________________________________
Cumulative # of
Cumulative Cum. rate Cum. rate
Hazard Hazard/ Hazard/
Time
# of # of patients
rate /1000 pat. /1000 pat.
rate/ 1000 pt-yr 1000 pt-yr
interval
occurrences occurrences left
/1000 pat. 95% L.C.L. 95% U.C.L.
1000 pt-yr 95% L.C.L. 95% L.C.L.
______________________________________________________________________________________________________________________
Yr.
0-0.5 403 403 138844
0.0000 0.0000 0.0000 6.6298 5.9825 7.2771
0.5-1
32 435 104300
3.3094 2.9869 3.6320 0.6609 0.4319 0.8899
1-2 36 471 89374
3.6387 3.2967 3.9808 0.4517 0.3042 0.5993
2-3 26
497 70013 4.0887
3.7166 4.4609 0.4173 0.2569 0.5778
3-4 20 517 54587
4.5043 4.0994 4.9091 0.4137 0.2324 0.5950
4-5 15 532 42107
4.9160 4.4729 5.3590 0.4246 0.2097 0.6394
5-6 11 543 28555
5.3384 4.8466 5.8301 0.4925 0.2015 0.7836
6-7 5 548 16111
5.8282 5.2578 6.3985 0.4331 0.0535 0.8128
7-8 4 552 6976
6.2587 5.5751 6.9423 0.9322 0.0187 1.8457
8-9 0 552 1606
7.1846 6.0492 8.3200 0.0000 - -
_______________________________________________________________________________________________________________________
Note: L.C.L = Lower Confidence Limit; U.C.L = Upper Confidence Limit
Post-text table 3.3-3: Life
table for incidence of severe leukopenia for Cohort 3
'
(Excluded
patients data meeting criteria 1, 2, 3)
______________________________________________________________________________________________________________________
Cumulative
# of Cumulative Cum. rate
Cum. rate Hazard Hazard/ Hazard/
Time
# of # of patients
rate /1000 pat. /1000 pat.
rate/ 1000 pt-yr 1000 pt-yr
interval
occurrences occurrences left
/1000 pat. 95% L.C.L. 95% U.C.L.
1000 pt-yr 95% L.C.L. 95% L.C.L.
______________________________________________________________________________________________________________________
Yr.
0-0.5 48 48 39260
0.0000 0.0000 0.0000 3.1238 2.2401 4.0075
0.5-1 4 52 22204
1.5607 1.1195 2.0018
0.4195 0.0084 0.8306
1-2 1 53 15935
1.7701 1.2836 2.2565 0.0839 0.0000 0.2483
2-3 4 57 7903
1.8538 1.3405 2.3672 0.7589 0.0152 1.5027
3-4 0 57 2638
2.6111 1.7092 3.5130 0.0000 - -
_______________________________________________________________________________________________________________________
Note: L.C.L = Lower Confidence Limit; U.C.L = Upper Confidence Limit
Post-text table 3.3-4: Life
table for incidence of severe leukopenia for all 3 Cohorts
with data
cut-off date of
(Excluded
patients data meeting criteria 1, 2, 3)
______________________________________________________________________________________________________________________
Cumulative # of
Cumulative Cum. rate Cum. rate
Hazard Hazard/ Hazard/
Time
# of # of
patients rate /1000 pat. /1000 pat.
rate/ 1000 pt-yr 1000 pt-yr
interval
occurrences occurrences left
/1000 pat. 95% L.C.L. 95% U.C.L.
1000 pt-yr 95% L.C.L. 95% L.C.L.
______________________________________________________________________________________________________________________
Yr.
0-0.5 451 451 178104
0.0000 0.0000 0.0000 5.9224 5.3758 6.4689
0.5-1 36 487 126504
2.9568 2.6843 3.2293 0.6212 0.4183 0.8241
1-2 37 524 105309
3.2664 2.9759 3.5570
0.4039 0.2737 0.5340
2-3 30 554 77916
3.6689 3.3508 3.9870 0.4440 0.2851 0.6029
3-4 20 574 57225
4.1112 3.7560 4.4663 0.4027 0.2262 0.5792
4-5 15 589 42107
4.5121 4.1160 4.9082 0.4246 0.2097 0.6394
5-6 11 600 28555
4.9347 4.4847 5.3846 0.4925 0.2015 0.7836
6-7 5 605 16111
5.4247 4.8898 5.9595 0.4331 0.0535 0.8128
7-8 4 609 6976
5.8554 5.2009 6.5098 0.9322 0.0187 1.8457
8-9 0 609 1606
6.7817 5.6633 7.9000 0.0000 - -
_______________________________________________________________________________________________________________________
Note: L.C.L = Lower Confidence Limit; U.C.L = Upper Confidence Limit
Post-text table 3.3-5
Summary
statistics for incidence of severe leukopenia [1]
By calendar year
With data
cut-off date of
(Excluding
patient's data met criteria 1, 2, and 3) [2]
Cohort: Cohorts 1 and 2
___________________________________________________________________________________________________
Category 1990 1991
1992 1993 1994
1995 1996
1997 1998
___________________________________________________________________________________________________
Number of new 9639.0
13763.0 22024.0 25444.0
19750.0 19603.0 19195.0
9426.0 0.0
patients started
Clozaril
% of new patients 100.0
61.7 53.8 41.7
27.3 24.9 22.1
11.5 0.0
[3]
Number of patients 9639.0
22290.0 40926.0 60992.0
72330.0 78742.0 86799.0
81864.0 68123.0
taking drug during
the year
Patient year 4462.7
13074.5 27357.4 44138.5
55718.8 63474.6 72097.9
70877.5 16522.4
Number of severe 38.0
75.0 107.0 86.0
56.0 67.0 77.0
40.0 6.0
leukopenia
Rate of severe 3.9 3.4
2.6 1.4 0.8
0.9 0.9 0.5
0.1
leukopenia / 1000
patients
Incidence / 1000 8.5
5.7 3.9 1.9
1.0 1.1 1.1
0.6 0.4
patient year
___________________________________________________________________________________________________
[1] Severe leukopenia is defined as WBC
counts < 1000/mm^3.
[2] Criteria 1: Excluded patients with only
one record of WBC;
Criteria 2: Excluded patients suspected
of starting with generic clozapine before Clozaril;
Criteria 3: Patients started on Clozaril,
but switched to generic after
will be excluded after the
first generic clozapine.
C:\NOVARTIS\CLOZARIL\STAT\PROGRAM\TABLES\APPEND_3\DRAFT19\SL_CALYR.SAS 13MAY03:
Post-text table 3.3-5 (Continued)
Summary
statistics for incidence of severe leukopenia [1]
By calendar year
With data
cut-off date of
(Excluding patient's data met
criteria 1, 2, and 3) [2]
Cohort: Cohort 3
________________________________________________________________
Category 1997 1998
1999 2000 2001
________________________________________________________________
Number of new 3206.0
12602.0 11786.0 8186.0
3480.0
patients started
Clozaril
% of new patients 100.0
82.3 53.2 36.8
21.0
[3]
Number of patients 3206.0
15313.0 22156.0 22263.0
16572.0
taking drug during
the year
Patient year 386.7 6852.1
13051.3 13966.0 6910.7
Number of severe 1.0
21.0 21.0 10.0
4.0
leukopenia
Rate of severe 0.3
1.4 0.9 0.4
0.2
leukopenia / 1000
patients
Incidence / 1000 2.6 3.1
1.6 0.7 0.6
patient year
________________________________________________________________
[1] Severe leukopenia is defined as WBC
counts < 1000/mm^3.
[2] Criteria 1: Excluded patients with only
one record of WBC;
Criteria 2: Excluded patients suspected
of starting with generic clozapine before Clozaril;
Criteria 3: Patients started on Clozaril,
but switched to generic after
will be excluded after the
first generic clozapine.
C:\NOVARTIS\CLOZARIL\STAT\PROGRAM\TABLES\APPEND_3\DRAFT19\SL_CALYR.SAS 13MAY03:
Post-text table 3.3-6
Summary
statistics for incidence of severe leukopenia [1]
After 6 month treatment
By calendar year
With data
cut-off date of
Cohort: Cohorts 1 and 2
___________________________________________________________________________________________________
Category 1990 1991
1992 1993 1994
1995 1996 1997
1998
___________________________________________________________________________________________________
Number of patients 4272.0
12840.0 27232.0 44495.0
58020.0 65225.0 74617.0
75785.0 67979.0
taking drug during
the year
Patient year 1074.0 7659.8
18176.2 33505.7 47170.0
55543.9 63940.7 66268.1
16230.0
Number of severe 1.0
7.0 18.0 16.0
18.0 27.0 34.0
22.0 6.0
leukopenia
Rate of severe 0.2 0.5
0.7 0.4 0.3
0.4 0.5 0.3
0.1
leukopenia / 1000
patients
Incidence / 1000 0.9
0.9 1.0 0.5
0.4 0.5 0.5
0.3 0.4
patient year
___________________________________________________________________________________________________
[1] Severe leukopenia is defined as WBC
counts < 1000/mm^3.
[2] Criteria 1: Excluded patients with only
one record of WBC;
Criteria 2: Excluded patients suspected
of starting with generic clozapine before Clozaril;
Criteria 3: Patients started on Clozaril,
but switched to generic after
will be excluded after the
first generic clozapine.
C:\NOVARTIS\CLOZARIL\STAT\PROGRAM\TABLES\APPEND_3\DRAFT19\SL6CALYR.SAS 13MAY03:
Post-text table 3.3-6 (Continued)
Summary
statistics for incidence of severe leukopenia [1]
After 6 month treatment
By calendar year
With data
cut-off date of